Technological Leapfrogging: A TB Imperative

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Technological Leapfrogging: A TB Imperative. Mel Spigelman. Dublin, Ireland Irish Forum/Royal College of Physicians 6 March 2014. Global Tuberculosis Epidemic. TB’s economic toll: >$16 billion a year. 2 billion people are infected with M.tb 9 million new active TB cases per year - PowerPoint PPT Presentation

Text of Technological Leapfrogging: A TB Imperative

TB Alliance

Dublin, IrelandIrish Forum/Royal College of Physicians6 March 2014Mel SpigelmanTechnological Leapfrogging: A TB Imperative2TBs economic toll: >$16 billion a year

2 billion people are infected with M.tb9 million new active TB cases per year1 million pediatric TB cases per year1.7 million people die per year0.5 million cases of MDR-TB per year (prevalent person to person transmission)Virulent XDR-TB spreading12 million people are M.tb/HIV co-infectedBiggest infectious killer of HIV patients and women of childbearing agePrimarily affects the poorest of the poorGlobal Tuberculosis Epidemic23502,763 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 regionTreatment 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)

TB Toll in Europe4Technological Leapfrogging: A TB ImperativeTB Therapeutics Unmet Medical Needs Current TherapyUnmet NeedsFormulations with correct dosing

4Technological Leapfrogging: A TB ImperativeFounded in 2000Not-for-profit Product Development Partnership (PDP); offices in New York and South AfricaEntrepreneurial, virtual approach to drug discovery and development; ~ 50 full time employeesLargest portfolio of TB drug candidates in history

$1 donated=$1.6 leveraged funds from other partnersTB Alliance


TB Alliance Mission6Technological Leapfrogging: A TB Imperative7Our Access StrategyAAA MandateTechnological Leapfrogging: A TB Imperative8TB Alliance VisionSuccess will require novel drug combinations Current Treatment6-30 MonthsNew Treatments in Development2-4 MonthsAspirational Goal7-10 Days

Technological Leapfrogging: A TB Imperative2014 Q1DiscoveryLead identificationLead OptimizationPhase 1Late DevelopmentPhase 3 Phase 2APRECLINICAL DEVELOPMENTPhase 2BREMox-TBNC-002NC-003AstraZeneca (AZ)Bayer Healthcare AG (Bayer)Beijing Tuberculosis and Thoracic Tumor Research InstituteCalibrDaiichi SankyoEisaiGlaxoSmithKline (GSK)Institute of Materia Medica (IMM)IMPAACTJanssen [Johnson & Johnson]Johns Hopkins University (JHU)Medical Research Council (MRC)Novartis Institute for Tropical Diseases (NITD)New York Medical College Rutgers UniversitySanofiShionogiStellenbosch UniversityTakeda PharmaceuticalsUniversity College London (UCL)University of Auckland University of Illinois at Chicago (UIC)University of Pennsylvania School of MedicineYonsei UniversityTB Alliance R&D Partners: Early DevelopmentPhase 4Optimized Pediatric FormulationsConfidential9TB Alliance: Major CollaboratorsTechnological Leapfrogging: A TB Imperative

SELECTED PARTNERS:DonorsPharmaTrial SitesAcademiaNatl Research InstitutesStakeholders101011Technological Leapfrogging: A TB ImperativeFor the first time in history, a significant clinical TB drug pipeline is availableAll 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

Changing the Way TB Drugs are Developed11Technological Leapfrogging: A TB Imperative12Discovery and Development ProcessNovel TB Drug Regimen DevelopmentDrug Candidate PoolDiscovery Phase II Phase III Single CompoundPreclinical Development Phase I EBACompound 1Compound 4Compound 3Compound 5Compound 2Regimen Identification in MiceRegimen BIdentification of New DrugCandidatesSelection of Potential New RegimensRegimen CRegimen ATechnological Leapfrogging: A TB Imperative13Novel TB Drug Regimen Development (Unified Drug Sensitive/Drug Resistant Development Path)As good as HRZE standard

Phase 2Pre clinicalPhase 1Phase 3Better Than HRZEStageTesting ModelStudy AttributesGo/No-Go Criteria:PK to supportdaily dosing

Clear effect to reduce CFU count

Technological Leapfrogging: A TB Imperative14Use animal models to identify most promising combinations (relapse models)Conduct full preclinical, Phase I and Phase II EBA evaluations of each drug singlyDose ranging in EBA studyExplore drug-drug interactions and, as appropriate, preclinical toxicology of the combinationTake combination (regimen) into clinical development (Phase II, III)Data from each step in development justifies proceeding to next stepUnite DS and MDR development paths when makes senseNovel Regimen Development:General ApproachTechnological Leapfrogging: A TB Imperative

