Cystic Fibrosis:The Modulator Era

 
Cystic Fibrosis:
 The Modulator Era
 
Jake Brockmeyer, PharmD, BCPS, BCPPS
Clinical Pharmacist Specialist, Cystic Fibrosis
March 9
th
, 2024
 
The Eras Era
 
The Modulator Era..
This may sound like a
reference to Taylor Swift as
she dominates the media
during her "Eras Tour"
However, the “Modulator
Era” started well before her
tour and this concept
starting showing up in CF
literature as early as 2015
.
So maybe Taylor actually
got the idea from us?
 
Learning Objectives
 
Understand the pathophysiology of CFTR protein as it
relates to Cystic fibrosis
 
Review FDA approved CFTR modulators
 
Describe pulmonary and extrapulmonary outcomes of
interest
 
3
 
Cystic Fibrosis (CF)
 
CF is a genetic disease caused
by variants of the CFTR gene
 
Must get copy of the gene
from both parents
 
1 in 2500 people born with CF
 
1 in 20 people are carriers of
one gene
 
4
 
www.cff.org/What-is-CF/Testing/Carrier-Testing-for-Cystic-Fibrosis/
 
Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR)
 
5
 
 
CFTR is a membrane
protein belonging to the
ABC transporter family
 
CFTR transports Cl
-
 out of
epithelial cells
 
CFTR is important to
balance the ionic
gradient and 
hydrate
epithelial lining of
various organs
 
Education Steering Group. http://www.cftr.info. Accessed 2016.
Zegarra-Moran O, Galietta LJV. CFTR pharmacotherapy. Cell Mol Life Sci. 2016.
 
 
CFTR - Mutation types
 
6
 
1
 
2
 
3
 
4
 
6
 
5
 
Schmidt BZ, Haaf JB, Leal T, et al. Cystic fibrosis transmembrane conductance
regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol.
2016;8:127-140
Mutations
There are over 2000 mutations that lead to dysfunctional CFTR
7
 
Mutations
 
8
 
Outcome of F508del mutation
 
Causes a defect in 
processing
leading to decreased number of
active proteins on the membrane
 
For the active proteins that do
make it, this mutation also disrupts
channel opening
 
Correcting CFTR activity in patients
with this mutation would require a
two-step approach
 
9
 
 
Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-
ivacaftor in patients with cystic fibrosis homozygous for
Phe508del CFTR. N Engl J Med. 2015;373(3):220-31.
 
Pulmonary Disease
 
10
 
The hallmark characteristic of CF
is chronic lung injury
 
 
Cyclical process of airway
obstruction, infection, and
inflammation that leads to fatal
tissue destruction
 
Schmidt BZ, Haaf JB, Leal T, Noel S. Cystic fibrosis transmembrane conductance
regulator modulators in cystic fibrosis: current perspectives. Clinical
Pharmacology: Advances and Applications. doi:
10.2147/CPAA.S100759
 
Other systems effected;
Pancreases
Liver
Reproductive
Sinus
Renal
GI Tract
 
Extrapulmonary Disease
 
11
 
Disease Progression
 
12
 
Liou TG. The Clinical Biology of Cystic Fibrosis
Transmembrane Regulator Protein: Its Role and Function in
Extrapulmonary Disease. Chest. 2019 Mar 1;155(3):605–16.
 
General Management of CF
 
13
 
Treatments and Therapies. Cystic Fibrosis Foundation.
https://www.cff.org/Life-With-CF/Treatments-and-Therapies
 
Symptomatic Treatment
 
14
 
Boeck KD. Cystic fibrosis in the year 2020: A
disease with a new face. 
Acta Paediatrica
.
doi:
10.1111/apa.15155
 
General Management of CF
 
15
 
Treatments and Therapies. Cystic Fibrosis Foundation.
https://www.cff.org/Life-With-CF/Treatments-and-Therapies
 
 
 
16
 
CFTR - Mutation types
 
17
 
1
 
2
 
3
 
4
 
6
 
5
 
Schmidt BZ, Haaf JB, Leal T, et al. Cystic fibrosis transmembrane conductance
regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol.
2016;8:127-140
Pharmacology of CFTR
18
Education Steering Group. Helping healthcare professionals
understand the role of genetic changes in CF. http://www.cftr.info.
Accessed December 2016.
Potentiator
Corrector
 
Pharmacology of CFTR
 
19
 
https://www.youtube.com/watch?v=7WTjQY0V4qI
 
Ivacaftor (Kalydeco)
 
20
 
Mechanism of Action
Ivacaftor is a CFTR potentiator that facilitates increased chloride
transport by potentiating the channel-open probability (or gating)
of the CFTR protein at the cell surface.
 
