Technological
Leapfrogging:
A TB Imperative
Mel Spigelman
Dublin, Ireland
Irish Forum/Royal College of Physicians
6 March 2014
Global Tuberculosis Epidemic
Primarily affects the poorest of the poor
• 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
TB’s economic toll: >$16 billion a year
2
TB Toll in Europe
• 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)
3
TB Therapeutics – Unmet Medical Needs
Current Therapy
Unmet Needs
4 drugs; ≥6 month therapy
Shorter, simpler therapy
Drug-Resistant, M(X)DRTB
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 HIVburden settings
Shorter, safer preventive therapy
Pediatric TB
Makeshift use of inappropriate
formulations
Drug-Susceptible TB
Technological Leapfrogging: A TB Imperative
Formulations with correct dosing
4
TB Alliance
$1 donated=$1.6 leveraged funds from other partners
• 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
Patients
Government
Pharma/
biotech
Companies
Academia
Technological Leapfrogging: A TB Imperative
Research
institutes
Donors
5
TB Alliance Mission
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)
Technological Leapfrogging: A TB Imperative
6
“AAA” Mandate
Our Access Strategy
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
Technological Leapfrogging: A TB Imperative
7
TB Alliance Vision
Current Treatment
New Treatments in
Development
Aspirational Goal
6-30
2-4
7-10
Months
Months
Days
Success will require novel drug combinations
Technological Leapfrogging: A TB Imperative
8
2014 Q1
Discovery
LEAD
IDENTIFICATION
ATP Synthesis
Inhibitors
Calibr
LEAD
OPTIMIZATION
PRECLINICAL
DEVELOPMENT
PHASE 1
Pharmacokinetics
of first-line drugs
in children < 5kg
Macrolides
Sanofi
TBA-354
Ureas
Sanofi
Preclinical TB
Regimen
Development
JHU
IMPAACT
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
Energy Metabolism Inhibitors
AZ/UPenn
POA Prodrugs
Yonsei
Diarylquinolines
Janssen/University
of Auckland/UIC
Indazoles
GSK
Late Development
Early Development
PHASE 2A
NC-003
Bedaquiline/
Clofazimine/
Pyrazinamide
PA-824/
Bedaquiline/
Clofazimine/
Pyrazinamide
PA-824/
Bedaquiline/
Clofazimine
PHASE 2B
NC-002
PA-824/
Moxifloxacin/
Pyrazinamide
(PaMZ)
PHASE 3
PHASE 4
REMox-TB
Optimized
Pediatric
Formulations
Moxifloxacin/
Rifampin/
Pyrazinamide/
Ethambutol
Bayer, MRC, UCL
Moxifloxacin/
Isoniazid/ Rifampin/
Pyrazinamide
Isoniazid
for children > 5kg
PA-824/
Bedaquiline/
Pyrazinamide
Pyrazinamide
for children > 5kg
Novel Structural
Series
NITD
Hit ID Program
Daiichi Sankyo
Hit ID Program
Takeda
Hit ID Program
Shionogi
Confidential
TB Alliance R&D Partners:
AstraZeneca (AZ)
Bayer Healthcare AG (Bayer)
Beijing Tuberculosis and Thoracic Tumor
Research Institute
Calibr
Daiichi Sankyo
Eisai
GlaxoSmithKline (GSK)
Institute of Materia Medica (IMM)
IMPAACT
Janssen [Johnson & Johnson]
Johns Hopkins University (JHU)
Medical Research Council (MRC)
Ethambutol
for children > 5kg
Bayer, MRC, UCL
DprE Inhibitors
Calibr
Cyclopeptides
Sanofi
Ethambutol/
Rifampicin/
Isoniazid/
Pyrazinamide
Rifampicin
for children > 5kg
for children > 5kg
Novartis Institute for Tropical Diseases (NITD)
New York Medical College
Rutgers University
Sanofi
Shionogi
Stellenbosch University
Takeda Pharmaceuticals
University College London (UCL)
University of Auckland
University of Illinois at Chicago (UIC)
University of Pennsylvania School of
Medicine
Yonsei University
TB Alliance: Major Collaborators
SELECTED PARTNERS:
Donors
Academia
Pharma
Nat’l Research Institutes
Technological Leapfrogging: A TB Imperative
Trial Sites
Stakeholders
10
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Changing the Way TB Drugs are
Developed
• 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
Technological Leapfrogging: A TB Imperative
11
Novel TB Drug Regimen Development
Discovery and Development Process
Discovery
Phase II  Phase III
Single Compound
Preclinical Development
 Phase I  EBA
Compound 1
Compound 2
Regimen A
Compound 3
Regimen B
Drug
Candidate
Pool
Compound 4
Compound 5
Regimen C
Regimen Identification in Mice
Identification of New Drug
Candidates
Selection of Potential New
Regimens
Technological Leapfrogging: A TB Imperative
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Novel TB Drug Regimen Development
(Unified Drug Sensitive/Drug Resistant Development Path)
Stage
Testing
Model
Study
Attributes
Go/No-Go
Criteria:
Pre clinical
Phase 1
Mouse Model
Healthy
Subjects
• Single drug
• Combo in
regimen
• Relapse free
sterilizing
activity
• Single and
repeat dose
• Safety,
tolerability
• PK
• Drug
Interactions
Phase 2
Monotherapy
EBA
• Single drug
• Dose ranging
• DS patients
only
PK to support
daily dosing
Combination/
Regimen EBA
• Optimized
dose
Regimen
• Test final
regimen
• DS patients
only?
