bonnie ramsey, m.d. cf endowed professor of pediatrics, university of washington school of medicine...
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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
Roadmap to a Cure (II)A Clinical Research Path Ensuring
Benefit for All Patients with CF
Faculty Disclosure
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:
Bonnie W. Ramsey, M.D.
12th Man TechnologiesAchaogenAiresApartiaBayer Healthcare AGCeltaxsysBristol – Myers SquibbCornerstone TherapeuticsEli LillyGenentechGilead SciencesGlaxoSmithKlineGrifols Therapeutics, IncHall Bioscience
Insmed Corporation*KaloBios*Rempex Pharmaceuticals, Inc.N30 Pharmaceuticals, LLCNikan PharmaceuticalsNordmarkNovartis Pharmaceuticals Corp. PharmagenesisPTC Therapeutics, Inc.*Pulmatrix Savara Pharmaceuticals*TalecrisVectura 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
TenaciousMucus
Periciliary Liquid(PCL)
Surface Epithelial
Cells
normal CF
CFTR
How much CFTR is enough?
Carriers
Adapted from Accurso et al JCF 2013 in press
Normal
CF
Pancreatic Insufficient
Pancreatic Sufficient
≈ 30% CFTR activity associated with symptom reduction
CF is Not One Genetic DisorderCFTR mutation classes
Adapted from http://www.umd.be/CFTR/W_CFTR/gene.html
Cl -Cl -Cl -
Cl -
Cl - Cl -
Normal
XClass I
synthesis
X
Class IImaturation
X
Class IIIregulation
X
Cl -Cl -
X
Class IVconductance
Cl -Cl -
Class Vquantity
‘severe’ mutationspancreatic insufficiency
decreased survival
‘mild’ mutationspancreatic sufficiency
So, there must be mutation specific treatment approaches
Reduced Quantity Reduced Function
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
Class I Class II Class V Class III Class IV
Little to noCFTR GatingSome
CFTR Conductance
Normal CFTR quantity and
function
Correctors PotentiatorsTreatment
approaches
Our challenge is finding therapies to correct CFTR for all CF mutations
CFFPR*Patients
First Allele Second Allele
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
First Allele Second Allele
*Cystic Fibrosis Foundation Patient Registry, 2012
CFFPR*Patients
First Allele Second Allele
*Cystic Fibrosis Foundation Patient Registry, 2012
Log scale
Our challenge is finding therapies to correct CFTR for all CF mutations
Cl -
Cl -Cl -Cl -Cl -
Cl -
Proof-of-concept for mutation-specific therapy Class III gating mutations- G551D
XMost 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
X
How Much CFTR is Enough?The Ivacaftor – G551D Benchmark
Adapted from Accurso et al New Engl J Med 2010
Study Baseline
150 mg
Ivacaftor has a profound impact on lung function
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203188Orig1s000SumR.pdf.Ramsey, New Engl J Med, 2011J Davis, AJRCCM, 2012
The ivacaftor effect persists for many months
See: McKone et al. NACFC 2013 Poster #227
Open Label Follow-On
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 to find candidates
High throughput screening
In vitro models: HBE Cells
In vitro models
Important lessons learned from approval of the CFTR potentiator ivacaftor
In vitro models
High throughput screening
in vivo Biomarkers (Sweat Chloride)
In vivo biomarkers
Important lessons learned from approval of the CFTR potentiator ivacaftor
In vitro models
High throughput screening
Clinical Outcome (Lung Function)
In vivo Biomarkers
Clinical Outcome
Important lessons learned from approval of the CFTR potentiator ivacaftor
In vitro models
High throughput screening
Approval
In vivo biomarkers
Clinical outcome
Approval
A successful drug approval pathway
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
CFFPR*Patients
19 homozygotes
1,138 patientsFirst Allele Second Allele
