US FDA committee recommends approval for tenofovir

The Antiviral Drugs Advisory Committee of the US Food and Drug Administration (FDA) on October 3, 2001 recommended unanimously to grant accelerated approval to Gilead Sciences’s nucleotide analogue drug tenofovir (Viread) for the treatment of HIV infection among antiretroviral treatment-experienced adult patients.

The FDA periodically grants accelerated (“fast-track “) approval to promising experimental drugs to make them available to patients with life-threatening conditions such as AIDS.

The FDA almost always accepts the recommendations of its advisory committees, and the recommendation for approval was widely anticipated. It appears certain that later this month the agency will formally approve tenofovir, making it the only anti- HIV drug to receive FDA approval in 2001. Last year, citing grave concerns about safety, the same FDA advisory committee rejected approval of Gilead Science ‘s lead drug, the nucleotide analogue adefovir dipivoxil, for the treatment of HIV infection, the only anti-HIV drug ever to be denied accelerated approval by FDA.

There was some controversy among committee members about whether the drug should be approved for the treatment of all HIV patients, regardless of their prior antiretroviral drug use. The committee eventually came down on the side of caution, with the majority of members (9)voting to recommend approval only for treatment-experienced adults. Two panel members voted to recommend approval of the drug among all adult HIV patients, including previously untreated patients.

In practice, once the drug is approved, physicians will be able to prescribe the drug to whatever patient population, in their best judgment, seems appropriate to them. In other words, tenofovir will be accessible to treatment-naïve patients (no prior anti-HIV drug use)as well as to the treatment-experienced.

Good resistance profile and probable good drug adherence

Gilead ‘s own studies showed a clear benefit in the treatment-experienced patient population who had HIV resistance mutations. The data presented showed resistance to tenofovir developed very slowly, if at all, occurring in only about 3 percent of those using the drug for 24 weeks. Tenofovir is dosed only once daily.

The mean HIV viral load decline was 0.6 log after 24 weeks of therapy among treatment-experienced patients using tenofovir 300 mg once daily in study 902 (53 participants)and in study 907 (367 participants). In study 902, this drop remained at 0.60 log at 48 weeks. Study 907 is still ongoing and has not reached the 48-week point.

Safety issues

Unlike the situation last year with its sister-drug, adefovir dipivoxil, the safety profile of tenofovir was not such a big issue at the FDA hearing. The most commonly reported side effects of tenofovir are asthenia, headache, nausea and diarrhoea. The frequency of these effects in the tenofovir-treated patients was similar to that among those on placebo. There was discussion among the panel members, experts and Gilead representatives during the hearing about the potential for tenofovir to eventually cause bone toxicity in humans. In doses much higher than those used in humans, tenofovir did exhibit bone toxicity in animals studied.This has not yet shown up in human subjects.

However, given its current conservative bent, the FDA has told Gilead that it wants to see follow-up data on the potential for bone toxicity among humans from tenofovir use, and Gilead has prudently agreed to do so in ongoing studies among treatment-naïve individuals.