Realizing Hope: New TB Cures in Development

Putting science to work for better, faster TB cures

Daniel Everitt, MD
IUATLD October 31, 2013

TB Alliance is a not-for-profit organization dedicated to the discovery and development of better, faster tuberculosis drugs that are available to those who need them.

TB Alliance Vision
Current Treatment New Treatments in Development Our Vision

6-30
Months

2-4
Months

7-10
Days

Shorter, simpler, HIV-compatible TB regimens that are adoptable, available, and affordable
Overview: TB Alliance 3

AAA Mandate: Our Access Strategy

Our commitment to patients, providers, and programs ensures our efforts benefit TB patients around the world. TB Alliance products will be:

Adoptable
into treatment policies and drug registries

Available
in public and private sectors

Affordable
cost effective for patients, countries, and donors
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Current TB therapy
Old
Long Complex Expensive
No new TB drugs developed in nearly 50 years

TB treatment today takes 6-30 months Many pills must be taken daily; Drug-resistant treatment includes daily injections Drug-resistant TB treatment can cost > $10,000 Long duration makes adherence difficult, breeds resistance; MDR-TB treatment often fails Treatments interact with commonly used ARVs, making treatment of co-infected patients challenging
Overview: TB Alliance 5

Inadequate
HIV-Incompatible

Current Therapy and Unmet Needs

Drug M(XDR)-TB Sensitive TB
4 drugs taken for 6 or more months Injections and drugs taken for more than 2 years, poorly tolerated Current Therapy

TB/HIV coinfection
Drug-drug interactions with ARVs

Latent TB Infection

Pediatric TB

9 months of isoniazid

No adequate dosing formulations

Shorter, simpler therapy

More effective, shorter, safer simpler regimens

Coadministration with ARVs

Shorter, more easily tolerated therapy

Adequate dosing regimens and formulations

Unmet Needs

TB Alliance programs seek to help all TB patient populations

TB Alliance Overview 6

Ineffective MDR-TB Treatment

Complex, toxic, and expensive
Example of a typical MDR-TB regimen

6 drugs, including 1 injection, for 6-9 months aim to directly observe 6 days/week
4 drugs given in the 18-month continuation phase (or longer) If HIV+, the patient may need to take 3 additional ARVs Less than 10% of MDR-TB patients receive proper care; of those, 1 in 3 still wont be cured
Overview: TB Alliance 7

Evolving Landscape
Promising first steps 50 years with no new TB drugs until First wave of TB drugs have obtained or are nearing regulatory approval
Bedaquiline Delamanid

Important first step: Drugs show potential to improve individual treatment, but more needs to be done to broaden those who can access and benefit from treatment Promising pipeline with many key advancements coming to fruition in 2014
TB Alliance Overview 8

2013 Q3
Discovery
LEAD IDENTIFICATION ATP Synthesis Inhibitors Calibr Energy Metabolism Inhibitors AZ/University of Penn 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 LEAD OPTIMIZATION PRECLINICAL DEVELOPMENT TBA-354

Early Development
PHASE 1 PHASE 2A PHASE 2B

Late Development
PHASE 3 PHASE 4

Mycobacterial Gyrase Inhibitors GSK

Pyrazinamide Analogs Yonsei University Diarylquinolines Janssen/University of Auckland/UIC Indazoles GSK DprE Inhibitors Calibr

NC-003
Bedaquiline/ Clofazimine/ Pyrazinamide PA-824/ Bedaquiline/ Clofazimine/ Pyrazinamide PA-824/ Bedaquiline/ Clofazimine PA-824/ Bedaquiline/ Pyrazinamide

NC-002
PA-824/ Moxifloxacin/ Pyrazinamide (PaMZ)

REMox-TB
Moxifloxacin/ Rifampin/ Pyrazinamide/ Ethambutol Bayer, MRC, UCL Moxifloxacin/ Isoniazid/ Rifampin/ Pyrazinamide Bayer, MRC, UCL

Optimized Pediatric Formulations

Isoniazid/ Rifampin/ Pyrazinamide/ Ethambutol

TBI-166 IMM Preclinical TB Regimen Development JHU

Cyclopeptides Sanofi
Macrolides Sanofi Novel Structural Series NITD Ureas Sanofi

TB Alliance R&D Partners:

AstraZeneca (AZ) Bayer Healthcare AG (Bayer) Beijing Tuberculosis and Thoracic Tumor Research Institute Calibr GlaxoSmithKline (GSK) Institute of Materia Medica (IMM) Janssen (Johnson & Johnson) Johns Hopkins University (JHU) Medical Research Council (MRC) Novartis Institute for Tropical Diseases (NITD) New York Medical College Rutgers University Sanofi Stellenbosch University University College London (UCL) University of Auckland University of Illinois at Chicago (UIC) University of Pennsylvania School of Medicine Yonsei University

Strong Momentum in TB Drug Research

Results of 3 landmark trials are expected in 2014 REMox TB trial Successful results would enable registration of 4month moxifloxacin-containing regimen for drug-sensitive TB; first treatment shortening in nearly 50 years NC-002 trial (PaMZ) Results of first trial to treat TB and some MDRTB patients with in less time. Successful results would lead to Phase 3 registration trial of PaMZ regimen NC-003 trial Testing of addition combination regimens; potential to further shorten treatment and expand the impact of bedaquiline.

