TB THERAPEUTICS RESEARCH Issues, Challenges, and Opportunities

1. TB THERAPEUTICS RESEARCHIssues, Challenges, and Opportunities TCRB/DAIDS/NIAID October, 2012

2. TB Clinical Trial Limitations? • Resources! • Resources! • Resources!

3. How do we get it done? Four Principles • Enhance/adapt existing global clinical research capacity and resources for TB • Coordination and Collaborations • Other sponsors (US/EU and pharmaceuticals) • International research agencies • Develop highly efficient clinical research strategies and trial designs • FOSTER INNOVATION

4. Forum to Coordinate Phase II/III Clinical Trials Planning - Initiated 9/11 Phase II combination study planning coordination • Efficiently/promptly sharing new study results • Discuss the specific combinations to be studied by each group and when • Anticipate barriers – plan timely studies to obtain necessary pre-clinical and clinical data • DDIs • Antagonism • Additive toxicities • **Additive Q-T interval prolongation**

5. Therapeutics - Phase II/III Planning Coordination Forum WHO, NGOs, etc. NIAID – ACTG, TBRU CDC – TBTC GATB Coordinate all Phase II combination studies FDA/EMA, etc. PHARMAs EDCTP – PanACEA UKMRC

6. Coordination and Collaborations Standardization/harmonization needed for efficient CT collaboration • Data elements, standards, endpoint criteria, AE grading • CDISC/HL7 TB Data Standards Project (2008) • Labproceduresfor diagnostics/endpoints, DST, QA, P+P • Stored samplecollection specifications and procedures • Drug quality policies for drugs not provided by study • Planningstrategies, agendas, key trials • Sitesurveys, qualifications/standards, training, monitoring

7. Site Capacity and Efficiency • Information sharing among sponsors • CPTR & WGND has initiated • Actively coordinate efforts for site • Evaluations • Preparation • Training • Participation in planned studies

8. CRITICAL ASPECT FOR PROGRESS Recognizing the relative roles of COMBINATION Developers in contrast to DRUG Developers and Providing new DRUG ACCESS to COMBO DEVELOPERS as soon as feasible

9. Study Issues – Phase II Trials IIA - up to 14 days – EBA / “Extended EBA” • Change in CFU/day in sputum IIB - 8-12 week combo studies • Culture conversion at 8 weeks - proportions • Time to culture conversion – survival analysis • *Serial quantitative colony counts – decline over time in CFU …. or TTP

10. Role of Phase IIA EBA Studies First 14days of a Classic Mouse Study mmm Best sterilizer?

11. And the winner is…  From McCune R M, Tompsett R, McDermott W J Exp Med1956; 104: 763-802.

12. Have become “POC” rite of passage • High EBA0-2 is unique for INH • EBA0-14 may not correlate with sterilizing • High or especially low • Dose ranging by EBA may be useless or hazardous for some drugs Role of EBA TRIALS

13. Combos – 2-Wk EBA vs. 8-Wk Phase IIB EBA TRIALS FOR COMBINATION REGIMENS • Not required for activity– not sufficiently predictive of sterilizing activity • Safety aspect - Careful monitoring of 2 week safety data for each participant is essential with any initial trial of new combos

14. EBA and Oxazoldinones • Oxazolidinones have LOW EBA0-14, but have potent sterilizing activity • Evaluating dose response by EBA is probably not detectable without a relatively huge N • Choosing dose by EBA may be impossible, meaningless, or WRONG • Dose “establishment” may need to be performed in Phase IIB  for example compare: • J + Z + Oxa Dose 1 J + Z + Oxa Dose 2

15. Phase IIB Combo Trials Many possible combinations to study • Issue How to evaluate efficiently? • Serial trials/amendments are too inefficient • Delays caused by protocol development (esp. in group setting) and approvals at all levels • Response Innovative, inclusive, new adaptive designs

16. Efficiency in Combination Development – Phase II B Features of Adaptive trials • Make changes allowed by protocol as guided by study data without amendment • Periodic ISMCinterim reviews – drop arms early if less active than control • Add new arms as per study criteria - Issue • Short trial length (usually 8 weeks) • Not enough new combinations yet to take optimal advantage of the “MAMS”-type design, esp. for MDR

17. Phase IIB Trials • Combination(s) vs. standard of care therapy • Issue No accepted MDR standard Rx • Sputum culture-based primary endpoint • Issue Use of “SSCC” by CFU on solid media to week eight has advantages, but is arduous/expensive

18. Use of TTP for 8 Weeks

19. Phase IIB Combo Trials Sputum culture-based 8week primary endpoint • Issues • 3 weeks or more to obtain culture data  CANNOT perform efficient, seamless Phase (IIa - IIb - III) adaptive transitions • Does not assess killing of non-replicating persisters (NPRs)  CANNOT adequately predict cure/relapse(Holy Grail biomarker)

