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Talking Up a Drug for This (and That)
By
ANDREW POLLACK
THE drug Actimmune would not appear to have great sales potential. It is approved to treat only two rare diseases that together afflict just 800 Americans. Yet sales nearly tripled last year, to $106 million, and its manufacturer expects them to exceed $160 million this year. Virtually all those sales are for an unapproved use: to treat idiopathic pulmonary fibrosis, a scarring of the lungs that afflicts 50,000 to 75,000 Americans and is often fatal. The sales have stirred controversy about the drug and its maker, a small company called InterMune. Some doctors and patients hail the drug because most patients have no other treatments available and face death from the disease. Critics, however, say the company has been overselling an unproven remedy at a cost to each patient of about $50,000 a year, for injections three times a week. "We've had patients who have been desperate enough to question mortgaging their house or giving up their life savings to get this treatment," said Dr. Jonathan B. Orens, medical director for lung transplants at Johns Hopkins Hospital in Baltimore. "It's our responsibility, ethically, to make sure patients aren't given treatments and false hopes that cost a lot of money." A clinical trial completed last year suggested that Actimmune can prolong the lives of some patients with pulmonary fibrosis. But the company concedes that the results of the trial were not strong enough for the drug to be approved to treat that disease. Still, when the trial's results were announced, the company predicted that sales of Actimmune would reach $400 million to $500 million a year, even without approval. The company has also been the subject of debate among investors, and so far, the doubters have been winning. InterMune's stock has lost half its value since October, closing on Friday at $18.62. Actimmune's sales represent an extreme case of what is known as off-label use. Doctors are allowed to prescribe a drug for unapproved uses, but drug companies cannot promote such uses, though in some cases they can provide educational material to doctors. But drawing the line is tricky, and regulations are in flux. The Food and Drug Administration says restrictions on off-label marketing may conflict with the right to free speech, and it is considering relaxing the rules. Some other drugs are sold mainly for nonapproved uses. Provigil, a drug from Cephalon that increases alertness, is approved only for narcolepsy, but most of its nearly $200 million in sales last year were for sleepiness linked to other conditions. More than 90 percent of the $119 million in sales of thalidomide, from Celgene, were for cancer, not for its approved use, leprosy. Most of the $2.3 billion in sales of Neurontin, from Pfizer, are for uses other than epilepsy, for which it is approved. Cephalon and Celgene have received reprimands from the F.D.A., and Pfizer has been sued over the issue. InterMune has never been warned by the F.D.A.; the company's backers say this shows that it is playing by the rules. Executives of the company say it is only responding to demand. "We don't market it" for pulmonary fibrosis, said W. Scott Harkonen, InterMune's chief executive, in an interview. "There's been a lot of interest in the medical community, and we've responded to those requests." But there is evidence that the company has actively stirred interest. At an investors' conference in September, it said its sales force included 60 pulmonary specialists to call on every lung doctor in the country — "all in the context of our education and awareness program," a company executive said. Its annual report for 2002 said profits on Actimmune were low because of royalties and "direct costs of marketing." InterMune has sponsored dinners at which doctors hear speeches by pulmonary fibrosis experts, who mention Actimmune. It has set up booths at pulmonology medical meetings. It financed the creation of a nonprofit patient advocacy group called the Coalition for Pulmonary Fibrosis. "They are using the education loophole in a way that becomes advertising and promotion," said Michael Rosenzweig, president of the Pulmonary Fibrosis Foundation, an advocacy group based in Chicago. The company has also set up a hot line for doctors and patients to order the drug, and it helps them win reimbursement from many insurers. "We have almost always been successful" in having patients reimbursed, said Dr. Talmadge E. King Jr., chief of medicine at San Francisco General Hospital. "Most of the time we have just sent them to InterMune." Dr. Harkonen said that InterMune had no control over the content of the dinner speeches and that the other activities were expected by doctors and patients. "We are committed to being leaders in the development of new therapies," he said. "To do that, we need a presence in the medical communities." InterMune's supporters say its activities help patients and raise awareness of a disease that is hard to diagnose. If that indirectly helps the company, they add, so be it. The supporters include many leading pulmonary fibrosis experts who are advisers to InterMune. "The company, in my opinion, has done a tremendous service for the disease," said Dr. Paul W. Noble, an associate professor of medicine at Yale who has given speeches sponsored by InterMune. Dr. King of San Francisco General, who is also a professor at the University of California at San Francisco and an adviser to InterMune, said, "I've always had the feeling the company put the right information out there." Actimmune is "not a miracle drug, but it does appear to prolong life in a subset of patients." One pulmonary fibrosis patient, Alan Raff, 74, of Coral Gables, Fla., says the drug has halted the progression of his disease for three years. Speaking of InterMune's activities, he said, "I don't know what's not to like, because in some cases it's saving lives." Patients with idiopathic pulmonary fibrosis face a grim death, usually two to five years after diagnosis. The scarring of the lungs makes it harder and harder for them to breathe, until they essentially suffocate. The only proven treatment is a lung transplant, but donated lungs are scarce. Steroids are often used — also off label — but many doctors say they do not work and have side effects. The comedian Jerry Lewis, who has