Amgen begins first leptin study in humans.

THOUSAND OAKS, Calif.--(BUSINESS WIRE)--May 20, 1996-- Amgen (NASDAQ:AMGN) today announced that it has begun human clinical trials of leptin, a recombinant form of the natural human protein produced by the obese (ob) gene and made in fat cells. Preclinical data suggest that leptin helps regulate body fat deposition and, as a result, produces weight loss through effects on metabolism and appetite.

The initial trial is designed primarily to evaluate safety and tolerability of leptin across a variety of weight categories of people who have no other medical complications. The study is being conducted at multiple centers in North America. This initial safety evaluation is likely to take until at least early 1997 to complete.

"Obesity is far more than a cosmetic inconvenience and affects one in three American adults. Millions of Americans are overweight to a varying degree, and for those most seriously overweight, obesity can be a complex, multi-faceted medical disorder and a growing health problem implicated in diabetes, high cholesterol and a variety of cardiovascular conditions," said Gordon Binder, chairman and chief executive officer.

"This study is the first step in a series over the next several years that will help define leptin's therapeutic potential as well as help us better understand the biological process of obesity," Binder added.

The start of this trial comes only one year after acquiring rights to develop and market products based on the ob gene and less than two years after that gene's discovery at The Rockefeller University in New York. "The short time frame for completion of the preclinical investigation of leptin reflects our commitment to fully exploring the potential of leptin as efficiently as possible," Binder said.

Leptin was reported in a series of articles in Science last July to reduce body weight and fat in obese mice with a defect in the ob gene as well as a lesser weight loss in normal-weight mice with no genetic defect. In addition, according to those studies, leptin normalized serum glucose, insulin and lipid levels in the obese animals who suffer from diabetes and lipid disorders.

In further unpublished studies conducted by Amgen, leptin reduced body weight and fat in normal-weight animals from several additional species. Reduction of body weight and fat in obese animals varied from substantial to insubstantial depending on the preclinical model of obesity and dose level used.

In April 1995, Amgen acquired an exclusive license from The Rockefeller University to develop and market products based on the discovery of the ob gene by a research team led by Jeffrey Friedman, M.D., Ph.D., head of Rockefeller's laboratory of molecular genetics and a Howard Hughes Medical Institute investigator.

Amgen is a global biotechnology company that discovers, develops, manufactures and markets human therapeutics based on advanced cellular and molecular biology.

This news release contains forward-looking statements that involve risks and uncertainties, including risks associated with preclinical development and other risks described from time to time in SEC reports filed by Amgen, including the 10-Q for the period ended March 31, 1996, and the 10-K for the year ended Dec. 31, 1995. -0-

Note to Editors: For more information on leptin, patients and health-care professionals can call Amgen's Professional Services Hotline (800/77-AMGEN or 800/77-26436). However, given the limited size of this first trial, callers will not be able to enroll in this trial by telephoning this number. -0-

BACKGROUNDER Leptin Development Program

Editor's Note: The purpose of the initial clinical study begun in May 1996 is to confirm the safety and tolerability of leptin in humans. Leptin's therapeutic benefits, if any, will take much longer to determine. Due to the large interest shown in leptin and Amgen's leptin program, this background document was developed to help the reader understand the objective of this first study, its likely length and the potential road map for following the leptin clinical trial program.

In May 1996, Amgen began initial human safety and tolerability studies of its recombinant form of leptin, an injected protein also commonly known as ob protein. This is the first step in what is likely to be a lengthy process of first evaluating leptin's safety and, later, its efficacy. Because leptin has demonstrated effects on serum glucose, insulin and lipid levels in some preclinical studies, it is possible that, subsequently, Amgen may decide to study the use of leptin as a potential treatment for other medical disorders that are related to obesity.

Only recently has obesity begun to be recognized as an important and complex medical problem that can lead to a variety of serious and potentially life-threatening medical disorders. Amgen is developing a new potential therapy for obesity called leptin, a recombinant form of a recently-discovered, naturally-occurring protein, believed to play a key role in regulating body weight. Several years of evaluation in humans will be necessary to fully evaluate leptin's clinical potential to treat obesity and to define more precisely its biological role in metabolism.

Medical Risk of Obesity In recent years, obesity has emerged as a major public health issue as a result of its strong links to serious diseases as well as its increasing prevalence. Individuals considered obese, people who weigh at least 20 percent in excess of their ideal body weight, are at increased risk of conditions such as non-insulin dependent diabetes mellitus (NIDDM), hypertension (high blood pressure), digestive disorders, a variety of cardiovascular ailments and certain forms of cancer. As a result, obesity contributes to an increased risk of mortality and exacts a high economic cost, estimated at more than a reported $40 billion annually in the United States. According to the third National Health and Nutrition Examination Study, an estimated 64 million adult Americans are considered obese, and another 20 million are considered overweight.

