TBI-223 / Global Alliance for TB Drug Development, Materia Medica - LARVOL DELTA

RAD-TB: Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=315 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Mar 2027 ➔ Aug 2027 | Trial primary completion date: Mar 2026 ➔ Nov 2026

Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

RAD-TB: Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=315 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Suspended ➔ Recruiting

Enrollment open • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

ACTG A5409 (RAD-TB): Study protocol for a phase 2 randomized, adaptive, dose-ranging, open-label trial of novel regimens for the treatment of pulmonary tuberculosis. (PubMed, Trials) - P2 | "Wave 1 of the RAD-TB platform aims to identify the optimal oxazolidinone(s), with regard to both efficacy and safety, to combine with the BPa backbone for the treatment of DS-TB. Subsequent waves of this platform trial may add a fourth drug to the regimen, study new diarylquinolines to substitute for bedaquiline, or study novel agents from other TB drug classes."

Journal • P2 data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

RAD-TB: Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=315 | Suspended | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Recruiting ➔ Suspended

Trial suspension • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

ACTG A5409 (RAD-TB): Study Protocol for a Phase 2 Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis. (PubMed, Res Sq) - P2 | "The experimental treatment arms will consist of a bedaquiline and pretomanid backbone (BPa) in combination with one of three oxazolidinones. Arm 2 will study linezolid (BPaL) at a dose of 600 mg daily, Arms 3A and 3B will study TBI-223 at 1200 mg and 2400 mg daily, respectively, and Arms 4A and 4B will study sutezolid at 800 mg and 1600 mg daily, respectively...Trials registration : ClinicalTrials.gov NCT06192160. Registered on January 5, 2024, https://clinicaltrials.gov/study/NCT06192160."

Journal • P2 data • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

RAD-TB: Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=315 | Recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Not yet recruiting ➔ Recruiting

Enrollment open • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Pharmacokinetics, tolerability, and safety of TBI-223, a novel oxazolidinone, in healthy participants. (PubMed, Antimicrob Agents Chemother) - P1 | "Sustained-release tablets achieved a mean AUC0-inf of 70%-80% relative to immediate-release tablets, with more than 50% lower mean Cmax. These results support further investigation of TBI-223 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03758612 and NCT04865536."

Journal • PK/PD data • Cardiovascular • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

RAD-TB: Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=315 | Not yet recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Trial completion date: Apr 2026 ➔ Mar 2027 | Trial primary completion date: Jun 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Dose optimization of TBI-223 for enhanced therapeutic benefit compared to linezolid in antituberculosis regimen. (PubMed, Nat Commun) - P1, P1/2, P3 | "TBI-223 preclinical and Phase 1 data (NCT03758612) are applied to the translational framework to predict clinical outcomes and optimize TBI-223 dosing in combination with bedaquiline and pretomanid. Results indicate that daily doses of 1200-2400 mg TBI-223 may achieve efficacy comparable to the BPaL regimen, with >90% of patients predicted to reach culture conversion by two months."

Clinical • Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

New Oxazolidinones for Tuberculosis: Are Novel Treatments on the Horizon? (PubMed, Pharmaceutics) - "The search identified sutezolid, tedizolid, delpazolid, eperezolid, radezolid, contezolid, posizolid and TBI-223, in addition to linezolid. Sutezolid, tedizolid, delpazolid and TBI-223 displayed promising preliminary results. Further clinical studies would be required to assess the safety profiles and optimize the dosing regimens."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

RAD-TB: Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=315 | Not yet recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) | Initiation date: Apr 2024 ➔ Sep 2024

Trial initiation date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis. (PubMed, Antimicrob Agents Chemother) - "In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

RAD-TB: A Randomized, Adaptive, Dose-Ranging, Open-Label Trial of Novel Regimens for the Treatment of Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=315 | Not yet recruiting | Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

New P2 trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The heme oxygenase-1 metalloporphyrin inhibitor stannsoporfin enhances the bactericidal activity of a novel regimen for multidrug-resistant tuberculosis in a murine model. (PubMed, Antimicrob Agents Chemother) - "Here, we evaluated the adjunctive HDT activity of a novel HO-1 inhibitor, stannsoporfin (SnMP), in combination with a novel MDR-TB regimen comprising a next-generation diarylquinoline, TBAJ-876 (S), pretomanid (Pa), and a new oxazolidinone, TBI-223 (O) (collectively, SPaO), in Mtb-infected BALB/c mice. SnMP was well tolerated and did not significantly alter gross or histological lung pathology. SnMP is a promising HDT candidate requiring further study in combination with regimens for drug-resistant TB."

IO biomarker • Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • CD38 • HMOX1

Practical and Scalable Two-Step Process for 6-(2-Fluoro-4-nitrophenyl)-2-oxa-6-azaspiro[3.3]heptane: A Key Intermediate of the Potent Antibiotic Drug Candidate TBI-223. (PubMed, Org Process Res Dev) - "This new approach to compound 1 avoids the previous drawbacks associated with the synthesis of 2-oxa-6-azaspiro[3,3]heptane (5), the major cost driver used in previous routes to TBI-223. The optimization and multigram scale-up results for this new route are reported herein."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

An Alternative Approach to Tablet Splitting and Grinding for Medication Administration. (PubMed, Int J Pharm Compd) - "We developed a new device comprised of a flexible receptacle, a tight-fitting cap, and a suction cup bottom to convert tablets into liquid preparations. Tuberculosis treatment drugs, TBAJ-876 and TBI-223, were dispersed within the device utilizing water and commonly available suspending vehicles...The effectiveness of the device was also evaluated using commercially available tablets of acetaminophen, amlodipine, glimepiride, metformin, and valsartan...Aliquots for partial dose delivery can be withdrawn accurately. These findings demonstrate that XTEMP-R can be used to accurately deliver doses of suspensions for patients who cannot swallow tablets."

