Title: 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
2The 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.
3Current 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
4TB 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
5Product 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
6TB 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
7TB 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
8Commitment 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
9TB Alliance Vision
10 days
2 4 months
Success will require novel multi-drug combinations
6 gt24 months
10TB Alliance Portfolio
November 2010
11TB 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)
13Historic 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
14Paradigm 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
15New 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
16How We Are Shifting the Paradigm
From Drugs to Regimens CPTR and NC-001
17Launch 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
18Critical 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)
20The 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)
21Significance 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
22Current 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 24The 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.
25Need 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)