Overview: TB Alliance

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REMox TB: A Global Phase 3 Trial

Results expected in 2014 Evaluating if a 4-month moxifloxacin-based regimen can perform as well as the current 6-month standard of care in drug-sensitive TB patients Potential to be the first new drug to treat drug-sensitive TB in nearly 50 years
shorten treatment by 33% higher cure rates & less emergence of MDR-TB reduce cost and burden to healthcare systems and patients

Conducted at 48 sites in 9 countries, built tremendous clinical, community capacity

Trial has been completed results are expected in 2014
Overview: TB Alliance 12

Innovative Paradigm: Drugs to Regimens

Testing pipeline of TB drugs together can reduce time needed to develop novel regimens from decades to years

Overview: TB Alliance

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Why Novel Regimens?

Benefits of new drug combinations Shorter, simpler, and safer treatment with better adherence
Ability to treat both drug-sensitive and drug-resistant disease with same regimen Dramatically cheaper MDR-TB treatment, making global scale-up feasible Compatible with HIV/AIDS medications Reduced burden to health care systems Improved outcomes & patient experiences

Overview: TB Alliance

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A Brief Primer on TB Drug Regimen Development Trials

Overview: TB Alliance

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Classic Phases of Drug Development

Development of a multi-drug regimen could take decades
Discovery Preclinical Clinical

Number of Projects

ONE

50

31

19

12

approved drug

Global TB Drug Pipeline

(10) 5 Years (7) (7) 1.5 Years (2) (6) 6 Years (2)

(Data based on: Brown, D.; Superti-Furga, G. Drug Discovery Today 2003, 8, 1067-1077)

The Community of Kibera, Kenya TB is a Disease of Poverty

17

51 year old Kenyan man with a cough, weight loss, confusion; wife died 3 years earlier with tuberculosis

18

Trial Medication Card

19

Tuberculosis (Acid Fast Bacillus AFB) from a Sputum Smear Under the Microscope

20

TB Colony Forming Units CFUs Now Countable from a Diluted Sputum Specimen

21

Novel Regimens in Development

NC-001 and NC-002 trials
PA-824+ Moxifloxacin + Pyrazinimide (PaMZ)
A two week trial revealed the regimen: kills 99% of TB bacteria in 2 weeks compares favorably to the standard of care validates paradigm of novel regimen development PaMZ is now being studied in an 8-week trial. This is the first trial to treat drug-sensitive and some drug-resistant patients with the same regimen.

Benefits could include:

Overview: TB Alliance

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The Regimen Pa-M-Z in NC-001

Pa-M-Z killed more TB bacteria in the first 2 weeks than any other regimen or combo tested

Adds support to body of evidence that Pa-M-Z may be more effective than existing treatments

Overview: TB Alliance

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NC-003 trial
Next generation regimens in the clinic NC-003 is a multiple-arm study testing additional new TB regimens with the NC-003: potential to even further shorten treatment for TB and MDR-TB Trial testing new 2-week EBA trial regimens
Trial includes multiple combinations consisting of bedaquiline, PA-824, pyrazinamide, and clofazamine Potential to expand the number of people that can benefit from bedaquiline

Overview: TB Alliance

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Pediatric TB

Todays Treatment Situation

NO safe, appropriately-dosed formulations of first-line TB drugs for children Adult treatments are cut or crushed to achieve desired dose
Unpalatable for small taste buds Difficult to dose correctly and consistently, encourages development of drug-resistant TB Results in improper or incomplete treatment, threatens child survival

No existing dosing recommendations for babies under 5kg

Gap of 7 years or more projected between launch of adult treatments and availability of child formulations
Overview: TB Alliance

Credit: Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Stellenbosch University

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Speeding treatments to end pediatric TB

Requires multi-faceted approach Understand and quantify the global TB pediatric burden Collaborate with manufacturers to develop correctly dosed, and formulated, affordable, qualityassured pediatric TB medicines Partner with regulators, countries, and donors to clarify pathways to speed access Use knowledge to shorten the long gap between the launch of adult and pediatric products
Engaging Manufacturers

Market Understanding

Clinical and Regulatory Understanding

Policy and Uptake by Countries

Engaging Countries and Donors

Information Exchange

Overview: TB Alliance

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Timeline for FDC of First-Line Pediatric Treatment:

Q2 2015: Dosage guidelines for children >5kg submitted to WHO PQ Q1 2014: Global TB market estimated
Q1 2014: Web portal launched

Q1 2016: WHO PQ approval

2013: Project Launch

Q1 2015: Global Stakeholders Meeting

Q1 2016: PmRN endorses paediatric TB regulatory pathway

2016: Final products available in the market

Q4 2013: MOU signed with first manufacturer

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TB Alliance Symposia at IUATLD 44

Updates on clinical research, community engagement, and pediatrics Engaging communities in TB research: concepts, value, & practice
Thursday, 31 October 2013, 09:00 - 17:00, Room 252B

Inclusion of children in national TB prevalence surveys

Thursday, 31 October 2013, 13:30 - 17:00 Room 251

FIND/TB Alliance: Alignment of DST and drug regimens

Thursday, 31 November 2013 13:00-17:00 Room: Hall Havane, level 3

MDR-TB in children and adolescent TB issues

Friday, 01 November 2013, 14:30 - 16:30 Room Amphithtre Bleu

Recent progress in TB clinical trials

Saturday, 02 November 2013, 08:00 - 10:00 Room Amphithtre Bleu

UNITAID/TB Alliance: Catalyzing the pediatric TB drug market

Saturday, 02 November 2013, 14:30 - 16:30Room 243

Overview: TB Alliance

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Thank you!