Sophie-Liliane Rosenke

Lancaster Medical School (Bailrigg) | Year 2 | Degree: M.D.

A new future for patients with cystic fibrosis

Cystic Fibrosis is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, causing the production of thick and sticky secretions into the airways. This leads to organ damage, including damage to the lungs, a major cause of early mortality. Only in the last decade, CFTR modulators were introduced, which can correct the underlying dysfunction of the CFTR gene in 90% of patients. There are currently four CFTR modulators approved in the UK: Kalydeco (the longest serving), Orkambi, Symkevi and lastly Kaftrio, introduced in 2021.
A systematic review of the literature revealed Kalydeco and Kaftrio have the greatest treatment benefit with improved lung function, reduced pulmonary exacerbations and improved symptoms overall. CFTR agents presented an overall favourable safety profile with low discontinuation rates when compared to placebo.
A greater treatment response was observed in young patients and simulations have suggested starting treatment at an early age could significantly increase life expectancy and reduce the huge life-long treatment burden of conventional symptomatic treatments. The current CFTR modulators do not have a significant effect on patients with rare CFTR mutations (10%), meaning treatment for these individuals still needs to be researched and developed.

Sophie-Liliane Rosenke

More information

Sophie-Liliane Rosenke

Lancaster Medical School (Bailrigg) | Year 2 | Degree: M.D.

A new future for patients with cystic fibrosis

DEFINITIONS

CF: Cystic Fibrosis

CFTR gene: Cystic Fibrosis Transmembrane Conductance Regulator gene
CFTR modulator/agent: a newer class of drugs acting on the defective CFTR gene

FEV₁: Forced Expiratory Volume refers to the volume an individual can exhale during a forced breath in 1 second.

PEx: Pulmonary Exacerbation, worsening of symptoms
SwCl: Sweat Chloride concentration, as people with CF tend to have raised sweat chloride levels
BMI: Body Mass Index (a measurement of an individuals weight in proportion to their height)

AIM

This research investigates the efficacy and tolerability of the currently available CFTR modulators which work to treat patients with CF.

Introduction

Epidemiology and Treatment development

Autosomal recessive disease
Affecting 1:2500 people
Cystic Fibrosis was first described in 1935. At the time it was untreatable and deadly in childhood.
Complications grow in severity with age and can occur in nearly every organ
The treatments started with being focused on the symptoms: pancreatic enzymes to prevent malnutrition to treating the underlying cause - defective CFTR gene
This lead to an increase in life expectancy over time (see graph)

CFTR Gene and Modulators

In 1989 the CF transmembrane conductance regulator (CFTR) gene was discovered - responsible for production of viscous and sticky mucous
With the introduction of newborn screening life expectancy has risen to approximately 40 years.
8 classes of CFTR mutations were detected, affecting different functions of the cells in the lungs
Most common mutation: Phe508del mutation which belongs to the classes II, III, IV
There are 4 CFTR agents currently available in the UK - Kalydeco (2016), Orkambi (2019), Symkevi (2020) and Kaftrio (2021) which are aimed at the population with the Phe508del mutation and other common ones (90% of CF population)

Methodology

Medline, PubMed and EMBASE, three databases were searched: "cystic fibrosis" OR “CF”, “CFTR modulators” OR “ivacaftor” OR “tezacaftor” OR “lumacaftor” OR “elexacaftor”, “efficacy” OR “safety"
Inclusion criteria: 1. Randomised control trial, 2. Measuring primary and secondary criteria (ppFEV₁, PEX, chloride sweat, BMI and adverse effects) and Full-Text Study
Exclusion criteria: Written in another language than English and not peer reviewed
Number of journals identified: 99, identified as relevant: 37, included in this review: 23

Findings

(Forced Expiratory Volume in 1 Second)

FEV₁

FEV₁ is a diagnostic tool assessing lung function. This was conducted in patients <12 years old. (Listed from top (most effective) to bottom (least effective))

Kaftrio: +13.8% from baseline and reduced PEx by 63%
Kalydeco: +10.6% from baseline and reduced PEx by 53%
Symkevi: +6.85% but Orkambi had no significant findings
PEx reduced by 30-35%, however if administered to non-Phe508del mutation patients, the results were insignificant

Adverse Events

(AE's)

Overall well tolerated.
Orkambi showed the most significant side effects with shortness of breath, cough and pulmonary exacerbations. Discontinuation rate: 4.2%

Sweat Chloride and Body Mass Index

(SwCl and BMI)

Used as a diagnostic tool and measures overall reduction. BMI measured as weight gain for CF patients is difficult. Youngest children had the best outcome overall.

