TB Alliance

Promise in the Pipeline

October 29, 2014

TB Alliance is a not-for-profit organization dedicated to the discovery

and development of better, faster, affordable tuberculosis drugs that
are available to those who need them.

Current TB Therapy

Old
Long
Complex

Expensive
Inadequate

Arsenal of drugs developed mostly in 1960s

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 & complex; breeds resistance & default; incompatible

with some HIV treatments; MDR-TB treatment often fails

TB Alliance: Promise in the Pipeline

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

TB Alliance: Promise in the Pipeline

Current Therapy and Unmet Needs

Unmet
Needs

Current
Therapy

Drug
TB/HIV
M(XDR)Latent TB Pediatric
Sensitive
coTB
Infection
TB
TB
infection
4 drugs taken
for 6 or more
months

Injections &
drugs taken
for 2+ years,
poorly
tolerated

Drug-drug
interactions
with ARVs

9 months of
isoniazid

No adequate
dosing
formulations

Shorter,
simpler
therapy

More
effective,
shorter, safer
simpler
regimens

Coadministratio
n with ARVs

Shorter, more
easily
tolerated
therapy

Adequate
dosing
regimens and
formulations

Diagnostic

Diagnostic
Diagnostic point
Rapid, accurate, affordable

Diagnostic
of care diagnostic

Diagnostic

TB Alliance programs seek to help all TB patient populations

TB Alliance: Promise in the Pipeline

Accelerating Progress: From Drugs to Regimens

TB Alliance is searching for the best combinations of novel drugs
TB must be treated with multi-drug combinations to prevent the development of
resistance
Todays pipeline of TB drugs can be tested together, speeding development of
novel TB regimens and reducing R&D from decades to years

TB Alliance: Promise in the Pipeline

Benefits of New Regimens

Positive impacts of new treatments are wide-reaching and multi-faceted

Simple Supply
Management

Reduced
Health
Systems
Burden

More Patient
Satisfaction

Better
Outcomes

Lower Cost

Fewer side
effects

Novel regimens can simplify TB treatment, facilitate its scale-up, and reduce its
burden on health systems
TB Alliance: Promise in the Pipeline

2014 Q4
Discovery
LEAD
IDENTIFICATION

LEAD
OPTIMIZATION

Late Development

Early Development
PRECLINICAL
DEVELOPMENT

PHASE 1

PHASE 2A

Pharmacokinetics
of first-line drugs
in children < 5kg

PHASE 3

PHASE 2B

STAND

NC-005

PHASE 4

Optimized
Pediatric
Formulations

ATP Synthesis
Inhibitors
Calibr

Macrolides
Sanofi

Whole-Cell Hit-toLead Program

Sanofi

Ureas
Sanofi

Whole-Cell Hit-toLead Program

GSK

Diarylquinolines
Janssen/University
of Auckland/UIC

RNA Polymerase
Inhibitors
Rutgers University

Indazoles
GSK

Ethambutol
for children > 5kg

Thiophene
Carboxamides
Calibr

Isoniazid
for children > 5kg

Energy Metabolism Inhibitors

AZ/Upenn
POA Prodrugs
Yonsei
InhA Inhibitors

Azaindoles
AZ

Cyclopeptides
Sanofi

Hit ID Program
Takeda
Mmmpl3 Inhibitors
Hit ID Program
Daiichi Sankyo
Hit ID Program
Shionogi

TBA-354

Preclinical TB
Regimen
Development
JHU

Stellenbsch
University

PA-824/
Bedaquiline/
Pyrazinamide

PA-824/
Moxifloxacin/
Pyrazinamide

Ethambutol/
Rifampicin/
Pyrazinamide
for children > 5kg
Isoniazid/
Rifampicin
for children > 5kg

Pyrazinamide
for children > 5kg

TB Alliance R&D Partners:

