- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Lamprene (clofazimine) / Novartis, Sirturo (bedaquiline) / J&J, Pharmstandard
Trial completion, Enrollment change, HEOR: PRACTECAL-EE: Economic Evaluation of New MDR TB Regimens (clinicaltrials.gov) - Apr 22, 2024 P2/3, N=73, Completed, Recruiting --> Completed | N=54 --> 137 Recruiting --> Completed | N=200 --> 73
- |||||||||| Journal: Advances in antibiotic therapy for tuberculosis (Pubmed Central) - Apr 2, 2024
Additionally, considering the extent of anatomical involvement and bacterial burden allows for strategies that involve variable treatment durations based on the severity of the disease. The new tuberculosis treatments thus appear to be shorter and more personalized.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Drug-resistant tuberculosis is a global cause of concern. (Pubmed Central) - Mar 10, 2024 However, emerging resistance against bedaquiline and pretomanid, among other factors, persists as ongoing concerns in the global fight against DR-TB. While the new regimens are groundbreaking, the sustained development of novel drugs targeting the most resistant forms of tuberculosis is of utmost importance for future efforts against DR-TB.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Developing a Platform to Evaluate Mycobacterial Drug Resistance Through Inducible Knockdown and Complementation of Essential and Non-essential Genes (San Diego Convention Center, Room 33A-C (Upper Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_7337; However their sensitivity is much lower for the constituents of the new BPaL regimen (40% for linezolid, 0% for bedaquiline/pretomanid) and new drugs in the clinical pipeline as few resistance associated variants (RAVs) for these drugs have been identified...Single guide RNAs (sgRNAs) were designed and cloned into a plasmid with expression induced by anhydrotetracycline (ATC)...CRISPRi knockdown of gyrA in both Msm and Mmar led to elimination of bacterial growth at all concentrations of moxifloxacin, while complementation with a mutated version restored growth...Conclusion CRISPRi inducible knockdown combined with plasmid complementation is a strategy that can be used to evaluate putative RAVs in both essential and non-essential genes. It has the potential to be used to rapidly evaluate multiple potential RAVs against new drugs in Mtb.
- |||||||||| telacebec (Q203) / Qurient
Telacebec's Contribution to Combination Drug Regimens Is Strain-Dependent in a Mouse Model of Tuberculosis (San Diego Convention Center, Room 33A-C (Upper Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_5048; In H37Rv-infected mice, addition of pyrazinamide or clofazimine significantly increased the bactericidal activity of the next-generation diarylquinoline TBAJ-587, while telacebec did not; nor did telacebec increase the activity of either diarylquinoline TBAJ-587 or TBAJ-876 combined with clofazimine. However, in HN878-infected mice, addition of telacebec significantly increased the activity of bedaquiline+clofazimine
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development
Journal, HEOR, Cost-effectiveness, Cost effectiveness: Cost-effectiveness of pretomanid-based regimen for highly drugresistant TB in a low-burden setting. (Pubmed Central) - Feb 6, 2024 The probability of the BPaL regimen being cost-effective was higher than the B-L-based regimen throughout the variation of WTP. BPaL therapy is likely the cost-effective option for HDR-TB treatment from the US healthcare sector perspective.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: An Update to Novel Therapeutic Options for Combating Tuberculosis: Challenges and Future Prospectives. (Pubmed Central) - Feb 4, 2024 After almost 4 decades since the approval of rifampicin as a potent drug for drugsusceptible tuberculosis, the first drug to be approved for drug-resistant tuberculosis is bedaquiline...Host-directed therapy and repurposed drugs are in trend as their pharmacological and toxicological properties have already been researched for some other diseases making the trial facile. This review discusses the remonstrance faced by researchers in developing a drug candidate with a novel target, the furtherance in tuberculosis research, novel anti-tuberculosis agents approved so far, and candidates on trial including the host-directed therapy, repurposed drug and drug combinations that may prove to be potential in treating tuberculosis soon, aiming to augment the awareness in this context to the imminent researchers.
