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

2. TB Clinical Trial Limitations?

3. How do we get it done? 3 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. Coordination Therapeutics - Phase II/III Planning Coordination Forum Coordinate all Phase II combination studies NIAID – ACTG, TBRU CDC – TBTC GATB EDCTP – PanACEA UKMRC PHARMAs FDA/EMA, etc. WHO, NGOs, etc.

6. Coordination and Collaborations 6 Standardization/harmonization needed for efficient CT collaboration Data elements, standards, endpoint criteria, AE grading – CDISC/HL7 TB Data Standards Project (2008) Lab procedures for diagnostics/endpoints, DST, QA, P+P Stored sample collection specifications and procedures Drug quality policies for drugs not provided by study Planning strategies, agendas, key trials Site surveys, 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. 8 Recognizing the relative roles of COMBINATION Developers in contrast to DRUG Developers and Providing new DRUG ACCESS to COMBO DEVELOPERS as soon as feasible CRITICAL ASPECT FOR PROGRESS

9. Study Issues – Phase II Trials 9 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 14 days of a Classic Mouse Study mmm Best sterilizer?

11. And the winner is… From McCune R M, Tompsett R, McDermott W J Exp Med 1956; 104: 763-802. 

12. Have become “POC” rite of passage High EBA 0-2 is unique for INH EBA 0-14 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 EBA 0-14, 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 ISMC interim 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 17

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? Rapid early treatment response markers to change paradigm from culture AND include killing of NRPs HOW? – Resuscitation promoting factors – Molecular-based (mRNS/rRNA, phages) – Imaging (PET-CT, PET-MRI) Lead IdentificationLead Optimization Preclinical Development Phase IPhase II*Phase III

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. T = -2 monthsT = 0 monthsT = 6 months 23 year old male enrolled in delayed linezolid arm: 20012003200520072009 HRZEPPtOCZ failure HZPPtCOHZKLfRbHLf failure 2009 DST R:HPSEREtCKORbMCp, S:Z(?) 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 23 PZA

24. Summary of PZA Day at CDC Thursday, December 15, 2011, CDC, Atlanta CDC/DTBE’s Lab Branch will work to improve reliability of culture-based/phenotypic PZA DST NIAID to help establish/coordinate sequencing of isolate collections among 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 24

25. Current Drugs for New Combos For DS/DR combos Bedaquiline Sutezolid and 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 25 Lead IdentificationLead Optimization Preclinical Development Phase IPhase II*Phase III

26. Therapeutics Development – Risks and Opportunities 26 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 27 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 28 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: – 1 st, 2 nd 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 1)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 32

33. Bactericidal and Sterilizing Dosing Phases Bactericidal Phase x 2 weeks INH* + Rifamycin + PZA (+ ?FQ) Sterilizing Phase x 6 weeks PZA + Bedaquiline # + clofazimine # + oxazolidinone or nitroimidazole NOW 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 33

34. Nanoformulation Engineering 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 Development Translational 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 36

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/O 2, 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. 38 PZA Workshop September 2012

39. 39 2-Pyrazinecarboxylic acid

40. 40 THANK YOU

41. TB and Impressionism

42. 42 BACK-UPS

43. 43

44. 44

45. MAMS-TB-001 Control (124): 2 months HRZE+ 4 months HR Arm 2 (62):3 months HRZQ 300mg + 3 months HR Arm 3 (62):3 months HR 20mg ZQ 300mg + 3 months HR Arm 4 (62):3 months HR 20mg ZM+ 3 months HR Arm 5 (62):3 months HR 35mg ZE+ 3 months HR Sites: 2 x Cape Town; 2 x Johannesburg; 3 x Tanzania Study start: November 2012; End: Sept. 2013 Sponsor: University of Munich (Michael Hoelscher) Chief Investigator: Martin Boeree One planned interim review by IDMC that could result in dropping arms + 6 months subsequent follow-up for all

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

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

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 48

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 49

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

51. Combination REGIMEN Development Acute Relapse Efficacy Preclinical Tolerance PK/DDIs Dose Adjustment Phase I DS TB - > 8 Weeks Quant. Cultures OR Time to Cx- OR SSCC PK/PD Clinical Endpoints Phase II A&B “EBA/SSCC*” Phase III MDR Trials 1) 8 weeks Then 2) 24+ weeks Combination “Approvals ” Pharm/Tox FOR MDR USE TB TREATMENT APPROVALS ACCELERATED FOR DS USE FULL FOR DS USE

52. 52 Fundamental Biology/Targets Drug Discovery Detection/ Quantitation Drug Sequencing/ Staging ? Immune-Based Therapy Improved Models/ Testing PZA

53. Clinical Research Planning Coordination Forum for TB Diagnostics Research TB Vaccine Collaborative Committee TB Therapeutics Phase II Research Coordination Forum Existing Partnerships  Critical Path to TB Regimens  Gates Foundation  US Federal TB Task Force  FDA/EMA  Stop TB Partnership WGs  Pharmaceutical Companies  Community-based, e.g. TAG New Coordinating Groups - Members  USG (NIAID, CDC, and Networks)  Gates PDPs (FIND, Aeras, GATB)  European Funders (EDCTP, MRC)

54. And now, we enter into the realm of the UNDEAD

55. Hell no, we won’t grow! Maybe come back again in 10 years or so? zzzzzzzz…

56. Research in Latent Tuberculosis Infection (LTBI) in the Setting of HIV Co-infection Tuberculosis Clinical Research Branch/TRP/DAIDS AIDS Research Advisory Committee March 14, 2012

57. LTBI initiative Objective: Define host (genetic and immunologic), microbiologic (immune evasive and metabolic adaptive) mechanisms and interactions involved with development, maintenance, and activation of LTBI in the context of HIV co-infection Mechanism: R01 Grant Type: New Duration of awards: 5 years Number of awards anticipated: 3-5 First year of cost: $1.5M/$2.0M

58. 58 Mouse Mouse EBA Studies Same arms will be compared in ACTG 5307

59. Global TB Drug Pipeline 1 Lead IdentificationLead Optimization Preclinical Development Phase IPhase II*Phase III Delamanid (OPC) Moxifloxacin Bedaquiline (TMC) SQ 109 PA 824 Levofloxacin Linezolid Sutezolid (PNU) HD Rifamycins BTZ 043 TBD 354 CPZEN-45 SQ641 SQ609 DC-159a Q201 Preclinical Development Discovery Clinical Development Nitroimidazoles Mycobacterial Gyrase Inhibitors Riminophenazines Diarylquinoline Translocase-1 Inhibitor MGyrX1 inhibitor InhA Inhibitor GyrB inhibitor LeuRS Inhibitor Summit PLC compounds Benzimidazoles 1 Projects that have not identified a lead compound series are considered to be in the screening phase of development and are not included. As of publication, there are 11 screening projects in progress as described on http://www.newtbdrugs.org/pipeline.php.http://www.newtbdrugs.org/pipeline.php *Initiation of drug combination studies AZD 5847