By Randall Osborne

Editor

A contest for shares of the rheumatoid arthritis (RA) market is shaping up, as Amgen Inc. steps into the fray with Phase II data that the company plans to use in its application to the FDA for a biologics license to market Kineret.

The drug is an interleukin-1 (IL-1) receptor antagonist. Others, such as Centocor Inc.'s Remicade (infliximab) and Immunex Corp.'s Enbrel (etanercept), work by blocking the activity of tumor necrosis factor (TNF), the second cytokine implicated in RA.

Amgen faces the usual challenge of distinguishing its drug in the marketplace by pointing to superior efficacy and safety if the data justify such claims as well as a larger task of convincing physicians and patients that the IL-1 strategy is more than worthwhile.

Jay Silverman, senior analyst with BancBoston Robertson Stephens in New York, said Amgen has a formidable job ahead.

"The robustness of the data [for Kineret] doesn't look as good as it did for Enbrel, or in some cases as good as Remicade, either," Silverman said. "It might be a drug of last resort, or one that could complement TNF inhibitors."

Amgen, of course, is loath to place Kineret in such a category although David Kaye, the company's associate director of corporate communications, acknowledged the task of gaining acceptance for the IL-1 drug among doctors and patients.

"There's a debate," he said. "We haven't had any new drugs in several decades, and the first ones out of the chute are TNF blockers. So people are thinking if you block TNF, you do the job. Immunex and others are doing a good job of making people focus on TNF [drugs] but, increasingly, they are remembering there's that other side of the equation."

The "other side" includes not only a new method of attack on RA, but decreased side effects. A 419-patient study, results of which were presented at a recent scientific meeting on rheumatology, showed 42 percent of patients receiving a Kineret injection once a day, when combined with methotrexate, achieved a meaningful clinical response, compared to 23 percent of those given placebo injections.

"Physicians ultimately will be the people who compare the safety and efficacy profiles, but we've seen no infection or sepsis issues at all," Kaye said. "The most commonly occurring side effect is an injection-site reaction."

The response to Kineret was impressive enough that Amgen entered into talks with the FDA, and then decided not to move ahead with a formal Phase III trial, Kaye said.

"It's a little unusual," Kaye said. "These trials, while one could consider them pivotal, were not designed as licensing trials."

Amgen has completed a European Phase II study, data from which have been published, and another Phase II study, data from which were disclosed at the rheumatology meeting.

"We compared multiple doses, [whereas] in most Phase III trials, you know your optimal dose, and you go forward with one dose to substantiate efficacy from earlier trials," Kaye said. "Even though we had 400-some patients, each dose cohort is not that large. Having said that, we've now done the two pivotal trials, and that's what we're going to file with. [The FDA has] agreed to look at the data in a submission."

Silverman said moving straight from Phase II trials into a regulatory filing is not unprecedented, but is "a little rare. They are large trials; combined, they are bigger than any of the Immunex or Centocor Phase IIIs." The distinctions between Phase II and Phase III trials have become "somewhat vague" anyway, he said.

Amgen will conduct follow-up studies, which will cut into the money saved by skipping the Phase III studies, but "even if [the company] saves $10 million or up to $50 million, it's not a lot of money for Amgen," Silverman said. "The more important thing is the time factor. Three or four months ago, [Kineret] wasn't on anybody's radar screen. It came out of nowhere. That [Amgen] can file on that data, and get the drug on the market by the end of next year, is the key."

Silverman said he expects Amgen to file a regulatory submission before the end of the year. "Then there's the 12-month window [before approval]," he said. "Because there are drugs out there, I don't know if it will get expedited."

Kaye said that, even for Amgen, the advantages are double to asking for approval on the basis of Phase II data, rather than on the more costly Phase III numbers. The strategy cuts costs and, therefore, risk.

"There are many drugs that looked good in Phase II that tanked in Phase III, and I don't know that we track how much individual trials cost," Kaye said. "It could be $20 million or more in a large Phase III trial."

Silverman named Remicade and Enbrel as Kineret's two main competitors in the treatment of RA, which affects more than 2 million people in the U.S., causing pain, swelling, stiffness and loss of function in the joints.

Remicade was approved earlier this month for use with methotrexate, in RA patients who do not respond to methotrexate alone. Analysts have said Remicade is likely to fall behind Enbrel, with estimated sales of about $150 million and $450 million, respectively, in a market that includes about 400,000 patients with severe forms of the disease.

Enbrel was approved and launched in November 1998 to treat moderate to severe RA that has not responded well to other treatments. The drug also was approved to be used with methotrexate. In May, the FDA included children and teen-agers (aged 4 through 17) in the indication for the treatment of moderately to severely active polyarticular-course juvenile rheumatoid arthritis.

In July, Immunex filed a supplemental biologics license application for Enbrel, seeking approval for an indication that shows Enbrel slows structural damage and improves the signs and symptoms of early, active disease. The new filing is based on a Phase III study that included 633 RA patients who had suffered from the disease for less than three years and had never been treated with methotrexate.

Kaye said the attention given to Enbrel and Remicade has caused another competitor to be overlooked. "I don't know why you don't include Arava," he said.

Hoechst AG's Arava, which is also a TNF inhibitor, was approved in September 1998. The German pharmaceutical giant demonstrated that the disease-modifying drug Arava can slow the progression of joint damage in severely arthritic patients.

Other strategies are being tried against RA. Valentis Inc. and Boehringer Ingelheim GmbH in September formed a collaboration to explore gene therapy for the disease, for example, but did not disclose details of the effort.

Silverman said that, although Kineret may be regarded by some as an also-ran, the drug is likely to gain increasingly wider acceptance.

"At the end of the day, it will find its niche," he said.