Vicriviroc (SCH-D)

Vicriviroc is a CCR5 antagonist originally developed by Schering-Plough’s  and previously known as SCH-D and SCH-417690. Merck & Co., Inc. acquired vicriviroc in its merger with Schering in late 2009.

Vicriviroc showed promising results in phase I and early phase II trials in highly treatment-experienced patients. However, the drug's development was halted after phase III trials showed little additional benefit compared to optimised background therapy in treatment-experienced patients, and phase II treatment-naïve trials also showed disappointing results.

In a phase I trial, participants receiving one of three doses of vicriviroc (VCV) monotherapy or placebo for 14 days had significantly decreased HIV viral load in all vicriviroc arms and viral suppression persisted for two to three days after stopping drug.¹

In the double-blinded phase II ACTG A5211 trial, 118 treatment-experienced participants with viral load equal or greater than 5000 copies/ml were randomised to receive one of three doses of vicriviroc plus a background regimen optimised for antiviral activity after a resistance test. That study found that between 27% to 37% of those receiving vicriviroc had a viral load below 50 copies/ml, compared with 11% in the placebo arm. There were 39 patients followed for more than two years while taking vicriviroc, of whom 60% maintained viral load below 50 copies/ml.²

The responses seen in this trial were better among those participants who added enfuvirtide (T-20, Fuzeon) for the first time to their regimen, resulting in an additional one-log reduction in viral load as compared to results from non-enfuvirtide users or those who entered the study with enfuvirtide experience.

VICTOR-E1 (Vicriviroc in Combination Treatment with an Optimized Antiretroviral Therapy Regimen in HIV- Infected Treatment-Experienced Subjects), another double-blind phase 2b trial, was an international study with 116 highly treatment-experienced participants with viral load greater than 1000 copies/ml despite stable ART. At 48 weeks, vicriviroc plus background therapy was significantly superior to optimised background therapy alone. It was determined that 30mg vicriviroc dosed once daily would be used in subsequent clinical trials.³

Extended 96-week safety and efficacy results from both the VICTOR-E1 and ACTG A5211 studies showed sustained viral suppression, durable CD4 cell count increases, and continued tolerability when vicriviroc was given with an optimised treatment background.⁴  

Earlier concerns about potential elevated risk for cancers, hepatotoxicity, seizures, or ischemic cardiovascular events were largely assuaged based on analysis of phase II and III trials including ACTG A5111, ACTG A5211, and VICTOR-E1, -E3 and -E4.^{5 6 7}

However, vicriviroc performed disappointingly in phase III trials VICTOR-E3 and E4. In these double-blind, placebo-controlled international trials, more than 800 treatment-experienced participants with resistance to at least two drug classes were randomised to either 30mg once-daily vicriviroc or placebo in combination with optimised background therapy. All patients had at least two active drugs, including a ritonavir-boosted protease inhibitor, in their background regimen; just over 60% had three active drugs.

At week 48, similar proportions of patients on vicriviroc and placebo achieved a viral load below 50 copies/ml: 64% and 62% respectively. Vicriviroc outperformed placebo in participants with two or fewer active drugs in their background therapy, with 70% in the vicriviroc arms and 55% in the placebo arms achieving undetectable viral load.⁵

Based on these results, Merck abandoned its intent to obtain a license for vicriviroc in treatment-experienced patients with the US Food and Drug Administration. Shortly thereafter, in July 2010, Merck announced that it was halting development of vicriviroc altogether. This followed disappointing findings from a study of vicriviroc in treatment-naïve patients as part of a nucleoside analogue-sparing regimen, in combination with atazanavir/ritonavir. Merck provided no details of the study outcomes in a letter to investigators announcing the cancellation of the drug development programme, but said the study results would be presented at a future scientific meeting.