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Sputum Biomarkers and Regulatory Innovation for MDR-TB Regimens

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Sputum Biomarkers and Regulatory Innovation for MDR-TB Regimens Sputum biomarkers and regulatory innovation for MDR-TB regimens RS Wallis, MD, FIDSA, FRCPE Chief Science Officer, Aurum Institute, Johannesburg [email protected] EMA TB workshop 26 Nov 2016, London 1 M2 culture as a predictor of treatment success • A 2015 analysis of 2 cohorts of 1.0 1712 MDR-TB patients found conversion to negative at 2 months 0.8 using solid culture medium was strongly associated with success 0.6 Kurbatova, vs failure or death (OR=3.6 overall, Lancet RM 0.4 4.1 in HIV-negative patients). 2015 • The PPV of M2 conversion for cure Failure or death 0.2 Success in the study dataset was 92%. Premaining culture pos • New regimens with superior 0.0 conversion at M2 therefore are highly likely to show superior 0 6 12 18 24 success rates. Months to initial conversion 2 M2 culture and duration as predictors of relapse 0 • A 2013 analysis of 24 trials pub- 40% 4 mo lished from 1973 to 1997 of 58 -1 6 mo regimens studied in 7793 patients 20% identified positive month 2 culture -2 10% status using solid medium (M2C) Wallis, and treatment duration as -3 5% PLoS One independent predictors of relapse. 2013 2% • Predictions took the form: -4 logit(relapse) = a+bx+cy, where 1% shading indicates 80% PI x=logit(M2C) and y=log(duration) -5 Predictedrecurrence rate (logit) 1% 2% 5% 10% 20% 40% -5 -4 -3 -2 -1 0 M2C positive (logit) 3 M2 culture and duration as predictors of relapse • The model was subsequently vali- -1 4 mo 20% 6 mo dated using independent data from 12 mo -2 6 studies of 12 regimens involving 10% 3907 patients. Predicted and ob- served relapses correlated at 0.94. -3 5% Wallis, • The model was robust and general- PLoS One -4 2% Ph2 FQ izable, as FQ trials were predicted OFLOTUB 2015 without prior FQ data, the TBRU 1% REMox -5 Rifaquin treatment shortening trial was .5% TBRU predicted without prior host data, Bangladesh and the Bangladesh regimen trials Predictedrecurrence rate (logit) -6 .5% 1% 2% 5% 10% 20% were predicted without prior MDR -6 -5 -4 -3 -2 -1 or clofazimine data. Observed recurrence rate (logit) 4 M2 culture and duration as predictors of relapse • TBRU treatment shortening trial: -1 4 mo 20% 6 mo 390 HIV-negative patients with non- 12 mo -2 cavitary disease at baseline and 10% negative cultures at M2 were ran- domly assigned to 4 or 6 months -3 5% total treatment. The study succeed- Wallis, PLoS One ed in showing low relapse rates -4 2% Ph2 FQ OFLOTUB 2015 overall (7.0% and 1.6%, respective- 1% REMox ly), but failed by finding that dura- -5 Rifaquin .5% TBRU tion was a predictor of relapse even Bangladesh in this low risk population. Predictedrecurrence rate (logit) -6 .5% 1% 2% 5% 10% 20% -6 -5 -4 -3 -2 -1 Observed recurrence rate (logit) 5 M2 culture and duration as predictors of relapse • Bangladesh regimen studies: -1 4 mo 20% 6 mo MDR-TB patients were enrolled into 12 mo -2 2 open label single arm cohort 10% studies of a 12-month clofazimine- containing regimen in Niger and -3 5% Cameroon. 149 cured patients were Wallis, PLoS One followed for >1 year post cure. M2C -4 2% Ph2 FQ OFLOTUB 2015 positive proportions were 6% and 1% REMox 13%. No relapses were detected. -5 Rifaquin .5% TBRU Bangladesh Predictedrecurrence rate (logit) -6 .5% 1% 2% 5% 10% 20% -6 -5 -4 -3 -2 -1 Observed recurrence rate (logit) 6 M2 culture and duration as predictors of relapse • We also found that the weighted -1 4 mo 20% 6 mo mean results of all four 4-month FQ 12 mo -2 arms in OFLOTUB, REMox and 10% Rifaquin could be predicted based on phase 2 data from 5 trials of 6 -3 5% FQ regimens involving 443 patients. Wallis, PLoS One -4 2% Ph2 FQ • Database now includes 30 studies, OFLOTUB 2015 70 regimens, and 11700 patients. 