Among obese individuals with several of these associated medical conditions, weight loss has been demonstrated to have favorable effects. For example, in NIDDM, a weight loss of more than 5 percent has been shown to improve the body's sensitivity to insulin. Although commonly-used weight control methods such as diet and exercise, as well as pharmacological approaches, often produce short-term success, the goal of sustained weight loss generally remains elusive.

Ob Gene Discovery and Leptin While the mechanism through which obesity occurs is straightforward -- an inequity between the body's caloric consumption and energy expenditure -- the cause is complex, involving factors such as genetics, metabolism, neurologic states such as satiety, as well as culture, individual behavioral factors and the environment. The molecular basis for obesity in humans is unknown, although the regulation of metabolism and appetite may involve many genes. Much of what is currently known has been learned from studies in animals.

The gene that encodes for the ob protein was cloned in 1994 by Jeffrey Friedman, M.D., Ph.D., and colleagues at the Howard Hughes Medical Institute and The Rockefeller University. The discovery was part of a research effort aimed at understanding a genetic defect in a specific strain of mice that exhibited severe obesity and NIDDM. It is called the ob/ob mouse because it carries two defective copies of the ob gene.

The ob/ob mouse has been the focus of research studies at a number of institutions for more than 40 years. In early studies, researchers found that when they surgically joined together blood vessels of normal and ob/ob mice, the ob/ob mice rapidly lost weight. The results suggested the presence of biologic activity in the blood of normal mice that may play a role in regulating appetite and metabolism. The results also indicated that the biologic activity in the ob/ob mice was either defective or absent.

After many years of searching, Dr. Friedman's team pinpointed the mouse ob gene and used the sequence to identify its human counterpart. Their research was published in December 1994 in the journal Nature. Dr. Friedman named the protein product of the ob gene "leptin," from the Greek work leptos, meaning thin. Amgen acquired an exclusive license to develop and market products based on the ob gene from The Rockefeller University in 1995.

Other Recently Cloned Genes Related to Obesity The ob gene is one of several genes recently identified as playing a role in obesity in animals. One such gene is tub, which was recently cloned by two research groups. This gene codes for an intracellular protein of unknown function.

Another such gene is called fat, which encodes for carboxypeptidase E, an enzyme involved in the activation of a number of prohormones, including insulin. A defect in this gene leads to both obesity and diabetes in mice.

Another gene is agouti, which is normally involved in controlling skin color in mice and whose abnormal expression throughout the body produces obesity through a mechanism that is not known.

The db gene which produces obesity similar to the ob gene, has been found to code for the receptor for the ob protein.

It is not clear at the present time that any of these new genes represents a clearer therapeutic opportunity than leptin.

Biology of Weight Regulation The precise mechanism by which ob protein acts is unknown and remains the subject of intensive study at many institutions. Research to date suggests that ob protein is produced only in adipose (fat) tissue. The protein may function as an element of a signaling pathway that informs the brain via a receptor (thought to be the db protein) of fat levels in the body. Under this scenario, a message that fat levels are high would signal the body to increase metabolism and to suppress appetite.

A recent study published in the New England Journal of Medicine, led by a team of researchers from Thomas Jefferson University, evaluated naturally-occurring ob protein levels in normal and obese human subjects. These investigators found that ob protein blood levels correlated with percentages of body fat and were, therefore, elevated in obese individuals. Amgen studies confirm this finding. Thus, one implication may be that yet more ob protein may be necessary to overcome the inability of these individuals to respond appropriately to their endogenous ob protein levels. A parallel to this is found in Type-II diabetes, in which patients do not respond properly to their own endogenous insulin but respond to supplemental insulin. The implications of this finding on leptin as a potential therapeutic are unknown and will be determined in future clinical studies.

Therapeutic Rationale for Leptin The interest in leptin as a potential therapeutic for obesity is based in part on the ob protein's activity as a natural, circulating protein. The interest is also based in part on studies in some animal models which demonstrate that injections of leptin, a recombinant form of the protein, result in weight loss, reductions in food intake and normalized measures of body metabolism.

In the July 1995 edition of the journal Science, research groups at Amgen, The Rockefeller University and F. Hoffmann LaRoche independently reported on leptin's weight-reducing activity in normal and obese mice.

In the Amgen studies, daily injections of leptin into ob/ob mice over a 28-day period produced dose-dependent reductions in body weight, percent body fat and food intake. In addition, leptin administration normalized the animals' metabolic rates, as well as their glucose and insulin levels. In lean animals receiving leptin, there was less weight loss and no change in measures of metabolism.

Similar results, reported by the Rockefeller group, demonstrated a 40 percent reduction in body weight in ob/ob mice after 33 days of daily injections compared with no change in body weight in a control group receiving saline injections. The Rockefeller group also tested leptin in db/db mice, which have defects in the ob protein receptor, but normal copies of the ob gene. In these mice, leptin had no effect on weight or metabolism. Results of studies conducted and reported by F. Hoffmann LaRoche demonstrated weight reduction using recombinant ob protein in a mouse model of diet-induced obesity.

