Download pptx - Technological Leapfrogging: A TB Imperative

Dublin, IrelandIrish Forum/Royal College of Physicians6 March 2014

Mel Spigelman

Technological Leapfrogging: A TB Imperative

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TB’s economic toll: >$16 billion a year

• 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

Primarily affects the poorest of the poorGlobal Tuberculosis Epidemic

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• 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)

TB Toll in Europe

4Technological Leapfrogging: A TB Imperative

Drug-Susceptible TB 4 drugs; ≥6 month therapy Shorter, simpler therapy

Drug-Resistant, M(X)DR-TB

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 HIV-burden settings

Shorter, safer preventive therapy

Pediatric TB Makeshift use of inappropriate formulations

TB Therapeutics – Unmet Medical Needs Current Therapy Unmet Needs

Formulations with correct dosing


• 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

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

Government

Research institutes

DonorsAcademia

Pharma/biotech

Companies

Patients

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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)

TB Alliance Mission


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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

Our Access Strategy“AAA” Mandate


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TB Alliance Vision

Success will require novel drug combinations

Current Treatment

6-30 Months

New Treatments in Development

2-4 Months

Aspirational Goal

7-10 Days


2014 Q1Discovery

LEAD IDENTIFICATION

LEAD OPTIMIZATION PHASE 1

Late DevelopmentPHASE 3 PHASE 2APRECLINICAL

DEVELOPMENT PHASE 2B

Moxifloxacin/ Isoniazid/ Rifampin/ PyrazinamideBayer, MRC, UCL

Moxifloxacin/ Rifampin/ Pyrazinamide/ Ethambutol Bayer, MRC, UCL

REMox-TBATP Synthesis Inhibitors Calibr

POA Prodrugs Yonsei

Whole-Cell Hit-to-Lead Program AZWhole-Cell Hit-to-Lead Program SanofiWhole-Cell Hit-to-Lead Program NITDWhole-Cell Hit-to-Lead Program GSKRNA Polymerase Inhibitors Rutgers UniversityEnergy Meta-bolism Inhibitors AZ/UPenn

Hit ID Program

Daiichi Sankyo

Hit ID Program Shionogi

Hit ID Program Takeda

MacrolidesSanofi

UreasSanofi

DiarylquinolinesJanssen/University of Auckland/UIC

IndazolesGSK

DprE Inhibitors Calibr

CyclopeptidesSanofi

Novel Structural SeriesNITD

TBA-354

Preclinical TB Regimen DevelopmentJHU

PA-824/ Moxifloxacin/ Pyrazinamide(PaMZ)

NC-002Bedaquiline/ Clofazimine/ Pyrazinamide

PA-824/ Bedaquiline/ Clofazimine/ Pyrazinamide

PA-824/ Bedaquiline/ Clofazimine

PA-824/ Bedaquiline/ Pyrazinamide

NC-003

AstraZeneca (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 University

TB Alliance R&D Partners:

Early DevelopmentPHASE 4

Optimized Pediatric

Formulations

Ethambutol for children > 5kg

Pyrazinamide for children > 5kg

Isoniazid for children > 5kg

Isoniazid/ Rifampicin for children > 5kg

Ethambutol/ Rifampicin/ Pyrazinamide for children > 5kg

Pharmacokinetics of first-line drugs in children < 5kgIMPAACT

Confidential

TB Alliance: Major Collaborators


SELECTED PARTNERS: Donors Pharma Trial SitesAcademia Nat’l Research Institutes Stakeholders

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• 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

Changing the Way TB Drugs are Developed


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Discovery and Development ProcessNovel TB Drug Regimen Development

Drug Candidate

Pool

Discovery Phase II Phase III Single CompoundPreclinical Development

Phase I EBACompound 1

Compound 4

Compound 3

Compound 5

Compound 2

Regimen Identification in Mice

Regimen B

Identification of New DrugCandidates

Selection of Potential New Regimens

Regimen C

Regimen A


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Mouse Model

• Single drug

• Combo in regimen

• Relapse free sterilizing activity

Healthy Subjects

• Single and repeat dose

• Safety, tolerability

• PK• Drug

Interactions

Monotherapy EBA

• Single drug

• Dose ranging

• DS patients only

Combination/Regimen EBA

• Optimized dose Regimen

• Test final regimen

• DS patients only?

