Despite the availability of more than 20 antiretroviral agents, the challenges of viral resistance and toxicities present the need for new agents with novel mechanisms of action.  The CCR5 inhibitors are a new class of antiretrovirals that have shown early promise in blocking HIV replication prior to viral entry into cells.

HIV-1 interacts with a cell-surface receptor, primarily CD4, and through conformational changes becomes more closely associated with the cell through interactions with other cell-surface molecules, such as the chemokine receptors CXCR4 and CCR5.

The experimental CCR5 inhibitor vicriviroc (VCV) from Schering-Plough has been studied to date in more than 750 patients in pharmacology or clinical trials and has demonstrated short-term anti-HIV activity.

In this study (ACTG 5211) a total of 118 treatment-experienced HIV patients (median viral load 36,380 copies/ml and CD4 146 cells/microliter) with R5-type virus at screening who were taking ritonavir-boosted PI-containing regimens were randomized in this double-blind, 48-week study to receive vicriviroc (5, 10 or 15 mg) dosed once daily or placebo, after the background antiretroviral regimen had been optimized at day 14. 

At day 14, the study primary endpoint, and 24 weeks, the secondary endpoint, median changes in HIV-1 RNA level from baseline (log10 copies/mL) were greater in the 5, 10 and 15 mg vicriviroc groups -0.87 and -1.51, -1.15 and -1.86 and -0.92 and -1.68, respectively, compared to the placebo group +0.06 and -0.29 (p<0.01). 

Mean CD4 cell counts increased at week 24 for the vicriviroc 5, 10 and 15 mg groups by +84, +142 and +142 respectively, compared to a decrease of -9 for the placebo group. 

The 5 mg dose of vicriviroc in this trial was discontinued early (patients were unblinded and could increase their vicriviroc dose to 15 mg).  In the study, eight patients on vicriviroc and two patients on placebo developed malignancies.  As a result, the independent Safety Monitoring Committee recommended that patients be informed of this information, unblinded to treatment assignment and continued to be followed.  Consequently, the study became open label on March 6, 2006.

At the 4^th IAS conference in Sydney, AU (July 22-25, 2007), Dr. Roy Gulick presented 48-week results on the use of vicriviroc in 118 treatment-experienced HIV patients with R5 virus and HIV viral load (VL) of >/=5000 copies/ml. All analyses are intent-to-treat.

Results

• At 48 weeks, patients in the 10 mg and 15 mg vicriviroc treatment groups achieved a median decrease in viral load of 1.92 and 1.44 (log10 copies/mL) and a median increase in CD4 cell count of 130 and 96 (cell/uL) from baseline, respectively. 
  
  
• More patients in the vicriviroc groups had undetectable virus at 48 weeks (HIV-1 RNA <400/<50 copies/ml) compared to those in the placebo group (57/37 percent and 43/27 percent vs. 14/11 percent, respectively);
  
  
• Fewer patients in the vicriviroc groups experienced virological failure compared to those in the placebo group (27 and 33 percent vs. 86 percent, respectively). 
  
  
• Grade 3/4 adverse events were similar across arms. 8 malignancies were previously reported (6 in the VCV arms; 2 in the placebo arm, 1 following VCV crossover); no new malignancies occurred and no cases of seizure were reported.

• 18 subjects were randomized (8% women; 34% non-whites) with median VL 36380 (4.56 log10) copies/ml and CD4 146 cells/uL.
  
  
• Of 20 subjects on VCV 10/15 mg with VL <50 copies/ml at 24 weeks, 14 (70%) continued <50 copies/ml at 48 weeks.
  
  
• Grade 3/4 adverse events were similar across arms. 8 malignancies were previously reported (6 in the VCV arms; 2 in the placebo arm, 1 following VCV crossover); no new malignancies occurred.
  
  
• Of 26 VCV subjects with R5 virus who experienced virologic failure, 9 (35%) had D/M or X4 virus.
  
  

Based on these findings, Dr. Gulick and colleagues concluded, “In treatment-experienced patients, VCV (10/15 mg) demonstrated potent virologic suppression, sustained over 48 weeks. These are the longest available follow-up data with a CCR5 inhibitor-based regimen.”

Commentary

“These 48-week data establish the durability of viral suppression with a vicriviroc-containing regimen in treatment-experienced patients with advanced HIV disease, and are the first to demonstrate the sustained effects of a CCR5-based regimen through 48 weeks,” said Roy Gulick, M.D., principal investigator and professor, Weill Medical College of Cornell University, New York, who presented the data at the 4^th IAS conference in Sydney.

Building on the ACTG study reported above, Schering-Plough Research Institute said the company is conducting an ongoing Phase II clinical trial of higher doses of vicriviroc in treatment-experienced HIV patients, with the goal of achieving further improvement in viral suppression. 

VICTOR-E1 (Vicriviroc in Combination Treatment with Optimized Antiretroviral Treatment Regimen in Experienced Subjects) is evaluating 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.  A total of 116 patients have been enrolled in this 48-week trial at sites throughout Europe and North and South America.

Based on results from the ACTG and VICTOR-E1 Phase II clinical trials, Schering-Plough will select a dose of vicriviroc to move forward into Phase III clinical development in treatment-experienced patients. 

07/27/07

References   
             
R Gulick, Z Su, C Flexner, and others (for the ACTG 5211 Team). ACTG 5211: phase II study of the safety and efficacy of vicriviroc (VCV) in HIV-infected treatment-experienced subjects: 48 week results. 4th IAS Conference. July 22-25, 2007. Sydney, AU. Abstract (oral) TuAb102.

Schering-Plough. Vicriviroc Demonstrates Potent Viral Suppression through 48 Weeks of Therapy in ACTG Phase 2 Study in Treatment-experienced HIV Patients. Press Release. July 24, 2007.

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