 
KALYDECO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018.
Potentiator
 
Ivacaftor (Kalydeco)
 
21
Potentiator
 
Ivacaftor (Kalydeco)
 
22
 
KALYDECO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018.
Potentiator
 
Lumacaftor/Ivacaftor (Orkambi)
 
23
Corrector
 
Mechanism of Action
Lumacaftor improves the conformational stability of F508del-
CFTR, resulting in increased processing and trafficking of mature
protein to the cell surface.
Ivacaftor is a CFTR potentiator that facilitates increased chloride
transport by potentiating the channel-open probability (or gating)
of the CFTR protein at the cell surface.
 
ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018.
Potentiator
 
Lumacaftor/Ivacaftor (Orkambi)
 
24
Corrector
 
ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018.
Potentiator
 
Lumacaftor/Ivacaftor (Orkambi)
 
25
Corrector
 
ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018.
Potentiator
 
Tezacaftor/Ivacaftor (Symdeko)
 
26
Corrector
 
SYMDEKO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018.
 
Mechanism of Action
Tezacaftor facilitates the cellular processing and trafficking of
normal and select mutant forms of CFTR (including F508del-CFTR)
to increase the amount of mature CFTR protein delivered to the
cell surface.
Ivacaftor is a CFTR potentiator that facilitates increased chloride
transport by potentiating the channel-open probability (or gating)
of the CFTR protein at the cell surface
Potentiator
 
Tezacaftor/Ivacaftor (Symdeko)
 
27
Corrector
 
SYMDEKO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018.
Potentiator
 
Tezacaftor/Ivacaftor (Symdeko)
 
28
Corrector
 
Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor–Ivacaftor in
Patients with Cystic Fibrosis Homozygous for Phe508del.
doi:10.1056/NEJMoa1709846
Potentiator
 
Elexacaftor/Tezacaftor/Ivacator (Trikafta)
 
29
Corrector
Corrector
 
TRIKAFTA [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2019.
 
Mechanism of Action
Elexacaftor and tezacaftor bind to different sites on the CFTR
protein and have an additive effect in facilitating the cellular
processing and trafficking of F508del-CFTR to increase the
amount of CFTR protein delivered to the cell surface compared to
either molecule alone.
Ivacaftor potentiates the channel open probability (or gating) of
the CFTR protein at the cell surface
 
 
Potentiator
 
Elexacaftor/Tezacaftor/Ivacator (Trikafta)
 
30
Corrector
Corrector
 
TRIKAFTA [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2019.
Potentiator
 
Elexacaftor/Tezacaftor/Ivacator (Trikafta)
 
31
Corrector
Corrector
 
Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor–Tezacaftor–Ivacaftor for
Cystic Fibrosis with a Single Phe508del Allele. New England Journal of Medicine.
October 2019. doi:10.1056/NEJMoa1908639
Potentiator
 
Modulator Era:
Outcomes of Interest
 
32
 
FEV1
 
33
 
Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic
fibrosis treated with ivacaftor: Data from national US and UK registries.
Journal of Cystic Fibrosis
. 2020;19(1):68-79. doi:
10.1016/j.jcf.2019.05.015
Potentiator
 
FEV1
 
34
 
Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic
fibrosis treated with ivacaftor: Data from national US and UK registries.
Journal of Cystic Fibrosis
. 2020;19(1):68-79. doi:
10.1016/j.jcf.2019.05.015
Potentiator
 
Pulmonary Exacerbations
 
35
 
Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic
fibrosis treated with ivacaftor: Data from national US and UK registries.
Journal of Cystic Fibrosis
. 2020;19(1):68-79. doi:
10.1016/j.jcf.2019.05.015
Potentiator
 
Hospitalizations
 
36
 
Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic
fibrosis treated with ivacaftor: Data from national US and UK registries.
Journal of Cystic Fibrosis
. 2020;19(1):68-79. doi:
10.1016/j.jcf.2019.05.015
Potentiator
 
Hospitalizations
 
37
 
Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic
fibrosis treated with ivacaftor: Data from national US and UK registries.
Journal of Cystic Fibrosis
. 2020;19(1):68-79. doi:
10.1016/j.jcf.2019.05.015
Potentiator
 
Manifestations
 
38
 
Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis
registries support disease modification by CFTR modulation with ivacaftor.
Thorax. 2018;73(8):731-740. doi:10.1136/thoraxjnl-2017-210394
Potentiator
 
FEV1 – Meta Analysis
 
39
 
Habib ARR, Kajbafzadeh M, Desai S,
Yang CL, Skolnik K, Quon BS. A
Systematic Review of the Clinical
Efficacy and Safety of CFTR
Modulators in Cystic Fibrosis. Sci Rep.
2019;9(1):7234. doi:10.1038/s41598-
019-43652-2
Corrector
Potentiator
Potentiator
 
OR
 
 
40
 
 
Sergeev V, Chou FY, Lam GY, Hamilton CM, Wilcox PG, Quon BS. The Extrapulmonary
Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic
Fibrosis. 
Annals ATS
. 2019;17(2):147-154. doi:
10.1513/AnnalsATS.201909-671CME
 
