The TB Drugs Pipeline:

1
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
2
The Threat of TB

• TB remains one of the worlds 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
• TBs complex and deadly interaction with HIV/AIDS
  has even further exacerbated the global TB
  epidemic
• There is an urgent unmet need for better
  treatments.

3
Current TB Therapy and Unmet Needs
Patient Population Current Therapy Unmet Needs
Drug-Susceptible TB 4 drugs 6 month therapy Shorter, simpler therapy
Drug-Resistant M(X)DR-TB Few drugs (including injectables) 18 months therapy toxicities Totally oral, shorter, more efficacious, safer and lower cost therapy
TB/HIV Co-Infection Drug-drug interactions with HIV medications Ability to easily co-administer TB regimens with ARVs
Latent TB Infection 6-9 months of treatment Shorter, safer therapy

• All treatments for active TB must be multidrug
  regimens
• Significant improvements in therapy are needed
  for all patient populations

4
TB Treatment Evolution
1950
2005
1970
1980

• 1952
• 1st regimen
• Streptomycin
• PAS
• Isoniazid

1974 BMRC Trials add R Z
1946 Strepto-mycin 1st used for TB
1998 Rifapentine approved
1963 Rifampin (R) discovered
1970 BMRC Trials add R
1961 Ethambutol (E) discovered
1954 Pyrazinamide (Z) discovered but liver
toxicity
Standard Regimen by 1960s based on 1952 drugs
Rx shortened to 9 months
Rx lasts from 12-24 months
5
Product Development Partnerships (PDPs)

• Non-profit enterprises to accelerate the RD 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
6
TB Alliance

• Founded in 2000
• Not-for-profit Product Development Partnership
  (PDP) headquartered in New York, with offices in
  Brussels and Pretoria
• Entrepreneurial, virtual drug development
  approach
• Largest portfolio of TB drug candidates in
  history

7
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

8
Commitment to AAA
Affordable

• Regimens must be sufficiently low cost to be
  procured in developing countries
• Ensured through negotiation of agreements,
  cost-of-goods considerations in development
  process

Adoptable

• Public programs and private sector must 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 must be made available to patients
  in countries that adopt them
• Ensured by developing a robust manufacturing and
  distribution plan with pharmaceutical partners,
  generics, countries, donors, and other actors

9
TB Alliance Vision
10 days
2 4 months
Success will require novel multi-drug combinations
6 gt24 months
10
TB Alliance Portfolio
November 2010
11
TB Alliance 3 Clinical Stage Compounds

• Moxifloxacin
• 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

12
(No Transcript)
13
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
14
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

15
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

Combination approach reduces time to market to as
little as 1/4th
16
How We Are Shifting the Paradigm
From Drugs to Regimens CPTR and NC-001
17
Launch of Critical Path to TB Drug Regimens
(CPTR)- BMGF, Critical Path Institute and TB
Alliance
US FDA Commissioner, Dr. Margaret Hamburg
18 March 2010
Please visit CPTRinitiative.org for more
information
18
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

19
(No Transcript)
20
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)
21
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

22
Current TB Therapy and Unmet Needs
This trial addresses at least three major unmet
needs in TB therapy
Patient Population Current Therapy Unmet Needs
Drug-Susceptible TB 4 drugs 6 month therapy Shorter, simpler therapy
Drug-Resistant M(X)DR-TB Few drugs (including injectables) 18 months therapy toxicities Totally oral, shorter, more efficacious, safer and lower cost therapy
TB/HIV Co-Infection Drug-drug interactions with HIV medications Ability to easily co-administer TB regimens with ARVs
Latent TB Infection 6-9 months of treatment Shorter, safer therapy

• Significant improvements in therapy are needed
  for all patient populations

23

• Thank You

24
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) ADOPT
ION/ AVAILABILITY National TB control programs
adopt the new drug/regimen.

25
Need for a Stronger Global TB Drug Pipeline
Number of Projects
Global TB Drug Pipeline (10) (7)
(7) (2) (6)
(2)
(Data based on Brown, D. Superti-Furga, G. Drug
Discovery Today 2003, 8, 1067-1077)