20. Phase II Combination Trials What is needed? Rapidearly treatment response markers to change paradigm from culture ANDinclude killing of NRPs HOW? • Resuscitation promoting factors • Molecular-based (mRNS/rRNA, phages) • Imaging (PET-CT, PET-MRI)

21. Mathematical modeling: MBL assay-determined bacterial decline for 111 patients using data from day 0 to day 56. Ribosomal RNA assay Honeyborne I et al. J. Clin. Microbiol. 2011; 49:3905-3911

22. 23 year old male enrolled in delayed linezolid arm: 2001 2003 2005 2007 2009 HRZE PPtOCZ HZPPtCO HZKLfRb HLf failure failure failure failure failure 2009 DST R:HPSEREtCKORbMCp, S:Z(?) T = -2 months T = 0 months T = 6 months Sm/C: ++/28 +++/15 -/- CONFIDENTIAL

23. PZA – Critical Drug • Best sterilizer and synergizer - Issue • Lack of reliable or rapid DST Rapid, accurate, affordable DST is critical to design best regimens for trials and for care PZA

24. Summary of PZA Day at CDCThursday, December 15, 2011, CDC, Atlanta • CDC/DTBE’s Lab Branch will work to improve reliability of culture-based/phenotypicPZA DST • NIAID to help establish/coordinate sequencing of isolate collectionsamong many partners •  comprehensive/global database for correlations • Develop clinical trial service laboratories to provide rapid turn-around pncA sequencing in Africa by 2013 • Foster development of more practical DST method • Use as a model for DST development for new drugs and to establish ongoing surveillance

25. Current Drugs for New Combos For DS/DR combos • Bedaquiline • Sutezolidand AZD-5847 • Nitroimidazoles • Clofazimine • PZA * • Moxi/Levofloxacin* – at optimal dose • SQ 109 Possible roles in DS combos Short-course INH Rifamycins – high dose RMP/RPT or rifabutin

26. Therapeutics Development –Risks and Opportunities Risks Choices of drugs/doses will be made based on the best available, but not perfect evidence Mouse model data (combo choices; INH truly antagonistic?) EBA studies (optimal dosing for EBA vs. sterilization) Opportunities Correlate outcomes of Phase III/IV CTs with conclusions made from animal (mouse) model and EBA-type studies Accept/improve these tools or find better tools

27. Combination Development and Drug Resistance Prevention of resistance • Drugs vary in potential for resistance development AND protection of partner drugs • These potentials have NOT been systematically evaluated in preclinical studies (usual mouse model) • Need routine evaluation of new combinations • Hollow fiber system (as well as for activity) • Highly selectively in the nude mouse model • Identify need to add “protection drug” to new combos - or not

28. Caution with some “New” Drug Classes Safety and efficacy concerns • Very long half-lives and high tissue concentrations • Consider more extended (not intensive) trial follow-up for safety and efficacy vs. experience with current drugs For combinations • Additive toxic effects and with long half-lives • Potentially additive Q-T interval prolongation (Bedaquiline + clofazimine) Difficult to study – when will peak effect occur and how long will increase last?

29. Pediatric TB Research Priorities: Treatment • Limited data on pharmacokinetics and safety of current and new TB drugs in children: • 1st, 2nd line, MDR drugs • Better pediatric TB drug formulations needed, especially for administration to young infants – (rather than liquid, solid-scored, crushable, dissolvable, films, inhalation, subcutaneous delayed release nanoparticles?) • Shorter and more optimal TB treatment regimens for drug sensitive/resistant TB (HIV-, HIV+ children) • Need studies of TB-antiretroviral drug interactions in HIV-infected children • Optimal management CNS disease and TB drug penetration into CNS

30. Critical Questions • How many new drugs will actually be fully approved after Phase III? • “have not reached a critical mass” • What impact will they make on duration? • Will resistance develop to the new drugs sooner rather than later?

