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TOP 25 COMPANIES AND BIOPHARMA REPORT.

01 PFIZER, INC.

Headquarters: New York, NY

twitter.com@pfizer_news

www.pfizer.com
HEADCOUNT:           92,400
YEAR ESTABLISHED:      1849
REVENUES:           $53,647     (+2%)
NET INCOME:         $11,153    (-48%)
R&D:                 $8,006     (+4%)

DRUGS APPROVED

DRUG                      INDICATION

Retacrit                  Anaemia in chronic kidney disease
                          (CKD) (dialysis)
Lorbrena                  Non-small cell lung cancer (NSCLC)
Vizimpro                  Non-small cell lung cancer (NSCLC)
Talzenna                  Breast cancer
Daurismo                  Leukaemia, acute myeloid (AML)
Seizalam                  Generalised seizures
Doxercalciferol           Hyperparathyroidism

DRUGS FILED

DRUG                      INDICATION

NuThrax                   Anthrax prophylaxis
Daptomycin                Skin infections
QUZYTTIR                  Urticaria
PHASE III

DRUG                      INDICATION

PF-04965842               Eczema/Dermatitis
PF-06425090               Clostridium difficile-associated diarrhoea
                          (CDAD)
Lagova                    Short stature in children, Adult growth
                          hormone deficiency
Rivipansel                Sickle cell disease
PF-06651600               Alopecia/Male pattern baldness
Tanezumab                 Pain, lower back, Pain, cancer-induced,
                          Osteoarthritis
PF-06482077               Pneumococcal infection prophylaxis
Fidanacogene
Elaparvovec               Haemophilia B
ATM-AVI                   Gram negative infections, Pneumonia
Tremelimumab              Non-small cell lung cancer (NSCLC), Head
                          & Neck cancer, Bladder cancer, Liver
                          cancer, Small cell lung cancer (SCLC)
Crenolanib                Gastro-intestinal stromal tumours (GIST)
Sulopenem Oral
Prodrug                   General bacterial indications, Urinary
                          tract infections (UTIs)
SHP647                    Ulcerative colitis, Crohn's disease
Sulopenem IV              General bacterial indications
Maralixibat               Cholestasis
S/GSK1265744
LAP                       HIV treatment
PF-06741086               Haemophilia A
AN5568/ SCYX-7158         i Trypanosomiasis

PF-05416266               Sickle cell disease
TPOXX                     Smallpox treatment

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

PF-06753512               Prostate Cancer
PF-06760805               Invasive Group B streptococcus infection
PF-06886992               Serogroups ABCWY
                          meningococcal infections
PF-06928316               Respiratory Syncytial Virus Infection
PF-06936308               Multiple Cancers
PF-06647020               Biologic Cancer
PF-06801591               Biologic Cancer Immunotherapy
PF-06821497               Cancer
PF-06863135               Biologic Multiple Myeloma
PF-06873600               Metastatic Breast Cancer
PF-06939999               Solid Tumors
PF-06952229               Cancer
PF-04518600               Biologic Cancer
PF-06763809               Psoriasis
PF-06817024               Biologic Atopic Dermatitis
PF-06826647               Inflammatory Bowel Disease
PF-06835375               Biologic Lupus
PF-06939926               Biologic Duchenne Muscular Dystrophy
PF-04447943               Sickle Cell Anemia
PF-06865571               Non-alcoholic Steatohepatitis
PF-06882961               Diabetes Mellitus- Type 2

DRUGS COMING OFF PATENT

DRUG      INDICATION             YEAR

Lyrica    epilepsy, neuropathy   2019
Chantix   smoking cessation      2020
Sutent    cancer                 2021

TOP SELLING DRUGS

DRUG          INDICATION             2018 SALES   (+/-%)

Prevnar 13    pneumoccal vaccine       $5,802       4%
Lyrica        epilepsy, neuropathy     $4,970      -2%
Ibrance       cancer                   $4,118       32%
Enbrel        rheumatoid arthritis     $2,112      -14
Lipitor       cholesterol              $2,062       8%
Xeljanz       arthritis                $1,774       32%
Chantix       smoking cessation        $1,085       9%
Sutent        cancer                   $1,049      -3%
Norvasc       hypertention             $1,024       11%
Premarin      menopause                $832        -15%


In 2018, Pfizer reported revenues of $53,647 billion, an increase of two percent, as several of its biggest-selling medicines and vaccines continued to grow, including Ibrance, Eliquis, Xeljanz and Prevnar 13. Pfizer also reported growth in emerging markets and in bio-similars, which helped to absorb $1.7 billion in lost revenue because of products that recently lost marketing exclusivity. Eight billion dollars was invested during the year in research and development (R&D).

During the year, Pfizer unveiled plans to reorganize into three businesses, which became effective at the beginning of the company's 2019 fiscal year, and are Pfizer Biopharmaceuticals Group, that now includes biosimilars and a new Hospital business unit for anti-infectives and sterile injectables; Upjohn, an off-patent branded and generic medicines business based in China that is bringing 20 of its most iconic brands to more than 100 markets around the world; and a Consumer Healthcare business aligned with the growing trend of consumers taking their health into their own hands.

Also on the consumer side of the business, at the end of the year Pfizer and GlaxoSmithKline entered a joint venture to create a global consumer healthcare company. The deal calls for Pfizer contributing its consumer healthcare business to GlaxoSmithKline's existing consumer healthcare business. The 2017 global sales for the combined business were approximately $12.7 billion. The deal is expected to close in the second half of 2019.

The joint venture will be a category leader in pain relief, respiratory, vitamin and mineral supplements, digestive health, skin health and therapeutic oral health. It's expected to be among the largest consumer healthcare players in key geographies, including the U.S., Europe, China, India and Australasia. The joint venture will operate globally under the GSK Consumer Healthcare name. Following the integration, GSK intends to separate the joint venture as an independent company.

As we moved into 2019, it was announced that Dr. Albert Bourla, chief operating officer at the time, would be taking over the reins of the stripped down Pfizer organization as its new chief executive officer, succeeding Ian Read. Under Mr. Read, Pfizer received 30 FDA approvals and amassed a pipeline with the potential for approximately 25-30 approvals through 2022, of which as many as 15 have the potential to be blockbusters.

STERILE MANUFACTURING INVESTMENT

In terms of growth, Pfizer is investing $465 million to expand its U.S. manufacturing with technically advanced sterile in-jectable pharmaceutical production facilities in Portage, MI, which will create approximately 450 new jobs over the next several years. Known as Modular Aseptic Processing (MAP), the new 400,000 square foot production facility expands Pfizer's presence in Portage, located in Kalamazoo County, where the company now employs more than 2,200 people at one of its largest plants.

MAP will incorporate technically advanced aseptic manufacturing equipment, systems and design, including multiple, self-contained modular manufacturing lines. This allows the manufacturing line in each module to be entirely separate from all other manufacturing lines. Construction is expected to be completed in 2021. After the facility is validated by regulatory agencies, production should begin in 2024.

The investment is part of Pfizer's overall plan to invest approximately $5 billion in U.S.-based capital projects as a result of the enactment of the Tax Cuts and Jobs Act. During the next six years, the company expects to invest approximately $1.1 billion in Kalamazoo County, which is in addition to the $1 billion it has invested in the site over the past decade.

The Portage site is a primary global supplier of sterile injectable, liquids and semi-solid medicines, and active pharmaceutical ingredients (APIs), producing more than 150 products. Its biggest product is Solu-Medrol, a widely used injectable anti-inflammatory medicine.

CANCER RESEARCH COLLABORATIONS

Pfizer remained active during the year on the cancer research front. It inked a deal worth up to $520 million with Kineta Immuno-Oncology (KIO), to develop RIG-I agonist immunotherapies for the treatment of cancer.

Leap Therapeutics entered into a collaboration with Pfizer and Merck KGaA to evaluate Leap's GITR agonist, TRX518, in combination with avelumab, a human anti-PD-Ll IgGl monoclonal antibody, and chemotherapy. Avelumab has received accelerated approval by the FDA for the treatment of patients with metastatic Merkel cell carcinoma (MCC) and previously treated patients with locally advanced or metastatic urothelial carcinoma (mUC), and is under further clinical evaluation across a range of tumor types under a global strategic alliance between Merck KGaA and Pfizer.

Daiichi Sankyo also entered into a clinical trial collaboration agreement with Pfizer and Merck KGaA to evaluate the combination of [fam-] trastuzumab deruxtecan (DS-8201), an investigational HER2 targeting antibody drug conjugate (ADC), in combination with the checkpoint inhibitor avelumab and/or an investigational Merck KGaA DNA damage response PDR) inhibitor, in patients with HER2 expressing or mutated solid tumors.

A separate research collaboration to conduct preclinical studies evaluating [fam-] trastuzumab deruxtecan in combination with avelumab, the DDR inhibitor and other investigational compounds in Merck KGaA's and Pfizer's pipelines is also underway.

Aside from cancer, during the year Pfizer also signed a $425 million flu vaccine deal with BioNTech AG, a biotech focused on precise immunotherapies for the treatment of cancer and infectious disease. The multi-year R&D collaboration's goal is to develop mRNA-based vaccines for the prevention of influenza (flu).

Caption: Pfizer's headquarters in Manhattan. The American multinational pharmaceutical giant is again the world's largest drug maker with nearly $54 billion in revenue.

02 NOVARTIS

Headquarters: Basel, Switzerland

twitter.com/novartis

www.novartis.com
HEADCOUNT:          125,161
YEAR ESTABLISHED:      1996
REVENUES:           $51,900     (+6%)
PHARMA REVENUES:    $44,751     (+6%)
NET INCOME:         $12,614    (+64%)
R&D:                 $9,074     (+1%)

DRUGS APPROVED

DRUG                   INDICATION

Lutathera              Neuroendocrine tumor
Aimovig                Migraine
Hyrimoz                Arthritis, rheumatoid, Psoriasis, Arthritis,
                       psoriatic, Ankylosing spondylitis, Crohn's
                       disease, Arthritis, juvenile idiopathic
                       (JIA), Ulcerative colitis

DRUGS FILED

DRUG                   INDICATION

Pretomanid             Tuberculosis (TB)
Brolucizumab           Wet age-related macular degeneration

PHASE III

DRUG                   INDICATION

Arzerra S.C.           Relapsing-Remitting MS (RRMS)
QAW039                 Asthma, Nasal polyp
PSMA-617               Prostate cancer
Capmatinib             Non-small cell lung cancer (NSCLC)
Crizanlizumab          Sickle cell disease
QMF149                 Asthma
ABL001                 Leukaemia, chronic myeloid (CML)
PDR001                 Melanoma
Lamprene               Tuberculosis (TB)
QGE031                 Urticaria
LMI070                 Spinal muscular atrophy
Onalta                 Neuroendocrine tumour
CAD106                 Alzheimer's disease
TKI258                 Renal cell carcinoma (RCC)
Bivalent Typhoid
Fever Vaccine          Typhoid
BGJ398                 Biliary cancer
QPI-1002               Kidney transplantation
CDZ173                 Other immune indications
CNP520                 Alzheimer's disease
AS-2                   Anaesthesia, general
Nerviano/ B-RAF        solid tumors

EARLY RESEARCH PROJECTS

DRUG                   INDICATION

AVXS-201               Rett syndrome
CFZ533                 solid organ transplantation
CAD106                 Alzheimer's disease
CNP520                 Alzheimer's disease
CSJ117                 severe asthma
ECF843                 dry eye
HDM201                 acute myeloid lymphoma
KAE609                 malaria
KAF156                 malaria
LJC242                 non-alcoholic steatohepatitis
LJN452                 non-alcoholic steatohepatitis
LMI070                 spinal muscular atrophy
LNP023                 IgA nephropathy
LOU064                 chronic spontaneous urticaria
MOR106                 atopic dermatitis
QBW251                 chronic obstructive pulmonary disease
SAF312                 chronic ocular surface pain
UNR844                 presbyopia
VAY736                 autoimmune hepatitis
VAY785                 non-alcoholic steatohepatitis
VPM087                 colorectal cancer
ZPL389                 atopic dermatitis
Zolgensma              IV formulation spinal muscular atrophy

DRUGS COMING OFF PATENT

DRUG        INDICATION             YEAR

Exjade      iron overload          2019
Afinitor    Renal cell carcinoma   2020
Galvus      Diabetes, type II      2022
Lucentis    Wet AMD                2022
Promacta    Thrombocytopaenic
            purpura, idiopathic    2023
Tasigna     Leukaemia, chronic     2023
            myeloid

TOP SELLING DRUGS

DRUG          INDICATION                  2018 SALES   (+/-%)

Gilenya       autoimmune disease            $3,341       5%
Cosentyx      Psoriasis, ankylosing
              spondylitis and psoriatic
              arthritis                     $2,837      37%
Lucentis      age-related macular
              degeneration                  $2,046       8%
Tasigna       chronic myeloid leukemia      $1,874       2%
Sandostatin   acromegaly                    $1,587      -2%
Gleevec       Leukaemia, chronic
              myeloid (CML)                 $1,561      -20%
Afinitor      oncology                      $1,556       2%
Galvus        diabetes                      $1,284       4%
Promacta      Thrombocytopaenic
              purpura, idiopathic (ITP)     $1,174      35%
Tafinlar      Melanoma                      $1,155      32%


With pharmaceutical sales of nearly $45 billion, Novartis slid into second just ahead of Roche in this year's report--up four spots from last year's sixth place ranking. Under the leadership of new chief executive, Vasant Narshimhan, 2018 saw Novartis involved in several deals that has the Swiss pharma giant focused more on medicines.

First it inked an $8.7 billion deal to acquire gene therapy company AveXis as part of its neuroscience strategy. AveXis is conducting several clinical studies for the treatment of spinal muscular atrophy, or SMA, an inherited neurodegenerative disease caused by a defect in a single gene. Their gene therapy candidate AVXS-101 has the potential to be the first one-time gene replacement therapy for SMA according to Novartis, and it currently has orphan drug designation from the U.S. Food and Drug Administration for the treatment of SMA.

The deal followed shortly after Novartis sold its stake in its consumer health-care joint venture to GlaxoSmithKline for $13 billion. The company also decided to spin off its Alcon eye-care unit and sold parts of its Sandoz generic-drugs unit, specifically the Sandoz U.S. dermatology business and generic U.S. oral solids portfolio, to Aurobindo Pharma USA for $800 million.

The Sandoz U.S. portfolios to be sold to Aurobindo include approximately 300 products as well as additional development projects. The sale includes the Sandoz U.S. generic and branded dermatology businesses as well as its dermatology development center. As part of the transaction, Aurobindo will acquire the manufacturing facilities in Wilson, NC, and in Hicksville and Melville, NY.

In another acquisition, Novartis bought cancer-drug maker Endocyte for $2.1 billion. Endocyte is a U.S. company developing a new treatment for prostate cancer. It specializes in radiopharmaceuticals, a new class of drug that carries radioactive substances directly to cancer cells so they can kill tumor cells at close range. It uses drug conjugation technology to develop targeted therapies with companion imaging agents, including 177LuPSMA-617, a potential first-in-class investigational radioligand therapy for the treatment of metastatic castration-resistant prostate cancer (mCRPC).

The prostate cancer drug bolsters its capability in the field, which it expects to be a key growth driver moving forward, and joins another late-stage radiopharmaceutical directed at a rare form of gut cancer, acquired when it bought Advanced Accelerator Applications S.A. for $3.9 billion at the end of 2017.

EXPANDING MANUFACTURING CAPACITY

At the end of 2018, Novartis announced it had made an offer for the Frerich contract development and manufacturing organization (CDMO), CellforCure, from its parent, LFB. CellforCure is one of the first and largest CDMOs producing cell and gene therapies in Europe.

The deal has subsequently closed for an undisclosed amount and includes the cell and gene manufacturing facility located in Les Ulis, France. CellforCure is now a wholly owned Novartis manufacturing site, joining the network of cell and gene therapy sites including Morris Plains, NJ in the U.S. and Stein, Switzerland, where construction continues to progress on the 79 million [euro] facility.

The deal builds on a previously signed agreement in July 2018. Novartis signed a deal with CellforCure to produce CAR-T cell therapies including Kymriah (tisagenlecleucel), the first CAR-T cell therapy approved by the U.S. Food and Drug Administration (FDA) and indicated for two distinct, difficult-to-treat cancers in the U.S., EU, Switzerland, Canada and Australia. Novartis and CellforCure have successfully completed technology transfer and Kymriah clinical supply production is expected to begin by mid-2019.

In addition to the CellforCure deal, Novartis has made several steps to strengthen and expand its cell and gene manufacturing, including signing a strategic licensing, collaboration and share purchase agreement with Cellular Biomedicine Group (CBMG) to manufacture and supply Kymriah in China; expanding an alliance with the Fraunhofer Institute in Germany to support manufacturing for clinical trials and post approval manufacturing; and a contract manufacturing collaboration in Japan.

PARTNERSHIP FOR VIRTUAL TRIALS

Novartis formed an alliance with Science 37 to initiate up to 10 new clinical trials over the next three years. The studies will blend virtual and traditional models, with increasing degrees of decentralization towards a mostly "site-less" model. Novartis was an early investor in Science 37 and together have already initiated virtual trials for cluster headache, acne and nonalcoholic steatohepatitis (NASH).

The new decentralized trials in the U.S. will focus on dermatology, neuroscience and oncology, leveraging Science 37's proprietary Network Oriented Research Assistant (NORA) technology, which enables patients to participate in studies using mobile devices and telemedicine services. Through this alliance, the companies plan to apply Science 37's customized enterprise software to some of the leading clinical development programs of Novartis.

According to the Center for Information & Study on Clinical Research Participation (CISCRP), only 2% of the eligible population in the U.S. participate in clinical trials. Those who do participate attend an average of 11 trial site visits in six months, representing a significant burden for both patients and trial centers. By bringing the trial to the patient, Novartis aims to decrease the burden of clinical trial participation on patients and trial centers.

Caption: Novartis headquarters in Basel, Switzerland. Novartis is a Swiss multinational pharmaceutical company ranking number two in Big Pharma sales in 2018.

03 ROCHE

Headquarters: Basel, Switzerland

twitter.com/Roche

www.roche.com
HEADCOUNT:          94,442
TOTAL REVENUES:    $57,734     (+7%)
PHARMA REVENUES:   $44,654     (+5%)
NET INCOME:        $11,035    (+23%)
R&D:               $12,281     (+6%)

DRUGS APPROVED

DRUG                      INDICATION

Xofluza                   Influenza
Trogarzo                  HIV treatment
DRUGS FILED

DRUG                      INDICATION

Entrectinib               Solid tumour indications, Non-small cell
                          lung cancer (NSCLC)

PHASE III

DRUG                      INDICATION

Risdiplam                 Spinal muscular atrophy
RG7716                    Macular oedema, Wet age-related macular
                          degeneration (AMD)
RG6042                    Huntington's disease
Ipatasertib               Prostate cancer, Breast cancer
Etrolizumab               Ulcerative colitis, Crohn's disease
Satralizumab              Neuromyelitis optica (NMO)
Idasanutlin               Leukaemia, acute myeloid (AML)
Balovaptan                Autism spectrum disorders (ASD)
Gantenerumab              Alzheimer's disease
RG6206                    Duchenne muscular dystrophy
Palovarotene              Bone repair & regeneration
Dalcetrapib               Hyperlipidaemia
HZN-001                   Grave's disease
Gefapixant                Cough/Common cold
MGL-3196                  Familial hypercholesterolaemia, Nonalcoholic
                          steatohepatitis (NASH), Liver fibrosis
QGE031                    Urticaria
Lucentis SR               Wet age-related macular degeneration
                          (AMD)
HMS5552                   Diabetes, type II (maturity onset)
Tearexaban                Thrombosis, deep vein (DVT), Pulmonary
                          embolism
RG6264                    Breast cancer

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

CHU                       solid tumors
RG6026                    relapsed or refractory non-hodgekin's
                          lymphoma
RG6058 tiragolumab        solid tumors in combination with tecentriq
RG6109                    acute myeloid leukemia
RF6114                    metastatic ER-positive and HER2-negative
                          breast cancer
RG6123                    solid tumors
RG6146                    oncology
RG6148                    HER2-positive breast cancer
RG6160                    relapse or refractory multiple myeloma
RG6171                    ER-positive and HER2-negative metastatic
                          breast cancer
RG6185                    solid tumors
RG6194                    metatatic HER2-positive cancers
RG7461                    solid tumors
RG6107 crovalimab         paroxysmal nocturnal hemoglobinuria
RG7828                    hematologic tumors
RG6151                    asthma
RG6173                    asthma
RG7835                    autoimmune diseases
RG7880                    inflammatory diseases
RG6147                    geographic atrophy
RG6127                    chronic hepatitis B infection
RG7861                    infections caused by staphylococcus aureus
RG7992                    metabolic diseases
RG6000                    amyotrophic lateral sclerosis
RG6237                    neuromuscular disorders

DRUGS COMING OFF PATENT

DRUG        INDICATION            YEAR

Herceptin   breast cancer         2019
Avastin     cancer                2019
Lucentis    macular degeneraton   2020
Esbriet     Pulmonary fibrosis,
            idiopathic            2021

TOP SELLING DRUGS

DRUG                INDICATION              2018 SALES   (+/-%)

MabThera
/Rituxan            rheumatoid arthritis      $6,905      -8%
Herceptin           cancer                    $7,140       0%
Avastin             breast cancer             $7,004       3%
Perjeta             breast cancer             $2,836      27%
Ocrevus             Relapsing-Remitting
                    MS (RRMS)                 $2,406      173%
Xolair              asthma                    $1,986      12%
Actemra/
RoActemra           rheumatoid arthritis      $1,847      12%
Lucentis            macular degeneraton       $1,697      18%
Activase/TNKase     myocardial infarction     $1,313       6%
Esbriet             Pulmonary fibrosis,
                    idiopathic                $1,054      19%


Roche's pharma sales grew 5% to $44.6 billion in 2018. Key growth drivers were the new multiple sclerosis medicine Ocrevus and cancer medicines Perjeta, Tecentriq, Alecensa as well as the new haemophilia medicine Hemlibra. With sales of $2.4 billion in its first full year on key markets, Ocrevus is the most successful new product launch in Roche's history.

