A Precision Medicine Approach to Optimize Modulator Therapy for Rare CFTR Folding Mutants

Abstract

Trikafta, a triple-combination drug, consisting of folding correctors VX-661 (tezacaftor), VX-445 (elexacaftor) and the gating potentiator VX-770 (ivacaftor) provided unprecedented clinical benefits for patients with the most common cystic fibrosis (CF) mutation, F508del. Trikafta indications were recently expanded to additional 177 mutations in the CF transmembrane conductance regulator (CFTR). To minimize life-long pharmacological and financial burden of drug administration, if possible, we determined the necessary and sufficient modulator combination that can achieve maximal benefit in preclinical setting for selected mutants. To this end, the biochemical and functional rescue of single corrector-responsive rare mutants were investigated in a bronchial epithelial cell line and patient-derived human primary nasal epithelia (HNE), respectively. The plasma membrane density of P67L-, L206W- or S549R-CFTR corrected by VX-661 or other type I correctors was moderately increased by VX-445. Short-circuit current measurements of HNE, however, uncovered that correction comparable to Trikafta was achieved for S549R-CFTR by VX-661 + VX-770 and for P67L- and L206W-CFTR by the VX-661 + VX-445 combination. Thus, introduction of a third modulator may not provide additional benefit for patients with a subset of rare CFTR missense mutations. These results also underscore that HNE, as a precision medicine model, enable the optimization of mutation-specific modulator combinations to maximize their efficacy and minimize life-long drug exposure of CF patients.

Targeting the E1 ubiquitin-activating enzyme (UBA1) improves elexacaftor/tezacaftor/ivacaftor efficacy towards F508del and rare misfolded CFTR mutants

“…We therefore transiently transfected eight different mutants into CFBE41o- cells, comparing the rescue induced by correctors alone or in combination with TAK-243. We considered four mutants (L206W, R347P, S492F, and M1101K) for which the FDA recently approved Trikafta treatment [ 10 ] (Fig. 6 A) and four mutants (N1303K, R334W, R560T, R1066C) not included in that approval (Fig.…”

“…7 ). This result once again shows how the cellular environment is crucial in predicting the response to a molecule, and that promising results obtained with CFBE41o- cells are not a guarantee of compound efficacy and should also be reproduced on patients’ cells [ 10 ].…”

“…In terms of its efficacy on other mutants displaying defective maturation and trafficking to the plasma membrane, pre-clinical results on primary cells show a highly variable response to Trikafta treatment, and it is more effective in improving CFTR-mediated current with some mutants such as M1101K and less with others, including N1303K [ 8 , 9 ], the most frequent class II mutant after F508del. The FDA recently agreed to extend the use of Trikafta to almost 200 different mutations which showed an increase in chloride transport to at least 10% of normal over baseline when expressed in Fisher rat thyroid cells and treated with the VX-445/VX-661/VX-770 combination [ 10 ]. It is worth noting that N1303K, as well as many other class II CFTR mutations, has not been included in this list.…”

Molecular dynamics and functional characterization of I37R-CFTR lasso mutation provide insights into channel gating activity

“…This is the first study to interrogate the potentiator action of VX-445 in intestinal organoids; however, previous studies have been performed in donor-derived bronchial and nasal epithelial cells and immortalized cell lines. The higher correction efficacy of VX-445 when compared with VX-809/VX-661 has previously been shown, although this is likely to be dependent on the CFTR variant ( Keating et al., 2018 ; Veit et al., 2020 , 2021b ). For instance, direct binding of VX-445 to NBD1 to stabilize and prevent the domain unfolding may make it more effective in correcting CFTR mutations that impact NBD1 function (such as F508del located in NBD1).…”

A year in review: Real world evidence, functional monitoring and emerging therapeutics in 2021

“…These preclinical studies suggest clinical benefit in patients with the above-mentioned mutations [20] , [21] , [22] . Conversely, in vitro results of some rare missense mutations show no additional effect on the adding of ELE, suggesting there will be no clinical benefit to the addition of ELE to tezacaftor-ivacaftor (TEZ-IVA) [23] . These studies support the use of in vitro models as a precision model, to predict the most beneficial combination of modulators for rare mutations and support the role of in vitro testing for clinical approval of modulators.…”