Clear effect to
reduce CFU count
Phase 3
Regimen 2Month Study
• DS and DR
sensitive to
regimen
• DS vs HRZE
standard
• DR for
consistency
As good as
HRZE standard
Technological Leapfrogging: A TB Imperative
Registration
• 2 to 4 month
treatment,
eg
• DS vs HRZE
for noninferiority
• DR for
consistency
Better Than HRZE
13
Novel Regimen Development:
General Approach
• 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
Technological Leapfrogging: A TB Imperative
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Launch of the Critical Path to TB Drug Regimens
(CPTR)
Technological Leapfrogging: A TB
Imperative
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Innovative Paradigm: From Drugs to Regimens
TB Alliance is searching for the best combinations of novel drugs
• 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
Technological Leapfrogging: A TB Imperative
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CPTR Structure
Critical Path to TB Drug Regimens
CPTR Regulatory
Science
Consortium
CPTR Drugs
Coalition
CPTR Research
Resources
Led by the Critical
Path Institute
Led by the TB
Alliance
Led by the Bill and
Melinda Gates
Foundation
Focus
 Data standards &
integration
 Biomarkers and
endpoints as disease
response assays
 Drug combination
testing and
development
 Clinical trials
infrastructure
 Resource mobilization
 Regulatory
harmonization
 Animal models
 Access and appropriate
use
 Pharmacology
 Disease progression
models
Technological Leapfrogging: A TB Imperative
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Pa824 – Moxifloxacin – Pyrazinamide
(PaMZ) Regimen Development
(a case study)
PaMZ Value Proposition
•
•
•
•
•
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%)
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Bactericidal Activity of Different Treatment
Regimens in the Mouse
9
8
Log10 CFU in Lungs
Untreated
7
RHZ
6
PaMZ
5
PaM
PaZ
4
MZ
3
R = rifampin
2
H = isoniazid
1
Z = pyrazinamide
0
0
4
Weeks
Technological Leapfrogging: A TB Imperative
8
Pa = PA-824
M = moxifloxacin
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PA-824 Two-week Monotherapy (logCFU)
Error Bar Plot Over Treatment for Mean EBA Regression
Technological Leapfrogging: A TB Imperative
21
PA-824 based Regimen Phase 2A: NC-001
Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207
• Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207
Pa-M-Z
Pa-Z-(M pbo)
J-Z
2 weeks of treatment
J -(Z pbo)
J-Pa
Rifafour
Technological Leapfrogging: A TB Imperative
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All Treatment Groups: Bi-linear Regression Mean of LogCFU
Over Day; Change from Baseline (Day X – Day 0)
Technological Leapfrogging: A TB Imperative
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NC-002: First Novel Combination “SSCC” Study
In patients with TB sensitive to Pa, M, and Z
Participants with newly diagnosed smear positive DS TB, and MDR TB
Pa(200mg)-M-Z
N=60
DS
Pa(100mg)-M-Z
N=60
2 months of treatment
Randomize
DR
Rifafour
N=60
Pa(200mg)-M-Z
N=50
Serial 16 hour pooled sputum samples for CFU Count
Z = pyrazinamide at 1500mg
Pa = PA-824
Technological Leapfrogging: A TB Imperative
M = moxifloxacin
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NC-002 Summary of Key Results and Plans
• 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)
Technological Leapfrogging: A TB Imperative
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NC-006 (STAND): Phase 3 Trial of Pa-M-Z
Participants with newly diagnosed smear positive DS- and MDR-TB
Pa(100mg)-M-Z
N=350
DS
Pa(200mg)-M-Z
N=350
4 months of
treatment
12 & 24 mos
f/u after
randomization
Pa(200mg)-M-Z
N= 350
Randomize
DR
Rifafour
N=350
6 months of treatment
Pa(200mg)-M-Z
N= up to 350
Z = pyrazinamide at 1500mg
Pa = PA-824
Technological Leapfrogging: A TB Imperative
M = moxifloxacin
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Regimens Consisting Entirely of
Novel Chemical Entities
Nix – TB
NiX-TB: Background
• 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
Technological Leapfrogging: A TB Imperative
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NiX-TB Program
• 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
Technological Leapfrogging: A TB Imperative
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STEP-TB
Speeding Treatments to End Pediatric- TB
Childhood TB
A Leading Cause of Childhood Mortality
• 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.
31
Daily treatment for a TB-HIV co-infected child
32
Current Efforts
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
Manufacturer
Engagement
Market
Understanding
Clinical and
Regulatory
Understanding
Policy and
Uptake by
Countries
Establish
Funding
Information
Exchange
33
STEP-TB Update and Next Steps
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, Sanofi
Policy and Uptake:
• WHO comprehensive treatment guidelines for pediatric TB to be finalized 1Q14
and rolled out in 2014
Advancing Development of Pediatric TB Treatments:
• Under 5kg PK study (IMPAACT)
• Accelerating development and regulatory pathways for novel drugs
Technological Leapfrogging: A TB Imperative
34
TB Alliance Supporters
UK aid
Bill & Melinda
Gates Foundation
National Institute of Allergy
and Infectious Disease
Global Health Innovative
Technology Fund
AIDS Clinical
Trial Group
Irish Aid
United States Agency for
International Development
United States
Food and Drug
Administration
European
Commission
Australian AID
Technological Leapfrogging: A TB Imperative
UNITAID
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Thank you!