National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention New TB Medications Neha Shah MD MPH Field Medical Officer Tuberculosis Control Branch California Department of Public Health Centers for Disease Control and Prevention PITCA September 2017
Outline New drugs Repurposed drugs Clinical trials underway
Goals of TB treatment trials From endtb.org
5 Part 1: New Drugs?
New Drugs Pipeline
New Drugs in Clinical Development Drug Class Comp any Status Bedaquiline diarylquinolone Janssen Phase 3 Delamanid nitroimidazole Otsuka Phase 3 Pretomanid nitroimidazole TB Alliance Phase 3 OPC-167832 carbostyril Otsuka Phase 2
Bedaquiline (BDQ) Mode of action: inhibits proton pump for ATP synthase Half life: 165 days Approved by US FDA for use in MDR TB
BDQ Optimized background treatment Number 79 patients 81 patients Median time to culture conversion 83 days 125 days Cure at week 120 58% 32% Serious adverse event 23% 19% Deaths 10 2
Bedaquiline By 2017, close to 10,000 patients have gotten BDQ Appears to be very safe Currently being used in several trials Nix-TB trial STREAM trial Expensive
Delamanid (DLM) Mode of action: mycolic acid synthesis inhibitor Half life: 20 30 hours Currently only approved in Europe
D 100 D200 Optimizing background regimen Dose 100 BID 200 BID Number 161 160 160 2 mo sputum culture conversion 64 (45.4%) 57 (41.9%) 38 (29.6%) QT prolongation 16 (9.9%) 21 (13.1%) 6 (3.8%)
Delamanid Only 1 patient in the US Limited international experience Clinical trials STREAM MDR-END Prevention trials Pediatric data
Pretomanid (Pa) Mode of action: mycolic acid synthesis inhibitor Half life: 16 20 hours Seems promising
Phase 2 OPC 167832 Mode of action: inhibition of cell wall biosynthesis Bactericidal against growing and intracellular bacilli In co-development with delamanid Unclear if will be tested with other drugs not owned by the company FDA granted fast-track status Can be used for MDR and DS TB Adapted from Dr Jeffrey Hafkin
Sutezolid Similar to linezolid Thought to be more effective and less toxic than linezolid Initial company stalled and intellectual property transferred Need to restart trials from beginning
Part 3: Repurposed Drugs
INH and Rifamycins High-dose INH 5, 10, 15 mg/kg for individuals with inha mutations ACTG in South Africa 2018 Rifampin Dosing escalation trials: 35, 20, and 10 mg/kg 30 mg/kg: reduced time to culture conversion and was safe Rifapentine 4 months replacing RIF with RPT or replacing EMB and RIF with MFX and RPT 2019 looking at relapse
FQN Opti-Q: optimal dose of levofloxacin: 11, 14, 17, 20 mg/kg Outcome: culture conversion 100 patients in Peru and South Africa Expected 2017
Linezolid (LZD) Optimal dosing ZeNix: 1200 daily, 600 daily, 1200 daily for 2 months, 600 daily for 2 months Six dosing schedules for DS TB: 300 daily, 300 BID, 600 daily, 600 BID, 1200 daily for 2 weeks, 1200 TIW for 2 weeks ACTG 5356: optimal dosing with DLM (300, 600, 1200) DS trials: Replacing EMB with LZD
Clofazimine (Cfz) Novartis applying for TB indication Renewed interest after short course regimen
Nitazoxanide and Carbapenems Nitazoxanide: antiparasitic and antivrial in phase 2; 14-day EBA studies for DS TB Carbapenems Imipenem and meropenem increasing being used Have to be given IV several times a day Faropenem oral under clinical trials
Part 2: New Regimens Drug Susceptible 26
DS Clinical Trials Goal: Shorten treatment Trial Regimen Duration Expected Outcome TBTC 31 Rifapentine daily instead of RIF Moxifloxacin instead of EMB 4 months 2019 Rifashort Dosing of RIF: 600, 1200, 1800mg 4 months 2018 TRUNCATE TB 5 arms: LZD, BDQ, FQN, CFZ, DLM, RPT 2-3 months?
Part 2: New Regimens MDR TB 29
STREAM Modified short course regimen ( Bangladesh ) Regimen Moxi instead of gatifloxacin BDQ and LFX instead of PRO and KM BDQ and LFX instead EMB Duration: 6 or 9 months Treatment outcome endpoint Expected results 2018 and 2021
NeXT-TB Linezolid, bedaquiline, levofloxacin, pyrazinamide and ethionamide/high dose isoniazid 6 9 months Endpoint: Treatment outcome at 24 months Expected results 2020
endtb 5 arms all with PZA for 9 months BDQ, LZD, MFX BDQ, CFZ, LZD, LFX BDQ, DLM, LZD, LFX DLM, CFZ, LZD, LFX DLM, CFZ MFX Endpoint: Treatment success Outcomes 2021
MDR-END Injectable-free DLM-based regimen DLM, LZD, LFX, PZA for 9 12 months Endpoint: Treatment success Outcomes 2019
TB-PRACTECAL 3 arms for 6 months BDQ, Pa, LZD, MFX BDQ, Pa, LZD, CFZ BDQ, PA, LZD Endpoint: Treatment success Unsure
Nix-TB 6 months of Pretomanid with BDQ and LZD Endpoint: Relapse-free cure Outcomes 2017 ZeNix: LZD dosing
Trials for MDR TB Trial Regimen Duration Outcome NEXT TB LZD, BDQ, LFX, PZA, ETA, INH (H) 6-9 months 2020 endtb 5 arms with PZA BDQ, LZD, MFX, CFZ, DLM 9 months 2023 Nix TB Pa, BDQ, LZD 6 months 2017 MDR END DLM, LZD, LFX, PZA 9-12 months 2019 PRACTECAL 3 arms: BDQ, Pz, LZD, MFX, CFZ 6 months? STREAM Bangladesh regimen modified (BDQ, LFX, MFX) 6-9 months 2018 and 2021
Summary
Summary Many new drugs and regimens in the pipeline Hopefully shorter treatments and regimens without an injectable are on the horizon Need to ensure availability in the US Pipeline is slow and need for new methods and quicker development process
Acknowledgements DO NOT try to remember all of this. Information is available online from Treatment Action Group Bob Horsburgh Family
Questions nshah6@cdc.gov