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Raltegravir (MK-0518) FDA Hearing Sept 5 2007
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Reported by Jules Levin
The morning session at the hearing just ended at 10 am where Merck and the FDA reported safety and efficacy analyses of phase II and III studies. There were no unexpected or surprising information, so everything appears to be going as expected. Merck reported as expected high efficacy in treatment-experienced patients just as we have seen in studies presented at conferences. Although the initial reports of an imbalance in malignancies were reported between the Raltegravir vs placebo arms in studies Merck reported followup analyses here showing this was due to longer exposure to drug therapy in studies. The FDA supported the Merck findings with regards to efficacy and malignancies. This afternoon will be the panel review and discussions and a vote by the panel on a recommendation to the FDA for approval. Usually the FDA is in accord with panel recommendations for approval.
Merck said there are "1.2 million with HIV; 10-15% of treated pts are failing therapy & have triple class resistance". HIV resistant to raltegravir remain sensitive to other ARTs. Terminal t1/2 about 9 hours, supporting twice daily dosing.
In the 2 phase III studies 700 patients had triple class resistant HIV, the primary analysis was at week 16. The primary endpoint was % of patients <400 c/ml and <50 c/ml was key secondary endpoint. 20-30% of patients had GSS=0, no genotypic sensitivity to any drugs, 20-30% had PSS=0, no phenotypic sensitivity to any drugs. Most patients had advanced HIV, CD4 counts 100-140, 90%+ had AIDS. 77% of patients achieved <400 c/ml at week 16, sustained at week 24. Compared to 42% in placebo group (p<0.001). 62% of patients taking raltegravir had <50 c/ml vs 35% in control group. Raltegravir was similarly effective regardless of baseline HIV RNA (<100,000>) or CD4 count. 57% (GSS=0) vs 85% (GSS=1) had <400 c/ml. FDA analysis reported the same. 605 of patients week 24 and week 24 analysis supports week 16 analysis. Of note use of darunavir or Fuzeon increased significantly (90% <400) % <400, and use of both resulted in 98% achieving <400 c/ml. Phase II study results have shown week 48 sustained efficacy.
FDA said no clear safety signal emerged in studies but since it's the first integrase inhibitor ongoing followup will take place. Here are links to the analyses by Merck and the FDA which were released prior to the hearings in their Briefing Documents. The data and findings in these documents are the same as reported this morning.
FDA Raltegravir Hearing Sept 5 Afternoon Session
The panel was better this time compared to for the Maraviroc hearing. This panel included Judy Feinberg and Marshall Glesby, and Tracy Swan from the community. At the open hearing part of the meeting two community provided helpful testimony, Matt Sharp and Lynda Dee. The first discussion this afternoon is what indication should raltegravir receive: accelerated approval for 'treatment-experienced' a broad indication or a more restrictive indication such as a more or highly experienced patient population; since the phase III studies were conducted in triple-class and highly resistant patients. Opinions from the panel are mixed on this question. One objection to a broad indication was made from a panelist saying if a patient used raltegravir right away failing a firstline regimen like Atripla the patient could develop integrase resistance, which would restrict the class for that patient in future therapy. Another objection was that there was no data from phase III except in triple-class experienced patients. The FDA said they will consider the panels objections in wording the indication as they feel they can incorporate the concerns in the label. It felt like the FDA would like to give a broader indication but mention some considerations discussed.
The next question was what additional studies the panelists would like to see. Studies in different clades, in larger numbers of African-Americans and other minority populations, and patients in Africa; better characterization of the resistance profile, how quickly resistance can develop; a study in second-line therapy; use of all ART drugs with TB therapy; blood-brain, CNS penetration; studies in women and in other geographic areas of the world; try to better understand if there any risks for malignancies; study in patients over 65 yrs old; although not mentioned I suggest study of class-sparing regimens.
The next question was how long post-marketing surveillance Risk Management Studies should be conducted. Merck suggested 3-5 years. Overall longer is better is something some panelists suggested and one panelist said to make sure the program is active.
