Four in Favor, Four Against; Long-Awaited Non-Nuke Receives Mixed Reviews at Agency Hearing
Clinical benefit elusive
In a November 22nd FDA hearing that harkened back to the bad old days of ddC, the Food and Drug Administration's Antiviral Drugs Advisory Committee considered an application for approval of delavirdine (trade name Rescriptor). Delavirdine is a non-nucleoside reverse transcriptase inhibitor (NNRTI), similar to Boehringer-Ingelheim's nevirapine, which was approved by the FDA in June, 1996.
Three randomized studies were presented to support the approval of delavirdine. Study 0021 compared AZT alone to AZT in combination with 200, 300, and 400 mg of delavirdine three times daily. Participants had 200-500 CD4+ cells (mean 325-340). Mean baseline HIV RNA was 5.2 log copies/ml, and about 60% had previously been treated with AZT. Participants taking AZT in combination with the higher doses of delavirdine had significant improvements in T-cell counts (average increase was about 40 cells), and HIV RNA levels (average decline was about 1 log).
In study 0017, 780 patients were treated with ddI or with ddI+delavirdine. These were more advanced patients, with < 300 CD4+ cells (average baseline count was about 140 cells), mean baseline HIV RNA of 5.8 log copies/ml, and average prior ddI experience of 4 months. Mean change in CD4+ count in patients taking ddI+delavirdine was significantly better than ddI monotherapy at weeks 4 and 8. Mean change in viral load was significantly better after week 4 (.9 log decrease). Sixty-one deaths occurred in the ddI group, and 66 deaths occurred in the ddI+delavirdine group: this was not statistically significant. According to Pharmacia & Upjohn (makers of delavirdine), the Data Safety and Monitoring Board (DSMB) recommended terminating the study because the protocol goals of showing a clinical outcome difference between the two regimens was unlikely to be achieved.
A third study compared four groups of patients, who were treated with AZT+delavirdine, ddI+delavirdine, AZT+ddI, or all three drugs together. Mean baseline CD4+ cell count was 285-303. HIV RNA data were not available. 63% of patients were treatment naive, 36% of patients had been treated with < 6 months of AZT monotherapy, and 1% had been treated with 6 months of ddI monotherapy. In an intent-to-treat analysis, patients treated with AZT+ddI+delavirdine and AZT+ddI had a significantly better CD4+ response than patients treated with AZT+delavirdine or with ddI+delavirdine. In an on-treatment analysis, patients treated with the triple therapy had a significantly better CD4 response than patients treated with AZT+ddI.
The major side effect seen in patients taking delavirdine is rash. This rash appears between two and four weeks after beginning treatment and is usually not serious enough to require patients to stop treatment. People taking Bactrim for PCP prophylaxis had an increased risk of a serious rash. Warning signs of a serious rash include high fever and rash on mucous membranes. For most people, treatment with antihistamines was sufficient to allow continuation of treatment through the rash.
Like other NNRTIs, delavirdine monotherapy rapidly leads to the emergence of delavirdine resistant HIV. When used in combination with other drugs, development of resistance may be delayed. The primary amino acid substitutions in the HIV reverse transcriptase gene following long-term in vitro delavirdine exposure appear at codons 103, 181, and 236. Treatment with delavirdine monotherapy or delavirdine+ddI produces mutations at codon 103 or a combination of mutations at codons 103 and 181. Treatment with AZT+delavirdine most frequently leads to mutations at codons 103 and 236, with the 181 mutation occurring in fewer than 2% of samples. Pharmacia & Upjohn asserts that delavirdine can re-sensitize nevirapine-resistant virus to nevirapine, however Boehringer-Ingelheim (nevirapine's manufacturer) believes that the nevirapine-resensitizing mutation in question rarely occurs in vivo, while more common mutations confer complete loss of sensitivity to both nevirapine and delavirdine.
Delavirdine is processed through the CYP3A pathway. Most protease inhibitors are also processed through CYP3A. Consequently, delavirdine probably interacts with most protease inhibitors. Unfortunately, Pharmacia & Upjohn only conducted brief pharmacokinetic and acute safety studies of delavirdine in combination with approved protease inhibitors.
In these studies, co-administration of delavirdine and saquinavir raised saquinavir levels by five times, producing blood levels of saquinavir that were comparable to those achieved in the Stanford high-dose saquinavir study. Co-administration of delavirdine and indinavir raised indinavir levels two-fold. Based on this observation, Pharmacia & Upjohn recommend that indinavir be dosed at 400-600 mg every eight hours, from the current recommended dose of 800 mg every eight hours. In addition, co-administration of ddI and delavirdine lowered ddI levels by 20%, and increased clarithromycin levels by two-fold. The following drugs are contraindicated in patients using delavirdine: alprazolam, astemizole, barbamazepine, cisapride, phenobarbitol, phenytoin, rifabutin, rifampin, terfenadine and triazolam.
In a consensus statement regarding approval, a group of five AIDS organizations, including the AIDS Action Council, the AIDS Treatment Data Network, the American Foundation for AIDS Research, Gay Men's Health Crisis and TAG, identified four key problems with the application:
Surrogate Marker Claim. Based on a meta-analysis of studies 0017 and 0021, Pharmacia & Upjohn asserted that a half-log reduction in viral RNA sustained for at least eight weeks would result in clinical benefit for at least a year. However, in study 0017, patients treated with delavirdine+ddI experienced a half-log drop in RNA (compared to patients treated with ddI monotherapy), and yet experienced no clinical benefit. Therefore, its clinical trial undermined the strength of this surrogate claim.
Indication. The proposed indication read "for use in combination with other antiretroviral agents in the treatment of HIV infection whenever antiretroviral therapy is warranted." The only data available about delavirdine in combination with protease inhibitors, however, was pharmacokinetic and acute safety data in HIV-negative patients. The data were sufficient to identify major interactions with saquinavir and indinavir, but not enough to allow for an assessment of the safety and efficacy of the combinations.
Confirmatory Trial. Pharmacia & Upjohn identified its on-going study of delavirdine+ AZT+ either ddI, ddC or 3TC compared to AZT+ either ddI, ddC, or 3TC as its pivotal trial intended to provide evidence of clinical benefit. This study is being conducted in Europe, Australia and South Africa. These countries, however, are just now beginning wide-spread use of protease inhibitors, which are prohibited in the study. The consensus group was concerned about the viability of this trial. They recommended that the company make every attempt to complete their planned clinical endpoint study, and that the company should undertake a clinical endpoint study using delavirdine and a protease inhibitor.
Resistance and Cross-Resistance. The consensus group was greatly concerned that Pharmacia & Upjohn had not adequately characterized the effects of resistance to delavirdine on sensitivity to other non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs), such as nevirapine and DuPont-Merck's up-coming DMP-266. The group recommended that Pharmacia & Upjohn work rapidly to develop further data on cross-resistance with NNRTIs, including bi-directional in vivo studies.
Based on the presentation by Pharmacia & Upjohn, four members of the committee voted to recommend approval of delavirdine, and four voted against. The FDA will have to review the application in the coming weeks, and make a decision.