oxazolidinones for tb: current status and future...
TRANSCRIPT
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
Linezolid
• A family of antimicrobials mostly targeting an early step in protein synthesis• Cycloserine technically oxazolidinone but
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
• Activity against TB demonstrated in non-clinical and clinical studies• Mitochondrial toxicity >21 days limits use
in TB treatment
Cycloserine
2-oxazolidinone
Developing Oxazolidinones for TBCompound Code-
Generic Brand Sponsor Development Status TB Activity/Trials
PNU-100766 Linezolid Zyvox Pfizer Multiple regimen Yes/Yes
TR-201 Tedizolid Sivextro Merck Pre-clinical efficacy Yes/No
PNU-100480 Sutezolid PfizerSequella
TB Alliance
Multiple regimen studies (PanACEA)
Yes/Yes
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 mg QD2
Delpazolid 800 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
MIC90 (µg/mL)1 0.25 0.5
References1. Zong et al. Anitmicrob Agents and Chemther(2018); 62(8): e00165-18 2. MacGowan AP. JAC(2003); 51 Supple. S2:ii7-ii253. 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(LegoChem Biosciences unpublished data)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
• 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
Lee et al. N Engl J Med(2012):367(16)a:1509-1518)
Regimen Trials(1)
5 Regimen Trials with linezolid about to begin recruiting or already recruiting
Two-month Regimens Using Novel Combinations to Augment Treatment Effectiveness for Drug-sensitive Tuberculosis (TRUNCATE-TB) NCT03474198 2018
Pulmonary DS 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 ChinaPragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) NCT02589782 2015 Pulmonary MDR MultipleSafety and Efficacy of Various Doses and Treatment Durations of Linezolid Plus Bedaquiline and Pretomanid in Participants With Pulmonary TB, XDR-TB, Pre-XDR-TB or Non-responsive/Intolerant MDR-TB (ZeNix) NCT03086486 2017
Pulmonary M(X)DR Multiple
5 Regimen Trials with linezolid already recruiting
Pharmacokinetic Study of Linezolid for TB Meningitis (SIMPLE)NCT02279875 2014
Pulmonary DS TB Indonesia
Pharmacometrics to Advance Novel Regimens for Drug-resistant Tuberculosis-PandrTB Tuberculosis (PandrTB) NCT03827811 2019
Pulmonary MDR TB South Africa
Patient-reported Experiences and Quality of Life Outcomes in the TB-PRACTECAL Clinical Trial (PRACTECAL-PRO) NCT03942354 2019
Pulmonary MDR TB Multiple
NGS-Guided(G) Regimens(R) of Anti-tuberculosis(A) Drugs for the Control(C) and Eradication(E) of MDR-TB (GRACE-TB) NCT03604848 2018
Pulmonary MDR TB China
Refining MDR-TB Treatment (T) Regimens (R) for Ultra(U) Short(S) Therapy(T) (TB-TRUST) NCT03867136 2019
Pulmonary RR TB China
Regimen Trials(2)
5 Regimen Trials with sutezolid about to begin recruiting or already recruiting
Trial DescriptionClinTrials
Registration Last Update Population LocationPanACEA Sutezolid Dose-finding and Combination Evaluation (SUDOCU) NCT03959566 2019
Pulmonary DS TB
S. Africa and Tanzania
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
The Individualized M(X) Drug-resistant TB Treatment Strategy Study (InDEX) NCT03237182 2017
Pulmonary 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
References1. Lee et al. N Engl J Med(2012):367(16)a:1509-1518)2. Song et al. EBioMedicine(2015); 2 1627–16333. 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
ReferenceBrown et al. mBio(2015); 6(6):e01741-17415
Faster clearance of delpazolid may reduce mitochondrial toxicity
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Pla
sm
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(ug
/mL)
6
Time(hr)
LCB01-0371, 400 mg
LCB01-0371, 800 mg
LCB01-0371, 1200 mg
Linezolid, 600 mg
MIC = 0.5 ug/mL
Mitochondrial protein synthesis inhibitionIC50 = 3.3 ug/mL
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