AstraZeneca (AZ)
Bayer Healthcare AG (Bayer)
Beijing Tuberculosis and Thoracic Tumor
Research Institute
Calibr
Daiichi Sankyo
GlaxoSmithKline (GSK)
Institute of Materia Medica (IMM)
IMPAACT
Janssen [Johnson & Johnson]
Johns Hopkins University (JHU)
Medical Research Council (MRC)

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

Four New Trials

Either just launched or soon to launch
STAND Phase 3 trial testing PaMZ
Estimated launch Q4 2014

NC005 Phase 2B (8-week) trial testing BPaZ

Launched October 2014

NIX-TB Trial to cure XDR-TB patients w/ completely novel regimen

Estimated launch Q4 2014/Q1 2015

TBA-354 Phase 1 study new drug candidate, healthy volunteers

Estimated launch Q4 2014/Q1 2015

Pediatric work ongoing

Discovery stage work ongoing

TB Alliance: Promise in the Pipeline

STAND: A Global Phase 3 Trial

Shortening Treatments by Advancing Novel Drugs

The STAND trial will test PaMZ

regimen
PaMZ = pretomanid, moxifloxacin,
and pyrazinamide

First Phase 3 trial to test a regimen in

patients with drug-sensitive and drugresistant TB (must be sensitive to
drugs in the regimen)
Holds potential to transform
treatment of both drug-sensitive and
especially drug-resistant TB

TB Alliance: Promise in the Pipeline

10

PaMZ: A Potential Game-Changer

Phase 3 STAND Trial expected to
launch in 2014, provided adequate
funding
Drug cost reduced by 90% or more in
some regions for MDR-TB
Reduced treatment time from 24
months to 4-6 months
Friendly with HIV drugs
No hospitalization
No injectables

No weight banding, easing supply

and administration

This new drug regimen could provide the

breakthrough we need to accelerate progress
against this deadly and dangerous disease.
--Bill Gates (April 23, 2014)

TB Alliance: Promise in the Pipeline

11

Where in the World is STAND?

The global Phase 3 STAND trial will be conducted at some 50 sites in 10 countries.
Partners include University College London, St. Andrews, Fosun, CSIR and others.
TB Alliance: Promise in the Pipeline

12

NC-005 trial: BPaZ

Phase 2b trial testing combinations of bedaquiline, pretomanid, and pyrazinamide
NC-005 tests regimens containing
bedaquiline, pretomanid, and
pyrazinamide with the potential to
even further shorten treatment for
TB and MDR-TB
2-month Phase 2b trial
Enrolls both drug-sensitive and
drug-resistant patients with the
potential to shorten, improve
treatment
Conducted at 10 sites in South
Africa, Tanzania, and Uganda
Launched October 2014
TB Alliance: Promise in the Pipeline

13

NIX-TB: Accelerating solutions for XDR-TB

New Investigational Drugs for XDR-TB
First clinical trial for a new XDR-TB
treatment
Tests universal regimens, with no
pre-existing resistance
Regimen includes bedaquiline,
pretomanid, and linezolid; may
substitute alternate oxazolidanone
when it becomes available
Potential to be a 6 month oral
treatment option for XDR-TB
NIX-TB will launch at 2-3 sites in
South Africa by late 2014/early
2015

Novel treatments to fight XDR-TB are urgently

needed. A 2014 Lancet study found nearly half of
XDR-TB patients died within a year of diagnosis, and
an additional 30% failed treatment or defaulted.

TB Alliance: Promise in the Pipeline

14

TBA-354
First new TB drug to enter clinical development since 2006
TBA-354 will begin Phase 1 clinical testing in healthy volunteers in late
2014/early 2015
First candidate to cross from discovery to clinical stage development in 8 years.
This is a gap in global TB drug pipeline

From same chemical class as pretomanid (nitroimidazole)

Potentially more potent than pretomanid

First drug candidate discovered by TB Alliance to reach clinical development

TB Alliance: Promise in the Pipeline

15

Community Engagement
TB Alliances CE program empowers people affected
by TB with knowledge and skills to promote
participation in TB drug research conducted in their
communities through
Small Grants Program: Supports site-level CE strategies
and Community Advisory Boards through funding,
guidance, and technical assistance
Research Literacy: Improves understanding of TB
research through intensive trainings
Cross-Site Engagement and Learning: Provides
opportunities for sites to learn from one another, and
to build new skills
Monitoring and Evaluation: Develop new tools to
measure the impact of CE clinical research outcomes.

