Technological Leapfrogging: A TB Imperative
Technological Leapfrogging: A TB Imperative Mel Spigelman Dublin, Ireland Irish Forum/Royal College of Physicians 6 March 2014 Global Tuberculosis Epidemic Primarily affects the poorest of the poor • 2 billion people are infected with M.tb • 9 million new active TB cases per year • 1 million pediatric TB cases per year • 1.7 million people die per year • 0.5 million cases of MDR-TB per year (prevalent person to person transmission) • Virulent XDR-TB spreading • 12 million people are M.tb/HIV co-infected • Biggest infectious killer of HIV patients and women of childbearing age TB’s economic toll: >$16 billion a year 2 TB Toll in Europe • 502,763 cases of TB and more than 44,000 TB deaths in the WHO European region in 2011 (4% of global burden) • 78,000 MDR-TB cases in the region • Treatment success rates of only 67.2%, 49.2% and 48.5% among new, previously treated and MDR-TB cases respectively • Concentrated in 18 priority countries: Armenia, Azerbaijan, Belarus, Bulgaria, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, Romania, Russia, Tajikistan, Turkey, Turkmenistan, Ukraine and Uzbekistan. • But even in EU countries: – Direct treatment costs/year: €536 890 315 ($712,260,000). – Indirect costs/year: An additional €5.3 billion euros ($7 billion) 3 TB Therapeutics – Unmet Medical Needs Current Therapy Unmet Needs 4 drugs; ≥6 month therapy Shorter, simpler therapy Drug-Resistant, M(X)DRTB Few effective drugs, include injectables; significant toxicity; ≥20 months therapy; Oral, shorter, more efficacious, safer, and lower cost therapy TB/HIV, Co-Infection Drug-drug interactions with HIV medications Ability to co-administer TB regimens with ARVs Latent TB Infection 6-9 months of treatment in high HIVburden settings Shorter, safer preventive therapy Pediatric TB Makeshift use of inappropriate formulations Drug-Susceptible TB Technological Leapfrogging: A TB Imperative Formulations with correct dosing 4 TB Alliance $1 donated=$1.6 leveraged funds from other partners • Founded in 2000 • Not-for-profit Product Development Partnership (PDP); offices in New York and South Africa • Entrepreneurial, virtual approach to drug discovery and development; ~ 50 full time employees • Largest portfolio of TB drug candidates in history Patients Government Pharma/ biotech Companies Academia Technological Leapfrogging: A TB Imperative Research institutes Donors 5 TB Alliance Mission Develop new, better treatments for TB Coordinate and act as catalyst for global TB drug activities Ensure that new regimens are Affordable, Adopted for use, and made widely Available (AAA strategy) Technological Leapfrogging: A TB Imperative 6 “AAA” Mandate Our Access Strategy Adoptable • Public programs and private sector accept and implement new regimens • Ensured through acceptability studies, engagement with local communities, and direct negotiations with country programs, WHO, and other stakeholders to bring about guideline change Available • New regimens are made available to patients in countries that adopt them • Ensured by developing a robust manufacturing and distribution plan with pharmaceutical partners, generic companies, countries, donors, and other partners Affordable • Regimens sufficiently low cost to be procured in developing countries • Ensured through negotiation of agreements, cost-of-goods considerations in development process Technological Leapfrogging: A TB Imperative 7 TB Alliance Vision Current Treatment New Treatments in Development Aspirational Goal 6-30 2-4 7-10 Months Months Days Success will require novel drug combinations Technological Leapfrogging: A TB Imperative 8 2014 Q1 Discovery LEAD IDENTIFICATION ATP Synthesis Inhibitors Calibr LEAD OPTIMIZATION PRECLINICAL DEVELOPMENT PHASE 1 Pharmacokinetics of first-line drugs in children < 