novel therapeutics for cystic fibrosis · cystic fibrosis: a chronic progressive multiorgan disease...
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Marcus A. Mall, MD, FERSDepartment of Pediatric Pulmonology, Immunology & Critical Care Medicine
Christiane Herzog Cystic Fibrosis Center Charité - Universitätsmedizin Berlin and
Berlin Institute of Health
Novel Therapeutics for Cystic Fibrosis
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Disclosures
• Personal fees as advisor or consultant from: Arrowhead Pharmaceuticals, Boehringer Ingelheim, Enterprise Therapeutics, Galapagos, Santhera, Sterna Biologicals, Vertex Pharmaceuticals
• Personal fees for lectures from: Boehringer Ingelheim, Celtaxys, Vertex Pharmaceuticals
• Non-personal fees for participation in clinical trials: Boehringer Ingelheim, Galapagos, Proteostasis, Vertex Pharmaceuticals
• Non-personal grants for research from: German Ministry for Education and Research (BMBF), German Research Foundation (DFG), National Institute of Health (NIH), Einstein Foundation Berlin
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Pavel Drevinek Isabelle Fajac Irmgard Eichler Jane Davies Ciaran O’Neill Steven Rowe
CZECH REPUBLIC FRANCE NETHERLANDS UNITED KINGDOM UNITED KINGDOM USA
Novel Therapeutics for Cystic Fibrosis
Bell SC et al. Lancet Respir Med. 2020;8:65–124
Scott Bell Felix Ratjen
AUSTRALIA CANADA
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Cystic Fibrosis: A Chronic Progressive Multiorgan Disease
Liver
Sinus
Lung
Sweat gland
Pancreas
Gastrointestinal (GI) tract
Reproductivetract
Cystic fibrosistransmembraneconductance regulator (CFTR)
Riordan JR, et al. Science. 1989O’Sullivan BP, Freedman SD. Lancet. 2009
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The Development of Symptomatic Therapies and Specialized CF CareA
ge (
year
s)
Pancreatic Enzymes
Antistaphylococcal antibioticsAntipseudomonal antibiotics
rhDNaseInhaled Tobramycin
Airway clearance
0
5
1015
20
25
30
35
40
1st pathologicdescription
CF geneidentified
Discoveryof high salt
in sweat
Sweat chloridetest developed
Azithromycin
HTS
AZLITIP
Colobreathe
Bronchitol
Inhaled colistin
Neonatalscreening
Mist tents
Centre care
NPD andCl transport
RCTs
Stuart Elborn, ECFS Plenary 2015 Chen J et al. Cell 2017
Precision Medicine
Novel CFTR-directed therapies
CFTR
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The Future of Cystic Fibrosis Care: Novel Therapeutics
• Development of CFTR-directed therapeutics for all patients with CF
• Clinical trial designs and future challenges in the era of highly effective
CFTR modulators
• The role of different stakeholders in drug development
• The cost of and access to novel therapeutics
• The anticipated future impact of CFTR-directed therapeutics
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The Basis: Understanding Mechanisms and Consequences of CFTR Dysfunction
Adapted from Elborn JS Lancet 2016 and Gentzsch M & Mall MA Chest 2018
Infection & inflammation
Mucus plugging
Bronchiectasis
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Proof of Concept for Highly Effective CFTR-directed Therapy: The Potentiator Ivacaftor in Patients with G551D Mutation
Ramsey B et al. NEJM 2011 Rowe SM et al., NEJM 2005
G551D (3%)
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Development of Drugs that Restore Function to the Most Common CFTR Mutation F508del: Corrector-Potentiator Combination Therapy
F508del (90%)
Efficacy ceiling of CFTR modulator therapy in patients with F508del mutation
Ivacaftor (G551D/other)Lumacaftor/Ivacaftor
(F508del/F508del)
Tezacaftor/Ivacaftor(F508del/F508del)
Ramsey BW et al. NEJM 2011, Wainwright CE et al. NEJM 2015, Taylor-Cousar JL et al. NEJM 2017, Taylor-Cousar JL et al. ERJ Open Res 2019
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Learnings from Basic Science Studies: F508del Mutation has Multiple Folding Defects
Mendoza JL et al. Cell 2012Rabeh WM et al. Cell 2012
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Triple Combination CFTR Modulator Therapy (Elexacaftor–Tezacaftor–Ivacaftor) in Patients with CF and One or Two F508del Alleles
F508del/Minimal functionF508del/F508del
F508del mutation has multiple folding defects
Mendoza JL et al. Cell 2012Rabeh WM et al. Cell 2012Davies JC et al. NEJM 2018Keating D et al. NEJM 2018
Phase 2 study results
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Phase 3 Trial of Elexacaftor–Tezacaftor–Ivacaftor in Patients with a Single F508del Allele
Middleton P et al. NEJM 2019
Study design
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Effects of Elexacaftor–Tezacaftor–Ivacaftor on Lung Function (FEV1) in Patients with a Single F508del Allele
Middleton P et al. NEJM 2019
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Effects of Elexacaftor–Tezacaftor–Ivacaftor on Pulmonary Exacerbations in Patients with a Single F508del Allele
Middleton P et al. NEJM 2019
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Effects of Elexacaftor–Tezacaftor–Ivacaftor on Sweat Chloridein Patients with a Single F508del Allele
