Original Article
Compassionate Use of Lumacaftor/Ivacaftor in Cystic Fibrosis: Spanish ExperienceUso compasivo de lumacaftor/ivacaftor en fibrosis quística: experiencia española

https://doi.org/10.1016/j.arbres.2018.05.004Get rights and content

Abstract

Background

The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs.

Methods

We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real-life in Spain. 20 CF patients were included, all aged 6 and upwards and presented with ppFEV1 < 40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125 mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months.

Results

The mean age was 26.65 (range of 10–45), while the mean ppFEV1 before the treatment was 32.4% and mean BMI was 19.9 kg/m2. We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor/ivacaftor, but no differences were found. However, a moderate association between days of intravenous antibiotic needed and the use of lumacaftor/ivacaftor (p = 0.001) was established. Indeed, under the lumacaftor/ivacaftor, patients required 5.8 days of intravenous antibiotic treatment compared to 14.9 days prior to study. Also, severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor/ivacaftor treatment (p = 0.003). Finally, 75% of the sample presented with AEs, which led 35% of the subjects to discontinue the treatment.

Conclusions

While treatment with lumacaftor/ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations, no improvement in ppFEV1 or BMI was found.

Resumen

Introducción

La mutación causante de fibrosis quística (FQ) más frecuente es la deltaF508 (F508del), presente en el 28% de los pacientes españoles con FQ. Aunque la literatura sobre estudios en vida real en pacientes de FQ homocigotos para F508del tratados con lumacaftor/ivacaftor es escasa, pone de manifiesto la necesidad de contar con mejores estrategias para prevenir los efectos adversos (EA) relacionados con el tratamiento, así como del desarrollo de nuevos fármacos.

Métodos

Se realizó un estudio observacional, retrospectivo multicéntrico para describir los efectos del tratamiento con lumacaftor/ivacaftor en vida real en España. Se incluyeron 20 pacientes con FQ, edad superior a los 6 años y ppFEV1 < 40%, procedentes de unidades de FQ de todo el país. Para los fines del estudio, fueron tratados con 2 comprimidos de lumacaftor/ivacaftor 200/125 mg/2 veces al día como parte de un programa de uso compasivo a lo largo de 2016. El criterio de valoración primario se midió en las muestras de todos los pacientes. Los datos de ppFEV1 se analizaron al inicio y cada 6 meses.

Resultados

La mediana de edad fue de 26,65 (rango: 10-45), mientras que la mediana de ppFEV1 antes del tratamiento fue del 32,4% y la mediana del IMC 19,9 kg/m2. No se encontraron diferencias al analizar los cambios de ppVEF1 e IMC desde el inicio y durante el tratamiento con lumacaftor/ivacaftor. Sin embargo, se estableció una asociación moderada entre los días requeridos de antibiótico intravenoso y el uso de lumacaftor/ivacaftor (p = 0,001). De hecho, con lumacaftor/ivacaftor, los pacientes requirieron 5,8 días de tratamiento intravenoso con antibiótico, comparado con los 14,9 días previos al estudio. Además, el número de exacerbaciones pulmonares graves que requirieron hospitalización fue estadísticamente menor con lumacaftor/ivacaftor (p = 0,003). Por último, el 75% de la muestra presentó EA, lo cual supuso la discontinuación del tratamiento en un 35% de los casos.

Conclusión

El tratamiento con lumacaftor/ivacaftor mejoró el número de exacerbaciones pulmonares severas, pero no supuso mejora ni en el ppFEV1 ni el IMC.

Introduction

Cystic fibrosis (CF) is a genetic disease, inherited in an autosomal recessive fashion, which causes the defective function of the cystic fibrosis transmembrane regulator (CFTR) protein. It affects approximately 1 in 5000 newborns in Europe. CF is caused by abnormalities in salt transportation that result from the defective CFTR protein, a chloride channel that regulates the salt content in the fluid that covers cell surfaces in the nose and lungs. Transport of ions such as sodium and chloride generates an electrical potential difference across the airway lining.

The most common mutation that causes CF is F508del, which affects 28% of Spanish CF patients, and causes various defects such as reductions in the folding and trafficking of the CFTR protein to the epithelial cell surface and defective channel gating.

Lumacaftor is a CFTR corrector which selectively increases the processing and trafficking of F508del CFTR to the cell surface. Ivacaftor is a CFTR potentiator which increases the channel opening probability of CFTR on the cell surface, facilitating chloride transport.

