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Hope in the Pipeline I Development of Drugs to Treat TB. IUALTD 2011 - J2J Symposium Daniel Everitt, MD TB Alliance. Development of Drugs to Treat TB Outline of Discussion. Current and historic regimens to treat TB Treatment needs for the future and our historic opportunity

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hope in the pipeline i development of drugs to treat tb

Hope in the Pipeline IDevelopment of Drugs to Treat TB

IUALTD 2011 - J2J Symposium

Daniel Everitt, MD

TB Alliance

development of drugs to treat tb outline of discussion
Development of Drugs to Treat TBOutline of Discussion
  • Current and historic regimens to treat TB
  • Treatment needs for the future and our historic opportunity
  • The steps and realities of TB drug development
    • Specific examples from TB Alliance collaborations
  • A paradigm shift for drug development
  • Drugs in the pipeline
  • Optimism for international collaboration to develop superior treatments for TB

2

treatment evolution for drug sensitive tb

1960

Standard Therapy

2 months: R, H, Z, E

+

4 months: R, H

Rx shortened to 6 months

Treatment Evolution for“Drug Sensitive” TB

1950

1970

1980

2005

1946

Strepto-mycin 1st used for TB

  • 1952
  • 1st regimen:
    • Streptomycin
    • PAS
    • Isoniazid (H)

1974

BMRC Trials

add R & Z

1998

Rifapentine approved

1963Rifampin (R) discovered

1970

BMRC Trials add R

1961Ethambutol (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

3

the burden of therapy for multi drug resistant tb
The Burden of Therapy for Multi-drug Resistant TB

Example of a typical regimen for MDR-TB

  • Intensive phase of 6-9 months – aim to directly observe 6 days/week:
    • Six drug combination, one given by injection
  • Continuation phase of 18 months:
    • Four drugs
  • A patient may need longer therapy if sputum is not clear of TB at month 4

Note: If the patient has HIV, he/she may need to take 3 additional anti-retroviral drugs

4

slide5

Current TB Therapy and Unmet Needs

  • Significant improvements in therapy are needed for all patient populations

5

tb alliance
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

GOVERNMENTS

PHARMA

BIOTECH

TB Alliance

ACADEMIA

INSTITUTES

FOUNDATIONS

6

tb alli ance mission
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

7

slide8

FDCs

TB Alliance Vision

10 days

2 – 4 months

Success will require novel multi-drug combinations

6 – 30 months

8

the need for new tb drugs
The need for new TB drugs

The need to ensure adherence can put a huge burden on patients

Shorter therapies equals > adherence, > cure, < burden on patients, and < emergence of drug resistance

9

slide10

What is Needed to Cure a Patient with TB?

Effective Medications

Adherence to Therapy (DOTS)

Health

Health Care System to Diagnose TB, Treat, and Confirm Cure

Financing of Medications and the Health Care System

10

classic phases of drug development
Classic Phases of Drug Development

Discovery

Preclinical

Clinical

ONE

approved

drug

50

31

19

12

7

4

2

Number of Projects

    • Global TB Drug Pipeline
  • (10) (7) (7) (2) (6) (2)

5 Years

1.5 Years

6 Years

(Data based on: Brown, D.; Superti-Furga, G. Drug Discovery Today 2003, 8, 1067-1077)

11

new development paradigm combination testing of novel regimens
New Development Paradigm: Combination testing of novel regimens
  • Under the new paradigm, the regimen, not an individual drug, becomes the unit of development
  • New drugs are tested in combinations in clinical trials simultaneously, rather than successively

Combination approach reduces time to market by ~3/4ths

12

tb drug regimen discovery and development process
TB Drug/RegimenDiscovery and Development Process

Discovery

Single Compound

Preclinical Development

 Phase I  EBA

Phase II  Phase III

Compound 1

Compound 2

Drug Candidate Pool

Regimen A

Compound 3

Regimen B

Compound 4

Regimen Identification

Compound 5

Regimen C

Identification of New Drug

Candidates

Selection of Potential New Regimens

drug development the preclinical phase
Drug Development – the Preclinical Phase
  • Many steps to develop a promising molecule
  • Safety evaluations typically done in two animal species (e.g. rat and dog)
  • Pharmacology studies to evaluate efficacy on a relevant endpoint
    • Aim to find a blood concentration that correlates with the maximum effect

14

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

phase 1 studies from the lab in to human tolerability pharmacokinetics often healthy volunteers
Phase 1 Studies – From the lab in to HumanTolerability, pharmacokinetics – often healthy volunteers

Example of Phase 1 Study -Single dose pharmacokinetics in healthy volunteers under fed and fasted conditions

phases 2 and 3 evaluate the effect of the drug in patients with the disease
Phases 2 and 3 – Evaluate the Effect of the Drug in Patients with the Disease
  • Some Key Considerations:
    • Where can we find patients with the disease?
    • Where can we find investigators who can do a clinical trial with high quality?
    • What do we measure to show the drug has been effective?