31. Fostering Innovation Outside of drug & combo development And addressing translational gaps

32. Not Classic Drug/Combo Development: Translational Gap Area • Deliver/maintain HIGH concentrations of active drugs at right place & time • Efflux pump inhibitors • Alternative delivery routes (inhalation) • Optimal sequencing/staging/duration of individual drugs in combos • Targeting tissues/cells/compartments/bacilli • New pro-drugs (e.g., POA)/formulations • Multiple payload and targeting NANOTECHNOLOGY

33. Bactericidal and Sterilizing Dosing Phases • Bactericidal Phasex 2 weeks INH* + Rifamycin + PZA (+ ?FQ) • Sterilizing Phasex 6 weeks PZA + Bedaquiline # + clofazimine# + oxazolidinoneor nitroimidazole Explore optimal timing/sequencing/staging of combinations in appropriate in appropriate models NOW *INH for few days? - ACTG 5307 will address # Bedaquline+clofaz – prolonged tissue levels after end of dosing period

34. NanoformulationEngineering • Several layer nanomaterial coating for multiple payloads – hydrophilic/phobic • Anti-TB drugs – in combinations • Immunomodulators or antigens • Drug efflux pump inhibitors, inhibit Ca and K efflux from lysozyme • Embedded surface molecules to • Activate immune cells • Decrease or increase adherence to or uptake by specific cell types (liver vs. lung) - targeted entry • Tissue/cell targeting allows delivery of agents not absorbed orally OR systemically toxic at usual doses • Sustained release of payload contents (less drugx2)

35. Beyond Drug/Combo DevelopmentTranslational Gap Area 2) Host-directed Therapies (HST) • Therapeutic vaccines • Small molecule host -directed therapies RE-PURPOSING, not new molecules

36. Adjunctive small molecule host -directed therapies Cytokine Zoo - inhibitors • TNF-α, IL-6 – Thalidomide derivatives*, telmisartan*, PDE inhibitors*, several in trials • TGF-β - Pirfenidone* • Leukotrienes – Curcumine(turmeric), zileuton* Host cell (macrophage) vulnerability/defenses • Imatimib* (TyrK inhibitor) Host tissue protection • MMP-1 inhibition *APPROVEDDRUG

37. Rationale for Specific, Small Molecule Adjunctive Immunomodulators in TB Rx • Improving TB-induced immune defects – Particularly for macrophages • May be particularly useful with immunodeficiency • Decreasing tissue pathology/sanctuaries (less inflammation, necrosis, caseation, granulomas… Better blood flow/O2, more permeable local environment, fewer inhibitory molecules…) • Improved bug clearance occurs in models • Improved immune cell function • Improved immune cell access • Improved anti-TB drug delivery to bacilli

38. PZA PZA Workshop September 2012

39. POA WORKSHOP POA 2-Pyrazinecarboxylic acid

40. THANK YOU PZA

41. TB and Impressionism

42. BACK-UPS

43. PZA

44. PZA

45. MAMS-TB-001 Sites: 2 x Cape Town; 2 x Johannesburg; 3 x Tanzania Study start: November 2012; End: Sept. 2013 Sponsor: University of Munich (Michael Hoelscher) ChiefInvestigator: Martin Boeree Control (124): 2 months HRZE + 4 monthsHR Arm 2 (62): 3 monthsHRZQ300mg+ 3 months HR Arm 3 (62): 3 monthsHR20mgZQ300mg+ 3 months HR Arm 4 (62): 3 monthsHR20mgZM + 3 months HR Arm 5 (62): 3 monthsHR35mgZE + 3 months HR • + 6 months subsequent follow-upfor all One planned interim review by IDMC that could result in dropping arms

46. GATB – NC-001 EBA Trial with Combinations - Pa 824 + PZA + Moxi

47. GATB - First Novel Combo SSCC: NC-002In patients with M.tb sensitive to Pa, M, and Z Pa(200mg)-M-Z Pa(100mg)-M-Z 2 months of treatment (plus 2-wk EBA substudy) randomize Rifafour Pa(200mg)-M-Z (MDR) Pa = PA-824; M = moxifloxacin; Z = pyrazinamide Z dose = 1500mg 47

48. GATB Trials NC-003 Study drugs/combos -14-day EBA trial: • PZA • Clofazimine • J + Pa 824 + PZA • J + Pa 824 + Clofazimine • J + PZA + Clofazimine • J + Pa 824 + PZA + Clofazimine - Sept. 2012 initiation

49. GATB Trials NC-004 Study drugs/combos -14-day EBA trial: • To be determined – combinations to include bedaquiline, nitroimidizoles, oxazolidinones…. • ? Levofloxacin doses, it not done by Opti-Q? • Initiation - Late this year New nitroimidazole(TBA 354) to replace PA 824 • Phase I – Late Fall 2012

50. Combination Drug Development Phase IIA “EBA” Phase IIB “SSCC” Pre-clinical Phase I Phase III Clinical Endpoints > 8 Weeks Quant. CxOR Time to Cx– OR SSCC PK/PD Pharm/Tox < 14 Days Quantitative Cultures PK/PD Tolerance PK/DDIs Dose Adjustment Acute Efficacy Relapse Acute Efficacy Relapse MDR Trials 1) 8 weeks Then 2) 24+ weeks DS TB Rx Combination “Approvals” MDR USE