By Jennifer Van Brunt

Good things come to those who wait — especially to biotech investors, who no doubt have seen the prices of their favored stocks continue to erode in the current financing environment. However, in marked counterpoint to the market's decidedly negative opinion of biotechnology stocks, the FDA has recognized the value of the new therapeutic products coming from this industry sector.

In just the last week, the agency approved for sale two important new biotech-derived drugs: Vitravene, a treatment for cytomegalovirus infection in AIDS patients and the first antisense therapeutic ever to get FDA's blessing; and Remicade, a monoclonal antibody to tumor necrosis factor-alpha and the first drug approved specifically for treating Crohn's disease, a severe and debilitating autoimmune disorder. As well, the agency's Arthritis Advisory Committee is set to convene on Sept. 16 to review Enbrel, a recombinant soluble tumor necrosis factor receptor, for treating active rheumatoid arthritis.

Courageous investors who bought Isis Pharmaceuticals Inc. (NASDAQ:ISIP), Centocor Inc. (NASDAQ: CNTO) or Immunex Corp. (NASDAQ:IMNX) back in the early days — Isis Pharmaceuticals came public in May 1991, Centocor in December 1982 and Immunex in July 1983 — and managed to hang on to their holdings through thick and thin, are about ready to reap the rewards of their patience.

Isis Gets Ready To Make Money...

Carlsbad, Calif.-based Isis Pharmaceuticals now joins the still-exclusive club of biotech companies with products on the market. Isis will sell Vitravene through its marketing partner Ciba Vision Corp., of Atlanta (a unit of Swiss pharmaceutical giant Novartis AG). Although the market for this new drug is projected to be fairly small — analysts at SG Cowen Securities Corp., in Boston, project first full year sales of $13 million, increasing to about $100 million by 2003 — the effect on Wall Street's perceptions may be significantly larger. The Cowen analysts predict that investors may, indeed, be amply rewarded, for the approval underscores the ultimate validity of antisense technology as a means to devise new drugs — and points more directly to the earnings that Isis may generate in the future from its many antisense-derived product candidates.

...And Centocor Keeps On Coming

For Centocor, Remicade becomes its third FDA-approved product — two of which it has developed itself. The first drug, ReoPro, initially approved by the FDA in December 1994 for preventing blood clots in the setting of high-risk angioplasty, has gone on to garner approvals for broader use in acute coronary settings. And the data on additional applications continue to roll in. Centocor's marketing partner, Eli Lilly & Co., of Indianapolis — with which Centocor splits proceeds 50/50 — rang up $254 million in ReoPro sales for fiscal 1997 and $101 million in sales in the second quarter of 1998.

In February 1998, Centocor added another FDA-approved product to its arsenal when it acquired the U.S. and Canadian rights to Roche Holding AG's second-generation thrombolytic, Retavase. Centocor has guided analysts to expect 1998 sales of $55 million to $65 million for this product.

Remicade, the third product in Centocor's arsenal, could generate $35 million in sales by the end of 1998 and $156 million in 2000, according to SG Cowen's Eric Schmidt. The patient population for Remicade — those 250,000 patients with moderate-to-severe and fistulizing Crohn's disease — is obviously fairly small. But because the demand for the product is high, and the patient population is underserved, Schmidt expects rapid market penetration.

There's another potential market for Remicade, however, and this one could be much larger. Centocor is also testing the chimeric monoclonal antibody as a treatment for refractory rheumatoid arthritis. The company will present Phase III results — anxiously awaited by patients, investors and analysts alike — in November at the annual meeting of the American College of Rheumatology in San Diego.

"The Phase II results [of Remicade in rheumatoid arthritis] were strong, but we're waiting for the longer-term efficacy and safety data. Low incidences of neutralizing antibodies and lymphoma invoked caution in the Phase II trial," commented SB Cowen's Schmidt. This caution also is reflected in Schmidt's U.S. market projections for the rheumatoid arthritis indication, which he said could amount to about $3 million in 1998 (off-label use), increasing to about $100 million by 2001. "Our consultants do expect some immediate off-label use in rheumatoid arthritis, as Remicade will be on the market before Enbrel is approved," Schmidt added.

