FDA Antiviral Drugs Advisory Committee Votes Not To Recommend Accelerated Approval for Adefovir

About 300 people gathered at this public hearing yesterday (November 1) at the Holiday Inn in Gaithersburg, MD. Scott Hammer, an ACTG researcher now with Columbia-Presbyterian Medical Center in NYC, chaired the meeting. About 5 pm, after a full day of discussion the ADAC voted in a one-sided decision of 13-1 not to recommend accelerated approval to the FDA for adefovir. The FDA does not have to follow their recommendation but usually does. If it appears at the hearing that the FDA disagrees with what appears to be the ADAC decision they frequently intervene at the hearing but in this case they did not. Gilead Sciences submitted an applcation to the FDA requestinbg accelerated approval for adefovir only in individuals who need salvage therapy.

Gilead Sciences opened the meeting by presenting their data that 60 mg of adefovir had antiviral activity, safety was adequate and well characterized, and that 3TC resistance could increase adefovir antiviral activity overcoming high-level AZT resistance.

The FDA presentation followed and presented their usual statistical analysis and refuted those claims. The FDA felt a small viral load reduction of about 0.30 log could have clinical benefit for some individuals. But, they said that of several studies in only 1 in experienced individuals did adefovir show activity. And in one naÔve study adefovir showed activity. In several other studies, adefovir did not show antiviral activity.. They said, although the nephrotoxicity associated with adefovir can be delayed by using 60 mg compared to 120 mg once daily, their analysis (Kaplan Meier curve) showed the ultimate frequency of nephrotoxicity will be the same for either dose. One appealing characteristic of adefovir was that in vitro and in small numbers of patients the presence of 3TC resistance (M184V mutation) could increase the antiviral activity of adefovir. The FDA said their analysis did not see this.

The FDA said that CPCRA 039 was not well designed enough to to accept the results of the study. The study failed to show activity for adefovir.

The FDA felt heartened that some community members expressed appreciation for their analysis in this case.

At this point in the hearing prospects for Gilead and adefovir appeared dim. Following was the discussion by the committee members and public testimony prior to the final vote. Apparently, the committee was not convinced by the Gilead case and the FDA analysis created enough questions or doubts. Only two committee members expressed supporting the Gilead application for accelerated approval. They felt there was a need for individuals with very limited treatment options for an additional option. One said the safety profile was adequately characterized and manageable, and adefovir has antiviral activity. 

Several committee members said adefovir could be a transitional therapy before new drugs are developed one to two years in the future. It appeared as if discontinuation rates were high for both doses and committee members expressed doubts that individuals could benefit from adefovir beyond one year.

The remainder of the committee did not feel convinced that 60 mg had anitviral activity or adequate activity. They felt that the safety concerns regarding potential nephrotoxicity were not well characterized. Dr Jeffrey Kopp, an expert in kidney research in the Metabolic Division at the NIH, testified that he had concerns about the potential for long-term kidney impairment in some individuals due to adefovir. It was reported that 3 individuals required dialysis after adefovir treatment. A couple of committee members said they might have voted to approve adefovir at the dose of 120 mg because they felt the case for safety and activity was adequate, but other committee members were not convinced of that either. The committee was concerned about safety beyond 1 year following initiation of adefovir therapy. The data past 1 year was too small. Although it was reported that 95% appear to ultimately resolve nephrotoxicity after a period of time, one committee member expressed concern about the other 5%.

At the hearing Gilead presented a patient management program which would recommend monthly patient visits to their doctorís office for monitoring the lab abnormalities associated with adefovir nephrotoxicity.

Data from ACTG 359 found unexpectedly that adefovir reduced delavidine blood levels which in turn may have reduced saquinavir blood levels. Although Gilead maintained that they do not see this observation in their studies, the question appeared unresolved at the hearing.

In the public testimony several doctors and their patients testified they felt adefovir was useful. A committee member responded by saying that the decision must be made by data. Two community advocates including Mike Marco of TAG and an advocate from France spoke against approval. Bill Bahlman spoke in favor of approval. I did not speak. A few years ago delavirdine was in a similar situation in that its antiviral activity was not evident from studies but safety was not a concern. The discussion at the FDA hearing was controversial but I spoke in favor of approval because I felt delavirdine had activity and potential utility. Additional studies have shown delavirdine has reasonable anitiviral activity and is safe. The drug received accelerated approval and additional studies have shown it significantly increases blood levels of protease inhibitors and may improve the potency and pharmacokinetics of protease inhibitors. It may be useful in salvage therapy in combination with a protease inhibitor. It may be helpful for individuals failing indinavir or nelfinavir because of low protease inhibitor blood levels. Agouron recently purchased delavirdine from Upjohn to explore this utility. However, adefovirís situation is different. 

In the end the committee and the FDA were not convinced by the available data that adefovir should be approved. They suggested that additional studies may be able to flesh out evidence supporting adefovir approval. The ADAC decision appears precedent setting in that I think this is the first time an antiretroviral for primary HIV infection has ben turned down by the ADAC. However, I don't think this has any long term negative implications. The FDA suggested at the hearing that they support the current system for HIV drug approval. 

I think Gilead has to regroup and decide if they want to conduct additional studies in HIV to address the doubts and questions about safety, activity and resistance. In early studies, adefovir has shown good antiviral activity against hepatitis B and combination therapy for HBV is desirable. I presume Gilead will continue to develop adefovir for HBV. The second Gilead nucleotide PMPA appears significantly more potent than adefovir and so far in early study results it appears to be safe. Will Gilead devote additional resources to adefovir development or will they use focus on PMPA? What about the thousands of people receiving adefovir in expanded access?