Speaker
First Plenary Session
THE PATIENT AND HEALTH TECHNOLOGY
ASSESSMENT: CHALLENGES AND
OPPORTUNITIES
Edward McKone, MSc, MD, FRCPI, FCCP
Consultant Respiratory Physician, National Referral Centre for
Adult Cystic Fibrosis, St. Vincent's University Hospital and
Senior Clinical Lecturer, University College Dublin, Dublin, Ireland
Ivacaftor in Patients with Cystic
Fibrosis and the CFTR-G551D
Mutation
Dr. Edward McKone MD, MSc
National Referral Center
for Adult Cystic Fibrosis,
St. Vincent’s University Hospital &
University College Dublin,
Ireland.
Overview
• Pathophysiology of Cystic Fibrosis
• Basic Genetics of CF
– Different types of mutations that cause CF
• Classic v non-classic CF
– Implications of different CF mutations
• Prognosis
• CFTR Mutation-based Therapy with
Ivacaftor
What is Cystic Fibrosis?
• Genetic condition caused
by mutations in the CFTR
gene
• CFTR gene codes for
CFTR protein
• Mutations in CFTR that
severely reduce CFTR
function cause CF
Fluid Layer (ASL)
Epithelial
Cells
Cilia (Hairs)
How do CFTR mutations
affect patients?
Lung Airway
The Lining of the Normal Lung
DNA
CFTR Protein
Assembly Line
CFTR
Na+/Cl-
Fluid Layer
Cilia (Hairs)
Normal
CFTR Gene
The “hairs” are
responsible for
clearing mucus and
bacteria out of the
lung
“MucoCiliary
Escalator”
Bacteria
Lung Epithelial Cell
Lung Airway
Normal Lung: Mucociliary Escalator
What happens in the CF lung?
CFTR Gene
Not Working
Not Enough
CFTR
Protein
Very Thick
Mucus
DNA
CFTR
Na+/Cl-
Lung Epithelial Cell
In CF, thick mucus
prevents the small
“hairs” from working
properly
Airway
CF Lung: Escalator unable to work
In the CF Lung: Over time.
Gene Defect
Not Enough
CFTR
Protein
Thick Mucus
Production
DNA
CFTR
Na+/Cl-
Bacterial
Infection
Chronic
Inflammation
Lung Epithelial Cell
Airway
Current Therapies for CF Lung Disease
Production or
Functional
Defect
Mucus
Overproduction
CFTR
Na+/Cl-
Bacterial
Infection
Chronic
Inflammation
Epithelial Cell
1. Physio
2. Dnase
3. 7% Saline
1. IVs
2. TOBI
3. Colistin
4. Aztreonam
Azithromycin
Airway
Prognosis in CF is Improving
The Genetics of Cystic Fibrosis
• CF is an autosomal
recessive condition
• Child with CF inherits two
CFTR mutations, one from
each parent
• If 2 carriers meet, 1 in 4
(25%) chance child will have
CF
• 1 in 2 (50%) of all children
will be carriers
• 1 in 4 children will have no
CFTR mutations
How Common is CF?
• Most common genetic condition affecting the lung
in Caucasians
• 70,000 worldwide with 1,200 CF patients in
Ireland and ~ 5000 in UK
• Irish rates high - carrier rate and large families
• CFTR mutation frequency varies across countries
and ethnic groups
Ethnic Origin
Carrier Frequency
Newborns with CF
Ireland
1 in 19
1 in 1,400
UK - Caucasian
1 in 25
1 in 2,500
US - Caucasian
1 in 29
1 in 3,200
US- African Origin
1 in 65
1 in 17,000
US-Asian
1 in 90
1 in 31,000
Making the Diagnosis of CF
The Sweat Chloride Test
• CFTR is predominantly a chloride channel
• Sweat test developed in1959 by Gibson
and Cooke
• Now replaced by Macroduct system for
sweat collection
• Positive sweat test is followed by CFTR
genetic testing
Normal
Borderline
Elevated
CF Unlikely*
Intermediate
Indicative of CF
Infancy
≤29mmol/L
30-59mmol/L
≥60mmol/L
Beyond Infancy
≤39mmol/L
40-59mmol/L
≥60mmol/L
Genetics Testing for Cystic Fibrosis
The CFTR Gene
Chromosome 7
7q31.2
1
6a
4 5 6b 7 8
2 3
13
9
10
11 12
0kBP
NH2
15
14a
17b
14b 16
23
17a 18
100kBP
MSD1
NBD1
R
19
20
21
22
200kBP
MSD2
NBD2
COOH
NBD = Nucleotide Binding Domains
MSD = Membrane Spanning Domains
24
CFTR Sequence Variations:
CF Population Allele Frequency
• F508del is the most common
disease causing CFTR
mutation.
• Next most common are the
G551D and G542X
F508del
69%
Other
10%
– each only seen in ~4% of patients
• The next 6 most common
mutations have a frequency of
only 1-2% in CF patients.
• Understanding the effect of the
CFTR mutation on protein
function has important clinical
implications.