Immunex Comes Up To Bat

Analysts who follow Seattle-based Immunex's fortunes are confident the FDA's advisory committee will recommend approval for Enbrel on Sept. 16. Although there are no guarantees, there's every reason for optimism. The agency has acted with considerable alacrity in regard to Enbrel: The FDA granted fast-track status to Enbrel on March 17, 1998; Immunex submitted its biologics license application (BLA) on May 7; the agency accepted the BLA for priority review on June 22; and now it has scheduled an advisory committee meeting for Sept. 16. That's pretty fast footwork for an agency that used to be best known for dragging its feet.

But it's taken considerably longer for Immunex to bring Enbrel to this point. Immunex scientists first cloned the gene for the tumor necrosis factor (TNF) receptor in 1989. It didn't hit the clinic until 1993. The biologic is a soluble version of the TNF receptor, linked to a portion of the human immune globulin IgG1; it regulates inflammation by blocking the interaction of TNF — known to be a pro-inflammatory cytokine — with the cells that respond to its signal. It's believed to interfere specifically with the inflammatory process in rheumatoid arthritis.

Immunex has demonstrated through a series of clinical trials that Enbrel does, indeed, relieve the suffering of patients with active rheumatoid arthritis. In Phase III trials, it significantly improved all measures of disease activity, as measured by scales established by the American College of Rheumatology. It reduced pain in 71 percent and joint swelling in 51 percent of those who received treatment over a six-month period.

Those Phase III trials have been expanded into open-label trials to increase the safety database for Enbrel, explained Peggy Phillips, senior vice president of pharmaceutical development and general manager of Enbrel. Included in the open-label trials are not only adults with active rheumatoid arthritis, but also patients in earlier stages of the disease and some pediatric patients, she added. Those two patient populations are from other late-stage trials: Immunex is just getting ready to unblind the results from the pediatric trial, and intends to submit the data as a supplement to the BLA by the end of 1998. As well, the company will see the data from the early-stage disease trial in the first half of 1999 and submit another supplement to the BLA in the second half of 1999, Phillips told BioWorld Financial Watch. The data from the open-label trials — as well as data from three placebo-controlled studies — will be presented to the advisory committee, she said.

Immunex is also conducting a trial of Enbrel in combination with methotrexate, the drug most commonly prescribed now for this patient population. "This study is important because it not only demonstrates safety of the combined regimen but also an increased efficacy. It offers the opportunity to give Enbrel to patients who are already on methotrexate," Phillips said.

Taken together, the data from all the trials on Enbrel show "an incredible consistency of response," she said. "The patients respond rapidly, within one or two weeks. The response is also durable, up to 18 months [or even longer in a few cases]. And there's a continued pattern of safety."

Immunex already markets two FDA-approved drugs. Leukine — a recombinant human granulocyte macrophage-colony stimulating factor —was granted its first marketing approval in March 1991, for use in autologous bone marrow transplants. The second drug, the synthetic anthracenedione chemotherapy drug Novantrone, was approved in November 1996 for treating hormone-refractory prostate cancer. But Immunex still hasn't turned the corner to profitability — a picture that will forever change if Enbrel gets approved.

The arthritis market is huge. There are an estimated 2.5 million individuals — mostly women — in the U.S. alone who suffer from this debilitating, often crippling disease; the worldwide patient population is estimated at 5 million. Analysts project annual sales of $500 million to $1 billion for Enbrel.

Not only is there an immense group of patients, but they are 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.

Immunex is not alone in its efforts to market a new drug for rheumatoid arthritis, but it's closest to the goal. Other drugs in advanced development include Celebra, being developed by G.D. Searle & Co., the Skokie, Ill.-based pharmaceutical division of Monsanto Co., and Arava, being developed by Hoechst Marion Roussel Inc., of Kansas City, a unit of Germany's Hoechst AG. On Aug. 24, the FDA granted priority review status to Celebra, which is the first in a new class of drugs that inhibit the enzyme cyclo-oxygenase 2 (COX-2), implicated in causing pain and inflammation. And on Aug. 7, an FDA advisory committee recommended approval of Arava — a DNA metabolite that targets pyrimidines — for treating active rheumatoid arthritis in adults.

Then there's Centocor's Remicade.