vertex program to discover and develop therapies for

1 ©2012 Vertex Pharmaceuticals, Incorporated

Vertex Program to Discover and Develop Therapies for Cystic

Fibrosis


Fibrosis

Eric Olson, Ph.D.VP, Cystic Fibrosis Vertex Pharmaceuticals, Inc.Cambridge, MA

Oct, 2012



Fibrosis


Fibrosis

Eric Olson, Ph.D.VP, Cystic Fibrosis Vertex Pharmaceuticals, Inc.Cambridge, MA

Oct, 2012


Outline

1. The strategy

2. Why CF made sense for Vertex

3. Our relationship with academic centers and the CF Foundation

4. Role of orphan drug status

5. Discovery and Development challenges

6. The US indication statement

7. General lessons


Milestones

2011

Patient describes her journey in CF and in

the Phase 3 trialCorrector + VX-770 combo early Phase 2 study results

Final positive Phase 3 STRIVE and

ENVISION study results announced; safety and efficacy profile examined

VX-770 Priority Review granted by

FDA

2012

Vertex begins planning for Phase 3

with corrector + VX-770

FDA approval –KALYDECOTM

is born!

Phase 2 corrector +

VX-770 combo final

data reported

2010

Large scale VX-770

manufacturing

G551D patients

complete 1 year of treatment

and enter 2 year

extension in clinical studies

VX-770 Phase 2 study published in

NEJM

2006

San Diego research team intensifies focus on CFTR

correction

Green light from the FDA clears VX-770 for dosing in people for the first time

2008

2007

VX-770 tested in G551D patients in

clinical study

Corrector clinical development

program begins

Positive Phase 2 VX-770 results

2009

First corrector clinical study

begins

Global Phase 3 program for

VX-770 begins

1983

Basic protein defect

2000

Collaborative agreement with CFFT

1989CFTR gene

2004

VX-770, a CFTR

potentiator, discovered at Vertex

2002

Potent, “drug-like”

CFTR modulators discovered at Vertex

2001Vertex

acquires Aurora

2005

VX-770 clears crucial “preclinical”

hurdles

Development team formed to advance

VX-770

1998

Aurora Biosciences begins developing CFTR modulator

approach


1. The strategy

Mutation Percent of Patients

F508del 88.5G542X 4.6G551D 4.4R117H 2.7N1303K 2.5W1282X 2.4R553X 1.8621+1G->T 1.81717-1G->A 1.73849+10kbC->T 1.62789+5G->A 1.33120+1G->A 1.0

50%F508/F508

40%F508/Other

Discovery and Develop a regimen that can restore CFTR function to the largest number of patients


Two classes of CFTR modulators

Adapted from Rowe et al. NEJM 2005

Correctors:Restore trafficking of F508del-CFTR

Potentiators:Increase the function of

F508del-CFTR


A potentiator could be developed for G551D patients

Mutation Percent of PatientsF508del 88.5G542X 4.6G551D 4.4R117H 2.7N1303K 2.5W1282X 2.4R553X 1.8621+1G->T 1.81717-1G->A 1.73849+10kbC->T 1.62789+5G->A 1.33120+1G->A 1.0

In vitro studies suggested that this

form may only need a potentiator….

…and there might be enough patients for a

development program


Milestones

2011






FDA

2012




is born!

Phase 2 corrector +

VX-770 combo final

data reported

2010

Large scale VX-770

manufacturing

G551D patients


and enter 2 year



NEJM

2006


correction


2008

2007


clinical study


program begins


2009


begins


VX-770 begins

1983


2000


1989CFTR gene

2004

VX-770, a CFTR


2002



2001Vertex

acquires Aurora

2005


hurdles


VX-770

1998


approach


2. Why CF made sense for Vertex

• Aligned with the corporate objective of focusing on potential transformational therapies

• Solid scientific foundation to build a drug discovery program upon, both external and internal

• Access to leading experts and knowledge through CF Foundation and clinical trial network (TDN)

• Risk reduced through CFF investment

• Dedicated patients and families

• Good commercial match, including ex-US


3. Our relationship with the CFF

• Formal collaborative agreement and governance

• Amended several times over the past 12 years

• Joint Research and Joint Development Committees

• Both organizations remained focused on the end game

• Flexibility was needed given different pressures on each organization

• Close communication and alignment across the different functions


4. Role of US orphan drug designation

• Visibility to the program

• PDUFA user fee waived

• Tax break for certain development expenses

• Exclusivity beyond that awarded for a new NCE

• Grant to help defray clinical study costs


5. Discovery and development challenges

• Little CF expertise at Vertex

• No defined preclinical, clinical path, regulatory or commercial paths

• Limited patient population

• Desire to progress to Phase 3 from a single, small Phase 2 study

• Outcomes for proof-of-concept and Phase 3


Milestones

2011






FDA

2012




is born!

Phase 2 corrector +

VX-770 combo final

data reported

2010

Large scale VX-770

manufacturing

G551D patients


and enter 2 year



NEJM

2006


correction


2008

2007


clinical study


program begins


2009


begins


VX-770 begins

1983


2000


1989CFTR gene

2004

VX-770, a CFTR


2002



2001Vertex

acquires Aurora

2005


hurdles


VX-770

1998


approach


6. The US IndicationKALYDECOTM (ivacaftor) Tablets

Initial U.S. Approval: 2012 ----------------------------INDICATIONS AND USAGE---------------------------

KALYDECO is classified as a cystic fibrosis transmembrane conductance regulator (CFTR)

potentiator. KALYDECO is indicated for the treatment of cystic fibrosis (CF) in patients age 6

years and older who have a G551D mutation in the CFTR gene. If the patient’s genotype is

unknown, an FDA-cleared CF mutation test should be used to detect the presence of the

G551D mutation. (1)

Limitations of Use:

• Not effective in patients with CF who are homozygous for the F508del mutation in the

CFTR gene. (1, 14)

• KALYDECO has not been studied in other populations of patients with CF.

Full prescribing information is available at www.kalydeco.com


7. General lessons

• Understanding genotype-phenotype relationships provided insights into the level of modulation to target with a drug

• The strategic importance of proof-of-concept outcome measures can not be overestimated

• Global studies may be needed to find enough patients and support regulatory requirements in multiple regions

• Be prepared to move to pivotal studies following a small PoCstudy

• New clinical and regulatory paradigms are needed for addressing those with the very rare mutations


Acknowledgements

Advisors

CFFTInvestigators and Their Staff

Patients and familiesCollaborators

vertex program to discover and develop therapies for

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