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Triple therapy safe, effective in cystic fibrosis with single Phe508del allele
Combination therapy with elexacaftor/tezacaftor/ivacaftor improved lung function and the rate of pulmonary exacerbations with minimal adverse effects in patients aged 12 years and older with cystic fibrosis with Phe508del-minimal function genotypes who did not previously respond to cystic fibrosis transmembrane conductance regulator modulator therapy, according to a study published in The New England Journal of Medicine.
In the phase 3, double-blind, randomized, placebo-controlled trial, the percentage of predicted FEV1 was 13.8 points higher among patients treated with elexacaftor/tezacaftor/ivacaftor (Trikafta, Vertex Pharmaceuticals), as compared with placebo, at 4 weeks (P < .001) and 14.3 points higher at 24 weeks (P < .001).
Further, after 24 weeks, the rate of pulmonary exacerbations was 63% lower (rate ratio = 0.37; P < .001) among patients in the treatment arm, with similar benefit observed for exacerbations leading to hospitalization treatment with IV antibiotics. The respiratory domain score on the Cystic Fibrosis Questionnaire–Revised was also 20.2 points higher with elexacaftor/tezacaftor/ivacaftor vs. placebo (P < .001).
Also at week 24, sweat chloride concentration was 41.8 mmol/L lower and BMI was improved among patients treated with elexacaftor/tezacaftor/ivacaftor, as compared with placebo (P < .001 for both).
Adverse events in the treatment group were mostly mild (33.2%) or moderate (50.5%). Two patients receiving elexacaftor/tezacaftor/ivacaftor discontinued treatment due to adverse events, including rash and portpulmonary hypertension in a patient with preexisting cirrhosis.
The trial was conducted at 115 sites in 13 countries from June 2018 to April 2019 and enrolled patients aged 12 years and older with cystic fibrosis and Phe508del-minimal function genotypes. The intervention period lasted 24 weeks, with patients randomly assigned elexacaftor 200 mg once daily in combination with tezacaftor 100 mg once daily and ivacaftor 150 mg every 12 hours or matched placebo.
“These results provide evidence that elexacaftor/tezacaftor/ivacaftor can modulate a single Phe508del allele in people with cystic fibrosis, thus addressing the underlying cause of disease in the large majority of patients,” the researchers wrote.
In an accompanying editorial, Francis S. Collins, MD, PhD, director of the NIH, noted that these findings move the medical community one step closer to providing safe, effective and targeted therapies to most patients with cystic fibrosis.
“This should be a cause for major celebration. Yet we must not abandon the patients with cystic fibrosis who have null mutations and will not have a response to these drugs,” he wrote. “Even beyond that, the ‘best day ever’ for all of us traveling down this long road together will be the day when the more than 70,000 persons with cystic fibrosis worldwide do not need to take drug therapy at all and there finally is a permanent cure for cystic fibrosis that works for everyone. Although the challenges are substantial, one can imagine such an ultimate approach involving in vivo somatic-cell gene editing of airway epithelial cells.” – by Melissa Foster
Disclosures: This study was funded by Vertex Pharmaceuticals. Middleton reports he received personal fees from Vertex. Please see the study for all other authors’ relevant financial disclosures. Collins reports he is listed as a co-inventor on the original patents on the CFTR gene but has donated all royalties to the Cystic Fibrosis Foundation, and patent ownership and all future royalties were irreversibly transferred to the Cystic Fibrosis Foundation in 2009.