Extrapulmonary Outcomes Overview
 
Pancreatic Exocrine Function (Fecal Elastase 1)
 
41
 
Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of
ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-
label, single-arm study. 
Lancet Respir Med
. 2016;4(2):107-115. doi:
10.1016/S2213-2600(15)00545-7
Potentiator
 
Pancreatic Function (Fecal Elastase 1)
 
42
Corrector
Corrector
 
Stephenson KG, Lingle AJ, Baumberger KA, et al. Changes in fecal elastase-1
following initiation of CFTR modulator therapy in pediatric patients with cystic
fibrosis. J Cyst Fibros. 2023;22(6):996-1001. doi:10.1016/j.jcf.2023.09.005
 
FE-1 levels rise in pediatric CF post-modulator therapy.
Indicates potential pancreatic function improvement.
Underlines the importance of early CFTR modulator
therapy.
Potentiator
 
BMI
 
43
 
Burgel P-R, Munck A, Durieu I, et al. Real-Life Safety and Effectiveness of
Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis. 
Am J Respir Crit
Care Med
. 2019;201(2):188-197. doi:
10.1164/rccm.201906-1227OC
Corrector
Potentiator
 
Nutrition / Growth
 
44
 
Tindall A, Bass R, Maqbool A, Stallings VA. Changes in nutrition and growth status
in young children in the first 12 weeks of ivacaftor therapy. J Cyst Fibros.
2023;22(6):989-995. doi:10.1016/j.jcf.2023.04.010
 
Followed 15 y
oung children (2-24 months)
with CF 
starting 
ivacaftor
Over the first 12 weeks of therapy,
significant weight gain and beneficial
changes in nutritional biomarkers
Supports ivacaftor's role in improving
growth patterns.
Comparable outcomes to non-CF children
 
Potentiator
 
Nutrition / BMI
 
45
Corrector
Corrector
 
Caley LR, Jarosz-Griffiths HH, Smith L, et al. Body mass index and nutritional
intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults
with cystic fibrosis. J Cyst Fibros. 2023;22(6):1002-1009.
doi:10.1016/j.jcf.2023.06.010
 
40 adult patients followed pre/post ELX/TEZ/IVA
BMI 
increase but consumption decreased
Suggesting increased BMI is caused mechanisms
affecting metabolism and energy balance
Potentiator
 
BMI - FFM
 
46
Corrector
Corrector
 
Proud D, Duckers J. Weight a minute: Exploring the effect on weight and body
composition after the initiation of elexacaftor/tezacaftor/ivacaftor in adults with
CF. J Cyst Fibros. 2023;22(5):847-850. doi:10.1016/j.jcf.2023.06.002
 
Adult CF patients initiating
ELX/TEZ/IVA.
Explores the effect on BMI
and body composition
Results reveal significant
increases in both fat mass
(FM) and fat-free mass (FFM)
among adults with CF,
Indicating changes beyond
mere BMI growth
Incorporating routine body
composition assessment in CF
care can offer more health
insights, enabling
personalized management
Potentiator
 
Vitamin Levels
 
47
Corrector
Corrector
 
Schembri L, Warraich S, Bentley S, Carr SB, Balfour-Lynn IM. Impact of
elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with
cystic fibrosis. J Cyst Fibros. 2023;22(5):843-846. doi:10.1016/j.jcf.2023.04.019
 
Significant increase in vitamin A levels after ETI
No significant change in vitamin 
D or E
Highlights the need for regular vitamin monitoring
Potentiator
 
Vitamin Levels
 
48
 
Francalanci M, Terlizzi V, Fevola C, et al. Nutritional Status and Circulating Levels
of Fat-Soluble Vitamins in Cystic Fibrosis Patients: A Cohort Study and Evaluation
of the Effect of CFTR Modulators. Children (Basel). 2023;10(2):252.
doi:10.3390/children10020252
 
CF patients various ages, impact of CFTR modulators
on nutritional status and fat-soluble vitamins.
ELX/TEZ/IVA therapy significantly improves
nutritional status and increases levels of all fat-
soluble vitamins in CF patients
Ivacaftor and Lumacaftor/ivacaftor did not show the
same improvements across vitamin D, A, and E
Corrector
Corrector
Potentiator
Potentiator
 
OR
Potentiator
 
OR
Corrector
 
CF Related Diabetes (CFRD)
 
49
 
Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic
fibrosis treated with ivacaftor: Data from national US and UK registries.
Journal of Cystic Fibrosis
. 2020;19(1):68-79. doi:
10.1016/j.jcf.2019.05.015
Potentiator
 
CF Related Diabetes (CFRD)
 
50
 
Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic
fibrosis treated with ivacaftor: Data from national US and UK registries.
Journal of Cystic Fibrosis
. 2020;19(1):68-79. doi:
10.1016/j.jcf.2019.05.015
Potentiator
 
