Abacavir: Accelerated Approval Recommended 7-2 by Panel Vote
This is a brief summary report on the hearing. A more detailed report will follow. On Monday Nov3, the ADAC (Anitiviral Drug Advisory Committee) voted 7-2 in favor of recommending that the FDA grant accelerated approval to abacavir.
Two new pieces of data were reported at the hearing by GW. Previously they reported at Geneva that at week 16 75% taking ABC+AZT/3TC had <400 copies/ml using the more stringent intent-to-treat analysis method. At the hearing they reported follow-up to week 24 showing comparable viral load data. Secondly, they reported for the first time publicly preliminary week 24 data comparing Crixivan+AZT/3TC to ABC+AZT/3TC. The arms remained blinded but 85% had <400 copies/ml in both arms when using the as-treated analysis method. Therefore, they appeared to be comparable at this preliminary stage of the study.
At several times during the all day meeting which started at 8:30am and ended about 3:30 pm it appeared as if the committee would not approve the drug. Strong concerns were raised about several issues:
1- hypersensivity. As you may know individuals at a rate of about 3% have experienced hypersensitivity. The committee expressed strong concern that it will be difficult to educate everyone adequately on how to recognize and manage hypersensitivity. The reaction is generally characterized " by fever and/or malaise and possibly accompanying skin rash. In its press release Glaxo Wellcome said" : a hypersensity reaction can be life threatening under certain circumstances....the symptoms get progressively worse if treatment continues. Patients experiencing this symptoms must contact their doctor immediately and must suspend taking ABC until a diagnosis of a hypersensitivity reaction is excluded. Symptoms of the reaction generally resolve following discontinuation". If hypersensitivity is recognized a person must stop the drug and not rechallenge. A problem arises when the person rechallenges or if they continue taking ABC in the face of the hypersenstivity side effects.
There was much discussion between the committee and GW about providing adequate education about recognition and management of the reaction to doctors, patients and other medical personnel. Some committee members expressed concern that it may not be possible to adequately inform all that needed to be informed. For example, some doctors who treat only a few HIV+ patients may not get adequate education; or, emergency room personnel needed to be educated. GW promised to provide a broad and comprehensive education program to the public.
2- antiviral activity in those heavily pre-treated with NRTIs. It appeared to me that the committee was not familiar with the cross-resistance data reported at the past Human Retrovirus Conference and at Geneva. GW presented several studies at yesterday's hearing in NRTI experienced adults and children showing that response to ABC may be little or none in some heavily pretreated individuals. The committee felt this might create a negative risk/benefit ratio considering the potential for hypersensitivity. But at the Retrovirus meeting research indicated that response to ABC in NRTI experienced people depends on several factors: baseline phenotypic ABC resistance; how much resistance they had to other NRTIs, how much prior NRTI experience they had. In this study individuals wih <8 fold resistance responded to ABC and those with >8 fold resistance did not. The NATAP web site has several detailed reports about thisdata. I went to the microphone at the FDA hearing to inform the committee about this data and support FDA approval for ABC.
3- GW presented data from the study comparing ABC+AZT/3TC to AZT/3TC where at week 16 the CD4 increase was greater in the AZT/3TC arm (about 113) than the ABC arm (about 83).
It remains unclear when ABC will be available in pharmacies because GW will have to design and present to the FDA two new studies for traditional approval. I am not certain if comercial availability is delayed until the FDA receives this.
Abacavir vs. Crixivan
At the FDA Advisory Panel hearing on Nov 2, Glaxo presented data for the first time on the study of abacavir+AZT/3TC vs Crixivan+AZT/3TC. Both arms remain blinded but the data appears preliminarily to be comparable for the two arms. At weeks 16 and 24, 85% in both treatment arms had <400 copies/ml using the on-treatment analysis. Using the intent-to-treat analysis, which reportedly includes all subjects who were randomized to treatment, 63% had less than 400 copies/ml at week 16 in both arms, and 60% had less than 400 copies/ml at week 24 in both arms.
Further explanation will help understand this data. 562 subjects were randomized in the study: 280 to arm A. Seventeen didn't start treatment after randomization. 57 discontinued at week 16, and 35/57 discontinued for adverse events.
In arm B 282 were randomized and 16 never started any study treatment. 58 discontinued by week 16, 34 due to AEs. By week 24, 66 in arm A and 66 in arm B had discontinued treatment. 36/66 in arm A and 37/66 in arm B discontinued due to adverse events. At week 16, 20% had discontinued study treatment and at week 24, 24% had discontinued treatment.
All subjects in the study, no matter to which arm they were randomized, took ABC + indinavir placebo or IDV + ABC placebo, and all had to adhere to the indinavir eating restrictions: no food for two hours befor and 1 hour after taking meds. The dropout rate was also 20%. Interesting information.