Dec. 21, 1999 (Atlanta) -- An experimental anti-HIV drug was moderately effective and too toxic for at least half the people who took it, but was it withdrawn from further development too soon? A study of the drug, published in The Journal of the American Medical Association (JAMA), shows that the drug might have been able to help HIV-infected people for whom other treatments no longer worked.
Gilead Sciences Inc. discontinued U.S. development of the drug, adefovir dipivoxil, after failing to win the approval of an FDA advisory committee. It was the first time such a committee ever rejected an AIDS therapy. The drug is still being considered as a possible treatment for hepatitis B.
The published study findings show that adefovir was effective when added to existing treatments in patients whose HIV levels remained high. But 60% of patients developed signs of kidney toxicity after taking the drug for 24 to 48 weeks.
"This particular drug shows potent antiretroviral activity in patients with HIV when given in combination with other agents," study co-author Stephen W. Lagakos, PhD, tells WebMD. "It can add to the existing antiviral effect of other drugs, that's very good. On the other hand, this drug has a side effect that occurs in a high percentage of patients that is not good."
Based on these results, adefovir would not be an appropriate first-line therapy. However, there currently are very few salvage options for patients failing other agents. Lagakos believes that the trial results show adefovir could be useful in such a setting.
"Patients who have failed on other antiretroviral drugs are in a desperate situation," says Lagakos, a researcher at the Harvard School of Public Health. "At some point people need help, and this drug has been shown to be effective in patients who have failed other drugs. There is a real risk of side effects, but they are reversible if you are aware of them."
There is evidence from other, smaller studies that a 60 mg dose of adefovir might be less toxic and have a lower incidence of side effects than the 120 mg dose used in the study. But this evidence, along with Lagakos' study, was too thin for an FDA advisory committee, which last month voted 13 to 1 against recommending adefovir for accelerated approval. Earlier this month, Gilead withdrew adefovir from further U.S. development (an application for European approval is still pending).
"It might be possible for [adefovir] to work at a lower dose level, but it's not clear," Lagakos says. "It may be this was the wrong dosage of this drug to test."
Lagakos believes that the committee gave too little consideration to the findings of the large trial now published in JAMA.
"The evidence in this study was unequivocal," he says. "I was very surprised by the advisory committee's findings. I am very concerned that they made the wrong decisions, unless there is data that I haven't seen."
Gilead spokeswoman Sheryl Meredith said the firm was disappointed by the advisory committee's findings. "We were very disappointed, given the basis of our application, that they were unable to see the positive risk/benefit ratio for this drug," Meredith tells WebMD. "We were encouraged by that study that adefovir would be able to benefit patients with few other options. We had nearly 10,000 patients that had enrolled in our expanded access program. There was clearly the need for a new compound."
Accompanying the study report is an editorial by John W. Mellors, MD, chief of infectious diseases and director of the AIDS program at the University of Pittsburgh Medical Center. The editorial suggests, but does not directly state, that careful analysis of the risk/benefit ratio for adefovir might have led to different conclusions than that of the FDA panel.
"I think that [adefovir] was a marginal drug, but it might have had a niche in those who [had tried many other treatments] with no other treatment options," Mellors tells WebMD. "It gets down to the question of whether you withhold salvage therapy from people with no other options."
The Mellors editorial also made the point that the FDA panel intended to send a message to drug companies that just because a drug is urgently needed, there must be sufficient data to justify its use.
"I think the message should be out there that we have to know the safety and activity at the indicated dose," Mellors says. "Just because the situation is extreme, the standard shouldn't be lowered for approval. That's the clear message that should get out."
At the same time, Mellors does not want drug companies to become discouraged from bringing to market new drugs for HIV salvage therapy.
"It should not in any way inhibit efforts to develop drugs in experienced patients," he says. "It would be a very big shame if that was what some corporations took home."
- Adefovir is no longer being developed in the U.S. as an AIDS therapy. It was too toxic, an FDA advisory panel thought, to justify its moderate benefit.
- There is a desperate need for new AIDS drugs, especially for people whose current treatment regimens have failed.
- Many new AIDS drugs are currently in development. The failure of adefovir is disappointing but should not discourage other drug companies from continuing their research, according to one expert.