Kalydeco in adults: -48.1 mmol/L and in children: -73.5 mmol/L, BMI: +0.8 kg/m²
Kaftrio: -39.1 mmol/L, BMI: 1.03 kg/m²
Symkevi: only -6.04 mmol/L but not significant in BMI
Orkambi: not significant in either

Graph showing improvement of FEV1 using Kalydeco over the span of 8 weeks

Graph showing improvement of SwCl using Kalydeco over the span of 8 weeks

Graph showing improvement of BMI using Kalydeco over the span of 8 weeks

Dicussion

Best primary outcomes seen in patients with common mutations (e.g. Phe508del) receiving Kaftrio and Kalydeco. Lung function (FEV₁ and PEx) improved as well as the patients quality of life. The younger population (12 months - 6 years) experienced the greatest improvements.

Orkambi and Symkevi were exclusively effective in Phe508del mutation, limiting the population size and the overall effectiveness.

Even though the CFTR modulators were well tolerated, for children <6 years old, Kalydeco is the only agent approved to be used. Nevertheless, this significantly prevents lung deterioration and causes a significant improvement in their quality of life.

A simulation model predicted, that the earlier treatment (Orkambi) is initiated, the median survival rate increases accordingly (up to +23.4 years). Early treatment can prevent lung function deterioration and consequently fatal future outcomes. This can be applied to all CFTR agents.

10% of the CF population carry different and more unique mutations which the CFTR modulators are not effective for, hence limiting the treatment options for those patients drastically. Research is continuing to expand and new possibilities are being explored, for example gene editing.

References

Cystic fibrosis symptoms and treatments [Internet]. Nhsinform.scot. 2021 [cited 8 December 2021]. Available from: https://www.nhsinform.scot/illnesses-and-conditions/lungs-and-airways/cystic-fibrosis#treating-cystic-fibrosis
De Boeck, K., 2020. Cystic fibrosis in the year 2020: A disease with a new face. Acta Paediatrica, 2020;109(5), pp.893-899
Pettit RS, Fellner C. CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014;39(7):500-11
Gramegna, A., Contarini, M., Aliberti, S., Casciaro, R., Blasi, F. and Castellani, C. From Ivacaftor to Triple Combination: A Systematic Review of Efficacy and Safety of CFTR Modulators in People with Cystic Fibrosis. International Journal of Molecular Sciences, 2020;21(16), p.5882
Dagenais R, Su V, Quon B. Real-World Safety of CFTR Modulators in the Treatment of Cystic Fibrosis: A Systematic Review. Journal of Clinical Medicine. 2020;10(1):23.
Lopes-Pacheco, M. CFTR Modulators: The Changing Face of Cystic Fibrosis in the Era of Precision Medicine. Frontiers in Pharmacology, 2020;10:1662
Habib, A., Kajbafzadeh, M. et al. A Systematic Review of the Clinical Efficacy and Safety of CFTR Modulators in Cystic Fibrosis. Scientific Reports, 2019;9(1):7234
Bierlaagh MC, Muilwijk D, Beekman JM, van der Ent CK. A new era for people with cystic fibrosis. Eur J Pediatr. 2021;180(9):2731-9.
Gavioli, E., Guardado, N., Haniff, F., Deiab, N. and Vider, E., A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators. Journal of Clinical Pharmacy and Therapeutics., 2020;46(2):286-294.
Kalydeco [Internet]. CF Trust. 2021 [cited 8 December 2021]. Available from: https://www.cysticfibrosis.org.uk/the-work-we-do/campaigning-hard/life-saving-drugs/kalydeco
Orkambi [Internet]. CF Trust. 2021 [cited 8 December 2021]. Available from: https://www.cysticfibrosis.org.uk/the-work-we-do/campaigning-hard/life-saving-drugs/orkambi
Symkevi [Internet]. CF Trust. 2021 [cited 8 December 2021]. Available from: https://www.cysticfibrosis.org.uk/the-work-we-do/campaigning-hard/life-saving-drugs/symkevi
FDA Approves Trikafta for Children Ages 6 Through 11 With Certain Mutations [Internet]. Cystic Fibrosis Foundation. 2021 [cited 8 December 2021]. Available from: https://www.cff.org/node/631
Triple combination therapy Kaftrio (Trikafta in the US) [Internet]. CF Trust. 2021 [cited 8 December 2021]. Available from: https://www.cysticfibrosis.org.uk/the-work-we-do/campaigning-hard/life-saving-drugs/triple-combination-therapy
Ramsey, B., Davies, J. et al. A CFTR Potentiator in Patients with Cystic Fibrosis and theG551DMutation. New England Journal of Medicine; 2011;365(18):1663-1672

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