Regimen 2-Month Study

• DS and DR sensitive to regimen

• DS vs HRZE standard

• DR for consistency

Registration

• 2 to 4 month treatment, eg

• DS vs HRZE for non-inferiority

• DR for consistency

Novel TB Drug Regimen Development (Unified Drug Sensitive/Drug Resistant Development Path)

As good as HRZE standard

Phase 2Pre clinical Phase 1 Phase 3

Better Than HRZE

Stage

Testing Model

Study Attributes

Go/No-Go Criteria: PK to support

daily dosingClear effect to

reduce CFU count


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• 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

Novel Regimen Development:General Approach


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

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Imperative


TB Alliance is searching for the best combinations of novel drugsInnovative Paradigm: From Drugs to Regimens

• 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

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Critical Path to TB Drug Regimens

CPTR Regulatory Science

Consortium Led by the Critical

Path Institute

CPTR Drugs Coalition

Led by the TB Alliance

CPTR Research Resources

Led by the Bill and Melinda Gates

Foundation

Focus

Data standards & integration

Biomarkers and endpoints as disease response assays

Animal models Pharmacology Disease progression

models

Drug combination testing and development

Clinical trials infrastructure

Resource mobilization Regulatory

harmonization Access and appropriate

use

CPTR Structure

Technological Leapfrogging: A TB Imperative 17

Pa824 – Moxifloxacin – Pyrazinamide(PaMZ) Regimen Development

(a case study)

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• 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%)

PaMZ Value Proposition

Bactericidal Activity of Different Treatment Regimens in the Mouse

0

1

2

3

4

5

6

7

8

9

0 4 8

Untreated

RHZ

PaMZ

PaM

PaZ

MZ

Log10 CFU in Lungs

Weeks

R = rifampin

H = isoniazid

Z = pyrazinamide

Pa = PA-824

M = moxifloxacin


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Error Bar Plot Over Treatment for Mean EBA RegressionPA-824 Two-week Monotherapy (logCFU)


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• Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207PA-824 based Regimen Phase 2A: NC-001

Pa-Z-(M pbo)

J-Z

J -(Z pbo)

J-Pa

2 weeks of treatment

Rifafour

Pa-M-Z


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All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0)


Participants 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 Z

Pa(200mg)-M-ZN=60

Pa(100mg)-M-ZN=60

RifafourN=60

Pa(200mg)-M-Z

N=50

Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin

2 months of treatment

Randomize

Serial 16 hour pooled sputum samples for CFU Count

DS

DR


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• 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)

NC-002 Summary of Key Results and Plans


Participants with newly diagnosed smear positive DS- and MDR-TBNC-006 (STAND): Phase 3 Trial of Pa-M-Z

Pa(100mg)-M-ZN=350

Pa(200mg)-M-ZN=350

RifafourN=350

Pa(200mg)-M-Z

N= up to 350

Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin


Randomize

DS

DR

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Pa(200mg)-M-ZN= 350


12 & 24 mosf/u afterrandomization


Nix – TB

Regimens Consisting Entirely of Novel Chemical Entities

• 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

NiX-TB: Background


• 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

NiX-TB Program

Technological Leapfrogging: A TB Imperative 29

STEP-TBSpeeding Treatments to End Pediatric- TB

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• 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.

A Leading Cause of Childhood MortalityChildhood TB

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Daily treatment for a TB-HIV co-infected child

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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

Current Efforts

Market Understanding

Clinical and Regulatory

Understanding

Manufacturer Engagement

Policy and Uptake by Countries

Establish Funding

Information Exchange

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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, SanofiPolicy and Uptake: • WHO comprehensive treatment guidelines for pediatric TB to be finalized 1Q14

and rolled out in 2014Advancing Development of Pediatric TB Treatments:• Under 5kg PK study (IMPAACT)• Accelerating development and regulatory pathways for novel drugs

STEP-TB Update and Next Steps


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TB Alliance Supporters

Bill & Melinda Gates Foundation

EuropeanCommission

United States Food and Drug Administration

Irish Aid

National Institute of Allergy and Infectious Disease

UK aidUnited States Agency for

International Development

AIDS Clinical Trial Group

Global Health Innovative Technology Fund

UNITAIDAustralian AID


Thank you!