ICAAC: Phase 1 study provides `proof of concept` for PRO 140, a monoclonal CCR5 antibody

In a single-dose Phase I study, the monoclonal CCR5 antibody PRO 140 has demonstrated favourable short-term safety and potent, dose-dependent antiviral effect. Larger human trials are planned. These preliminary findings were presented in an oral session this week at the 47^th Interscience Conference on Antimicrobial Agents and Chemotherapy.

Antiretrovirals in the CCR5 inhibitor class prevent binding and entry of HIV into cells by blocking the cellular coreceptor CCR5. PRO 140 is a CCR5 monoclonal antibody being developed by ProGenics which is distinct from other developmental CCR5 inhibitors in several ways. It has different binding sites and mechanism of action, and is therefore likely to display a distinct resistance pattern from other oral CCR5 antagonists.

PRO 140 is a larger molecule which therefore must be delivered by injection; however, this will likely allow for less frequent dosing and avoid interactions with food and other drugs. While an intravenous formulation of PRO 140 is currently being tested, the manufacturer intends the drug to be delivered by simpler subcutaneous injection by the time it comes to market.

The US Food & Drug Administration has designated PRO 140 for fast-track approval.

PRO 140 has been shown to potently block HIV entry in vitro. Here, a randomised, double-blind study evaluated the antiviral safety, tolerability, pharmacokinetics and pharmacodynamics, and preliminary efficacy of a single dose of PRO 140 in asymptomatic, HIV-positive individuals.

All participants had CD4 cell count nadirs below 200 cells/mm³, current CD4 cells counts above 250 cells/mm³, and viral loads greater than 5000 copies/ml. The relatively healthy group was required not to have had any AIDS-defining illness, and not to have been on antiretroviral therapy in the previous three months.

A total of 39 such individuals were randomized in a 3:10 ratio to receive a single intravenous infusion of placebo or a dose of 0.5, 2 or 5 mg/kg of PRO 140.

PRO 140 was generally well tolerated; according to the report there were no serious adverse effects, dose-limiting toxicities, or obvious pattern of adverse effects. One participant experienced a "self-limiting" flu-like reaction including fever, nausea and vomiting; another patient developed anti-PRO 140 antibodies.

There was a short-term, dose-dependent reduction in viral load associated with use of PRO 140. Mean maximum changes in HIV RNA of -0.39, -0.58, -1.20 (p=0.0002), and -1.83 log₁₀ copies/ml (p<0.0001) were observed for the placebo, 0.5, 2 and 5 mg/kg dose groups, respectively. The duration as well as the magnitude of the virologic response was proportional to the magnitude of the dose. Individual HIV RNA reductions ranged up to 2.5 log₁₀ copies/ml at both 2 and 5 mg/kg.

On average, reductions of greater than 1 log₁₀ copies/ml were maintained for between two and three weeks. Viral loads reached a nadir at nine days post-treatment, at which point mean PRO 140 serum levels were 1.4 and 4.1 μg/ml in the two highest dose groups. The bodily half-life of PRO 140 was estimated to be roughly 4 days at the 5 mg/kg dose.

All participants had virus that was phenotypically susceptible to PRO 140 at baseline; by the end of the study there were no changes in viral susceptibility (i.e., there was a less than twofold change in viral IC₅₀ in all participants).

All PRO 140-treated individuals had exclusively R5-tropic virus before the dose was administered. At study end, one out of nine in the placebo group and one out of 30 in the treatment group had developed dual/mixed tropic virus.

The researchers concluded that PRO 140 has displayed "potent, rapid, prolonged, dose-dependent, highly significant antiviral activity," and that this study "provides proof of concept for PRO 140 as a potent and long-acting antiretroviral agent." Further studies are intended to investigate higher doses, combinations with other antiretroviral drugs, a subcutaneous formulation, and more detailed resistance analyses.