5kg Macrolides Sanofi TBA-354 Ureas Sanofi Preclinical TB Regimen Development JHU IMPAACT Whole-Cell Hit-toLead Program AZ Whole-Cell Hit-toLead Program Sanofi Whole-Cell Hit-toLead Program NITD Whole-Cell Hit-toLead Program GSK RNA Polymerase Inhibitors Rutgers University Energy Metabolism Inhibitors AZ/UPenn POA Prodrugs Yonsei Diarylquinolines Janssen/University of Auckland/UIC Indazoles GSK Late Development Early Development PHASE 2A NC-003 Bedaquiline/ Clofazimine/ Pyrazinamide PA-824/ Bedaquiline/ Clofazimine/ Pyrazinamide PA-824/ Bedaquiline/ Clofazimine PHASE 2B NC-002 PA-824/ Moxifloxacin/ Pyrazinamide (PaMZ) PHASE 3 PHASE 4 REMox-TB Optimized Pediatric Formulations Moxifloxacin/ Rifampin/ Pyrazinamide/ Ethambutol Bayer, MRC, UCL Moxifloxacin/ Isoniazid/ Rifampin/ Pyrazinamide Isoniazid for children > 5kg PA-824/ Bedaquiline/ Pyrazinamide Pyrazinamide for children > 5kg Novel Structural Series NITD Hit ID Program Daiichi Sankyo Hit ID Program Takeda Hit ID Program Shionogi Confidential TB Alliance R&D Partners: AstraZeneca (AZ) Bayer Healthcare AG (Bayer) Beijing Tuberculosis and Thoracic Tumor Research Institute Calibr Daiichi Sankyo Eisai GlaxoSmithKline (GSK) Institute of Materia Medica (IMM) IMPAACT Janssen [Johnson & Johnson] Johns Hopkins University (JHU) Medical Research Council (MRC) Ethambutol for children > 5kg Bayer, MRC, UCL DprE Inhibitors Calibr Cyclopeptides Sanofi Ethambutol/ Rifampicin/ Isoniazid/ Pyrazinamide Rifampicin for children > 5kg for children > 5kg Novartis Institute for Tropical Diseases (NITD) New York Medical College Rutgers University Sanofi Shionogi Stellenbosch University Takeda Pharmaceuticals University College London (UCL) University of Auckland University of Illinois at Chicago (UIC) University of Pennsylvania School of Medicine Yonsei University TB Alliance: Major Collaborators SELECTED PARTNERS: Donors Academia Pharma Nat’l Research Institutes Technological Leapfrogging: A TB Imperative Trial Sites Stakeholders 10 o g g n g A T B m p e a v e Changing the Way TB Drugs are Developed • For the first time in history, a significant clinical TB drug pipeline is available • All presently utilized TB drugs have either poor pharmaceutical profiles or significant existing resistance • Optimized novel regimens are needed to address requirements for meaningful treatment improvements for drug sensitive and resistant disease • Current TB drug development approach replaces or adds one drug at a time, requiring decades to introduce a new regimen • New paradigm needed for rational selection and development of new TB therapies Technological Leapfrogging: A TB Imperative 11 Novel TB Drug Regimen Development Discovery and Development Process Discovery Phase II Phase III Single Compound Preclinical Development Phase I EBA Compound 1 Compound 2 Regimen A Compound 3 Regimen B Drug Candidate Pool Compound 4 Compound 5 Regimen C Regimen Identification in Mice Identification of New Drug Candidates Selection of Potential New Regimens Technological Leapfrogging: A TB Imperative 12 Novel TB Drug Regimen Development (Unified Drug Sensitive/Drug Resistant Development Path) Stage Testing Model Study Attributes Go/No-Go Criteria: Pre clinical Phase 1 Mouse Model Healthy Subjects • Single drug • Combo in regimen • Relapse free sterilizing activity • Single and repeat dose • Safety, tolerability • PK • Drug Interactions Phase 2 Monotherapy EBA • Single drug • Dose ranging • DS patients only PK to support daily dosing Combination/ Regimen EBA • Optimized dose Regimen • Test final regimen • DS patients only? Clear effect to reduce CFU count Phase 3 Regimen 2Month Study • DS and DR sensitive to regimen • DS vs HRZE standard • DR for consistency As good as HRZE standard Technological Leapfrogging: A TB Imperative Registration • 2 to 4 month treatment, eg • DS