Glucose Control (
CFRD)
 
51
Corrector
Corrector
 
Salazar-Barragan M, Taub DR. The Effects of Elexacaftor, Tezacaftor, and
Ivacaftor (ETI) on Blood Glucose in Patients With Cystic Fibrosis: A Systematic
Review. Cureus. 2023;15(7):e41697. doi:10.7759/cureus.41697
 
Systematic review
included both pediatric
and adult CF patients
treated with ELX/TEZ/IVA
Assessed effects on
glucose control in CF
patients showing
significant improvements
in glycemic measures,
which suggests potential
benefits in managing
CFRD
Potentiator
 
Chronic rhinosinusitis (CRS)
 
52
Corrector
Corrector
 
43 patients on ELX/TEZ/IVA in
Germany
ELX/TEZ/IVA improves both
subjective and objective sinunasal
symptoms in CF patients
Demonstrates marked
improvements in SNOT-22 scores
after ~9 months (2-16 months)
Children <18 had lower SNOT-22
score at baseline
Potentiator
 
Bode SFN, Rapp H, Lienert N, Appel H, Fabricius D. Effects of CFTR-modulator
triple therapy on sinunasal symptoms in children and adults with cystic fibrosis.
Eur Arch Otorhinolaryngol. 2023;280(7):3271-3277. doi:10.1007/s00405-023-
07859-4
 
Chronic rhinosinusitis (CRS)
 
53
Corrector
Corrector
 
Stone RG, Short C, Davies JC, McNally P. Chronic rhinosinusitis in the era of CFTR
modulator therapy. J Cyst Fibros. Published online September 8, 2023:S1569-
1993(23)00877-9. doi:10.1016/j.jcf.2023.08.009
 
A systematic review of 22 studies
children/adults
Improved symptom scoring
(SNOT20 & SNOT22)
Improved imaging scores (CT and
MRI)
 
Potentiator
Potentiator
 
OR
Potentiator
 
OR
Corrector
 
Stapleton AL, Kimple AJ, Goralski JL, et al. Elexacaftor-Tezacaftor- Ivacaftor
improves sinonasal outcomes in cystic fibrosis. Journal of Cystic Fibrosis.
2022;21(5):792-799. doi:10.1016/j.jcf.2022.03.002
 
Structural Changes
 
54
Corrector
Corrector
 
Middleton PG, Simmonds NJ. Cystic fibrosis modulator therapy can reverse cystic
bronchiectasis. Respirol Case Rep. 2023;11(7):e01172. doi:10.1002/rcr2.1172
 
Small case series (UK/AUS)
ETI therapy shows potential
to reverse cystic
bronchiectasis.
Highlights dynamic airway
changes with CFTR
dysfunction
Preliminary findings, needs
future study
 
1.
Right cyst improvement
2.
removed from lung transplant list
3.
TEZ/IVA to ELX/TEZ/IVA
Potentiator
 
Chest CT
 
55
Corrector
Corrector
 
Gushue C, Eisner M, Bai S, et al. Impact of Elexacaftor-Tezacaftor-Ivacaftor on
lung disease in cystic fibrosis. Pediatr Pulmonol. 2023;58(8):2308-2316.
doi:10.1002/ppul.26485
 
Cohor
t included 67 pwCF (16-
35 years old)
Significant improvements in
FEV, BMI, and reductions in
Pseudomonas aeruginosa and
MRSA positivity within 
1 year
of ELX/TEZ/IVA therapy.
Chest CT scans showed
reductions in bronchial wall
thickening, mucous plugging,
and hyperinflation
Potentiator
 
Pulmonary Ventilation
 
56
Corrector
Corrector
 
Klimeš F, Voskrebenzev A, Gutberlet M, et al. Effect of CFTR modulator therapy
with elexacaftor/tezacaftor/ivacaftor on pulmonary ventilation derived by 3D
phase-resolved functional lung MRI in cystic fibrosis patients. Eur Radiol.
2024;34(1):80-89. doi:10.1007/s00330-023-09912-6
 
Germany group - effects of
ELX/TEZ/IVA therapy on
pulmonary ventilation
Utilized
 3D phase-resolved
functional lung MRI
Authors conclude
endobronchial mucus
reduction mainly responsible
for regional ventilation
improvement 8–16 weeks
after 
initiation of therapy
Potentiator
 
MRI Insights
 
57
Corrector
Corrector
 
Heidenreich JF, Kuhl PJ, Grunz JP, et al. Lung Function in Patients with Cystic
Fibrosis before and during CFTR-Modulator Therapy Using 3D Ultrashort Echo
Time MRI. Radiology. 2023;308(1):e230084. doi:10.1148/radiol.230084
 
16 cystic fibrosis patients
evaluated before and during
ELX/TEZ/IVA therapy 3D
Ultrashort Echo Time MRI.
Demonstrates the feasibility
3D UTE MRI to assess lung
function changes in CF
Significant decrease in MRI
ventilation inhomogeneity
and ventilation defect
percentage (VDP) observed
post-treatment, indicating
improved lung function.
Potentiator
 
