By Jennifer Van Brunt

Editor

Two biotechnology companies that spent years battling in court over rights to a method for making fully human monoclonal antibodies are now set to wage a war of a different sort in the clinic. Both Medarex Inc. and Abgenix Inc. started Phase I clinical trials last month on potential new therapies for rheumatoid arthritis (RA). Both companies' products are fully human monoclonal antibodies produced in transgenic mice; as such, they are the first of a new breed of monoclonals to be tested in humans. But they are far from the only biotech-derived products in development for treating this devastating disease. While these two are the newest to enter human testing, many others are in more advanced stages of development. At the far end of that spectrum lies Enbrel, created by Seattle-based Immunex Corp. (NASDAQ:IMNX), which is already on the market. Another Remicade, produced by Centocor Inc. (NASDAQ:CNTO), of Malvern, Pa. is before the FDA for use as an arthritis treatment and has already been approved for treating Crohn's disease. Both products address tumor necrosis factor-alpha (TNF-a), a pro-inflammatory cytokine.

Medarex (NASDAQ:MEDX), of Annandale, N.J., produced its potential RA treatment, MDX-CD4, via its HuMAb-Mouse technology. The antibody, which targets CD4+ T cells, is being developed in collaboration with the Japanese pharmaceutical company Eisai Co. Ltd. That alliance, however, was originally forged in 1993 between Eisai and GenPharm International Inc., which Medarex acquired in the fall of 1997. In fact, it was GenPharm's HuMAb-Mouse technology that was the draw; through this method, it's possible to generate high-affinity, fully human antibodies to a target antigen in about three to six months.

Medarex initiated its Phase I trial in RA patients who are refractory to other therapies including one of the disease-modifying drugs on Jan. 28. The product is being tested initially as a stand-alone therapy, explained Michael Appelbaum, Medarex's CFO and executive vice president. The anti-CD4 antibody is intended to downregulate the interaction between T cells and the immune cells that promote the production of TNF-a.

GenPharm's technology was also the subject of a three-year lawsuit, initiated in 1994 by Cell Genesys Inc., of Foster City, Calif., then Abgenix's parent company (and still a majority shareholder), and settled in 1997. As a result, the parties entered an agreement that included a worldwide, royalty-free cross license to all issued and related patent applications pertaining to the generation of fully human monoclonal antibodies in genetically modified strains of mice. This resolution finally allowed each company to pursue its technology in full force. In the interim, however, many promising projects were put on hold including trials of MDX-CD4.

Abgenix (NASDAQ:ABGX), located in Fremont, Calif., used its XenoMouse technology to create its RA candidate, the human antibody ABX-IL8. ABX-IL8 binds to interleukin-8, a cytokine involved in such inflammatory states as psoriasis, inflammatory bowel disease and RA. According to Abgenix, elevated levels of IL-8 in the synovial fluid of RA patients have been reported to correlate with the number of infiltrating immune cells. And that's just where this product is going, for the protocol calls for injection of ABX-IL8 into the knee joints of a small number of patients with moderate to severe RA. The patients in this trial have already failed prior therapies, including NSAIDS, explained Jeff Davis, Abgenix's vice president of research. But they can continue taking steroids during the trial, as long as they have been stable for the 30 days prior to the initiation of antibody therapy.

Abgenix already has some relevant clinical information on the safety of its fully human antibody from its Phase I trials in psoriasis patients. Earlier this month, clinical investigator Gerald Krueger, of the University of Utah, reported those results at the Hawaii Dermatology Seminar meeting in Maui. Importantly, the product proved both safe and well tolerated, with no evidence of immune reaction (human anti-human antibody response, or HAHA) in the 33 patients with moderate to severe psoriasis included in the dose-escalating trial. A Phase I/II multidose trial is under way.

These are only a few of the many products that biotech companies are testing against rheumatoid arthritis, which afflicts about 2.5 million individuals in the U.S. alone and perhaps as many as 5 million worldwide. The market is huge and it's underserved. There is no cure for the disease and many patients stop responding to available therapies after a few years or cannot tolerate the side effects of drugs like methotrexate.

By and large, the biotech drugs under development are aimed at treating the underlying cause of RA, which is generally acknowledged to be an autoimmune disease. As such, they are not currently being positioned as first-line treatments. That ranking goes to a slew of products already on the market starting with common aspirin or ibuprofen for treating pain and inflammation. These are the nonsteroidal anti-inflammatory drugs, of which there are probably about two dozen on the market. "Most patients with arthritis go on NSAIDs," explained Anthony Butler, an analyst at New York-based Lehman Brothers. When NSAIDS lose their effectiveness, patients will often add on a disease-modifying drug, he continued. And they can use methotrexate, a cancer drug, which acts as an immunosuppressant. But when even that becomes insufficient, physicians may turn to drugs designed to counter the body's immune attack on itself, including the anti-TNF therapies such as Enbrel or even Remicade, Butler said.

Meanwhile, big pharma companies are making their mark in this market by developing drugs to treat the symptoms. One of those drugs is already enormously successful.

Initial sales of the wildly popular arthritis drug Celebrex have been so robust that the newly approved product could soon overtake even the impotence medication Viagra as the fastest-selling drug on launch. Prescriptions are being filled so rapidly that health-care analyst Hemant Shah now projects that sales of Celebrex could surpass the $1 billion mark in its first year on the market. And this is even before the official product rollout, which started just last week. St. Louis-based Monsanto Co., whose pharmaceutical unit G.D. Searle & Co. Inc. developed the drug, is co-marketing Celebrex with Pfizer Inc., of New York. Approved by the FDA on the last day of 1998, the medication is the first in a new class of arthritis drugs known as COX-2 (cyclooxygenase-2) inhibitors. It's able to treat the pain and inflammation of osteoarthritis and rheumatoid arthritis without causing the often serious side effects ulcers and gastrointestinal bleeding seen with nonsteroidal anti-inflammatory drugs.

Celebrex won't have the spotlight to itself for long, however. Merck & Co. Inc.'s COX-2 inhibitor, Vioxx, is scheduled to come before an FDA advisory panel soon, for treating pain and inflammation in a variety of conditions. And there's another new arthritis drug on the market: Hoechst AG's Arava, a DNA metabolite that targets pyrimidines, 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. *

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