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PRO 140 associated with potent antiviral activity in patients with HIV
The CCR5 monoclonal antibody could be the first self-administered antiviral.
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Single-dose CCR5 monoclonal antibody PRO 140 was well tolerated and showed potent, prolonged dose-dependent antiviral activity in patients with HIV in a phase-1 study.
The study was the first trial of the PRO 140 (Progenics Pharmaceuticals) in patients with HIV. The results, demonstrating significant viral load reductions, were presented at the International AIDS Society Conference, held recently in Sydney.
Participant viral loads decreased an average 1.7 logs10 (98%) after 10 days. The most significant reduction in one patient was 2.5 logs10.
“To our knowledge, these are the largest viral load reductions reported for just one dose of any HIV agent,” William C. Olson, PhD, vice president of research and development at Progenics Pharmaceuticals, said while presenting the results in Sydney. “Viral load reductions of about one log were observed at day 5 and then continued for two to three weeks post-dosing.”
Progenics plans to present the additional pharmakinetic results of the recent trial at the upcoming Interscience Conference on Antimicrobial Agents and Chemotherapy this month. PRO 140 has already shown favorable tolerability and pharmacokinetic profiles in studies of healthy participants.
“Putting this all together would suggest at least that weekly or even every other week dosing of PRO 140 would be predicted to provide antiviral drug levels,” Olson said. “That’s exciting because it means potentially subcutaneous PRO 140 would be able to provide the first long-acting, self-administered therapy for HIV.”
PRO 140, a potent and long-acting antiretroviral agent, is now a designated FDA fast track drug candidate.
“I could spend the entire session describing how PRO 140 is different from small molecule CCR5 antagonists, such that these two in many respects, represent distinct classes of CCR5 inhibitors,” Olson said. “Suffice it to say that there are fundamental differences in the way in which PRO 140 and small molecule CCR5 antagonists recognize CCR5 and inhibit R5 HIV.”
Patients with CCR5 tropic virus
Olsen and his colleagues recruited 39 patients with HIV for the study. Each patient had easily measurable levels of virus which required CCR5 for entry. Thirty-one of the patients were men; 17 were black and 19 were white. Median age was 40.3 years.
At baseline, patients had median CD4 counts of 480 cells and median HIV RNA of entry was 27,000 copies/mL. All participants had only CCR5-tropic virus, no AIDS-defining illness and had no antiretroviral therapy for at least three months prior.
Patients were randomly selected to receive single intravenous infusion of PRO 140 in 0.5 mg/kg, 2 mg/kg, and 5 mg/kg nominal doses or placebo in sequential ascending cohorts. The patients were followed for 59 days.
HIV RNA decreased more than 10-fold in several of the patients in the ascending dose treatment groups. The 5 mg/kg per dose group had a 1.83 log10 reduction.
“We saw a nice dose response relationship with a 100% dose rate at the top dose group,” Olson said.
Antiviral effects were associated with PRO 140 serum concentrations and CCR5 receptor occupancy. Mean maximum viral loads decreased by 0.39 logs10 in the placebo group, 0.58 logs10 in the .5 mg/kg group, 1.20 logs10 in the 2 mg/kg group, and 1.83 logs10 in the 5 mg/kg group.
A trend of CD4 cell increase was observed in the high dose group. “This manifested itself as a 129-cell increase or a 29% increase at day 8, and these levels persisted at three weeks post-dosing,” Olson said.
Potent antiviral suppression often leads to redistribution of CD4 cells, which could be the reason for the marked increase.
“Regardless of the mechanism, we are encouraged by the fact that the trend is in the right direction,” Olson said.
No drug-related serious adverse events or detectable patterns of toxicity were observed.
For more information:
- Saag MS, Jacobson JM, Thompson M, et al. Antiviral effects and tolerability of the CCR5 monoclonal antibody PRO 140: A proof of concept study in HIV-infected individuals. Presented at: The International AIDS Conference on HIV Pathogenesis, Treatment and Prevention; July 22-25, 2007; Sydney.