By Jennifer Van Brunt

Editor

Leading biotechnology company Amgen Inc. (NASDAQ:AMGN) reported another quarter of solid earnings last week. Its earnings per share jumped by nine percent from the first quarter of 1997, from $0.65 to $0.71. Sales of its two lead products continued to improve, as well. Red blood cell booster Epogen came in at $304 million, up four percent from the first quarter of 1997. And Neupogen, a white blood cell booster that has just received approval from the FDA for its fifth indication, reaped sales of $261 million for the quarter, a gain of seven percent from the comparable quarter last year. Both these drugs are billion-dollar blockbusters, a status that each first attained in 1996.

Sales of Amgen's newest drug, however, are far from encouraging: Infergen, a non-naturally occurring, consensus alpha interferon for treating chronic hepatitis C infection, managed to garner only $1 million in sales for the first quarter of 1998. This was less than it reaped in 1997 — between FDA approval in October and the end of December, Amgen recorded $3 million in Infergen sales, much of which the Thousand Oaks, Calif. company attributed to pipeline-filling.

This low volume of Infergen sales is actually not unexpected. In fact, according to biotech analysts who follow Amgen's fortunes — as well as the company's CEO himself — the product has entered a market arena that is already occupied by two entrenched products for the same indication. "Infergen is going up against well-established competitors, so it's uptake [by the market] is slow," explained CEO Gordon Binder in an interview on CNBC last week. This is a different type of market for Amgen; the product is not the first of its kind to hit pharmacy shelves and it may never get to be a blockbuster.

Those competing products already on the market — Madison, N.J.-based Schering-Plough Corp.'s Intron A (recombinant interferon alpha-2b) and Nutley, N.J.-based Hoffmann-La Roche Inc.'s Roferon-A (recombinant interferon alpha-2b) — have already established a firm hold. Intron A was approved for treating chronic hepatitis C infection in February 1991; Roferon was approved for that indication in November 1996. But Infergen will have to do more than just carve a wedge out of the competitors' pie to really establish a significant presence as a therapy for treating chronic hepatitis C infection. It will also have to be proven superior in performance. And, for a variety of reasons, that's turning out to be a tough task.

An Insidious Disease

Many of those reasons center on the nature of the disease itself and the difficulties inherent in treating it. Hepatitis C virus (HCV) infection is a serious health problem, in the United States and elsewhere in the world. But although the disease and its outcomes — especially cirrhosis of the liver and even liver cancer — have been recognized for some time, the actual identification of the hepatitis C virus did not occur until 1989. Government agencies estimate that about four million individuals in the United States (and a staggering 100 million worldwide) are chronically infected with the virus; of those four million, roughly 8,000 - 10,000 die every year. About 85 percent of those infected will develop chronic liver disease, and of those about 10 to 20 percent eventually develop cirrhosis. Of those, from one to five percent will develop liver cancer. Before identification of the virus per se, most individuals in the U.S. contracted the virus through donated blood and blood products, with sexual transmission and sharing of needles by drug users contributing to the overall number of cases. Even though the nation's blood supply is now routinely screened for HCV — a practice that has reduced the overall incidence of infection — there are still about 30,000 new cases each year in the U.S. And since most individuals infected with HCV don't even know they have the disease, and symptoms might not appear for 20 years, there's a huge number of potential patients now incubating.

In fact, the crisis is so real that the newly appointed Surgeon General David Satcher warned Congress about it in his speech last month. Satcher told Congress that he has "directed the Centers For Disease Control and Prevention to develop educational programs for health care professionals and for the public at large to support recognition, diagnosis, counseling and testing of those at risk...We will aggressively pursue the people we believe have been exposed."

Therapies Less Than Perfect

Unfortunately, even the FDA approved therapies don't work in all patients. It's estimated that only about 20 to 30 percent of chronically infected individuals actually respond to alpha-interferon therapy. And of those patients who do respond to alpha-interferon therapy, only about 10 to 20 percent attain durable responses as defined by a continued absence of viral RNA in the blood six months after the full treatment regimen.

