Ibalizumab: 48-week phase 3 results in 27 participants with MDR HIV

13 November 2018. Related: Conference reports, Antiretrovirals.

Simon Collins, HIV i-Base

Ibalizumab is a monoclonal antibody that was recently approved in the US under an orphan drug status for treatment of multidrug resistant HIV.

The phase 3 results from the registrational TMB-301 study were recently published reporting with 43% of 40 treatment-experienced participants sustaining viral load <50 copies/mL at week 24 by ITT analysis (median 1.8 log drop) and 55% by completer analysis (median 2.5 log drop), using ibalizumab with optimised background therapy. [1]

Entry criteria included having multidrug resistance (to at least three classes) and on virologically failing ART. Baseline characteristics included median viral load of 36,000 copies/mL with 7/40 >100,000 copies/mL. Median CD4 count was 73 cells/mm³with 2/40 <100 cells/mm³and 13/40 <10 cells/mm³. Median duration of HIV infections was 23 years (range: 2 to 30). More than 90% of participants had major mutations to each of the NRTI, NNRTI and PI classes and more than 70% had drug resistance to integrase inhibitors.

An oral presentation at Glasgow 2018 included longer follow up for 27 participants out to 48-weeks in the open label expanded access extension (TBM-311). Although new participants joined the expanded access study, this presentation only included results from those who rolled over from the phase 3 TMB-301 study. From weeks 25-48, ibalizumab was continued at a 800 mg IV dose every two weeks, with optimised background therapy. [2]

The most important results – and the clearest new data from the presentation – was that 15/27 participants who had undetectable viral load at week 25, continued to maintain undetectable viral load to week 48. Three participants also discontinued early due to withdrawn consent or investigator decision – for reasons that were all judged not related to ibalizumab.

No new safety concerns ware reported with no drug-related discontinuations.

However, no individual details were presented on the remaining 9/27 participants who had detectable viral load at week 25, in terms of viral load, CD4 count or development of drug resistance.

Further details were presented in a poster for participants in the TMB-301 study that didn’t achieve the early primary endpoints of >0.5 log copies/mL viral suppression at days 7, after the initial loading dose of ibalizumab (at 2000 mg) was added as monotherapy to the baseline failing ART. [3]

Overall, although mean viral load reduction was 1.1 log copies/mL, 7/40 participants (see baseline criteria outlined above) did not achieve >0.5 log copies/mL after a week of monotherapy.

Of these, 4/7 did report more significant viral suppression after the background regimen was optimised after the 7-day monotherapy. These were generally participants with lower baseline viral load and whose treatment optimisation included a switch to different drugs, including twice-daily dolutegravir. This makes it difficult to understand the contribution made by ibalizumab.

comment

These results confirm that ibalizumab can contribute to long-term viral suppression if used as part of a combination with other active HIV drugs.

However, the lack of data overall, including baseline susceptibility to ibalizumab, is not helpful, including in the NEJM paper, especially given the extremely low numbers of people who are in this study.

The limited dataset overall, warrants more detailed results to be clearly presented for all participants. Further follow-up analysis are planned for week-96.

Ibalizumab was filed with the EMA in August 2018 for a decision on EU approval. [4]

References

1. Emu B et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-1. N Engl J Med 2018; 379:645-654
   DOI: 10.1056/NEJMoa1711460/ (16 August 2018).
   https://www.nejm.org/doi/full/10.1056/NEJMoa1711460

2. Cohen Z et al. Analysis of patients completing the ibalizumab phase 3 trial and expanded access program. Glasgow HIV Congress 2018, 28 – 31 October 2018. Late breaker oral abstract O345.

3. DeJesus E et al. Outcomes of patinets not achieving primary endpoint from an ibalizumab phase 3 trial. Glasgow HIV Congress 2018, 28 – 31 October 2018. Poster abstract P064.

4. HTB. FDA approves ibalizumab in the US to treat multidrug HIV resistance. (06 March 2018).
   https://i-base.info/htb/33659