Enabling CF Therapeutic Development PRESTON W. CAMPBELL, III, M.D. Executive Vice President for Medical Affairs No Disclosures
Cystic Fibrosis In 1955 In 1955 most children with CF did not live long enough to go to school
Cystic Fibrosis Today Median survival is almost 40 years of age One half of all patients are adults Eight CF therapies are now FDA approved One new CF therapy treats the basic defect and more are in the pipeline
How did this happen?
CF Care Was Organized Peer-reviewed centers Multidisciplinary teams Web-based registry collects relevant data Published evidencebased guidelines Robust quality improvement program Care Center Network Established in 1960
CF Foundation Patient Registry Proved Invaluable Epidemiologic research: informs disease progression and best practice ( > 100 publications) Informs study design Query tool at sites to screen for trial eligibility Matched control group for open-label studies of investigational agents Tool for phase IV studies to meet post-marketing requirements/commitments
Median Survival Age of CF Patients 40 35 30 25 20 15 10 5 0 <1 1 10 16 1940 1950 1960 1970 1980 1990 2000 2010 Year 18 29 32 38 Source: Cystic Fibrosis Foundation, National Patient Registry
Research Investments are Critical to Advance Science and Targets Number of Articles Published Number of Articles Published Number of Articles Published Cystic Fibrosis Publications in Medical/Scientific Journals 1980 - Research Development Program established 1985 - CF basic defect described 1989 - CF gene (CFTR) cloned 1990 s - CFTR biology advances rapidly 2000 s Research consortia formed (Manhattan like projects) 1400 1200 1000 800 600 400 200 0 1955 1965 1975 1985 1995 2005 Year Year
Scientific Discoveries Link CFTR Function and Lung Pathophysiology Cl -, Na +, H 2 0 Normal Airway Mucus layer moves bacteria, viruses and particles out of the airway CFTR Protein Cl -, Na +, H 2 0 CF Airway Mucus accumulates Blocks small airway Traps bacteria Inflammation Bronchiectasis Mucus Plug in Airway Robinson & Bye. Pediatr Pulmonol 2002;33:293-306
Therapeutics Era Begins in 1990s Pulmozyme approved 1994 TOBI approved 1997 These therapies address CF symptoms Despite significant advances in understanding CFTR, translational efforts that target basic defect were lacking
CF Foundation Begins Therapeutic Development Program (TDP) in 1999 Designed to attract industry partners to focus on CFTR as a target Components of TDP Financial assistance Research tools Scientific advisory committee Therapeutic development network TDP model now used by many disease foundations Favorably reviewed by Harvard Business Review
Therapeutics Development Network (TDN) Established in 1998 to ensure safe and efficient performance of CF clinical trials 77 clinical trial sites Coordinating center Biostatistical unit Independent data safety monitoring board
Competencies Required for CF Trials sweat chloride testing membrane physiology microbiology cytology inflammatory markers infant pulmonary function diagnostic imaging biostatistics trial design/logistics
The TDN has completed 70 clinical trials, enrolling over 9000 subjects
CFF- funded Vertex Program An example of putting scientific advances, TDP and TDN to work
Therapeutic Approaches by Class F508del CFTR Processing Corrector CFTR Potentiators Rowe SM, et al., New Engl J Med 352(19): 1992-2001, 2005 Translational Readthrough
Vertex Program Goals Orally bioavailable drugs Two CFTR targets: Potentiators: Increase opening (gating) of CFTR channels Correctors: Increase number and function of CFTR channels at the cell surface Cl- VX-770 Cl- Cl- ClCl- Cl- Cl- Cl- ClCl- G551D Cl- Cl- VX-809 Cl- F508del Cl- Cl- ClCl-
High-Throughput Screening >10,000 Primary Assays/day
Untreated VX-770 Untreated CFTR Activity (% wt-cftr) Potentiator VX-770 Increases G551D CFTR Activity to 50% of Normal in the Laboratory 120 G551D/F508del-HBE Wild-type-HBE (normal) 100 80 60 40 20 We think 10-25% may be enough to see clinical benefit 0
Ivacaftor Phase 3 Results in CF Patients with G551D Mutation No safety concerns 16% relative improvement in lung function 55% less likely to have pulmonary exacerbation Weight gain of seven pounds over 48 weeks Patients felt significantly better Sweat chloride dropped below diagnostic level N Engl J Med 2011; 365:1663-72