On the regulatory front, the Swiss pharma giant received several major approvals during the year. In the fourth quarter, FDA gave the green light to Tecentriq in combination with Avastin for a specific form of lung cancer. The regulator also granted accelerated approval for leukaemia drug Venclexta, and approved Xofluza, which is used to treat the flu.

At the end of the year it was announced that Roche's CEO, Daniel O'Day, was stepping down from the helm after being with the company for more than 30 years in various roles. William Anderson succeeded him as the new chief executive at the start of 2019, having previously served as CEO of Genentech since 2017.

ONCOLOGY ACQUISITIONS

In 2018, Roche concluded several oncology-focused transactions to advance its personalized healthcare strategy with three U.S.-based acquisitions.

Three years after buying a majority stake in Foundation Medicine for more than $1 billion as part of a research and development collaboration, Roche acquired the rest of the company in a $2.4 billion follow-on deal for the business, which selects cancer treatments for patients based on their genetic profile.

The deal came on the heels of Roche's $1.9 billion acquisition of oncology-focused electronic health record (EHR) software developer Flatiron Health. They make oncology-specific EHR systems, most notably an information exchange platform which allows researchers to access and learn from patient records. The company's message is that large amounts of data could be used to speed up and, in some cases, replace certain clinical trials where patients are randomly assigned to a specific treatment.

Roche also entered an agreement to acquire Ignyta, a U.S. based pharmaceutical company focused on developing cancer therapies, for $1.7 billion. The acquisition expands Roche's oncology portfolio globally. Ignyta will continue its operations in San Diego and will be responsible for the ongoing study of entrectinib, its most advanced cancer drug being studied in a range of solid tumor types. The company also has a portfolio of drugs in early stage of development that use gene therapy to kill the underlying diseases that drive cancer tumor growth. Ignyta employs an integrated "Rx/Dx" approach that combines precision medicines (Rx) and in-house molecular diagnostics (Dx) to both identify and target hard-to-treat cancers in hard-to-find patients.

RESEARCH COLLABORATIONS

Roche entered several cancer research collaborations during the year. In the cellular therapy arena, it formed a deal with SQZ Biotechnologies to jointly develop and commercialize certain products based on antigen presenting cells (APCs) created by the SQZ platform for the treatment of oncology indications. The companies are also expanding a 2015 collaboration to jointly develop therapeutics derived from peripheral blood mononuclear cells (PBMCs).

With Kymab Group, Roche entered a clinical trial agreement, under which it will provide its PD-L1 blocking antibody atezolizumab for use in combination in Kymab's upcoming Phase I-II clinical studies combining its lead investigational anti-ICOS antibody therapy KY1044 in patients with advanced solid cancers. Kymab will be responsible for conducting the clinical trials, and both companies will share data from the trials. Kymab continues to retain all commercial rights to KYI044.

Syapse and Roche entered into a multi-year strategic collaboration to help make precision medicine available to more cancer patients. Syapse and Roche will work jointly to develop software products and analytics solutions to provide the tools and insights healthcare providers need to practice precision medicine at scale, with the goal of improving patient outcomes. The companies will initially focus on four product programs: real-world evidence, so that physicians can make better care decisions; better understanding the health economics impact and patient outcomes of precision medicine; advancing electronic patient-reported outcomes to understand precision medicine's effect on health-related quality of life; and accelerating clinical trial enrollment by matching patients to precision trials at the point of care.

Roche entered research deals in therapeutic areas other than cancer as well during the year. In diabetes, it partnered with Zealand Pharma for the Phase 3 trials with dasiglucagon for treatment of congenital hyperinsulinism (CHI). Zealand is responsible for conducting the Phase 3 trials, while Roche Diabetes Care provides its Accu-Chek Combo pump system for this study.

Icagen entered into a license and collaboration agreement with Roche to develop and commercialize small molecule ion channel modulators for the treatment of neurological disorders. The program incorporates Icagen's platform for ion channels and is directed at a specific novel ion channel target expressed in neurons.

With BioMed X, Roche entered a research collaboration in the field of immunology. BioMed X launched a global call for applications to establish a new biomedical research group in Heidelberg, Germany with the goal of developing novel approaches for the treatment of several immune-mediated diseases.

Caption: Roche bolstered its oncology portfolio during the year, striking deals to buy Foundation Medicine, Flatirion Health and Ignyta. (Courtesy of Roche)

04 JOHNSON & JOHNSON

Headquarters: New Brunswick, NJ

twitter.com/JNJComm

www.jnj.com
HEADCOUNT:         135,100
REVENUES:          $81,581    (+7%)
PHARMA REVENUES:   $40,734   (+12%)
NET INCOME:        $15,297    (N/M)
R&D:               $10,775    (+2%)

DRUGS APPROVED

DRUG                      INDICATION

Erleada                   HIV treatment
Motegrity                 Prostate cancer
Symtuza                   Constipation

DRUGS FILED

DRUG                      INDICATION

Cabotegravir &
Rilpivirine               HIV treatment

PHASE III

DRUG                      INDICATION

Ponesimod                 Relapsing-Remitting MS (RRMS)
Aprocitentan              Hypertension (HTN)
Dapivirine                HIV prophylaxis
Redectane                 Nuclear imaging
Seladelpar                Primary biliary cirrhosis (PBC)
Rilpivirine LAI           HIV treatment
MOR202                    Multiple myeloma
Pimodivir                 Influenza
MVA-BN Filo               Ebola haemorrhagic
                          fever (EHF) prophylaxis
Monovalent Ebola
Vaccine                   Ebola haemorrhagic
                          fever (EHF) prophylaxis
Daratumumab
Enhanze                   Multiple myeloma, Amyloidosis
Zejula                    Prostate cancer
TOP1630                   Dry eye
Ad26.Mos4.HIV             HIV prophylaxis
Abiraterone-
Apalutamide FDC           Prostate cancer
Paliperidone
6-month Injectable        Schizophrenia
Uptravi IV                Pulmonary hypertension
TD-1473                   Ulcerative colitis

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

Ipilimumab                prostate cancer
Pimodivir                 Kidney Failure, Chronic
JNJ-64300535              Hepatitis B, Chronic
JNJ-63723283              Neoplasm
JNJ-67571244              Leukemia, Myeloid, Acute
JNJ-67856633              Leukemia, Lymphocytic, Chronic, B-Cell
JNJ-64619178              Neoplasms, Non-Hodgkin Lymphoma,
                          Myelodysplastic Syndromes
JNJ-64407564              Hematological Malignancies
JNJ-63733657              Alzheimer Disease
JNJ-63709178              Leukemia, Myeloid, Acute
JNJ-61186372              Non-Small-Cell Lung Cancer
JNJ-68284528              Multiple Myeloma

DRUGS COMING OFF PATENT

DRUG              INDICATION              YEAR

Invega Sustenna   Schizophrenia           2019
Prezista          HIV                     2019
Simponi           Arthritis, rheumatoid   2022
Stelara           Psoriasis               2023

TOP SELLING DRUGS

DRUG              INDICATION              2018 SALES   (+/-%)

Stelara           psoriasis                 $5,156      29%
Remicade          rheumatoid arthritis      $4,890      -15%
Zytiga            prostate cancer           $3,498      40%
Xarelto           deep vein thrombosis,
                  pulmonary embolism        $2,477      -1%
Invega Sustenna   schizophrenia             $2,429      10%
Simponi           rheumatoid arthritis      $2,084      14%
Darzalex          Multiple myeloma          $2,025      63%
Prezista          HIV/AIDS                  $1,955       7%
Imbruvica         oncology                  $1,486      41%
Opsumit           hypertension              $1,215      112%


Johnson & Johnson's (J&J) pharmaceutical segment sales in 2018 were $40.7 billion, an increase of 12% from 2017. U.S. sales accounted for $23.3 billion while international sales were $17.4 billion, an increase of 8.4% and 18% respectively. The pharma segment is focused on six therapeutic areas: immunology, infectious diseases and vaccines, neuroscience, oncology, cardiovascular and metabolism and pulmonary hypertension, a new therapeutic area, which was established with the $30 billion acquisition of Actelion in June 2017.

During the year, FDA approved J&J's cardiovascular drug Invokana (canagliflozin). The drug is meant to reduce the risk of major adverse cardiovascular events, including heart attack, stroke or death due to a cardiovascular cause in adults with type 2 diabetes who have established cardiovascular disease. It is the first and only oral diabetes treatment approved with this indication. FDA also signed off on a Janssen Phase lb/2 trial to evaluate a chimeric antigen receptorT cell (CAR-T) therapy in patients with relapsed or refractory multiple myeloma

In terms of acquisitions, while 2018 didn't witness anything on the level of the Actelion deal a year earlier, J&J did buy BeneVir Biopharm for as much as $1 billion. BeneVir uses itsT-Stealth Oncolytic Virus Platform to engineer oncolytic viruses tailored to infect and destroy cancer cells. Janssen intends to advance preclinical candidates as standalone therapies and in combination with other immunotherapies for the treatment of solid tumor cancers. BeneVir will maintain a research presence in Rockville, MD and become part of the Janssen Oncology Therapeutic Area.

RESEARCH AND DEVELOPMENT PARTNERSHIPS

During the year J&J entered a number of partnerships to advance its research and development activities. Biopharma Ireland Limited joined a global co-development and commercialization agreement with Janssen Biotech, one of the Janssen Pharmaceutical Companies of J&J, for TD-1473 and related back-up compounds for inflammatory intestinal diseases, including ulcerative colitis and Crohn's disease. The deal could be worth up to $1 billion and will see the two companies jointly develop and commercialize TD-1473 in inflammatory intestinal diseases, with the two companies sharing profits in the U.S. and expenses related to a potential Phase 3 program.

Arrowhead Pharmaceuticals entered into a license and collaboration agreement with Janssen to develop and commercialize ARO-HBV. In addition, Arrowhead entered into a research collaboration and option agreement with Janssen to potentially collaborate for up to three additional RNA interference (RNAi) therapeutics against new targets to be selected by Janssen. The transactions have a combined potential value of over $3.7 billion for Arrowhead.

argenx, a clinical stage biotech, entered a $1.6 billion global collaboration and license agreement for cusatuzumab (ARGX-110), an anti-CD70 SIMPLE AntibodyO, with Cilag GmbH, an affiliate of Janssen. Cusatuzumab is currently in development in a Phase 1/2 combination study with Vidaza for newly diagnosed, elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) who are unfit for chemotherapy.

MeiraGTx entered into a research collaboration and evaluation agreement with Janssen to use their proprietary riboswitch technology to engineer regulatable gene therapy constructs encoding proprietary gene sequences from Janssen. Evaluation of the performance of these constructs will determine the utility of this approach in future product development. MeiraGTx's gene regulation platform is a potentially transformative technology that incorporates an on/off switch for gene expression into the gene therapy vector which can then be activated using a small molecule. In this way, gene therapies can be switched on and off according to the patients' need and the dosing requirements of the therapy. Temporal control overlaying spatial regulation of gene expression has the potential to increase the utility and flexibility of gene therapy.

Together with Theravance Biopharma, J&J will develop TD1473, a first-in-class oral, gastrointestinal (GI) restricted pan-Janus kinase OAK) inhibitor for the treatment of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC).

NEW ASIA PACIFIC HO

Expanding its global footprint, and reflecting positive growth overseas, in May 2018 J&J opened its new Asia Pacific headquarters in Singapore. The new 15,800 square meter facility will bring together more than 1,000 employees from Johnson & Johnson's pharmaceuticals, medical devices and consumer businesses in one single location to spearhead new ideas and frameworks for healthcare of the future. The headquarters will feature a Design Lab, Leadership Lab, and Human Performance Institute. Johnson & Johnson's Asia Design Lab will be the first design lab outside of the U.S.

The new Singapore HQ has also been selected as the location for Johnson & Johnson's first global development center known as the Leadership Lab. The Leadership Lab aims to conduct over 200 leadership development classes and train 4,000 Asian leaders annually. As a think-tank, the Leadership Lab will create links with universities, research groups, governments, healthcare organizations and other partners to co-create new healthcare models and solutions to prototype capabilities required to author the next chapter of healthcare innovation in Asia.

The regional headquarters will also include Asia Pacific's first Human Performance Institute (HPI), offering proprietary leadership development initiatives to participants outside of Johnson & Johnson, with the goal to train 150,000 people in Singapore by 2020.

Caption: J&J maintained its spot at number four in this year's ranking on $40.7 billion in 2018 revenue.

05 SANOFI

Headquarters: Paris, France

twitter.com/sanofi

www.sanofi.com
HEADCOUNT:          104,226
YEAR ESTABLISHED:      2004
REVENUES:           $39,419    (-2%)
NET INCOME:          $4,925    (+1%)
R&D:                 $6,742    (+8%)

DRUGS APPROVED

DRUG                      INDICATION

Libtayo                   Skin cancer, non-melanoma
Vaxelis                   Diphtheria prophylaxis, Hepatitis B pro
                          phylaxis, Haemophilus influenzae type b
                          (Hib) prophylaxis, Pertussis/Whooping
                          cough, Polio prophylaxis, Tetanus

DRUGS FILED

DRUG                      INDICATION

Isatuximab                Multiple myeloma

PHASE III

DRUG                      INDICATION

Fitusiran                 Haemophilia A, B
Sutimlimab                Anaemia, haemolytic
Efpeglenatide             Diabetes, type II (maturity onset)
GZ402666                  Pompe's disease
GZ402671                  Polycystic kidney disease (PKD)
MEDI8897                  RSV infections
Fasinumab                 Osteoarthritis, chronic pain
Rabies VRVg               Rabies
TetraMen-T                Meningitis prophylaxis
Picoplatin                Small cell lung cancer (SCLC)
Evinacumab                Familial hypercholesterolaemia
Mavorixafor               General haematological indications
VN-0105                   Haemophilus influenzae type b (Hib) pro
                          phylaxis, Diphtheria prophylaxis,
                          Pertussis/Whooping cough,
                          Polio prophylaxis,
                          Teta nus prophylaxis
Vutrisiran                Amyloidosis
Ozoralizumab              Arthritis, rheumatoid

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

SAR2720                   solid tumors
SAR440234                 leukemia
SAR441000                 solid tumors
BIW001                    hemophilia A
ST400                     beta thalassemia
BIW003                    sickle cell disease
SAR443060                 amyotrophic lateral sclerosis
Next Gen PCV              pneumococcal conjugate vaccines

Virus Type 2 Vaccine      HSV-2 therapeutic vaccine
Respiratory Syncytial
  Virus Vaccine           vaccines for infants 4-months and older
SAR441169                 psoriasis
SAR439459+
cemiplimab                advanced solid tumors
  cemiplimab(l) +
REGN4018                  ovarian cancer
SAR439859+
  palbociclib             metastatic breast cancer
sutimlimab                immune thrombocytopenic purpura
SAR443060                 Alzheimer's disease
SAR441169                 psoriasis
SAR441344                 multiple sclerosis
SAR408701                 mAb solid tumors
SAR439459                 advanced solid tumors
REGN5458                  relapsing refractory multiple myeloma
REGN4018                  ovarian cancer

DRUGS COMING OFF PATENT

DRUG       INDICATION            YEAR

Jevtana    Prostate cancer       2021
Aubagio    Relapsing-Remitting
           MS (RRMS)             2023
Myozyme    Pompe's disease       2023
Apidra     Diabetes, type I
           (juvenile onset)      2023

TOP SELLING DRUGS

DRUG        INDICATION             2018 SALES   (+/-%)

Lantus      diabetes                 $4,211      -19%
Pentacel    vaccines                 $2,066       0%
Influenza
Vaccines    vaccines                 $2,017       12%
Aubagio     Relapsing-Remitting
            MS (RRMS)                $1,945       10%
Lovenox     thrombosis               $1,730      -3%
Plavix      heart attack, stroke     $1,701       2%
Myozyme /
Lumizyme    Pompe disease            $992         11%
Toujeo      diabetes                 $992         8%
Dupixent    Eczema/Dermatitis        $931         276%
Fabrazyme   Fabry disease            $892         9%


Revenue fell slightly for Sanofi in 2018 as it continued to restructure its operations to focus on mature markets and across emerging markets. The French pharma major reported sales of $39.4 billion, down 2% from the year prior, and slid two spots to number five in this year's ranking.

During the year, Sanofi changed the organizational structure of two of its global business units, creating a new primary care unit that combines the product portfolios of the existing diabetes and cardiovascular unit with established products. The new primary care unit will focus exclusively on mature markets.

Sanofi also created a second new global business unit called China and emerging markets. This newly-formed business will focus on the growth opportunities in emerging markets, particularly in China, which is Sanofi's second largest market after the U.S.

In-line with these plans to focus efforts on emerging markets, particularly China, Sanofi launched global R&D operations in the country during the year. The new Global R&D Operations Hub is focused on digitalization and big data analysis and located in Chengdu, Sichuan province, China. The new R&D operations in China will serve as Sanofi's third pillar of Sanofi Global Clinical Sciences and Operations, joining facilities in France and the U.S.

The 66 million [euro] investment will support the clinical research and development of Sanofi's drugs by focusing on the management of global multi-center clinical trials data and files. The hub will bring together global data and analysis in an effort to accelerate the availability of trial results, from Phase I to Phase IV.

The Chengdu Hub will target therapeutic areas including diabetes and cardiovascular diseases, vaccines, oncology, immunology and inflammation, rare diseases, multiple sclerosis and neurology. It will leverage global cutting-edge biological technology for polypeptides, gene therapy, monoclonal antibodies and multi-specific antibodies. The Hub plans to recruit 300 local pharmaceutical R&D professionals by 2020.

In another major investment, Sanofi is pouring nearly $400 million into the construction of a new state-of-the-art vaccine manufacturing facility at the Sanofi Pasteur Canadian headquarters in Toronto, Ontario, Canada. The new facility will allow Sanofi Pasteur, the vaccines global business unit of Sanofi, to meet the growing demand of five-component acellular pertussis (5-acP) antigen. Upon completion in 2021, the new building will also be equipped to produce the antigens used in the diphtheria and tetanus vaccines.

M&A DEALS AND DIVESTMENTS

Sanofi signed a few acquisition and divestment agreements during the year as part of its refocused strategy. The largest deal in terms of dollars was the $11.6 billion acquisition of Bioverativ, a biopharma company focused on therapies for hemophilia and other rare blood disorders. Bioverativ was created from Biogen's hemophilia-focused spinoff launched in early 2017.

Hemophilia represents the largest market for rare diseases, with approximately 181,000 people affected worldwide, and is expected to grow above 7% per year through 2022. Bioverativ has approximately $10 billion in annual sales. It's extended half-life therapies, Eloctate and Alprolix for the treatment of hemophilia A and B, respectively, represented the first major advancements in the hemophilia market in nearly two decades when launched.

In 2016, Bioverativ generated $847 million in sales and $41 million in royalties.

Sanofi believes factor replacement therapy will remain the standard of care in hemophilia for many years due to its safety and increasingly superior long-acting profile. Sanofi will be able to leverage Bioverativ's clinical expertise and commercial platform to advance fitusiran, an investigational RNA interference (RNAi) therapeutic for hemophilia A and B, with or without inhibitors.

Bioverativ's pipeline includes a Phase III program for cold agglutinin disease, and early stage research programs and collaborations in hemophilia, and other rare blood disorders, including sickle cell disease and beta thalassemia.

In another acquisition, Sanofi purchased Ablynx, a biopharma company focused on the discovery and development of nanobodies, for approximately $4.8 billion. Sanofi said the acquisition is part of its innovation efforts focused on technologies addressing multiple disease targets with single multi-specific molecules.

Nanobodies are a new class of next-gen biologics. Ablynx's nanobody technology supports an extensive pipeline of more than 45 proprietary and partnered candidates for a range of therapeutic areas such as hematology, inflammation, immuno-oncology and respiratory diseases. Eight nanobodies have entered clinical development.

On the divestment front, Sanofi sold its European generics business to Advent International for roughly 1.9 billion [euro], as part of a continued effort to focus on its core areas of global medicines and emerging markets, specialty care and diabetes and cardiovascular. Sanofi's chief executive officer at the time, Olivier Brandicourt*, had planned to sell the business back in 2015 as part of the refocusing effort. Since then, Sanofi also sold its animal health business Merial, purchased Boehringer Ingelheim's consumer health assets, and made the aforementioned acquisitions of Ablynx and Bioverativ.

