Roadmap to a Cure (II)
A Clinical Research Path Ensuring
Benefit for All Patients with CF
Bonnie Ramsey, M.D.
CF Endowed Professor of Pediatrics, University of
Washington School of Medicine
Director, CFF Therapeutics Development Network
Coordinating Center
October 18, 2013
Faculty Disclosure
Bonnie W. Ramsey, M.D.
In my capacity as Director of the Cystic Fibrosis Foundation Therapeutics
Development Network Coordinating Center, I have received grants or
contracts from the following companies in the past 3 years:
12th Man Technologies
Achaogen
Aires
Apartia
Bayer Healthcare AG
Celtaxsys
Bristol – Myers Squibb
Cornerstone Therapeutics
Eli Lilly
Genentech
Gilead Sciences
GlaxoSmithKline
Grifols Therapeutics, Inc
Hall Bioscience
Insmed Corporation*
KaloBios*
Rempex Pharmaceuticals, Inc.
N30 Pharmaceuticals, LLC
Nikan Pharmaceuticals
Nordmark
Novartis Pharmaceuticals Corp.
Pharmagenesis
PTC Therapeutics, Inc.*
Pulmatrix
Savara Pharmaceuticals*
Talecris
Vectura Ltd.
Vertex Pharmaceuticals Incorporated*
*Companies mentioned in this presentation
Our Dream
All patients with Cystic Fibrosis will live
full, healthy lives.
Mucociliary clearance and obstruction
Periciliary
Liquid
(PCL)
Surface
Epithelial
Cells
CFTR
normal
Tenacious
Mucus
CF
How much CFTR is enough?
Pancreatic
Insufficient
CF
Pancreatic
Sufficient
Carriers
Normal
≈ 30% CFTR activity associated with symptom reduction
Adapted from Accurso et al JCF 2013 in press
CF is Not One Genetic Disorder
CFTR mutation classes
Cl -
Cl -
Cl -
Cl -
Cl -
Cl -
Cl -
X
XX
Class III
regulation
Class IV
conductance
Cl -
Cl -
X
X
Normal
Cl -
Class I
synthesis
Class II
maturation
Class V
quantity
‘severe’ mutations
‘mild’ mutations
pancreatic insufficiency
decreased survival
pancreatic sufficiency
Adapted from http://www.umd.be/CFTR/W_CFTR/gene.html
So, there must be mutation specific
treatment approaches
Reduced Quantity
Normal CFTR
quantity and
function
Treatment
approaches
Little to no
CFTR
Some
CFTR
Class I
Class II
Class V
Correctors
Reduced Function
Gating
Class III
Conductance
Class IV
Potentiators
MacDonald et al. Pediatr Drugs 2007;9:1-10; Zielenski. Respiration 2000;67:117-33; Welsh et al. Cystic fibrosis In: Valle et al,
eds. OMMBID. McGraw-Hill Companies Inc;2004:part 21,chap 201; O’Sullivan et al. Lancet 2009;373:1891-1904
Our challenge is finding therapies to
correct CFTR for all CF mutations
CFFPR*
Patients
Among 25,976 patients with at least one allele recorded in the 2012 CFFPR
*Cystic Fibrosis Foundation Patient Registry, 2012
Patients with two copies of F508del
predominate in the US
CFFPR*
Patients
*Cystic Fibrosis Foundation Patient Registry, 2012
Our challenge is finding therapies to
correct CFTR for all CF mutations
CFFPR*
Patients
Log scale
*Cystic Fibrosis Foundation Patient Registry, 2012
Proof-of-concept for mutation-specific therapy
Class III gating mutations- G551D
Cl -
Cl Cl -
Cl -
Cl -
XX
Cl -
Most common CF gating mutation
Mutant protein is present on the
epithelial cell surface - ion
transport is reduced
High throughput screening of small
molecules identified ‘potentiators’:
molecules that increased G551D function
at the cell surface
How Much CFTR is Enough?
The Ivacaftor – G551D Benchmark
Study Baseline
150 mg
Adapted from Accurso et al New Engl J Med 2010
Ivacaftor has a profound impact on
lung function
J Davis, AJRCCM, 2012
Ramsey, New Engl J Med, 2011
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000SumR.pdf.
