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Oxazolidinones for TB Oxazolidinones for TB: Current Status and Future Prospects 12th International Workshop on Clinical Pharmacology of Tuberculosis Drugs London, UK 10 September 2019 Lawrence Geiter, PhD Disclosures • Currently contract consultant with LegoChem Biosciences, Inc., Daejeon, Korea (LCB01-0371/delpazolid) • Previously employed with Otsuka Pharmaceutical Development and Commercialization, Inc. (delamanid, OPC-167832, LAM assay) What are Oxazolidinones • A family of antimicrobials mostly targeting an early step in protein synthesis • Cycloserine technically oxazolidinone but 2-oxazolidinone different MOA and chemical properties • New generation oxazolidinones bind to both 50S subunit and 30S subunit • Linezolid (Zyvox) and Tedizolid (Sivestro) approved for drug resistant skin infections and community acquired pneumonia Cycloserine • Activity against TB demonstrated in non- clinical and clinical studies • Mitochondrial toxicity >21 days limits use in TB treatment Linezolid Developing Oxazolidinones for TB Compound Generic Brand Sponsor Development Status TB Code- Activity/Trials PNU-100766 Linezolid Zyvox Pfizer Multiple regimen Yes/Yes TR-201 Tedizolid Sivextro Merck Pre-clinical efficacy Yes/No PNU-100480 Sutezolid Pfizer Multiple regimen studies Sequella Yes/Yes (PanACEA) TB Alliance LCB01-0371 Delpazolid LegoChem Bio EBA trial recruitment completed Yes/Yes TBI-223 - Global Alliance SAD trial launched Yes/Yes AZD5847 Posizolid AstraZenica Completed EBA Yes/No RX-1741 Radezolid Melinta IND for vaginal infections ?/No RBX-7644 Ranbezolid Rabbaxy None found ?/No MRX-4/MRX-1 Contezolid MicuRx Skin infections Yes/No U-100592 Eperezolid ? No clinical trials ?/No PK of Oxazolidinones in Development for TB Steady State PK Parameters Parameter Linezolid 600 Delpazolid 800 mg QD2 mg QD3 Cmax (mg/L) 17.8 8.9 Cmin (mg/L) 2.43 0.1 Tmax (h) 0.87 0.5 T1/2 (h) 3.54 1.7 AUC0-24 (µg*h/mL) 84.5 20.1 1 MIC90 (µg/mL) 0.25 0.5 References 1. Zong et al. Anitmicrob Agents and Chemther(2018); 62(8): e00165-18 2. MacGowan AP. JAC(2003); 51 Supple. S2:ii7-ii25 3. Choi Y, et al. JAC(2018); 73:183-190 In Vivo Evidence of Efficacy for TB • Bactericidal activity in the lung of C7&BL6 mice i.v. infection model of linezolid, sutezolid and delpazolid administered 2 weeks after infection for 4 weeks (LegoChem Biosciences unpublished data) Early Bactericidal Activity Log (QD dose) EBA 0-2 % HRZE EBA EBA 0-14 % HRZE EBA EBA 0-2/EBA 0-14 Linezolid (600 mg) log 0.18 26.9% 0.27 28.9% 0.66 Sutezolid (1200 mg) log 0.05 9.3% log 0.068 34.5% 0.74 Delpazolid (800 mg) log 0.22 40.0% log 0.93 24.9% 0.24 Posizolid (1200 mg ) +log 0.07 Undef. log 0.07 2.7% - Linezolid added to OBR Lee et al. N Engl J Med(2012):367(16)a:1509-1518) • 41 XDR-TB patients non-responsive to 6 months of therapy • Randomized to start LZD 600 mg QD immediately or after 2 months • Patients achieving SCC randomized to LZD 300 mg or 600 mg QD Results for Linezolid added to OBR Lee et al. N Engl J Med(2012):367(16)a:1509-1518) Regimen Trials(1) 5 Regimen Trials with linezolid already recruiting Two-month Regimens Using Novel Combinations to Augment Treatment Pulmonary DS Effectiveness for Drug-sensitive Tuberculosis (TRUNCATE-TB) NCT03474198 2018 TB Multiple Treatment Shortening of MDR-TB Using Existing and New Drugs (MDR-END) NCT02619994 2015 Pulmonary MDR Korea The Effect of 18-month Regimen Containing 6 Anti-tuberculosis Drugs for Patients With MDR-TB NCT03830671 2019 Pulmonary MDR China Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) NCT02589782 2015 Pulmonary MDR Multiple Safety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary TB, XDR-TB, Pre- Pulmonary XDR-TB or Non-responsive/Intolerant MDR-TB (ZeNix) NCT03086486 2017 M(X)DR Multiple 5 Regimen Trials with linezolid about to begin recruiting or already recruiting Pulmonary Pharmacokinetic Study of Linezolid for TB Meningitis (SIMPLE) NCT02279875 2014 DS TB Indonesia Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis- Pulmonary PandrTB Tuberculosis (PandrTB) NCT03827811 2019 MDR TB South Africa Patient-reported Experiences and Quality of Life Outcomes in the TB-PRACTECAL Pulmonary Clinical Trial (PRACTECAL-PRO) NCT03942354 2019 MDR TB Multiple NGS-Guided(G) Regimens(R) of Anti-tuberculosis(A) Drugs for the Control(C) and Pulmonary Eradication(E) of MDR-TB (GRACE-TB) NCT03604848 2018 MDR TB China Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T) Pulmonary (TB-TRUST) NCT03867136 2019 RR TB China Regimen Trials(2) 5 Regimen Trials with sutezolid about to begin recruiting or already recruiting ClinTrials Trial Description Registration Last Update Population Location PanACEA Sutezolid Dose-finding and Combination Evaluation Pulmonary DS S. Africa and (SUDOCU) NCT03959566 2019 TB Tanzania The Effect of 18-month Regimen Containing 6 Anti- Pulmonary tuberculosis Drugs for Patients With MDR-TB NCT03830671 2019 MDR China Pragmatic Clinical Trial for a More Effective Concise and Less Pulmonary Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) NCT02589782 2015 MDR Multiple The Individualized M(X) Drug-resistant TB Treatment Strategy Pulmonary Study (InDEX) NCT03237182 2017 XDR/MDR TB S Africa Nix Trial and Pretomanid approval • Nix-TB tests a three-drug regimen consisting of bedaquiline, linezolid, and pretomanid administered for six months • Approval by FDA based on 109 patient study with no concurrent controls • Nine clinical trials required for final approval • Is the bar for approval set too low • May provide clear pathway for approval of new oxazolidinones: a non-inferiority trial with a substitute oxazolidinone could lead to approval in small RCT if toxicity is lower Toxicity (1) • Toxicity of greatest concern is mitochondrial toxicity • Use of linezolid for longer than 2-3 weeks limited by adverse events such as bone marrow suppression, peripheral neuropathy, and optic neuropathy, all associated with inhibition of mitochondrial protein synthesis • 81% of patients in Nix trial experienced peripheral neuropathy (22% severe) and 64% had a dosing interruption References 1. Lee et al. N Engl J Med(2012):367(16)a:1509-1518) 2. Song et al. EBioMedicine(2015); 2 1627–1633 3. Brown et al. mBio(2015); 6(6):e01741-17415 Toxicity (2) • Hollow fiber model of mitochondrial toxicity also shows correlation of toxicity with trough concentrations • Human myeloid leukemia cell line with platelet properties (K562 cells) are used in the hollow fiber system to assess mitochondrial toxicity Reference Brown et al. mBio(2015); 6(6):e01741-17415 Faster clearance of delpazolid may reduce mitochondrial toxicity 16 LCB01-0371, 400 mg 14 LCB01-0371, 800 mg (ug/mL) 12 LCB01-0371, 1200 mg Linezolid, 600 mg 10 concentration 8 6 Plasma Plasma Mitochondrial protein synthesis inhibition 4 IC50 = 3.3 ug/mL 2 MIC = 0.5 ug/mL 0 0 2 4 6 8 10 12 Time(hr) Plasma concentration of Delpazolid & Linezolid (Healthy human, phase 1 study) Summary • Oxazolidinones are effective against M. tuberculosis • The inclusion of linezolid in several regimens has shown increased efficacy • Mitochondrial toxicity will limit the use of oxazolidinones to M(X)DR regimens • If an oxazolidinone with little to no toxicity is developed, it could accelerate the development of a pan-TB regimen.
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