Sanofi also sold off its UK contract manufacturing organization (CMO) business. Recipharm bought the manufacturing center and business in Holmes Chapel, UK. The site manufactures flutiform for Vectura Group. As part of the transaction, Sanofi entered into a long-term supply agreement for the products currently manufactured at the facility, including metered dose inhalers and nasal sprays.

* Note: As this issue goes to press, Paul Hudson will begetting ready to take over the chief executive role upon Mr. Brandicourt's retirement.

Caption: Sanofi Pasteur, the vaccines division of the multinational pharmaceutical company, is investing 350 million [euro] in a new manufacturing facility.

06 MERCK

Headquarters: Whitehouse Station, NJ

twitter.com/Merck

www.merck.com
HEADCOUNT:          69,000
REVENUES:          $42,294     (+5%)
PHARMA REVENUES:   $37,689     (+6%)
NET INCOME:         $6,220    (>100%)
R&D:                $9,752     (-6%)

DRUGS APPROVED

DRUG                      INDICATION

Delstrigo                 HIV treatment
Pifeltro                  HIV treatment
llumya                    Psoriasis
Vaxelis                   Diphtheria prophylaxis, Hepatitis B pro
                          phylaxis, Haemophilus influenzae type b
                          (Hib) prophylaxis, Pertussis/Whooping
                          cough, Polio prophylaxis, Tetanus

DRUGS FILED

DRUG                      INDICATION

Relebactam                Gram negative infections
Ubrogepant                Migraine
Lusduna                   Diabetes, type I (juvenile onset), type II
MK-7655A                  General bacterial indications

PHASE III

DRUG                      INDICATION

V114                      Pneumococcal infection prophylaxis
Vericiguat                Congestive heart failure (CHF)
Gefapixant                Cough/Common cold
Ibrexafungerp             Candidiasis, Aspergillosis infections
Serlopitant               Other dermatoses, Pruritus,
                          Eczema/Dermatitis, Psoriasis
Sarasar                   Hepatitis D treatment
QMF149                    Asthma
Instiladrin               Bladder cancer
Atogepant                 Migraine
Selumetinib               Other neurological indications,
                          solid tumors

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

MK-7684                   Neoplasms
MK-4280                   Neoplasms
M4344                     advanced solid tumor
MK-7264                   Obstructive Sleep Apnea
MK-2060                   Kidney Failure, Chronic
MK-8558                   HIV-1 infection
V114                      Pneumococcal Infections
V160                      Cytomegalovirus Infections
MK-5475                   Pulmonary Arterial Hypertension
MK-4334                   Alzheimer's Disease
M6495                     Osteoarthritis, Knee

DRUGS COMING OFF PATENT

DRUG        INDICATION                  YEAR

Noxafil     fungal infections           2019
RotaTeq     Rotaviral gastroenteritis   2019
Bridion     Anaesthesia, reversal       2021
Januvia     diabetes                    2022
Janumet     diabetes                    2022

TOP SELLING DRUGS

DRUG            INDICATION              2018 SALES   (+/-%)

Keytruda        cancer                    $7,171       88%
Januvia         diabetes, obesity         $3,686       -1%
Gardasil        HPV vaccine               $3,151       37%
Janumet         diabetes, obesity         $2,228        3%
Isentress       HIV/AIDS                  $1,140       -5%
Bridion         Anaesthesia, reversal     $917         30%
Pneumovax       vaccines                  $907         10%
NuvaRing        contraception             $902         19%
Simponi         rheumatoid arthritis      $893          9%
Zetia/vytorin   cholesterol               $857        -36%


Merck's worldwide pharma sales were $37.7 billion in 2018, an increase of 6% compared with 2017. Growth was driven primarily by higher oncology drug sales, particularly from star pupil Keytruda--sales skyrocketed 88% from the year before to reach $7.2 billion. Revenue related to Lynparza and Lenvima also helped bottom line growth. Other revenue generators included higher sales of vaccines, driven primarily by human papillomavirus (HPV) vaccine Gardasil/Gardasil 9, as well as higher sales in the hospital acute care franchise, attributable to Bridion and Noxafil.

Growth in 2018 was hindered by declines in the virology franchise, including lower sales of hepatitis C virus treatment Zepatier, as well as lower sales of shingles vaccine Zostavax. Generic and biosimilar competition for cardiovascular drugs Zetia and Vytorin, and immunology product Remicade, also hurt growth.

During the year, Merck continued to build its oncology portfolio through acquisition and collaboration. In February it bought virus-based cancer drug firm Viralytics for $394 million. The deal gave Merck full rights to Cavatak, Viralytics' investigational on-colytic immunotherapy that is based on the company's proprietary formulation of an oncolytic virus that has been shown to preferentially infect and kill cancer cells. Cavatak is currently being evaluated in multiple Phase 1 and 2 trials, with Keytruda--the two companies formed a partnership back in 2015 to study the use of the Cavatak and Keytruda combination in melanoma, prostate, lung and bladder cancers.

With Dragonfly Therapeutics, Merck entered a deal to discover immunotherapies for solid tumor cancers, under which Merck has the option to license exclusive worldwide rights to products developed using Dragonfly's TriNKET technology platform for a number of solid-tumor programs.

Moderna Therapeutics and Merck expanded their 2016 collaboration to develop and commercialize personalized messenger RNA (mRNA) cancer vaccines to now include shared antigen mRNA cancer vaccines including mRNA-5671, Moderna's mRNA KRAS cancer vaccine. The two companies will now advance jointly mRNA-5671 in human studies, and plan to conduct combination studies with additional immuno-oncology therapies.

Evelo Biosciences entered into a clinical trial collaboration with Merck to evaluate EDP1503 in combination with Keytruda in multiple cancer indications; Rexahn Pharmaceuticals also entered into a clinical trial agreement to evaluate the combination of its RX-5902 and Keytruda in a Phase 2 breast cancer trial; Immutep and Merck are evaluating the combination of Immutep's lead immunotherapy product candidate eftilagimod alpha with Keytruda; and with Eisai, Merck partnered for the worldwide co-development and co-commercialization of cancer drug Lenvima--the companies will develop and commercialize Lenvima jointly, both as monotherapy and in combination with Keytruda.

REGULATORY MILESTONES AND CLINICAL PROGRESS

Keytruda continued to spread its wings during the year with multiple new indications across several tumor types, including approval from FDA for the treatment of cervical cancer, a type of non-Hodgkin lymphoma, hepatocellular carcinoma, Merkel cell carcinoma, and in combination with chemotherapy for the treatment of a type of lung cancer. It also received approvals from the European Commission, as well as Chinese and Japanese regulators.

Lynparza, which is being developed in a collaboration with AstraZeneca, received FDA approval for use in breast cancer and ovarian cancer. Additionally, Lenvima was approved in the U.S., EU, Japan and China for the treatment of hepatocellular carcinoma. The FDA and EC also approved two new HIV-1 medicines: Delstrigo, a once-daily fixed dose combination tablet of doravirine, lamivudine and tenofovir disoproxil fumarate; and Pifeltro (doravirine), a new non-nucleoside reverse transcriptase inhibitor to be administered in combination with other antiretroviral medicines.

In addition to the recent approvals, Merck has continued to advance its late-stage pipeline with several regulatory submissions. Keytruda is under review in the U.S. in combination with axitinib for renal cell carcinoma and has been granted Priority Review by the FDA.

The company's Phase 3 oncology programs includes Keytruda in the therapeutic areas of breast, cervical, colorectal, esophageal, gastric, hepatocellular, mesothelioma, nasopharyngeal, ovarian, renal and small-cell lung cancers; Lynparza for pancreatic and prostate cancer; and Lenvima in combination with Keytruda for endometrial cancer.

Additionally, the company has candidates in Phase 3 clinical development in several other therapeutic areas, including V114, a vaccine for pneumococcal disease that received Breakthrough Therapy designation; MK-7264, gefapixant, a selective, nonnarcotic, orally-administered P2X3-receptor agonist being developed for the treatment of refractory, chronic cough; and MK1242, vericiguat, an investigational treatment for heart failure.

On the drug discovery front, Merck and IRBM formed a new agreement in the peptide therapeutics area, continuing their long-standing history of collaboration that began in 2010.

According to the companies, there has been increasing interest in peptide research over the last 15 years. The pharma industry continues to make significant preclinical and clinical investments in peptide-based therapeutics for different areas, including metabolic diseases, oncology and cardiovascular disease. Over the last decade there have been numerous technological advancements in this field. Now characteristics that were previously considered a liability for peptides, such as screening systems for lead identification, half-life, stability, solubility, formulation and delivery routes, are no longer considered insurmountable obstacles.

IRBM has built broad expertise in peptide drug development, from initial target identification to the development of a clinical candidate with the required properties in terms of specificity, potency, pharmacokinetics, metabolism and toxicology. For this project, IRBM will be applying its expertise in phage display peptide library design and screening and in chemical peptide synthesis and optimization, to identify potential peptide leads for a specific Merck target.

Caption: Merck reported positive revenue growth in 2018 backed by strong sales of cancer drug Keytruda.

07 ABBVIE

Headquarters: North Chicago, IL

twitter.com/abbvie

www.abbvie.com
HEADCOUNT:           30,000
YEAR ESTABLISHED:      2013
REVENUES:           $32,753     (+16%)
NET INCOME:          $5,687      (+7%)
R&D:                $10,329    (+106%)

DRUGS APPROVED

DRUG                   INDICATION

Orilissa               Endometriosis

DRUGS FILED

DRUG                   INDICATION

Leronlimab             HIV treatment
Upadacitinib           Arthritis, rheumatoid

PHASE III

DRUG                   INDICATION

Veliparib              Breast cancer, Non-small cell lung cancer
                       (NSCLC), Ovarian cancer, Lung cancer
Eltoprazine            Attention deficit disorder/hyperactivity
                       (ADD/ADHD)
Abexinostat            Renal cell carcinoma (RCC)
Rova-T                 Small cell lung cancer (SCLC)
ABBV 951               Parkinson's disease

EARLY RESEARCH PROJECTS

DRUG                   INDICATION

ABBV-157               immune-mediated diseases
ABBV-011               small-cell lung cancer
ABBV-085               solid tumors
ABBV-151               solid tumors
ABBV-155               solid and hematologic tumors
ABBV-167               solid and hematologic tumors
ABBV-181               solid tumors
ABBV-2029              solid and hematologic tumors
ABBV-321               solid tumors
ABBV-368               solid tumors
ABBV-428               solid tumors
ABBV-621               solid and hematologic tumors
ABBV-647               solid tumors
ABBV-744               acute myeloid leukemia and metastatic
                         castration-resistant prostate cancer
ABBV-927               solid tumors
ABBV-0805              Parkinson's disease
ABBV-951               Parkinson's disease
Elezanumb (ABT-555)    spinal cord injury
ABBV-4083              filarial diseases
CF Combo               cystic fibrosis

DRUGS COMING OFF PATENT

DRUG      INDICATION             YEAR

Humira    rheumatoid arthritis   2023

DRUGS COMING OFF PATENT

DRUG      INDICATION             YEAR

Humira    rheumatoid arthritis   2023


AbbVie's revenues grew 16% to $32.8 billion in 2018 driven primarily by sales growth related to Mavyret, Imbruvica and Venclexta and the continued strength of Humira. The arthritis blockbuster again topped the 2018 list of top selling drugs, raking in $19.9 billion in sales--an increase of 8.2%. Bio-similar competition is expected to hurt Humira sales in 2019, but is not expected to be an issue in the U.S. until 2023.

Cancer drugs Imbruvica and Venclexta both reported positive growth. Imbruvica revenue was $3.6 billion, an increase of 39.5%, driven by market share growth in front-line chronic lymphocytic leukemia (CLL) and other approved indications. Venclexta increased its sales by more than 100% in 2018 primarily due to market share gains following FDA and EMA approvals in combination with Rituxan. Hep C drug Mavyret's sales increased by more than 100% in 2018 after its approval by FDA and EMA in the second half of 2017 as well as further geographic expansion in 2018. Mavyret's penetration into the market hurt revenues of fellow hep C drugViekira, whose sales decreased by 76% in 2018.

GROWTH CATALYSTS

AbbVie's pipeline includes more than 60 compounds or indications in development across immunology, oncology and neuroscience, with additional targeted investments in cystic fibrosis and women's health.

AbbVie achieved a number of regulatory milestones for several key products in 2018, including regulatory approvals for cancer drugVenclexta in combination with Rituxan (rituximab) and in combination with azacitidine or decitabine; Imbruvica was also approved in combination with rituximab for cancer treatment. In addition, the company introduced Orilissa, the first FDA-approved oral treatment in over a decade for the management of moderate to severe pain associated with endometriosis.

With more than 30 programs in mid- and late-stage development, some highlights from AbbVie's pipeline advancements in 2018 including having completed registrational studies and submitted regulatory applications for the company's next-generation immunology assets, upadacitinib and risankizumab, in rheumatoid arthritis and psoriasis, respectively. In addition, the company initiated several Phase 3 programs for these assets including studies for upadacitinib in atopic dermatitis and ulcerative colitis, as well as risankizumab in Crohn's disease.

EXTENDS R&D ALLIANCE WITH CALICO

AbbVie and Calico extended their collaboration to discover, develop and market new therapies for patients with age-related diseases, including neurodegeneration and cancer.

Calico is the Alphabet-backed life sciences company that is led by former Genentech chairman and chief executive officer Arthur D. Levinson, Ph.D. Calico has a research and development facility in the San Francisco Bay Area and more than 150 employees.

The collaboration has been extended for an additional three years. Calico will be responsible for research and early development until 2022 and will advance collaboration projects through Phase Ha through 2027. AbbVie will continue to support Calico in its early R&D efforts and, following completion of Phase Ha studies, will have the option to manage late-stage development and commercial activities. Both parties will share costs and profits. AbbVie and Calico will each commit to contribute an additional $500 million to the collaboration.

Since 2014, the collaboration has produced more than two dozen early-stage programs addressing disease states across oncology and neuroscience and yielded new insights into the biology of aging.

In other R&D tie-ups, AbbVie and Calibr entered a collaboration to develop T-cell therapies aimed primarily at cancer, including solid tumors, leveraging advanced precision medicine technology. AbbVie gains exclusive access to Calibr's switchable CAR-T platform for up to four years. The companies will work together to develop T-cell therapies directed to solid tumor targets identified by AbbVie. AbbVie also has the option to develop additional cell therapies toward AbbVie-nominated targets and license existing Calibr cell therapy programs under development for hematological and solid cancers, including Calibr's lead program.

Calibr plans to enter this lead candidate into clinical studies for lymphoma in 2019. In addition, the agreement provides AbbVie with an option to acquire an exclusive license to Calibr's switchable CAR-T platform and programs within the first four years of the collaboration. The companies will share responsibility for preclinical development, and AbbVie is responsible for clinical development and commercialization. Calibr is eligible to receive success-based milestone payments and royalties.

Calibr's cell therapy program is designed to enhance safety, versatility and efficacy through a proprietary modular "switchable" CAR-T cell that uses antibody-based switch molecules to control the activation and antigen specificity of CAR-T cells. Calibr's technology may enable the development of universal CAR-T-based treatments across several types of hematological and solid tumor indications.

With Voyager Therapeutics, AbbVie entered an exclusive strategic collaboration and option agreement to develop and commercialize vectorized antibodies directed against tau for the treatment of Alzheimer's disease and other neurodegenerative diseases. The collaboration combines AbbVie's monoclonal antibody expertise, global clinical development and commercial capabilities with Voyager's gene therapy platform that enables generating adeno-associated viral (AAV) vectors for the treatment of neurodegenerative diseases.

In healthy individuals, tau is an abundant protein in the brain that promotes cellular stability and function. In the diseased brain, altered tau accumulates, resulting in impaired brain function and neuronal cell loss. One of the limitations with current biologic therapies for neurodegenerative diseases is that only a small amount of drug makes it into the brain. This collaboration aims to develop a potential one-time treatment using Voyager's gene therapy platform to reduce tau pathology through the delivery of an AAV vector antibody that encodes the genetic instructions to produce anti-tau antibodies within the brain.

Lastly, AbbVie took over full development and commercial responsibility for its collaboration with Galapagos to discover and develop new therapies to treat cystic fibrosis (CF).The investigational program comprises several clinical and preclinical compounds originally discovered and developed jointly by AbbVie and Galapagos. Galapagos will not pursue further research and development in CF, but is eligible for future milestones and royalties on commercialized programs. Galapagos retains the right to future development of GLPG-2737 in non-CF indications. AbbVie is eligible to receive undisclosed future milestones and royalties in non-CF indications.

Caption: Arthritis blockbuster Humira was again the top selling drug of 2018 with nearly $20 billion in sales.(Courtesy of Abbvie)

08 GLAXOSMITHKLINE

Headquarters: Brentford, Middlesex, UK

twitter.com/GSK

www.gsk.com
HEADCOUNT:           95,490
YEAR ESTABLISHED:      2000
REVENUES:           $40,992     (+1%)
PHARMA REVENUES:    $30,807     (+2%)
NET INCOME:          $5,381     (-2%)
R&D:                 $5,178    (-14%)

DRUGS APPROVED

DRUG                      INDICATION

Krintafel                 Malaria

DRUGS FILED

DRUG                      INDICATION

Travivo                   Depression
Cabotegravir
  & Rilpivirine           HIV treatment

PHASE III

DRUG                      INDICATION

GSK2857916                Multiple myeloma
Daprodustat               Anaemia in chronic kidney disease (CKD)
                          (dialysis), Anaemia in chronic kidney
                          disease (CKD) (non-dialysis)
Fostemsavir
  Tromethamine            HIV treatment
Dostarlimab               Ovarian cancer
GSK3196165                Arthritis, rheumatoid
Camvia                    CMV infections
Vynpenta                  Vasculitis
Staxyn                    Erectile dysfunction
S/GSK1265744 LAP          HIV treatment, Pre-exposure
                          prophylaxis (PrEP)
Entinostat                Breast cancer
Arzerra S.C.              Relapsing-Remitting MS
cAd3-EBO Z                Ebola haemorrhagic fever
                          (EHF) prophylaxis

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

1795091                   cancer
3368715                   cancer
35371420                  cancer
2636771                   cancer
3145095                   pancreatic cancer
TSR-033                   cancer
3036656                   tuberculosis
3810109                   HIV infection
2831781                   ulcerative colitis
3358699                   rheumatoid arthritis
2983559                   inflammatory bowel disease
3858279                   pain in osteoarthritis
nemiralisib               activated PI3K delta syndrome
3511294                   asthma
2292767                   respiratory diseases
3439171                   muscle repair

DRUGS COMING OFF PATENT

DRUG        INDICATION                   YEAR

Priorix     MMR prophylaxis              2019
Veramyst    Rhinitis, seasonal allergy   2021
FluLaval    Influenza prophylaxis        2022
Rotarix     Rotaviral gastroenteritis    2022
Benlysta    Systemic lupus
            erythematosus                2023

TOP SELLING DRUGS

DRUG                  INDICATION             2018 SALES   (+/-%)

Triumeq               HIV                      $3,535      11%
Seretide/Advair       asthma, COPD             $3,234      -20%
Tivicay               HIV                      $2,188      21%
Breo Ellipta          COPD                     $1,454      12%
Hepatitis franchise   Hepatitis A, B           $1,079      21%
Shingrix              Shingles prophylaxis     $1,047      n/a
Ventolin              asthma                   $984         0%
Pediarix              pediatric vaccine        $908        -5%
Lamictal              anti-epileptic           $824        -2%
Flovent               respiratory              $794         3%


GlaxoSmithKline (GSK) reported revenue of $40.9 billion, up just 1% from the year before. The standout was Shingrix, GSK's vaccine for shingles, which had sales of $1.0 billion in its launch year. HIV medicines also continued to grow with $3.5 billion in sales for Triumeq, GSK's new top seller, and $2.2 billion forTivicay.

With the decline if its flagship product Advair, GSK continues to build its new respiratory portfolio with Trelegy Ellipta, the new three-in-one medicine for chronic obstructive pulmonary disease (COPD), and Nucala, GSK's biologic medicine for severe asthma. In addition to the positive launches of Shingrix and Trelegy Ellipta, GSK reported a strong start to sales of HIV drug Juluca.

During the year GSK implemented a new R&D approach to focus on science of the immune system, human genetics and advanced technologies. In fact, it made significant progress in reshaping its pharmaceuticals R&D portfolio to reflect this new strategy with 33 of 46 new medicines now targeting modulation of the immune system.

As part of the its ongoing prioritization and strengthening of its pharmaceuticals pipeline, GSK transferred its portfolio of approved and investigational rare disease gene therapies to Orchard Therapeutics. GSK became an investor in Orchard as a result, receiving a 19.9% equity stake along with a seat on the company's board. GSK and Orchard will exchange manufacturing, technical and commercial insights and learnings on the development of gene therapy medicines to ensure the success of the assets.