Microbiology
 
58
 
Singh SB, McLearn‐Montz AJ, Milavetz F, et al. Pathogen acquisition in
patients with cystic fibrosis receiving ivacaftor or lumacaftor/ivacaftor.
Pediatric Pulmonology
. 2019;54(8):1200-1208. doi:
10.1002/ppul.24341
 
Patients receiving ivacaftor or
lumacaftor/ivacaftor for CF
had significantly delayed
acquisition of P. aeruginosa
and S. aureus after modulator
drugs were released.
Corrector
Potentiator
 
Respiratory Cultures
 
59
Corrector
Corrector
 
Beck MR, Hornick DB, Pena TA, Singh SB, Wright BA. Impact of
elexacaftor/tezacaftor/ivacaftor on bacterial cultures from people with cystic
fibrosis. Pediatr Pulmonol. 2023;58(5):1569-1573. doi:10.1002/ppul.26362
 
University of Iowa
Reduction in P. aeruginosa
culture positivity.
No significant change in
MRSA and MSSA positivity.
ELX/TEZ/IVA therapy may
influence the bacterial
landscape in CF respiratory
cultures
Limitation: decrease in
Sputum and increase in
Throat swabs
Potentiator
 
Cardiovascular Risk
 
60
Corrector
Corrector
 
Despotes KA, Ceppe AS, Donaldson SH. Alterations in lipids after initiation of
highly effective modulators in people with cystic fibrosis. Journal of Cystic
Fibrosis. 2023;22(6):1024-1026. doi:10.1016/j.jcf.2023.10.002
 
41 patients on HEMT
HEMT shown to increase
total cholesterol and LDL in
CF patients.
No significant change in
HDL levels.
Authors highlights
cardiovascular risk factor
management.
Potentiator
Potentiator
 
OR
 
Gastrointestinal
 
61
Corrector
Corrector
 
Calthorpe RJ, Goodchild N, Gleetus V, et al. A grumbling concern: an international
survey of gastrointestinal symptoms in cystic fibrosis in the modulator era. NIHR
Open Res. 2023;3:18. doi:10.3310/nihropenres.13384.1
 
International survey, 164
responses (88 pwCf, 22
family, 54 HCP)
Gastrointestinal symptoms
persist in CF despite CFTR
modulators.
Frequent symptoms
include gas and stomach
rumbling.
Authors call for better
symptom management
strategies.
 
Potentiator
 
Liver Disease (CFRLD)
 
62
Corrector
Corrector
 
Tewkesbury DH, Scott J, Barry PJ, et al. Effects of elexacaftor/tezacaftor/ivacaftor
on liver fibrosis markers in adults with cystic fibrosis. J Cyst Fibros. Published
online September 19, 2023:S1569-1993(23)00910-4.
doi:10.1016/j.jcf.2023.09.006
 
Mixed results on liver fibrosis
markers; APRI increased, no
significant change in LSM or
GPR.
Results appear 
improved in
more severe CFLD patients
but small number studied
L
ack of data on the impact of
highly effective CFTR
modulation on the clinical
course of established liver
disease in CF.
Potentiator
 
Unplanned Pregnancies
 
63
Corrector
Corrector
 
Daccò V, Alicandro G, Trespidi L, Gramegna A, Blasi FA. Unplanned pregnancies
following the introduction of elexacaftor/tezacaftor/ivacaftor therapy in women
with cystic fibrosis. Arch Gynecol Obstet. 2023;308(5):1657-1659.
doi:10.1007/s00404-023-07153-y
 
ELX/TEZ/IVA introduction led to
increased unplanned pregnancies
in women with CF challenging
previous perceptions of
subfertility.
The rise in pregnancies may be
attributed to a reduced focus on
the possibility of conception
rather than contraceptive failure.
Highlights the need for enhanced
fertility discussions and
contraceptive guidance for
women with CF undergoing ETI
treatment.
Potentiator
 
Healthcare Expenditure
 
64
Corrector
Corrector
 
Demonstrates significant reductions in pulmonary exacerbations
and associated healthcare costs after ELX/TEZ/IVA therapy.
Highlights the decreased need for hospitalizations and outpatient
visits, showcasing the therapy's profound impact on improving
patient outcomes and reducing healthcare burdens.
Potentiator
 
Schechter MS, Sabater-Anaya N, Oster G, et al. Impact of
Elexacaftor/Tezacaftor/Ivacaftor on Healthcare Resource Utilization and
Associated Costs Among People With Cystic Fibrosis in the US: A Retrospective
Claims Analysis. Pulm Ther. 2023;9(4):479-498. doi:10.1007/s41030-023-00241-z
 