vs HRZE for noninferiority • DR for consistency Better Than HRZE 13 Novel Regimen Development: General Approach • Use animal models to identify most promising combinations (relapse models) • Conduct full preclinical, Phase I and Phase II EBA evaluations of each drug singly – Dose ranging in EBA study • Explore drug-drug interactions and, as appropriate, preclinical toxicology of the combination • Take combination (regimen) into clinical development (Phase II, III) – Data from each step in development justifies proceeding to next step – Unite “DS” and “MDR” development paths when makes sense Technological Leapfrogging: A TB Imperative 14 Launch of the Critical Path to TB Drug Regimens (CPTR) Technological Leapfrogging: A TB Imperative 15 Innovative Paradigm: From Drugs to Regimens TB Alliance is searching for the best combinations of novel drugs • Multi-drug combinations prevent the development of resistance • A critical mass of novel TB compounds are available to enable novel regimen development • Potential to reduce R&D timelines from decades to years Technological Leapfrogging: A TB Imperative 16 CPTR Structure Critical Path to TB Drug Regimens CPTR Regulatory Science Consortium CPTR Drugs Coalition CPTR Research Resources Led by the Critical Path Institute Led by the TB Alliance Led by the Bill and Melinda Gates Foundation Focus Data standards & integration Biomarkers and endpoints as disease response assays Drug combination testing and development Clinical trials infrastructure Resource mobilization Regulatory harmonization Animal models Access and appropriate use Pharmacology Disease progression models Technological Leapfrogging: A TB Imperative 17 Pa824 – Moxifloxacin – Pyrazinamide (PaMZ) Regimen Development (a case study) PaMZ Value Proposition • • • • • Effective against DS and MDR-TB ARV Compatible Oral, FDC-Compatible Regimen Marked reduction in time for MDR-TB therapy (75%) Marked reduction in cost of MDR-TB therapy (>90%) 19 Bactericidal Activity of Different Treatment Regimens in the Mouse 9 8 Log10 CFU in Lungs Untreated 7 RHZ 6 PaMZ 5 PaM PaZ 4 MZ 3 R = rifampin 2 H = isoniazid 1 Z = pyrazinamide 0 0 4 Weeks Technological Leapfrogging: A TB Imperative 8 Pa = PA-824 M = moxifloxacin 20 PA-824 Two-week Monotherapy (logCFU) Error Bar Plot Over Treatment for Mean EBA Regression Technological Leapfrogging: A TB Imperative 21 PA-824 based Regimen Phase 2A: NC-001 Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207 • Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207 Pa-M-Z Pa-Z-(M pbo) J-Z 2 weeks of treatment J -(Z pbo) J-Pa Rifafour Technological Leapfrogging: A TB Imperative 22 All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0) Technological Leapfrogging: A TB Imperative 23 NC-002: First Novel Combination “SSCC” Study In patients with TB sensitive to Pa, M, and Z Participants with newly diagnosed smear positive DS TB, and MDR TB Pa(200mg)-M-Z N=60 DS Pa(100mg)-M-Z N=60 2 months of treatment Randomize DR Rifafour N=60 Pa(200mg)-M-Z N=50 Serial 16 hour pooled sputum samples for CFU Count Z = pyrazinamide at 1500mg Pa = PA-824 Technological Leapfrogging: A TB Imperative M = moxifloxacin 24 NC-002 Summary of Key Results and Plans • Pa-M-Z Regimen was statistically significantly better than the HRZE control for the primary and 3/5 key secondary endpoints – Reduction in colony counts over 56 days – Time to culture conversion – Culture conversion to negative at 8 weeks • Safety comparable to control • Positive End-of Phase-2 meetings with FDA (1/23/14) • Positive EMA Scientific Advice (March 5, 2014) Technological Leapfrogging: A TB Imperative 25 NC-006 (STAND): Phase 3 Trial of Pa-M-Z Participants with newly diagnosed smear positive DS- and MDR-TB Pa(100mg)-M-Z N=350 DS Pa(200mg)-M-Z N=350 4 months of treatment 12 & 24 mos f/u after randomization