Progenics Announces Results from First Clinical Trial of CCR5 Inhibitor PRO 140

On April 24, the Antiviral Drug Advisory Committee of the U.S. Food and Drug Administration (FDA) voted to recommend accelerated approval of Pfizer's maraviroc (Celsentri). While maraviroc is the first CCR5 inhibitor to be considered for approval, it is not the only drug of its class in the development pipeline.

PRO 140 is a humanized monoclonal antibody designed to block the ability of HIV to infect cells by inhibiting virus-cell binding. We have designed PRO 140 to target a distinct site on CCR5 without interfering with the normal function of CCR5 on cells.

On May 1, Progenics Pharmaceuticals announced promising data from a Phase Ib clinical trial of its CCR5 blocker, PRO 140. This agent is a genetically engineered monoclonal antibody that binds to the CCR5 co-receptor on the surface of host cells, thereby preventing HIV from using the receptor to gain entry.

In this study, HIV RNA levels remained suppressed for 2-3 weeks after dosing of PRO 140 as monotherapy, suggesting the drug might be administered weekly or less. A drawback of the monoclonal antibody approach is that PRO 140 must be injected, rather than taken as a pill like maraviroc and similar agents.

The FDA has granted PRO 140 “fast track” status and further clinical trials are scheduled to start later this year.

Below is an excerpt of a press release from Progenics describing the Phase Ib study results:

Progenics Announces Positive Results in Clinical Trial of Novel HIV Therapy

Single dose of CCR5 monoclonal antibody PRO 140 significantly reduced viral load for prolonged period in HIV-infected individuals

TARRYTOWN, NY -- (BUSINESS WIRE) -- May 1, 2007 - Progenics Pharmaceuticals, Inc. (NASDAQ: PGNX) today announced positive results from the first clinical trial of its investigational drug, PRO 140, in individuals infected with the human immunodeficiency virus (HIV), the causative agent of AIDS.

Patients receiving a single 5.0 mg/kg dose of PRO 140 achieved an average maximum decrease of viral concentrations in the blood of 98.5% (1.83 log₁₀), with individual reductions ranging up to 99.7% (2.5 log₁₀). In these patients, reductions in viral load of greater than 90% (1.0 log₁₀) on average persisted for two to three weeks after dosing. In addition, PRO 140 was generally well tolerated in this phase 1b proof-of-concept study. PRO 140 was granted Fast Track status from the U.S. Food and Drug Administration (FDA), and Progenics plans to initiate additional clinical testing in the second half of 2007.

"This study establishes clear proof of concept for PRO 140 as a potent antiretroviral agent with extended activity following a single dose," said Scott M. Hammer, MD, Chief, Division of Infectious Diseases and Harold C. Neu Professor of Medicine, Columbia University College of Physicians and Surgeons, New York City. "The primary goal of HIV therapy is to provide maximal and durable suppression of viral replication. Based on this study, PRO 140 has the potential to add to the armamentarium of drugs that can help achieve this goal in patients living with HIV, including those whose treatment options are limited by drug resistance."

PRO 140 is a humanized monoclonal antibody that binds CCR5, the principal portal used by HIV to enter cells. Viral-entry inhibition using a long-lived antibody represents a promising novel approach to treating HIV infection. Unlike currently available antiretroviral drugs, PRO 140 does not target the virus, but rather binds to the CCR5 receptor on healthy immune system cells and thereby protects them from viral infection. HIV in the bloodstream that cannot enter a host cell is rendered harmless and rapidly cleared from the body. In contrast to PRO 140's mechanism of action as a viral-entry inhibitor, most antiretroviral drugs are designed to slow viral replication inside already-infected immune cells.

Clinical trial design and study results

This multi-center, double-blind, randomized, placebo-controlled phase 1b trial examined three single intravenous escalating doses of PRO 140: 0.5 mg/kg, 2.0 mg/kg and 5.0 mg/kg. The study was designed to assess the safety, tolerability, pharmacology and antiviral activity of PRO 140 and was conducted at 10 sites in the United States. Thirty-nine HIV-infected individuals who had taken no anti-retroviral therapy within the preceding three months and who had plasma HIV RNA levels (viral loads) greater than or equal to 5,000 copies/mL were enrolled to receive PRO 140 monotherapy or placebo. All patients were screened prior to the study for the presence of virus that utilizes only CCR5 as the entry coreceptor. Of the 13 patients in each cohort, 10 patients received PRO 140 and three received placebo.