In other business news, GSK entered a deal to create a consumer healthcare joint venture with Pfizer and bought out Novartis' stake in GSK Consumer Healthcare. The combination of the iconic brands of GSK and Pfizer will create one of the largest consumer healthcare players in key geographies including the U.S., Europe, China, India and Australasia. Pfizer will contribute its consumer healthcare business to GlaxoSmithKline's existing consumer healthcare business. The 2017 global sales for the combined business were approximately $12.7 billion. Pfizer receives a 32% equity stake in the joint venture.

The joint venture will be a category leader in pain relief, respiratory, vitamin and mineral supplements, digestive health, skin health and therapeutic oral health.

Following the integration, GSK said it intends to separate the joint venture as an independent company. GSK may also sell all or part of its stake in the joint venture in a contemporaneous IPO.

PUMPED UP PIPELINE

GSK strengthened its pipeline through business development initiatives with 23andMe and Tesaro. First, bolstering its cancer assets, GSK added the ovarian cancer drug Zejula to its portfolio when it paid $5.1 billion for Tesaro. The deal significantly strengthens GSK's pharmaceutical business, accelerating the build of its pipeline and commercial capability in oncology. Zejula (niraparib), a major marketed product, is an oral poly ADP ribose polymerase (PARP) inhibitor that is currently approved in the U.S. and Europe. Clinical trials to assess the use of Zejula in "all-comers" patient populations, as a monotherapy and in combinations, for the significantly larger opportunity of first line maintenance treatment of ovarian cancer are also underway.

With 23andMe, GSK entered a multi-year collaboration expected to identify novel drug targets, tackle new subsets of disease and enable rapid progression of clinical programs. The four-year collaboration will focus on research and development of innovative new medicines and potential cures, using human genetics as the basis for discovery. The collaboration will combine 23andMe's large-scale genetic resources and advanced data science skills, with the scientific and medical knowledge and commercialization expertise of GSK. The goal of the collaboration is to gather insights and discover novel drug targets driving disease progression and develop therapies for serious unmet medical needs based on those discoveries.

With over 5 million customers, 23andMe offers those with an interest in genetics the opportunity to learn more about their personal genetic profile. 23andMe customers can also choose to participate in research and contribute their information to a unique and dynamic database, which is now the world's largest genetic and phenotypic resource.

GSK brings extensive drug discovery and development capabilities across a broad range of diseases and modalities, including small molecule, biopharmaceuticals and cell and gene therapies. It will apply its technologies, including access to additional data sources, in-house target validation and genetics expertise, and utilize its manufacturing, commercial operations and scale to support partner activities across research and development.

R&D ALLIANCES

GSK entered several research collaborations during the year, some of which are highlighted here. A research pact with Fimbrion Therapeutics led to the identification of an orally available, small molecule development candidate for the treatment and prevention of urinary tract infections. The discovery partnership began its joint research efforts in July 2016.

A three-year extension was made to a tie-up with Neomed-Labs. Under the terms of this renewed agreement, Neomed-Labs will develop immunotools (antigens), immunochemical assays as well as functional assays and undertake the clinical testing for several GSK vaccine projects at the clinical stage.

Neomed-Labs is a spin-out from GSK's Clinical Laboratory Services since April 2015 with a three-year original agreement. Following a successful transition from GSK, Neomed-Labs became a fully independent CRO in 2017 and is now collaborating with major global vaccine manufacturers.

With Syngene International, another global contract research services company, GSK formed a multiyear R&D agreement that will focus on accelerating the discovery of new drug candidates using Syngene's discovery services platforms. Syngene will setup a customized discovery research laboratory to support projects across several therapeutic areas. A team of Syngene scientists will work closely with GSK's global R&D teams on discovery research projects to identify new drug candidates with the potential to address some of the world's most pressing healthcare needs.

Lastly, GSK entered a technology agreement with LabCorp's Covance Drug Development business. GSK will use Covance's Xcellerate Monitoring, Xcellerate Insights, and Xcellerate Clinical Data Hub solutions in a software-as-a-service (SaaS) model. A key component of the technology licensed by GSK is Xcellerate Monitoring, Covance's implementation of risk-based monitoring, which enables assessment and mitigation of risk at the study, site and patient level. It also allows sponsors to strategically guide site monitoring resources and build quality and efficiency into their clinical trials, from commencement to completion.

Caption: The GlaxoSmithKline headquarters building in Brentford, West London. The British global pharmaceuticals company reported just a 1 % increase in revenue last year.

09 LILLY

Headquarters: Indianapolis, IN

twitter. com/EliLillyCo

www.lilly.com
HEADCOUNT:    38,680
REVENUES:    $24,556    (+7%)
EARNINGS:     $3,232    (NM)
R&D:          $5,307    (-1%)

DRUGS APPROVED

DRUG                             INDICATION

Olumiant                         Arthritis, rheumatoid
Emgality                         Migraine, Cluster headaches
Vitrakvi                         solid tumors

DRUGS FILED

DRUG                             INDICATION

Lasmiditan                       Migraine
Nasal Glucagon                   Hypoglycaemia
Empagliflozin &
Linagliptin &
Metformin XR                     Diabetes, type II (maturity onset)
Tadalafil Versafilm              Erectile dysfunction

PHASE III

DRUG                             INDICATION

LY3298176                        Diabetes, type II (maturity onset)
Mirikizumab                      Psoriasis, Ulcerative colitis,
                                 Crohn's disease
Pegilodecakin                    Pancreatic cancer
Flortaucipir F 18                Nuclear imaging
Solanezumab                      Alzheimer's disease
Tradipitant                      Eczema/Dermatitis
Tanezumab                        Pain, lower back, Pain,
                                 cancer-induced, Osteoarthritis

EARLY RESEARCH PROJECTS

DRUG                             INDICATION

Aur A Kinase Inhibitor cancer
BTLA Agonist
Antibody                         immunology
Dual Amylin
  Calcitonin Receptor
    Agonist                      diabetes Mellitus
ID01 Inhibitor                   cancer
Oxyntomodulin                    diabetes Mellitus
TIM-3 Monoclonal
  Antibody                       cancer
BAFF/IL-17
Bispecific Antibody              immunology
Cancer                           oncology
ERK Inhibitor                    cancer
IL-23/CGRP
  Bispecific Antibody            immunology
PACAP38 Antibody                 pain
Basal Insulin Acylated           diabetes Mellitus
CD200R Antibody
  Agonist                        immunology
GDF15 Agonist                    diabetes
IL-2 Conjugate                   immunology
PD-1 Antibody
  Agonist                        immunology
BTK Inhibitor                    cancer
CXCR1/2 Ligands
Monoclonal Antibody              immunology
GGG Tri-Agonist
Diabetes                         diabetes
O-GlcNAcase
  Inhibitor Alzheim's            neurodegeneration
PD-L1/TIM-3
  Bispecific Antibody            cancer

DRUGS COMING OFF PATENT

DRUG      INDICATION        YEAR

Eraxis    Candidiasis       2020
Livalo    Hyperlipidaemia   2021
Alimta    Mesothelioma      2022

TOP SELLING DRUGS

DRUG         INDICATION             2018 SALES   (+/-%)

Trulicity    diabetes                 $3,199      58%
Humalog      diabetes                 $2,997       5%
Alimta       cancer                   $2,133       3%
Cialis       erectile dysfunction     $1,822     -21 %
Forteo       osteoporosis             $1,576      -10%
Humulin      diabetes                 $1,331       0%
Taltz        Psoriasis                $938        68%
Cyramza      stomach cancer           $821         8%
Basaglar     diabetes                 $801        85%
Cymbalta     anxiety, depression      $708        -6%


Ascending the ranks, Eli Lilly's products are performing well and key late stage assets are advancing. Despite generic competition for one of the company's best-selling products, Cialis, and slipping sales for flagship insulin products Humalog and Humulin, and other established brands, Forteo, Cymbalta, and Erbitux, revenues for the year were up 7%. Burgeoning sales of psoriasis and psoriatic arthritis drug Taltz, up 68% for the year, and diabetes products Trulicity, Basaglar, and Jardiance, up 58%, 85%, and 47%, respectively, helped to offset established product declines.

Also, newly launched breast cancer drugVerzenio is off to good start, and Emgality, approved in September for migraine prevention, and more recently for preventing episodic cluster headaches, offers tremendous potential with estimated peak annual sales of approximately $700 million. Lilly's numerous late stage assets include another promising migraine drug, lasmiditan, pending approval, and, in addition to expanded indications for top sellers, such Alimta, promising new candidates include mirikizumab, an immunology therapy being studied in Crohn's disease, and tanezumab being studied in osteoarthritic, back, and cancer pain.

Additionally, broadening its oncology portfolio, the pending $8 billion acquisition of Loxo Oncology will provide Lilly entry into precision medicine with approved and investigational medicines.

STRATEGIC INITIATIVES

In addition to the pending acquisition of Loxo Oncology, Lilly has recently made several strategic moves, including the divestiture of its Animal health business, Elanco, which raised $1.5 billion in its stock market debut, and the sale of antibiotic assets in China for $375 million.

The Loxo Oncology acquisition was the largest in a series of strategic transactions to expand its oncology pipeline with externally sourced, first-in-class therapies. Loxo's pipeline of targeted medicines is focused on cancers that are uniquely dependent on single gene abnormalities that can be detected by genomic testing.

Among its assets, LOXO-292, an oral RET inhibitor that has been granted Breakthrough Therapy designation by the FDA for three indications, has an initial potential launch in 2020. RET fusions and mutations occur across multiple tumor types, including certain lung and thyroid cancers as well as a subset of other cancers.

Also, Vitrakvi, an oral TRK inhibitor developed and commercialized in collaboration with Bayer, was recently approved by the FDA. Vitrakvi is the first treatment that targets a specific genetic abnormality to receive a tumor-agnostic indication at the time of initial approval. LOXO-195, a follow-on TRK inhibitor is also being studied by Loxo and Bayer for acquired resistance to TRK inhibition, and has a potential launch in 2022.

This past March, Elanco Animal Health became a fully independent company. The spin-off is intended to provide a greater focus on Lilly's human pharmaceuticals business, which the company is heavily investing in.

Lilly recently sold the rights in China for two legacy antibiotics, Ceclor andVancocin, as well as a manufacturing facility in Suzhou, to Eddingpharm, a China-based specialty pharmaceutical company, in a transaction valued at $375 million.

R&D ADVANCES

Thanks to a recent head-to-head study, Talz is performing even better than expected. Talz surpassed Humira in reducing PsA disease activity by half and completely clearing patient skin after 24 weeks, according to data from a Phase IIIB/TV study. Thirty-six percent of the 234 trial patients treated with Taltz achieved both markers at 24 weeks, compared to 28% of Humira patients. Taltz also achieved its secondary endpoints of matching Humira in disease activity and surpassing it in clearing skin.

Representing a significant approval for Lilly, Emgality injection was approved by the FDA for the treatment of episodic cluster headache in adults. Emgality is an innovative therapeutic approach for this neurologic disease and the first and only calcitonin gene related peptide antibody approved by the FDA for two distinct headache disorders. Emgality was first approved by the FDA in September 2018 for the preventive treatment of migraine.

Also, Cyramza received approval from the FDA as a single agent for the treatment of patients with hepatocellular carcinoma (HCC), marking the fifth FDA approval for Cyramza. Importantly, the FDA has also removed the boxed warning from the labeling, which should boost sales further.

Additionally, the FDA approved a new indication for top seller Alimta in combination with Merck's Keytruda for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer, with no EGFR or ALK genomic tumor aberrations.

From its pain portfolio, Lilly and Pfizer achieved positive results from a Phase III study evaluating tanezumab in moderateto-severe chronic low back pain, meeting the primary endpoint demonstrating a statistically significant improvement in pain. Furthermore, Lilly has acquired several pain assets, gaining rights to CNTX-0290 from Centrexion Therapeutics for $47.5 million upfront and as much as $575 million in potential development milestones. CNTX-0290 is a small molecule somatostatin receptor type 4 (SSTR4) agonist currently in Phase I testing as a potential non-opioid treatment for chronic pain conditions.

Lilly also acquired all assets related to Hydra Biosciences' program of TRPA1 antagonists, currently being studied for the potential treatment of chronic pain syndromes.

Lilly has not given up on its diabetes therapeutic endeavors. Lilly bolstered its diabetes portfolio with Chugai's oral GLP-1 agonist, OWL833, a Phase I-ready asset being studied in type 2 diabetes. Also, Lilly and Boehringer recently submitted a NDA for the fixed-dose combination tablet of empagliflozin, linagliptin and metformin extended release for type 2 diabetes.

COLLABORATIONS

Lilly has several immunology alliances underway leveraging platform technologies of partner companies. A global alliance with Avidity aims to develop new medicines in immunology and other indications leveraging Avidity's technology platform to potentially overcome barriers to the delivery of oligonucleotides and target genetic drivers of disease.

A research collaboration leveraging Aduro's cGAS-STING Pathway Inhibitor program aims to develop immunotherapies for autoimmune and other inflammatory diseases. Additionally, an agreement with AC Immune will research tau aggregation inhibitor small molecules for the potential treatment of Alzheimer's disease and other neurodegenerative diseases leveraging AC Immune's Morphomer platform technology.

Caption: Lilly reported revenues of nearly $25 billion in 2018, a growth of 7%.

10 AMGEN

Headquarters: Thousand Oaks, OA

twitter.com/Amgen

www.amgen.com
HEADCOUNT:           21,500
YEAR ESTABLISHED:      1980
REVENUES:           $23,747    (+4%)
NET INCOME:          $8,394     (NM)
R&D:                 $1,182    (+13%)

DRUGS APPROVED

DRUG                   INDICATION

Aimovig                Migraine

DRUGS FILED

DRUG                   INDICATION

ABP 710                Arthritis, rheumatoid, Ankylosing
                       spondylitis, Crohn's disease, Ulcerative
                       colitis, Psoriasis, Arthritis, psoriatic,
                       General cancer indications

PHASE III

DRUG                   INDICATION

Renexus                General eye disorders
Blisibimod             IgA nephropathy
Rilotumumab            Non-small cell lung cancer (NSCLC)
Ganitumab              Bone cancer (Osteosarcoma)
Tremelimumab           Non-small cell lung cancer (NSCLC), Head
                       & neck cancers, Bladder cancer, Hepa
                       toma, liver cancer, Small cell lung cancer
                       (SCLC)
Tezepelumab            Asthma
Brazikumab             Crohn's disease
CNP520                 Alzheimer's disease

EARLY RESEARCH PROJECTS

DRUG                   INDICATION

AMG 119                small-cell lung cancer
AMG 212                prostate cancer
AMG 404                hematology/oncology
AMG 427                acute myeloid leukemia
AMG 570                systemic lupus erythematosus
AMG 596                glioblastoma
AMG 701                multiple myeloma
AMG 966                inflammatory bowel diseases
AMG 160                prostate cancer
AMG 330                acute myeloid leukemia
AMG 420                multiple myeloma
AMG 510                solid tumors
AMG 592                inflammatory diseases
AMG 598                obesity
AMG 757                small-cell lung cancer
AMG 176                hematologic malignancies
AMG 397                hematologic malignancies
AMG 424                multiple myeloma
AMG 562                non-Hodgkin's lymphoma
AMG 594                heart failure
AMG 673                acute myeloid leukemia
AMG 890                cardiovascular disease
IMYGIC                 mid-to-late-stage
                       metastatic melanoma

DRUGS COMING OFF PATENT

DRUG        INDICATION                   YEAR

Vectibix    Colorectal cancer            2020
Nexavar     Renal cell carcinoma
            (RCC)                        2020
Nplate      Thrombocytopaenic purpura,
            idiopathic (ITP)             2022

TOP SELLING DRUGS

DRUG         INDICATION               2018 SALES   (+/-%)

Enbrel       rheumatoid arthritis       $5,014      -8%
Neulasta     chemotherapy induced
             neutropenia                $4,475      -1%
Prolia       bone cancer                $2,291      16%
Aranesp      chemotherapy induced
             anemia                     $1,877      -9%
Xgeva        bone cancer                $1,786      13%
Sensipar/
Mimpara      renal disease              $1,774       3%
Epogen       anemia                     $1,010      -8%
Kyprolis     multiple myeloma           $968        16%
Nplate       immune thromboytopenia     $717        12%
Vectibix     colorectal cancer          $691         8%


While Amgen's newer drugsProlia, Xgeva, Blincyto, Kyprolis continue to drive growth, its mature flagship products are facing rising competition. Sales of Neulasta and Neupogen are declining due to biosimilar competition from several companies, including Mylan and Coherus Biosciences. Several others face generic competition as well, including Enbrel, Aranesp and Epogen. Meanwhile, sales of Amgen's new migraine drug, Aimvoig, were unimpressive in the first quarter of 2019, and it's up against strong competition from Lilly's Emgality andTeva's Ajovy.

Amgen is successfully advancing its pipeline with the approval of osteoporosis drug Evenity in April, and Kanjinti, a biosimilar of Roche's breast cancer drug Herceptin, in June. This is the third biosimilar from Amgen's portfolio to receive approval, providing the potential for long-term revenues. Amgen expects to launch additional biosimilars in 2019.

As part of an effort to bolster its R&D efforts, Amgen recently offered to acquire Nuevolution, a drug discovery platform biotech company based in Denmark, for approximately $167 million. The Nuevolution board has recommended accepting the offer and Amgen expects to settle by July 15. The two companies have collaborated since October 2016 for drugs targeting multiple indications including two cancer programs. Having Nuevolution's discovery platform in-house may aid Amgen's discovery efforts for small molecules against difficult-to-drug targets and make the process more efficient.

Additionally, to further enhance its manufacturing capabilities, Amgen is expanding its campus in West Greenwich, RI with a new $160 million next-gen biomanufacturing plant that will be the first of its kind in the U.S. It will manufacture products for the U.S. and global markets. Amgen plans to incorporate multiple innovative technologies into a single facility, which is expected to be built in half the construction time with approximately half of the operating cost required of a traditional plant. Next generation biomanufacturing plants require a smaller manufacturing footprint offering environmental benefits such as reduced water and energy consumption, and lower levels of carbon emissions.

Among its more significant approvals, Amgen and UCB gained FDA approval for EVENITY for the treatment of osteoporosis in postmenopausal women at high risk for fracture. EVENITY is the first and only bone builder with a unique dual effect that both increases bone formation and to a lesser extent reduces bone resorption (or bone loss) to rapidly reduce the risk of fracture.

In October, the FDA approved the expanded indication for KYPROLIS to include a once-weekly dosing option in combination with dexamethasone for patients with relapsed or refractory multiple myeloma. The approval was based on Phase IE data demonstrating that KYPROLIS achieved superior progression-free survival and overall response rates, with a comparable safety profile, versus twice-weekly. The FDA reviewed the application under its Real-Time Oncology Review and Assessment Aid pilot programs, which aim to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible.

Also, Amgen's BLINCYTO gained approval for relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in Japan, and an expanded indication as a monotherapy to include adult patients with Philadelphia chromosome negative (Ph-) CD19 positive B-cell precursor acute lymphoblastic leukemia (ALL) by the European Commission. Developed by a joint venture between Amgen and Astellas Pharma Inc., BLINCYTO is the first-and-only bispecific T cell engager (BiTE) immunotherapy construct approved globally. It's also the first approved immunotherapy from Amgen's BiTE platform, an approach that helps the body's immune system target cancer cells.

Amgen and its biosimilar partner Allergan, recently received approval from the FDA for Kanjinti, a biosimilar of Roche's breast cancer drug, Herceptin, for all approved indications of the reference product, HER2 adjuvant and metastatic breast cancer, and HER2 metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Since December of last year, the FDA approved four biosimilar versions of Herceptin including Kanjinti: Pfizer's Trazimera, Merck/Samsung Bioepis' Ontruzant, and Celltrion/ Teva's Herzuma).

Kanjinti is the third biosimilar from Amgen's portfolio to receive approval in the U.S. and Europe, joining Amjevita (a biosimilar of Abbvie's Humira) and Mvasi (a biosimilar of Roche's cancer drug Avastin). Currently, Amgen has 10 biosimilar products in its portfolio and a biosimilar version of Johnson & Johnson/Merck's Remicade (ABP 710) is under review in the U.S. and EU.

The collaboration with Allergan includes the development and commercialization of four oncology antibody biosimilars. A biosimilar version of Roche's Rituxan is in late-stage development for non-Hodgkin's lymphoma and rheumatoid arthritis.

Innovative oncology efforts are advancing as well. Amgen recently reported early data from a Phase I trial of AMG 510 showing promising activity in a study of 35 patients targeting one of the most commonly mutated genes in cancer. Analysts are suggesting it has the potential to be the next cancer blockbuster. Out of 10 lung cancer patients receiving Amgen's AMG 510 in the earlystage study, five went into partial remission and another four saw their disease stabilize. One patient experienced a complete remission four months after treatment. Representing a 90% disease control rate which is quite remarkable for a Phase I trial.

MG 510 targets KRAS G12c mutation, which accounts for about 13% of non-small cell lung cancers and 3% to 5% of colorectal cancers, and has been the subject of research for decades. While Amgen's results in colon cancer were less robust, ifs still too early to tell.