- |||||||||| SY054 - Chemotherapy and other options for drug-resistant tuberculosis (Hall H) - Feb 1, 2024 - Abstract #ECCMID2024ECCMID_381;
In addition, it can be considered to prevent the occurrence of drug-resistant TB during the latent infection stage. These advances, alongside concerted public health efforts, are vital in the global fight against drug-resistant TB.
- |||||||||| Review, Journal: Rapid Diagnosis of Drug-Resistant Tuberculosis-Opportunities and Challenges. (Pubmed Central) - Jan 22, 2024
The global implementation of regimens comprising these novel drugs in the absence of rapid phenotypic drug resistance profiling has generated a new set of diagnostic challenges and heralded a return to culture-based phenotypic DST. In this review, we describe the available tools for rapid diagnosis of drug-resistant tuberculosis and discuss the associated opportunities and challenges.
- |||||||||| Preclinical, Journal: A minimal PBPK model to accelerate preclinical development of drugs against tuberculosis. (Pubmed Central) - Jan 19, 2024
Discrepancies in plasma and lung levels for the latest BPaMZ and HPMZ regimens have been analyzed in terms of their impact on preclinical experiment design and on PK/PD indices. The framework we developed requires limited drug- and species-specific information to reconstruct accurate PK dynamics, delivering a unified viewpoint on anti-TB drug distribution at the site-of-action and a flexible fit-for-purpose tool to accelerate model-informed drug design pipelines and facilitate translation into the clinic.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Journal: Global adoption of 6-month drug-resistant TB regimens: Projected uptake by 2026. (Pubmed Central) - Jan 9, 2024 However, national efforts to scale-up, case-finding, monitoring, drug-susceptibility testing, and implementation of new treatments will be essential for ensuring they are accessible to all eligible patients in the coming years and goals for ending TB are met. There is an urgent need to engage communities in capacity building and demand generation.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Lamprene (clofazimine) / Novartis, Sirturo (bedaquiline) / J&J, Pharmstandard
P2/3 data, P2b data, Journal, Head-to-Head: Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial. (Pubmed Central) - Nov 19, 2023 P2/3 The 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development
Journal: Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting Mycobacterium tuberculosis. (Pubmed Central) - Nov 13, 2023 We were able to circumvent the requirement for F-dependent Ddn activity using compounds that contained non-nitro groups, identifying a key feature to be modified to avoid this predominant resistance mechanism. These studies provide the foundation for the development of a new class of 1,2,4-triazole compounds for the treatment of tuberculosis.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development, Sirturo (bedaquiline) / J&J, Pharmstandard
Preclinical, Journal: Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid. (Pubmed Central) - Oct 18, 2023 The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development
Journal: Short and Efficient Synthesis of the Antituberculosis Agent Pretomanid from (R)-Glycidol. (Pubmed Central) - Sep 22, 2023 Starting from readily available protected (R)-glycidols and 2-bromo-4-nitro-1H-imidazole, pretomanid could be prepared in a linear three-step synthesis in up to 40% isolated yield. In contrast to most syntheses reported so far, deprotection and cyclization were performed in a one-pot fashion without any hazardous steps or starting materials.
- |||||||||| pretomanid (PA-824) / Global Alliance for TB Drug Development
Preclinical, Journal: Discovery and characterization of antimycobacterial nitro-containing compounds with distinct mechanisms of action and in vivo efficacy. (Pubmed Central) - Aug 23, 2023 Unlike pretomanid which depends only on deazaflavin-dependent nitroreductase (Ddn), these nitrofurans depend on Ddn and possibly another F-dependent reductase for activation...Two of the compounds, HC2233 and HC2234, were found to have potent, sterilizing activity against replicating and non-replicating Mtb in vitro, but a proposed mechanism of action could not be defined. In a pilot in vivo efficacy study, HC2210 was orally bioavailable and efficacious in reducing bacterial load by ~1 log in a chronic murine TB infection model.
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