Journal • Infectious Disease • Pediatrics • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Side-by-Side Profiling of Oxazolidinones to Estimate the Therapeutic Window against Mycobacterial Infections. (PubMed, Antimicrob Agents Chemother) - "New oxazolidinones are in clinical development for the treatment of tuberculosis and nontuberculous mycobacterial (NTM) infections, as a replacement for linezolid and tedizolid, which cause mitochondrial toxicity after prolonged treatment. Here, we carried out side-by-side measurements of mitochondrial protein synthesis inhibition and activity against clinically relevant mycobacterial pathogens of approved and novel oxazolidinones. We found a large range of selectivity indices suggesting TBI-223 and sutezolid as promising candidates against tuberculosis and NTM lung disease caused by Mycobacterium kansasii."

Journal • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Next-Generation Diarylquinolines Improve Sterilizing Activity of Regimens with Pretomanid and the Novel Oxazolidinone TBI-223 in a Mouse Tuberculosis Model. (PubMed, Antimicrob Agents Chemother) - "Replacing linezolid or TBI-223 with sutezolid in combination with TBAJ-587 and pretomanid significantly reduced the proportion of mice relapsing. In combination with pretomanid and TBI-223, TBAJ-876 at 6.25 mg/kg was equipotent to TBAJ-587 at 25 mg/kg. We conclude that replacement of bedaquiline with these more efficacious and potentially safer diarylquinolines and replacement of linezolid with potentially safer and at least as efficacious oxazolidinones in the clinically successful BPaL regimen may lead to superior regimens capable of treating both drug-susceptible and drug-resistant TB more effectively and safely."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Increasing access to the next generation of life-saving tuberculosis medications through techno-economically guided synthetic process improvements (ACS-Sp 2023) - "To help improve access to these medicines globally, we have set out to improve the synthetic process for most of the medicines that comprise two potential new TB regimens and will describe our efforts to improve access to the TB drugs Pretomanid, Bedaquiline, Sutezolid, and TBI-223 by applying our techno-economically driven synthetic design and optimization strategies. The synthetic improvements are focused on optimizing for cost and manufacturability, rather than applying a more traditional academic approach of focusing on publication impact and novelty. These improvements to the overall TB regimen may improve access to the overall regimen by removing key cost-drivers, supply constraints, or manufacturing bottlenecks that plagued the previously disclosed routes."

Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis. (PubMed, Drugs) - "An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided...Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating..."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The Novel Oxazolidinone TBI-223 Is Effective in Three Preclinical Mouse Models of Methicillin-Resistant Staphylococcus aureus Infection. (PubMed, Microbiol Spectr) - "Taken together, these findings indicate that this new agent may provide an additional option against MRSA infections. Future studies in larger animal models and clinical trials are warranted to translate these findings to humans."

Journal • Preclinical • Dermatology • Infectious Disease • Musculoskeletal Diseases • Orthopedics

Study to Evaluate Safety, Tolerability, and the PK Profile of TBI-223 in Healthy Subjects (clinicaltrials.gov) - P1 | N=28 | Completed | Sponsor: Global Alliance for TB Drug Development | Recruiting ➔ Completed | Trial completion date: Dec 2021 ➔ Mar 2022 | Trial primary completion date: Dec 2021 ➔ May 2021

Trial completion • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The pipeline of new molecules and regimens against drug-resistant tuberculosis. (PubMed, J Clin Tuberc Other Mycobact Dis) - "The clinical development and regulatory approval of bedaquiline, delamanid and pretomanid over the last decade brought about significant progress in the management of drug-resistant tuberculosis, providing all-oral regimens with favorable safety profiles...Investigational drugs in clinical development that target clinically validated mechanisms, such as second generation oxazolidinones (sutezolid, delpazolid, TBI-223) and diarylquinolines (TBAJ-876 and TBAJ-587) promise improved potency and/or safety compared to the first-in-class drugs. Compounds with novel targets involved in diverse bacterial functions such as cell wall synthesis (DrpE1, MmpL3), electron transport, DNA synthesis (GyrB), cholesterol metabolism and transcriptional regulation of ethionamide bioactivation pathways have advanced to early clinical studies with the potential to enhance antibacterial activity when added to new or established anti-TB drug regimens. Clinical validation of preclinical in vitro..."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Study to Evaluate Safety, Tolerability, and the PK Profile of TBI-223 in Healthy Subjects (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Global Alliance for TB Drug Development; Trial primary completion date: Sep 2021 ➔ Dec 2021

Clinical • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Study to Evaluate Safety, Tolerability, and the PK Profile of TBI-223 in Healthy Subjects (clinicaltrials.gov) - P1; N=36; Recruiting; Sponsor: Global Alliance for TB Drug Development; Trial completion date: Sep 2021 ➔ Dec 2021; Trial primary completion date: May 2021 ➔ Sep 2021

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis