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Vicriviroc CCR5 Drug, 24 Week Results in Treatment-Experienced; New Study with Higher Doses Starting
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This report is a press release from Schering-Plough (I checked all data) combined with comments and data added by me.
Jules Levin
XVI Intl AIDS Conference, Toronto, Aug 17, 2006
SUMMARY.
-VCV (5, 10, 15 mg with RTV) demonstrated potent 14-day virologic suppression
-following optimization of background ART, VCV (10, 15 mg with RTV) demonstrated sustained antiretroviral activity over 24 weeks or more.
-subjects with dual/mixed tropism has a reduced response.
-VCV was generally well-tolerated
-there were 5 malignancies in the Vicriviroc arm and 2 in the placebo arm. The relationship of VCV to malignancy remains uncertain.
"VICRIVIROC DEMONSTRATES POTENT AND SUSTAINED VIRAL SUPPRESSION IN ACTG PHASE II CLINICAL STUDY IN TREATMENT-EXPERIENCED HIV PATIENTS"
First 24-Week Results with a CCR5 Receptor Antagonist Reported
Schering-Plough Initiates New VICTOR-E1 Phase II Study To Evaluate Higher Doses
TORONTO, Aug. 17, 2006 - Schering-Plough today reported that results from an ongoing Phase II clinical trial showed vicriviroc, its investigational CCR5 receptor antagonist, demonstrated potent and sustained viral suppression after 24 weeks of therapy in 118 treatment-experienced HIV patients, when administered in once-daily doses in combination with an optimized ritonavir-boosted protease inhibitor (PI)-containing antiretroviral regimen. In the study, viral load decrease was significantly greater for patients in each vicriviroc group compared to the control group at day 14 and at week 24 (p<0.01), and was not different between the vicriviroc groups (p>0.05) (ITT). Although there was no statistical difference in the viral load reductions between the three vicriviroc arms, a higher rate of virologic failure and emergence of X4 virus was observed at the lowest dose of 5 mg.
This is the first trial with a CCR5 receptor antagonist for HIV to report 24-week treatment results. Researchers from the NIH-sponsored Adult AIDS Clinical Trial Group (ACTG), which is conducting the study, presented the data here today during a late-breaker session at the XVI International AIDS Conference.
"We are encouraged by the durability of viral suppression observed through 24 weeks in this study of patients with significantly advanced HIV disease," said Roy Gulick, M.D., principal investigator and associate professor, Weill Medical College of Cornell University, New York. "The promise of new antiviral agents with novel mechanisms of action and unique resistance profiles is particularly important for treatment-experienced HIV patients, who need new treatment options, and we look forward to the further clinical evaluation of vicriviroc in combination with conventional antiretroviral regimens."
A total of 118 heavily treatment-experienced HIV patients (median viral load 36,380 copies/ml and CD4 146 cells/uL) with R5-type virus taking ritonavir-boosted PI-containing regimens were randomized in the double-blind, 48-week study. (33% of patients were Fuzeon-experienced. 92% of patients in study were men; 66% were white, 20% black, 12% Hispanic). Change in viral load after addition of vicriviroc (5, 10 or 15 mg) dosed once daily (QD) or placebo was measured at 14 days, and then at 12 and 24 weeks, after the background antiretroviral regimen had been optimized at day 14.
At day 14, the primary endpoint of the study, the mean HIV-1 RNA change from baseline (log10 copies/mL) for the vicriviroc 5, 10 and 15 mg QD arms were decreases of -0.87, -1.15 and -0.92, respectively, compared to an increase of +0.06 for the placebo arm. At week 24, the mean HIV-1 RNA change (log10 copies/mL) for vicriviroc 5, 10 and 15 mg QD arms were declines of -1.51, -1.86 and -1.68, respectively, compared to a decrease of -0.29 for the placebo arm. Mean CD4 cell counts increased at week 24 for the vicriviroc 5, 10 and 15 QD mg arms by +84, +142 and +142 respectively, compared to a decrease of -9 for the placebo group. Emergence of detectable X4-type virus was detected in 8 (27 percent), 3 (10 percent) and 2 (7 percent) of patients in the vicriviroc 5, 10 and 15 QD mg arms, compared to 1 (4 percent) in the placebo arm. Five of the 8 patients in the 5 mg QD arm demonstrated the emergence of X4 virus prior to optimization of their background regimen.