Quality of Life
 
65
Corrector
Corrector
 
Gruber W, Welsner M, Blosch C, et al. Long-Term Follow-Up of Health-Related Quality of Life and Short-Term Intervention
with CFTR Modulator Therapy in Adults with Cystic Fibrosis: Evaluation of Changes over Several Years with or without 33
Weeks of CFTR Modulator Therapy. Healthcare (Basel). 2023;11(21):2873. doi:10.3390/healthcare11212873
 
Adult cystic fibrosis patients undergoing ELX/TEZ/IVA
ETI therapy significantly enhances health-related quality of life
across various domains
Comparatively, patients not receiving ETI show little change in
psychosocial domains and a non-significant decrease in physical
domains
Potentiator
 
Conclusion / Future Directions
 
The Modulator Era is upon us and looks bright
 
CFTR modulators are changing the direction of Cystic fibrosis
disease progression in many ways outside of pulmonary
impacts
 
Thera-typing of ineligible patients continues and is crucial to
close the last gaps in coverage
 
Gene editing offers a potential option for ineligible patients
in years to come
 
CF Education Day
2019
 
5 years ago!
Cheers to many more
Thank you for listening
 
67
 
Questions?
 
Jake Brockmeyer, PharmD, BCPS, BCPPS
Clinical Pharmacist Specialist, Cystic Fibrosis
March 9th, 2024
 
Jbrockmeyer@stanfordchildrens.org
Slide Note
Embed
Share

Cystic Fibrosis (CF) is a genetic disease caused by variants in the CFTR gene. CFTR is a crucial membrane protein responsible for chloride transport in epithelial cells, impacting organ function. The Modulator Era focuses on CFTR modulators approved by the FDA for treating CF and improving outcomes. Learn about CF pathophysiology, CFTR mutations, and the importance of balanced ion gradients in managing CF. Explore the impact of CFTR dysfunction on pulmonary and extrapulmonary health.


Uploaded on May 14, 2024 | 0 Views


Download Presentation

Please find below an Image/Link to download the presentation.

The content on the website is provided AS IS for your information and personal use only. It may not be sold, licensed, or shared on other websites without obtaining consent from the author. Download presentation by click this link. If you encounter any issues during the download, it is possible that the publisher has removed the file from their server.

E N D

Presentation Transcript


  1. Cystic Fibrosis: The Modulator Era Jake Brockmeyer, PharmD, BCPS, BCPPS Clinical Pharmacist Specialist, Cystic Fibrosis March 9th, 2024

  2. The Eras Era The Modulator Era.. This may sound like a reference to Taylor Swift as she dominates the media during her "Eras Tour" However, the Modulator Era started well before her tour and this concept starting showing up in CF literature as early as 2015. So maybe Taylor actually got the idea from us?

  3. Learning Objectives Understand the pathophysiology of CFTR protein as it relates to Cystic fibrosis Review FDA approved CFTR modulators Describe pulmonary and extrapulmonary outcomes of interest 3

  4. Cystic Fibrosis (CF) CF is a genetic disease caused by variants of the CFTR gene Must get copy of the gene from both parents 1 in 2500 people born with CF 1 in 20 people are carriers of one gene www.cff.org/What-is-CF/Testing/Carrier-Testing-for-Cystic-Fibrosis/ 4

  5. Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) CFTR is a membrane protein belonging to the ABC transporter family CFTR transports Cl-out of epithelial cells CFTR is important to balance the ionic gradient and hydrate epithelial lining of various organs Education Steering Group. http://www.cftr.info. Accessed 2016. Zegarra-Moran O, Galietta LJV. CFTR pharmacotherapy. Cell Mol Life Sci. 2016. 5

  6. CFTR - Mutation types Mechanism 4 1 premature insertion of a stop codon 6 3 2 defective protein processing and trafficking 3 altered CFTR gating and reduced CFTR opening probability 2 4* altered CFTR channel conductance 5* affecting mRNA splicing 1 5 6 increased CFTR turnover * - mild disease Schmidt BZ, Haaf JB, Leal T, et al. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol. 2016;8:127-140 6

  7. Mutations There are over 2000 mutations that lead to dysfunctional CFTR 7

  8. Mutations 8

  9. Outcome of F508del mutation Causes a defect in processing leading to decreased number of active proteins on the membrane For the active proteins that do make it, this mutation also disrupts channel opening Correcting CFTR activity in patients with this mutation would require a two-step approach Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor- ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-31. 9

  10. Pulmonary Disease The hallmark characteristic of CF is chronic lung injury Cyclical process of airway obstruction, infection, and inflammation that leads to fatal tissue destruction Schmidt BZ, Haaf JB, Leal T, Noel S. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clinical Pharmacology: Advances and Applications. doi:10.2147/CPAA.S100759 10

  11. Extrapulmonary Disease Other systems effected; Pancreases Liver Reproductive Sinus Renal GI Tract 11

  12. Disease Progression Liou TG. The Clinical Biology of Cystic Fibrosis Transmembrane Regulator Protein: Its Role and Function in Extrapulmonary Disease. Chest. 2019 Mar 1;155(3):605 16. 12