Furthermore, several interesting early research collaborations are underway. Most recently, a collaboration with Intermountain Health aims to rapidly develop new medicines. Amgen's subsidiary deCODE genetics will have access to the genomes of 500,000 participants from a study carried out by Intermountain Healthcare. Amgen hopes to use this data to uncover new insights into specific diseases and develop new medicines that reach the right disease targets. The collaboration aims to improve success rates and reduce drug development cycle times. To date, Amgen has accelerated the development timeline from early preclinical work through clinical development with several of its molecules, including AMG 510, currently in Phase I.

In October, Amgen made an equity investment of $66 million in Oxford Nanopore Technologies, a UK-based company advancing a new generation of portable genetic sequencing technology to perform direct, real-time sequencing of DNA and RNA. de-CODE Genetics uses Oxford's sequencing technologies to conduct genome research, including the identification and validation of new targets. The investment aligns with Amgen's strategic focus on using human genetics to develop new medicines.

Caption: Amgen's 4% growth to $23.7 billion in 2018 sales rounds out this year's top 10 companies.

11 BRISTOL-MYERS SQUIBB

Headquarters: New York, NY

twitter.com/bmsnews

www.bms.com
HEADCOUNT:           23,300
YEAR ESTABLISHED:      1887
REVENUES:           $22,561    (+9%)
NET INCOME:          $4,952    (NM)
R&D:                 $6,345    (-2%)

DRUGS FILED

DRUG                   INDICATION

Travivo                Depression
Lumateperone           Schizophrenia

PHASE III

DRUG                   INDICATION

BMS-986165             Psoriasis
Relatlimab             Melanoma
BMS-986205             Melanoma, Bladder cancer
Sparsentan             Focal segmental glomerulosclerosis
                       (FSGS), IgA nephropathy
Brivanib               Hepatoma, liver cancer
Pamrevlumab            Pancreatic cancer,
                       Pulmonary fibrosis, idiopathic
Tremelimumab           Non-small cell lung cancer (NSCLC), Head
                       & neck cancers, Bladder cancer,
                       Hepatoma, liver cancer, Small cell lung
                       cancer (SCLC)
Anifrolumab            Systemic lupus erythematosus (SLE)
Fostemsavir
Tromethamine           HIV treatment
Rimegepant             Migraine
RG6206                 Duchenne muscular dystrophy
Bempegaldesleukin      Melanoma, Renal cell carcinoma (RCC)
BHV-3500               Migraine

EARLY RESEARCH PROJECTS

DRUG                   INDICATION

APJ Agonist            cardiovascular
FPR-2 Agonist          cardiovascular
LPA1 Antagonist        fibrotic diseases
BTK Max                immunoscience
RORyT                  immunoscience
S1P1 Agonsit           immunoscience
TLR 7/8 Antagonist     immunoscience
TYK2 Inhibitor         immunoscience
Anti-CD73              oncology
Anti-CTLA-4 NF         oncology
Anti-CTLA-4 Probody    oncology
Anti-ICOS              oncology
Anti-TIGIT             oncology
Anti-TIM-3             oncology
BET Inhibitor          oncology
CD80/-CD3
  Oncolytic Virus      oncology
EP4 Antagonist         oncology
HuMax-IL8              oncology
NLRP3 Agonist          oncology
STING Agonist          oncology

DRUGS COMING OFF PATENT

DRUG       INDICATION             YEAR

Orencia    rheumatoid arthritis   2021
Atripla    HIV                    2021
Simponi    rheumatoid arthritis   2022
Onglyza    diabetes               2023
Stelara    psoriasis              2023

TOP SELLING DRUGS

DRUG         INDICATION               2018 SALES   (+/-%)

Opdivo       melanoma, lung cancer,
             renal cancer             $6,735       36%
Eliquis      deep vein thrombosis
             and pulmonary embolism   $6,438       32%
Sprycel      leukemia                 $2,000       0%
Orencia SC   rheumatoid arthritis     $1,381       11%
Yervoy       oncology                 $1,330       7%
Orencia      rheumatoid arthritis     $1,329       8%
Baraclude    hepatitis B              $744         -29%
Reyataz      HIV/AIDS                 $427         -39%
Empliciti    multiple myeloma         $247         7%
Nulojix      kidney transplant        $138         31%


Moving up in the ranks this year, Bristol-Myers Squibb is making headway in its efforts to become a premier specialty Biopharma company, overcoming losses associated with its Hep C franchise and culminating in the Opdivo era. For the past several years BMS held steady at 14, inching closer to the top 10 this year, and now with the pending $74 billion Celgene acquisition, potentially to the top five in 2020.

In 2018, double digit growth for prioritized brands Opdivo, which grew by $443 million, Eliquis, which grew by $342 million, Yervoy, which grew by $115 million, as well as Orencia, helped to offset significant declines in established brands Baraclude, Reyataz, Sustiva, and Hepatitis C franchises (for which revenues have all but disappeared), representing a total of $1.5 billion in lost revenue as compared to 2017.

Continued growth in the first quarter of 2019, with revenues up 14%, reaffirms the trajectory of the company's priority brands. Eliquis grew by $419 million, up 28%, Opdivo grew by $290 million, up 19%,Yervoy grew by $135 million, up 54%, and Orencia and Sprycel, were up 8% and 5%, respectively.

The Mega M&A news on January third, when BMS announced plans to acquire Celgene in a transaction valued at approximately $74 billion, will result in leading franchises in oncology (in both solid tumors and hematologic malignancies) led by Opdivo and Yervoy as well as Revlimid and Pomalyst; Immunology and Inflammation (led by Orencia and Otezla) and Cardiovascular Disease with Eliquis. The acquisition also expands Phase III assets with six expected near-term product launches representing more than $15 billion in revenue potential. Furthermore, Celgene's Revlimid, for the treatment of multiple myeloma, is one of the world's best-selling drugs. Sales were $9.7 billion in 2018, up 18%.

Following the acquisition, Thomas Lynch Jr., BMS'chief scientific officer will leave the company on October 1st. Rupert Vessey, a Celgene research executive will serve as president, Research & Early Development, overseeing drug discovery and the early clinical development. He will report to CEO Giovanni Caforio, and serve as a member of the leadership team. For late-stage assets, oncology expert Samit Hirawat, will service as chief medical officer, joining the company from Novartis.

Additional post-closing changes include, Nadim Ahmed from Celgene, who will manage the combined company's hematology business. The rest of the combined company's commercial side, including its cancer, immunology and cardiovascular businesses, will be managed by Chris Boerner, currently BMS'chief commercial officer. David Elkins, currently the chief financial officer of Celgene, will serve as executive vice president and chief financial officer.

R&D ADVANCES

The company continues to expand indications for its top seller Opdivo, and in April announced four-year survival results from pooled analyses of four studies in patients with previously-treated advanced non-small cell lung cancer who were treated with Opdivo.

In August of last year, the FDA approved Opdivo as the first and only immuno-oncology treatment option for patients with metastatic small cell lung cancer (SCLC) whose cancer has progressed after platinum-based chemotherapy. Approval for this indication was granted under accelerated approval based on overall response rate and duration of response.

Small cell lung cancer is one of two main types of lung cancer and accounts for about 10% to 15% of all lung cancers. It's an aggressive disease that often goes undetected until the cancer is advanced.

Additional indications for Opdivo now include melanoma and kidney cancer. In July, it was approved by the European Commission (EC) for the adjuvant treatment of melanoma with involvement of lymph nodes or metastatic disease for both BRAF mutant and wild-type melanoma patients. With this decision, Opdivo became the first PD-1 therapy to receive a EC approval in the adjuvant setting, gaining its eighth indication across six distinct tumor types. Also, in January, the EC approved the combination of Opdivo plus Yervoy for the first-line treatment of patients with intermediate- and poor-risk advanced renal cell carcinoma.

BMS is also evaluating the Opdivo/Yervoy combo in late stage trials in castration-resistant prostate cancer and advanced or metastatic renal cell carcinoma. Also, in partnership with Infinity Pharmaceuticals, a Phase II trial is evaluating Opdivo in combination with Infinity's IPI-549 in patients with advanced urothelial cancer.

Despite its many successes, several indications for Opdivo fell short. BMS withdrew its supplemental Biologics License Application for the Opdivo and low-dose Yervoy combo for the treatment of first-line advanced non-small cell lung cancer (NSCLC) in patients with tumor mutational burden. After discussions with the FDA, further evidence on the relationship between TMB and PD-L1 is required to fully evaluate the impact of Opdivo plus Yervoy in this indication.

Also, in May, a Phase III trial evaluating Opdivo plus radiation versus temozolomide plus radiation in patients with newly diagnosed 06-methylguanine-DNA methyltransferase (MGMT)-unmethylated glioblastoma multiforme (GBM), did not meet its primary endpoint of overall survival (OS) at final analysis. Likewise, a Phase II trial evaluating Opdivo versus Opdivo plus Yervoy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, did not meet its primary endpoints.

Sprycel, the company's next highest-selling oncology drug, gained an additional hematology indication. In January, the FDA expanded the indication for Sprycel tablets to include the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination with chemotherapy, and shortly thereafter received the same approval by the EC.

EARLY RESEARCH EFFORTS

BMS and Tsinghua University are collaborating to discover therapeutic agents against novel targets for autoimmune diseases and cancers. The collaboration brings together their respective scientific expertise and capabilities with a focus on validating new targets and generating early drug candidates for clinical development. Ts-inghua University will conduct research on projects and BMS will have an option to exclusively license therapeutic resulting agents.

The collaboration expands an existing relationship that began in 2012 focused on autoimmune target discovery, structural biology research, as well as the science of mapping the 3D protein structure of biological molecular targets.

Lastly, a clinical collaboration with Compugen is evaluating Compugen's COM701, an investigational anti-PVRIG antibody, in combination with Opdivo in patients with advanced solid tumors, including non-small cell lung, ovarian, breast and endometrial cancer. In conjunction with this collaboration, BMS will make a $12 million equity investment in Compugen. Should Opdivo prove successful in treating ovarian and breast cancer, the sky is the limit for this breakthrough therapy.

Caption: The deal to acquire Celgene for $74 billion could see BMS move into the top five pharma companies in the coming years.

12 GILEAD SCIENCES

Headquarters: Foster City, CA

twitter.com/gileadsciences

www.gilead.com
HEADCOUNT:           11,000
YEAR ESTABLISHED:      1987
REVENUES:           $22,127    (-15%)
NET INCOME:          $5,455    (+18%)
R&D:                 $5,018    (+34%)

DRUGS APPROVED

DRUG                      INDICATION

Biktarvy                  HIV
Symtuza                   HIV

PHASE III

DRUG                      INDICATION

Filgotinib                Arthritis, rheumatoid, Crohn's disease
                          Ulcerative colitis
Selonsertib               Nonalcoholic steatohepatitis (NASH)
Brincidofovir             Smallpox treatment
Momelotinib               Myelofibrosis
Andecaliximab             Stomach cancer
Cilofexor                 Sclerosing cholangitis

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

GS-6207                   HIV/AIDS
Vesatolimod               HIV/AIDS
GS-9722                   HIV/AIDS
GS-4224                   hepatitis B virus
Axicabtagene
ciloeucel                 diffuse large B-cell lymphoma
KTE-X19                   chronic lymphocytic leukemia
KITE-718                  solid tumor
KITE-439                  solid tumor
GS-4875                   inflammatory bowel disease

DRUGS COMING OFF PATENT

DRUG       INDICATION    YEAR

Truvada    HIV           2019
Epclusa    Hepatitis C   2019
Harvoni    Hepatitis C   2019
Atripla    HIV           2021

TOP SELLING DRUGS

DRUG       INDICATION                 2018 SALES   (+/-%)

Genvoya    HIV treatment              $4,624       26%
Truvada    HIV treatment              $2,997       -4%
Epclusa    Pre-exposure prophylaxis
           (PrEP)                     $1,966       -44%
Odefsey    Hepatitis C treatment      $1,598       44%
Descovy    Liver cirrhosis            $1,581       30%
Harvoni    HIV treatment              $1,222       -72%
Atripla    HIV treatment              $1,206       -33%
Biktarvy   Hepatitis C treatment      $1,184       n/a
Letairis   HIV treatment              $943         6%
Ranexa     HIV treatment              $758         6%


Climbing out of a two-year downturn, the light at the end of the tunnel revealed itself in the first quarter of 2019, with revenues up 4% to $5.3 billion and earnings up 28% to $2.0 billion. Still recovering financially from HCV franchise declines, Gilead has finally returned to growth thanks to its flagship FUV franchise andYescarta, its first commercially available CAR-T cancer therapy.

While chronic hepatitis C virus (HCV) product sales, which consist of Epclusa, Harvoni,Vosevi, and Sovaldi, were down nearly 60% to $3.7 billion in 2018, and down 26% in the first quarter of 2019 to $790 million, HIV product sales were up 12% to $14.6 billion for the year, primarily due to the launch of Biktarvy and the continued uptake of Descovy, Genvoya and Odefsey. In 1Q19, HIV product sales were up 13% to $3.6 billion, thanks to Biktarvy.

Yescarta, a chimeric antigen receptor (CAR) T cell therapy launched in the U.S. in October 2017 to treat large B-cell lymphoma, generated $264 million in sales in 2018. Resulting from the 2017 acquisition of Kite Pharma, Yescarta was the second gene therapy approved by the FDA and the first for certain types of non-Hodgkin lymphoma (NHL).Yescarta generated $96 million in sales in the first quarter compared to $40 million in 1Q18.

Kite Pharma, a Gilead company, is significantly expanding its ability to manufacture a variety of CAR-T therapies, including Yescarta, for both clinical and commercial use with a new biologics facility in Urbana, MD. Kite specializes in cancer treatments and the facility will focus on chimeric antigen receptor T (CAR-T) therapies, which uses a patient's white blood cells to destroy cancer cells. Producing these therapies requires complex processes and the new facility aims to better meet these specifications. It will become part of Kite's commercial manufacturing network that includes sites in CA and the Netherlands. Yescarta is also being investigated in solid tumors. To date, CAR-T therapies have only proven successful in blood cancers.

EXECUTIVE MOVES

As of March 1, 2019, Daniel O'Day took the helm as Gilead's chairman and chief executive officer, succeeding John F. Milligan, Ph.D., who stepped down after a 28-year career with the company. Mr. O'Day previously served as CEO of Roche Pharmaceuticals, a position he held since 2012, and prior to that led Roche Diagnostics. His career spans three decades of leadership roles across North America, Asia Pacific and Europe.

In other recent executive moves, Gilead appointed Johanna Mercier as its new chief commercial officer, joining the senior leadership team on July 1, and succeeding Laura Hamill, who is departing from Gilead after less than a year in the role.

Also, Robin Washington, executive vice president and chief financial officer, plans to retire from her role, effective March 1,2020, and Alessandro Riva, MD, executive vice president, Oncology Therapeutics, has decided to leave the company to pursue another opportunity. The company has yet to name successors for these two roles.

R&D

Updates to Gilead's HIV and liver diseases programs include approvals in China of Harvoni for the treatment of HCV genotype 1-6 infection, Vemlidy for the treatment of chronic HBV infection, and Descovy for the treatment of HIV-1 infection. Also, findings from two studies support the further development of GS-6207, a first-in-class, investigational capsid inhibitor, which may represent a novel approach to HIV treatment due to its long-acting characteristics and potent antiviral activity seen in vitro.

However, recent results from a Phase III study evaluating the safety and efficacy of selonsertib, an investigational, once daily, oral inhibitor of apoptosis signal-regulating kinase 1 (ASK1), for patients with bridging fibrosis due to nonalcoholic steatohepatitis (NASH), did not meet its primary endpoint of improvement in fibrosis without worsening of NASH.

Gilead's oncology and cell therapy programs recently achieved promising study results from a Phase I/II study evaluating KTEX19, an investigational CD19 chimeric antigen receptor T cell therapy, in relapsed or refractory acute lymphoblastic leukemia. With a median follow-up of 15 months following a single infusion of KTE-X19, 69% of patients achieved complete tumor remission, and the rate of undetectable minimal residual disease in patients who achieved complete tumor remission was 100%.

Also, two-year efficacy and safety data of Yescarta in patients with refractory large B-cell lymphoma, showed 39% of patients were in an ongoing response with a median follow up of 27 months.

Additionally, results from an ongoing Phase III study of filgotinib, an investigational, oral, selective JAK1 inhibitor, in moderate-to-severe active rheumatoid arthritis, achieved its primary endpoint of patients achieving an American College of Rheumatology 20 percent response (ACR20) at Week 24. The proportion of patients achieving the primary endpoint was significantly higher for filgotinib 200 mg plus MTX and filgotinib 100 mg plus MTX compared with MTX alone.

Lastly, a Phase II study of filgotinib in severe active ankylosing spondylitis (AS) achieved its primary endpoint of significantly greater improvements in AS Disease Activity Score at Week 12, with a mean change from baseline of -1.5 versus -0.6 for those treated with placebo. More patients receiving filgotinib also achieved an ASAS20 response compared to those treated with placebo.

MAJOR INVESTMENTS

In its most recent deal, Gilead will pay Nurix Therapeutics $45 million up front and as much as $2.3 billion in milestones under a global strategic collaboration to develop and commercialize a pipeline of innovative targeted protein degradation drugs for cancer and other challenging diseases. Dysregulated and/or mutated proteins play a central role in the development and progression of many human diseases. Nurix's technology platform is focused on the manipulation of the ubiquitin system and its component E3 ligases, the key enzymes responsible for controlling protein levels in human cells.

Under an alliance with Agenus, Inc. focused on the development and commercialization of novel immuno-oncology therapies, Agenus will receive $150 million upfront including $30 million equity investment, and the agreement also includes approximately $1.7 billion in potential milestones.

A strategic collaboration with Scholar Rock Holding Corp. aims to discover and develop highly specific inhibitors of transforming growth factor beta activation for the treatment of fibrotic diseases. Scholar Rock will receive $80 million upfront in payments, including the purchase of Scholar Rock stock, and the company is eligible to receive up to an additional $1.4 billion in potential payments across three programs.

Moreover, a global strategic collaboration with Tango Therapeutics aims to develop and commercialize a pipeline of innovative targeted immuno-oncology treatments. Tango will receive $50 million upfront and is eligible to receive approximately $1.7 billion in additional payments across all programs.

Finally, Gilead is not giving up on nonalcoholic steatohepatitis (NASH) and has partnered with several companies to help advance its efforts. Gilead and Novo Nordisk are collaborating on a clinical trial combining compounds from their respective pipelines in NASH. The trial will combine Novo Nordisk's semaglutide (GLP-1 analogue) and Gilead's cilofexor (FXR agonist) and firsocostat (ACC inhibitor). The companies are also exploring the potential to collaborate on preclinical research to advance understanding of the disease.

Under a licensing and collaboration deal withYuhan Corp. to develop novel NASH candidates, Gilead acquired global rights to small molecules against two targets for $15 million upfront and up to an additional $770 million in potential milestones.

Lastly, Gilead and insitro partnered to discover and develop NASH therapies leveraging insitro's Human (ISH) platform to create disease models for NASH and discover targets that have an influence on clinical progression and regression of the disease. The insitro Human (ISH) platform applies machine learning, human genetics and functional genomics to generate and optimize unique models to drive discovery and development. Gilead can advance up to five targets identified through this collaboration.

Caption: Truvada sales fell, but were offset by Gilead's other HIV medicine, Genvoya, which grew 26% during the year.

13 ASTRAZENECA

Headquarters: London, UK

twitter.com/astrazeneca

www.astrazeneca.com
HEADCOUNT:           64,400
YEAR ESTABLISHED:      1999
REVENUES:           $22,090    (-2%)
NET INCOME:          $2,050    (-29%)
R&D:                 $5,932    (+3%)

DRUGS APPROVED

DRUG                    INDICATION

Lumoxiti                Leukaemia, hairy cell (HCL)
Lokelma                 Hyperkalaemia

DRUGS FILED

DRUG                    INDICATION

PT010                   COPD

PHASE III

DRUG                    INDICATION

DS-8201                 Breast cancer
Tezepelumab             Asthma
Tremelimumab            Non-small cell lung cancer (NSCLC), Head
                        & neck cancers, Bladder cancer, Hepa
                        toma, liver cancer, Small cell lung cancer
                        (SCLC)
Savolitinib             Renal cell carcinoma (RCC)
Selumetinib             Other neurological indications
Zemfirza                Glioblastoma multiforme, Ovarian cancer
AZD4547                 Non-small cell lung cancer (NSCLC)
BHV3241                 Other neurological indications, Parkinson's
                        disease
Tralokinumab            Eczema/Dermatitis
Anifrolumab             Systemic lupus erythematosus (SLE)
Brazikumab              Crohn's disease
PT001                   Asthma
PT005                   COAD/COPD
GemRIS                  Bladder cancer
MEDI8897                RSV infections
AZD3759                 Non-small cell lung cancer (NSCLC)
FKB-238                 Non-small cell lung cancer (NSCLC)
SAIT101                 Non-Hodgkin lymphoma (NHL)
PT027                   Asthma

EARLY RESEARCH PROJECTS

DRUG                    INDICATION

AZD0156                 solid tumors
AZD4573                 hematological malignancies
AZD4635                 solid tumors

AZD9496                 breast cancer
Imfinzi + dabrafenib
  + trametinib          melanoma
Imfinzi + azacitidine   myelodysplastic syndrome
MEDI0562                solid tumors
MEDI3726                prostate cancer
MEDI7247                hematological malignancies
adavosertib             solid tumors
oleclumab               solid tumors
AZD4831                 heart failure
AZD9977                 CV disease
MEDI7219                type-2 diabetes
AZD1402                 asthma
MEDI3506                COPD
AZD0284                 psoriasis
MEDI0700                systemic lupus erythematosus
MEDI1814                Alzheimer's disease
MEDI7352                osteoarthritis pain
AZD5634                 cystic fibrosis

DRUGS COMING OFF PATENT

DRUG       INDICATION      YEAR

Faslodex   breast cancer   2019
Byetta     diabetes        2020
Onglyza    diabetes        2023

TOP SELLING DRUGS

DRUG         INDICATION        2018 SALES   (+/-%)

Symbicort    asthma            $2,561       -9%
Crestor      cholesterol       $1,433       -39%
Nexium       acid reflux       $1,702       -13%
Brilinta     antiplatelet      $1,321       22%
Farxiga      type 2 diabetes   $1,316       29%
Tagrisso     lung cancer       $1,860       95%
Pulmicort    asthma            $1,286       9%
Faslodex     breast cancer     $1,028       9%
Zoladex      prostate cancer   $752         2%
Lopressor    hypertension      $654         1%


While AstraZeneca's total revenue for 2018 was off 2% ($22.1 bn) compared to last year, product sales were actually up 4%, climbing to $21.0 billion. The UK-based pharma major also ended the year on a high note, with a strong performance in the fourth quarter, including product sales growth of 5% and total revenue growth of 11%.

