maria c. freire, ph.d. august 23, 2012 bethesda, maryland engaging communities in drug development:...

Maria C. Freire, Ph.D.

August 23, 2012

Bethesda, Maryland

Engaging Communities in Drug Development: Observations from the Field

A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N


Overview

• Background – Drug Development 101• Case Study: Tuberculosis• AAA Strategy• Lessons Learned

2


3

PR

E-

DIS

CO

VE

RY

5,000 – 10,000250

COMPOUNDS5

1 FDA-APPROVED

DRUG

DISCOVERY PRE-CLINICAL FDA REVIEWPHASE I PHASE II PHASE III

3 – 6 YEARS 6 – 7 YEARS 0.5 – 2 YEARS

NUMBER OF VOLUNTEERS

20 - 100 100 - 500 1,000 – 5,000

IND NDA

MFG

PO

ST

MA

RK

ET

ING

SU

RV

EIL

LA

NC

E

PHASE IV

Drug Development Pipeline



4

PR

E-

DIS

CO

VE

RY

DISCOVERY PRE-CLINICAL FDA REVIEW

PHASE I PHASE II PHASE III


MFG



5

PR

E-

DIS

CO

VE

RY




IND NDA

MFG

PO

ST

MA

RK

ET

ING

SU

RV

EIL

LA

NC

E

PHASE IV



6

PR

E-

DIS

CO

VE

RY




IND NDA

MFG

PO

ST

MA

RK

ET

ING

SU

RV

EIL

LA

NC

E

PHASE IV


20 - 100 100 - 500 1,000 – 5,000


7

PR

E-

DIS

CO

VE

RY




20 - 100 100 - 500 1,000 – 5,000

IND NDA

MFG

PO

ST

MA

RK

ET

ING

SU

RV

EIL

LA

NC

E

PHASE IV



8

PR

E-

DIS

CO

VE

RY

5,000 – 10,000250

COMPOUNDS5

1 FDA-APPROVED

DRUG




20 - 100 100 - 500 1,000 – 5,000

IND NDA

MFG

PO

ST

MA

RK

ET

ING

SU

RV

EIL

LA

NC

E

PHASE IV



Drug Development Costs

1975 1987 2000 20050

200

400

600

800

1000

1200

1400

$100M

$300M

9

Mill

ions

(C

onst

ant $

Yea

r 20

00)

$800M

$1.3B

Source: J. DiMasi and H. Grabowski

10

Case Study: Tuberculosis


Tuberculosis

• 2 billion people are infected with M.tb

• 8 million new active TB cases a year

• 1.4 million people die a year – 1 person per 25 sec.

• ~ 400,000 cases of MDR-TB a year

• 12 million persons are TB/HIV co-infected

• Biggest infectious killer of TB/HIV patients and women of childbearing age

A Disease of Poverty


Current TB Drug Therapy

• Active TB 6 months of therapy (INH, rifampin, pyrazinamide, ethambutol)

• MDR-TB Individualized, prolonged therapy, few available drugs, poorly

tolerated and difficult to administer

• XDR-TBIndividualized, prolonged therapy – when one exists

• TB/HIV co-infection Treatment as in active TB, but drug interactions with ARVs

make simultaneous therapy difficult

• Latent TB 9 months of INH therapy

Lengthy and Cumbersome


TB Drug Development Pipeline

13

PR

E-

DIS

CO

VE

RY




IND NDA

MFG

PO

ST

MA

RK

ET

ING

SU

RV

EIL

LA

NC

E

PHASE IV

X

X

X


TB Drug Development 2001 Landscape

14

PR

E-

DIS

CO

VE

RY


PHASE I PHASE II PHASE III MFG



15

PR

E-

DIS

CO

VE

RY



Usualactors:

AcademiaGovernmentBiotechPharma

BiotechPharma

GovernmentBiotechPharma

GovernmentPharma


NIH/NIAIDInstitut PasteurAlbert EinsteinUCLAUCSF

Others?...

NIH/NIAIDTAACF(SRI, GNL, HDC, CSU, RTI)

NIH TBTCCDCWHO

Aventis Novartis Lupin Other Indian Pharma PharmaciaAHPGlaxoDaiichiLocal producers

In TB:

Source:: Boston Consulting Group

Primary Involvement

Secondary Involvement



16

PR

E-

DIS

CO

VE

RY



Usualactors:


BiotechPharma


GovernmentPharma



Others?...


