Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor Therapy in Three Subjects with the Cystic Fibrosis Genotype Phe508del/Unknown and Advanced Lung Disease

Abstract

We evaluated the effectiveness and safety of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in three subjects carrying the Phe508del/unknown CFTR genotype. An ex vivo analysis on nasal epithelial cells (NEC) indicated a significant improvement of CFTR gating activity after the treatment. Three patients were enrolled in an ELX/TEZ/IVA managed-access program, including subjects with the highest percent predicted Forced Expiratory Volume in the 1st second (ppFEV1) < 40 in the preceding 3 months. Data were collected at baseline and after 8, 12 and 24 weeks of follow-up during treatment. All patients showed a considerable decrease of sweat chloride (i.e., meanly about 60 mmol/L as compared to baseline), relevant improvement of ppFEV1 (i.e., >8) and six-minute walk test, and an increase in body mass index after the first 8 weeks of treatment. No pulmonary exacerbations occurred during the 24 weeks of treatment and all domains of the CF Questionnaire-Revised improved. No safety concerns related to the treatment occurred. This study demonstrates the benefit from the ELX/TEZ/IVA treatment in patients with CF with the Phe508del and one unidentified CFTR variant. The preliminary ex vivo analysis of the drug response on NEC helps to predict the in vivo therapeutic endpoints.

Effect of Trikafta on bone density, body composition and exercise capacity in CF: A pilot study

“…In a retrospective study of severe CF patients on compassionate therapy with Trikafta, 6MWT increased by a mean of 42 m 36 . A pilot study in three patients found that treatment with Trikafta led to significant improvement in 6MWT 37 . These results could correlate to the significant improvement in breathing indices post Trikafta.…”

Cystic fibrosis year in review 2021

“…Expanding usage of ETI to population not studied in the original clinical trials, use for PwCF and ADL, based primarily on a FEV1pp <40% or referral/evaluation for lung transplantation demonstrated improvements in FEV1pp [30][31][32][33][34] , BMI [31][32][33][34] , CFQ-R 32,34 , and decreases in antibiotic use/exacerbations 32,34 . Where reported, oxygen use was decreased/eliminated 32,34 , with one study demonstrating a decrease in noninvasive ventilation use 31 . Most importantly, transplantation status primarily changed in a positive direction, with decreases in transplant related discussions, referrals, and wait list numbers [30][31][32][33] .…”

Proximity Profiling of the CFTR Interaction Landscape in Response to Orkambi

“…Despite the development of therapeutic regimens, patient quality of life remains limited and even the most successful compounds do not achieve wild type (WT) level conductance [ 5 , 6 ]. The ∆F508 deletion mutation accounts for the majority of the CF population, making up approximately 70% of all patients, although its prevalence varies depending on the geographical origin of the patients [ 7 , 8 ]. ∆F508-CFTR is a class II mutation known for its trafficking defect caused by misfolding and ER retention and degradation [ 8 ].…”

“…∆F508-CFTR is a class II mutation known for its trafficking defect caused by misfolding and ER retention and degradation [ 8 ]. In 2015, ivacaftor-lumacaftor (Orkambi) was approved for use in patients aged 12 years or higher and homozygous for the ∆F508 mutation and was recently extended to include those aged 6–11 years old [ 7 , 9 ]. Orkambi is a combination treatment consisting of a small molecule corrector compound (VX-809, lumacaftor) that promotes protein stability and forward trafficking [ 10 ], and a small molecule potentiator (VX-770, ivacaftor) that promotes the open state of the channel [ 10 ].…”

“…Orkambi is a combination treatment consisting of a small molecule corrector compound (VX-809, lumacaftor) that promotes protein stability and forward trafficking [ 10 ], and a small molecule potentiator (VX-770, ivacaftor) that promotes the open state of the channel [ 10 ]. Ivacaftor (Kalydeco) is also approved for use on its own for the treatment of for CF patients aged four months or older with a gating variant [ 7 ]. Orkambi is associated with a variable clinical response [ 11 , 12 ].…”