Vicriviroc Fails to Beat Stiff Competition, Merck Will Not File for Treatment-experienced Approval

		SUMMARY: Merck's investigational CCR5 antagonist vicriviroc did not demonstrate non-inferiority to an optimized background regimen plus placebo among treatment-experienced participants in the twin VICTOR trials, according to a report at the 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010) taking place this week in San Francisco. But vicriviroc did perform well among patients with fewer active background drugs, raising the issue of how high the bar for new drugs should be set in an era of highly effective therapies.

By Liz Highleyman

Vicriviroc is an entry inhibitor designed to block HIV from using one of the 2 surface co-receptors (CCR5 and CXCR4) the virus uses to enter CD4 T-cells. Maraviroc (Selzentry) is the sole approved drug in this class. Vicriviroc has had a bumpy road through the development process, facing concerns about suboptimal efficacy and adverse events including certain malignancies.

The VICTOR-E3 and VICTOR-E4 studies were identical Phase 3 trials conducted in different geographical regions in North America, Latin America, Europe, and South Africa.

The 2 trials combined enrolled more than 800 treatment-experienced participants with documented resistance to at least 2 antiretroviral drug classes. They were randomly assigned (2:1) to take either 30 mg once-daily vicriviroc or placebo, in combination with an optimized background regimen, for 48 weeks.

Participants were required to have at least 2 active drugs in their background regimen, 1 being a ritonavir-boosted protease inhibitor (the small boosting dose of ritonavir was not counted as a separate drug). A majority of patients (about 60%), however, used a background regimen containing 3 or more active drugs.

Patients were allowed to include newer drugs such as darunavir (Prezista, used by about 40% in both trials) and raltegravir (Isentress, used by about 40% in VICTOR-E3 and just under 30% in VICTOR-E4). Where these agents were widely available, it becomes much easier to construct an active regimen, since they are more likely to still be active in people who have developed resistance to older drugs.

The analysis presented at CROI focused on a modified intent-to-treat (ITT) population of 721 participants (from both trials combined) who had exclusively CCR5-tropic HIV as determined using the original Trofile assay (tropism was confirmed at the end of the study using the new higher-sensitivity Trofile-ES, but those data are still blinded).

About 70% of study participants were men, a majority were white (about 65% in VICTOR-E3 and about 55% in VICTOR-E4), and the average age was 43 years. At baseline, the average HIV viral load was about 40,000 copies/mL and the mean CD4 cell count was approximately 260 cells/mm3.

Results

	At 48 weeks, 64% of participants in the vicriviroc arms achieved viral load < 50 copies/mL, compared with 62% in the placebo arms (P = 0.6, not a statistically significant difference).
	Looking at HIV RNA < 400 copies/mL, the corresponding response rates were 72% and 71%, respectively.
	Based on these findings, vicriviroc did not reach the pre-defined threshold for non-inferiority to placebo.
	Vicriviroc did show an advantage, though, in participants with fewer active drugs in their background regimen.
	Among people with <2 active background drugs, 70% in the vicriviroc arms achieved viral load < 50 copies/mL, compared with 55% in the placebo arms, which was a statistically significant difference (P = 0.02).
	Among people >3 active background drugs, however, results were similar to the overall rates, 61% versus 65%, respectively.
	CD4 cell counts increased by 138 cells/mm3 in the vicriviroc arms and 129 cells/mm3 in the placebo arms, again not a significant difference.
	About 25% of participants did not complete the full 48 weeks of treatment for the following reasons:
	Treatment failure: 46% in the vicriviroc arms vs 60% in the placebo arms; Adverse events: 14% vs 8%, respectively; Loss to follow-up: 14% vs 13%, respectively; "Administrative" reasons: 25% vs 19%, respectively.
	Rates of "protocol-defined virologic failure" were 15% in the vicriviroc arms and 16% in the placebo arms.
	Frequency of resistance to drugs in the optimized background regimen was about 20% in both the vicriviroc and placebo arms.
	Vicriviroc was well-tolerated overall, with adverse event types and frequencies similar to those observed in the placebo arms.
	Among all treated participants, 38% in the vicriviroc arms and 41% in the placebo arms experienced any adverse events (AE).
	AEs of interest seen at similar rates in the vicriviroc and placebo arms included:
	Seizures (0 vs 1 patient, respectively); Malignancies (1% in both arms); Liver toxicity (10% vs 9%, respectively); Abnormal blood lipids (6% vs 7%, respectively).

Based on these findings, the investigators concluded that vicriviroc was well-tolerated in both Phase 3 studies, but "did not meet the primary efficacy endpoint."

However, they added, the optimized background regimen in these trials included more potent antiretroviral drugs than those used in earlier Phase 2 trials of vicriviroc or Phase 3 trials of recently approved drugs.

"For subjects with 2 or fewer available active drugs, vicriviroc provided additional opportunity to achieve full viral suppression," the researchers concluded. "With the success of recently available therapies for treatment-experienced subjects, new agents will require novel study designs to demonstrate efficacy."

In their printed abstract, they wrote, "Future trials designed for advanced patients must account for changes in the therapeutic landscape."

As previously reported, Merck informed investors in January that it does not plan to seek U.S. Food and Drug Administration (FDA) approval of vicriviroc for treatment-experienced patients. The company said it would, however, continue to evaluate vicriviroc as first-line therapy for treatment-naive patients.

"While these results are disappointing, it is becoming increasingly difficult for an additional HIV medicine to demonstrate a significant incremental benefit as the fourth or fifth drug added to optimized background therapy," Merck's director of clinical research Lisa Dunkle said in a company press release. "We will further evaluate these results to better understand these findings and define a potential path forward for vicriviroc."

Therapeutic Concepts PA, Houston, TX; Federal University of Sao Paulo, Brazil; University of Cologne, Germany; Desmond Tutu HIV Foundation, Cape Town, South Africa; Merck Research Labs, Kenilworth, NJ.

2/19/10

References
J Gathe, R Diaz, G Fatkenheuer, and others. Phase 3 Trials of Vicriviroc in Treatment-experienced Subjects Demonstrate Safety but Not Significantly Superior Efficacy over Potent Background Regimens Alone. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 54LB.

Other source
Merck. Merck Reports Initial Results of Phase III Studies with Vicriviroc in Treatment-Experienced HIV-Infected Patients. Press release. February 17, 2010.