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Gene Therapy and Small Molecules Used in the Treatment of Cystic Fibrosis
Published in Yashwant Pathak, Gene Delivery, 2022
Manish P. Patel, Uma G. Daryai, Mansi N. Athalye, Praful D. Bharadia, Jayvadan Patel
Correctors improve CFTR folding either by direct binding or by adapting protein homeostasis (Mijnders, Kleizen, and Braakman, 2017). This modulator corrects the misfolded CFTR protein, thereby restoring it to its original three-dimensional form. Thus, it accelerates the functioning of the CFTR protein through its movement toward the cell surface (Almughem et al., 2020). These also increase gating and conductance. The first two correctors identified by high-throughput screening of a small-molecule library were bis-aminomethylbithiazole C4 (Corr-4a) and quinazolinole C3 (VRT-325) (Mijnders, Kleizen, and Braakman, 2017). VX-809 (Lumacaftor) is the first corrector to undergo extensive trials (Shanthikumar and Massie, 2017). It is used to correct the F508del mutation, the most common type of CF mutation. This helps avoid the ER-mediated degradation of the CFTR macromolecule by enhancing the interaction between the NBD1, MSD1, and MSD2 domains (Almughem et al., 2020). VX-661 is considered to be an improved VX-809 analog. The correctors, VX-440, VX-152, and VX-659, are also studied in clinical trials (Mijnders, Kleizen, and Braakman, 2017). Correctors GLPG2222 and GLPG2851 (C1) are additive to GLPG2737 and GLPG3221 (C2) and may be combined in therapy. GLPG2222 have structural similarities with VX-809 and VX-661 but is known to be more potent. Combinations of C1, C2, and a potentiator developed by Galapagos/ AbbVie significantly increase chloride transport over Orkambi (VX-809 and VX-770) in vitro (Mijnders, Kleizen, and Braakman, 2017). Corrector modulators are usually used in combination with potentiator modulators in CF treatment. Examples are the FDA-approved Orkambi® (lumacaftor combined with ivacaftor) and Symdeko™ (tezacaftor combined with ivacaftor) (Almughem et al., 2020). The tezacaftor/ivacaftor combination has been shown to have fewer side effects, such as chest tightness and drug interactions, than lumacaftor/ivacaftor (Cystic Fibrosis Foundation ) Tezacaftor, in combination with Lumacaftor and Ivacaftor, have shown a promising moderate improvement (Fiore et al., 2019). On October 21 2019, the US Food and Drug Administration approved a new triple-combination therapy (elexacaftor/tezacaftor/ivacaftor), including two correctors and one potentiator combination, for individuals with CF who are aged 12 years and older and have at least one allele with the F508del mutation (2019 PATIENT REGISTRY ANNUAL DATA REPORT, 2021). The efficacy of Trikafta in patients with cystic fibrosis aged 12 years and older was manifested in two trials. The first trial consisted of a 24-weeks randomized, double-blind, placebo-controlled trial done on 403 patients who had an F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein which is not responsive to ivacaftor or tezacaftor/ivacaftor alone. The second trial was a 4-weeks randomized, double-blind, active-controlled trial with 107 patients who had two identical F508del mutations (U.S. Food & Drug Administration, 2019)
Managing cystic fibrosis in children aged 6-11yrs: a critical review of elexacaftor/tezacaftor/ivacaftor combination therapy
Published in Expert Review of Respiratory Medicine, 2023
Kamyron D. Jordan, Edith T. Zemanick, Jennifer L. Taylor-Cousar, Jordana E. Hoppe
In healthy volunteers, the pharmacokinetics (PK) of elexacaftor, tezacaftor and ivacaftor were similar to those with cystic fibrosis. Drug exposures and time to steady state were also found to be similar in adolescents (12–17 years) and adults (18 years and older) [41]. Elexacaftor and ivacaftor concentration is increased in the setting of food (moderate fat) by 1.9-to 2.5-fold (elexacaftor) and 2.5-to 4-fold (ivacaftor) [40]. Therefore, it is recommended that CFTR modulators be dosed with fat containing foods and pancreatic enzymes (in those who are pancreatic insufficient). Elexacaftor, tezacaftor, and ivacaftor maximum concentrations are reached in 6, 3, and 4 hours after dosing, respectively. Steady state for the medication components is obtained within 14 (elexacaftor, dosed daily), 8 (tezacaftor, dosed daily) and 3.5 (ivacaftor, dosed twice a day) days [41].
Emerging medicines to improve the basic defect in cystic fibrosis
Published in Expert Opinion on Emerging Drugs, 2022
Isabelle Fajac, Isabelle Sermet-Gaudelus
The next breakthrough came from a triple combination associating a new corrector called elexacaftor to tezacaftor and ivacaftor (Table 1). Phase II and phase III placebo-controlled trials showed that this orally administered triple combination was well tolerated and a gain of 13% in FEV1 after 4 weeks of treatment was observed in patients with only one F508del mutation and another mutation on the other allele leading to no functional CFTR protein [28,29]. Elexacaftor combined with tezacaftor and ivacaftor is approved for patients bearing at least one F508del mutation and aged 6 years and older in the US and in EU. Similarly to what happened with ivacaftor and based on in vitro data, the FDA expanded the list of rare mutations that were approved for treatment with elexacaftor, tezacaftor, and ivacaftor.
Pediatric respiratory medicine
Published in Canadian Journal of Respiratory, Critical Care, and Sleep Medicine, 2021
Tamizan Kherani, Sze Man Tse, Martha L. McKinney
Publication of the phase three trials for the triple combination modulator elexacaftor/tezacaftor/ivacaftor was the major event of 2019, and advances in cystic fibrosis transmembrane regulator (CFTR) modulator therapies continued in 2020. A trial of ivacaftor in infants aged 4 to < 12 months confirmed that it is safe in these very young children, and even showed a signal for improvement in pancreatic function in some subjects.15 Other trials included a phase three trial of ivacaftor-tezacaftor in children ages 6-11 years with two F508del or one F508del and one residual function mutation, extending the age groups studied for this combination.16 An open-label phase three extension study for the triple combination of elexacaftor/tezacaftor/ivacaftor showed a similar safety profile to the initial study and persistence of the positive effects on outcomes including FEV1 and pulmonary exacerbation out to >24 weeks.17 At the end of 2020, elexacaftor/tezacaftor/ivacaftor was submitted for Health Canada approval.