NIH TBTCCDCWHO


In TB:


Primary Involvement


The Intervention – a PDP

17


Types of PPPs• Basic Knowledge/Research

– SNP Consortium

• Product Development Partnerships (PDPs)– TB Alliance

• Improvement of Access to Health Products– GAVI

• Global Coordinating/Funding Mechanisms– Global Fund ATM

• Health Services Strengthening– Global Campaign for Microbicides

• Public Education and Advocacy– Corporate Council on Africa

• Regulation, Quality and Standards– Anti-Counterfeit Drug Initiative

www.ippph.org


TB Alliance: a PDP

Operates as a virtual company1

Develops drug candidates and novel regimens that represent a sufficient improvement to change the field

2

Fosters discovery & development of new treatments by all stakeholders

3

Ensures AAA4

Operating Principles


10 days

Vision

2 months6 months

Faster and Simpler Treatment for TB

FDCs


Profile of the New Drug/Combination

• Simplify/shorten treatment < 2 months• Effective against drug resistant-TB• Co-administered with ARVs• Shorten/improve latent TB treatment• Easily adopted in the field

Novel drug combinations are required

A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 23

Strategy

• In-license, support or form partnerships with owners of IP to develop TB drugs;

• Provide funding, know-how and project management;

• Outsource development worldwide – CROs and/or Partners, public and private (US, New Zealand, South Africa, India, Switzerland, Spain, etc.);

• Funding from private sources and governments;• Governed by AAA

Novel Drug Development Paradigm


TB Drug Development

24

PR

E-

DIS

CO

VE

RY



Usualactors:


BiotechPharma


GovernmentPharma



Others?...


NIH TBTCCDCWHO


In TB:


Primary Involvement


2001 Landscape


TB Drug Development

25

PR

E-

DIS

CO

VE

RY



Usualactors:


BiotechPharma


GovernmentPharma



• Sequella: SQ-109• TBTC-Pfizer- several Univ: Linezolid• Lupin: LL-3858

• Otsuka: OPC-67683• TBA: PA-824• TBTC-Sanofi Aventis: Rifapentine • Tibotec (J&J): TMC-207

• OFLOTUB- EC-Lupin-TDR: Gatifloxacin• TBA-Bayer-TBTC- JHU-BMRC-UCL: Moxifloxacin• TBTC-VA: Latent Infection



Others?...

Astra-ZenecaIDRIJHULillyNITD (Novartis)Rutgets –HHMI-NIHSequella (3)TAACF – NIAID –SRITBA-IDRITBA-IMCASTBA-IMM-BTTTRI-UICTBA-GSK (4)TBA-GSK-TXA&MTBA-UA-CSTBA-UIC-PennUIC (2)Vertex (3)

LillyJATACSRI SASequella (3)TBATBA-UA-UICPFIZER

In TB:

10 years later

Available, Affordable, Adopted:The AAA Strategy

26


AAA Strategy

• Develop cost effective, affordable new anti-tuberculosis therapies;

• Ensure equitable availability of new TB treatments especially for patients in high-burden countries:

• Work closely with communities, governments and National TB Program coordinators to ensure the future drugs will be adopted into TB Programs.

A L B E R T A N D M A R Y L A S K E R F O U N D A T I O N 28

AAA Strategy

•Consider cost of goods and manufacturing to focus on developing regimens which are likely affordable for governments and patients.

Affordability

Availability

Adoption

•Promote regimen accessibility in country without duplicating existing efforts and within existing infrastructure where possible.

•Only acting in roles where the Alliance can build credibility, capacity and capability to act.

•Focus on developing markedly improved treatments. •Engage the community, advocates, patients and other

key opinion leaders. •Engage international community on guidelines and

support conversations with local experts as required.

The Alliance will:


Known Bottlenecks and Hurdles

29

• Insufficient engagement of local communities and key clinical opinion leaders in clinical development;

•Lack of political will;

•Lack of clear and robust investment case to guide global and national decision making;

• Inadequate knowledge and awareness by key decision makers, including patients and advocates;

• Inaccurate demand forecasting leading to unreliable and insufficient supply;

• Increase in projected cost;

•Negative impact on incumbent businesses (e.g., generic manufacturers);

•Negative impact on other health programs and local capacity;

•Other…

Key examples


Stage I – Development to policy

Successful Adoption strategy

Stage II – Policy to implementation

Ensure processes and policies are in place to allow for the quick introduction of new regimen

Deliver reliable supply of regimen to patients in need

Ensure patient and physician compliance and efficacy of regimen delivery

5

6

Identify key desirable characteristics of treatment regimen from perspective of end-users and policy makers, and ensure these are reflected in research and development goals and activities.

Build fact base and inform key decision-makers, patients, advocates, public and private sector thought leaders of new regimen profile and value.

Help ensure regulatory approval and global and national guideline adoption.

Adoption Strategy

1

2

3

4

Examples of Activities


Factors shaping AdoptionLessons learned

Decreasing ability to inform clinical development

Increasing ability to accurately forecast demand and market environment.

Consistent need throughout to develop stakeholder and community awareness and engagement

1

2

3

Pre-clinical Reg. Approval

Thank you!

32


Building a Portfolio

• Public Announcement

• BOD – Formal Review

• Portfolio Committee

• SAC, Consultants

• BD, RFAs, Unsolicited Proposals

DEAL

Investment Approval

Due Diligence

& Negotiations

Scientific and Technical Review

Proactive Scouting

Non-blocked IP positions for all projects


Deals structured depending on stage of development, investment, burden of activity, etc.