pulmonary fibrosis, has become bloated from the steroids. InterMune, based in Brisbane, Calif., south of San Francisco, is one of a new breed of companies that do not invent drugs but instead license neglected drugs from bigger companies. Though the company has two other drugs on the market, Actimmune accounts for the vast bulk of its sales. Actimmune is a protein called gamma interferon developed by Genentech, the biotechnology pioneer, which licensed it to Connetics, a small drug company. Dr. Harkonen, who worked at Connetics, persuaded it to license the drug to InterMune, which he formed in 1998. Though InterMune initially envisioned using the drug to treat infectious disease or cancer, its plans changed in 1999, when a paper published in The New England Journal of Medicine reported striking results from a small trial for pulmonary fibrosis. The trial had only 18 patients, but the 9 who received the drug all had improved lung function, while those in the control group worsened. The company also started the Coalition for Pulmonary Fibrosis, the advocacy group. As first reported by TheStreet.com, the executive director, Mark Shreve, worked for Edelman Public Relations, which represented InterMune, and the coalition at first was based in Edelman's San Francisco office. The Internal Revenue Service filing for 2001 from the coalition reports only one donation — $187,000 from InterMune — with $170,000 of it being paid to Edelman. In an interview, Mr. Shreve said that he had quit Edelman and now ran the coalition from his home near Scottsdale, Ariz. He said that there were now many other donors. The coalition's chairman, Dr. Marvin Schwarz of the University of Colorado, also an InterMune adviser, said the group was not a marketing front. "The coalition has never made a statement about the drug that I'm aware of," he said. The big trial, involving 330 patients, ended last year and was intended to see whether the drug improved lung function. But the lungs of those who took Actimmune were not significantly better than the lungs of patients who received a placebo. Somewhat unexpectedly, however, patients who took Actimmune often lived longer. That result was not statistically significant over all. But in a subset of patients with milder disease, there was a large and statistically significant difference: only six who got the drug died, compared with 21 who got a placebo. The company trumpeted the results in a news release in August. The stock soared, nearly doubling by the end of October. A committee of independent doctors who had monitored the trial to assure patient safety quickly accused the company of exaggerating the drug's benefits while playing down side effects, like a greater incidence of nonfatal pneumonia, doctors involved in the trial say. Dr. Thomas R. Fleming, a biostatistician at the University of Washington and the chairman of the committee, said that he was bound by a confidentiality agreement. But he said, "I do think the subsequent reports the company has given do provide a much more detailed perspective of what was learned at the trial." The results have led to a quandary for doctors and patients. Some doctors say it is dangerous to jump to conclusions about survival because the trial was not designed to measure that. Skeptics also wonder how the drug could prolong life if it did not improve lung function. "It's not clear what to make of the mortality data," said Dr. Fernando J. Martinez of the University of Michigan, an adviser to InterMune. He said he suspected that the drug did have some effect, but he has concerns that company marketing officials continue to provide snippets of data before complete results have been published. Still, some doctors say the hint of a survival benefit is too strong to ignore. "We're talking about a population that has no shot," said Dr. Richard Miller, chief of pulmonology at St. Michael's Medical Center in Newark. "Something is better than nothing." InterMune has said that 3,000 patients were being treated with Actimmune at the end of 2002, up from 2,500 three months earlier. Some doctors say that even if the drug does not work, it is worth trying because it is generally safe. But French doctors reported recently that four patients who took the drug had deteriorated rapidly and died. Those patients, however, were far sicker than the ones in InterMune's trial. Karen Burnard of Finesville, N.J., said she thought Actimmune had contributed to the death in March of her brother, Jack Dwyer, a 64-year-old middle-school teacher who lived in Alloway, N.J. Actimmune made him sick and unable to eat, Ms. Burnard said. "Food tasted like metal, and by the end he had lost 57 pounds," she said. He stopped taking the drug, she said, but by then was too sick to qualify for a lung transplant. Recent developments have dimmed Wall Street's view of the company's prospects. In January, InterMune announced that the survival benefit conferred by the drug on patients with milder disease had diminished somewhat when they were followed for three to five additional months, though the difference was still statistically significant. At the end of January, David A. Cory, the senior vice president for sales and marketing, left InterMune, the company said, to "pursue other opportunities." On March 31, the company said in its annual report that it no longer believed that Actimmune could achieve $400 million to $500 million in annual sales based on the clinical trial results. Moreover, competition is developing. Among the drugs expected to be tested are Tracleer, sold by Actelion of Switzerland for pulmonary hypertension; Gleevec, the promising cancer drug from Novartis; and Enbrel, the big-selling arthritis treatment from Amgen. InterMune has said that it is planning another trial, so it will be at least three years before it can seek F.D.A. approval for Actimmune's use in pulmonary fibrosis. Investors will be closely watching InterMune's first-quarter results, to be announced on Tuesday, and presentations at the American Thoracic Society meeting in mid-May. In a news release, the company has promised that exciting data will be announced there that may explain how Actimmune works. That may persuade the doubters and promote its use. But the debate among doctors and patients and on Wall Street is likely to continue. Copyright
© 2002 Global Action on Aging
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