Transformational Treatments for Cystic Fibrosis

Stratified/Personalised/Precision Medicine J Stuart Elborn Queen’s University Belfast and BHSCT.

The Cystic Fibrosis (CFTR) Gene

Identified 1989 Chromosome 7 27 exons Encodes for CFTR Protein

>1800 mutations described

F508del/F508del

G551D/F508del

CF Airway Disease: Pathophysiology Normal

CF

Classes of CFTR mutations (>2000 in total)

Boyle MP, De Boeck K. The Lancet Respiratory medicine. 2013

Improved Survival with Treatment Innovation Incremental Modest Benefits

Stratified/Precision Medicine for CF

Advances in therapy have been incremental • Individual benefit is modest but cumulative • Life expectancy greatly increased

RCTs

Centre care

Age (years)

Mist tents

40 35 30 25 20 15 10 5 0

Neonatal screening

1st pathologic description

NPD and Cl transport

CF gene identified

Ivacaftor Colobreathe Bronchitol TIP AZLI

HTS Azithromycin Inhaled Tobramycin

1st successful pregnancy Sweat chloride rhDNase test developed Inhaled colistin Discovery antipseudomonal antibiotics of high salt antistaphylococcal antibiotics in sweat

Airway clearance Pancreatic Enzymes

Belfast CF Centre

Symptom-based CF Therapies

First Generation Partners

Vertex Screening Strategy •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-

ClCl-

Cl-

ClCl-

G551D

Cl-

Cl-

VX-809 Cl-

F508del

Cl- Cl-

ClCl-

Class III CFTR Mutations

CFTR protein

X ClCl-

Molecular Defect

Amino acid substitution or missense mutations causing defective CFTR protein regulation

Functional Consequence

Decreased CFTR protein channel opening (gating defect)

Examples of Mutations

G551D, G551S, G1349D

Golgi

mRNA

CFTR Gene

Phase 3 Results (G551D) FEV1

PEx

CFQ-R

wt

Ramsey, B…Elborn JS et al. New Engl J Med (2011), 365: 1663-1672

2012 - FDA Approves Ivacaftor

Mucociliary Clearance: The Movie Baseline

Ivacaftor - 3 months Trachea

Courtesy of Dr. Tim Corcoran, U. Pittsburgh

Ivacaftor Lung Function Benefit Persists

See: McKone et al. NACFC 2013

Ivacaftor Expansion Timeline % Population

2012- G551D 2013 – other gating mutants Predicted: 2014- R117H 2015-2016 – residual function

4% (6%) 5% (1%)

8% (16%) 15% (20%)

What About the Most Common Mutation - F508del? 50% of patients have F508del mutations on both alleles 80% of patients have at least one F508del mutation

F508del results in little to no CFTR protein at the cell surface Cl–

CFTR Cl–

Normal quantity of CFTR channels at the cell surface

Golgi

Proteasome

Few F508del-CFTR channels at the cell surface ER

Nucleus 16

Vertex Pharmaceuticals Incorporated VX809 NDA ISE: ISE for Lumacaftor in Combination with Ivacaftor

Key secondary endpoints & additional analyses, TRAFFIC/TRANSPORT Pooled Figure 3.2.1.1 Absolute Change from Baseline in Percent Predicted FEV1 (Percentage Points) at Each Visit Full Analysis Set

Proportion of Event-free Subjects Absolute Change in ppFEV1, LSMeans (+/- 95% CI)

6

Lung function TTF Pulmonary exacerbation

5

4

Exacerbations Events requiring hospitalization

1.0

Events requiring IV antibiotics

39 to 61% reduction for patients in combination groups

3

0.9

45 to 56% reduction for patients in combination groups –45% –56% P5,000 Gating/ R117H/ Residual CFTR

>2,000 G551D

KALYDECO

ivacaftor monotherapy

ivacaftor + corrector

Next gen correctors triple combinatons

Complex regimens

4

Challenges For Stratified Medicine in CF • Range in disease severity among people with the same CFTR mutations ⁻ Modifier genes ⁻ Environment • Stage of disease at time of treatment • Cost/access of therapies • Adherence to therapies

Translational Research in CF Thanks to • All the people with CF and parents who participated in clinical trials • PIs (TDN & ECFS-CTN) • study teams who participated in clinical trials to improve treatment for CF • Industry/academic partnerships