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
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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.
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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:
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.
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
• 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