| |
Maraviroc Recommended for Accelerated Approval Unanimously by FDA Panel: panel discussions
|
| |
| |
Reported by Jules Levin
April 24, 2007
The FDA Antiviral Drug Advisory Committee met today in Silver Spring, Maryland and voted unanimously to recommend accelerated approval of Maraviroc, the first CCR5 inhibitor HIV drug, by the FDA. Noting the particular need for this new drug in patients with HIV drug resistance who need new therapy regimens. It was mentioned that 25,000 to 40,000 patients would be in need of this drug based on data of the number of patients with extensive and multi-drug resistance. We probably will hear from the FDA within a few months. The FDA usually follow advise by this panel so we can expect FDA approval.
The FDA and Pfizer both reported there was no evidence of malignancy problems related to Maraviroc compared to placebo. There appeared to be modest elevations of ALT associated with Maraviroc compared to placebo, but the FDA said it might be similar to placebo. One of the panelists said there were a few cases of LFT or hepatic events but in general the overall data did not show evidence of ALT elevations associated with Maraviroc. There did not appear to be an additional concern in coinfected patients but the number of coinfected patients in the phase III studies was relatively small, so the panel suggested post-approval studies in coinfected patients, and PK studies in coinfected patients.
Pfizer said there is no evidence of tropism switch while on maraviroc therapy, saying pre-existing X4 virus at low levels in reservoirs appear to be responsible for patients who failed therapy in studies with X4 virus. The FDA reported a significant number of patients who failed maraviroc on study failed with CXCR4 after having CCR5 identified at baseline. But the FDA also suggested it does appear most of these patients had undetectable X4 in their reservoir before going on therapy in the study and the X4 emerged on therapy. Many patients if not all I think I recall reverted to R5 after stopping maraviroc.
The FDA reported seeing some increased numbers of infections associated with Maraviroc use such as herpes simplex and candidiasis. Pfizer suggested this could be associated with improved immune systems in patients taking Maraviroc. The FDA reported some increased incidence of cardiac ischemic events, more low level elevations in cholesterol and LDL. The study results showed blacks did not achieve as much reduction in viral loads as whites although they did have significant benefits in viral load reductions compared to placebo, but the numbers of black patients studied were small.
Pfizer is committed to I think 5 years post-approval studies to follow safety, malignancies, maraviroc use in coinfected patients, additional PK studies, and immune function. Potential interactions with Viagra were discussed, particularly in the context of postural hypotension and cardiac issues, and in patients with hypertension.
A study in treatment-naive patients is ongoing.
The panel turned to a discussion of data presented earlier today that reduced viral response rates in some patient subpopulations was associated with lower trough levels of maraviroc, but a panelist said that is different than showing response rate will increase if drug dosing is increased. In the discussion this morning the FDA suggested a number of various factors that could be potentially involved. So the panel discussed dosing recommendations. The panel recommended post-approval studies to explore the question of whether increased dosing should be considered for these patients, but voted to support the dosing recommended by Pfizer in their application for accelerated approval.
The panel discussion turned to how to use the tropism assay and there was quite a bit of diverse opinions expressed so I'll just say the panel did agree that much more should be learned over time with the use of this brand new drug and its unique mechanism of action. Apparently using the tropism assay before going on therapy with maraviroc will be recommended. Howard Mayer of Pfizer spoke to the utility of periodic tropism testing while on therapy. He appeared to say periodic testing while on therapy is not useful. I would say to also consider the information reported by Pfizer that patients revert to R5 from X4 after stopping therapy. I think post-approval studies are needed to understand this issue.
The panel discussions are in response to questions posed for discussion by the FDA. The final question raised by the FDA is since background optimized therapy has become very optimized with all the new drugs, how do we conduct future studies: do we have OBT or do we compare a new experimental drug to a particular drug like for example maravrioc or the Merck integrase. I think the panel was not prepared to answer this question, but it's a good question. Having so many new good drugs will complicate study design for heavily experienced patients. The meeting ended at 4:20pm, 20 minutes past the deadline.
|
|
| |
| |
|
|
|