The ivacaftor effect persists for many
Open Label Follow-On
months
See: McKone et al. NACFC 2013 Poster #227
Effect of 150 mg BID ivacaftor on
hospitalization rate in G551D patients
From the GOAL presentation and kindly provided by S. Rowe
Important lessons learned from approval
of the CFTR potentiator ivacaftor
High throughput screening
In vitro models
In vitro
HBEscreening
Cells
Highmodels:
throughput
to find candidates
Important lessons learned from approval
of the CFTR potentiator ivacaftor
High throughput screening
In vitro models
In vivo biomarkers
in vivo Biomarkers (Sweat Chloride)
Important lessons learned from approval
of the CFTR potentiator ivacaftor
High throughput screening
In vitro models
In vivo Biomarkers
Clinical Outcome
Clinical Outcome (Lung Function)
Important lessons learned from approval
of the CFTR potentiator ivacaftor
High throughput screening
In vitro models
In vivo biomarkers
Approval
Clinical outcome
A successful drug
approval pathway
Approval
Yet, questions remain
• For example, sweat chloride and lung function changes correlate poorly
for individual patients
Durmowicz Chest 2013
Ivacaftor coverage of G551D
mutations in the US
1,138 patients
CFFPR*
Patients
19 homozygotes
*Cystic Fibrosis Foundation Patient Registry, 2012
Progress towards our goal
Ivacaftor
G551D
4.4%*
95.6%
Remaining
*- at some point in their lives (no data in infants and young children)
Cystic Fibrosis Foundation Patient Registry, 2012
Are there other patients with CF who may
benefit from ivacaftor monotherapy?
• Other gating mutations
• Infants and toddlers with G551D
• Mutations, like R117H, that result in residual CFTR
function
Ivacaftor coverage of other gating
mutations
• In vitro studies have shown that ivacaftor improves
chloride transport in CF cells with other CFTR gating
mutations1
• G178R, S549N, S549R, G551S, G970R, G1244E, S1251N,
G1349D, S1255P
• KONNECTION Study: Blinded, placebo-controlled 8
week crossover study of ivacaftor in other CFTR gating
mutations with open label extension2
• At 8 weeks, FEV1 change from baseline favored ivacaftor
treatment by 10.7% predicted (P < .0001)
• Comparable to ivacaftor treatment effect seen at 24 weeks in
G551D patients (10.6% predicted, P < .0001)
Study Status: Crossover portion complete, supplemental New Drug Application filed
1- Yu et al. J Cyst Fibros. 2012;11(3):237-45.
2- DeBoeck et al. NACFC 2013 Symposium 3.15 and Poster #241
Kindly provided by Vertex Pharmaceuticals
Ivacaftor Phase 3 Study: VX770-108
KIWI (2-5 years)
• A two-part, open-label study to evaluate the safety,
pharmacokinetics, and pharmacodynamics of ivacaftor
• Patients with CF aged 2 through 5 years with a CFTR gating
mutation:
• G551D, G178R, S549N, S549R, G551S, G970R,
G1244E, S1251N, G1349D, S1255P
Part A
Part B
Multiple dose
safety and PK trial
Week -4
Week 0
Ivacaftor
Wk 12
Wk 24
Study Status: Fully enrolled with data anticipated second quarter 2014
Kindly provided by Vertex Pharmaceuticals
Phase 3 Study: R117H mutations - Konduct
• Multi-center, randomized, double-blind, placebo-controlled study
(1:1)
Screen
Follow
Up
Ivacaftor 150mg q12h
Run
In
Placebo
W-5
W-2
0
W2
W4
W8
W16
W24
W28
Key Inclusion Criteria
•
•
•
≥ 6 years of age
Sweat chloride ≥60 mmol/L
At least 1 R117H allele
