Compiled Responses for Q&A
Topic: Access
Subject: Feasibility of leveraging TB Alliance access initiatives for other TB, and even non-TB, technologies
Response: Yes. Access platforms are designed with capabilities for broader use. The PeerLINC Knowledge Hub, for example, already includes training modules for broader MDR-TB treatment support. Discussions are underway to adapt SLASH-TB, a TB Alliance health economics tool developed with Swiss TPH, for use beyond adopting new TB treatments.
Subject: Risk of “adoption fatigue” impacting countries’ willingness to adopt future treatment innovations
Response: Countries have expressed willingness to adopt SPaL for DR-TB; in addition to treatment shortening, reductions in side effects and patient monitoring were identified as benefits. Research to-date finds high excitement about ultra-short LAI regimens and a high willingness to adopt.
Topic: Communities
Subject: Deepening meaningful engagement with TB survivors, civil society, and advocates
Response: TB survivors and community advocates play a powerful role in the fight against TB. National policies strongly shape patient outcomes, and organized patient and activist communities can help influence those policies. Engaging with these groups is not only important to TB Alliance – it is essential to driving an effective TB response.
Topic: Discovery
Subject: Potential role and impact of artificial intelligence (AI) in drug discovery and development
Response: TB Alliance is already leveraging AI in drug discovery – identifying targets/pathways, immune system targeting) and for molecule design to help progress compounds toward development and Investigational New Drug (IND) filings.
Subject: Plans to look at tRNA-synthetase inhibitors (e.g. ganfeborole) as a substitute for oxazolidinones?
Response: We have tested combinations with ganfeborole in collaboration with GSK and JHU. The compound is currently in clinical development by GSK and any future trials will be driven by GSK.
Subject: How to address disparities between TB/DR-TB strains in the lab and in the real-world to improve the reliability of preclinical data?
Response: Once a candidate is selected, we test against a panel of 96 clinical strains and include the data in our Investigator’s Brochure.
Topic: Long-Acting Injectables (LAIs)
Subject: Plans to study acceptability/tolerability of long-acting injectables (LAIs), and gather qualitative data to support eventual access?
Response: Animal tolerability studies and acceptability work have been initiated and are ongoing. Signs thus far have been positive. Continued work of this kind is essential because product development is not worth investing in if those products aren’t acceptable to end users.
Subject: Feasibility and impact on resistance of combining multiple drugs into an LAI
Response: Currently, the planned application is multiple injections (one at a time) in one visit after the oral lead-in. This is based on technological realities to date; combining multiple agents into an LAI for TB would require additional technical innovation.
Topic: Pretomanid and the BPaL/M Regimens
Subject: Status of development of pediatric formulations and lessons learned for accelerating approval of sorfequiline in priority populations
Response: Recent efforts have been made to accelerate pediatric development of pretomanid. Expanded inclusion criteria are planned to be included in Phase 3 trials.
Subject: Plans for BPaL/M fixed dose combinations
Response: FDCs have proved to be very helpful in TB as well as other infectious diseases, especially those requiring multi-drug therapy. Expectedly, we have seen very strong interest in BPa and BPaM FDC from multiple countries, including the highest burden countries. However, we have had difficulty raising funding to support the development of FDC formulations.
Topic: Sorfequiline
Subject: Plans to make sorfequiline available to other research consortia for combinations beyond “SPaL”
Response: TB Alliance is in discussion with multiple groups. It is important, however, to use sorfequiline within rigorous regimen development, not as an add-on to failing regimens, to avoid driving drug-resistance.
Subject: Long-term data on safety/tolerability of sorfequiline
Response: NC-009 data represents the longest term data to date – trial participants were followed for up to a year post-therapy. No unique safety signals were identified in NC-009. The upcoming Phase 3 trial will expand the safety database substantially.
Subject: Data relating to sorfequiline/bedaquiline cross-resistance
Response: The compounds share a mechanism of action, but evidence suggests that sorfequiline is significantly more potent. Sorfequiline may have a higher barrier to resistance and may be able to treat strains that are resistant to bedaquiline. This question will be more thoroughly assessed in the upcoming Phase 3 clinical trial.
Subject: Plans for DST testing
Response: While TB Alliance is not directly involved in developing molecular tests for diarylquinoline resistance, we have contributed to the WHO Catalogue of Mutations in the M. tuberculosis Complex and Their Association with Drug Resistance, which helps guide the development of such tests. Based on the data available so far, we have observed the same resistance-associated mutations for bedaquiline and sorfequiline. All mutants we have identified with increased minimum inhibitory concentration (MICs) to bedaquiline also showed increased MICs to sorfequiline. This suggests that molecular tests developed for bedaquiline resistance will likely be useful also for sorfequiline. However, the MIC threshold used to define susceptibility may differ between the two drugs, since sorfequiline appears to be more potent.
Subject: Sorfequiline for TPT
Response: Both sorfequiline and TBAJ-587 are being studied preclinically for TPT. We plan to move at least one of these into the clinic after we see what the preclinical data shows.
Subject: Existence of lesion data for drug penetration into cavities for TB disease patients
Response: There has been no direct measurement of lesion penetration of sorfequiline in TB patients. However, there are data on the penetration of sorfequiline into caseated lesions in animal models of TB. In the absence of human data, the animal lesion penetration data has been combined with human pharmacokinetic data and used to model penetration in patients. This is described here: https://academic.oup.com/jid/article/232/3/e431/8156692?login=false#google_vignette
The peer-reviewed paper concludes that our results indicate that the next-generation diarylquinolines in clinical development reach bactericidal concentrations in superficial and deep caseum more rapidly than bedaquiline, either penetrating deeper layers of caseum (TBAJ-587) or shortening the window of suboptimal concentrations posttreatment (sorfequiline). These desirable properties are expected to reduce opportunities for the emergence of resistance in time and space. The simulations of clinically plausible dosing strategies could inform the design of TBAJ-based clinical trials aiming at treatment shortening for patients with cavitary disease.
Topic: Sutezolid
Subject: Plans for development of sutezolid
Response: Sutezolid remains “in contention” as an oxazolidinone with potential advantages to those currently approved. Presently, data don’t yet compel substitution for linezolid, but TB Alliance is actively watching emerging studies and other linezolid replacement candidates.