3849+10kbC>T
1.4%
G551D
4%
R117H 1.4%
G542X
4%
621+1G>T
1.5%
W1282X
3%
N1303K
2%
R553X
2%
McKone et al. Lancet 2003
CFTR Mutations can be grouped
together according to function
Normal
Class I
No Synthesis
G542X
Class II
Increased
Degradation
DF508
Class III
Class IV
Class V
Defective
Regulation
G551D
2-3%
of
Normal
CFTR
Abnormal
Conductance
R117H
Reduced
Synthesis/
Trafficking
A455E
10-12%
of
Normal
CFTR
Adapted from Hospital Practice,1997.
Prognosis: CFTR Functional Class
Predicts Mortality
25
Standardized Mortality Rate
• US CFF Registry
17,853 patients
• Grouped by CFTR
Functional Class
• Class IV and V
associated with
lower mortality
* = p<0.001
20
15
*
*
10
5
0
Class I
Class II
Class III
Class IV
Class V Unclassified
McKone et al. Lancet 2003
Survival by CFTR Genotype
• Grouped by Genotype
•
“Severe” CFTR (Class I-III)
•
“Milder” CFTR (Class IV-V)
• Significant differences in
RR=2.3 (1.8-2.8)
p<0.001
survival and median age at
death between the cohorts.
• Median Survival
• 37 years with “Severe”
• 56 years with “Milder”
McKone et al, Chest 2006
Population frequency of Different
Class of CFTR Mutation (n=17,853)
Class II
55%
Class I
10%
Unknown
Class
27.5%
Class III (4%)
Class IV (2%) Class V (1.5%)
McKone et al. Lancet 2003
Class III Mutations: G551D
The Discovery of Ivacaftor
Venture Philanthropy meets Pharma
• 1998 Cystic fibrosis foundation
approached Aurora Biosciences
– Small biotec in San Diego looking at small
molecule high-throughput screening
– 2000 $45 million to Aurora to screen for
potential drug candidates for CF
• 2001 Aurora acquired by Vertex
Pharmaceuticals
• $75 million to Vertex from CFF for R&D
Class III Mutations: G551D
• Class III mutation
• Gating Defect in CFTR protein
function
• CFTR protein expressed
on surface of cell
• Insufficient opening time
• Dramatic increases in
opening time with addition
of ivacaftor (VX-770)
• CFTR Potentiator
Van Goor F et al. PNAS 2009;106:18825-18830
A Phase 3, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study to Evaluate the Efficacy and Safety of
VX-770 in Subjects with Cystic Fibrosis and the G551D
Mutation
• RCT of Ivacaftor v Placebo in patients with
G551D Mutation
• 161 patients treated for 1 year
• Age 12 and older; FEV1 40-90% predicted
Ramsey et al. NEJM. 2011
A Phase 3, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study to Evaluate the Efficacy and Safety of
VX-770 in Subjects with Cystic Fibrosis and the G551D
Mutation
Ramsey et al. NEJM. 2011
A Phase 3, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study to Evaluate the Efficacy and Safety of
VX-770 in Subjects with Cystic Fibrosis and the G551D
Mutation
• Substantial improvements in Lung Function
and Weight at 48 weeks of Ivacaftor
• Effects on Lung Function seen in 15 days
Ramsey et al. NEJM. 2011
A Phase 3, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study to Evaluate the Efficacy and Safety of
VX-770 in Subjects with Cystic Fibrosis and the G551D
Mutation
• Substantial improvements in time to first CF
pulmonary exacerbation – 26% absolute change
Ramsey et al. NEJM. 2011
A Phase 3, Randomized, Double-Blind, Placebo-Controlled,
Parallel-Group Study to Evaluate the Efficacy and Safety of
VX-770 in Subjects with Cystic Fibrosis and the G551D
Mutation
• Significant improvements in Sweat Chloride
to below threshold for diagnosis of CF
Ramsey et al. NEJM. 2011
Individual Patient Responses to
Ivacaftor
Ramsey et al. NEJM. 2011
Ivacaftor in Children between 6 and
11 years old – ENVISION Study
• ENVISION Trial shows
– Identical in structure to STRIVE
– Children aged 6 to 11
– FEV1 between 40% and 105%
• Results
– Improvements in lung function and nutrition
similar to STRIVE
• Licensed for use in G551D in Europe in
August 2012 for all age > 6 years old.
Davies et al. AJRCCM 2013
Where are we now?
2 year open label study of Ivacaftor in G551D CF Patients
PERSIST Trial now including 3 years of Treatment.
• Improvements in Lung function seen at 144
weeks of therapy in all age groups
• Similar effects in placebo group rolling over
McKone et al. Presented at NACFC 2013
2 year open label study of Ivacaftor in G551D CF
Patients – 3 years of Treatment.
• Improvements in weight seen at 144 weeks of
therapy in all age groups
• Similar effects in placebo group rolling over
McKone et al. Presented at NACFC 2013
2 year open label study of Ivacaftor in G551D CF
Patients – 3 years of Treatment.
McKone et al. Presented at NACFC 2013
2 year open label study of Ivacaftor in G551D CF
Patients – 3 years of Treatment.
McKone et al. Presented at NACFC 2013
Conclusions
• Ivacaftor is very effective in CFTR-G551D patients
• Substantial improvements in lung function & weight
both of which are independent determinants of longterm survival in CF
• Significant improvement in exacerbations and QoL
• Reduction in Sweat Chloride to below diagnostic
threshold for diagnosis of CF
• To date - effects on lung function and weight
sustained for 3 years