FEV1 at screening
• 6 – 11 years old, 40 to 105 % predicted
• ≥ 12 years old, 40 to 90% predicted
Study Status: Fully enrolled with first results expected by end of 2013
Kindly provided by Vertex Pharmaceuticals
Potential coverage of ivacaftor: infants and
children, other gating mutations, R117H
G551D/R117H 6.8%
93.2%
Remaining
Cystic Fibrosis Foundation Patient Registry, 2012
CFTR proteins with Class II mutations
do not reach the cell surface
Cl -
Cl -
Cl -
Cl -
Cultured F508del/F508delhuman bronchial epithelial cells
Cl -
Cl -
cilia
X
Normal
CFTR
F508del
Class II mutation
Van Goor et al., PNAS 2011
cytoplasmic
F508del CFTR
nuclei
F508del dominates the Class II common
mutations
G551D/R117H 6.8%
9.9%
Remaining
5.1%
F508del
Heterozygotes
40.1%
(10,409 in US)
F508del
Homozygotes
48.0%
(12,469 in US)
Cystic Fibrosis Foundation Patient Registry, 2012
Lumacaftor increases the amount of
F508del-CFTR at the cell surface
Cultured F508del/F508del-human
bronchial epithelial cells
cilia
CFTR
nuclei
untreated
Van Goor et al., PNAS 2011
+ lumacaftor
The function of lumacaftor corrected
F508del-CFTR can be further enhanced
by a CFTR potentiator
Chloride transport
(% Normal CFTR)
F508del/F508del-HBE (N = 7 donor bronchi)
35
30
25
20
15
10
5
0
Baseline
Van Goor et al., PNAS 2011
Lumacaftor
Lumacaftor +
Ivacaftor
Phase 2: lumacaftor with and without
ivacaftor in F508del homozygotes
Boyle et al NACFC 2012
Lumacaftor + ivacaftor Phase 3 studies:
VX809-103 & 104, TRAFFIC & TRANSPORT
Randomized, placebo-controlled double-blind Phase 3 studies in F508del homozygotes
TRAFFIC (103)
TRANSPORT (104)
Rollover/Extension
Up to 96 Weeks
lumacaftor 600mg QD +
ivacaftor 250mg q12h
Homozygous
F508del
lumacaftor 400mg q12h +
ivacaftor 250mg q12h
lumacaftor 600mg QD +
ivacaftor 250mg q12h
OR
lumacaftor 400mg q12h +
ivacaftor 250mg q12h
placebo
●
Week 1
Primary Endpoints:
24
– Relative change in FEV1 % predicted through Week 24 compared to placebo
●
Examples of Key Secondary Endpoints:
– Absolute change in body mass index (BMI) from baseline at Week 24
– Number of pulmonary exacerbations through Week 24
– Safety and tolerability assessments
Study Status: Fully enrolled and data anticipated mid 2014
Kindly provided by Vertex Pharmaceuticals, Inc.
CFTR correctors
• Good news: significant progress in
patients who have two F508del mutations
• Ongoing challenges:
• Correction is a multi-step process which
may require more than one drug
• If a patient has only one F508del mutation
(i.e., F508del heterozygote), the overall
clinical response is often reduced.
Strategic planning for back-up correctors
began 4 years go
• Reviewed lessons learned from first generation
correctors
• Created road map for more robust second
generation compounds
• Strong partners in place
• Amazing progress
 Novel screens developed
 Up to 6 million compounds will be reviewed
Wild-type CFTR channel formation
Folding and assembly of membrane and
cytoplasmic domains
M1
M1
M1 M2
M1 M2
N1
N1
N1
M1
Phenylalanine
508
CL1
Reaches
cell surface
N2
M2
CL4
M= membrane spanning domain
N= nuclear binding domain
F508
N1
Thomas et al. FEBS Lett. 1992;312(1):7-9. Du et al. Nat Struct Mol Biol. 2005;12(1):17-25
Rabeh et al. Cell. 2012;148(1-2):150-63.
Mendoza et al. Cell. 2012;148(1-2):164-74.
