(133) Significant Clinical Response to Elexacaftor-Tezacaftor-Ivacaftor (ELX/TEZ/IVA) in Five CF Patients Carrying the Class II- N1303K Mutation

Background: Significant improvement in lung function, nutrition status, quality of life and sweat chloride test was shown in patients carrying the F508del CFTR mutation treated with the combination of elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA). [1-3]. In 2019, the use of ELX/TEZ/IVA for those patients was approved by the FDA, and recently, the label was expanded for patients carrying at least one of the responsive misprocessing CFTR mutations,[4] not including the N1303K, a class II mutation associated with abnormal CFTR processing. The N1303K-CFTR protein fails to undergo complex glycosylation leading to cytoplasmic degradation with no, lack or minimal function of CFTR. For people with the N1303K mutation, recent in vitro analysis with patient-derived nasal epithelial cell culture showed a significant increase in CFTR function following 48 hours of treatment with ELX/TEZ/IVA. However, there was negligible improvement in CFTR protein processing suggesting that the increase in function was due to potentiation of the function of membrane residual CFTR proteins, and not due to improved protein processing.[5]

Methods: Five patients (age 9-31 years), compound heterozygous for N1303K and W1282X in three, C24556C >TP.E819X, and 3121-1A >G, from two CF centers in Israel, who started off-label treatment with ELX/TEZ/IVA, were described.

Results: Significant clinical improvement was demonstrated in all shortly after the initiation of ELX/TEZ/IVA. On average, forced expiratory volume in 1 second (FEV1) increased by 22.6%, compared to predicted 0.012% (CI 11-35%, p-value = 0.0026, Figure), weight increased by 1.88 kg (CI -19–22, p-value = 0.41), LCI decreased by 4.7 (CI -14-5, p-value = 0.15), and sweat chloride decreased only by 4.25 (CI -12–6, p-value = 0.21), after 4-8 weeks.

Conclusions: Despite the controversial in vitro results from the literature, and despite no substantial change in sweat chloride values, significant clinical improvement was shown immediately in all five patients heterozygous for the N1303K and a second non-responding mutation, treated with ELX/TEZ/IVA. Consequently, these findings may support the opportunity for ELX/TEZ/IVA treatment for people carrying the N1303K mutation. Further randomized control clinical trials are required in order to confirm our results.

Acknowledgements:

References: [1] Keating D, Marigowda G, Burr L, et al. VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N Engl J Med 2018; 379:1612-1620. DOI: 10.1056/NEJMoa1807120

[2] Middleton PG, Mall MA, Dřevínek P, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med 2019; 381:1809-1819. DOI: 10.1056/NEJMoa1908639

[3] Heijerman HJM, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet. 2019 November 23; 394(10212): 1940–1948. doi:10.1016/S0140-6736(19)32597-8

[4] TRIKAFTA prescribing information. [cited 2022 Jan 14]; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212273s004lbl.pdf

[5] Laselva O, Bartlett C, Gunawardena TNA, et al. Rescue of multiple class II CFTR mutations by elexacaftor+tezacaftor+ivacaftor mediated in part by the dual activities of elexacaftor as both corrector and potentiator. Eur Respir J. 2021 Jun 17;57(6):2002774. doi: 10.1183/13993003.02774-2020