*Cystic Fibrosis Foundation Patient Registry, 2012
Progress towards our goal
Cystic Fibrosis Foundation Patient Registry, 2012
IvacaftorG551D4.4%*
*- at some point in their lives (no data in infants and young children)
95.6%Remaining
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)
1- Yu et al. J Cyst Fibros. 2012;11(3):237-45.2- DeBoeck et al. NACFC 2013 Symposium 3.15 and Poster #241
Study Status: Crossover portion complete, supplemental New Drug Application filed
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
Study Status: Fully enrolled with data anticipated second quarter 2014
Part BIvacaftor
Week 0 Wk 12Week -4 Wk 24
Part AMultiple dose
safety and PK trial
Kindly provided by Vertex Pharmaceuticals
Phase 3 Study: R117H mutations - Konduct• Multi-center, randomized, double-blind, placebo-controlled study
Key Inclusion Criteria
• ≥ 6 years of age• Sweat chloride ≥60 mmol/L • At least 1 R117H allele
Study Status: Fully enrolled with first results expected by end of 2013
RunIn
Ivacaftor 150mg q12h
Placebo
(1:1)
ScreenFollow
Up
W-5 W-2 0 W2 W4 W8 W16 W24 W28
FEV1 at screening• 6 – 11 years old, 40 to 105 % predicted• ≥ 12 years old, 40 to 90% predicted
Kindly provided by Vertex Pharmaceuticals
Potential coverage of ivacaftor: infants and children, other gating mutations, R117H
Cystic Fibrosis Foundation Patient Registry, 2012
93.2%Remaining
G551D/R117H 6.8%
cytoplasmicF508del CFTR
Cultured F508del/F508del-human bronchial epithelial cells
Van Goor et al., PNAS 2011
CFTR proteins with Class II mutations do not reach the cell surface
Cl -Cl -Cl -
Cl -
Cl - Cl -
NormalCFTR
XF508del
Class II mutation
cilia
nuclei
F508del dominates the Class II common mutations
F508delHomozygotes
48.0%
F508delHeterozygotes
40.1%
5.1%9.9%Remaining
Cystic Fibrosis Foundation Patient Registry, 2012
(10,409 in US)
(12,469 in US)
G551D/R117H 6.8%
Van Goor et al., PNAS 2011
Lumacaftor increases the amount of F508del-CFTR at the cell surface
Cultured F508del/F508del-human bronchial epithelial cells
CFTR
cilia
nuclei
untreated + lumacaftor
Van Goor et al., PNAS 2011
The function of lumacaftor corrected F508del-CFTR can be further enhanced by a CFTR potentiator
F508del/F508del-HBE (N = 7 donor bronchi)
Chl
orid
e tr
ansp
ort
(% N
orm
al C
FT
R)
05
101520253035
Baseline 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
TRAFFIC (103)TRANSPORT (104)
Randomized, placebo-controlled double-blind Phase 3 studies in F508del homozygotes
● Primary Endpoints:
– 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
lumacaftor 600mg QD + ivacaftor 250mg q12h
lumacaftor 400mg q12h + ivacaftor 250mg q12h
placebo
Rollover/ExtensionUp to 96 Weeks
lumacaftor 600mg QD + ivacaftor 250mg q12h
ORlumacaftor 400mg q12h +
ivacaftor 250mg q12h
Week 1 24
HomozygousF508del
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
36
N1 N2
CL1 CL4
F508
Wild-type CFTR channel formationFolding and assembly of membrane and
cytoplasmic domains
Reachescell surface
Thomas et al. FEBS Lett. 1992;312(1):7-9. Du et al. Nat Struct Mol Biol. 2005;12(1):17-25Rabeh et al. Cell. 2012;148(1-2):150-63. Mendoza et al. Cell. 2012;148(1-2):164-74.
Phenylalanine508
M1
M1 M2
M1
N1 N1
M1 M2
N2
M1 M2
N1
M= membrane spanning domainN= nuclear binding domain
Multiple correctors may be required for optimal F508del folding
Okiyoneda, Nature Chem Biol 2013
cotranslational folding posttranslational folding
M1
N1
M1 M2
N1
R
M1 M2
N1
RN2
M1 M2
N1
RN2Target 2
M1 M2
N1
R
M1 M2
N1
R
N2
Target 3
M1 M2
N1
RN2
M1 M2
N1
R
N2
Folded CFTR
Target 1
A second corrector further enhances in vitro F508del CFTR function
F508del/G542XF508del/F508del
Kindly provided by Vertex Pharmaceuticals, Inc.