Launch of the Critical Path to TB Drug Regimens (CPTR)


Technological Leapfrogging: A TB ImperativeTechnological Leapfrogging: A TB ImperativeTB Alliance is searching for the best combinations of novel drugsInnovative Paradigm: From Drugs to RegimensMulti-drug combinations prevent the development of resistanceA critical mass of novel TB compounds are available to enable novel regimen development Potential to reduce R&D timelines from decades to years


CPTR StructureTechnological Leapfrogging: A TB Imperative17Pa824 Moxifloxacin Pyrazinamide(PaMZ) Regimen Development

(a case study)19Effective against DS and MDR-TBARV CompatibleOral, FDC-Compatible RegimenMarked reduction in time for MDR-TB therapy (75%)Marked reduction in cost of MDR-TB therapy (>90%)

PaMZ Value PropositionBactericidal Activity of Different Treatment Regimens in the Mouse

Log10 CFU in LungsWeeksR = rifampinH = isoniazidZ = pyrazinamidePa = PA-824M = moxifloxacin

20Technological Leapfrogging: A TB Imperative21

Error Bar Plot Over Treatment for Mean EBA Regression

PA-824 Two-week Monotherapy (logCFU) Technological Leapfrogging: A TB Imperative22Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207

Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207

PA-824 based Regimen Phase 2A: NC-001

Pa-Z-(M pbo)


J -(Z pbo) J-Pa2 weeks of treatmentRifafourPa-M-ZTechnological Leapfrogging: A TB Imperative23All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X Day 0)

Technological Leapfrogging: A TB Imperative23Participants with newly diagnosed smear positive DS TB, and MDR TB

NC-002: First Novel Combination SSCC StudyIn patients with TB sensitive to Pa, M, and ZPa(200mg)-M-ZN=60Pa(100mg)-M-ZN=60

RifafourN=60 Pa(200mg)-M-ZN=50 Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin2 months of treatmentRandomizeSerial 16 hour pooled sputum samples for CFU CountDSDR24Technological Leapfrogging: A TB Imperative25Pa-M-Z Regimen was statistically significantly better than the HRZE control for the primary and 3/5 key secondary endpointsReduction in colony counts over 56 daysTime to culture conversionCulture 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)NC-002 Summary of Key Results and PlansTechnological Leapfrogging: A TB ImperativeParticipants with newly diagnosed smear positive DS- and MDR-TB

NC-006 (STAND): Phase 3 Trial of Pa-M-ZPa(100mg)-M-ZN=350Pa(200mg)-M-ZN=350

RifafourN=350 Pa(200mg)-M-ZN= up to 350 Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin4 months of treatmentRandomizeDSDR26Pa(200mg)-M-ZN= 3506 months of treatment12 & 24 mosf/u afterrandomizationTechnological Leapfrogging: A TB ImperativeNix TB Regimens Consisting Entirely of Novel Chemical EntitiesDS-TB is a curable disease; MDR-TB is a curable disease, although treatment harder to implementHighly resistant TB offers opportunity to further speed up the testing of promising TB drug regimensXDR / TDR-TB is a disease where existing treatment options are limited: >75% mortality in South AfricaOptimal therapy should consist of at least 3 drugs to which M.tb is susceptibleCritical mass of new chemical entities without pre-existing resistance are currently in development or just approved, but not readily availableAim is to help XDR-TB patients now under carefully controlled conditions while advancing understanding of entirely novel regimensTreat for cure in XDR-TB patientsDefinitive treatment and follow upPotentially most rapid path to approvalSimultaneously pursue forward development pathway in DS/DR

NiX-TB: Background 28Technological Leapfrogging: A TB ImperativeInitial regimen universal sensitivityDiarylquinoline bedaquilineNitroimidazole Pa-824Oxazolidinone 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 outcomesValue propositionUniversal regimen for all TB patients with active disease (no pre-existing resistance)3-4 month regimen pre-clinicallyOral, once dailyAffordable NiX-TB ProgramTechnological Leapfrogging: A TB Imperative29STEP-TBSpeeding Treatments to End Pediatric- TB31One of the top 10 causes of childhood deaths globally530,000-810,000 pediatric TB cases annually:Possibly 20-40% of the burden in some countriesChildren with TB are the neglected of the neglected:Under-diagnosedUnder-reportedInappropriately treatedTB is a leading killer of children with HIVThe young are susceptible to the deadliest forms of