Antivirals
Comparator Arm Suboptimal in Tipranavir Trial
By FDA Advisory Committe
May 19, 2005, 08:48

Patient resistance to comparator protease inhibitors used in Boehringer Ingelheim's Aptivus (tipranavir) pivotal trials will likely be a central issue in the Antiviral Drugs Advisory Committee's review of the HIV agent.

"In both RESIST trials combined, 87% of the subjects were possibly/definitely resistant to the assigned comparator protease inhibitor," FDA's briefing document for the May 19 meeting states.

The open-label trials were designed to evaluate tipranavir boosted with ritonavir plus an optimized background regimen versus a comparator PI/r plus an optimized background regimen.

However, "in actuality, the results should be interpreted more as tipranavir/r versus a partially active control with both arms utilizing a large variety of optimized background regimen (n = 161 different drug combinations as per FDA statistical analysis)," the document states.

Boehringer Ingelheim "had difficulty enrolling the RESIST trials as designed to compare tipranavir/r to an active CPI/r, so they amended the protocol to allow subjects with no available sensitive PI, as per their genotype, to enroll," FDA explained.

While the amendment allowed for complete enrollment of RESIST 1 and 2, "most of the [comparator] patients entered the trial already genotypically resistant to their assigned PI. Therefore, the [comparator] arm is not truly an active control arm, but a suboptimal control arm."

As a result "the studies must be evaluated for superiority," FDA said. BI is seeking accelerated approval in heavily pre-treated patients.

Despite finding a lower 24-week response rate in both trials than that reported by the company, FDA's analysis continued to show a statistically significant result for the Aptivus regimen in RESIST 1 and 2.

In RESIST 1, the company found that 41.5% of tipranavir patients had a confirmed 1 log drop in HIV RNA vs. 22.3% for the comparator. RESIST 2 results were similar, with a 41% response rate for tipranavir vs. 14.9% for the comparator (p less than 0.0001 for both trials).

The agency's analysis lowers the response rates to 36% for tipranavir vs. 16% in RESIST 1 and 32% vs. 13% in RESIST 2 (p less than 0.001 for both).

"We believe that the FDA analysis differs from the applicant's results primarily due to [a] group of subjects who had initial lack of virologic response during [the] first 8 weeks," FDA said, referencing an "escape clause" in the studies that counted discontinuations as treatment failures at week 24.

The design issues cited by the agency could apply to future development of HIV agents for heavily pretreated groups. FDA is asking the committee to discuss lessons learned from tipranavir's development with regard to the "use of escape clauses resulting in a diminishing comparator arm."

The agency will also ask the committee to discuss several safety concerns, including tipranavir/ritonavir drug-drug interactions, "monitoring and management of hepatotoxicity," and further investigation and characterization of a "safety signal of rash in females."

Hepatotoxicity has been a safety concern throughout the tipranavir development program, FDA noted. "At this time, FDA exploratory analyses examining the possible baseline risk factors' are ongoing."

Aptivus has also been associated with gastrointestinal adverse events and elevated triglycerides.

Aptivus would be the second non-peptidic protease inhibitor; Pfizer's Viracept (nelfinavir) was approved in 1997.

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