TB Alliance: Promise in the Pipeline

16

Childhood TB
Children with TB are the neglected of the neglected
TB is one of the top 10 killers of children worldwide

NO safe, appropriately-dosed formulations of firstline TB drugs for children

In 2012, WHO reports an estimated 530,000
children acquired TB, and 74,000 children died
(among HIV-negative children)
Due to diagnostic and reporting challenges, many
suspect the figures are much higher
Children are susceptible to the most severe and fatal
forms of the disease
disseminated TB & TB meningitis results in deafness,
blindness, and arrested mental development

TB Alliance: Promise in the Pipeline

17

Improving Todays Pediatric Treatments

Child-appropriate TB treatment is urgently needed

NO safe, appropriately-dosed, easyto-administer first-line TB drugs for

children
Adult treatments are often cut or
crushed to achieve desired dose
No existing dosing
recommendations for babies under
5kg
Credit: Desmond Tutu TB Centre, Department of Paediatrics and Child Health,
Stellenbosch University

Gap of 7 years or more projected

between launch of adult treatments
and availability of child formulations

TB Alliance: Promise in the Pipeline

18

Speeding Treatments to End Pediatric TB

Increasing access to correctly dosed, affordable, child-friendly TB medicines
TB Alliance, with the World Health Organization, aim to improve access to
appropriate pediatric TB treatments. Our multi-pronged approach includes:
Catalyzing the Market:
Understanding patient burden and market dynamics
Securing manufacturer commitments

Developing New Drugs

Correct dosage & dispersible form for HRZ, HR, and E
Shorten gap between approval of adult vs. pediatric products

Influencing Uptake
Ensuring guideline change is linked to product availability
Securing funding for product and implementation

We seek to deliver correctly formulated, child-friendly TB treatments for all

first-line drug-sensitive TB
TB Alliance: Promise in the Pipeline

19

AAA Mandate
TB Alliance 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
TB Alliance: Promise in the Pipeline

20

Figure 1
Annual Global Plan Research Funding Targets versus 2013 Funding

$800,000,000
$740,000,000

$600,000,000

$400,000,000 $420,000,000
$380,000,000

$340,000,000
$200,000,000

$255,428,811
$137,658,205

$0

$67,771,567
Basic Science New Diagnostics New Drugs
Global Plan Annual Targets

$80,000,000
$95,172,788 $71,754,311
New Vaccines Operational
Research
2013 Funding

Funding for TB R&D is woefully inadequate

Table 4

20052013 NIH Funding for Selected Infectious Diseases (in USD millions)
Research Area

2005

2006

2007

2008

2009*

2010*

2011

2012

2013

Tuberculosis

$158

$150

$188

$142

$216

$224

$209

$218

$207

$2,921

$2,902

$2,906

$2,928

$3,338

$3,407

$3,059

$3,074

$2,898

HIV/AIDS

*Includes American Recovery and Reinvestment Act stimulus funds

Source: NIH Estimates of Funding for Various Research, Condition, and Disease Categories (RCDC).
Available from: http://report.nih.gov/categorical_spending.aspx.

Despite TBs close relationship with HIV/AIDS, it is

drastically underfunded by comparison

TB Alliance Supporters
Thanks to all those who support our mission for better, faster-acting TB treatment

UK aid

Bill & Melinda

Gates Foundation

National Institute of Allergy

and Infectious Diseases

Global Health Innovative

Technology Fund

AIDS Clinical
Trial Group

Department of
Foreign
Affairs
and
TB Alliance:
Promise
in the Pipeline
Trade, Australia

UNITAID

United States Agency for

International Development

United States
Food and Drug
Administration

European
Commission

Irish Aid

23

Thank you!