Early promise for Progenics' MAb HIV entry inhibitor
This article was originally published in Scrip
Progenics Pharmaceuticalshas presented positive interim results from two separate Phase II trials of subcutaneous and intravenous formulations of PRO 140 – a novel humanised monoclonal antibody CCR5 antagonist – in treatment-naive HIV patients. The data were presented at the joint meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) and the Infectious Diseases Society of America (IDSA) in Washington, DC.
The company plans to meet the US FDA in early 2009 in order to design pivotal Phase IIb/III trials of PRO 140 and is looking to select either the subcutaneous or intravenous formulation to continue to this stage.
"Both formulations are favourable. Our decision will be based on safety, efficacy and commercial viability," said Dory Lombardo, corporate affairs manager.
"Intravenous PRO140 has to be dosed monthly at a clinic, whereas the subcutaneous formulation could be self-administered weekly or bi-weekly, although, in these trials, the subcutaneous injection was slightly less potent than the intravenous."
advantages?
Other CCR5 antagonists available are small molecules, such as Pfizer's Selzentry (maraviroc), and Schering-Plough'svicriviroc (in Phase III).
Unlike small-molecule CCR5 antagonists which are associated with liver toxicity, and are required to carry a black box warning on their labels (Scrip Online, August 10th, 2007), Progenics claim PRO 140 has not been linked to liver damage.
The company believes that its monoclonal antibody is advantageous because it binds to the same portion of CCR5 as HIV – acting as a competitive inhibitor and also permitting normal chemokine binding to continue, which is important in the modulation of inflammation. Small molecules, however, bind a hydrophobic pocket formed by the transmembrane helices of CCR5 and inhibit HIV-1 via allosteric mechanisms, interfering with normal chemokine binding.
Progenics claims that PRO 140 is the first monoclonal antibody CCR5 antagonist to be developed, and it appears to be the only one in the clinic. The company would not disclose whether it is considering a partnership with another firm in order to progress it through pipeline.
intravenous formulation
The intravenous Phase II trial was randomised, placebo-controlled and enrolled 31 patients who were screened for the presence of R5 tropic virus and absence of X4, had received no antiretroviral therapy for at least three months and had HIV-1 RNA viral loads of greater than 5,000 copies/ml.
HIV is either R5 tropic and uses CCR5 co-receptor to facilitate CD4 cell entry, or X4 tropic – where the virus gains entry via the CXCR4 co-receptor. Throughout the progression of HIV, it is common for the virus to switch from R5 to X4 tropism. It is also possible to be dual infected with R5 and X4 viruses, CCR5 antagonists are not effective in the presence of X4.
Patients received a single dose of either placebo, 5mg/kg of PRO 140 or 10 mg/kg of PRO 140 and were monitored for 58 days. An interim analysis to provide proof of concept data was performed after the first dose on the first 15 subjects (five from each dosing arm) treated.
All subjects treated with 5mg/kg experienced >1.0log
Following a single dose of 10mg/kg, patients maintained a >10log
In comparison with placebo, intravenous doses were generally well tolerated; no drug-related serious adverse events or dose-limiting toxicity were reported.
subcutaneous formulation
The subcutaneous Phase II trial of PRO 140 enrolled 44 HIV patients that met the same entry requirements as those for the intravenous study. Patients were randomised to receive to receive three weekly doses of 162mg of PRO 140, two bi-weekly doses of 324mg of PRO 140, three weekly doses of 324mg of Pro 140, or placebo, and again an interim analysis was performed.
At 324mg bi-weekly dosing, patients achieved a 1.34log
All of the subjects treated with 324mg (p=0.0079) weekly and 67% (not significant) of 324mg bi-weekly achieved a maximum viral load reduction >1.0log
"The findings underscore the efficacy with which PRO 140 blocks HIV's access to CCR5 and healthy cells in vivo," said researcher Dr Jeffrey Jacobson, chief of the division of infectious diseases and HIV medicine at Drexel University College of Medicine.
"The antiviral and safety data for subcutaneous PRO 140 are highly encouraging. Many patients are excited by the potential for a potent and well-tolerated therapy that could be self-administered."