Vertex Program to Discover and
Develop Therapies for Cystic
Fibrosis
Oct, 2012
Eric Olson, Ph.D.
VP, Cystic Fibrosis
Vertex Pharmaceuticals, Inc.
Cambridge, MA
1 ©2012 Vertex Pharmaceuticals, Incorporated
Vertex Program to Discover and
Develop Therapies for Cystic
Fibrosis
Oct, 2012
Eric Olson, Ph.D.
VP, Cystic Fibrosis
Vertex Pharmaceuticals, Inc.
Cambridge, MA
2 ©2012 Vertex Pharmaceuticals, Incorporated
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
3 ©2012 Vertex Pharmaceuticals, Incorporated
Milestones
1983
VX-770 tested in
G551D patients in
clinical study
Vertex
acquires
Aurora
2001
Basic protein
defect
2002
Potent,
“drug-like”
CFTR
modulators
discovered
at Vertex
2007
CFTR gene
2004
2000
VX-770, a
CFTR
potentiator,
discovered
at Vertex
1998
Aurora Biosciences
begins developing
CFTR modulator
approach
Positive Phase 2
VX-770 results
2006
2005
Development team
formed to advance
VX-770
4 ©2012 Vertex Pharmaceuticals, Incorporated
Green light from the FDA
clears VX-770 for dosing
in people for the first time
San Diego research
team intensifies
focus on CFTR
correction
VX-770 clears
crucial “preclinical”
hurdles
G551D
patients
complete
1 year of
treatment
and enter 2
year
extension in
clinical
studies
2011
Final positive Phase 3
STRIVE and
ENVISION study
results announced;
safety and efficacy
profile examined
2010
VX-770
Phase 2 study
published in
NEJM
Large scale
VX-770
manufacturing
2009
Global Phase 3
program for
VX-770 begins
Corrector + VX-770 combo
early Phase 2 study results
VX-770 Priority
Review granted by
FDA
Corrector clinical
development
program begins
2008
Collaborative
agreement
with CFFT
1989
Patient describes her
journey in CF and in
the Phase 3 trial
First corrector
clinical study
begins
FDA approval –
KALYDECOTM
is born!
Phase 2
corrector +
VX-770
combo final
data reported
2012
Vertex begins
planning for Phase 3
with corrector +
VX-770
1. The strategy
Mutation
Percent of
Patients
F508del
88.5
G542X
4.6
G551D
4.4
R117H
2.7
N1303K
2.5
W1282X
2.4
R553X
1.8
621+1G->T
1.8
1717-1G->A
1.7
3849+10kbC->T
1.6
2789+5G->A
1.3
3120+1G->A
1.0
5 ©2012 Vertex Pharmaceuticals, Incorporated
50%
40%
F508/F508 F508/Other
Discovery and Develop a
regimen that can restore
CFTR function to the
largest number of patients
Two classes of CFTR modulators
Potentiators:
Increase the
function of
F508del-CFTR
Correctors:
Restore trafficking
of F508del-CFTR
Adapted from Rowe et al. NEJM 2005
6 ©2012 Vertex Pharmaceuticals, Incorporated
A potentiator could be developed for G551D patients
Mutation
Percent of Patients
F508del
88.5
G542X
4.6
G551D
4.4
R117H
2.7
N1303K
2.5
W1282X
2.4
R553X
1.8
621+1G->T
1.8
1717-1G->A
1.7
3849+10kbC->T
1.6
2789+5G->A
1.3
3120+1G->A
1.0
7 ©2012 Vertex Pharmaceuticals, Incorporated
In vitro studies
suggested that this
form may only need a
potentiator….
…and there might be
enough patients for a
development
program
Milestones
1983
VX-770 tested in
G551D patients in
clinical study
Vertex
acquires
Aurora
2001
Basic protein
defect
2002
Potent,
“drug-like”
CFTR
modulators
discovered
at Vertex
2007
CFTR gene
2004
2000
VX-770, a
CFTR
potentiator,
discovered
at Vertex
1998
Aurora Biosciences
begins developing
CFTR modulator
approach
Positive Phase 2
VX-770 results
2006
2005
Development team
formed to advance
VX-770
8 ©2012 Vertex Pharmaceuticals, Incorporated
Green light from the FDA
clears VX-770 for dosing
in people for the first time
San Diego research
team intensifies
focus on CFTR
correction
VX-770 clears
crucial “preclinical”
hurdles
G551D
patients
complete
1 year of
treatment
and enter 2
year
extension in
clinical
studies
2011
Final positive Phase 3
STRIVE and
ENVISION study
results announced;
safety and efficacy
profile examined
2010
VX-770
Phase 2 study
published in
NEJM
Large scale
VX-770
manufacturing
2009
Global Phase 3
program for
VX-770 begins
Corrector + VX-770 combo
early Phase 2 study results
VX-770 Priority
Review granted by
FDA
Corrector clinical
development
program begins
2008
Collaborative
agreement
with CFFT
1989
Patient describes her
journey in CF and in
the Phase 3 trial
First corrector
clinical study
begins
FDA approval –
KALYDECOTM
is born!
Phase 2
corrector +
VX-770
combo final
data reported
2012
Vertex begins
planning for Phase 3
with corrector +
VX-770
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
9 ©2012 Vertex Pharmaceuticals, Incorporated
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
10 ©2012 Vertex Pharmaceuticals, Incorporated
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
11 ©2012 Vertex Pharmaceuticals, Incorporated
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
12 ©2012 Vertex Pharmaceuticals, Incorporated
Milestones
1983
VX-770 tested in
G551D patients in
clinical study
Vertex
acquires
Aurora
2001
Basic protein
defect
2002
Potent,
“drug-like”
CFTR
modulators
discovered
at Vertex
2007
CFTR gene
2000
2004
VX-770, a
CFTR
potentiator,
discovered
at Vertex
1998
Aurora Biosciences
begins developing
CFTR modulator
approach
Positive Phase 2
VX-770 results
2006
2005
Development team
formed to advance
VX-770
13 ©2012 Vertex Pharmaceuticals, Incorporated
Green light from the FDA
clears VX-770 for dosing
in people for the first time
San Diego research
team intensifies
focus on CFTR
correction
VX-770 clears
crucial “preclinical”
hurdles
G551D
patients
complete
1 year of
treatment
and enter 2
year
extension in
clinical
studies
2011
Final positive Phase 3
STRIVE and
ENVISION study
results announced;
safety and efficacy
profile examined
2010
VX-770
Phase 2 study
published in
NEJM
Large scale
VX-770
manufacturing
2009
Global Phase 3
program for
VX-770 begins
Corrector + VX-770 combo
early Phase 2 study results
VX-770 Priority
Review granted by
FDA
Corrector clinical
development
program begins
2008
Collaborative
agreement
with CFFT
1989
Patient describes her
journey in CF and in
the Phase 3 trial
First corrector
clinical study
begins
FDA approval –
KALYDECOTM
is born!
Phase 2
corrector +
VX-770
combo final
data reported
2012
Vertex begins
planning for Phase 3
with corrector +
VX-770
6. The US Indication
KALYDECOTM (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
14 ©2012 Vertex Pharmaceuticals, Incorporated
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 PoC
study
• New clinical and regulatory paradigms are needed for addressing
those with the very rare mutations
15 ©2012 Vertex Pharmaceuticals, Incorporated
Acknowledgements
CFFT
Investigators and Their Staff
Advisors
Patients and families
Collaborators
16 ©2012 Vertex Pharmaceuticals, Incorporated