17

doctors working in the world
Doctors Working in the World

www.worldmapper.org

20

slide22

How Are We Exposed to the TB Bacteria?

Most TB is spread in droplets from the lungs of persons infected with active TB.

22

slide23
51 year old Kenyan man with a cough, weight loss, confusion; wife died 3 years earlier with tuberculosis

23

slide27

Tuberculosis (Acid Fast Bacillus – “AFB”) from a Sputum Smear Under the Microscope

27

pa 824 phase 2 dose selection 2 week study in patients with tb to choose a dose for later studies
PA-824: Phase 2 Dose Selection2 week study in patients with TB to choose a dose for later studies

RHZE

32

from a single drug to a multi drug regimen to treat tuberculosis
From a Single Drug to a Multi-Drug Regimen to Treat Tuberculosis
  • Study NC-001 Just Completed
    • A Phase 2 study of the 3-drug regimen in patients over a 2 week period
      • PA-824 combined with moxifloxacin and pyrazinamide
      • Results will be presented at IUATLD Symposium #46, Sunday
  • Next Step – a 2 month study of the regimen compared to the standard 4 drug combination

33

implications of study nc 001 for a regimen to treat ds mdr tb
Implications of Study NC-001 for a Regimen to Treat DS & MDR TB
  • PaMZ is a well tolerated viable regimen to advance for further testing in both DS & MDR patients sensitive to the regimen
  • It is safe and feasible to progress from a study of a single drug in patients to a study of that drug in a full regimen as a next step
  • The mouse model was predictive of the bacterial-killing activity of single drugs and regimens in this short-term human study
slide35

TB Alliance Portfolio

Discovery

Clinical Development

Preclinical Development

Lead identification

Lead Optimization

Target Or Cell-Based Screening

Clinical Phase I

Clinical Phase II

Clinical Phase III

TBA-354U. of Auckland/ U. Ill Chicago

Moxifloxacin (+ H, R, Z)

Bayer

Natural Products

IMCAS

Whole-Cell Hit to Lead Program

GSK

Mycobacterial Gyrase Inhibitors

GSK

PA-824

Novartis

Preclinical TB Regimen Development JHU/U. Ill Chicago

TMC207

Tibotec

Moxifloxacin (+ R, Z, E)

Bayer

TB Drug Discovery Portfolio

NITD

THPP Series

GSK

Gyrase B Inhibitors

AZ

Topoisomerase I Inhibitors

AZ/NYMC

PA-824/Pyrazinamide

Pyrazinamide Analogs

Yonsei

TMC207/Pyrazinamide

Folate Biosynthesis Inhibitors AZ

Diarylquinolines

Tibotec/U. of Auckland

Riminophenazines

IMM/BTTTRI

Whole-Cell Hit to Lead Program

AZ

PA-824/TMC207

RNA Polymerase Inhibitors

AZ

PA-824/Moxifloxacin/Pyrazinamide

Energy Metabolism Inhibitors AZ/U. Penn

Novel TB regimen development

Current first-line TB treatment consists of: isoniazid (H) + rifampicin (R) + pyrazinamide (Z) + ethambutol (E)

35

slide36

The Global TB Development Pipeline

From the Stop TB Partnership Working Group on New Drugs

36

a new regimen approved by regulatory agencies is not enough
A New Regimen Approved by Regulatory Agencies is Not Enough
  • How does the new regimen fit in the current WHO/country therapy recommendations?
  • What will be the barriers to acceptance?
  • Who are the decision makers?
  • What work needs to be done before a new regimen is approved?

37

what countries want value proposition study published august 2009

What Countries Want Value Proposition StudyPublished August 2009

  • Most stakeholders would welcome treatment shortening as the primary goal.
  • Unacceptable trade-offs in all countries:
  • Decreased efficacy
  • Additional safety concerns or side effects requiring monitoring or expensive adjuvant therapies
  • Significant drug interactions with other commonly-used drugs (including ARVs)
  • Unacceptable trade-offs in some countries:
  • Treatment frequency significantly different from current TB program (e.g., India)
  • Unavailability in fixed-dose combination (FDC)

38

our aaa mandate
Our “AAA” Mandate

Affordability

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

Adoption

  • 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

Availability

  • 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

39

slide40

40 Years Has Been Too Long to Wait!

Shorter, effective, safe regimens for TB therapy are within sight if we work together toward this compelling goal

40