Middleton P et al. NEJM 2019
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Effects of Elexacaftor–Tezacaftor–Ivacaftor on Quality of Life (CFQ-R)in Patients with a Single F508del Allele
Middleton P et al. NEJM 2019
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Adverse Events Observed in Elexacaftor–Tezacaftor–Ivacaftor Phase 3 Study
Middleton P et al. NEJM 2019
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Phase 3 Trial of Elexacaftor–Tezacaftor–Ivacaftor in Patients with CF Homozygous for the F508del Mutation
Study design
Heijerman HGM et al. Lancet 2019
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Effects of Elexacaftor–Tezacaftor–Ivacaftor on Lung Function and Sweat Chloride in Patients Homozygous for the F508del Mutation
Lung function (FEV1) Sweat chloride
• The FDA approved elexacaftor-tezacaftor-ivacaftor (Trikafta) triple combination therapy for patients 12 years and older with a single F508del mutation on October 21, 2019
• Up to 90% of patients can be treated with highly effective CFTR modulator therapy in the future
Heijerman HGM et al. Lancet 2019
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Adapted from Sloane PA and Rowe SM Curr Opin Pulm Med 2010
Conceptual Framework for the Development of Highly Effective CFTR-directed Therapeutics
Expression amplifiers
Potentiators
Potentiators
CorrectorsPTC suppressors
CFTR gene replacement strategies:• mRNA replacement• Full gene replacement• Gene editing
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The Role of Different Stakeholders in Drug Development
• Scientists (genetics, biochemistry, physiology): applied basic science to understand the basic CF defect and developed tools to screen for compounds improving mutant CFTR function
• Patient organisations: US CF Foundation has funded pharmaceutical companies to develop drugs Patient organisations and learned societies: established clinical trial networks (TDN and ECFS CTN)
• Clinicians, caregivers, and patients have been actively involved in building patients cohorts, developing and validating outcome measures, and by dedicating time to clinical trials
• Pharmaceutical companies: Orphan drug designation and other incentives have attracted industry to develop drugs for CF
• Regulatory bodies: International cooperation between FDA and EMA in place to accelerate the translation of scientific progress into timely access to novel treatments for patients with CF
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The CF Drug Development Pipeline
US Cystic Fibrosis Foundation Drug Development Pipeline
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Clinical Trial Designs and Future Challenges in the Era of Highly Effective CFTR Modulators
• Phase 2: 4-8 week dose-ranging studies in adult patients to determine safety, functional rescue of CFTR activity and early clinical benefit
• Phase 3: 24-48 week studies in patients > 6 years to determine safety and long term clinical benefit (ppFEV1 as primary endpoint)
• Open label studies in patients < 6 years: PK, safety
Current ‘gold standard’: Randomised, double-blind, placebo-controlled trial
Future challenges related to emergence of effective CFTR modulators as standard of care:
How should new CFTR-directed compounds be tested?
• Are placebo-controlled trials still acceptable for patients?
• Are head-to-head active comparator trials against existing CFTR modulators feasible?
How should trials of novel compounds targeting mucus plugging, inflammation and infection be tested?
• Patients may feel so well they do not wish to enrole in future trials
• Clinical effects of interventions may be difficult to detect on background of improved health
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Patient-derived Model Systems to Advance Personalized Medicine for Patients with Ultra-rare CFTR Mutations
Cholon DM and Gentzsch M J Cyst Fibros 2018Clancy JP et al. J Cyst Fibros 2019Chen KG et al. Drug Discov Today 2019
• Determine responsiveness of ultra-rare CFTR mutations to CFTR-directed therapeutics
• Select ‘best’ of emerging CFTR modulators and/or combinations for individual patient with CF
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The Anticipated Future Impact of CFTR-directed Therapeutics
• Unprecedented possibility of treating patients with CF with drugs thatrestore the function of mutant CFTR in all affected organs
• This mode of action provides strong rationale for use of CFTRmodulators as the new backbone of care for patients with responsiveCF genotypes
• The clinical benefit of these CFTR-directed drugs will likely depend on
i) the efficacy of restoration of CFTR function
ii) the initiation of therapy with regard to the stage of disease
iii) long-term safety and tolerability
How will novel CFTR-directed therapeutics be used in future CF care, how will theyaffect the clinical phenotype, and to what extent they can replace the current gold-standard symptomatic therapies for CF?