The next question asked for pros and cons of potential treatment strategies in future clinical trials: studies looking at nuke-sparing, 2 drug regimens; concern was expressed by a panelist that raltegravir studies have so far included nukes so study without nukes raised a concern by one member; study of 2-drug regimen of raltegravir+atazanavir; Bob Yarchoan suggested any 2-drug regimen study should go on for long-time to assure for safety; investigate strategies for second-line raltegravir therapy. The question of naive use was discussed a bit.
The last question asked how to increase enrollment of women and minorities in studies. The panel agreed that studies should represent the patient communities affected by HIV. It was mentioned that this concern has been raised before and it was expressed that it is a question of concern. But there were few good suggestions. It was said how difficult it is to enroll and retain minority patients in studies and this could require investment, adherence might be an issue. It was brought up that CPCRA and other studies in such study networks can enroll more women and minorities, but more infrastructure and hence financial investment would be required, and a 9-month pivotal study may be a difficult situation for this to happen. The FDA said they have no capacity to require certain percentages of patient populations. The FDA said it is important to discuss the issue, for sponsors in the audience to hear suggestions from the panel, but again no good suggestions were raised by the panelists; only that the companies should enroll larger patient populations of women and minorities, and the FDA should be able to require it. One suggestion was required stratified recruitment of 25% women & 50% African-Americans. Of course it was said that the number of patients in the stratifications would not necessarily be large enough to be statistically significant. One panelist said he felt the efficacy in the Raltegravir studies convinced him that it was good across all patient groups, but perhaps numbers weren't large enough to convince him on safety. A concern was raised that study participation by minorities can be difficult, but that more effort might help. More targeting of patient populations should work. Dr Anderson said the data does not show a lower response for Raltegravir in women. It was summarized that perhaps the FDA could get more teeth to accomplish this.
The meeting just ended without a vote on recommending approval. I am surprised but checking with the list of questions there is no question asking panelists to vote on whether or not they support approval. I guess the data is so convincing that approval is a done deal, the only question being wording of the label and what post-marketing studies and surveillance should look like.
The FDA Briefing Document says:
Special Populations
The effects of HIV status, age, gender, weight, and race on raltegravir pharmacokinetics were assessed by evaluation of raltegravir plasma trough concentrations in Phase 2/3 trials. The data indicate age, gender, weight, race and HIV status do not have an impact on raltegravir exposure. No clinically important effect of moderate hepatic insufficiency on the raltegravir pharmacokinetic profile was observed in a study of subjects with Child Pugh scores of 7 to 9. No dosage adjustment is recommended for patients with mild to moderate hepatic insufficiency. No clinically important effect of severe renal insufficiency on the raltegravir pharmacokinetic profile was observed in a study of subjects with 24-hour creatinine clearance of <30 mL/min/1.73 m2. No dosage adjustment is recommended for patients with renal insufficiency.
The Merck Briefing Document says:
Efficacy in Special Populations
Efficacy analyses by gender, race, viral subtype (B versus non-B clade), and geographic region demonstrated potent efficacy of raltegravir as compared to placebo and this efficacy did not appear different in any of the subgroups analyzed (Figure 16). Given the limited number of patients 65 years or older studied (N=9), assessment of efficacy of raltegravir in this patient population could not be made. There were no data in the pediatric patient population (age <16) and no data in pregnant HIV-infected women. Appendix 13, Appendix 14, and Appendix 15 contain the supporting data.
From the Merck Briefing Document:
Risk Management Planned Actions
To address the important safety issues, Merck & Co., Inc. proposes a comprehensive Risk
Management Plan that includes the following activities:
1) Routine Pharmacovigilance:
Post-marketing reports of IRS, HIV resistance and/or virologic failure, known and
potential drug interactions, pregnancy outcomes, and any other important safety
issues that are identified will be reviewed and evaluated on an ongoing basis. Clinical study data pertaining to any of these targeted safety issues will also be monitored and evaluated. For the first 3 years following licensure post-marketing and clinical study reports/data on these issues will be discussed in the 6-month Periodic Safety Update Reports (PSURs).
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