Eunsol Yang (1), Rob C. van Wijk (1), Jacqueline P. Ernest (1), Annamarie Bustion (1), Véronique Dartois (2), Eric Nuermberger (3), Rada M. Savic (1)
(1) Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, United States of America (2) Center for Discovery and Innovation, Hackensack Meridian School of Medicine, Hackensack Meridian Health, Nutley, New Jersey, United States of America (3) Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
Objectives: Bedaquiline (BDQ) is the first-in-class diarylquinoline approved for tuberculosis treatment. Notably, the BDQ-containing regimen in combination with pretomanid and linezolid (BPaL) has provided the first short-course oral treatment option for drug-resistant tuberculosis. However, as resistance to BDQ has emerged, there is a need for an alternative diarylquinoline agent. TBAJ-587 is a novel diarylquinoline drug under development for the treatment of tuberculosis. As a promising candidate, TBAJ-587 demonstrated greater efficacy than BDQ, whether used alone or in combination with pretomanid and linezolid, in a mouse model of tuberculosis [1]. Previously, we established a translational pharmacology platform enabling reliable preclinical-to-clinical predictions of Phase 2A early bactericidal activity (EBA) under monotherapy and subsequently extended our platform to predict Phase 2B time to culture conversion (TTCC) under combination therapy [2-4]. Here, we leveraged our translational platform to predict the clinical efficacy of TBAJ-587, both as monotherapy and in a combination regimen with pretomanid and linezolid (TBAJ-587-PaL), and to compare it with that of BDQ and another novel diarylquinoline in Phase 2, TBAJ-876.
Methods: We integrated a suite of preclinical dose-ranging pharmacokinetic (PK) and pharmacodynamic (PD) data from BALB/c mice under TBAJ-587 monotherapy and treatment with the TBAJ-587-PaL regimen. PD data included longitudinal bacterial burden measurements in subacute infection models. A mouse PK-PD model, incorporating bacterial dynamics, was developed to describe an exposure-response relationship for TBAJ-587 monotherapy and the TBAJ-587-PaL regimen, respectively. Translational predictions of Phase 2 clinical outcomes at clinically relevant doses of TBAJ-587 were performed by linking the mouse PK-PD model with a population PK model developed with Phase 1 single-ascending dose data [5]. Clinical EBA under TBAJ-587 monotherapy was simulated in 500 virtual patients with the same distribution of baseline bacterial burden utilized in the development of our monotherapy translational platform [3], and clinical TTCC under the TBAJ-587-PaL regimen was simulated in 2278 patients with individual-level baseline bacterial burden obtained from Phase 3 Study 31/A5349 [6]. For comparison with TBAJ-587, translational predictions of clinical outcomes of BDQ and TBAJ-876 were also conducted utilizing in-house monotherapy and regimen models in the same manner [3]. Model development and simulation was performed using a nonlinear mixed-effect modeling approach with NONMEM v7.5.1 through PsN v5.3.0.
Results: The exposure-response relationship of TBAJ-587 under either monotherapy or the TBAJ-587-PaL regimen was well described by the direct maximum effect (Emax) model. The monotherapy model indicated that TBAJ-587 has potency superior to BDQ and comparable to TBAJ-876. It was found that TBAJ-587 at 100 mg daily used in monotherapy would match EBA response for BDQ at the labeled dose or TBAJ-876 at 50 mg daily. In combination with PaL, TBAJ-587 was expected to exert shorter TTCC than BDQ. It was predicted that 95% of patients would achieve culture conversion within 5 weeks under the TBAJ-587-PaL regimen containing more than 25 mg of TBAJ-587, whereas it would take 7 weeks under the approved BPaL regimen. The dose-response simulations for the regimen with PaL showed that TBAJ-587 would enable similar or marginally quicker TTCC in comparison with TBAJ-876 at the same dose. Interestingly, our validated translational site-of-action modeling platform [7] revealed that compared to BDQ, TBAJ-587 and TBAJ-876 reach the efficacy target, minimum concentration to kill 90% bacteria in caseum (casMBC90), faster and are also eliminated from the caseum more rapidly, thus reducing the chance of lingering sub-efficacious concentrations that could lead to bacterial resistance.
Conclusions: Our translational platform allowed us to predict Phase 2 clinical outcomes of TBAJ-587 when used in monotherapy or in combination with the PaL regimen, compared to BDQ and TBAJ-876. The current findings suggest the potential of TBAJ-587, similarly to TBAJ-876, to offer more potent and shorter treatment regimens with a lower risk of resistance development, serving as an alternative to BDQ. Our integrated translational approach will provide a valuable rationale for dose selection and regimen optimization of TBAJ-587 for future Phase 2 and 3 clinical trials.
References:
[1] Xu, Jian, et al. “Comparative Efficacy of the Novel Diarylquinoline TBAJ-587 and Bedaquiline against a Resistant Rv0678 Mutant in a Mouse Model of Tuberculosis.” Antimicrobial Agents and Chemotherapy 65.4 (2021): 10-1128.
[2] Zhang, Nan, et al. “Mechanistic modeling of Mycobacterium tuberculosis infection in murine models for drug and vaccine efficacy studies.” Antimicrobial agents and chemotherapy 64.3 (2020): 10-1128.
[3] Ernest, Jacqueline P., et al. “Translational predictions of phase 2a first-in-patient efficacy studies for antituberculosis drugs.” European Respiratory Journal 62.2 (2023).
[4] PAGE 31 (2023) Abstr 10551 [www.page-meeting.org/?abstract=10551].
[5] PAGE 31 (2023) Abstr 10347 [www.page-meeting.org/?abstract=10347].
[6] Dorman, Susan E., et al. “Four-month rifapentine regimens with or without moxifloxacin for tuberculosis.” New England Journal of Medicine 384.18 (2021): 1705-1718.
[7] PAGE 31 (2023) Abstr 10621 [www.page-meeting.org/?abstract=10621]
Reference: PAGE 32 (2024) Abstr 11059 [www.page-meeting.org/?abstract=11059]
Poster: Drug/Disease Modelling - Other Topics