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Monoclonal Antibody PRO 140 Suppresses HIV Viral Load with Once-weekly Dosing

Subcutaneous injections of PRO 140, a humanized monoclonal antibody that blocks the CCR5 co-receptor and inhibits HIV entry into cells, reduced viral load significantly more than placebo, according to a study described in the May 15, 2010 Journal of Infectious Diseases. PRO 140 worked well when administered once-weekly, offering proof-of-concept for an antiretroviral therapy that can be taken less often than current drugs.

HIV uses 2 co-receptors, designated CCR5 and CXCR4, along with the CD4 cell surface receptor to enter cells. Maraviroc (Selzentry) is the first approved drug that prevents HIV entry by blocking CCR5. PRO 140 works by a similar principle, but uses monoclonal (all identical) antibodies, rather than a drug molecule, to block the co-receptor.

Jeffrey Jacobson from Drexel University College of Medicine and colleagues conducted the first clinical trial to evaluate whether subcutaneous (under the skin) administration of PRO 140 would inhibit HIV. Prior studies have shown that intravenously administered PRO 140 has potent antiviral activity, but subcutaneous administration would be much more practical and allow patients to administer the drug themselves at home.

The investigators designed a randomized double-blind, placebo-controlled study that included 44 patients with HIV viral load > 5000 copies/mL (median 25,100 copies/mL) and CD4 cell counts > 300 cells/mm3 (median 410 cells/mm3); 15 were treatment-experienced, the rest had not previously used ART. Tropism testing showed that participants had exclusively CCR5-using virus, and they had not been on antiretroviral therapy (ART) for at least the past 12 weeks.

Participants were randomly assigned to receive subcutaneous injections of placebo or 3 doses of PRO 140: 162 mg once-weekly for 3 weeks, 324 mg once-weekly for 3 weeks, or 324 mg every other week for 2 doses. Investigators monitored PRO 140 serum concentrations, antiviral activity, and safety over 58 days of follow-up.

Results

• Subcutaneous PRO 140 demonstrated potent and prolonged antiretroviral activity.
• Significant antiviral effects were observed following the first dose, and viral load decreased with continued dosing.
• 89% of patients in the 324 mg once-weekly arm and 75% in the 324 mg every other week arm achieved > 1 log decrease in viral load (compared with none in the placebo group).
• Mean maximum viral load reductions according to dose were as follows (all statistically significant relative to placebo):
  • 162 mg once-weekly: 0.99 log;
  • 324 mg once-weekly: 1.65 log;
  • 324 mg every other week: 1.37 log;
  • placebo: 0.23 log.
• The maximum viral load reduction increased to 1.60 logs when 3 patients later determined to have CXCR4-tropic virus (that is, they should not have been eligible for the study) were excluded.
• CD4 cell count increased in all PRO 140 dose groups, but the changes were not statistically significant.
• PRO 140 was generally well-tolerated, with no drug-related serious adverse events or dose-limiting toxicities.
• Injection site reactions reported by more than 5% of participants were induration or hard swelling (20%), pain (9%), and irritation (7%).
• These reactions were mild, transient, and self-resolving, and occurred with similar frequency in the PRO 140 and placebo groups.
• Viral load remained suppressed between successive PRO 140 doses, including the every other week interval.
• The mean PRO 140 half-life in the body was 3.4 days for the 162 mg once-weekly dose and 3.7 days for 324 mg once-weekly.

Based on these findings, the study authors concluded, "This trial demonstrates proof of concept for a monoclonal antibody administered subcutaneously in HIV-1 infected individuals."

"Subcutaneous PRO 140 offers the potential for significant dose-dependent HIV-1 RNA suppression and infrequent patient self-administration," they added.

"Viral load reductions and antiviral response rates increased as the total amount of PRO 140 administered over 3 weeks was increased from 486 mg (162 mg weekly) to 648 mg (324 mg biweekly) to 932 mg (324 mg weekly)," they elaborated in their discussion.

"Because trough [lowest] concentrations increased after repeat subcutaneous dosing, a loading dose potentially could be used to increase the initial rate of virologic suppression," they continued. "After an initial loading dose, potent virologic suppression and steady-state trough concentrations of PRO 140 might be attainable with subcutaneous maintenance doses similar to those examined here."

Drexel University College of Medicine, Philadelphia, PA; AIDS Research Consortium of Atlanta, Atlanta, GA; Quest Clinical Research, San Francisco, CA; University of Alabama, Birmingham, AL; Montefiore Medical Center and Einstein/Montefiore Center for AIDS Research, Bronx, NY; Progenics Pharmaceuticals, Tarrytown, NY.

5/7/10

Reference

JM Jacobson, MA Thompson, JP Lalezari, and others. Anti–HIV-1 Activity of Weekly or Biweekly Treatment with Subcutaneous PRO 140, a CCR5 Monoclonal Antibody. Journal of Infectious Diseases 201(10): 1481-1487 (Abstract). May 15 2010.