O’Sullivan BP, Freedman SD. Lancet. 2009
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The Role of Efficacy of Restoration of CFTR Function
Wilschanski M et al. AJRCCM 2006, Ramsey B et al. NEJM 2011, Graeber SY et al. AJRCCM 2018, Masson A et al. J Cyst Fibros 2019, Keating D et al. NEJM 2018, Bell SC et al. LRM 2020
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The Role of Efficacy of Restoration of CFTR Function
Ivacaftor (G551D/other) andElexacaftor/Lumacaftor/Ivacaftor
(F508del/MF)
Lumacaftor/Ivacaftor(F508del/F508del)
Ultimate goal to achieveoptimal benefit
Wilschanski M et al. AJRCCM 2006, Ramsey B et al. NEJM 2011, Graeber SY et al. AJRCCM 2018, Masson A et al. J Cyst Fibros 2019, Keating D et al. NEJM 2018, Bell SC et al. LRM 2020
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The Potential of Early Therapy in Young Children with CF
• AREST CF and other observational studies demonstrated that CF lung disease starts in early infancy suggesting early interventionmay be most effective
• Implementation of CF newborn screening has created a uniquewindow of opportnity for early diagnosis and intervention fromearly infancy
• Sensitive outcome measures such as the lung clearance index(LCI) have become available to detect early abmormalities in lung function and response to therapy in young children
• Controlled testing of early intervention with novel targeted therapies hasbecome possible
• Preventive/early therapies have high potential to delay or even preventirreversible lung damage in future generations of people with CF
Sly PD et al, AJRCCM 2009Elborn JS Lancet 2016Hoo AF et al. Thorax 2012 Stanojevic S et al. AJRCCM 2017Stahl M et al. AJRCCM 2019
CF non-CF
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The Potential of Early CFTR-directed Therapy is Supported by Studies in the CF Ferret
Starting ivacaftor therapy in utero prevents onset of CF-like lung disease after birth
Withdrawal of ivacaftor therapy after birthproduces CF-like lung disease
Sun X et al. Sci Transl Med. 2019
CF Ferret with G551D
Mutation
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The Cost of and Access to Novel Therapeutics
• Health-care professionals, patients and theirfamilies expect timely access to new therapies
• Health-care budgets are limited and payers needto consider the effect of reimbursement decisionson all patients
• The currently extremely high cost of CFTRmodulators has delayed or completely preventedthe access even in high income countries
https://www.theguardian.com/society/2019/aug/12/cystic-fibrosis-drugs-rejected-nhs-scotland-orkambi-symkevi
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Global Access to Novel Therapeutics
Ivacaftor
Lumacaftor/Ivacaftor
Tezacaftor/Ivacaftor
Bell SC et al. Lancet Respir Med. 2020
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The Cost of and Access to Novel Therapeutics
• Recommendations to improve health technology assessment: - Demonstration of long-term clinical effectiveness - Greater transparency as to how prices are determined - Budget impact analysis
• Finding solutions to global access will be crucial to ensure allpeople with treatable CFTR mutations can benefit fromtransformative medicines, including patients in LMICs
• Needed to avoid the unintended consequences of negative reimbursement decisions: - Counterfeit drug production and distribution - Uncontrolled use by patients who are denied access in their own health-care system
https://www.theguardian.com/society/2019/jun/04/families-create-buyers-club-for-cut-price-cystic-fibrosis-drug
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Remaining Challenges with Novel Therapeutics for CF
• To develop medicines that restore CFTR function in all people with CF irrespective of CFTR genotype
• To increase the effectiveness of current CFTR-directed therapeutics with the ultimate goal of achieving full restoration of CFTR function for optimal clinical benefits
• To develop preventive strategies for the use of CFTR-directed therapeutics in infants and young children with CF, which may prevent or delay irreversible damage of the lungs and other affected organs
• To identify to what extent current symptomatic therapies can be discontinued in patients treated with medicines that restore CFTR function
• To provide global access to these transformative therapies to all people with CF
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Future Opportunities with Novel Therapeutics for CF
• To treat people with CF with medicines that target the basic molecular defect of a growing spectrum of CFTR mutations in all affected organ systems
• To leverage early diagnosis by NBS for early treatment with CFTR-directed therapeutics that are likely to have the greatest long-term benefits
• To slow the progression of CF multiorgan disease, reduce disease burden and improve quality of life by initiating transformative therapies in people with CF
• To transform CF from a fatal disease to a treatable chronic disease through highly efficacious CFTR-directed medicines and specialized multidisciplinary care
• To provide a model for successful development of transformative medicines for other severe genetic diseases
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Pavel Drevinek Isabelle Fajac Irmgard Eichler Jane Davies Ciaran O’Neill Steven Rowe
CZECH REPUBLIC FRANCE NETHERLANDS UNITED KINGDOM UNITED KINGDOM USA
Bell SC et al. Lancet Respir Med. 2020;8:65–124
Scott Bell Felix Ratjen
AUSTRALIA CANADA
Thank You!