Experimental HIV Entry Inhibitor PRO 140 Demonstrates Favorable Activity in Phase 2 Trial

By Liz Highleyman

The investigational HIV entry inhibitor PRO 140 has demonstrated potent anti-HIV activity in a Phase 2 clinical trial, according to a late-breaker poster presented last month at the 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008).

PRO 140, being developed by Progenics Pharmaceuticals, is a recombinant (genetically engineered) monoclonal antibody that binds to the CCR5 cell surface co-receptor and prevents CCR5-tropic strains of HIV from using the co-receptor to enter cells. Some strains of HIV can use the CXCR4 coreceptor (CXCR4 tropism) or both CCR5 and CXCR4 (dual/mixed tropism), and CXCR4-tropic virus tends to emerge as disease progresses.

Unlike small-molecule CCR5 antagonists such as maraviroc (Selzentry), PRO 140 inhibits HIV entry at concentrations that do not appear to block the natural immune activity of CCR5, and it is not metabolized by the liver.

In the study presented at ICAAC, researchers compared the antiviral activity and tolerability of 5 mg/kg and 10 mg/kg intravenous (IV) doses of PRO 140. The study included 31 patients with exclusively CCR5-tropic virus, baseline HIV RNA > 5000 copies/mL, CD4 count > 300 cells/mm3, and no antiretroviral therapy for at least 12 weeks. Participants were randomly assigned to receive single doses of 5 mg/kg PRO 140, 10 mg/kg PRO 140, or placebo, and were followed for 58 days post-treatment.

The poster described an interim analysis of data from the first 15 treated patients (5 per arm). Among this group, the mean baseline viral load was about 35,500 copies/mL and the mean CD4 count was about 400 cells/mm3.

Results

• Mean maximum log10 reductions in HIV RNA were 1.90 (range 1.44-2.17) in the 5 mg/kg PRO 140 arm and 2.17 (range 2.09-2.26) in the 10 mg/kg PRO 140 arm, compared with 0.48 (range 0.15-0.73) in the placebo arm (both P < 0.0001).

• At day 12, mean log10 changes in HIV RNA were -1.88, -2.01, and +0.06, respectively (P < 0.0001).

• All patients treated with 5 mg/kg PRO 140 experienced a greater than 1.0 log10 maximum reduction in viral load, while those who received 10 mg/kg experienced a greater than 2.0 log10 maximum reduction (both P = 0.0079).

• Through day 22, the mean viral load reduction was 1.55 log10 in the 10 mg/kg PRO 140 arm (P = 0.0005).

• PRO 140 was generally well-tolerated, with no drug-related serious adverse events or dose-limiting toxicities.

"The data confirm the antiviral activity reported previously for 5 mg/kg PRO 140," the investigators concluded. "A 10 mg/kg dose increased the duration of antiviral effect."

The antiviral activity in the 5 mg/kg PRO 140 arm of this study was similar to the mean 1.83 log10 viral load reduction with the same dose observed in an earlier Phase 1b study, which was initially presented at the 2007 International AIDS Society meeting in Sydney, Australia, and published in more detail in the November 1, 2008 Journal of Infectious Diseases. Doubling the dose produced more potent and long-lasting antiviral activity.

But IV dosing is inconvenient for patients, and the company is also testing a subcutaneous (SC) formulation of PRO 140 that is injected under the skin rather than into a vein. In this trial, 44 patients were randomly assigned to receive 3 once-weekly doses of 162 mg or 324 mg PRO 140; 2 bi-weekly doses of 324 mg PRO 140, or placebo.

Progenics recently announced interim data from the first 20 patients in this study, showing a mean maximum viral load reduction of 1.77 log10 for patients treated with 3 once-weekly 324 mg subcutaneous doses (P = 0.0006). 100% of patients treated with 324 mg once-weekly PRO 140, and 67% of those treated with 324 mg bi-weekly, experienced a greater than 1.0 log10 reduction in viral load (P = 0.0079 and 0.061, respectively). In both the 324 mg once-weekly and bi-weekly dose arms, a greater than 1.0 log10 viral load reduction was maintained for 2 weeks after the last dose. Here, too, PRO 140 was generally well-tolerated, with a minority of patients reporting mild injection site reactions.

"The viral load reductions observed for intravenous PRO 140 are similar in magnitude to those observed for our most potent HIV drugs at this stage of development," said lead investigator Jeffrey M. Jacobson, MD, in a press release issued by Progenics. "The findings underscore the efficiency with which PRO 140 blocks HIV's access to CCR5 and healthy cells in vivo. In addition, the antiviral and safety data for subcutaneous PRO 140 are highly encouraging."

A major potential benefit of PRO 140 is its long-lasting activity, which may allow it to be administered as seldom as once monthly using the IV route or once-weekly by subcutaneous injection. The company indicated that full data from both ongoing Phase 2 trials are expected by early 2009 and will be used to select an optimum dose for further clinical development.

Drexel Univ. College of Med., Philadelphia, PA; AIDS Research Consortium of Atlanta, Atlanta, GA; Univ. Miami, Miami, FL; Univ. Alabama, Birmingham, AL; Montefiore Med. Ctr., Bronx, NY; Jacobi Medical Center, Bronx, NY; Albany Med. Ctr., Albany, NY; Quest Clinical Res., San Francisco, CA; Univ. Cincinnati, Cincinnati, OH; NorthStar Med. Ctr., Chicago, IL; University of Rochester, Rochester, NY; University of Maryland, Baltimore, MD; Progenics Pharmaceuticals, Tarrytown, NY.

11/11/08

References

JM Jacobson, MA Thompson, MA Fischl, and others. Antiviral Activity and Tolerability of 5 mg/kg and 10 mg/kg Doses of PRO 140, a Humanized Monoclonal Antibody to CCR5. 48th International Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2008). Washington, DC. October 25-28, 2008. Abstract H-1269a.

JM Jacobson, MS Saag, MA Thompson, and others. Antiviral Activity of Single-Dose PRO 140, a CCR5 Monoclonal Antibody, in HIV-Infected Adults. Journal of Infectious Diseases 198(9). November 1, 2008.

Other source
Progenics Pharmaceuticals. Progenics Reports Positive Interim Phase 2 Results for Two Dosage Forms of Novel HIV Therapy PRO 140. Press release. October 26, 2008.