By Kim Coghill

Washington Editor

GAITHERSBURG, Md. ¿ Despite a modest efficacy rate in clinical trials, a government panel recommended approval of Amgen Inc.¿s once-daily injection for symptoms and signs of active rheumatoid arthritis.

In a 6-to-2 vote, with one abstention, the FDA¿s Arthritis Advisory Committee Thursday gave Amgen, of Thousand Oaks, Calif., the go-ahead to commercialize Kineret (anakinra) for patients 18 and over. The FDA makes the final decision and is not bound by the committee¿s vote.

Much of the controversy and comments from panel members surrounded efficacy of Kineret, a recombinant human protein that antagonizes the receptor associated with interleukin-1. Rheumatoid arthritis patients produce too much IL-1, a protein that leads to bone and cartilage erosion.

¿The issue is whether the modest efficacy is worth the risk to patients who will be taking shots every day,¿ said David Felson, committee member and professor of medicine and public health at Boston University School of Medicine. ¿There are risks of pneumonia or leukopenia. This has low efficacy with toxicity greater than drugs that are already approved.¿

Felson and Jennifer Anderson, research professor of public health at Boston University, voted against approval. Ildy Katona, professor of pediatrics and medicine, and chairman of the department of pediatrics at Uniformed Services University of Health Sciences in Bethesda, Md., abstained.

Leona Malone, the committee patients¿ representative, said she supports approval because, ¿it is just the idea of having something else available. It is extremely frustrating when you hear of other products working for other people, and you have nothing.¿

Nigel Harris, acting chairman and dean of the department of internal medicine at Morehouse School of Medicine in Atlanta, said although the benefit of Kineret is modest and there are some safety concerns, ¿I don¿t feel alarmed enough not to approve [it].¿

In analyzing Amgen¿s clinical trials, the FDA reported that Kineret is helpful in reducing signs and symptoms of rheumatoid arthritis and it is generally well tolerated. A majority of patients using Kineret suffered some injection site reaction, most mild to moderate with some patients suffering severe reactions. Also, there were some instances of leukopenia.

Panel members generally agreed that as patients begin taking Kineret, there should be some guidance and monitoring of risks related to leukopenia.

Analysts suggest that Kineret potentially could generate up to $200 million for Amgen, a global company that reported $859 million in sales last quarter, up from $807 million for the same quarter 2000.

Other therapies on the market for the same indication are Seattle-based Immunex Corp.¿s Enbrel (etanercept), which generates about $730 million annually, and New Brunswick, N.J.-based Johnson & Johnson¿s Remicade, which is worth about $700 million annually. The committee today will discuss post-market trial data for both Enbrel and Remicade (infliximab).

Analysts said Kineret likely will be used by the 20 percent to 30 percent of patients who fail with Enbrel or Remicade.

Amgen filed the Kineret biologics license application in December 1999 based on Phase II data from a 419-patient study. According to the company, the study showed that 42 percent of patients who received a daily injection of Kineret combined with methotrexate achieved a meaningful clinical response compared to 23 percent in the placebo group. (See BioWorld Today, Nov. 16, 1999.)

But upon its review of the Phase II application, the FDA said inconsistencies in safety and efficacy data prompted the agency to require additional information for approval.

So on Feb. 28, 2001, Amgen submitted Phase III data from a 500-patient efficacy study and a 1,300-patient safety study.

The 500-patient Phase III trial was a randomized, double-blind, controlled study comparing Kineret (100 mg) with placebo in patients with active rheumatoid arthritis receiving stable doses of methotrexate. The trial was conducted at 106 sites in the United States, Canada and Australia, and the primary endpoint was radiographic outcome in 12 months. The larger Phase III trial of 1,300 patients was an international trial conducted at 169 sites in Australia, Belgium, Canada, Germany, Ireland, the Netherlands, Sweden, the UK and U.S. It was a double-blind, randomized, placebo-controlled study that ran three years. The hypothesis was that Kineret would not present serious safety issues.

Other Amgen products are Epogen (epoetin alfa), an anemia therapy for patients on dialysis, and Neupogen (filgrastim), used to decrease the incidence of infection during many types of cancer chemotherapy treatment.

In June, the European Commission approved Aranesp (darbepoetin alfa) for the treatment of anemia associated with chronic kidney failure including patients on and not yet on dialysis. Upon approval, it was immediately launched in Germany, the UK, Austria, Denmark, Finland, Netherlands and Sweden, and the company expects it to be available within the year in Italy, Spain and France. Amgen continues to discuss Aranesp¿s label with the FDA.