Pretomanid Passes FDA Ad Com as New Tuberculosis Treatment
Committee: Antimicrobial Drugs Advisory Committee
Indications: Pretomanid is a nitroimidazooxazine antimycobacterial drug indicated, as part of a combination regimen with bedaquiline and linezolid, in adults for the treatment of pulmonary extensively drug-resistant (XDR), treatment-intolerant or nonresponsive multidrug-resistant (MDR) TB.
Question 1: Has the applicant provided substantial evidence of the effectiveness and sufficient evidence of the safety of pretomanid as part of a combination regimen with bedaquiline and linezolid, in adults for the treatment of pulmonary extensively drug resistant (XDR) or treatment-intolerant or nonresponsive multidrug-resistant (MDR) tuberculosis?
Vote Results: Yes 14 No 4 Abstain 0
Drug/Device: Drug
Sponsor: The Global Alliance for TB Drug Development, Inc.
FDA Documents:
Background:
Tuberculosis (TB) is the world’s leading cause of mortality by infectious diseases. According to the WHO, TB was responsible for an estimated 1.6 million deaths worldwide in 2017. While drug-susceptible TB is curable, factors such as poor treatment adherence, incorrect prescribing practice, and premature discontinuation of the treatment have contributed to the rise in drug-resistant (DR) types of TB, which are much more difficult to treat. Prior to 2018, the WHO-recommended treatment regimen for DR-TB was complex and lengthy (i.e. at least 18 months with daily injection in the first 6 months) but with extremely poor prognosis. Therefore in 2018, based on increasing evidence of the effectiveness, the WHO reprioritized the list of recommended drugs for MDR-TB regimens to include bedaquiline and linezolid in the first tier of prioritized drugs. However, these drugs were used as “add-ons” to regimens that were still highly complex and lengthy. The sponsor proposes that the current indication, pretomanid, when used in conjugation with bedaquiline and linezolid (BPaL), will be an effective, well-defined regimen for treatment of MDR- or XDR-TB. With shorter treatment duration, simpler administration method, and a more manageable safety profile, BPaL appears to be the promising new DR-TB treatment regimen that allows for successful completion of treatment and improved rates of favorable outcomes.
Unique Challenges:
Study design and assessment of efficacy:
Evidence from an ongoing phase 3, single-arm, multi-center trial (Nix-TB) was used to assess the safety and efficacy of bedaquiline plus linezolid plus pretomanid (BPaL) regimen in patients with pulmonary XDR-TB or TI/NR MDR-TB. Separate analysis plans were devised for evaluation of safety and efficacy. Efficacy was assessed in the first 45 participants who either completed 6 months of follow-up after the end of treatment or those who died or relapsed. Safety was assessed in all 109 eligible participants. As all patients in Nix-TB received a B-L-Pa regimen, the trial was not designed to provide clinical evidence for the contribution of pretomanid to the regimen but was meant to assess the efficacy of the three-drug regimen. Effectiveness was defined as the rate of favorable outcomes reaching or exceeding the pre-defined threshold of 50%.
The agency questioned the appropriateness of the threshold. In order to address the concerns raised by FDA, the applicant first conducted a systematic literature review to obtain rate of historical successful treatment in previous DR-TB studies. Although the applicant did not attempt a formal meta-analysis, a DerSimonian and Laird random effects model was fitted and yielded an estimate for the historical success rate of 28% for the treatment of XDR-TB with a 95% CI of 21-34%. This evidence provided some support for the pre-specified threshold of 50% being appropriately conservative. To address the limitations of systematic review such as inter-study heterogeneity, as well as temporal and geographical differences from the current trial, the applicant submitted an analysis comparing the effect of BPaL with historical controls, and a sensitivity analysis by control matching using propensity scores. In both instances, the rates of favorable outcomes were much higher in the Nix-TB group than the control groups, providing strong support of the efficacy of the BPaL regimen over other treatments.
Safety:
Based on non-clinical, animal studies, the agency requested the applicant to evaluate the safety profile of BPaL with a special focus on hematologic, hepatic, ophthalmic, neurologic, cardiac, dermatologic, and gastrointestinal effects. Safety assessment was performed among all 109 eligible participants in the Nix-TB study. Additionally, 10 phase 1 studies among healthy adults in the U.S. and two phase 2 studies conducted in South Africa were pooled to investigate the safety profile of pretomanid. Although 6 deaths (5.5%) occurred in the Nix-TB study, there were no additional safety findings of clinical significance in the pooled phase 1 and phase 2 trials. As such, it was concluded that the concern for safety of pretomanid and therefore the BPaL regimen as a whole was low.
Comments:
- Given the strong evidence of its efficacy and low concern in the safety profile, 14 of the advisory committee members voted in favor of the approval of the BPaL treatment regimen for patients diagnosed with XDR-TB.
- This approval was principally based on the evidence from an ongoing single-arm phase 3 study. Before submitting an NDA, there were several agreements between the applicant and the FDA to support this NDA. This agreement included the following three conditions:
- "The applicant and the Agency agreed that an interim clinical study report (CSR) providing safety and efficacy data on the first 45 subjects assessed for the primary efficacy endpoint in the ongoing single-arm Phase 3 trial (Nix-TB) in patients with XDR-TB and TI/ NR MDR-TB would be acceptable to support an NDA submission.”
- “In addition, the Agency agreed that an addendum to the CSR with updated efficacy and safety data on all 109 enrolled subjects could be included in the initial NDA submission.”
- “To support the efficacy outcomes in Nix-TB, the applicant agreed to provide a literature summary and case-matched analysis of historical control data for XDR-TB patients.”