Remaining CFTR genotypes
G551D, R117H, F508del90.1%
9.9%Remaining
NonsenseMutations
8.8%
7.1%Remaining
2.8%
Class I nonsense mutations
Adapted from Schmitz A, Famulok M. Nature 2007
Nonsense mutation
Readthrough compound
Shortened proteinFull-length protein
Ataluren (PTC 124) induces functional CFTR protein in nonsense (Class I) -mutation-mediated mouse model of CF
Du X et al., PNAS 2008
atalurencontrol
No Chloride Channel Activity
Chloride Channel Activity
Transepithelial Short-Circuit Current
Novel molecule discovered by high throughput screening
Induces selective dose-dependent ribosomal readthrough of premature stop codons but not normal stop codons
Activity in nonsense-mutation-mediated mouse models of CF and DMD
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
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
Week 48 ∆ = 5.7%p = 0.008*
Week 48 ∆ = -1.4%p = 0.43*
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
CFFPR*Patients
First Allele Second Allele
*Cystic Fibrosis Foundation Patient Registry, 2012
How close are we to our goal using allele-specific approaches?
> 90% are covered
Both alleles One allele Unidentified alleles
CFFPR*Patients
First Allele Second Allele
*Cystic Fibrosis Foundation Patient Registry, 2012
How close are we to our goal using allele-specific approaches?
Both alleles One allele Unidentified AND MISSING alleles
1,768 patients
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
Vertex is currently using this approach to study ivacaftor response in patients with residual CFTR function and splice variants
• Single-center, randomized, double-blind, multiple within-subject (N-of-One) crossover study in patients with rare mutations
ActiveDrug
Cycle 1 Cycle 2
Daily Home Monitoring
Open-Label
Wk 16Wk -2 Wk 24 Wk 12 Wk 8 Wk 4 Day 1
Key outcome measures:• Primary: Change from baseline in % predicted FEV1 after 2
weeks of treatment• Multiple secondary outcomes may be measured
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?
• 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
Normal Airway CF Airway
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
US oral azithromycin study completed
dry powder tobramycin approved
dry powder colistimethate
approved (EMA)
aztreonam for inhalation solution approved
Phase 3 study of inhaled levofloxacin completedPhase 3 multi-cycle study of liposomal amikacin for inhalation (LAI) in
206 patients is ongoingInhaled 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
Can gallium complement in vivo antibiotics treating P. aeruginosa?
• 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
green = alivered = dead
Gallium Tobramycin
inside killed
outside killed
Kindly provided by Pradeep Singh
IV gallium improves CF lung function from baseline in infected patients
Kindly provided by Chris Goss
ManagementChange
ExperimentalIntervention
Epidemiology & Outcomes
Detection
Beyond Pseudomonas: Developing therapies for other emerging pathogens
P. aeruginosa
NTM MRSA
S. maltophilia A. xylosoxidans
B. cepacia complex
LiPuma, Chronic Airways Infection 2007
Pathway from identification of “new” CF pathogen to change in practice
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 diseaseBinder, AJRCCM 2013
Olivier, AJRCCM 2002Griffith, AJRCCM 2007
Nontuberculous mycobacteria (NTM): Liposomal amikacin for inhalation (LAI):
* 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
12 Weeks
D1
12 Weeks
Follow-Up
4 Weeks
Phase 2 Study (TR02-112)
1:1
D84
D85 D169
Screening* Day -42 to Day -4
LAI QD + Usual Care
Placebo QD + Usual Care
LAI QD + Usual Care
90 subjects stratified by CF vs. Non-CF, MAC vs. M. abscessus
Efficacy Endpoint:Reduction in bacterial density
Kindly provided by Insmed Corp.
Advances in Anti-Inflammatory Therapies
Inflammatory signaling in the normal lung
Konstan and SaimanNACFC 2009; Plenary Session IIAdapted from Ziady and Davis. Prog in Resp Res 2006
Konstan and SaimanNACFC 2009; Plenary Session IIAdapted from Ziady and Davis. Prog in Resp Res 2006
Inflammatory signaling in the CF lung
Signaling in the infected CF lung
Adapted from Ziady and Davis. Prog in Resp Res 2006Konstan 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 Australia CF Federation
European Clinical Trials
Network
Canada>3,800
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)
USA>27,000
UK>9,500
New Zealand>400
Australia>3,100
Norway>250 Europe*
>19,000
*- 20 countries, 10 of which have country registries
WE ARE ALMOST THERE!
Acknowledgements:
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
Many thanks to the patients and families who participatein our studies, to the clinical sites for all their hard work, and
to the following individuals who contributed to this presentation.
A special thanks to Dutch VanDevanter and Laurel Feltz
Thanks!