Improving Translation in TB Drug Development Through Quantitative Modeling. CPTR Workshop 2016, Washington DC

Transcription

1 Improving Translation in TB Drug Development Through Quantitative Modeling Lessons from Recent Phase III TB Trials CPTR Workshop 2016, Washington DC Christian Lienhardt Global TB Programme WHO, Geneva, Switzerland GLOBAL TB PROGRAMME

2 Need for shorter TB treatments Shorter, highly potent regimens to: Increase access to and adherence to treatment, and decrease default rates Decrease drug resistance Decrease toxicity and safety issues (SLD) Decrease TB control programme costs Appropriate treatment of patients and effective introduction of new drugs and regimens are premised on accurate and rapid diagnosis. GLOBAL TB PROGRAMME

3 Strategies for developing shorter regimens Optimize use of existing drugs New drugs New regimens GLOBAL TB PROGRAMME

4 Existing drugs that may be used more optimally Rifamycins is 10 mg/kg the optimal dose for rifampicin? is rifampicin the optimal drug in its class? Fluoroquinolones which fluoroquinolone? as replacement for ethambutol? as replacement for isoniazid? GLOBAL TB PROGRAMME

5 A Pioneer Step: TRC trials for potential ofloxacin-based shortened regimens 529 patients enrolled; 416 in efficacy analysis, 341 followed for relapse x 24 months GLOBAL TB PROGRAMME Ind J Tuberc 2002;49:27-38.

6 Activity of Moxifloxacin in Combination Therapy in Mouse 10 9 Log CFU in entire lung logs Untreated 2RHZ+4RH 2RHZM+4RHM 2RMZ+4RM Duration of treatment (mos.) Grosset, AJRCCM 2004

7 Effects of replacing ethambutol with moxi- or gatifloxacin in the first-line therapy of TB OFLOTUB Phase II-SSCC Study Brazil/JHU Orphan Drug Study % with Negative Culture Week of Treatment Moxi 0/74 9/69 (13.0%) 17/70 (24.3%) 31/67 (46.3%) 37/69 (53.6%) 35/61 (57.4%) 45/65 (69.2%) 48/62 (77.4%) 59/64 (92.2%) EMB 0/72 2/68 (2.9%) 2/66 (3.0%) 11/66 (16.7%) 20/65 (30.8%) 21/64 (32.8%) 40/66 (60.6%) 42/66 (63.6%) 45/61 (73.8%) % Diff % CI - (1.2, 19.0) (10.4, 32.1) (14.7, 44.6) (6.6, 39.1) (7.6, 41.5) (-7.6, 24.9) (-1.8, 29.4) (5.6, 31.3) INH/RIF/PZA + Moxi 400 mg vs. ethambutol Rustomjee et al, IJTLD 2008;12: Conde et al., Lancet 2009,373:1183-9

8 Effects of substituting moxifloxacin for INH or ethambutol in the first-line therapy of TB MHRZ vs. EHRZ TBTC Study 27 TBTC Study 28 Burman et al. Am J Respir Crit Care Med 2006, 174: MRZE vs. HRZE Dorman et al. Am J Respir Crit Care Med 2009; 180:273

9 Phase 3 Trials of Fluoroquinolones to shorten TB treatment OFLOTUB Trial: Randomized, open-label non-inferiority trial (6% NI margin) Regimens: 2RHZG / 2RHG 2RHZE / 4RH Control REMox TB Trial: Randomized, double-blind non-inferiority trial (6% NI margin) Regimens: 2RHZM / 2RHM INH Arm 2RMZE / 2RM Eth Arm 2RHZE / 4RH - Control Rifaquin Trial: Randomized, open-label equivalence trial Regimens: 2RZEM / 2RPT (900) M - BIW 2RZEM / 4RPT (1200) M - QW 2 RHZE / 4RH Control GLOBAL TB PROGRAMME

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11 Proportion unfavourable at 18 months post-randomisation: difference from control (95% CI) Nimmo C, et al, Lancet Infectious Diseases 2015

12 Relapses occur early in failing regimens Merle et al., NEJM 2014;371: GLOBAL TB PROGRAMME

13 Relapses occur early in failing regimens ReMox: time to culture conversion vs. time to unfavorable outcome Gillespie et al., NEJM 2014;371: GLOBAL TB PROGRAMME

