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!