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Technological Leapfrogging: A TB Imperative. Mel Spigelman. Dublin, Ireland Irish Forum/Royal College of Physicians 6 March 2014. Global Tuberculosis Epidemic. TB’s economic toll: >$16 billion a year. 2 billion people are infected with M.tb 9 million new active TB cases per year

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technological leapfrogging a tb imperative

Technological Leapfrogging: A TB Imperative

Mel Spigelman

Dublin, Ireland

Irish Forum/Royal College of Physicians

6 March 2014

global tuberculosis epidemic
Global Tuberculosis Epidemic
  • TB’s economic toll: >$16 billion a year
  • 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

Primarily affects the poorest of the poor

tb toll in europe
TB Toll in Europe
  • 502,763 cases of TB and more than 44,000 TB deathsin 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)
tb therapeutics unmet medical needs
TB Therapeutics – Unmet Medical Needs

Current Therapy

Unmet Needs

Formulations with correct dosing

Technological Leapfrogging: A TB Imperative

tb alliance
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

Technological Leapfrogging: A TB Imperative

tb alliance mission
TB Alliance Mission

Technological Leapfrogging: A TB Imperative

aaa mandate
“AAA” Mandate

Our Access Strategy

Technological Leapfrogging: A TB Imperative

tb alliance vision
TB Alliance Vision

Current Treatment

New Treatments in Development

Aspirational Goal

6-30Months

2-4Months

7-10Days

Success will require novel drug combinations

Technological Leapfrogging: A TB Imperative

2014 q1
2014 Q1

Discovery

Late Development

Early Development

Phase 4

Phase 3

Lead identification

Lead Optimization

PRECLINICAL DEVELOPMENT

Phase 1

Phase 2A

Phase 2B

NC-003

Optimized Pediatric Formulations

NC-002

REMox-TB

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 MateriaMedica(IMM)

IMPAACT

Janssen [Johnson & Johnson]

Johns Hopkins University (JHU)

Medical Research Council (MRC)

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

Confidential

tb alliance major collaborators
TB Alliance: Major Collaborators

SELECTED PARTNERS: DonorsPharmaTrial SitesAcademiaNat’l Research InstitutesStakeholders

Technological Leapfrogging: A TB Imperative

changing the way tb drugs are developed
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

Technological Leapfrogging: A TB Imperative

11

novel tb drug regimen development
Novel TB Drug Regimen Development

Discovery

Phase II  Phase III

Single Compound

Preclinical Development

 Phase I  EBA

Compound 1

Drug Candidate Pool

Compound 2

Regimen A

Compound 3

Regimen B

Compound 4

Regimen C

Compound 5

Regimen Identification in Mice

Identification of New Drug

Candidates

Selection of Potential New Regimens

Discovery and Development Process

Technological Leapfrogging: A TB Imperative

novel tb drug regimen development unified drug sensitive drug resistant development path
Novel TB Drug Regimen Development (Unified Drug Sensitive/Drug Resistant Development Path)

Stage

Pre clinical

Phase 1

Phase 2

Phase 3

Testing Model

Study Attributes

Go/No-Go Criteria:

PK to support

daily dosing

As good as

HRZE standard

Clear effect to

reduce CFU count

Better Than HRZE

Technological Leapfrogging: A TB Imperative

novel regimen development general approach
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

launch of the critical path to tb drug regimens cptr
Launch of the Critical Path to TB Drug Regimens (CPTR)

Technological Leapfrogging: A TB Imperative

innovative paradigm from drugs to regimens
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

cptr structure
CPTR Structure

Technological Leapfrogging: A TB Imperative

pamz value proposition
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%)
bactericidal activity of different treatment regimens in the mouse
Bactericidal Activity of Different Treatment Regimens in the Mouse

Log10 CFU in Lungs

R = rifampin

H = isoniazid

Z = pyrazinamide

Pa = PA-824

M = moxifloxacin

Weeks

Technological Leapfrogging: A TB Imperative

pa 824 two week monotherapy logcfu
PA-824 Two-week Monotherapy (logCFU)

Error Bar Plot Over Treatment for Mean EBA Regression

Technological Leapfrogging: A TB Imperative

pa 824 based regimen phase 2a nc 001
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-Z-(M pbo)

Pa-M-Z

J-Z

2 weeks of treatment

J -(Z pbo)

J-Pa

Rifafour

Technological Leapfrogging: A TB Imperative

all treatment groups bi linear regression mean of logcfu over day change from baseline day x day 0
All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0)

Technological Leapfrogging: A TB Imperative

nc 002 first novel combination sscc study in patients with tb sensitive to pa m and z
NC-002: First Novel Combination “SSCC” StudyIn 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

Pa(100mg)-M-Z

N=60

DS

Rifafour

N=60

2 months of treatment

Pa(200mg)-M-Z

N=50

Randomize

DR

Serial 16 hour pooled sputum samples for CFU Count

Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin

Technological Leapfrogging: A TB Imperative

nc 002 summary of key results and plans
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

nc 006 stand phase 3 trial of pa m z
NC-006 (STAND): Phase 3 Trial of Pa-M-Z

Participants with newly diagnosed smear positive DS- and MDR-TB

Pa(200mg)-M-Z

N= 350

Pa(100mg)-M-Z

N=350

4months of treatment

Pa(200mg)-M-Z

N=350

12 & 24 mos

f/u after

randomization

DS

Rifafour

N=350

Pa(200mg)-M-Z

N= up to 350

6months of treatment

Randomize

DR

Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin

Technological Leapfrogging: A TB Imperative

nix tb background
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

nix tb program
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

step tb

STEP-TB

Speeding Treatments to End Pediatric- TB

childhood 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.

current efforts
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

step tb update and next steps
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

tb alliance supporters
TB Alliance Supporters

United States Agency for International Development

Bill & Melinda Gates Foundation

Irish Aid

UK aid

United States

Food and Drug Administration

National Institute of Allergy and Infectious Disease

AIDS Clinical

Trial Group

European

Commission

Global Health Innovative Technology Fund

UNITAID

Australian AID

Technological Leapfrogging: A TB Imperative