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

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

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

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

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

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

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

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%)

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

Learnings from Basic Science Studies: F508del Mutation has Multiple Folding Defects

Mendoza JL et al. Cell 2012Rabeh WM et al. Cell 2012

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

Phase 3 Trial of Elexacaftor–Tezacaftor–Ivacaftor in Patients with a Single F508del Allele

Middleton P et al. NEJM 2019

Study design

Effects of Elexacaftor–Tezacaftor–Ivacaftor on Lung Function (FEV1) in Patients with a Single F508del Allele

Middleton P et al. NEJM 2019

Effects of Elexacaftor–Tezacaftor–Ivacaftor on Pulmonary Exacerbations in Patients with a Single F508del Allele

Middleton P et al. NEJM 2019

Effects of Elexacaftor–Tezacaftor–Ivacaftor on Sweat Chloridein Patients with a Single F508del Allele

Middleton P et al. NEJM 2019

Effects of Elexacaftor–Tezacaftor–Ivacaftor on Quality of Life (CFQ-R)in Patients with a Single F508del Allele

Middleton P et al. NEJM 2019

Adverse Events Observed in Elexacaftor–Tezacaftor–Ivacaftor Phase 3 Study

Middleton P et al. NEJM 2019

Phase 3 Trial of Elexacaftor–Tezacaftor–Ivacaftor in Patients with CF Homozygous for the F508del Mutation

Study design

Heijerman HGM et al. Lancet 2019

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

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

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

The CF Drug Development Pipeline

US Cystic Fibrosis Foundation Drug Development Pipeline

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

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

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

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

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

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

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

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

Global Access to Novel Therapeutics

Ivacaftor

Lumacaftor/Ivacaftor

Tezacaftor/Ivacaftor

Bell SC et al. Lancet Respir Med. 2020

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

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

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

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!