  13. General Management of CF Treatment Types Specific Therapies Airway Clearance Breathing techniques Chest physiotherapy/vests Inhaled and Oral Medications Bronchodilators Mucolytics Antibiotics Steroids Pancreatic Enzymes Pancrelipase (Creon, Pancreaze, Zenpep, etc) CFTR Modulators Potentiators: Ivacaftor Correctors: Lumacaftor, Tezacaftor, Elexacaftor Treatments and Therapies. Cystic Fibrosis Foundation. https://www.cff.org/Life-With-CF/Treatments-and-Therapies 13

  14. Symptomatic Treatment Boeck KD. Cystic fibrosis in the year 2020: A disease with a new face. Acta Paediatrica. doi:10.1111/apa.15155 14

  15. General Management of CF Treatment Types Specific Therapies Airway Clearance Breathing techniques Chest physiotherapy/vests Inhaled and Oral Medications Bronchodilators Mucolytics Antibiotics Steroids Pancreatic Enzymes Pancrelipase (Creon, Pancreaze, Zenpep, etc) CFTR Modulators Potentiators: Ivacaftor Correctors: Lumacaftor, Tezacaftor, Elexacaftor Treatments and Therapies. Cystic Fibrosis Foundation. https://www.cff.org/Life-With-CF/Treatments-and-Therapies 15

  16. 16

  17. CFTR - Mutation types Mechanism 4 1 premature insertion of a stop codon 6 3 2 defective protein processing and trafficking 3 altered CFTR gating and reduced CFTR opening probability 2 4* altered CFTR channel conductance 5* affecting mRNA splicing 1 5 6 increased CFTR turnover * - mild disease Schmidt BZ, Haaf JB, Leal T, et al. Cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis: current perspectives. Clin Pharmacol. 2016;8:127-140 17

  18. Corrector Potentiator Pharmacology of CFTR Education Steering Group. Helping healthcare professionals understand the role of genetic changes in CF. http://www.cftr.info. Accessed December 2016. 18

  19. Pharmacology of CFTR https://www.youtube.com/watch?v=7WTjQY0V4qI 19

  20. Potentiator Ivacaftor (Kalydeco) Mechanism of Action Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. KALYDECO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 20

  21. Potentiator Ivacaftor (Kalydeco) 21

  22. Potentiator Ivacaftor (Kalydeco) KALYDECO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 22

  23. Corrector Potentiator Lumacaftor/Ivacaftor (Orkambi) Mechanism of Action Lumacaftor improves the conformational stability of F508del- CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 23

  24. Corrector Potentiator Lumacaftor/Ivacaftor (Orkambi) ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 24

  25. Corrector Potentiator Lumacaftor/Ivacaftor (Orkambi) ORKAMBI [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 25

  26. Corrector Potentiator Tezacaftor/Ivacaftor (Symdeko) Mechanism of Action Tezacaftor facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface SYMDEKO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 26

  27. Corrector Potentiator Tezacaftor/Ivacaftor (Symdeko) SYMDEKO [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2018. 27

  28. Corrector Potentiator Tezacaftor/Ivacaftor (Symdeko) Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del. doi:10.1056/NEJMoa1709846 28

  29. Corrector Potentiator Corrector Elexacaftor/Tezacaftor/Ivacator (Trikafta) Mechanism of Action Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface TRIKAFTA [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2019. 29

  30. Corrector Potentiator Corrector Elexacaftor/Tezacaftor/Ivacator (Trikafta) TRIKAFTA [package insert]. Boston, MA: Vertex Pharmaceuticals Inc.; 2019. 30

  31. Corrector Potentiator Corrector Elexacaftor/Tezacaftor/Ivacator (Trikafta) Middleton PG, Mall MA, D ev nek P, et al. Elexacaftor Tezacaftor Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. New England Journal of Medicine. October 2019. doi:10.1056/NEJMoa1908639 31

  32. Modulator Era: Outcomes of Interest 32

  33. Potentiator FEV1 Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 33

  34. Potentiator FEV1 Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 34

  35. Potentiator Pulmonary Exacerbations Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 35

  36. Potentiator Hospitalizations Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 36

  37. Potentiator Hospitalizations Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 37

  38. Potentiator Manifestations Bessonova L, Volkova N, Higgins M, et al. Data from the US and UK cystic fibrosis registries support disease modification by CFTR modulation with ivacaftor. Thorax. 2018;73(8):731-740. doi:10.1136/thoraxjnl-2017-210394 38

  39. Corrector Potentiator OR FEV1 Meta Analysis Potentiator Habib ARR, Kajbafzadeh M, Desai S, Yang CL, Skolnik K, Quon BS. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Sci Rep. 2019;9(1):7234. doi:10.1038/s41598- 019-43652-2 39

