EULAR congress had major focus on rheumatoid arthritis.
Tofacitinib: First-in-Class; Awaiting FDA Approval
Dr. Joel Kremer, chief of medicine at Albany Medical College in N.Y., reported on Pfizera[euro](tm)s JAK3 inhibitor tofacitinib (formerly tasocitinib). The Janus kinase (JAK) pathway contributes to systemic inflammation, and therefore targeting this intracellular pathway helps to reduce the symptoms of RA. Dr. Kremer stated "we hope that after carefully considering the benefit/risk equation, this compound will provide an additional valuable treatment option for patients who have experienced inadequate response to prior treatments." Data from the late-breaking abstract demonstrated that in a Phase III, 6 month study, tofacitinib reduced the signs and symptoms of RA in three primary endpoints compared to a placebo. In the first primary endpoint, the 315-patient treatment cohort improved with an ACR20 response of 52%, while on the twice daily 5mg dose compared to the placebo group (no response reported).
In the second primary endpoint, clinical remission of disease was achieved by 11% of patients on 5mg tofacitinib twice daily, who scored less than 2.6 on the Disease Activity Score compared to 2% of patients on the placebo. In the third primary endpoint, patients receiving 5mg tofacitinib showed a 0.46 decline in Health Assessment Questionnaire Disability Index scores compared to a 0.21 decline in placebo patients. Even though this study did not include an active comparator, previous studies indicate that tofacitinib is comparable to Humira in terms of efficacy. According to Pfizer, tofacitinib has more safety data available, given its stage of development, than any other RA drug currently on the market. The company also maintains that tofacitinib has a safety profile that is comparable to Humira despite there being 12 deaths in Phase III trials, two of which were cardiac related.
Even with serious adverse reactions involving cardiac and liver events, we expect that tofacitinib will gain FDA approval in late Q3 2012. However, the agency has raised questions about both the safety and efficacy of this drug, and may require some level of post-market surveillance as part of the approval process. Given these unresolved issues, tofacitinib will likely be limited to patients that are TNF- inhibitor-naA-ve or early diagnosed until additional long-term safety data is available.
TAK1: A Potential New Pathway and Drug Delivery Method
The signaling kinase pathway known as TAK1 or transforming growth factor-beta as a novel drug target for RA was discussed by Gabriel Courties, MS, of the INSERM laboratory in Montpellier, France. TAK1 is a downstream mediator of the response of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF) which are pro-inflammatory cytokines found in RA. Early stage results of the small interfering RNA molecule (siRNA) TAK1 inhibitor in animal models showed reduction in Th1 and Th17 lymphocytes by 35% and 75% respectively, compared to placebo animal models. Clinically, the TAK1 inhibitor reduced inflammation and cartilage and bone erosions. Reductions in inflammatory cytokines IL-6 and TNF were also reported. This type of therapy generally does not have a systemic effect on the entire immune system if the siRNA is stable due to chemical modification, therefore it will be beneficial to RA patients who are susceptible to high co-morbidity, thus meeting an unmet need for the treatment of adult RA.
There are no siRNA-derived therapies approved for the treatment of adult RA, and therefore GlobalData believes this selectively delivered therapy of immunomodulation will be of interest to follow through clinical studies.
Revising the ACR Guidelines Towards Early Treatment Paradigms
A recommendation for the revamp of the 1987 ACR diagnostic criteria was discussed by a 22-member joint task force designated by the ACR and EULAR committees. GlobalData feels this task-force must make a committed goal to approve and release new guidelines in the near future to coincide with that of the recent update to the 2008 ACR treatment recommendations. The task force stressed that if the ACR guidelines are revised, physicians will be able to turn to the already familiar serological tests which look for RA biological markers (including rheumatoid factor and anti-citrullinated protein antibodies) to identify which patients may respond to disease-modifying drugs (DMARDs) such as the gold-standard, first-line methotrexate. Utilizing these tests right away, instead of relying on features such as joint erosion and subcutaneous nodule signs, will allow aggressive treatment before the disease becomes chronic and causes irreversible joint damage.
In this new model, the committee also identified several levels of joint involvement that are in such the pattern of the joint involvement that indicates the development of RA. The panel of experts said that joint involvement specifically in the wrist and knuckles, acute-phase reactants, and serological markers were the greatest predictors of RA. The group agreed that classic signs and symptoms of morning stiffness and duration of symptoms were not influential as predictors. The new criteria can also take into account geographic differences and other variations in the way RA presents in the clinical setting. The validation can be established by studies using patient cohorts, retrospective epidemiological studies, or clinical trial data.
In the end, it seems as though the experts agreed with Dr. Alan Silman of the University of Manchester in England as he said, we can't wait two years, we probably can't wait a year, before a diagnosis...our aim is to prevent the disease...we should be treating with disease-modifying drugs to prevent chronicity, to prevent damage". (PR)
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|Title Annotation:||European League Against Rheumatism|
|Date:||Jul 14, 2012|
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