Development of New Regimens for Tuberculosis Chief Scientific Officer Global Alliance for TB Drug Development 40 Wall Street, 24th Floor New York, NY 10005 USA 1 Outline What are the unmet needs in TB therapy? What are the approaches in TB drug development? How to identify novel TB regimens Summary 2 Part 1: What are the unmet needs in TB therapy? 3 1
TB is a global disease 12 million active TB cases; 650,000 are multidrug-resistant TB (MDR-TB) 98% of TB deaths occur in the developing world India and China have the highest TB and MDR-TB burdens Africa has the highest rates of infection, HIV/TB co-infection, and death Highest rates of MDR-TB and extensively drug-resistant TB (XDR-TB) are in Europe 4 TB is a multidimensional problem Drug Sensitivity Drug-sensitive TB (DS-TB) Latent TB Stage of Infection Drug-resistant TB (DR-TB) Active TB HIV- HIV+ HIV Status 5 Current TB therapies active TB Drug-sensitive TB (DS-TB) 2HRZE/4RH; or 2HRZE/4HRE in settings with high isoniazid resistance TB therapy, plus antiretroviral therapy (ART); drug-drug interactions (DDI) Drug-resistant TB (DR-TB) >18 months empirical MDR-TB regimen or drug sensitivity test (DST) guided individualized therapy MDR-TB therapy, plus ART; 6-10 daily medications for >18 months, high levels of toxicity and drug-drug interactions HIV- HIV+ 6 H = Isoniazid, R = Rifampicin, Z = Pyrazinamide, E = Ethambutol 2
Current TB therapies latent TB Drug-sensitive TB (DS-TB) 9 months, daily or twice weekly of H; 4 months, daily of R; or 3 months, once weekly of HP 9 months, daily or twice weekly of H; or 3 months, once weekly of HP for patients not taking ART Drug-resistant TB (DR-TB) Lack of appropriate diagnostics and treatment Lack of appropriate diagnostics; close contacts to DR-TB cases should be treated with >2 drugs to which the source isolate is susceptible HIV- HIV+ 7 H = Isoniazid, R = Rifampicin, P = Rifapentine Complicated, individualized therapies are needed based on DST and HIV statuses; difficult to implement, particularly in developing world Improper treatments are common due to lack of affordable and reliable diagnostics and rapid DST DS-TB treatment is lengthy (6-9 months), complicated, and challenged by the development of drug resistance DR-TB (MDR- and XDR-TB) treatment is lengthy (>18 months), toxic, inconvenient (including injectables), and expensive Treatment of TB/HIV co-infected patients is complicated with high pill burden and toxicity; complicated by drug-drug interactions Shorter, simpler and universal therapies (active against both DS- and DR- TB and free of DDI) that are less dependent on DST are highly desirable 8 Unmet needs in TB therapy Desired regimen profiles Shorter duration: Active against drug persistence populations Active against both DS- and DR-TB: Novel mechanism of action Co-administration with ART: Low potential for drug-drug interactions Convenient: Orally bioavailable, once daily or less frequent dosing Safe: Good safety and tolerability profile Affordable: Low cost of goods 9 3
Part 2: What are the approaches in TB drug development? 10 Process for TB drug development Drug Discovery Preclinical Development Clinical Development Discovery Pre-clinical Phase I Phase II Phase III Single Drug Drug Combination 11 Late-stage development (after human proof-of-concept) needs to be conducted in combination with other TB drugs to prevent the development of drug resistance Conventional approach 1 Replacing an existing drug (D) with a new drug (X) from current regimen (DS-TB) X D ABCD ABCX Examples: 2RHZE/4RH 2RHZM/2RHM (REMoxTB trial) 2RHZE/4RH 2RMZE/2RM (REMoxTB trial) 2RHZE/4RH 2RHZG/2RHG (OFLUTOB trial) M = Moxifloxacin G = Gatifloxacin 12 For REMox, see www.clinicaltrials.gov/ct2/show/nct00864383 For OFLUTOB, see www.clinicaltrials.gov/ct2/show/nct00216385 4
Conventional approach 2 Adding a new drug (X) to current regimen (MDR-TB) EFGH X EFGHX Examples: BR BR+J (Bedaquiline trial) OBR OBR+O (Delamanid trial) BR = Background Regimen, OBR = Optimized Background Regimen J = TMC207 (Bedaquiline), O = OPC67683 (Delamanid) 13 For TMC207, see www.clinicaltrials.gov/ct2/show/nct01600963?term=tmc207&rank=7 For OPC67683, see www.clinicaltrials.gov/ct2/show/study/nct00685360?term=opc67683&rank=1 14 Conventional approach: issues DS-TB: limited improvement over current regimens (e.g., REMoxTB and OFLUTOB trials) Potential for shortening therapy from 6 to 4 months Drug resistance Drug-drug interaction DR-TB: limited improvement; difficult to implement (e.g., Bedaquiline and Delamanid MDR-TB trials) Improvement in efficacy over current regimens More complicated treatment More expensive New approach Replacing entire regimen with a novel regimen XYZ ABCD ABCD XYZ Examples: 2RHZE/4RH 4PaMZ (NC-001 and NC-002) Pa = PA-824, M = Moxifloxacin, Z = Pyrazinamide 15 For NC-002, see www.clinicaltrials.gov/ct2/show/nct01498419?term=pa-824&rank=5 5