The side effects are unpleasant enough that many potential patients refuse treatment or stop therapy once they have begun. These include fever, headache, muscular pain, anorexia, fatigue, chills, weakness, nausea, hair loss, depression and even dramatic personality changes.

There's obviously a lot of room for improvement in therapy for HCV infection. And that's what Amgen is aiming to accomplish with Infergen. According to a December 1997 report by biotech analysts Tim Wilson and Eric Schmidt, of New York-based UBS Securities LLC, Amgen is basing its initial commercialization effort with Infergen on two factors: That Infergen produces better clinical outcomes than the competing alpha interferons in the most prevalent hepatitis C genotypes in the U.S.; and that the repeat treatment outcomes data with Infergen are superior to those with the competing agents.

According to Schmidt's report, Infergen clearly produces better end of treatment results than Intron A on the genotypes that are most prevalent in the U.S. (genotypes 1a and 1b); however, it is not statistically different than Intron A at producing sustained responses in those genotypes.

New Data

Like its competitors with FDA-approved drugs (and many more with experimental therapies), Amgen has continued to study its therapy in the clinic. The latest clinical study, conducted at the University of Miami School of Medicine and other locations, focused on the retreatment of HCV-infected patients with Infergen. The data have just been published in the April 1998 issue of the journal Hepatology.

This was an open-label study; it assessed the ability of a high dose of Infergen to elicit a sustained response in patients with chronic hepatitis C infection who had either not responded to previous interferon therapy or had relapsed after discontinuation of therapy (with either Infergen at the FDA-approved, nine microgram dose or with Intron A, three million units).

The results demonstrated that after 48 weeks of treatment with a high dose of Infergen — 15 micrograms — nearly 60 percent of patients who initially responded to interferon treatment but eventually relapsed, successfully achieved a sustained response. The study also showed that even some patients who had not responded to previous interferon therapy were able to respond to treatment with high-dose Infergen for 48 weeks. As well, the side effect profile was no worse than usual.

"Our data demonstrate that a higher dose of Infergen is safe and effective and can achieve a meaningful sustained response in hepatitis C patients who have failed or relapsed following previous interferon treatment," explained K. Rajender Reddy, a University of Miami professor and a co-author of the Hepatology article. According to Reddy, the majority of patients who relapse do so within three months following the completion of therapy; thus, a virus-free sustained response six months out is meaningful.

However, it's impossible to actually ascertain whether Infergen is a more effective therapy than Intron A because the two drugs were not studied in a head-to-head trial. "There are a few reasons to believe that Infergen might be better than conventional interferon based on in vitro studies that demonstrate it has higher antiviral potency," Reddy told BioWorld Financial Watch. "But to prove that in the clinic, one would have to do a head-to-head comparison with comparable doses."

According to the UBS report, Infergen clearly produces better end of treatment results than Intron A on the genotypes that are most prevalent in the U.S. (genotypes 1a and 1b); however, it is not statistically different than Intron A at producing sustained responses in those genotypes. As well, the results of the retreatment trial appear to be only marginally different than those obtained with other alpha interferons in the treatment of relapsed patients, although they are better than the results obtained in prior studies on retreating non-responders. Schmidt concluded that Amgen's retreatment data may provide it with a modest marketing advantage in the retreatment of non-responders, but not with relapsed patients.

The Field

Amgen has already filed for an expanded label to increase the duration of treatment of Infergen; in fact, it did so well before the FDA approved the six month regimen for Infergen last October. Intron-A is currently approved for 18 to 24 months' of administration and Roferon-A has been approved for 12 months' treatment. But the National Institutes of Health, which convened a National Consensus Development Conference on Management of Hepatitis C in March 1997, has recommended that non-responders should not be retreated with alpha interferon alone but rather be enrolled in clinical trials of investigational combination therapies. This includes most particularly the combination of Intron A with ICN Pharmaceuticals Inc.'s Rebetol (ribavirin); recent clinical trials have demonstrated that the addition of ribavirin greatly enhances the efficacy of Intron A — apparently it nearly doubled the sustained response six months after treatment. On the down side, the side effect profile seems to be even more noxious than that for Intron A alone. And that could well signify that there's still room for competition — especially from Infergen.

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