Product sales growth for the year can be attributed to the strong performance of new medicines (+81%) and the sustained strength of emerging markets (+12%), particularly China sales, which were up by 28% for the year. Oncology sales increased by 50% with Tagrisso and Lynparza each doubling in sales, along with promising performance from Imfinzi. Asthma drug Fasenra sales reached $297 million in its first hill launch year.

Looking further into AstraZeneca's oncology performance, Tagrisso sales of $1.8 billion represented growth of 95%. Based on its performance in 2018, AstraZeneca anticipates it to be its biggest-selling medicine in 2019. Lynparza sales of $647 million grew 118%, driven by expanded use in the treatment of ovarian cancer and the medicine's first approvals for use in the treatment of breast cancer. Imfinzi sales of $633 million grew from $19 million the year before, reflecting ongoing launches.

Also in oncology news, AstraZeneca strengthened its development and commercialization collaboration with Innate Pharma in October 2018. The agreement extension enriched AstraZeneca's immuno-oncology portfolio with preclinical and clinical assets. It obtained full oncology rights to the first-in-class humanized anti-NKG2A antibody, monalizumab. It also gained option rights to IPH5201, an antibody targeting CD39, as well as four preclinical molecules from Innate Pharma's pipeline. In addition, Innate licensed the U.S. and EU commercial rights to recently FDA-approved cancer drug Lumoxiti, which was launched in the U.S. in the fourth quarter.

On the divestment front, AstraZeneca sold a few pieces of its portfolio at the end of the year to sharpen its focus in oncology. In November, it completed an agreement to divest the prescription medicine rights to Nexium in Europe, as well as the global rights (excluding the U.S. and Japan) to Vimovo, to Griinenthal. AstraZeneca received payments of $700 million for Nexium and $115 million for Vimovo. During the same month AstraZeneca struck a $1.5 billion deal with Sobi for the rights to its infant drug Synagis. In December, it completed an agreement with Covis Pharma to sell its rights to asthma medicine Alvesco, and nasal relief drugs Omnaris and Zetonna, for $350 million.

DRUG DISCOVERY TIE-UPS

Medlmmune, the global biologics research and development arm of AstraZeneca, entered an exclusive license agreement with Compugen, a provider of predictive discovery and development of first-in-class therapeutics for cancer immunotherapy, for the development of bi-specific and multi-specific immuno-oncology antibody products. Compugen is providing an exclusive license to Medlmmune for the development of bi-specific and multi-specific antibody products derived from a Compugen pipeline program. Medlmmune has the right to create multiple products under this license and will be solely responsible for all research, development and commercial activities under the agreement.

In other discovery news, AstraZeneca adopted Horizon Discovery's Edit-R crRNA libraries as part of its initiative to establish a functional genomics discovery platform. AstraZeneca also joined the Genomics Discovery Initiative (GDI), a collaborative functional genomics screening community facilitated by Horizon. AstraZeneca has been evaluating Horizon's Edit-R human whole genome crRNA library for gene knockout since late 2017, and added the company's platform of arrayed synthetic crRNA libraries for CRISPR-mediated transcriptional activation (CRISPRa).The libraries offer a tool for functional genomic screens in drug discovery, providing deeper insight into biological mechanisms for the purpose of understanding disease progression, host-pathogen relationships, drug interactions, and pathway analysis.

Also, Bicycle Therapeutics is expanding its collaboration with AstraZeneca to include additional targets in respiratory and cardio-metabolic diseases. The original collaboration was signed in late 2016 and with the expansion has a potential value in excess of $1 billion. Under the terms of the collaboration, Bicycle is responsible for identifying targets for an undisclosed number of respiratory, cardiovascular and metabolic diseases specified by AstraZeneca, while AstraZeneca is responsible for further development and product commercialization.

Lastly, Ionis Pharmaceuticals licensed its Generation 2.5 IONIS-AZ5-2.5 to AstraZeneca. IONIS-AZ5-2.5 is an antisense drug designed to inhibit an undisclosed target to treat a genetically associated form of kidney disease. Astra-Zeneca is responsible for developing and commercializing IONISAZ5-2.5.

AstraZeneca entered a couple clinical collaborations during the year as well. With Bavarian Nordic it formed a new collaboration to investigate CV301, the company's targeted immunotherapy candidate, and durvalumab (IMFINZITM), AstraZeneca's PDL1 inhibitor, in combination with maintenance chemotherapy for patients with metastatic colorectal or pancreatic cancers. Also, Syndax Pharmaceuticals entered a clinical collaboration with AstraZeneca to evaluate the safety and efficacy of durvalumab in combination with SNDX-6352, Syndax's monoclonal antibody inhibitor of Colony-Stimulating Factor 1 Receptor (CSF1R), across a variety of solid tumors.

Caption: AstraZeneca's R&D site in China. Sales in the country were up 28% for the year. (Courtesy AstraZeneca)

14 BAYER

Headquarters: Leverkusen, Germany

twitter.com/Bayer

www.bayerpharma.com
HEADCOUNT:          116,998
YEAR ESTABLISHED:      1971
REVENUES:           $45,278    (+13%)
PHARMA REVENUES:    $19,154    (-1%)
NET INCOME:          $1,934    (-77%)
R&D:                 $6,000    (+16%)

DRUGS APPROVED

DRUG                      INDICATION

Jivi                      Haemophilia A
Vitrakvi                  Solid tumor indications

DRUGS FILED

DRUG                      INDICATION

Darolutamide              Prostate cancer

PHASE III

DRUG                      INDICATION

Finerenone                Diabetic nephropathy
Vericiguat                Congestive heart failure (CHF)
Molidustat                Anaemia in chronic kidney
                          disease (CKD) (dialysis),
Entinostat                Breast cancer
Staxyn                    Erectile dysfunction
Vilaprisan                Uterine fibroids
LMTX                      Alzheimer's disease, Dementia,
                          frontotemporal
MQB-015                   Onychomycosis

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

TRK Inhibitor             cancer
Rogarantinib              cancer
PTEFb Inhibitor           cancer
ATR Inhibitor             cancer
DHODH Inhibitor           cancer
Copanlisib                cancer
Regorafenib               cancer
Anetumab
  Ravtansine              cancer
CD22-Targeted
Thorium Conjugate         cancer
MSLN-Targeted
  Thorium Conjugate       cancer
PSMA-Targeted
  Thorium Conjugate       cancer
CEACAM6 fb
  Antibody                cancer
ILDR2 fb
  Antibody                cancer
FXIa Inhibitor            anticoagulation
Anti-FXI Antibody         anticoagulation
Vasopressin Receptor
  Antagonist              heart failure
sGC Activator 2           Pulmonary hypertension
P2X3 Antagonist 1         endometriosis
P2X3 Antagonist 2         endometriosis
P2X4 Antagonist           endometriosis
IRAK4 Inhibitor 1         endometriosis
FVIII Gene Therapy        hemophilia
sGC Activator 3           acute respiratory distress syndrome
PEG-ADM Inhale            acute respiratory distress syndrome
TASK Channel
  Blocker 2               obstructive sleep apnea
IRAK4 Inhibitor 2         rheumatoid arthritis
sGC Activator 1           chronic kidney disease
Vasopressin V1a
  Receptor Antagonist     chronic kidney disease

DRUGS COMING OFF PATENT

DRUG       INDICATION             YEAR

Zetia      hyperlipidaemia        2019
Nexavar    renal cell carcinoma   2020
Xofigo     prostate cancer        2022

TOP SELLING DRUGS

DRUG             INDICATION              2018 SALES   (+/-%)

Xarelto          atrial fibrillation     $3,689       17%
Eylea            macular degeneration    $2,581       21%
Mirena           women's health          $1,350       6%
Kogenate         hemophilia              $1,010       -8%
Nexavar          oncolgy                 $841         -11%
Yasmin           contraception           $755         3%
Precose          diabetes                $733         16%
Adalat           hypertension            $722         -1%
Asprin Cardio    Myocardial infarction
                 prophylaxis             $658         0%
Betaferon        multiple sclerosis      $643         -13%


After Bayer made the mega $63 billion deal for Monsanto, turning it into the world's largest agro-chemical maker and seed producer, it was forced to make some major overhauls.

The company announced at the end of the year it would be axing 12,000 jobs throughout the crop science, pharma and consumer units. Of the job losses, roughly 1,250 were in pharma with 350 related directly to a new manufacturing facility in Wuppertal, Germany that the company will not use, focusing all recombinant factor VIII production at its Berkeley, CA site instead.

In addition, as this issue went to press Bayer had already sold off the iconic Coppertone skin care brand and was still looking for a buyer for the Dr. Scholl's foot care brand and its animal health unit. China's Fosun International, parent of Fosun Pharma, was on the hunt for the animal health business, looking to partner with private equity to make an offer--the sale could be worth nearly $8 billion if it goes down.

With all the shake-ups, pharma sales were off by just one percent for the year ($19.2 bn) when factoring in exchange rates. Growth in pharma is being driven primarily driven by its top selling drug Xarelto and Eylea, with several promising late-stage R&D pipeline candidates. Sales of the oral anticoagulant Xarelto were up 17% and eye medicine Eylea climbed 21% while cancer drugs Stivarga and Xofigo, and the pulmonary hypertension treatment Adempas advanced by 13.5%.

Looking ahead to the eventual loss of exclusivity for Xarelto and Eylea, Bayer is amping up its oncology pipeline. At the end of 2017 it made a deal with Loxo Oncology to develop and commercialize larotrectinib and LOXO-195, Loxo Oncology's franchise of highly selective TRK inhibitors for patients with TRK fusion cancers. A year later, in November 2018, FDA approved larotrectinib, which is now sold under the brand name Vitrakvi.

More good news came on the cancer treatment front when Bayer reported positive results of the Phase III study of darolutamide, a novel androgen receptor antagonist of for the oral treatment of prostate cancer that is being developed jointly by Bayer and the Finnish biopharmaceutical company Orion Corporation.

Research and development of new immunotherapy approaches in oncology continued through a partnership with Compugen Ltd., a company focused on predictive discovery and development of therapeutics for cancer immunotherapy. COM902, its lead anti-TIGIT antibody, advanced into manufacturing for an investigational new drug (IND) application that was anticipated in 2019. The companies entered into a process development and manufacturing service agreement to produce COM902 for future use in clinical trials.

With the University of Texas MD Anderson Cancer Center it signed a five-year collaboration agreement to accelerate the development of novel targeted treatments based on patient or tumor characteristics for which current therapies have not shown satisfactory clinical efficacy. Bayer will contribute early stage as well as clinical assets from its development pipeline for further clinical development at MD Anderson Cancer Center. The MD Anderson Cancer Center will bring in its translational and clinical expertise to help accelerate ongoing and future clinical trials.

BEYOND CANCER

Bayer entered a few collaborations during the year outside the cancer realm. With the Broad Institute of MIT and Harvard, Bayer launched the joint Precision Cardiology Laboratory, which will pursue novel scientific insights to enable the development of new therapies for patients with cardiovascular diseases such as heart failure. Heart failure--a general diagnosis given when the heart doesn't pump effectively--is a composite of multiple factors, and as such requires new tools and methods to gain deeper knowledge to benefit patients. The scientists at the joint laboratory will combine Broad Institute's methods for basic science discovery such as single cell sequencing and clinical expertise with Bayer's long experience in drug development to discover new potential therapeutics.

Furthermore, Bayer and Haplogen GmbH, a Vienna-based biotechnology company, entered into a multi-year research collaboration agreement to identify new drug candidates for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD). COPD is a common and heterogeneous respiratory disease that causes breathlessness and predisposes to exacerbations and serious illness. Respiratory viral infections are one frequent cause of COPD exacerbations. One possible treatment approach for COPD exacerbations is to disrupt the multiplication of the responsible virus by inhibiting its replication. The goal of the research alliance is to develop new antiviral compounds addressing the high unmet medical need in reducing COPD exacerbations.

At the start of 2019, Bayer and Kyoto University agreed on a strategic research alliance to jointly identify new drug targets for the treatment of pulmonary diseases such as idiopathic pulmonary fibrosis. The goal of the research alliance is to identify specific targets and pathways that are causing the disease and to discover new treatments to modulate these pathways and prevent further lung functions decline. Bayer has an option for the exclusive use of the collaboration results.

Caption: Bayer continues to undergo major restructuring after its $63 billion purchase of Monsanto.

15 TEVA

Headquarters: Petach Tivka, Israel

twitter.com/tevapharm

www.tevapharm.com
HEADCOUNT:           42,535
YEAR ESTABLISHED:      1901
REVENUES:           $18,854    (-16%)
LOSS:                $2,472     (NM)
R&D:                 $1,213    (-32%)

DRUGS APPROVED

DRUG                      INDICATION

Ajovy                     migraine

DRUGS FILED

DRUG                      INDICATION

Eptinezumab               migraine

PHASE III

DRUG                      INDICATION

Fasinumab                 Osteoarthritis, chronic pain
Multikine                 Head & neck cancers
NeuVax                    Breast cancer
TV-46000                  Schizophrenia

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

TV-46046                  contraception
Omacetaxine +
  Cytarabine and
  Idarubicin              acute myeloid leukemia
Arsenic trioxide          chronic myelogenous leukemia
Metronidazole             bacterial vaginosis

DRUGS COMING OFF PATENT

DRUG       INDICATION            YEAR

Treanda    Leukaemia,            2022
           chronic lymphocytic

TOP SELLING DRUGS

DRUG                 INDICATION               2018 SALES   (+/-%)

Copaxone             Relapsing-Remitting
                     MS                       $2,366       -38%
Bendeka              Leukaemia, chronic
                     lymphocytic
                     Non-Hodgkin
                     lymphoma                 $642         -2%
Methylphenidate
  Hydrochloride      Attention deficit
                     disorder/hyperactivity
                     (ADD/ADHD)               $481         -29%
ProAir HFA           Asthma                   $397         -21%
Austedo              Huntington's disease,
                     Tardive dyskinesia       $204         750%
Methylphenidate
  Hydrochloride      Attention deficit
                     disorder/hyperactivity
                     ADD/ADHD)                $192         -58%
QVAR RediHaler       Asthma                   $190         n/a
Daptomycin           Skin infections,
                     Endocarditis             $167         45%
Metoprolol
  Succinate          Hypertension             $132         -13%
Sildenafil Citrate   Erectile dysfunction     $122         205%


Teva's revenues in 2018 were $18.8 billion, a decrease of 16% compared to 2017, mainly due to generic competition to multiple sclerosis drug Copaxone, a decline in revenues in the U.S. generics business and loss of revenues following the divestment of products and discontinuation of activities, all of which are part of a global restructuring effort announced by the Israeli generics giant at the end of 2017. In terms of sales, the beginning of 2019 didn't show signs of hope. Revenues of $4.3 billion in the first quarter of 2019 continued the downward trend, marking a decrease of 15%.

GLOBAL RESTRUCTURING

At the time its plans were unveiled, Teva said it would undergo a major overhaul of its operations, restructuring in an effort to significantly reduce costs and simplify its organization, as it faced $35 billion of acquisition-related debt stemming from the $40.5 billion purchase of Allergan in 2016. The plan called for cutting $3 billion in costs by the end of 2019, including the elimination of 14,000 positions globally, more than 25% of Teva's total workforce. The majority of cuts occurred in 2018, but have carried over into this year as well.

Teva said it plans to pump up its generics portfolio globally, specifically in the U.S., through price adjustments and/or product discontinuation. It also continues to accelerate the restructuring of its manufacturing and supply network, including the closures or divestments of a significant number of manufacturing plants in the U.S., Europe, Israel and growth markets.

Teva said it will also close or divest a significant number of R&D facilities, headquarters and other office locations across all geographies. The company will also review all R&D programs in generics and specialty, to prioritize core projects and terminate other, non-core assets.

In one instance, Teva and Procter & Gamble agreed to terminate the PGT Healthcare partnership that the two companies established in 2011 to market OTC medicines. PGT Healthcare had grown into a significant presence in over 50 countries, mainly in Europe and Asia, using market-leading brands such as Vick's and ratiopharm. However after nearly seven years working together, the companies concluded that their priorities and strategies were no longer closely aligned. Each company took back its own brand and product assets to re-establish independent OTC businesses.

As part of the global restructuring process, during the year Teva unveiled plans to consolidate its North America Commercial business into New Jersey. Teva will establish its North America headquarters in Parsippany-Troy Hills, including more than 1,000 jobs and the transfer and creation of more than 800 positions. Teva accepted an offer of a 10-year and $40 million in tax savings incentives from the NJ Economic Development Authority to move forward with the plan. The moved marked yet another step forward and in-line with Teva's global restructuring effort to drive savings, restore financial security and stabilize its business by reducing the number of sites it operates to unify and simplify the organization, as well as improve productivity and efficiencies.

R&D

In 2018, Teva and Insilico Biotechnology entered an agreement to apply Insilico's technology for predictive biomanufacturing to create and implement more efficient production processes of Teva's biopharmaceutical therapeutics. Insilico's solutions for predictive bio-manufacturing are one of the key technologies to convert this value into higher quality therapies and to bring them faster to market. Insilico's Digital Twins of biopharmaceutical production processes employ metabolic models of producer organisms in combination with flexible process models and artificial intelligence to create optimized production processes by computational simulations. The collaboration will run for three years and will be based at Insilico's sites in Stuttgart, Germany and at Teva's West Chester, PA, location.

In another deal to bolster its biomanufacturing operations, Teva teamed up with Genedata, a provider of bioinformatics enterprise software, to use its workflow platform to streamline the identification, engineering, and characterization of novel biopharmaceuticals drugs. Teva will use Genedata Biologics as their backbone system across their antibody discovery operations. In addition, the platform will enable a thorough assessment of a drug candidate's developability profile and facilitate handovers to the Teva development and manufacturing organization.

In September 2018, Teva received approval from the FDA for its AJOVY (fremanezumab-vfrm) injection for the preventive treatment of migraine in adults. AJOVY, a humanized monoclonal antibody that binds to calcitonin gene-related peptide (CGRP) ligand and blocksits binding to the receptor, is the first and only anti-CGRP treatment for the prevention of migraine.

Teva also received approval from the FDA at the end of the year for its ProAir Digihaler (albuterol sulfate 117 meg) inhalation powder, the first and only digital inhaler with built-in sensors which connects to a companion mobile application and provides inhaler use information to people with asthma and COPD. ProAir Digihaler is indicated for the treatment or prevention of bronchospasm in patients aged four years and older with reversible obstructive airway disease, and for prevention of exercise-induced bronchospasm (EIB) in patients aged four years and older. The device contains built-in sensors that detect when the inhaler is used and measure inspiratory flow. This inhaler-use data is then sent to the companion mobile app using Bluetooth Wireless Technology so patients can review their data over time, and if desired, share it with their healthcare professionals.

