On May 13, 2003, an FDA advisory committee met outside of Washington, D.C. to consider the approval of a new protease inhibitor, atazanavir (ATV). The drug was mostly well received by the committee; efficacy in treatment naive patients was applauded and a recommendation for approval voted unanimously. The sponsor, Bristol-Myers Squibb (BMS), was congratulated by the FDA for testing the drug in diverse treatment populations and against formidable comparators.
But data for treating treatment-experienced patients was wanting. Although BMS put up slides about 24-week safety and efficacy of ritonavir (RTV) boosted ATV in treatment-experienced patients, the FDA hadn't enough time to review the data, and so it was not officially presented to the committee. Yet, there it was. So, while unboosted ATV was clearly inferior to Kaletra, no one can really say yet if boosting ATV with RTV fixes the problem -- although many were inclined to believe that it does. There's a bit of mystery here, and I think that suits BMS just fine.
The lipid-neutral qualities of ATV are nothing short of amazing compared to others in the PI class, and this will drive acceptance by physicians. There is a danger of the drug being oversold as a remedy for lipodystrophy if BMS is willing to allow confusion between lipids and lipoatrophy to settle in -- there's no proven link. Again, the lipid profile of ATV boosted with ritonavir was left in the shadows.
The unique resistance profile in treatment naive people is the icing on the cake. There's a lot more to learn about ATV resistance, but so far it's surprisingly good news. Hints of PI hypersusceptability after the I50L mutation emerges are the sprinkles on the icing. However, for people with prior PI mutations, none of this applies; they have their own pathway that leads to PI cross-resistance.
The concern over high bilirubin levels that caused reversible jaundice in a large proportion of trial participants is quieting down; expert consensus says it's not a problem in itself. But this drug is going to give quite a few people yellow eyeballs. Patient acceptance will be key.
Atazanavir also has a new brand name: Reyataz. Apparently someone thought this is better than Zrivada, the name that BMS had previously announced. A lot of people already call it "Taz" so the new name was probably selected to take advantage of that. More details from the hearing in the next issue.
Tipranavir Urgent Access
The Tipranavir (TPV) phase III clinical trial called RESIST 1 is in the process of opening at 31 sites in the U.S. for individuals with multi-drug resistant HIV. In addition, a small safety study has opened to provide access for people needing TPV who are not eligible for the large trial or who do not live near a city where the trial is being conducted. Unfortunately, due to drug supply problems, only 140 individuals will be accepted into the safety study, which has entry criteria of CD4 count below 50 and HIV RNA above 10,000 copies. Applicants who are eligible for RESIST 1 and live within 100 miles of a trial site will be excluded from the safety study. Patients on the safety study will be assessed monthly for tolerability and toxicity by the same criteria used in RESIST. Tipranavir is taken with 200 mg ritonavir to boost blood levels of TPV. The safety study will only supply tipranavir; participants must obtain ritonavir from their treating physician.
A larger expanded access program that may be able to provide tipranavir for several thousand patients is planned for early 2004 if all proceeds well with the Phase III trials. Approval could possibly come by early 2005.
Patients who have access to Fuzeon (T-20) are eligible for RESIST and will be randomized separately to assure their even distribution within the trial, however patients may not add T-20 after beginning their RESIST regimen.
Schering has pulled a switch in their CCR5 entry inhibitor development program. SCH-C, which had been slowed by a concern with QT heart rhythm prolongation problems, has been shuffled back to let SCH-D take the fast track. Schering had downplayed the heart issue in meetings with community members, but much skepticism remained. SCH-D is a different molecule with much better activity in laboratory studies and, so far, no safety issues. Phase I trials are in progress. Recent reports indicate that only 1/10th the amount of SCH-D had similar activity to a given amount of SCH-C. Like every other HIV drug, however, resistance to SCH-D has been produced in lab tests. The switch is a disappointment because it pushes back Schering's entry inhibitor program by at least a year, but so far the new candidate seems to have a more realistic chance of achieving approval.
X4 Take 2
Anormed has filed an investigational new drug (IND) application with the FDA for its CXCR4 entry inhibitor, AMD-070. A previous Anormed compound, AMD3100, was dropped in 2001 after heart rhythm problems appeared during its first human trials. AMD-070 is a completely new drug with high specificity for CXCR4. In lab studies it effectively blocked HIV infection of X4-bearing cells by both X4 and dual X4/R5-using HIV. The drug is orally available and had a 10-hour half-life in dogs. First human study should begin this year.