The primary efficacy endpoint was the reduction in plasma HIV RNA level as measured by the Roche Amplicor assay. The results were positive, dose-dependent, and highly statistically significant for the two highest doses tested. HIV-infected individuals who received 5.0 mg/kg of PRO 140 achieved an average maximum decrease of viral load of 1.83 log₁₀ (98.5%; p<0.0001), with individual reductions ranging up to 2.5 log₁₀ (99.7%). At nine days post-treatment, these same individuals achieved a mean viral load reduction of 1.70 log₁₀ (98%; p<0.0001). In this cohort, mean viral load was suppressed by 1.0 log₁₀ (90%) within four days of dosing and persisted at or below the 1.0 log₁₀ level of reduction for two to three weeks in patients before returning to baseline at approximately 30 days. The response rate among the treatment groups (percentage of patients with [at least a] 1 log₁₀ decrease in HIV RNA at any time) increased with PRO 140 dose, reaching a maximum of 100% in the highest dose cohort (p<0.0001).

* P values are from an analysis of variance model (ANOVA), pairwise two-sided t tests comparing each treatment group to placebo after the overall F test was found to be statistically significant. Log₁₀ changes in HIV RNA are calculated relative to baseline.

In this study, PRO 140 was generally well tolerated and no drug-related serious adverse events were reported. A more detailed discussion of the study results is planned for an upcoming scientific conference.

"These clinical findings with PRO 140 in HIV infection represent a major achievement for Progenics and a further strengthening of our drug pipeline," said Paul J. Maddon, MD, PhD, Progenics' Founder, Chief Executive Officer and Chief Science Officer, and who played a significant part in the discovery of CCR5's role in HIV infection. "As an HIV/AIDS researcher for more than two decades, I was particularly gratified to see these results from our proprietary PRO 140 antibody, as they represent the largest reported single-dose mean reduction in viral load for any antiretroviral drug. We look forward to future clinical testing of PRO 140 in individuals across various stages of HIV infection. We thank the patients and investigators who participated in this clinical trial, as well as Progenics' research and clinical teams and scientific collaborators who developed PRO 140. We also are grateful for funding from the National Institute of Allergy and Infectious Diseases which supported our PRO 140 preclinical and clinical programs."

About PRO 140

PRO 140 is a humanized monoclonal antibody discovered by Progenics' scientists that binds CCR5 on immune system cells and shields the cells from HIV infection. CCR5 is a receptor for chemokines, members of a family of molecules that direct the migration of immune cells towards sites of inflammation in the body. Progenics and its collaborators discovered the role of CCR5 in HIV infection in 1996.

In laboratory studies, PRO 140 has demonstrated potent, broad-spectrum antiviral activity against approximately 100 genetically diverse HIV strains, isolated directly from infected individuals, which use the CCR5 portal. In these preclinical models, PRO 140 was shown to protect both primary T-cells and macrophages, immune system cells that provide the major targets for HIV infection in vivo. In the laboratory, PRO 140 has shown synergistic activity when combined with small-molecule CCR5 antagonists in development. Importantly, in vitro testing also demonstrated that PRO 140 inhibited viruses that were resistant to small-molecule CCR5 antagonists. Unlike other CCR5 entry inhibitors currently in development, PRO 140 inhibits HIV entry at concentrations that do not block the natural activity of CCR5 in vitro.

PRO 140 has been designated a Fast Track product by the FDA for the treatment of HIV infection. The FDA Fast Track Development Program facilitates development and expedites regulatory review of drugs intended to address an unmet medical need for serious or life-threatening conditions. With Fast Track designation for PRO 140, Progenics can take advantage of several programs at FDA to streamline the regulatory review process and to work more closely with the Agency on product development plans.

Source
 

Progenics Pharmaceuticals (via BusinessWire). Progenics Announces Positive Results in Clinical Trial of Novel HIV Therapy. Press release. May 1, 2007.