Chair, DR-TB STAT Task Force Rollout of Novel Drugs and Regimens for DR-TB: Implications for Scale-Up Jennifer Furin, MD., PhD Chair, DR-TB STAT Task Force Harvard Medical School, Department of Global Health and Social Medicine

Objectives Describe novel therapeutics in TB and their advantages over current SOC Discuss progress of introduction in comparison with goals, including challenges to scale-up Review promising novel therapeutic strategies and timelines for launch Discuss goals for success in 2016-2020 including how STBP can assist with reaching these goals

Novel Therapeutic Strategies: Exciting Times for DR-TB! Bedaquiline Delamanid Shortened Regimen PA-824 Carbapenems Dose optimization of linezolid Advantages: improved outcomes, toxicity management, shorter overall regimens

DR-TB STAT Formed in April, 2015 in response to the “Call to Action” to accelerate access to new drugs for MDR-TB Officially adopted as a GDI task force in July 2015 Multiagency participation Activities include monitoring and support for new drug introduction Budgets 50K in 2015, 55K in 2016 Most work donated or done pro bono

Bedaquiline Progress 5234 as of September 1, 2016 60% in South Africa, 20% Russia 4663 orders from GDF As of May 1, 2016, BDQ has been registered in 12 countries including Armenia, the European Union, India, Macau, Peru, Philippines, Russia, South Africa, South Korea, Taiwan, Turkmenistan, the United States, Uzbekistan. Dossiers have been submitted to an addition 17 countries Dossiers have been submitted in Azerbaijan, Bangladesh, Belarus, China, Colombia, Hong Kong, Indonesia, Kazakhstan, Mexico, Moldova, New Zealand, Tanzania, Thailand, Uganda, Viet Nam. Of note, a dossier submitted in Kyrgyzstan was rejected on the basis that there was no phase III data. Additionally a joint application has been submitted for the following countries via a WHO pilot project for collaborative registration: Burundi, Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania

Bedaquiline Map

Delamanid 363, all in MSF or PIH sites 1018 orders from GDF DLM has been registered in Japan, South Korea, Hong Kong, and the European Union and is not registered in any high-burden countries. Dossiers have been submitted for registration in the Philippines, Indonesia, Turkey and Vietnam.

Delamanid Map

Global Progress: BDQ and DLM

BDQ and DLM versus Minimum Estimated Goal

Access Gap Patients in desperate need Companies see no market (i.e. “cannot even give drug away”) Revealed multiple opportunities to contribute to MDR-TB treatment scale-up overall

Three types of countries “Go” countries “Slow” countries “No” countries

Challenges to Successful Intro Lack of urgency Process for updating recommendations and guidelines—delayed BDQ updates, peds guidance, 2016 update without mention of new drugs Genuine confusion over the WHO recommendations “Exceptionalization” of new drugs, focus on protecting drug GLCs: actively block and stop treatment with new drugs, not aware of emerging data Persisting perceptions that these drugs are dangerous of difficult to use Persisting concerns about active PV TA but is it the right kind? Affordable price necessary but not sufficient Courtesy of Tara Loyd

Shortened MDR-TB Regimens Recommended by the WHO in May, 2016 for specific group of patients (but no mention of complementary use of new drugs) Based on observational cohort data from a number of Francophone African countries, Bangladesh, but all used slightly different regimens in populations with limited exposure to SLDs, low rates of SLD resistance STREAM trial results due in late 2017

Implementation Plans Pilot programs started or being planned in multiple countries Scale-up occurring in most sites where the observational cohorts occurred Logisitical challenges around access to SLDST, management of patients while awaiting SLDST, what to do in settings with high rates of PZA/EMB/Ethio resistance High rates of AEs still seen (41% hearing loss) Substitution of other drugs in regimen (i.e. BDQ)

Future Possibilities Phase III delamanid trial, Q4 2017/ Q1 2018 endTB trial: October 2016-results 2021 PRACTECAL: Q4 2016-results 2021 Next: enrolling-results 2020 A5343: enrolling—results 2019 A5356: planned NiX: enrolling—results 2018 MDR-END: Q4 2016—results 2020 STAND: clinical hold Delamanid safety and PK in children (almost complete) Bedaquiline saefty and PK in children (just started) Prevention trials: V-QUIN, CHAMP, PHOENiX

Novel Formulations Pediatric TB: 150,000 courses already ordered SLDs: very little interest in newly development formulations PedDRTB dosing system Gel formulations in early development Often more expensive Reveals major gaps in diagnosis and treatment of DR-TB in children -

Need to Address Barriers to Rollout Now Or it will be 2030 before these interventions are in place! Improved monitoring and support around novel interventions Streamlined process for updating WHO recommendations Service-based model of TA Inclusion of implementation experts

Specific Requests to STBP For DR-TB STAT, earlier release of adequate funding Civil society pressure/demand generation Human rights framework on access to benefits of science Utilization of expert networks (STAT, Sentinel) “TB REACH”-like process for scaling up novel interventions

Thank you! jenniferfurin@gmail.com