ENBREL

It targets tumor necrosis factor or TNF,a boodstream protein that causes much of rheumatoid arthritis' inflammation, by sopping up excess TNF before it can damage patient's joints.

Minocycline also partially blocks TNF alpha

MONTREAL, QC -- June 25, 1998 -- A study of Immunex Corp.'s Enbrel(TM) shows that the drug was generally well-tolerated by rheumatoid arthritis patients receiving long-term therapy with dosing up to 18 months.

These new interim open label data were presented at the annual Pan American Congress of Rheumatology (PANLAR) meeting in Montreal, QC., by Dr. Larry Moreland, a rheumatologist and investigator at the University of Alabama at Birmingham.

Rheumatoid arthritis disease activity was also measured in this on-going open-label safety study. Seventy-two patients completed 18 months. Ninety-three percent experienced 20 percent reduction in tender joints, and 88 percent experienced 20 percent reduction in swollen joints. Seventy-five percent of the patients experienced 50 percent reduction in tender joints and 74 percent experienced 50 percent reduction in swollen joints. Injection site reactions were mild and infrequent. Adverse events were not outside of those expected in this population, and are consistent with other Enbrel studies.

This open-label study includes 105 patients, 72 of whom have now completed 18 months on Enbrel. There are 11 study sites in the United States.

Designed to evaluate the long-term safety and activity of Enbrel for the treatment of RA, patients were treated with 25 mg of Enbrel twice weekly in this on-going study. Patients qualified for participation in this study had active RA and had failed at least one DMARD. In addition, patients had to have been previously treated with Enbrel in other trials of the drug. These results are based on investigational data as analysed by Immunex. These data have not been reviewed by the FDA as part of an application for regulatory approval.

Rheumatoid arthritis is a devastating disease that affects 2.5 million people in the United States and five million people world-wide. It is a disease of the immune system that occurs more often in women than men and has no known cure. The economic impact of this disease is also significant, since patients may begin to develop the disease in their 30s or 40s. In a recent study, 50 percent of RA patients became disabled and were unable to work 10 years after diagnosis.

Enbrel is thought to interfere specifically with the inflammatory process in RA. In RA, excess TNF combines with cell surface TNF receptors and produces a cascade of damaging inflammatory effects on joints.

Enbrel is a protein-based drug comprising only human amino acid sequences. Enbrel is a recombinant version of the soluble human p75 TNF receptor, linked to the Fc portion of human IgG1. It competitively inhibits the binding of TNF to its cell surface receptors, and thereby inhibits TNF biologic activity.

WASHINGTON, MD -- November 10, 1997 -- Immunex Corporation announced the results of a Phase III clinical study and a 12-month safety study of an investigative new treatment for severe rheumatoid arthritis (RA) called Enbrel(TM), showing that the drug reduces painful joint counts in 50 percent of its patients.

Data from these studies were presented at the 61st Annual Science Meeting of the American College of Rheumatology (ACR), taking place in Washington, D.C. this week.

The patients studied suffered from advanced RA and had already failed at least one, but no more than four disease modifying, anti-rheumatic drugs (DMARDs). Ninety percent of the patients had previously been treated with methotrexate -- a mainstay of RA treatment. Of the 2.5 million Americans with RA, approximately 500,000 fit into the advanced category. The results of the Phase III and 12 month study are consistent with the results of previously reported Phase II data published in the New England Journal of Medicine on July 17, 1997.

The Phase III study was a double-blind, placebo-controlled and randomized trial that studied the effects of six months of Enbrel therapy. This pivotal study included 234 patients at 13 sites. Enbrel was administered by subcutaneous injection twice per week throughout the six-month period. The patients were divided into three groups: the first received a placebo; the second received 10 mg doses of Enbrel; and, the third received 25 mg doses of the drug. Primary and secondary endpoints of the study were met.

In the Phase III study, patients with advanced RA treated with the 25 mg dose experienced a 71 percent reduction in their painful joint counts compared to patients in the placebo group who experienced only a six percent reduction. Reduction in swollen joint counts was experienced by 51 percent of patients treated with the 25 mg dose, while patients on placebo experienced a two percent reduction. Patients treated with the 10 mg dose experienced a 55 percent reduction in their painful joint counts and a 49 percent reduction in swollen joint counts. Numbers reported are median values.

In the 12-month study, both the tender and swollen joint counts declined early in the treatment. This improvement was for as long as 12 months. As part of this long-term safety study, more than 50 patients have been treated with Enbrel for 12 months. The drug was found to be generally well tolerated, with primarily non-complicating side-effects.

Select measurements of RA symptoms, including joint pain, joint swelling, and patient and physician global assessment, are combined in a composite score called American College of Rheumatology (ACR) 20. A 20 percent improvement in ACR response is used to measure patient improvement and was the primary endpoint at three months in this study. In the Phase III study, 62 percent of the patients in the 25 mg group reached 20 percent improvement by ACR criteria, compared to 23 percent of the patients in the placebo group. Of patients who were treated with the 10 mg dose, 45 percent experienced at least a 20 percent improvement.

A secondary endpoint measured the percentage of patients reaching 20 percent improvement by ACR criteria after six months of treatment. At that point in time, 59 percent of patients reached ACR20 at the 25 mg dose, compared to 11 percent on placebo. Fifty-one percent of the patients at the 10 mg dose reached ACR20 at six months.

The Phase III study also reported how many patients experienced a 50 percent improvement on these composite measurements, called ACR50. After three months of treatment on Enbrel, 41 percent of the patients receiving the drug at the 25 mg dose had at least a 50 percent improvement, compared to eight percent of the placebo group. At the six month time point, 40 percent of the patients receiving the 25 mg dose had 50 percent improvement, compared to five percent of the placebo group having similar improvement. Of patients receiving the 10 mg dose, 13 percent reached ACR50 at three months and 24 percent reached ACR50 at six months.

To qualify for the Phase III study, patients had to have active rheumatoid arthritis at screening. Also, doses of corticosteroids and/or non-steroidal anti-inflammatory drugs (NSAIDs) were kept stable for any patients who were receiving such treatment. Patients in the study had not received DMARD therapy for at least a month prior to beginning treatment with Enbrel. Side effects reported during the study were generally minor and did not complicate the treatment. Most frequently reported were injection site reactions and minor colds. All colds resolved without interruption of therapy and no patients dropped out of the study due to them.

Rheumatoid arthritis affects 2.5 million people in the United States and five million people worldwide. It is a disease of the immune system that occurs more often in women than men. There is no known cure, and current drugs do not address the underlying cause of the disease. Unfortunately, many patients stop responding to, or cannot tolerate the side effects of, current therapies after a few years. The economic impact of this disease is also significant for patients who may begin to develop the disease in their 30s or 40s. Some patients are unable to work 10 years after a diagnosis of rheumatoid arthritis.

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