N2
36
Multiple correctors may be required for
optimal F508del folding
cotranslational folding
M1
M1
N1
N1
M2
M1
M2
Target 2
M1
N1
M1
M2
N1
N2
M1
M2
N2
N1
M2
N1
N2
R
R
N1
N2
M1 M2
N2 N1
R
R
Target 3
Okiyoneda, Nature Chem Biol 2013
M2
R
R
R
Target 1
M1
posttranslational folding
Folded CFTR
A second corrector further enhances
in vitro F508del CFTR function
F508del/F508del
F508del/G542X
Kindly provided by Vertex Pharmaceuticals, Inc.
Remaining CFTR genotypes
Nonsense 9.9%
MutationsRemaining
8.8%
G551D, R117H,
F508del
90.1%
2.8%
7.1%
Remaining
Class I nonsense mutations
Nonsense mutation
Readthrough
compound
Shortened protein
Adapted from Schmitz A, Famulok M. Nature 2007
Full-length protein
Ataluren (PTC 124) induces functional
CFTR protein in nonsense (Class I) mutation-mediated mouse model of CF
 Novel molecule
discovered by high
throughput screening
 Induces selective dosedependent ribosomal
readthrough of
premature stop codons
but not normal stop
codons
 Activity in nonsensemutation-mediated
mouse models of CF
and DMD
Du X et al., PNAS 2008
control
ataluren
Transepithelial
Short-Circuit Current
No Chloride
Channel Activity
Chloride
Channel Activity
Ataluren Phase 3: Mean relative change
in FEV1 % predicted at week 48
Konstan, M. – European CF Conference, Dublin 2012
Kindly provided by Temitayo Ajayi, PTC Pharmaceuticals
Inhaled aminoglycosides may affect
ataluren response
Week 48 ∆ = 5.7%
p = 0.008*
Week 48 ∆ = -1.4%
p = 0.43*
In 2014, PTC is initiating an ataluren Phase 3 efficacy and
safety trial in patients not receiving inhaled aminoglycosides
Konstan, M. – European CF Conference, Dublin 2012
Kindly provided by Temi Ajayi
Class I (nonsense mutation) next
generation possibilities
• Cystic Fibrosis Foundation has initiated new discovery
programs with both academic and industry
partners
• With support from CFF, University of Alabama
and Southern Research Institute, are currently
screening approved drugs for read-through
activity
• in vitro proof of concept studies using primary
nasal epithelial cell cultures from Y 122 X
homozygotes to test topical gentamicin effect in
progress*
* personal communication – Isabelle Sermet-Gaudelus
How close are we to our goal using
allele-specific approaches?
Both alleles
One allele
Unidentified alleles
CFFPR*
Patients
*Cystic Fibrosis Foundation Patient Registry, 2012
> 90% are covered
How close are we to our goal using
allele-specific approaches?
Both alleles
One allele
Unidentified AND MISSING alleles
1,768 patients
CFFPR*
Patients
*Cystic Fibrosis Foundation Patient Registry, 2012
100% of patients with CF should
have two identified mutations –
the Mutation Analysis Program
• Genetic testing is available free of charge
to all U.S. patients with CF who do not
have 2 identified mutations
• For more information, go to cff.org
http://www.cff.org/LivingWithCF/AssistanceResources/MAP
CFTR2: An Emerging Tool for
Diagnosis, Prognosis, and Therapeutics
(supported by CFF)
http://www.cftr2.org/
What about other rare mutations?
Personalized medicine 2013 and beyond
Clinical trial model for screening
drug effects on rare alleles
Model for studying rare mutations:
Individual (n=1) trials for clinical response
to CFTR modulators
•
Single-center, randomized, double-blind, multiple within-subject (N-of-One)
crossover study in patients with rare mutations
Cycle 1
Cycle 2
Open-Label
Active
Drug
Home Monitoring
Wk -2
Day 1
Daily
Wk 4
Wk 8
Wk 12
Wk 16
Wk 24
Key outcome measures:
• Primary: Change from baseline in % predicted FEV1 after 2
weeks of treatment
• Multiple secondary outcomes may be measured
Vertex is currently using this approach to study ivacaftor response
in patients with residual CFTR function and splice variants
Kindly provided by Vertex Pharmaceuticals, Inc.
