HIV – Pro-140
Pfizer’s CCR5 antagonist maraviroc was the first anti-HIV treatment that works by blocking the virus’s entry to the cell
When Pfizer’s CCR5 antagonist maraviroc (Celsentri/Selzentry) reached the market three years ago, it was the first anti-HIV treatment that works by blocking the virus’s entry to the cell rather than attacking part of the viral lifecycle. Several other companies have tried and failed to make small molecule drugs that target this G-protein coupled receptor.
An alternative approach is being taken by Progenics Pharmaceuticals – creating a humanised monoclonal antibody that blocks CCR5. Interestingly, it appears to retain antiviral activity in maraviroc-resistant isolates of HIV-1.1
In a randomised, double blind, placebo-controlled, dose escalating study, 39 patients with HIV-1, who had had no antiretroviral therapy for three months and in whom only CCR5-tropic HIV-1 was detectable, were given intravenous single doses of 0.5, 2 or 5 mg/kg of the antibody, or placebo.2 It was generally well tolerated, and gave potent, rapid, prolonged and dose-dependent antiviral activity. Reductions in mean viral load of at least 10-fold were seen within four days of dosing, and these persisted for two to three weeks.
In another trial, subcutaneous administration was investigated in 44 patients of a similar profile to the first trial.3 They were given 162 or 324mg of the antibody or placebo weekly for three weeks, or 324mg every other week for two doses, by subcutaneous infusion. Again, significant viral reductions were seen, and viral loads remained suppressed between the doses. It was generally well tolerated.
Results of a Phase IIa study have recently been reported.4 In the randomised, double blind, placebo-controlled trial, 31 subjects (again with a similar profile) were given single intravenous infusions of 5 or 10mg/kg.
Again, good reductions in viral load were seen, and viral loads reached their lowest level 12 days after treatment. They remained significantly reduced right through to day 29 for both treated groups. It was generally well tolerated, and there were no dose-limiting toxicities.
references
1. P. Pugach et al. Virology 2008, 377, 401
2. J.M. Jacobson et al. J. Infect. Dis. 2008, 198, 1345
3. J.M. Jacobson et al. J. Infect. Dis. 2010, 201, 1481
4. J.M. Jacobson et al. Antimicrob. Agents Chemother. 2010, 54, 4137