Change in sweat chloride concentration mmol/l (mean, 95% CI) Change from Baseline in Sweat Chloride with Ivacaftor 5 0-5 -10-15 -20-25 Placebo Ivacaftor Treatment effect through Week 24 47.9 mmol/l P < 0.0001 Treatment effect through Week 48 48.1 mmol/l P < 0.0001-30 -35-40 -45-50 -55-60 Day 15 Week 8 Week 16 Week 24 Week 32 Week 40 Week 48 Estimates are model-based. Points and 95% CI are unadjusted (raw) Key secondary endpoint in gold
Ramsey et al 2011 Lung Function Improves with Ivacaftor
Ramsey et al 2011 Lung Function Improvement By Rx
2012 - FDA Approves Ivacaftor Drug Information Association www.diahome.org
Two Year Ivacaftor Lung Function Results
CF Foundation Begins GOAL Study Visit 1 Decision made to start ivacaftor? (before end of study enrollment) yes no Visit 2 Day 1 Visit 3 Visit 4 Visit 5 Pre- Dose First dose of ivacaftor ivacaftor not prescribed 1 month after Day 1 3 months after Day 1 6 months after Day 1 Visit 1b Core Study Measures Additional Sub-Study Measures Clinical outcome Sweat chloride Quality of life CFQ-R SNOT-20 CFRSD Biomarker collection Serum Plasma DNA Urine Sputum MCC/Rheology visits 2,3,4 Radionuclear mucociliary clearance Micro-rheology Bulk rheology Intestinal ph visits 2, 3 Intestinal ph by radiofrequency transmitter Sweat Rate visits 1 to 4 Sweat evaporimetry Exploratory sweat outcomes Sputum Inflammation & Microbiome visits 2, 5 Induced sputum Inflammatory mediators Sputum microbiome
Expanding the Benefit of Ivacaftor Ivacaftor Could Help These Mutational Classes Trials started 15% or more of patients may benefit Rowe SM, et al., NEJM 2005;352(19):1992-2001
What about the most common mutation - F508del?
VX-809 Corrector & Ivacaftor Potentiator Effect on F508del CFTR Activity Cl- ClCl- VX-770: Increases channel opening of corrected F508del-CFTR ClCl- Cl- ClCl- Cl- Cl- Cl- ClCl- ClCl- Cl- 20 10 0 Corrector + VX-770 Cl- 30 Corrector Cl- 40 Untreated Corrector: Increases cell surface density and function of F508del-CFTR Activity F508del-CFTRActivity F508-CFTR (% wild-type CFTR) F508del-HBE F508-HBE
VX 809/Ivacaftor FEV1 Results VX-809 600mg once-daily in F508del homozygous patients VX-809 600mg qd or placebo VX-809 600mg qd + ivacaftor 250mg q12h or placebo Mean absolute change from baseline in percent of predicted FEV1 Treatment effect = effect of active therapy minus effect of placebo NS, not significant; qd, once-daily; q12h, every 12 hours Vertex Press Release, June 28, 2012. 8 6 4 2 0-2 -4 Treatment effect (Day 0 28) 2.0 points P = 0.36 Active treatment Placebo Day 0 Day 28 Day 56 Study day Treatment effect (Day 28 56) + 8.6 points P < 0.001
VX-809/Ivacaftor Phase 2 Results VX-809 well tolerated in combination with ivacaftor FEV1 improved 8.6% as compared to placebo (p= 0.001) in highest dose homozygous combination group Results support Phase 3 trials Homozygous F508del patients, n= 1000, 6 month duration, followed by open label extension Trials starting this month
Percent of Population CFTR Modulation Expansion 100 90 95% 80 70 60 50 40 30 65% 65% VX809/Kalydeco (F508/0ther) VX809/Kalydeco (F508/F508) Kalydeco 20 10 0 8% 15% 4% 2013 2014 2015 2016 2017 Year Available To Patients
Discovery/Screening Review Post-marketing New Drug Development Pre-IND Synthesis and Purification Phase 1 20% Pre-IND Success Rate 50% Clinical Studies Success Rate Phase 2 Phase 3 NDA 80% Success Rate Animal Testing Short-term Long-term Avg: 5-7 yrs Avg: 6-7 yrs Avg: 1 yr Standard Avg: 6 mo Priority
Second Generation CFTR Screening Program Pharma and Biotech Partnerships in place CFF Consortia have developed many of the high throughput discovery screens being used All programs have scientific advisory boards Targets are F508 and stop codon mutations Ultimate goal is to effectively treat 100% of patients
Challenges in Developing Therapies for Orphan Diseases Identifying, characterizing, and reaching very small target populations CF Care Center Network CF Patient Registry Identifying biologically relevant targets Research grants Research Development Program Research consortia Developing clinical trial tools Clinical Research Network (TDN) Outcome measures (SOPs and core labs) Biostatistical Unit and TDN expertise for trial design Drug discovery Therapeutic Development Program Forcing collaboration between academia and industry
% Predicted Lung Function The Benefits of New Therapies 100 90 80 70 60 50 40 30 20 10 0 10 20 30 40 50 60 Age (years)
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