TRAFFIC and TRANSPORT were two phase 3 trials, both of which were multi-national, randomised, double-blind, placebo-controlled, parallel group studies in which lumacaftor and ivacaftor were orally administered for 24 weeks.1 Both studies revealed improvements in percent predicted forced expiratory volume in 1 s (ppFEV1), nutritional status and pulmonary exacerbation rates. The patients included for both studies were 12 and upwards, with a ppFEV1  40%. A subsequent efficacy analysis showed decreased values in ppFEV1 < 40% between screening and baseline in fewer than 10% of the patients. At week 24, improvements in the absolute change in ppFEV1 were observed. Increases in body-mass index (BMI) and a reduction in the number of pulmonary exacerbation events were also observed in both the lumacaftor/ivacaftor dose groups compared with the placebo group. The treatment was generally well tolerated, although the incidence of some respiratory adverse events (AEs) was higher under lumacaftor/ivacaftor than with placebo.2

Between 24 October 2013 and 7 April 2016, 1030 patients from the TRANSPORT and TRAFFIC studies enrolled in PROGRESS, and 1029 subjects subsequently received at least one dose of the drug under study.3 The subjects of the study were treated with lumacaftor 400 mg/ivacaftor 250 mg every 12 h. The most common adverse events observed were infective pulmonary exacerbations, cough, increased sputum and haemoptysis. The results showed a slight improvement in ppFEV1 and BMI in week 96, with a reduction of the annual rate of ppFEV1 decline in lumacaftor/ivacaftor treated patients compared to matched controls.

There has been little research regarding the benefits of lumacaftor/ivacaftor outside of clinical trials and even less data on its safety and effectiveness among patients with ppFEV1 lower than 40%. We therefore sought to obtain data on real-life initiation of lumacaftor/ivacaftor in CF adults with severe lung disease in Spain, where lumacaftor/ivacaftor has been available for compassionate use since February 2016.

The European Medicines Agency (EMA) defines “compassionate use” as a treatment option that allows the use of an unauthorised medicinal product which is under development. In Spain, compassionate use is permitted under the following conditions:

  • The patient must have a chronically or seriously debilitating disease or one that is considered to be life-threatening, and which cannot be treated satisfactorily with authorised products.

  • The product must be subject to an application for marketing authorisation, or undergoing clinical trials.

  • The sponsor of the clinical trials or the applicant for marketing authorisation must have consented to supply the product for compassionate use.

While there are few real-life studies on CF patients who are homozygous F508del treated with lumacaftor/ivacaftor, those that have been undertaken have revealed more respiratory-related AEs and initial declines in lung function compared to the results of clinical trials. Approximately 20–25% patients did not tolerate the treatment due to respiratory AEs,4 which demonstrates the need for better strategies to prevent these effects, as well as the development of newer drugs with better AE profiles. Against this background, our cohort of patients should be closely monitored following initiation of lumacaftor/ivacaftor treatment.

Section snippets

Methods

We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real life in Spain.

The inclusion criteria were as follows: CF patients, male or female, aged at least 6 years old at the time of signing informed consent form, homozygous for the F508del-CFTR mutation with ppFEV1 value <40%, adjusted for age, sex, and height at screening and able to understand and comply with the protocol requirements. Beyond this, patients who had

Results

20 patients started lumacaftor/ivacaftor 200/125 mg treatment. The mean age was 26.65 (range 10–45 years old), the mean ppFEV1 before the treatment was 32.4% and mean BMI 19.9 kg/m2. 60% of the cohort was female, 100% had chronic bronchial infection, 60% by Pseudomonas aeruginosa and 35% by Staphylococcus aureus, 30% had diabetes. Almost all the patients used nebulised antibiotics, 55% DNAse, 90% hypertonic saline and 30% oxygen (Table 1). We analysed the absolute changes in ppFEV1 and BMI during

Discussion

The treatment with lumacaftor/ivacaftor resulted in an improvement of some factors in our CF patients who are F508del homozygous with severe lung diseases, and reported less days of i.v. antibiotics in severe pulmonary exacerbations.

Pulmonary exacerbation (PEx) is a hallmark of cystic fibrosis. The incidence of PEx seems to increase with age.5 In an analysis of data from 11.692 consecutive CF patients included in a large prospective multicentre database (Epidemiologic Study of Cystic Fibrosis),6

Conflict of interest

Rosa María Girón-Moreno has received honoraria for workshops from Vertex, Teva, Zambon and Esteve.

Esther Quintana-Gallego has received honoraria for workshops and expert comitte from Chiesi, Gilead, Novartis, Praxis y Vertex.

Luis Maiz has received honoraria for workshops from Vertex.

Marta María García-Clemente has received honoraria for workshops from GSK and Chiesi.

Carmen Luna-Paredes has received honoraria for workshops and participate in advisory boards from Vertex.

Pedro Mondejar-López has

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