Our Goal: Develop Disease Modifying
Therapies for 100% of Patients with CF
• Other non-allele specific therapeutic
approaches are being pursued to achieve this
goal
 gene replacement
 gene repair
 mRNA replacement
 protein replacement
• An excellent example: UK Cystic Fibrosis
Gene Therapy Consortium
Current status of UK CF Gene Therapy
Consortium double blind, placebo
controlled multidose trial
• Nebulized treatment regimens
− CFTR+liposome in 5ml of 0.9% saline
− 0.9% saline alone (placebo)
• Twelve monthly doses
• Eligible patients
− Diagnosis of CF
− Age: > 12 years
• Primary endpoint , FEV1
• Current status: 123 patients dosed
• Results available in Autumn 2014!
Kindly provided by Eric Alton
Beyond CFTR: will we still need new
therapies to treat symptoms of CF?
Normal Airway
CF Airway
• Yes, because CFTR modulators are not expected to reverse existing organ
dysfunction (lung, pancreas, liver, GI tract)
• Prevention of organ damage is critical until CFTR modulator therapy is available to
100% of patients in infancy
CFF Pipeline is critical to patients with CF
cff.org
clinicaltrials.gov
Advances in Anti-microbial Therapies
Pseudomonas aeruginosa
Advances in antibiotics to treat
Pseudomonas aeruginosa (Pa)
tobramycin inhalation
solution approved
aztreonam for inhalation
solution approved
US oral azithromycin
study completed
dry powder
tobramycin
approved
dry powder
colistimethate
approved (EMA)
Phase 3 study of inhaled levofloxacin completed
Phase 3 multi-cycle study of liposomal amikacin for inhalation (LAI) in
206 patients is ongoing
Inhaled aztreonam/tobramycin cycling study in process
Symposium S11, Friday 10:40am: What have we learned from recent antimicrobial trials?
A novel target to disarming Pa: Gallium
nitrate
• Iron (Fe) is essential for bacterial growth and biofilm formation
• Gallium is a similar size as Fe but not biologically active
• Gallium replaces Fe in essential functions and disables the bacteria
• An FDA-approved formulation of gallium is available
• Gallium and conventional antibiotics kill different biofilm
subpopulations
Gallium
inside killed
Tobramycin
green = alive
red = dead
outside killed
Can gallium complement in vivo antibiotics treating P. aeruginosa?
Kindly provided by Pradeep Singh
IV gallium improves CF lung function
from baseline in infected patients
Kindly provided by Chris Goss
Beyond Pseudomonas: Developing
therapies for other emerging pathogens
S. maltophilia
A. xylosoxidans
NTM
MRSA
B. cepacia complex
P. aeruginosa
Detection
Epidemiology
& Outcomes
Experimental
Intervention
Management
Change
Pathway from identification of “new” CF pathogen
to change in practice
LiPuma, Chronic Airways Infection 2007
Survival by methicillin-resistant Staph
aureus (MRSA) prevalence in CF
Dasenbrook et al, JAMA 2010
Studying MRSA interventions
• Three ongoing trials assessing MRSA treatment strategies
• ‘Eradication’ of initial MRSA infection(Sponsor: CFFT)
• STAR-Too study ( M. Muhlebach and C. Goss)
• Testing the efficacy and durability of an oral antibiotic regimen
at 14 US sites
• ‘Eradication’ of established MRSA
infection(Sponsor:CFFT)
• Persistent MRSA Eradication Protocol ( E. Dasenbrook and M
Boyle)
• Testing efficacy of 28 days inhaled vancomycin and oral
antibiotics at 2 US sites
• Chronic suppression of established MRSA infection
(Sponsor: Savara Corp)
• Dry powder inhaled vancomycin( AeroVanc)
• Testing change in sputum MRSA density and lung function
Non-tuberculous mycobacteria
• Prevalence 13-23% in patients with CF worldwide
− Annual screening culture recommended for patients who
expectorate sputum and/or receive chronic macrolides
• Most common species in CF
− Mycobacterium avium complex (MAC) in 64%
− Mycobacterium abscessus in 36%
