The TB Drugs Pipeline:

From Drugs to Regimens (CPTR and NC-001)

Dr. Ann Ginsberg

Chief Medical Officer, TB Alliance
November 12, 2010
Berlin, Germany
 The Threat of TB
• TB remains one of the world’s deadliest infectious
diseases – second only to HIV/AIDS – killing one person
every 20 seconds
• Each year, TB kills more than 1.8 million people, and
there are 9.4 million new cases, primarily in developing
countries
• TB’s complex and deadly interaction with HIV/AIDS has
even further exacerbated the global TB epidemic
• There is an urgent unmet need for better treatments.
 Current TB Therapy and Unmet Needs
Patient Population Current Unmet
Therapy Needs
Drug-Susceptible TB 4 drugs; ≥6 month therapy Shorter, simpler therapy

Drug-Resistant Few drugs (including injectables); Totally oral, shorter, more

M(X)DR-TB ≥18 months therapy; toxicities efficacious, safer and lower
cost therapy

TB/HIV Drug-drug interactions with HIV Ability to easily co-administer

Co-Infection medications TB regimens with ARVs

Latent TB 6-9 months of treatment Shorter, safer therapy

Infection

► All treatments for active TB must be multidrug regimens

► Significant improvements in therapy are needed for all patient populations
 TB Treatment Evolution

1950 1960 1970 1980 2005

1946 1952 1963 Rifampin 1970 1974 1998

Strepto- 1 regimen: BMRC Trials Rifapentine
st
(R) discovered BMRC
mycin 1st • Streptomycin Trials add R & Z approved
used for TB • PAS 1961 add R
• Isoniazid Ethambutol (E)
Standard Therapy
1954 discovered
2 months: R, H, Z, E
Pyrazinamide (Z) +
discovered – but liver 4 months: R, H
toxicity

Standard Regimen by 1960s based on 1952 drugs

Rx shortened to 6 months

Rx shortened to 9 months
Rx lasts from 12-24 months
 Product Development Partnerships
(PDPs)

 Non-profit enterprises to accelerate the R&D and adoption of new,

affordable global health products
 Create and manage partnerships and resources across public, private
and philanthropic sectors
 Utilize a portfolio management approach to maximize efficiency and
prioritize resources to the most promising candidates
 Act as a catalyst to advance the field of new “tools” for all participants

 PDPs are a proven model to fill critical scientific gaps and

accelerate the development and delivery of new health technologies
 TB Alliance
• Founded in 2000 GOVERNMENTS

• Not-for-profit Product PHARMA

BIOTECH

Development Partnership
(PDP) headquartered in New
York, with offices in Brussels TB
and Pretoria Alliance

• Entrepreneurial, virtual drug ACADEMIA INSTITUTES

development approach
• Largest portfolio of TB drug FOUNDATIONS

candidates in history
 TB Alliance Mission

• Develop new, better treatments for TB that are:

– faster-acting and less complex
– compatible with anti-retrovirals for HIV/AIDS coinfection
– active against drug sensitive and drug resistant strains
• Ensure that new regimens are affordable, adopted for
use, and made widely available
• Coordinate and act as catalyst for global TB drug
development activities
 Commitment to “AAA”
• Regimens must be sufficiently low cost to be procured in
developing countries
Affordable • Ensured through negotiation of agreements, cost-of-goods
considerations in development process

• Public programs and private sector must accept and

implement new regimens
Adoptable • Ensured through acceptability studies, engagement with local
communities, and direct negotiations with country programs,
WHO, and other stakeholders to bring about guideline change

• New regimens must be made available to patients in countries

that adopt them
Available • Ensured by developing a robust manufacturing and
distribution plan with pharmaceutical partners, generics,
countries, donors, and other actors
 TB Alliance Vision
FD
Cs

10 days
2 – 4 months

Success will require

6 – >24 months
novel multi-drug
combinations
 TB Alliance Portfolio
Discovery Preclinical Clinical Development
TARGET OR CELL-BASED Development
SCREENING LEAD IDENTIFICATION LEAD OPTIMIZATION CLINICAL PHASE I CLINICAL PHASE II CLINICAL PHASE III

Natural Products Whole-Cell Hit to Lead Mycobacterial Gyrase Nitroimidazoles PA-824 Moxifloxacin (+ H, R, Z)
IMCAS Program Inhibitors U. of Auckland/ Novartis Bayer
GSK GSK U. Ill Chicago
Protease Inhibitors Malate Synthase InhA Inhibitors Preclinical TB TMC207 Moxifloxacin (+ R, Z, E)
IDRI Inhibitors GSK Regimen Development Tibotec Bayer
GSK/TAMU JHU/U. Ill Chicago

TB Drug Discovery Portfolio Diarylquinolines PA-824/Pyrazinamide

NITD Tibotec/U. of Auckland

Topoisomerase I Gyrase B Inhibitors Riminophenazines TMC207/Pyrazinamide

Inhibitors AZ IMM/BTTTRI
AZ/NYMC
Folate Biosynthesis Pyrazinamide Analogs PA-824/
Inhibitors Yonsei Moxifloxacin/
AZ Pyrazinamide