14 Trial regimen Treatment duration 2 month culture negativity (%) Relapse rates (%) 2EHRZ/6HE (Study A) EHRZ/4HR (Study A) EHRZ/4HR (RIFAQUIN) EMRZ/4P1M1 (RIFAQUIN) EMRZ/2P2M2 (RIFAQUIN) EHRZ/4HR (OFLOTUB) GHRZ /2GRH (OFLOTUB) EHRZ/4HR (REMOX) MHRZ/2MHR (REMOX) EMRZ/2MR (REMOX) SHR (MRC Study R)

15 TBRU - Randomized, Open Label Phase 3 Trial of Shortening standard chemotherapy from 6 to 4 months HIV-, DS, non-cavitary TB adults Patients culture neg after 2 mos of Rx randomly assigned to - stop treatment at 4 mths or - receive an additional 2 mths of treatment (total 6 months Rx) - Relapses occurred a median of 5 mths after completion of treatment (range 4 to 20 mos). - all relapses were fully drug susceptible TB at the time of relapse. K-M analysis of 386 patients who completed assigned treatment and contributed post-treatment follow-up time Johnson J. AJRCCM 2009

16 Time to stable culture conversion on MGIT liquid and solid media provisory results 35mg/kg of rifampicin resulted in an increased likelihood of, and shorter time to culture conversion in liquid media, not in solid Courtesy of Michael Hoelscher and Martin Boeree, 2015

17 TBTC Study 29X P20 mg/kg P15 mg/kg P10 mg/kg RIF10 mg/kg Courtesy of Susan Dorman, 2014

18 Are we using the right endpoints and at the right time? Proportion culture converted Sputum culture conversion rate Boeree et. al CROI February 25th 2015 Hazard ratios differ between 8 and 12 weeks Adapted from Gillespie et. al NEJM October 23rd % Hard to treat week 8 week 12 Relapse time Courtesy of Michael Hoelscher, 2015

19 Early SCC as surrogate marker of treatment outcome Regimens of equal duration Analysis of culture results as surrogate endpoints across all trials. Logs odds ratio of a poor outcome plotted against log odds ratio of a positive culture. Fitted line is weighted by the precision of the estimates, and this precision is represented by the diameter of the circles around each point. The dotted line represents the 95% confidence interval on the slope. GLOBAL TB PROGRAMME Phillips, PLoS ONE 2013

20 Wallis et al, PLoS One 2013

21 Phillips et al. BMC Medicine (2016) 14:19

22 One size does not fit all! Merle et al, NEJM 2014

23 A negative culture at two months on solid media does not equate with absence of viable MTB in the host (LOD issue).

24 Number of pathogens Are we measuring the right mycobacterial subpopulations? Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics or stresses but can regrow under appropriate conditions. A lengthy treatment duration treatment failures question the validity of microbiological endpoints B C D months Limit of detection: Liquid culture is likely more sensitive than solid Zhang. Emerging Microbes and Infections (2014) 3, e3; doi: /emi

25 Drug Penetration in the Lungs Dr. Veronique Dartois Bedaquiline Clofazimine Moxifloxacin Rifampicin Single dose Steady state Pyrazinamide C C Caseum diffusion Accumulation in cellular layers 27 Future TB regimens: is the fight lost already?

26 Main messages / lessons learnt from recent fluoroquinolone trials Failure of the 3 FQ trials question how decisions are made to move novel regimens to pivotal phase III trials in the drug development pathway. The 2-month culture conversion surrogate marker was not confirmed to predict treatment shortening by 2-months 2-month culture conversion provides no information on the activity of the continuation phase: if the drug is bactericidal, it can mislead in terms of ability to shorten treatment (e.g. FQ) if the drug is sterilizing, 2 months culture conversion may not be measuring the subpopulation on which the drug works best Fluoroquinolones are active against M. tuberculosis, but do not appear to add sterilizing activity GLOBAL TB PROGRAMME

27 Main messages / lessons learnt from recent fluoroquinolone trials Striking difference observed between results in liquid vs. solid culture PK/PD analyses are critical using drug exposure to understand intermediate endpoints in addition to dose selection is key examining the relation between dose and treatment duration for efficacy endpoints Dynamic Complexity of lung granulomas and ability of drug to reach site of action Markers that are better individual- and trial-level surrogates are also needed preferably measured at the end of treatment to give greater confidence in moving novel regimens to expensive phase III trials. Joined CPTR/WHO meta-analysis project using TB-PACTS GLOBAL TB PROGRAMME

28 Acknowledgements Martin Boeree Dick Chaisson Gerry Davies Michael Hoelscher Payam Nahid Patrick Philips Rada Savic Cherise Scott Melvin Spigelman Andrew Vernon Bob Wallis

29 Thank you for your attention!