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ICAAC 2011: Monoclonal Antibody Ibalizumab May Hold Promise for Treatment-Experienced HIV Patients

Ibalizumab (also known as TMB-355, formerly TNX-355) -- an antibody-based therapy for HIV -- was well-tolerated and significantly reduced viral load over 24 weeks when used with optimized background therapy, researchers reported at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011) last month in Chicago.

These findings could be good news for heavily treatment-experienced individuals with extensive resistance to current antiretroviral drug classes, but the absence of a placebo control arm means further studies are necessary to clarify the benefit of ibalizumab. One advantage is that it may only need to be taken once every 2 to 4 weeks.

Stanley Lewis, Chief Medical Officer of TaiMed Biologics USA, and colleagues conducted a randomized, double-blind, Phase 2b trial (Study TMB-202) to determine an optimum dosing regimen for ibalizumab.

Ibalizumab is a non-immunosuppressive humanized monoclonal antibody that binds to domain 2 of the CD4 cell surface receptor, thereby blocking HIV entry into host cells; its mechanism of action, however, is not fully understood.

A prior Phase 2a trial -- presented five years ago at the International AIDS Conference in 2006 -- demonstrated that weight-adjusted doses of ibalizumab produced significantly greater viral load reduction than placebo when both were combined with an optimized background regimen (OBR).

This analysis included 113 highly treatment-experienced participants; most (89%) were men, 62% were white, and the average age was 48 years. Mean viral load was high, above 100,000 copies/mL, and average CD4 count was low, at 109 cells/mm³. Patients had been HIV positive for an average of 17 years and had documented resistance to at least 1 nucleoside/nucleotide reverse transcriptase inhibitor (NRTI), 1 non-nucleoside reverse transcriptase inhibitor (NNRTI), and 1 protease inhibitor.

Unlike the Phase 2a trial, participants in this study were randomly allocated to receive intravenous infusions of ibalizumab at 2 fixed doses, either 800 mg every 2 weeks or 2000 mg every 4 weeks, both for 24 weeks. All patients also received an OBR that contained at least 1 active agent.

Results

• Treatment with both doses of ibalizumab significantly reduced HIV RNA over 24 weeks:
  • Mean viral load reduction: -1.6 log in the 800 mg arm and -1.5 log in the 2000 mg arm;
  • Proportion of patients with > 1 log HIV RNA reduction: 63% vs 57%, respectively;
  • Proportion with viral load < 50 copies/mL: 44% vs 28%, respectively;
  • Proportion with viral load < 400 copies/mL: 58% vs 46%, respectively.
• Average CD4 cell gains were 37 cells/mm³ in the 800 mg arm and 40 cells/mm³ in the 2000 mg arm.
• Ibalizumab was generally well-tolerated, with no drug-related deaths or serious adverse events, premature treatment discontinuations, infusion site reactions, or evidence of immunogenicity.
• Some serious laboratory abnormalities were observed, but researchers concluded these were not clinically relevant.
• The most common treatment-emergent adverse events were skin rash, diarrhea, headache, nausea, and upper respiratory symptoms, with no significant differences between arms.
• Most adverse events were mild-to-moderate.

Based on these findings, the investigators concluded, "Treatment with ibalizumab 800 mg [every 2 weeks] + OBR and 2000 mg [every 4 weeks] + OBR was well tolerated and resulted in significant viral load reductions over 24 weeks."

While fewer than half of participants achieved undetectable viral load according to the current standard < 50 copies/mL threshold, combining ibalizumab with other active agents may provide added antiviral potency otherwise unavailable to people with multidrug-resistant virus.

"The observed results are clinically meaningful in treatment-experienced patients with limited options," they added. "These data support continued development of ibalizumab as a new agent for treating HIV in treatment-experienced patients."

After primary endpoint data was collected, participants had the option to continue ibalizumab as part of an investigator-sponsored Investigational New Drug (IND) protocol. Researchers observed durable virological and immunological responses with no safety-related discontinuations during extended follow-up.

Study TMB-108, a Phase 1 trial of healthy HIV negative volunteers, is now underway, testing a new formulation of ibalizumabthat will allow for more convenient subcutaneous (under the skin) rather than intravenous administration. A similar study, A5299, will test the subcutaneous formulation in HIV positive participants.

Investigator affiliations: AIDS Healthcare Foundation, Los Angeles, CA; Therapeutic Concepts, Houston, TX; Research Access Network, Houston, TX; Kaiser Permanente, Los Angeles, CA; TaiMed Biologics USA, Irvine, CA.

10/4/11

Reference

H Khanlou, J Gathe, S Schrader, S Lewis, et al. Safety, efficacy, and pharmacokinetics of ibalizumab in treatment-experienced HIV-1 infected patients: A phase 2b study. Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2011). Chicago, September 17-20, 2011. Abstract H2-794b.