  40. Extrapulmonary Outcomes Overview Sergeev V, Chou FY, Lam GY, Hamilton CM, Wilcox PG, Quon BS. The Extrapulmonary Effects of Cystic Fibrosis Transmembrane Conductance Regulator Modulators in Cystic Fibrosis. Annals ATS. 2019;17(2):147-154. doi:10.1513/AnnalsATS.201909-671CME 40

  41. Potentiator Pancreatic Exocrine Function (Fecal Elastase 1) Davies JC, Cunningham S, Harris WT, et al. Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open- label, single-arm study. Lancet Respir Med. 2016;4(2):107-115. doi:10.1016/S2213-2600(15)00545-7 41

  42. Corrector Potentiator Corrector Pancreatic Function (Fecal Elastase 1) FE-1 levels rise in pediatric CF post-modulator therapy. Indicates potential pancreatic function improvement. Underlines the importance of early CFTR modulator therapy. Stephenson KG, Lingle AJ, Baumberger KA, et al. Changes in fecal elastase-1 following initiation of CFTR modulator therapy in pediatric patients with cystic fibrosis. J Cyst Fibros. 2023;22(6):996-1001. doi:10.1016/j.jcf.2023.09.005 42

  43. Corrector Potentiator BMI Burgel P-R, Munck A, Durieu I, et al. Real-Life Safety and Effectiveness of Lumacaftor Ivacaftor in Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2019;201(2):188-197. doi:10.1164/rccm.201906-1227OC 43

  44. Potentiator Nutrition / Growth Followed 15 young children (2-24 months) with CF starting ivacaftor Over the first 12 weeks of therapy, significant weight gain and beneficial changes in nutritional biomarkers Supports ivacaftor's role in improving growth patterns. Comparable outcomes to non-CF children Tindall A, Bass R, Maqbool A, Stallings VA. Changes in nutrition and growth status in young children in the first 12 weeks of ivacaftor therapy. J Cyst Fibros. 2023;22(6):989-995. doi:10.1016/j.jcf.2023.04.010 44

  45. Corrector Potentiator Corrector Nutrition / BMI 40 adult patients followed pre/post ELX/TEZ/IVA BMI increase but consumption decreased Suggesting increased BMI is caused mechanisms affecting metabolism and energy balance Caley LR, Jarosz-Griffiths HH, Smith L, et al. Body mass index and nutritional intake following Elexacaftor/Tezacaftor/Ivacaftor modulator therapy in adults with cystic fibrosis. J Cyst Fibros. 2023;22(6):1002-1009. 45 doi:10.1016/j.jcf.2023.06.010

  46. Corrector Potentiator Corrector BMI - FFM Adult CF patients initiating ELX/TEZ/IVA. Explores the effect on BMI and body composition Results reveal significant increases in both fat mass (FM) and fat-free mass (FFM) among adults with CF, Indicating changes beyond mere BMI growth Incorporating routine body composition assessment in CF care can offer more health insights, enabling personalized management Proud D, Duckers J. Weight a minute: Exploring the effect on weight and body composition after the initiation of elexacaftor/tezacaftor/ivacaftor in adults with CF. J Cyst Fibros. 2023;22(5):847-850. doi:10.1016/j.jcf.2023.06.002 46

  47. Corrector Potentiator Corrector Vitamin Levels Significant increase in vitamin A levels after ETI No significant change in vitamin D or E Highlights the need for regular vitamin monitoring Schembri L, Warraich S, Bentley S, Carr SB, Balfour-Lynn IM. Impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in children with cystic fibrosis. J Cyst Fibros. 2023;22(5):843-846. doi:10.1016/j.jcf.2023.04.019 47

  48. Corrector Potentiator Corrector OR Vitamin Levels Potentiator Corrector OR CF patients various ages, impact of CFTR modulators on nutritional status and fat-soluble vitamins. ELX/TEZ/IVA therapy significantly improves nutritional status and increases levels of all fat- soluble vitamins in CF patients Ivacaftor and Lumacaftor/ivacaftor did not show the same improvements across vitamin D, A, and E Potentiator Francalanci M, Terlizzi V, Fevola C, et al. Nutritional Status and Circulating Levels of Fat-Soluble Vitamins in Cystic Fibrosis Patients: A Cohort Study and Evaluation of the Effect of CFTR Modulators. Children (Basel). 2023;10(2):252. doi:10.3390/children10020252 48

  49. Potentiator CF Related Diabetes (CFRD) Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 49

  50. Potentiator CF Related Diabetes (CFRD) Volkova N, Moy K, Evans J, et al. Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries. Journal of Cystic Fibrosis. 2020;19(1):68-79. doi:10.1016/j.jcf.2019.05.015 50

Related


More Related Content

giItT1WQy@!-/#giItT1WQy@!-/#giItT1WQy@!-/#giItT1WQy@!-/#giItT1WQy@!-/#