16 Process for novel regimen development Drug discovery Compound class 1 Compound class 2 Compound class 3 Compound class 4 Compound class 5 Candidate selection Drugs to regimens Single compound preclinical development Phase I EBA Available Drug Candidate Pool Regimen Mouse model combo EBA Regimen development Phase IIb Phase III Regimen selection Regimen A Regimen B Regimen C Advantages: dramatic improvement over current therapies, addresses the majority of unmet needs Potential to treat both DS- and DR-TB Dramatically shortens duration of therapy Potential to address DDI with ART Challenges: a higher risk approach to studying multiple new drugs in the same regimen Scientific challenges Regulatory issues Intellectual property issues in working with multiple sponsors 17 New approach: advantages and challenges Part 3: How to identify novel TB regimens 18 6
Drug classes available for regimen development Orally active compounds with human PoC: Known class (Pre-existing drug-r) Rifampicin/Rifapentine Isoniazid Pyrazinamide Ethambutol Moxifloxacin/Gatifloxacin Novel class (No pre-existing drug-r) Clofazimine Linezolid/PNU-100480 Bedaquiline PA-824/Delamanid SQ109 19 A total of 330 potential 3- and 4-drug combinations based on 10 classes of compounds (one member from each class with a single dose) The need for prioritization using preclinical models Drug to regimen An unbiased, data-driven approach: Clinical studies 20 Preclinical Dev Phase I (SAD) Single dose PK/safety Combo (Mouse Acute Model) Bactericidal Activity: Initial Screening Combo (Mouse Relapse Model) Sterilizing Activity: Duration of Therapy Phase I (MAD) Multiple dose PK/safety PK Interaction Confirmation of Efficacy Secondary Infection Model Preclinical studies Phase II (Single EBA) Human PoC (single drug) Combo Safety Combination Specific Safety Human PoC (regime) Phase II (Combo EBA) http://new.tballiance.org/newscenter/view-brief.php?id=616 Mouse infection model M. Tuberculosis aerosol infection Rx start Measuring CFU in lung Day -14 Day 0 M1 M2 M3 M4 M5 (15) (15) (15) (15) 15 mice held for 3 months without treatment and then sacrificed to determine permanent cure without relapse 21 7
PaMZ bactericidal activity in mouse model Lung CFU R = Rifampicin H = Isoniazid Z = Pyrazinamide Pa = PA-824 M = Moxifloxacin 22 Week Eric Nuermberger, et al., Antimicrob Agents Chemother. 2008 April; 52(4): 1522 1524 PaMZ sterilizing activity in mouse model Treatment a Proportion (%) of mice cured after treatment for: 4 mos 5 mos 6 mos 2RHZ/4RH 10/20 (50) 20/20 (100) 20/20 (100) 2PaMZ/4PaM 20/20 (100) b 20/20 (100) 20/20 (100) a Drug doses (mg/kg): R, 10; H, 25; Z, 150; M, 100; and Pa, 100; All drugs were given orally 5 days a week b P < 0.01 versus regimen 1 23 Eric Nuermberger, et al., Antimicrob Agents Chemother. 2008 April; 52(4): 1522 1524 PaMZ combination EBA design (NC-001) Study Arms PaMZ Pa: PA-824 M: Moxifloxacin Z: Pyrazinamide PaZ (M pbo) Rx for 2 Weeks RHZE Visits Day -9-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 29 105 Pre-treatment Treatment Follow Up 24 Andreas H Diacon, et al. Lancet, 2012; 380 (9846): 986-93 8
PaMZ combination EBA results (NC-001) Bi-linear regression: LogCFU changes from baseline 25 Andreas H Diacon, et al. Lancet, 2012; 380 (9846): 986-93 Current TB therapies are lengthy, complicated and challenged by drug resistance and drug-drug interaction problems; difficult to implement, particularly in developing world Shorter, simpler and totally oral therapies that are active against both DS- and DR-TB, less dependent on DST and free of DDI are highly desirable Conventional approaches in TB drug development by replacing or adding a new drug into current regimens provide limited improvement over current therapies A new approach that focuses on novel regimen development by replacing all or most drugs from the current regimens with new drugs can bring dramatic improvement over current therapies 26 Summary Thank you! 27 9
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