• Impact of infection of CF lung disease
− Associated with nodular bronchiectasis and /or cavitary disease
by chest CT
− More rapid decline in lung function with M. abscessus
• Treatment
− MAC
 Asymptomatic patients may require no treatment
 Symptomatic patients usually respond to multi-antibiotic regimens
− M. abscessus
 no drug regimen is proven to be effective for M. abscessus lung disease
Binder, AJRCCM 2013
Olivier, AJRCCM 2002
Griffith, AJRCCM 2007
Nontuberculous mycobacteria (NTM):
Liposomal amikacin for inhalation (LAI):
Phase 2 Study (TR02-112)
12 Weeks
Screening*
1:1
Day -42 to Day -4
12 Weeks
LAI QD +
Usual Care
Placebo QD +
Usual Care
D1
D84
90 subjects stratified by CF vs. Non-CF,
MAC vs. M. abscessus
4 Weeks
LAI QD +
Usual Care
D85
Follow-Up
D169
Efficacy Endpoint:
Reduction in bacterial density
* Inclusion criteria:
• NTM culture-positive at screening
• 2007 ATS/IDSA criteria with nodular bronchiectasis and/or cavitary disease by chest CT
• 3+ positive NTM cultures in prior 2 years, at least one within prior 6 months
• Receiving ATS/IDSA guideline-based treatment for ≥6 months prior to screening
Kindly provided by Insmed Corp.
Advances in Anti-Inflammatory Therapies
Inflammatory signaling in the normal lung
Adapted from Ziady and Davis. Prog in Resp Res 2006
Konstan and Saiman
NACFC 2009; Plenary Session II
Inflammatory signaling in the CF lung
Adapted from Ziady and Davis. Prog in Resp Res 2006
Konstan and Saiman
NACFC 2009; Plenary Session II
Signaling in the infected CF lung
Adapted from Ziady and Davis. Prog in Resp Res 2006
Konstan and Saiman
NACFC 2009; Plenary Session II
Current progress in reducing airway
inflammation
• One proven efficacious therapy
• High dose ibuprofen slows FEV1 rate of decline in
children1 and is associated with improved survival2
• Progress has been slow
• Very complex, redundant system
• Current clinical trial endpoints not well-suited to
measuring anti-inflammatory effects
• Timeline is much longer (i.e., months to years)
• Biomarkers such as neutrophil elastase, though
encouraging, are not yet validated as surrogate efficacy
endpoints
• Studies of several approved therapies have been
unsuccessful
1- Konstan et al JAMA 1995,
2- VanDevanter et al NACFC 2012
Reducing airway inflammation: the
next steps
• Points of future emphasis
• Encourage innovation in this area
• KB001A – targeting P aeruginosa Type III
secretion pathway is currently in Phase 2 for
CF1
• Alpha-1-antitrypsin development continues
• CFF is initiating a strategic planning process
in 2014 to re-evaluate the approach to
development of anti-inflammatory therapies
1- Milla et al Pediatr Pulmonol 2013
Our Success Has Been and Will Continue
to Be a World-Wide Effort
The international community is making a huge
investment in future research: Clinical Trials Networks
CFF Therapeutic
Development
Network
European
Clinical Trials
Network
Australia CF
Federation
The international community is making a huge
investment in future research: National CF registries
Recent estimates of CF patients in registries world wide (2009-2012 data)
Canada
>3,800
UK
>9,500
Norway
>250
Europe*
>19,000
Australia
>3,100
USA
>27,000
New Zealand
>400
*- 20 countries, 10 of which have country registries
Acknowledgements:
Many thanks to the patients and families who participate
in our studies, to the clinical sites for all their hard work, and
to the following individuals who contributed to this presentation.
Fred van Goor
Steve Rowe
Chris Goss
Jill Van Dalfsen
Renu Gupta
Mike Boyle
Charles Johnson
Isabel Sermet-Gaudelus
Alex Elbert
Temitayo Ajayi
Eric Alton
Cystic Fibrosis
Foundation
Taneli Jouhikainen
Frank Accurso
A special thanks to Dutch VanDevanter and Laurel Feltz
Thanks!