Ibalizumab, a humanized IgG4 monoclonal antibody, blocks the entry of HIV-1 by non-competitive binding to CD4. It was filed for approval in EU in May 2018 for the treatment of HIV-1 infections in treatment experienced patients.
According to a perspective, recognising the need for more streamlined clinical trial designs in patients with multidrug-resistant (MDR) HIV infection who are at risk for illness and death because of their limited remaining treatment options. FDA representatives consulted with interested parties to discuss ideas for acceptable approaches to drug development for this population and this resulted in a streamlined trial design. The current study of ibalizumab, was designed following these recommendations but important limitations of such a design need to be borne in mind.
Four design elements distinguish such streamlined trials from HIV drug registration trials for new drugs in patients without MDR HIV infection:
1. Because the patients being targeted are rare in US, a sample size commensurate with the population with MDR HIV in this country is acceptable.
2. The primary virologic efficacy assessment occurs 7 to 14 days after initiation of treatment with the investigational drug or placebo (added to a failing background regimen). In the case of ibalizumab, patients served as their own controls, with a 7-day period of continued use of the failing background regimen preceding the addition of ibalizumab.
3. Immediately after the primary efficacy time point, participants begin receiving an individualized optimized background regimen, which is tailored on the basis of resistance testing.
4. Durability and safety analyses are conducted after 24 weeks of treatment, rather than 48 weeks.
Such a trial design is considered to facilitate an efficient assessment of safety and efficacy in extensively treated patients with MDR HIV whilst minimising the risks associated with trial participation, such as emerging viral resistance and disease progression.
The perspective notes that the trial fingings provide evidence that ibalizumab could provide benefit to extensively treated patients with MDR HIV infection and that the benefits likely outweigh the risks. However, the complexity of the patient population, the small trial size, and limitations of the trial design resulted in uncertainty about ibalizumab’s safety profile and the durability of treatment response. It adds that given these issues and the high risk of disease progression and death in this patient population, some degree of uncertainty regarding ibalizumab’s contribution to durability of response is acceptable, and probably inevitable. Post-marketing pharmacovigilance will be important in better defining the efficacy and safety profile of ibalizumab.