TROPISM:
At screening: 118 (100%) were R5 only
At study entry: 102 (86%) were R5 only, 12 (10%) dual/mixed, 4 (4%) missing.
On initial study rx (n=106), 13 subjects changed tropism: 1 placebo, 7 VCV 5 mg, 3 VCV 10 mg, 2 VCV 15 mg.
VIRAL RESPONSES at week 24: R5 tropic at entry (n=71): -1.83 logs;
dual/mixed tropic at entry (n=10): -0.77 logs (p=.01).
There was no significant difference for grade 3 or 4 adverse events among 4 arms (pairwise comparisons, p>0.6).
The 5 mg QD dose of this trial was discontinued early due to suboptimal efficacy (patients were dose-escalated to 15 mg QD) (and due to trend for increased co-receptor switches) and the study as a whole was unblinded in March 2006 after recommendation from the Study Monitoring Committee, based on reports of five malignancies (two Hodgkin's disease, one with prior Hodgkin's disease; two non-Hodgkin's disease, one with prior Hodgkin's disease; and one gastric adenocarcinoma) among vicriviroc recipients. Notes from Jules Levin: One patient on VCV 15 mg with Hodgkin's disease developed non-Hodgkin's lymphoma. 1 on VCV 10 mg with Hodgkin's disease developed recurrent Hodgkin's disease. 1 on VCV 15 mg developed gastric adenocarcinoma. 1 on VCV 5 mg developed non-Hodgkin's lymphoma. 1 on VCV 5 mg developed Hodgkin's disease. 2 subjects randomized to placebo developed malignancies: 1 subject on placebo developed multiple cutaneous saquamous cell carcinomas. 1 subject on placebo for 7 months, who then took VCV 10 mg for 3 months, discontinued VCV for lack of response, and 1 month later developed localized perianal squamous cell carcinoma
The ACTG (including an independent safety monitoring committee) concluded causal association between vicriviroc and the malignancies could not be determined by this study. Coupled with evidence of significant virologic activity and CD4 count increases, a decision was made to continue the trial with the 10 and 15 mg doses. Open-label follow-up of patients continues; the median length of study treatment at the time of this analysis was more than 40 weeks for the 10 and 15 mg vicriviroc treatment groups.
VICTOR-E1 Trial Initiated to Evaluate Higher Doses to Achieve Incremental Benefit in Treatment-Experienced HIV Patients
Based on the ACTG study reported above and extensive pharmacokinetic and pharmacodynamic data, Schering-Plough Research Institute has initiated a new Phase II clinical trial of higher doses of vicriviroc in treatment-experienced HIV patients, with the goal of achieving incremental improvement in viral suppression. VICTOR-E1 (Vicriviroc in Combination Treatment with Optimized Antiretroviral Treatment Regimen in Experienced Subjects) will evaluate the safety and efficacy of vicriviroc (20 mg and 30 mg once daily) compared to placebo in combination with an optimized ritonavir-boosted, protease inhibitor-containing antiretroviral regimen. The primary objective of the study is to evaluate the antiviral activity of vicriviroc as measured by the decline of viral load (log10 copies/mL) from baseline at 12 and 24 weeks. A total of 120 patients who are currently failing an antiretroviral treatment regimen will be enrolled in the 48-week trial. The study is being conducted at sites throughout Europe and North and South America.
For additional information on the ongoing VICTOR-E1 trial and trial sites, please visit http://www.clinicaltrials.gov.
About Vicriviroc
Vicriviroc is an extracellular inhibitor of HIV infection that is believed to block entry of infectious virions into uninfected CD4 cells via antagonism of the CCR5 co-receptor. Despite the availability of more than 25 antiretroviral agents, the challenges of viral resistance and toxicities underscore the need for new agents with novel mechanisms of action. VICTOR-E1 and other vicriviroc studies in the drug's development program will further evaluate its utility against HIV disease when used in combination with antiretroviral drugs. Vicriviroc has been studied to date in more than 650 patients in pharmacology or clinical trials.
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