16 NOVO NORDISK

Headquarters: Bagsvaerd, Denmark

twitter.com/novonordisk

www.novonordisk.com
HEADCOUNT:           43,202
YEAR ESTABLISHED:      1989
REVENUES:           $17,127    (flat)
NET INCOME:          $5,916    (+1%)
R&D:                 $2,267    (+6%)

DRUGS FILED

DRUG                      INDICATION

Semaglutide Oral          Diabetes, type II (maturity onset),
                          General cardiovascular indications

PHASE III

DRUG                      INDICATION

Somapacitan               Short stature in children,
                          Adult growth hormone deficiency
Semaglutide
Transdermal               Diabetes, type II (maturity onset),
                          Obesity

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

OG2023SC                  type 2 diabetes
LAISema                   diabetes
PYY 1562                  obesity
GG-co-agonist 1177        obesity
Tri-agonist 1706          obesity
PYY 1875                  obesity

DRUGS COMING OFF PATENT

DRUG       INDICATION    YEAR

Levemir    diabetes      2019
Tretten    Factor XIII
           deficiency    2021
Victoza    diabetes      2023

TOP SELLING DRUGS

DRUG            INDICATION                  2018 SALES   (+/-%)

Victoza         diabetes                    $3,857       10%
NovoRapid       diabetes                    $2,974       -2%
Levemir         diabetes                    $1,774       -17%
NovoMix 30      diabetes                    $1,503       -4%
Human insulin
& devices       diabetes                    $1,469       -4%
Tresiba         diabetes                    $1,274       14%
NovoSeven       Haemophilia A, B            $1,249       -11%
Norditropin
SimpleXx        Short stature in children   $1,083       7%
Saxenda         obesity                     $613         58%
Insulin
Analogues       diabetes                    $508         10%


Revenue was flat for Novo Nordisk in 2018 at $17.1 billion. The Danish firms sells medicines mainly in diabetes, which accounted for almost $15 billion worth of group sales. Victoza again was the companies top seller, raking in $3.9 billion, a 10% growth from the year before. The newly launched diabetes medicine Tresiba performed well, climbing 14% to $1.2 billion. However, the fastest grower in the portfolio was the new obesity drug Saxenda--it's $613 million in sales marked a 58% growth.

During the year, Novo Nordisk continued to broaden its diabetes portfolio and pipeline. In February 2018, it launched Ozempic, a new once-weekly GLP-1, in the U.S. The type 2 diabetes drug has now been launched in 11 countries in Europe and North America. In November, Novo Nordisk completed the Phase Ilia PIONEER program for oral semaglutide, a new once-daily GLP1 tablet also for people with type 2 diabetes. Novo Nordisk submitted the oral semaglutide file around the end of first quarter 2019 to FDA and requested priority review.

Also, Novo Nordisk struck a deal with Evotec AG to discover and develop novel small molecule therapies to treat diabetes and obesity, as well as co-morbidities such as nonalcoholic steatohepatitis (NASH), cardiovascular diseases, and diabetic kidney disease. Evotec will apply its drug discovery platform to design novel, safe and efficacious products. Once suitable preclinical candidates are selected, Novo Nordisk will use Evotec's INDiGO platform to move through preclinical studies to enter IND registration.

In an effort to grow the bio side of its business--group biopharmaceuticals sales decreased by 5% during the year to $2.8 billion--Novo Nordisk eliminated approximately 250 jobs in the U.S.

The company said it made the move as it continues to witness more modest growth in its diabetes franchises in recent years as a result of pricing pressures in the U.S., which accounts for approximately half of its revenue. One hundred of the staff reductions are from back-office positions in the company's U.S. headquarters in Princeton, NJ, and the remaining 150 are among diabetes treatment support positions. The company previously announced plans to cut 400 staff in Denmark and China, also as part of an effort to focus on investments in biologics and technology innovation.

Novo Nordisk also expanded its biopharm business with an agreement to acquire the U.S. and Canadian rights to Macrilen, the first FDA-approved oral growth hormone receptor indicated for the diagnosis of Adult Growth Hormone Deficiency (AGHD), a rare endocrine disorder, from Strongbridge Biopharma.

Expanding its capabilities in biotechnology innovation, Novo Nordisk purchased Berkeley Lights'Beacon Optofluidic platform to accelerate workflows in cell line development and to use the platform for future protein and antibody discovery.

17 TAKEDA

Headquarters: Osaka, Japan

twitter. com/TakedaPharmaDe

www.takeda.com
HEADCOUNT:           27,230
YEAR ESTABLISHED:      1781
REVENUES:           $15,967    (+2%)
NET INCOME:          $1,684    (+62%)
R&D:                 $2,935    (+4%)

DRUGS APPROVED

DRUG              INDICATION

Takhzyro          Hereditary angioedema
Motegrity         Constipation

PHASE III

DRUG              INDICATION

TAK-003           Dengue fever prophylaxis
SHP655            Thrombocytopaenic purpura,
                  thrombotic (TTP)
TAK-609           Hunter syndrome
TAK-721           Eosinophilic oesophagitis
Camvia            CMV infections
SHP647            Ulcerative colitis, Crohn's disease
TAK-640           Conjunctivitis, infectious
Cenicriviroc      Nonalcoholic steatohepatitis (NASH)
Tedopi            Non-small cell lung cancer (NSCLC)
Maralixibat       Cholestasis

EARLY RESEARCH PROJECTS

DRUG              INDICATION

TAK-573           relapsed refractory multiple myeloma
TAK-164           gastrointestinal malignancies
TAK-981           multiple cancers
TAK-951           nausea and vomiting
Kuma062           celiac disease
TAK-018           Chron's disease
TAK-681           short bowel syndrome
TAK-671           acute pancreatitis
TAK-531           Hunter syndrome
TAK-653           treatment-resistant depression
TAK-418           Kabuki syndrome
MEDI-1341         Parkinson's disease
VWE-120101        Huntingtion's disease
TAK-426           Zika vaccine

DRUGS COMING OFF PATENT

DRUG       INDICATION    YEAR

Uloric     gout          2019
Dexilant   acid reflux   2020

TOP SELLING DRUGS

DRUG           INDICATION                         2018 SALES   (+/-%)

Entyvio        ulcerative colitis, Crohn's
               disease                            $2,428       34%
Velcade        multiple myeloma                   $953         -7%
Leuprorelin    prostate cancer, breast cancer,
               endometriosis                      $790         -1%
Azliva         hypertension                       $639         11%
Dexilant       acid reflux                        $624         5%
Ninlaro        multiple myeloma                   $561         34%


The largest, and only mega-deal of 2018 was Takeda's $62 billion acquisition of Dublin, Ireland-based Shire. The deal, announced in May and finalized in January 2019, propels Takeda into the top 10 pharma companies and is one of the largest overseas acquisition deals ever in Japanese history. Projected sales for 2019 are in the $30 billion range.

With the Japanese pharma market lagging, Takeda's purchase gives it an expanded geographic footprint, scale, and most importantly, a bigger foothold in the U.S. To offset pricing pressures in the U.S., the deal bolsters Takeda's portfolio of rare disease therapeutics, currently viewed as an under-saturated market of high value due to regulatory incentives and high drug prices.

In addition to creating leading positions in rare diseases and plasma-derived therapies, complementing strengths in oncology and vaccines, the deal bolsters its portfolios in gastroenterology and neuroscience as well.

While the Shire deal was being worked out, in September Takeda unveiled plans to move its U.S. headquarters and 1,000 employees from the suburbs of Chicago to the Boston area, where most of Shire's operations existed--3,000 of its employees in Lexington and Cambridge. The Japanese pharma giant is now the largest biopharma firm in the Boston area, which has overtaken rival California as the number one biotech hub in the world.

Takeda continued to diversify its cancer research activities with collaborations in immuno-oncology, an area of key strategic focus for the company. An alliance with Memorial Sloan Kettering aims to discover and develop novel CAR-T products for multiple myeloma, acute myeloid leukemia and solid tumor indications.

It also exercised an option under a research collaboration with Noile-Immune Biotech, licensing NIB-102 and NIB-103 for the treatment of various solid tumor indications, and will co-develop these CAR-T cell therapies with Noile using their "Prime" CAR-T platform. The company plans to gain regulatory approval for human testing of NIB-102 by the end of this year.

Through collaboration with external partners and the newly established translational cell therapy engine, Takeda is laying the foundation to deliver a rich pipeline of early-stage assets in the coming years.

18 ALLERGAN

Headquarters: Dublin, Ireland

twitter.com/Allergan

www.allergan.com
HEADCOUNT:           16,900
YEAR ESTABLISHED:      2015
REVENUES:           $15,787    (-1%)
LOSS:                $5,086    (NM)
R&D:                 $2,266    (+8%)

DRUGS FILED

DRUG                      INDICATION

Ubrogepant                Migraine
Cabazitaxel Injection     Prostate cancer

PHASE III

DRUG                      INDICATION

Rapastinel                Depression
Atogepant                 Migraine
Bimatoprost SR            Glaucoma
Abicipar                  Wet age-related macular degeneration
                          (AMD)
Relamorelin               Gastroparesis
Cenicriviroc              Nonalcoholic steatohepatitis (NASH)
ABP798                    Non-Hodgkin lymphoma (NHL), Arthritis,
                          rheumatoid
Vitaros                   Erectile dysfunction
Zydena                    General cardiovascular indications
Vadadustat                Anaemia in chronic kidney disease (CKD)
                          (non-dialysis)
ATM-AVI                   Gram negative infections
Qapzola                   Bladder cancer
Presbysol                 Refractive error, presbyopia
Brazikumab                Crohn's disease

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

Dalbavancin               Bacterial Infections
AGN-151587                Leber Congenital Amaurosis 10
RST-001                   Advanced Retinitis Pigmentosa
AGN-241751                Major Depressive Disorder
ABI-M201                  Ulcerative Colitis
Ceftaroline Fosamil       Hematogenously Acquired Staphylococcus

DRUGS COMING OFF PATENT

DRUG        INDICATION      YEAR

Botox       Blepharospasm   2020
Bystolic    Hypertension    2021
Combigan    Glaucoma        2023

TOP SELLING DRUGS

DRUG           INDICATION                 2018 SALES   (+/-%)

Botox
Therapeutics   chronic migraine,
               overactive bladder         $3,577       13%
Restasis       dry eye                    $1,262       -14%
Linzess        irritable bowel syndrome   $785         9%
Lumigan        ocular hypertension        $684         -1%
Bystolic       hypertension               $586         -5%


Just as this issue was getting ready to fly, AbbVie shook up the pharma world with its $63 billion acquisition of Allergan. The Botox-maker, and biggest name in medical aesthetics, helps AbbVie diversify a portfolio that includes the world's best-selling drug, Humira, which soon faces generic competition in Europe. The combined company will consist of several franchises with leadership positions across immunology, hematologic oncology, medical aesthetics, neuroscience, women's health, eye care and virology.

The mega-deal comes after Allergan tried to become more efficient by reducing costs and streamlining operations. At the beginning of 2018 it unveiled a restructuring plan that called for the elimination of 1,000 jobs as part of the effort. It also recently unloaded its generics business toTeva for $40 billion in 2016.

In September 2018 Allergan also divested products in its dermatology unit to Almirall, S.A. for $550 million. The products include Aczone, Tazorac, Azelex and Cordran Tape, as well as sarecycline, a new chemical entity currently under FDA review for the treatment of acne.

Allergan recorded $15.7 billion in revenues in 2018, a drop of 1% from the year before. Its top selling product is Botox, a cosmetic filler with pharmaceutical indications for chronic migraine and overactive bladder, which grew 13% with $3.5 billion in sales. The year wasn't so good for Allergan's other top seller, dry eye drug Restasis, which saw its revenue drop 14% to $1.2 billion.

A major highlight during the year saw Allergan and Amgen together win European approval for MVASI (biosimilar bevacizumab). MVASI is the first biosimilar bevacizumab approved by the EC and is approved for the treatment of certain types of cancers, including in combination with chemotherapy or other therapies for metastatic carcinoma of the colon or rectum, metastatic breast cancer, non-squamous non-small cell lung cancer, renal cell cancer, ovarian, fallopian tube, or primary peritoneal cancer, or metastatic carcinoma of the cervix.

In September 2017, MVASI became the first anti-cancer biosimilar, as well as the first biosimilar bevacizumab, to be approved by the FDA. Amgen and Allergan are collaborating on the development and commercialization of four oncology biosimilars.

In acquisition news, Allergan bolstered its medical aesthetics portfolio, specifically facial injectables, when it paid $195 million for Bonti, Inc., a clinical-stage biotech focused on novel, neurotoxin programs for aesthetic and therapeutic applications.

19 CELGENE

Headquarters: Summit, NJ

twitter.com/celgene

www.celgene.com
HEADCOUNT:            8,852
YEAR ESTABLISHED:      1986
REVENUES:           $15,281    (+18%)
NET INCOME:          $4,046    (+38%)
R&D:                 $5,673    (-4%)

DRUGS FILED

DRUG              INDICATION

Luspatercept      Thalassaemia,
                  Myelodysplastic syndrome
Ozanimod          Relapsing-Remitting MS
Fedratinib        Myelofibrosis

DRUGS IN PHASE III

DRUG              INDICATION

Liso-cel          Non-Hodgkin lymphoma
ide-cel           Multiple myeloma
Tislelizumab      Hepatoma, Non-small cell
                  lung cancer, Oesophageal,
                  Liver, Stomach, Bladder cancer,
                  Small cell lung cancer
CC-486            Myelodysplastic syndrome,
                  Leukaemia, lymphomas
Marizomib (IV)    Glioblastoma multiforme
PDA-001           Crohn's disease
T Cell Therapy    Solid tumor indications

EARLY RESEARCH PROJECTS

DRUG              INDICATION

CC-93269          relapsed/refractory mutiple myeloma
GEM333            acute myeloid leukemia
CC-90002          non-Hodgekin's lymphoma
Avadomide         diffuse large B-cell lymphoma
CC-90010          non-Hodgekin's lymphoma
CC-90011          solid tumors
CC-90006          psoriasis

DRUGS COMING OFF PATENT

DRUG        INDICATION                 YEAR

Thalomid    leprosy                    2019
Revlimid    Myelodysplastic syndrome   2022
Abraxane    Breast cancer              2022

TOP SELLING DRUGS

DRUG        INDICATION                 2018 SALES   (+/-%)

Revlimid    multiple myeloma,
            mantle cell lymphoma       $9,685       18%
Pomalyst    multiple myeloma           $2,040       26%
Otezla      psoriasis                  $1,608       26%
Abraxane    breast, lung,
            pancreatic cancer          $1,062       7%
Vidaza      myelodysplastic syndrome   $594         -5%
Thalomid    leprosy                    $114         -14%


The year 2019 had barely begun when on January 3, BMS said it was paying roughly $74 billion to acquire Celgene, creating a top 10 company and a leading specialty biopharma in the areas of cancer, inflammatory and immunologic disease and cardiovascular disease.

The combined company offers leading oncology franchises in both solid tumors and hematologic malignancies with Opdivo and Yervoy as well as Revlimid and Pomalyst; a top five immunology and inflammation franchise with Orencia and Otezla; and the number one cardiovascular franchise led by Eliquis. The portfolio will include nine products with more than $1 billion in annual sales and significant potential for growth in the core disease areas of oncology, immunology and inflammation and cardiovascular disease.

When the news was announced, near-term launch opportunities included six expected product launches: two in immunology and inflammation, TYK2 and ozanimod; and four in hematology, luspatercept, liso-cel (JCAR017), bb2121 and fedratinib.

Together, the company will also have expanded capabilities in small molecule design, biologics/synthetic biologics, protein homeostasis, antibody engineering and cell therapy.

In 2018, growth was driven by strong product sales including Revlimid, $9.6 billion, up 18%; Pomalyst, $2 billion, up 26%; Otezla, $1.6 billion, up 26%; and Abraxane, $1 billion, up 7%.

Early in 2018, Celgene acquired Impact Biomedicines and its fedratinib for myelofibrosis and polycythemia vera, for $7 billion.

Celgene also plans to open a Research Incubator and Collaboration Center offering entrepreneurs lab space, resources and support to scientists and companies with potentially transformational approaches to accelerate medical innovations. Set to open this year, the facility houses 16,000 sq.-ft. of shared and fully equipped lab facilities on its campus in Summit, NJ.

Celgene formed several R&D partnerships, including a long-term discovery and development deal to identify new therapeutics in oncology with Evotec leveraging its preclinical discovery platform. This includes a phenotypic screening platform with unique compound libraries and associated target de-convolution capabilities. Celgene entered another discovery tie-up with Evotec in the field of targeted protein degradation that will leverage Evotec's Ranomics platform to identify drug targets that are traditionally difficult to track. The platform applies proteomics and transcriptomics at industrial scale to profile and select promising drug candidates based on cell profiles.

20 BOEHRINGER-INGELHEIM

Headquarters: Ingelheim, Germany

twitter.com/Boehringer

www.boehringer-ingelheim.com
HEADCOUNT:           50,370
YEAR ESTABLISHED:      1817
REVENEUS:           $20,014    (-3%)
PHARMA REVENUES:    $15,204    (flat)
NET INCOME:          $2,373     (NM)
R&D:                 $3,619    (+3%)

DRUGS FILED

DRUG                      INDICATION

Empagliflozin &
Linagliptin &
Metformin XR              Diabetes, type II (maturity onset)

PHASE III

DRUG                      INDICATION

Volasertib                Leukaemia, acute myeloid (AML)
MOR208                    Non-Hodgkin lymphoma (NHL)
Bl 695502                 Non-small cell lung cancer (NSCLC),
                          Colorectal cancer
Bl 655130                 Ulcerative colitis, Psoriasis
Capsaicin/ Diclofenac     Pain, acute
Inhaled Fentanyl          Pulmonary fibrosis, idiopathic,
                          General respiratory disorders

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

GLP1R/GCGR
agonist                   cardiometabolic diseases
Amylin analog             cardiometabolic diseases
EmpaLinaMet XR            cardiometabolic diseases
MRNA vaccine              cancer
PD-1 antibody             cancer
Cysteine protease
  inhibitor               respiratory diseases
Non-receptor tyrosin
  kinase inhibitor        respiratory diseases
IL36R antibody            immunology
Nuclear receptor
  antagonist              immunology
TRPC 4/5 inhibitor        central nervous system diseases

DRUGS COMING OFF PATENT

DRUG       INDICATION           YEAR

Aptivus    HIV                  2019
Spiriva    COPD, asthma         2019
Pradaxa    pulmonary embolism   2021

TOP SELLING DRUGS

DRUG         INDICATION             2018 SALES   (+/-%)

Spiriva      COPD, asthma           $2,849       -11%
Pradaxa      atrial fibrillation    $1,755       8%
Trajenta     type 2 diabetes        $1,650       18%
Jardiance    type 2 diabetes        $1,726       51%
Ofev         idiopathic pulmonary
             fibrosis               $1,299       25%
Micardis     hypertension           $942         -5%
Glyxambi     diabetes               $493         143%


Boehringer Ingelheim ended 2018 with flat pharma sales of $15.2 billion. As in previous years, the respiratory medicine Spiriva achieved the highest sales contributions with $2.8 billion, but this was an 11% drop from the year before due mostly to patent expiry. All other major products in Boehringer's portfolio performed well. The anticoagulant Pradaxa was the next top seller with $1.8 billion in sales followed by type 2 diabetes drugs Jardiance, which grew 51% to $1.7 billion and Trajenta, which grew 18% to $1.6 billion. Rounding out the companies billion dollar performers was idiopathic pulmonary fibrosis treatment Ofev, which recorded $1.3 billion, up 25%.

In June 2018, Boehringer unveiled major investment plans on the biologics R&D front, pumping roughly $262 million into a new Biologicals Development Center (BDC) at the company's site in Biberach, Germany. The BDC is part of the company's long-term strategy to grow its biologics pipeline, specifically immune oncology and immunology. The company's share of new biologics has been consistently increasing over the past few years and has now reached 40%.

The BDC will integrate biologics analytical and process development as well as manufacturing for clinical studies into one unit, while at the same time increasing development capacity. Following a staggered launch beginning in 2020, the new building will be home to 500 employees.

The new BDC adds to a number of major recent investments in its global biopharmaceuticals network aimed at increasing mammalian cell culture capabilities. This includes a large scale biopharmaceutical facility in Vienna, Austria, a new biopharmaceutical facility in Shanghai, China, and the expansion of existing large scale biopharmaceutical capacities in Fremont, CA.

On the cancer research front, Boehringer and Vanderbilt University expanded an existing collaboration to develop anti-cancer compounds, and formed a collaboration with OSE Immunotherapeutics to jointly develop OSE-172, a cancer immunotherapy.

In terms of filings, FDA granted Fast Track to Boehringer's nintedanib for the treatment of systemic sclerosis with associated lung disease. In addition, positive results were reported from a Phase III study confirming that Cyltezo, the first biosimilar from Boehringer to be approved by FDA, is equivalent to Humira. This is the first U.S. study to investigate an interchangeability designation for an adalimumab biosimilar.