Pa(200mg)-M-Z N= 350 Randomize DR Rifafour N=350 6 months of treatment Pa(200mg)-M-Z N= up to 350 Z = pyrazinamide at 1500mg Pa = PA-824 Technological Leapfrogging: A TB Imperative M = moxifloxacin 26 Regimens Consisting Entirely of Novel Chemical Entities Nix – TB NiX-TB: Background • DS-TB is a curable disease; MDR-TB is a curable disease, although treatment harder to implement • Highly resistant TB offers opportunity to further speed up the testing of promising TB drug regimens • XDR / TDR-TB is a disease where existing treatment options are limited: >75% mortality in South Africa – Optimal therapy should consist of at least 3 drugs to which M.tb is susceptible – Critical mass of new chemical entities without pre-existing resistance are currently in development or just approved, but not readily available – Aim is to help XDR-TB patients now under carefully controlled conditions while advancing understanding of entirely novel regimens • Treat for cure in XDR-TB patients – Definitive treatment and follow up – Potentially most rapid path to approval • Simultaneously pursue forward development pathway in DS/DR Technological Leapfrogging: A TB Imperative 28 NiX-TB Program • Initial regimen – universal sensitivity – Diarylquinoline – bedaquiline – Nitroimidazole – Pa-824 – Oxazolidinone – linezolid • Initiate study in 2014 with XDR-/TDR-TB at select centers with aim of cure • Highly selected centers - intensive data collection, long-term follow up with definitive outcomes • Value proposition – Universal regimen for all TB patients with active disease (no pre-existing resistance) – 3-4 month regimen pre-clinically – Oral, once daily – Affordable Technological Leapfrogging: A TB Imperative 29 STEP-TB Speeding Treatments to End Pediatric- TB Childhood TB A Leading Cause of Childhood Mortality • One of the top 10 causes of childhood deaths globally • 530,000-810,000 pediatric TB cases annually: – Possibly 20-40% of the burden in some countries • Children with TB are the neglected of the neglected: – Under-diagnosed – Under-reported – Inappropriately treated • TB is a leading killer of children with HIV • The young are susceptible to the deadliest forms of TB. 31 Daily treatment for a TB-HIV co-infected child 32 Current Efforts Understand the global TB epidemic in kids Incentivize global suppliers to enter the market Integrate childhood TB into national TB control and child survival strategies Ensure appropriate, improved treatments reach children in need Advocate for an end to the neglect of childhood TB Manufacturer Engagement Market Understanding Clinical and Regulatory Understanding Policy and Uptake by Countries Establish Funding Information Exchange 33 STEP-TB Update and Next Steps Market Intelligence: • 4 studies completed • Additional studies in 2014/2015 on barriers to manufacturer involvement, procurement in non-GDF countries, refinement of data on current and potential market size, etc. Ensuring Product Supply: • MOU with Svizera; Agreement with Macleods anticipated Q1 2014 • Negotiations progressing with Lupin, Sandoz, Sanofi Policy and Uptake: • WHO comprehensive treatment guidelines for pediatric TB to be finalized 1Q14 and rolled out in 2014 Advancing Development of Pediatric TB Treatments: • Under 5kg PK study (IMPAACT) • Accelerating development and regulatory pathways for novel drugs Technological Leapfrogging: A TB Imperative 34 TB Alliance Supporters UK aid Bill & Melinda Gates Foundation National Institute of Allergy and Infectious Disease Global Health Innovative Technology Fund AIDS Clinical Trial Group Irish Aid United States Agency for International Development United States Food and Drug Administration European Commission Australian AID Technological Leapfrogging: A TB Imperative UNITAID 35 Thank you!
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