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TB THERAPEUTICS RESEARCH Issues, Challenges, and Opportunities TCRB/DAIDS/NIAID October, 2012 TB Clinical Trial Limitations? 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 3 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** Therapeutics - Phase II/III Planning Coordination Forum NIAID – ACTG, TBRU CDC – TBTC PHARMAs WHO, NGOs, etc. Coordinate all Phase II combination studies EDCTP – PanACEA UKMRC GATB FDA/EMA, etc. Coordination and Collaborations 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 6 Site Capacity and Efficiency • Information sharing among sponsors – CPTR & WGND has initiated • Actively coordinate efforts for site –Evaluations –Preparation –Training –Participation in planned studies 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 8 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 9 Role of Phase IIA EBA Studies First 14 days of a Classic Mouse Study mmm Best sterilizer? And the winner is… From McCune R M, Tompsett R, McDermott W J Exp Med 1956; 104: 763-802. Role of EBA TRIALS • 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 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 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 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 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 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 Use of TTP for 8 Weeks 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) Phase II Combination Trials Lead Identification Lead Optimization Preclinical Development Phase I Phase II* Phase III 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) 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 23 year old male enrolled in delayed linezolid arm: 2001 2003 HRZE PPtOCZ failure failure 2005 2007 HZPPtCO HZKLfRb failure failure 2009 HLf failure 2009 DST R:HPSEREtCKORbMCp, S:Z(?) T = -2 months Sm/C: ++/28 T = 0 months +++/15 CONFIDENTIAL T = 6 months -/- PZA – Critical Drug PZA • 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 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 Current Drugs for New Combos Lead Identification Lead Optimization Preclinical Development Phase I Phase II* Phase III 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 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 26 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 27 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? 28 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, solidscored, 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 HIVinfected children • Optimal management CNS disease and TB drug penetration into CNS 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? Fostering Innovation Outside of drug & combo development And addressing translational gaps 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 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 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 period33 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) Beyond Drug/Combo Development Translational Gap Area 2) Host-directed Therapies (HST) • Therapeutic vaccines • Small molecule host -directed therapies RE-PURPOSING, not new molecules 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 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 PZA Workshop September 2012 38 WORKSHOP 2-Pyrazinecarboxylic acid 39 THANK YOU PZA 40 TB and Impressionism BACK-UPS 42 43 PZA 44 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) Chief Investigator: Martin Boeree Control (124): 2 months HRZE + 4 months HR Arm 2 (62): Arm 3 (62): Arm 4 (62): Arm 5 (62): + 3 months HR + 3 months HR + 3 months HR + 3 months HR 3 months HRZQ300mg 3 months HR20mgZQ300mg 3 months HR20mgZM 3 months HR35mgZE + 6 months subsequent follow-up for all One planned interim review by IDMC that could result in dropping arms GATB – NC-001 EBA Trial with Combinations - Pa 824 + PZA + Moxi GATB - First Novel Combo SSCC: NC-002 In patients with M.tb sensitive to Pa, M, and Z Pa(200mg)-M-Z randomize Pa(100mg)-M-Z 2 months of treatment (plus 2-wk EBA substudy) Rifafour Pa(200mg)-M-Z (MDR) Z dose = 1500mg Pa = PA-824; M = moxifloxacin; Z = pyrazinamide 47 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 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 Combination Drug Development Pre-clinical Acute Efficacy Pharm/Tox Relapse Efficacy Acute Relapse Phase I Tolerance PK/DDIs Dose Adjustment Phase IIA “EBA” Phase IIB “SSCC” Phase III < 14 Days Quantitative Cultures > 8 Weeks Quant. Cx OR Time to Cx – Clinical Endpoints PK/PD OR SSCC PK/PD MDR Trials 1) 8 weeks Then 2) 24+ weeks MDR USE DS TB Rx Combination “Approvals” Combination REGIMEN Development Preclinical Pharm/Tox Efficacy Acute Relapse Phase I Tolerance PK/DDIs Dose Adjustment Phase II A&B “EBA/SSCC*” Phase III DS TB - > 8 Weeks Quant. Cultures OR Time to Cx- OR SSCC PK/PD MDR Trials 1) 8 weeks Then 2) 24+ weeks Clinical Endpoints TB TREATMENT APPROVALS ACCELERATED FOR DS USE FOR MDR USE FULL FOR DS USE Combination “Approvals” Drug Discovery ? Immune-Based Therapy Improved Models/ Testing PZA Detection/ Quantitation Drug Sequencing/ Staging Fundamental Biology/Targets 52 Clinical Research Planning Coordination New Coordinating Groups Members USG (NIAID, CDC, and Networks) Gates PDPs (FIND, Aeras, GATB) European Funders (EDCTP, MRC) 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 And now, we enter into the realm of the UNDEAD zzzzzzzz… Hell no, we won’t grow! Maybe come back again in 10 years or so? 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 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 Mouse EBA Studies Figure 2. Mouse EBA on INH essentiality 8.5 8.0 log10 CFU/ lung 7.5 7.0 6.5 6.0 5.5 Control 14 RHZE 2RHZE/ 12RZE 2RHZE/ 12RZME 5.0 4.5 4.0 0 2 4 7 11 14 Days Same arms will be compared in ACTG 5307 58 Global TB Drug Pipeline1 Discovery Lead Identification •Summit PLC compounds •Benzimidazoles 1 Projects Preclinical Development Lead Optimization •Nitroimidazoles •Mycobacterial Gyrase Inhibitors •Riminophenazines •Diarylquinoline •Translocase-1 Inhibitor •MGyrX1 inhibitor •InhA Inhibitor •GyrB inhibitor •LeuRS Inhibitor Preclinical Development •BTZ 043 •TBD 354 •CPZEN-45 •SQ641 •SQ609 •DC-159a •Q201 Clinical Development Phase I •AZD 5847 Phase II* Phase III •Bedaquiline (TMC) •SQ 109 •Delamanid (OPC) •PA 824 •Levofloxacin •Moxifloxacin •Linezolid •Sutezolid (PNU) •HD Rifamycins 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. *Initiation of drug combination studies