1% REMox -5 Rifaquin .5% TBRU • M2C is the sole TB treatment Bangladesh biomarker meeting the criteria of Predictedrecurrence rate (logit) -6 .5% 1% 2% 5% 10% 20% Chau et al for “known valid”. Clin Cancer Res 2008 -6 -5 -4 -3 -2 -1 Observed recurrence rate (logit) 7 Innovation to combat drug-resistant infections • 25 years ago, the creation of new regulatory approval mechanisms (conditional authorization and accelerated approval) relieved ethically unacceptable bottlenecks in HIV ARV drug development. • They permitted the substitution of a biomarker for a clinical endpoint, thus expediting new treatments for serious or life-threatening diseases based on phase 2 data, but did not eliminate the requirement to conduct phase 3 trials. • We now face a similar crisis for drug-resistant bacterial infections. • 2 innovative mechanisms (Adaptive Pathways and Special Medical Use) promise expedited approvals restricted to patients with high unmet need and few treat- ment alternatives, based on limited clinical data. Approvals are tied to a require- ment to report outcomes, but not to phase 3 trials. Approvals may expand to additional populations as additional safety and efficacy data are gathered. 8 Innovation to combat drug-resistant infections Approved by FDA in 2015 for complicated intra-abdominal and urinary infections based on 2 ph2 trials, each with 100 Avycaz-treated patients. “As only limited clinical safety and efficacy data are available, reserve Avycaz for use in patients who have limited or no alternative treatment options” Approved by FDA in 2015 for mucormycosis based on 1 single arm open label trial with 37 patients and only historical controls. (Marty, LID 2016) Provisionally recommended by WHO in 2016 as a part of short-course regimens for selected MDR-TB patients despite the complete lack of randomized controlled phase 3 trial data, the absence of regulatory approvals of clofazimine for TB, and some uncertainty as to how patients are to be determined eligible. 9 Sutezolid as a test case for adaptive pathways • A linezolid analog with superior anti-TB activity in preclinical studies and superior safety in phases 1-2, acquired by Sequella from Pfizer in 2013. • Sutezolid is a potentially important component of new “pan-TB” regimens comprised entirely of new agents without pre-existing resistance • Consistent with the recently published WHO target profile for such regimens, and with the designation as a high priority area for TB research by funders • Aurum Institute is exploring ways to support development of sutezolid as a part of a new pan-TB regimen with delamanid and bedaquiline (SDB) 10 Sutezolid as a test case for adaptive pathways License 1 Study 3 License 2 Study 4 License 3 Adaptive Open label Adaptive Open label Full Study 1 Study 2 pathway cohort pathway cohort approval 14d study 2mo study licensing study of licensing study of of SDB of PK, QT, of efficacy of SDB for SDB in of SDB for SDB in for pan- safety, & and safety, MDR-TB MDR-TB pan-TB pan-TB TB EBA of in MDR-TB, multiple of SDB, BR+ 2-3 drug sutezolid, License 1 Study 3 License 2 Duration combos and BR+ Conditional Phase 3 trial FullDuration approval of placebo authorizainformed- of sutezolid sutezolid+BRinformed tionby study of 2 vs placebo forby studyMDR- 3TB sutezolidand tested in MDR-TB and tested +BRin study for 3 patients in study 4 MDR-TB receiving BR 11 MDR-TB as a test case for adaptive pathways • Major global unmet medical needs would be addressed • Creating a new, shorter, more effective TB regimen not requiring DST • Shortening by 2-3 years patient access to this regimen • An existing global infrastructure can be harnessed • Dedicated hospitals, trained physicians, mandated prescribing policies • Globally accepted mechanisms for outcome reporting • Normative roles of multiple international and national bodies • Precedented engagement of TB control programs to test new regimens under “real-life” conditions • Fully qualified biomarker • Success in MDR-TB can be readily adapted/expanded to DS-TB 12 Questions for discussion • Superior culture conversion formed the basis of the conditional/accelerated authorizations of bedaquiline and delamanid. Is M2C sufficiently validated to advance a novel pan-TB regimen via the adaptive pathway? • It is generally required that combination treatments justify each component by showing its contribution to the desired outcome. Is the sutezolid+BR arm of study 2 necessary and sufficient for this purpose? • In adaptive licensing, the benefit-risk balance informs the selection of patient populations and the size of required safety and efficacy databases. Is the progression from MDR-TB to pan-TB appropriate for the adaptive development of an entirely novel regimen? If so, how many subjects need be included in study 2 to proceed with the first adaptive pathway licensing for MDR-TB? 13 [email protected] 14 .
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