KRICT Chiron/Novartis GSK NITD JHU Abbott Bayer, CDC, JHU,

EDCTP

• IP Assignment• In-licensing• Sponsored R&D• Collaborative R&D• Research Tools• Freedom to Operate• Multi-Party/CT

Sample deal structuresProduct Development Partnerships


Substitution to Revolution


Target DistributionAreas of Investment


Substitution Strategy

6 years

24 yearsABCD EFG

ABCD BCDE CDE DEF EFG

E A

6 years

B

6 years

F C

6 years

G D

Conventional TB Clinical Development Paradigm


Alternative TB Clinical Development Paradigm

ABCD BCDE

E A

CDE

B

EFG

CDFG

6 - 10 yearsABCD EFG

From Substitution to Revolution


TB Alliance Portfolio

TARGET OR CELL-BASED SCREENING

Natural ProductsIMCAS

Whole-Cell Hit to Lead ProgramGSK

NitroimidazolesU. of Auckland/ U. Ill Chicago

PA-824Novartis

Moxifloxacin (+ H, R, Z)Bayer

Topoisomerase I InhibitorsAZ/NYMC

Whole-Cell Hit to Lead ProgramAZ

Mycobacterial Gyrase InhibitorsGSK

InhA InhibitorsGSK

TMC207Tibotec

Moxifloxacin (+ R, Z, E)Bayer

Protease InhibitorsIDRI

Phenotypic Hit to Lead ProgramU. Ill Chicago

DiarylquinolinesTibotec/U. of Auckland

PA-824/PyrazinamideTB Drug Discovery PortfolioNITD

RiminophenazinesIMM/BTTTRI

TMC207/PyrazinamideGyrase B InhibitorsAZ

Pyrazinamide AnalogsYonsei

PA-824/Moxifloxacin/Pyrazinamide

Folate Biosynthesis Inhibitors AZ

Malate Synthase InhibitorsGSK/TAMU

RNA Polymerase InhibitorsAZ

Menaquinone Biosynthesis Inhibitors CSU

Energy Metabolism Inhibitors AZ/U. Penn

LEAD IDENTIFICATION LEAD OPTIMIZATION CLINICAL PHASE I CLINICAL PHASE II CLINICAL PHASE III

Preclinical TB Regimen Development JHU/U. Ill Chicago

AstraZeneca (AZ)Bayer Healthcare AG (Bayer)Beijing Tuberculosis and Thoracic Tumor Research Institute (BTTTRI)Colorado State University (CSU)GlaxoSmithKline (GSK)Infectious Disease Research Institute (IDRI)Institute of Materia Medica (IMM)Institute of Microbiology, Chinese Academy of Sciences (IMCAS)Johns Hopkins University (JHU)

Johnson & Johnson / Tibotec (Tibotec) New York Medical College (NYMC)Novartis Institute for Tropical Diseases (NITD)Novartis Pharmaceutical (Novartis)Texas A&M University (TAMU)University of Auckland (U. of Auckland)University of Illinois at Chicago (U. Ill Chicago)University of Pennsylvania School of Medicine (U. Penn)Yonsei University (Yonsei)

Novel TB regimen development

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

Clinical DevelopmentDiscovery

OUR R&D PARTNERS

Preclinical Development

The largest ever

Courtesy Mel Spigelman


PA-824 Case Study


PA-824

• Novel nitromidazole (-pyran)• Distinct mechanism of action • In-licensed from Chiron in 2002

N

N O

O

O2N

OCF3

PA-824


Chiron-TB Alliance Deal

• The Technology:– Novel anti-TB family – Developed by Pathogenesis, Inc.– Issued patents

• The Deal:– In-licensing deal for all patent rights to TB– Upfront fees and royalty sharing– Defined scientific milestones– Grant-Back option– Manufacturing rights– No royalties in Developing World


Outsourcing of PA-824 Development

*


Moxifloxacin Case Study


Moxifloxacin

• Fluoroquinolone antibiotic• Orally active• Once-a-day dosage• Approved in 104 countries for the treatment of

bacterial respiratory and skin infections


Moxifloxacin for TB

• Novel mechanism of action: kills M.tb. by inhibition of DNA gyrase

• In vivo studies showed moxifloxacin reduced treatment time by two months when substituted for isoniazid

• Safe to use with antiretroviral agents since it is not metabolized by the cytochrome P-450 enzyme system


Bayer/TB Alliance Partnership

• Clinically assess the efficacy and safety of moxifloxacin as a front-line agent for the treatment of TB

• If successful, register moxifloxacin for a TB indication• Committed to making the product affordable and

accessible to patients in the developing world


Evaluated Clinical Trial Sites

maria c. freire, ph.d. august 23, 2012 bethesda, maryland engaging communities in drug development:...

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