ICAAC: Vicriviroc safe, effective after 2 years, phase III studies start soon

Vicriviroc, an experimental drug that blocks use of the CCR5 receptor by HIV, shows safety and efficacy for two years in treatment-experienced patients, according to data released this week at the 47^th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.

Manufacturer Schering Plough announced that the drug, which had been under safety suspicions following an unexplained excess of cancers in patients who received the drug in phase II trials, will enter phase III studies within the next month.

The data presented this week represent the longest follow-up of any agent in the new class of drugs called CCR5 antagonists. These drugs block the CCR5 receptor on lymphocytes that HIV must use in order to gain access to the CD4 cells of the immune system.

Because the CCR5 receptor is part of the immune system’s network of regulatory pathways that involve chemicals called chemokines, there has been concern that long-term side-effects might result from use of CCR5 antagonists.

So, when several cases of cancer were seen in treatment-experienced patients taking vicriviroc in a clinical trial in 2005, the development of vicriviroc was slowed down while researchers and regulators tried to determine whether the drug was responsible for these cancers.

Forty-eight week results of ACTG 5211, a study which randomised treatment-experienced patients to receive one of three doses of vicriviroc plus a background regimen optimised for anti-viral activity after a resistance test, were presented at the International AIDS Society conference in Sydney in June.

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. Five cancers were seen in the vicriviroc arm, predominantly in patients with a previous history of malignancy.

Findings from the ACTG 5211 study presented at ICAAC by Trip Gulick of Cornell-Weill Medical College, New York, showed that in 39 treatment-experienced patients followed for more than two years while taking vicriviroc, 60% still had viral load below 50 copies/ml, CD4 counts had risen by an average of 84 cells/mm³ and no further cases of lymphoma had occurred.

Six patients in the follow-up study experienced tropism shifts, two to CXCR4-tropic virus and four to mixed tropic virus.

Schering-Plough is now ready to take the drug forward into phase III studies that will form the basis for a licensing application, it said on Monday in a press release.

The two Phase III studies, known as VICTOR-E3 and VICTOR-E4 (Vicriviroc in Combination Treatment with an Optimized Antiretroviral Therapy Regimen in HIV- Infected Treatment-Experienced Subjects), will evaluate the virologic benefit of adding vicriviroc 30 mg once daily to an optimised background therapy compared to a control group receiving new optimised background therapy alone. This is a higher dose than the top dose studied in the phase IIb dose-ranging study, which assigned patients to 5, 10 or 15mg doses..

The studies will also evaluate the safety and tolerability of vicriviroc compared to placebo. The optimised background therapy must include at least two drugs that are active, based on susceptibility testing.

Patients in VICTOR-E3 and VICTOR-E4 must have documented resistance to at least two of the three antiretroviral drug classes or six months or more of experience with at least two of the following: one nucleoside analogue, one non-nucleoside reverse transcriptase inhibitor or two protease inhibitors (excluding low-dose ritonavir); and must have a viral load above 1,000 copies/ml. The optimised background therapy must include a protease inhibitor boosted by ritonavir and at least two drugs that are active, based on susceptibility testing.

Patients coinfected with hepatitis C may be included in the studies and there are no exclusions of commonly prescribed drugs or need for dose adjustments based on the known vicriviroc drug-drug interaction profile. The studies will enroll approximately 375 patients each at more than 160 sites in North America, South America, Europe, Australia and South Africa.