Prescrire International - Free Special Edition - 2022

MARKETING AUTHORISATIONS

NEW SUBSTANCE Ivacaftor + tezacaftor + elexacaftor ( kaftrio °) in cystic fibrosis with at least one F508del mutation Respiratory symptoms alleviated in the short term

Compare before deciding Cystic fibrosis is a serious genetic disorder, with an autosomal recessive pattern of inheritance. It is caused by mutations in the gene that encodes the CFTR (cystic fibrosis transmembrane conductance regulator) protein. This protein plays a role in the transport of ions across cell membranes, particularly through chloride channels. The most common mutation is the F508del (or deltaF508) mutation. There is no known cure for cystic fi brosis as of late 2021 (1-4). A number of drugs referred to as CFTR “modulators” were authorised in the European Union in the 2010s: the CFTR “po tentiator” ivacaftor , which is claimed to promote the opening of chloride channels; and the CFTR “correctors” lumacaftor and tezacaftor , which are thought to facilitate maturation of the CFTR protein and its transport to the cell surface (1-3). Patients homozygous for F508del: fewer exacer bations with ivacaftor + a CFTR corrector. In patients homozygous for the F508del mutation, a combination of ivacaftor and a CFTR corrector reduces the incidence of pulmonary exacerbations that require intravenous antibiotic therapy or hospitalisation. For example, in a 24-week randomised trial, 1 exacerbation was prevented for every 4 patients treated with ivacaftor + tezacaftor for one year, comparedwith patients who received placebo (1). The potential long-term effects of this treatment, especially on cystic fibrosis progression, have not been adequately evaluated and therefore remain unknown (1). Patients heterozygous for F508del: uncertain harm-benefit balance of ivacaftor alone or iva caftor + tezacaftor. The level of CFTR protein activity in patients who are heterozygous for the F508del mutation de pends on which mutation they have on their other CFTR allele. The CFTR protein is said to have “minimal” function when this other mutation results in no CFTR protein production or in a CFTR protein with greatly reduced activity. None of the CFTR modulators has proven efficacy in these situations (3).

OFFERS ANADVANTAGE In patients with cystic fibrosis and at least one F508del mutation in the CFTR gene, triple therapy comprising ivacaftor + tezacaftor + elexacaftor

alleviated respiratory symptoms in comparative trials, none of which had a duration of more than 24weeks. Triple therapy with these drugs was more effective by this measure than the comparator, which was tailored to patients’ CFTR mutations. A reduced incidence of pulmonary exacerbations was demonstrated, mainly in a trial in patients hetero zygous for the F508del mutation and a mutation resulting in minimal CFTR protein function. The adverse effects of this combinationmainly include upper respiratory tract infections, hepatic disorders, rash, muscle disorders. It is also involved in many drug interactions. Any longer-termadverse effects, or the possible effect on disease progression, are not yet known. KAFTRIO° - ivacaftor + tezacaftor + elexacaftor tablets • 75 mg of ivacaftor + 50 mg of tezacaftor + 100 mg of elexacaftor per tablet Vertex Pharmaceuticals ■ CFTR potentiator + CFTR correctors ■ Indication : cystic fibrosis in patients aged 12 years and older who have at least one F508del mutation in the CFTR gene. [EU centralised procedure - orphan drug] ■ Dosage : in general, two tablets of Kaftrio° ( ivacaftor + tezacaftor + elexacaftor ) in themorning and one tablet of Kalydeco° (containing 150mg of ivacaftor ) in the evening, taken with fat-containing food.

Full review(4 pages) available to subscribers at english.prescrire.org ▶ Translated from Rev Prescrire December 2021 Volume 41 N° 458 • Pages 885-889

Prescrire Int • March 2022

Prescrire International Special Edition 2022 • Page 3