Clinical Trial Program Amgen began human studies with leptin in May 1996 following various preclinical studies. This initial human study, which is being conducted at several centers, is designed primarily to establish leptin's safety and tolerability. The initial study, which is being conducted under an Investigational New Drug Application (IND) submitted to the U.S. Food and Drug Administration (FDA), is not expected to be completed before early 1997. Future studies will be designed and conducted based on the findings of this first trial and will evaluate the efficacy of leptin and whether other appropriate disease targets should include diabetes, hyperlipidemia and/or cardiovascular conditions.

The clinical testing process to determine leptin's potential role in treating obesity is expected to last several years and involve an extensive series of human trials. These studies will also help advance the understanding of leptin's potential role in metabolism and appetite control.

Leptin's Place in Amgen Pipeline At the end of 1995, Amgen had seven product candidates in clinical trials. By year-end 1996, the company expects to have as many as 12 potential products in clinical trials, including leptin. The company has two products on the market: NEUPOGEN (R) (Filgrastim), which selectively stimulates the production of infection-fighting white blood cells known as neutrophils and is used to help prevent infection in cancer patients receiving chemotherapy, and EPOGEN (R) (Epoetin alfa), which stimulates the production of red blood cells and is used to combat anemia experienced by chronic renal failure patients on dialysis. Amgen has multiple product candidates in clinical development for Amgen's major areas of research focus: hematopoietic (blood cell growth) factors, neurobiology and inflammation.

NOTE: This document contains forward-looking statements that involve risks and uncertainties, including risks associated with preclinical development and other risks described from time to time in SEC reports filed by Amgen, including the 10-Q for the period ended March 31, 1996, and the 10-K for the year ended Dec. 31, 1995.

OTHER PRODUCT CANDIDATES

Hematopoietic Factors/Oncology

MGDF  Phase I/II Amgen's Megakaryocyte Growth and Development Factor, a novel platelet growth factor under study to determine whether it is safe and effective in reducing the severity and duration of thrombocytopenia (too few platelets), a side effect of some forms of chemotherapy.

NESP (Novel Erythropoiesis Stimulating Protein) 1997 Phase I (anticipated) a non-naturally occurring recombinant protein being explored for its potential to stimulate production of red blood cells.

SCF Phase III (Stem Cell Factor) may be useful in augmenting the effects of NEUPOGEN (R) (Filgrastim) in stimulating the production of stem cells, the developmental precursors of all blood cells, in cancer patients undergoing some forms of chemotherapy to reduce the number of cell collection procedures required.

CELL SEPARATOR Phase I Device used to separate tumor cells from blood removed from patients with cancer, thus reducing risk of relapse after reinfusion.

KGF (Keratinocyte Growth Factor) Phase I Recombinant form of a naturally-occurring epithelial tissue growth factor that may be useful in treating mucositis, a side effect of some forms of chemotherapy and radiotherapy in which the membranes lining the mouth, throat or gastrointestinal tract are damaged.

Neurobiology

BDNF  Phase III (Brain-Derived Neurotrophic Factor) may reduce the rate of deterioration in respiratory function in people with amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease. ALS is a life-threatening disorder that causes rapid degeneration of the motor neurons that control voluntary muscle action and respiration. BDNF is being developed with Regeneron Pharmaceuticals, Inc.

NT-3 Phase I/II (Neurotrophin-3) may be useful in treating people suffering from peripheral neuropathies (including diabetic peripheral neuropathy) to promote the survival and maintenance of sensory nerves which transmit impulses from receptors in the muscles, joints, skin and sense organs to the spinal cord and brain. It is being developed with Regeneron Pharmaceuticals, Inc.

GDNF  1996 Phase I (anticipated) (Glial-Derived Neurotrophic Factor) has been shown in preclinical studies to have potent activity on dopamine neurons in the midbrain -- the neurons whose destruction produces the symptoms of Parkinson's Disease. In other preclinical studies, GDNF has shown promise in protecting motor neurons from cell death and in stimulating improved function. Studies in humans are planned to determine whether GDNF is safe and effective in treating Parkinson's Disease.

Inflammation

IL-1ra Phase II (Interleukin 1 receptor antagonist) A recombinant form of a naturally-occurring anti-inflammatory protein with potential for the treatment of rheumatoid arthritis.

TNF-bp (Tumor Necrosis Factor Binding Protein) A potential treatment for rheumatoid arthritis.

Other INFERGEN (R) License Application filed An interferon developed to treat chronic hepatitis C.

NORCALCIN (TM) Phase I/II Potentially useful for the treatment of hyperparathyroidism (HPT), a disorder that causes excessive secretion of parathyroid hormone from the parathyroid gland, leading to elevated serum calcium or hypercalcemia. Licensed from NPS Pharmaceuticals, Inc.



CONTACT: Amgen, Thousand Oaks

David Kaye, 805/447-6692 (media)

Denise Powell, 805/447-4346 (investors)