The Cystic Fibrosis Unit of Vall d'Hebron has participated in a Phase III clinical trial whose results have been published in The New England Journal of Medicine. The combination of Elexacaftor-Tezacaftor-Ivacaftor (Kaftrio) for the treatment of cystic fibrosis has demonstrated its efficacy in patients with at least one Phe508del mutation, which is the most frequent, regardless of the second mutation, thus broadening the spectrum of patients who can be treated with this drug.

The Spanish Ministry of Health has agreed to its financing for its use in Spain this month and this study is one of those that has contributed to its approval in these patients, which means that between 70 and 75% of people with cystic fibrosis will benefit from this treatment. Dr. Antonio Álvarez, Coordinator of the Cystic Fibrosis Adult Unit of the Vall d'Hebron University Hospital and researcher of the Pneumology group of Vall d'Hebron Recerca has participated in the publication.

Cystic fibrosis is the most common genetic disease in the Caucasian population, and occurs when there are 2 mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, located on the long arm of chromosome 7. This gene codes for the CFTR protein, which behaves as a chloride channel on the surface of the membranes of epithelial cells. This protein acts as a regulator of salt and water transport across numerous epithelia. Its absence or malfunction leads to dehydration of the different secretions of the epithelia, which causes them to be dense and viscous and will eventually damage the organs that are affected, especially the respiratory, digestive and reproductive systems. It is a serious pathology with no curative treatment, in which the life expectancy of the patients is limited.

Kaftrio is a modulator composed of two correctors (Elexacaftor and Tezacaftor) and a potentiator (Ivacaftor) of the chloride channel that manages to restore its function, so it partially corrects the alteration that motivates the whole physiopathology of cystic fibrosis. It manages, therefore, to treat the cause of the disease and not its consequences, as do bronchodilators, antibiotics, or drugs that fluidize secretions or pancreatic enzymes. "Kaftrio is one of those few drugs that appear from time to time, which are characterized by their high therapeutic value and represent a change and a revolution for a disease for which there is no effective treatment of the cause, as is the case of cystic fibrosis," explains Dr. Álvarez. It is also a safe drug with few side effects.

The results of the different clinical trials that have been carried out have shown an improvement in lung function, measured by forced expiratory volume, of between 10 and 14% on average, as well as an improvement in the body mass index and a reduction in exacerbations of 40-60% on average. "Undoubtedly, these values have a direct impact on the improvement of patients' quality of life and also on their survival," assures Dr. Álvarez. Another very significant fact is that the sweat test, which measures the concentration of chlorine in sweat and is a diagnostic test that confirms the disease, can become negative or enter the range of indeterminate values when patients are under treatment with Kaftrio, which demonstrates the recovery of the activity of the CFTR protein.

The trial involved patients over 12 years of age and, because of their age, in many cases they already have some irreversible lung damage, so the drug will be useful in slowing the progression of the disease and therefore delaying or even avoiding the need for a lung transplant in the future. Currently, the FDA has just approved its use also in children aged 6 to 11 years and clinical trials are underway with the same drug in boys and girls aged 2 to 5 years. As Dr. Álvarez points out, "we hope that, if the drug is administered early, when the children have not yet developed damage, this will be avoided, since with the treatment we manage to make their pulmonary physiology similar to that of a child without cystic fibrosis".

The study involved 258 patients over 12 years of age from 96 centers in Europe, North America and Australia. It is a Phase III, double-blind, randomized, active-controlled trial involving patients with a Phe508del mutation in the CFTR gene and with another gating or residual function mutation (i.e., the channel is present but does not function properly). Previously, its effectiveness had already been demonstrated in patients with two Phe508del mutations or in patients with one Phe508del mutation and another minimal function mutation (in which the channel is absent or does not function).

After a 4-week pretreatment period with Ivacaftor or Tezacaftor-Ivacaftor, patients were randomized to receive either Elexacaftor-Tezacaftor-Ivacaftor (132 patients) or active control (i.e., pretreatment) (126 patients) for another 8 weeks.

The group receiving Elexacaftor-Tezacaftor-Ivacaftor had a predicted FEV1 (Forced Expiratory Volume in second 1) percentage that was higher by 3.7 percentage points relative to baseline and by 3.5 percentage points relative to active control and a sweat chloride concentration 22.3 mmol per liter relative to baseline and lower by 23.1 mmol per liter relative to active control. The change from baseline on the Cystic Fibrosis Quality of Life Questionnaire with Elexacaftor-Tezacaftor-Ivacaftor was 10.3 points and with the active control was 1.6 points. The incidence of adverse events was similar in the two groups.

The Cystic Fibrosis Unit of Vall d'Hebron

The Cystic Fibrosis Unit of Vall d'Hebron, formed by the Pediatric Unit, coordinated by Dr. Silvia Gartner, and the Adult Unit, coordinated by Dr. Antonio Álvarez, participates in most of the international clinical trials that contribute to the approval of the drugs used in the treatment of Cystic Fibrosis.

It has been in operation since 1994 and currently controls more than 400 patients, which makes it the largest CF Unit in Spain and one of the most experienced in the management of these patients.

It is the only Spanish center specialized in cystic fibrosis, which is part of the European Reference Network on Respiratory Diseases (ERN Lung - CF). It is also the only Cystic Fibrosis Unit in Spain accredited by the Clinical Trial Network - European Cystic Fibrosis Society (CTN - ECFS) which brings together the 57 most experienced CFUs from 17 European countries.

In 2018 they proceeded to the renovation and expansion of the entire CF Unit, following European standards and adapting to the current needs of the disease, this thanks to the support of the Daniel Bravo Andreu Private Foundation and the Societat Catalana de Fibrosis Quística.