21 BIOGEN

Headquarters: Cambridge, MA

twitter.com/biogenidec

www.biogenidec.com
HEADCOUNT:            7,800
YEAR ESTABLISHED:      2003
REVENUES:           $13,453    (+10%)
NET INCOME:          $4,431    (+75%)
R&D:                 $2,597    (+15%)

DRUGS APPROVED

DRUG                   INDICATION

Trogarzo               HIV

DRUGS FILED

DRUG                   INDICATION

Lusduna                Diabetes I, II
Vumerity               Relapsing-Remitting MS (RRMS)

DRUGS IN PHASE III

DRUG                   INDICATION

BIIB093                Stroke, acute, Cerebral oedema
BIIB074                Pain, neuropathic
Tofersen               Amyotrophic lateral sclerosis
BAN2401                Alzheimer's disease
Elenbecestat           Alzheimer's disease
SB8                    Non-small cell lung cancer

EARLY RESEARCH PROJECTS

DRUG                   INDICATION

BIIB061                multiple sclerosis
BIIB076                Alzheimer's disease
BIIB078                amyotrophic lateral sclerosis
BIIB080                Alzheimer's disease
BIIB095                neuropathic pain
BIIB110                spinal muscular atrophy

TOP SELLING DRUGS

DRUG         INDICATION                2018 SALES   (+/-%)

Tecfidera    multiple sclerosis        $4,274       1%
Avonex       multiple sclerosis        $1,915       -11%
Tysabri      multiple sclerosis        $1,864       -6%
Spinraza     spinal muscular atrophy   $1,724       95%
Eticovo      rheumatoid arthritis      $485         31%
Plegridy     multiple sclerosis        $448         -9%


A steady growth trajectory has Biogen up in the rankings this year. In addition to its flagship multiple sclerosis franchise, the continued global launch of spinal muscular atrophy drug Spinraza, which contributed $518 million in revenues in the first quarter, up 42%, is driving growth.

Biogen continues to diversify its pipeline in neuromuscular diseases and movement disorders, and, with the recent acquisition of Nightstar Therapeutics, specialty ophthalmology. By the end of 2020 the company expect results across its clinical programs in MS, progressive supranuclear palsy, ALS, Parkinson's, pain, cognitive impairment in schizophrenia, epilepsy, stroke, and lupus.

In June, Biogen completed the acquisition of Nightstar Therapeutics, a gene therapy company focused on adeno-associated virus (AAV) treatments for inherited retinal disorders, in a transaction valued at approximately $800 million. Biogen added two mid--to late-stage clinical assets as well as preclinical programs in ophthalmology. NST's lead asset is NSR-REP1 for the treatment of choroideremia, a rare, degenerative, X-linked inherited retinal disorder, which leads to blindness and has no approved treatments. NSR-RPGR is NST's second clinical program for X-linked retinitis pigmentosa, which is also a rare inherited retinal disease with no approved treatments.

Further investing in its biosimilar business, under an asset transfer deal with its collaboration partner Samsung BioLogics, assets of Samsung Bioepis were transferred to Biogen on November 7th for approximately $677 million. Samsung Bioepis was founded in 2012 as an 85:15 joint venture between Samsung BioLogics and Biogen. Last June Biogen raised its stake in Bioepis, increasing its ownership to 49.9 percent.

Under the successful alliance, Biogen became the first company in Europe with approved biosimilars referencing the three most prescribed anti-TNF biologic treatments, with the launch of IMRALDI, a biosimilar referencing Abbvie's Humira.

After evaluating its manufacturing strategy, in March, Biogen sold its large-scale biologics manufacturing operations in Hillerad, Denmark, to Fujifilm Corp. for up to $890 million. As part of the deal, Fujifilm will use the Hillerad site to produce commercial products for Biogen, such asTYSABRI, and other third-party products.

In unfortunate R&D news, the discontinuation of aducanumab for Alzheimer's disease was a big disappointment. Biogen and partner Eisai discontinued global Phase III trials after futility analysis indicated the trials were unlikely to meet their primary endpoint.

On the upside, Biogen is a few months away from expanding its MS franchise with Vumerity, which has an FDA target action date in 4Q19. Recent Phase III study results showed Vumerity significantly reduced disease activity in newly diagnosed relapsing multiple sclerosis patients.

To support research efforts in neurological diseases, an alliance with C4 Therapeutics will investigate the use of C4's protein degradation platform to develop new treatments for neurological conditions, such as Alzheimer's and Parkinson's. Biogen will pay C4 up to $415 million in upfront and potential milestones.

Additionally, Biogen paid $74 million upfront to Skyhawk for research services and an exclusive license to therapeutic candidates for multiple sclerosis, spinal muscular atrophy and other neurological diseases to be developed using SkySTAR platform, which offers a new approach to target neurological conditions using selective RNA-modulating small molecules.

22 ASTELLAS

Headquarters: Tokyo, Japan

twitter.com/AstellasUS

www.astellas.com
HEADCOUNT:           16,243
YEAR ESTABLISHED:      2005
REVENUES:           $11,781    (flat)
NET INCOME:          $2,249    (+22%)
R&D:                 $1,882    (-6%)

DRUGS PENDING

DRUG                      INDICATION

Xospata                   relapsed, refractory acute myeloid leukemia

PHASE III

DRUG                      INDICATION

IMAB362                   Stomach cancer, Gastro-intestinal adeno
                          carcinoma, Oesophageal cancer
Enfortumab Vedotin        Bladder cancer
Crenolanib                Gastro-intestinal stromal tumours (GIST),
                          Leukaemia, acute myeloid (AML),
                          Soft tissue sarcoma

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

ASP8374/PTZ-201           cancer
ASP1948/PTZ-329           cancer
ASP1951/PTZ-522           cancer
ASP9801                   cancer
ASP0892                   peanut allergy
ASP3772                   prevention of pneumococcal disease
ASP0367/MA-0211           duchenne muscular dystrophy
ASP1235/AGS62P1           acute myeloid leukemia
MucoRice-CTB              diarrhea prophylaxis

DRUGS COMING OFF PATENT

DRUG         INDICATION           YEAR

Vesicare     overactive bladder   2019
Myrbetriq    overactive bladder   2022

TOP SELLING DRUGS

DRUG         INDICATION              2018 SALES   (+/-%)

Xtandi       prostate cancer         $3,004       13%
Prograf      liver transplantation   $1,431       -1%
Myrbetriq    overactive bladder      $1,328       17%
Vesicare     overactive bladder      $857         -7%
Mycamine     Candidiasis             $311         -16%
Micardis     hypertension            $204         -18%


Astellas reported flat revenues of $11.7 billion for 2018. It's prostate cancer drug Xtandi was again its top seller with $3 billion in sales, up 13%, while development is ongoing to expand the indication to earlier stages of prostate cancer.

The year kicked off for Astellas closing its $450 million purchase of Mitobridge at the end of January 2018. At the time, the two companies had an existing R&D collaboration in place focused on developing drugs that target mitochondrial function. These drug candidates have the potential to treat genetic, metabolic or neurodegenerative disorders as well as conditions of aging. MA-0211, the most advanced program emerging from the collaboration, was in Phase 1 studies for Duchenne Muscular Dystrophy (DMD).

The year continued with the Japanese pharma major on the acquisition hunt and bolstering its cell and gene therapy capabilities. It acquired Universal Cells, gaining the proprietary Universal Donor Cell technology to create cell therapy products that do not require Human Leukocyte Antigen (HLA) matching, potentially overcoming a huge treatment challenge by reducing the risk of rejection.

Next, Astellas inked a deal for UK-based gene therapy company Quethera, which is focused on developing novel treatments for ocular disorders. Astellas gains Quethera's ophthalmic gene therapy program, which uses a recombinant adeno-associated viral vector system (rAAV) to introduce therapeutic genes into target retinal cells for the treatment of glaucoma.

At the end of the year, Astellas purchased Potenza Therapeutics following the successful outcome of a collaboration agreement to build a portfolio of novel immuno-oncology (IO) therapies. The clinical IO therapies developed may also provide a platform for IO combinations with Astellas' existing non-IO programs for life cycle management and future novel IO combinations. Together the companies discovered and developed three investigational new drugs (INDs) with the potential to treat various cancers that are non-responsive or resistant to the current generation of IO therapies. These programs target immune stimulation, immune checkpoint inhibition, and regulatory T cell function and include: ASP8374/ PTZ-201, an anti-TlGIT antibody and ASP1948/PTZ-329, an antiNRP1 antibody, both of which are currently in Phase I studies; and ASP1951/PTZ-522, a novel format GITR agonistic antibody, which has achieved IND clearance.

During the year, Astellas expanded its cell and gene therapy infrastructure on three fronts, beginning construction of new research, development and manufacturing facilities, in Japan and the U.S. The Center for Active Ingredient for Biopharmaceuticals will be built at the Toyama Technology Center of Astellas Pharma Tech, a production subsidiary of Astellas. It will be capable of manufacturing antibodies for use in both clinical trial materials and commercial products, while also manufacturing products that include other modalities such as cell therapy. The new Center for Multimodality CTM, at the Tsukuba Biotechnology Research Center of Astellas in Japan, will be responsibile for the manufacture of CTM for use in early-stage clinical trials designed for the purpose of developing cell therapies and gene therapies for patients in Japan, U.S. and Europe. Lastly, the Astellas Institute for Regenerative Medicine, a center of the R&D of regenerative medicine and cell therapy located in Massachusetts, will move to a new location within the state and will be upgraded.

23 OTSUKA

Headquarters: Tokyo, Japan

www.otsuka.com
HEADCOUNT:           31,800
YEAR ESTABLISHED:      1921
REVENUES:           $11,710    (+4%)
NET INCOME:            $982    (+4%)
R&D:                 $1,959    (+4%)

DRUGS APPROVED

DRUG                      INDICATION

REXULTI                   schizophrenia
Samsca/JINARC/
JYNARQUE                  Autosomal Dominant
                          Polycystic Kidney Disease

DRUGS FILED

DRUG                      INDICATION

LONSURF                   gastric cancer

PHASE III

DRUG                      INDICATION

brexpiprazole             major depressive disorder, adjunctive
                          therapy, agitation associated with
                          Alzheimer-type dementia
TAS-116                   gastrointestinal stromal tumor
ASTX727                   myelodysplastic syndrome
fremanezumab              migraine
TAS-118                   gastric cancer
SGI-110                   acute myeloid leukemia
ASTX727                   Myelodysplastic syndromes
tolvaptan                 Syndrome of inappropriate antidiuretic
hormone secretion
vadadustat                renal anemia
delamanid                 Multidrug-resistant tuberculosis
QPF-105                   Peripheral parenteral nutrition

EARLY RESEARCH PROJECTS

DRUG                      INDICATION

TAS0313                   solid cancer
TAS0728                   solid cancer
ASTX029                   solid cancer
TBI-1301                  synovial sarcoma
TBI-1501                  acute lymphoblastic leukemia
OPC-167832                tuberculosis

TOP SELLING DRUGS

DRUG                INDICATION       2018 SALES   (+/-%)

Ability Maintena,   schizophrenia,   $2,307       36%
Rexulti, Samsca     hyponatremia
Jinarc


Revenue in Otsuka's pharmaceutical segment was up 4% for the year at $11.7 billion. In the company's main area of psychiatry and neurology, sales of antipsychotic agent Ability Maintena grew 36% to $2.3 billion. Also, the new antipsychotic agent Rexulti was launched in April 2018 for schizophrenia.

Otsuka's research areas are in psychiatric and neurological diseases, hematological cancers, and kidney, cardiovascular, and infectious diseases. The company is placing an emphasis on discovery and development platforms for antibody development as a means to increase the efficiency of drug discovery across its programs and in addition to conventional R&D processes.

Towards efforts to diversify its portfolio, Otsuka acquired clinical stage biotech Visterra for approximately $430 million. The company's Hierotope platform, comprised of novel computational and experimental technologies, enables the design and engineering of precision antibody-based therapies that specifically bind to, and modulate, disease targets that are not adequately addressed by current technologies in antibody therapeutics. Visterra's pipeline includes programs targeting IgA nephropathy and other kidney diseases, cancer, chronic pain and infectious diseases.

During the year Otsuka reinforced its commitment to provide new advancements in digital medicine products and care models to address the needs of patients suffering from severe mental illness. With Proteus Digital Health, based in CA, it signed an expanded global collaboration for the further development and commercialization of a portfolio of medicines including the Ability Mycite (aripiprazole tablets with sensor) offering, which received NDA approval from the FDA in November 2017.

In another deal Otsuka America and Click Therapeutics signed a collaboration agreement for Otsuka and Click to develop and commercialize a prescription digital therapeutic for treatment of Major Depressive Disorder (MDD).This collaboration will leverage Click's ability to discover and validate a software application and deploy it commercially, with Otsuka's expertise in developing approved prescription therapies for patients with serious mental illnesses.

Otsuka says digital therapeutics align naturally with psychiatry and have significant potential to transform mental healthcare. Together, with its partners, Otsuka aims to bring to market a new offering that will provide a novel treatment for patients with MDD.

On the cancer research front, Osaka University and Otsuka Pharmaceutical entered into a licensing agreement for novel CAR-T cell therapy for multiple myeloma. It also teamed up with Takara Bio for co-development and sales rights in Japan to NYESO-1 siTCR and CD19 CAR gene therapies.

Expanding its global reach, Otsuka announced during the year the establishment of a new foreign subsidiary, Otsuka Pharmaceutical (Singapore), which held an opening ceremony on in May 2018.

24 MYLAN

Headquarters: Canonsburg, PA

twitter.com/MylanNews

www.mylan.com
HEADCOUNT           35,000
YEAR ESTABLISHED      1970
REVENUES:          $11,434    (-4%)
NET INCOME:           $353    (-49%)
R&D:                  $705    (-10%)

DRUGS APPROVED

DRUG                     INDICATION

Yupelri                  COAD/COPD
Symfi Lo                 HIV
Cimduo                   HIV treatment
Symfi Lo                 HIV treatment
Vancomycin HCL           Staphylococcal infections

DRUGS FILED

DRUG                     INDICATION

Dolutegravir,
  Emtricitabine &
    TenofowAlafenamide   HIV
BPaL                     Tuberculosis (TB)

DRUGS IN PHASE III

DRUG                     INDICATION

Aspart                   Diabetes, type I (juvenile onset)
M710                     Macular oedema
TPM/Daptomycin           Skin infections, Bacteraemia

TOP SELLING DRUGS

DRUG           INDICATION                    2018 SALES   (+/-%)

Glatiramer
Acetate        Multiple Sclerosis               $541      372%
EpiPen         Anaphylaxis,
               General allergy indications     $218       -49%
Esomeprazole
Magnesium      GERD, Ulcers                     $202      -3%
Fentanyl       Pain                             $193      -6%
Zonalon        Pruritus                         $173      13%


It was a challenging year for Mylan, plagued with valsartan recalls, remediation efforts, and ongoing drug shortages for EpiPen. Financially, the first quarter revealed the company's tribulations are far from over, with revenues down 7% to $2.5 billion and a loss of $25 million, as compared to earnings of $87.1 million in 1Q18. North America sales were down 6% and sales in Europe were down 14% primarily driven by a competitive environment and the impact of the $58.8 million Morgantown plant remediation activities, partially offset by new product sales, including Wixela Inhuband Fulphila (biosimilar to Neulasta), and increased market share on Glatiramer Acetate Injection.

On November 20, Mylan initiated a voluntarily recall of certain valsartan-containing products due to detected trace amounts of an impurity, N-nitrosodiethylamine (NDEA), (classified as a probable human carcinogen) contained in the API Valsartan, manufactured by Mylan Laboratories. Valsartan is used for the treatment of high blood pressure, heart failure, and to reduce cardiovascular mortality following a heart attack.

In December, the recall was expanded to include another 104 lots, including Amlodipine and Valsartan Tablets, Valsartan Tablets and Valsartan and Hydrochlorothiazide Tablets.

Additionally, Mylan's manufacturing license for valsartan was suspended by European authorities after NDEA was found in some batches of the hypertension drug made at the company's facility in Hyderabad, India.

Also in November, the company received a warning letter from the FDA relating to its manufacturing facility in Morgantown, West Virginia, citing problems with cleaning and quality control systems. As part of the ongoing restructuring and remediation activities, Mylan discontinued a number of products from the site while transferring some products to other sites. That being said, Mylan does not expect to have any significant new product launches from the site in 2019.

To top that off, May 10th 2019 marked one year of the EpiPen shortage, which is expected to drag on. According to a statement last August, Mylan's manufacturing partner Meridian Medical Technologies, a Pfizer company, continued to experience interruptions in the production of EpiPen (epinephrine injection, USP) and EpiPen Jr. At that time, over the past few months, there was intermittent supply as the company explored several options with Pfizer to help stabilize supply. Sterile injectables require a highly complex and technical manufacturing and assembly process and despite the company's best efforts, further supply shortages were anticipated. In June, Pfizer and Mylan announced that they are working with the FDA to extend the expiration dates by four months on all lots of EpiPen, with the exception of EpiPen Jr., in an effort to help alleviate shortages.

In more recent bad news, in May, 44 states filed a lawsuit alleging pharmaceutical companies colluded to fix the prices on their generic drugs, in which Mylan is a defendant. According to a UBS estimate, Mylan faces litigation charges of $1.1 billion.

On the bright side, Mylan and Fujifilm Kyowa Kirin Biologics Co. were granted marketing authorization from the EU for Hulio, a biosimilar to AbbVie's Humira, for all indications. Mylan plans to launch Hulio across various markets in Europe on or after October 16. Humira is the world's top-selling drug with nearly $20 billion in sales in 2018.

25 DAIICHI-SANKYO

Headquarters: Tokyo, Japan

twitter.com/DaiichiSankyoJP

www.daiichisankyo.com
HEADCOUNT:          14,887
YEAR ESTABLISHED:     2005
REVENUES:           $8,659    (flat)
NET INCOME:           $688    (-14%)
R&D:                $2,129    (+10%)

DRUGS APPROVED

DRUG             INDICATION

Vanflyta         relapsed, refractory acute
                 myeloid leukemia

DRUGS FILED

DRUG             INDICATION

Pexidartinib     bone cancer
Quizartinib      acute myeloid leukemia

PHASE III

DRUG             INDICATION

DS-8201          breast cancer
Tesetaxel        breast cancer
VN-0105          Haemophilus influenzae type b (Hib)
                 prophylaxis
Heartcel         Congestive heart failure
Pentavac         Diphtheria prophylaxisr

DRUGS COMING OFF PATENT

DRUG       INDICATION   YEAR

Nexium     GERD         2019
Relenza    Influenza    2019

TOP SELLING DRUGS

DRUG         INDICATION                 2018 SALES   (+/-%)

Lixiana      deep vein thrombosis       $1,061       53%
Nexium       GERD                       $706         -10%
Benicar      Hypertension               $486         -45%
Namenda      Alzheimer's disease        $453         3%
Injectafer   Anaemia, iron-deficiency   $399         29%
Loxonin      Musculoskeletal
             inflammation               $275         -16%
Venofer      Anaemia in chronic
             kidney disease             $261         -7%
Prolia       Osteoporosis               $247         18%
Inavir       Influenza                  $164         -28%


It was busy and transformative year for Daiichi-Sankyo, as it returns to the top 25, and 2019 is shaping up to be another year of change for the company. Daiichi recently made organizational changes to oversee strategic priorities that aim to deliver seven new molecular entities in oncology by 2025. Sunao Manabe took the helm as CEO on June 17th succeeding George Nakayama, who will continue to serve as chairman.

As part of its efforts to establish a more efficient production system and become a global pharma innovator with a competitive advantage in oncology, Daiichi transferred and sold domestic manufacturing and assets for 41 long-listed products, from antacids to antibiotics, to Alfresa Pharma Corp. for $78 million. Daiichi has been focusing on oncology, targeting 500 billion yen ($4.5 billion) in annual sales from the business in fiscal 2025 from 20 billion yen in 2017.

In June, Ministry of Health, Labor and Welfare (MHLW) of Japan approved VANFLYTA (quizartinib) for the treatment of relapsed/refractory FLT3-ITD acute myeloid leukemia (AML), as detected by an MHLW-approved test. Quizartinib is aimed at treating AML patients with a specific genetic mutation called FLT3.

However, in May, independent experts on an advisory panel to the U.S. FDA voted 8-3 against the treatment after assessing data presented by the company. The FDA is not bound by these recommendations and the NDA for quizartinib is currently under FDA Priority Review. A decision is expected by August 25, 2019. On June 24, Daiichi received a Complete Response Letter from the FDA and will determine the next steps in the U.S.

Separately, an advisory committee voted 12-3 in favor of the approval of pexidartinib, another treatment from Daiichi, that aims to treat a type of rare, non-cancerous tumor usually affecting joints and limbs. If approved by the FDA, pexidartinib would be the first and only therapy for tenosynovial giant cell tumor, which is associated with severe morbidity or functional limitations, and not amenable to improvement with surgery. Pexidartinib is among the seven new molecular entities that Daiichi is committed to delivering from its oncology pipeline by 2025.

A clinical trial collaboration with Merck KGaA and Pfizer is evaluating the combination of trastuzumab deruxtecan (DS8201), an HER2 targeting antibody drug conjugate (ADC), in combination with the checkpoint inhibitor avelumab and/or an investigational Merck KGaA, DNA damage response (DDR) inhibitor, in patients with HER2 expressing or mutated solid tumors. A separate research collaboration is evaluating trastuzumab deruxtecan in combination with avelumab, the DDR inhibitor and other investigational compounds in Merck KGaA's and Pfizer's pipelines.

Additionally, a global development and commercialization agreement with AstraZeneca is exploring trastuzumab deruxtecan for multiple HER2 expressing cancers including breast and gastric cancer, as well as non-small cell lung and colorectal cancer. The companies will jointly develop and commercialize trastuzumab deruxtecan as a monotherapy or a combination therapy. Daiichi Sankyo will be responsible for manufacturing and the supply of trastuzumab deruxtecan.
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Date:Jul 1, 2019
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