medwireNews: A greater number of cystic fibrosis disease variants may respond to short-term treatment with elexacaftor–tezacaftor–ivacaftor than currently approved by European and US guidelines, show findings from a compassionate use program in France.
The treatment is only approved for use in Europe in people with at least one cystic fibrosis transmembrane conductance regulator (CFTR) F508del variant, while the US FDA has approved elexacaftor–tezacaftor–ivacaftor for those with at least one of 177 rare variants, the investigators remark.
However, the program results show that over half of individuals with cystic fibrosis without a CFTR F508del variant had positive clinical and symptomatic changes after receiving the combination CFTR modulator and chloride channel opener agent, and most of these had no FDA-approved variant.
“This finding, supported by previous data from this programme and other reports, shows that the list of FDAapproved variants is not comprehensive,” write Pierre-Régis Burgel, from Cochin Hospital in Paris, France, and colleagues in The Lancet Respiratory Medicine.
They continue: “Elexacaftor–tezacaftor–ivacaftor might therefore be effective in many people with cystic fibrosis with nonFDAapproved variants.”
A total of 479 people in France aged over 6 years (median age 23 years, 38% younger than 18 years; 52% male) with cystic fibrosis and without a CFTR F508del disease variant, received a 4–6-week course of elexacaftor–tezacaftor–ivacaftor during the program. Less than a quarter (24%) of the cohort had an FDA-approved disease variant and 92% were CFTR-modulator treatment naive.
In all, 290 (56%) participants responded to elexacaftor–tezacaftor–ivacaftor, as determined by a centralized adjudication committee that assessed a combination of clinical outcomes. Of note, almost all (98%) of those with at least one FDA-approved disease variant who had not been treated with a CFTR modulator at baseline responded to treatment.
Sweat chloride concentration reduced significantly in treatment responders with or without at least one FDA-approved disease variant compared with non-responders without approved CFTR variants, by an average 44.5, 20.5, and 1.8 mmol/L, respectively.
Lung function, indicated by percentage of predicted forced expiratory volume (ppFEV1) also improved significantly in those who responded to elexacaftor–tezacaftor–ivacaftor treatment, rising from 72% before treatment to 89% in people with least one FDA-approved disease variant, and from 65% to 80% in those without. This compared with an increase from 65% to 67% in non-responders.
The participants’ weight increased significantly after elexacaftor–tezacaftor–ivacaftor treatment, regardless of whether they had an FDA-approved disease variant or not, increasing by a mean 1.6 and 1.4 kg, respectively, versus 0.5 kg for non-responders.
None of the study participants stopped taking treatment because of adverse effects, report Burgel et al, with the most common side effects being cutaneous rash (6%) and headache or mild mental health problems, such as difficulty sleeping or anxiety (3%).
Overall, the team identified 251 CFTR variants in the cohort, including 42 approved by the FDA for elexacaftor–tezacaftor–ivacaftor use. This corresponds to “the genetic makeup of the French cystic fibrosis population, which does not represent worldwide genetic diversity, particularly of ultrarare variants,” write Burgel et al.
They conclude: “We hereby propose creating and developing an international database that assembles all individual-level reports and case series in people with cystic fibrosis with rare CFTR variants who received CFTR modulators.
“Integrating these data with data obtained from in vitro models will help to determine the responsiveness of rare variants to CFTR modulators.”
In an accompanying comment, Katherine Odem-Davis (Seattle Children’s Research Institute, Washington, USA) and Jennifer Taylor-Cousar (National Jewish Health, Denver, Colorado, USA) agree that “[i]n the era of genotype-specific treatments for cystic fibrosis, disparities are increasing because variants that are rare or understudied, or both, are more likely to be present in individuals from minoritised ethnic groups, making many ineligible for approved CFTR modulators.”
They acknowledge that although cost and tolerance can be barriers to treatments such as elexacaftor–tezacaftor–ivacaftor in many low- and middle-income countries, Burgel and team’s approach “shows a potential pathway to increasing the availability of these life-changing therapies to more people with cystic fibrosis.”
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Lancet Respir Med 2024; doi:10.1016/ S2213-2600(24)00208-X Lancet Respir Med 2024; doi:10.1016/ S2213-2600(24)00243-1