Whole-Cell Hit to Lead

Program
AZ
RNA Polymerase
Inhibitors
AZ/Rutgers
Energy Metabolism Novel TB
Inhibitors
AZ/U. Penn
regimen development
Phenotypic Hit to Lead
Program
U. Ill Chicago
Menaquinone
Biosynthesis Inhibitors
CSU

November 2010
 TB Alliance – 3 Clinical Stage
Moxifloxacin
Compounds
•Phase of Development: 3
•Partner: Bayer
•Potential use against DS- and MDR-TB; currently being tested in DS-TB

PA-824
•Phase of Development: 2
•Partner: In-licensed from Chiron, which was subsequently acquired by Novartis
•New mechanism of action
•Potential use against DS-, MDR- and XDR-TB

TMC-207
•Phase of Development: 2
•Partner Tibotec/Johnson & Johnson
•New mechanism of action
•Potential use against DS-, MDR- and XDR-TB, currently being tested in both DS
and MDR patients
Clini
 Historic Opportunity

For the first time in history, the

opportunity exists to develop truly
novel regimens, containing multiple
new chemical entities with novel
mechanisms of action

TB treatment of 2-4 months

 Paradigm Change in TB Drug
Development

 Current TB drug development approach

replaces one drug at a time, requiring decades
to introduce a new regimen that consists of
multiple novel agents
 New paradigm needed for rational selection
and development of new combinations
 New Development Paradigm:
Combination testing of novel regimens
• Under the new paradigm, the regimen, not an individual drug, is the
unit of development
• New drugs are tested in combinations in clinical trials simultaneously,
rather than successively

Combinati
on
approach
reduces
time to
market to
as little as
1/4th
How We Are Shifting the Paradigm

…From Drugs to Regimens:

CPTR and NC-001

Launch of Critical Path to TB Drug
Regimens (CPTR)
- BMGF, Critical Path Institute and TB Alliance

18 March 2010 US FDA Commissioner,

Dr. Margaret Hamburg

Please visit: CPTRinitiative.org for more information

 Critical Path to TB Drug Regimens
(CPTR)
 Accelerates the development of new regimens by testing promising new drugs together,
rather than by sequential testing of individual drugs
 Overcomes intellectual property barriers to private sector collaboration
 Commitment to access puts patients before profits
 Collaboration maximizes synergy, reduces cost, increases efficiency
 Engages regulatory authorities to develop new pathways and guidances for combination
testing and approval
 Endorsed by donors, governments, multilaterals, corporations, civil society, and non-
profits
 A model for other therapeutic areas that require combinations, such as cancer and
hepatitis
The New Opportunity: trial NC-001
For the first time, there is an opportunity to treat
both drug-sensitive (DS-TB) and multidrug-
resistant TB (MDR-TB) with the same regimen,
and alter the course of the TB pandemic by
shortening and simplifying treatment worldwide

3-drug regimen in NC-001 =

Moxifloxacin (TB Alliance, Bayer) + PA-824 (TB Alliance) +

Pyrazinamide (existing antibiotic)
 Significance of NC-001 Trial
Potential to:
• treat DS-TB and MDR-TB with the same regimen: would simplify
treatment and delivery
• shorten treatment for drug-sensitive and MDR-TB to less than 6
months
• simplify treatment for people with TB/HIV (should not have
significant interactions with antiretrovirals – no rifampicin)
• enable scale-up of MDR-TB treatment - shorter, simpler (no
injectables), more affordable treatment for MDR-TB

 Sets stage for new era in TB drug development: new drugs

tested in combination, enabling delivery of new treatments in
years vs. decades
 Current TB Therapy and Unmet Needs
This trial addresses at least three major unmet needs in TB therapy
Patient Population Current Unmet
Therapy Needs
Drug-Susceptible TB 4 drugs; ≥6 month therapy Shorter, simpler therapy

Drug-Resistant Few drugs (including injectables); Totally oral, shorter, more

M(X)DR-TB ≥18 months therapy; toxicities efficacious, safer and lower cost
therapy

TB/HIV Drug-drug interactions with HIV Ability to easily co-administer TB

Co-Infection medications regimens with ARVs

Latent TB 6-9 months of treatment Shorter, safer therapy

Infection

► Significant improvements in therapy are needed for all patient populations

Thank You
 The Drug Development Process
Phase II

DISCOVERY: Identify lead structural series; optimize activity in vitro, efficacy in animals, and
other pharmacological properties. Perform preclinical safety studies allowing filing of a new
drug application. Use combination testing to identify the best potential new regimens for
clinical development.

PHASE I: Test drug candidates and regimens in small numbers of healthy volunteers for
safety, tolerability, and pharmacokinetic properties.

PHASE II: Evaluate single drug candidates (Phase IIa) and multidrug regimens (Phase IIb) in
TB patients for potential efficacy and further assessment of safety.

PHASE III: Test multidrug regimens in large numbers of TB patients for efficacy and safety.

REGULATORY APPROVAL: Regulatory authorities license the drug/regimen after reviewing

all preclinical and clinical results (also called registration)

ADOPTION/ AVAILABILITY: National TB control programs adopt the new drug/regimen.

 Need for a Stronger Global TB Drug
Pipeline
Discovery Preclinical Clinical
Number of Projects

ONE
50 31 19 12 7 4 2 approved
drug

Global TB Drug Pipeline

(10) (7) (7) (2) (6) (2)

5 Years 1.5 Years 6 Years

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