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Current and future CFTR therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Marne C. Hagemeijer, Gimano D. Amatngalim, Jeffrey M. Beekman
Clearly, opportunities for the development of better corrector compounds exist. Indeed several pharmaceutical companies are developing novel CFTR correctors. Tezacaftor (VX-661, Vertex Pharmaceuticals) is a novel oral corrector compound that acts on F508del-CFTR and intended for combination therapy with ivacaftor. The chemical structure of tezacaftor is depicted in Figure 14.5b. Mono- or combination therapy of tezacaftor in F508del homozygous or F508del/G551D CF subjects demonstrated that tezacaftor does not induce CYP3A activity (which will be discussed in the next section) and was well absorbed, with steady-state levels of the drug detected after approximately 2 weeks (97). Recent phase III clinical trial results demonstrated that a combination therapy of tezacaftor and ivacaftor in CF subjects with a single copy or two copies of the 508del-CFTR mutation resulted in a significant improvement in lung function (98). Galapagos NV together with AbbVie have various correctors and potentiators in their clinical portfolio. GLPG2222 (GLPG2222/ABBV-2222) is a promising type 1 (early) corrector currently in clinical development. The compound itself was well tolerated as an oral suspension in healthy volunteers and CF subjects with at least one F508del-CFTR allele and readily absorbed in the body, with a mean apparent elimination half-life of 12 hours and steady-state levels being obtained within 2 days. The pharmacokinetic data supports a once daily dosing regimen and, in contrast to lumacaftor but similar to tezacaftor, GLPG2222 does not induce CYP3A activation (99,100). Another corrector currently in clinical development is FDL169 from Flatley Discovery Lab. When compared to lumacaftor, this compound demonstrated similar efficacy and potency in primary F508del-CFTR HBECs (101,102) but it was present at higher levels in the lungs of rats when compared to lumacaftor after treatment (102,103). In contrast to lumacaftor, FDL169 does not bind as much to human serum proteins, and CFTR corrected in CF-HBE cells by FDL169 were less affected by ivacaftor-induced decrease of CFTR correction (see “Potentiating the open probability of the channel”) (102). Phase I clinical trials with FDL169 have been completed. Proteostasis Therapeutics has an investigational CFTR corrector called PTI-801 in development. This compound is similar to FDL169 and can also prevent F508del-CFTR instability due to ivacaftor treatment and was able to complement other CFTR modulators in an in vitro setting (74).
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)
Development of elexacaftor – tezacaftor – ivacaftor: Highly effective CFTR modulation for the majority of people with Cystic Fibrosis
Published in Expert Review of Respiratory Medicine, 2021
Peter G Middleton, Jennifer L. Taylor-Cousar
The major metabolite of elexacaftor, M23-elexacaftor, circulates in plasma with levels of ~35 to 50% of the parent compound. As M23 has a similar potency to elexacaftor, it is considered pharmacologically active. Tezacaftor has three major circulating metabolites in humans, M1-tezacaftor, M2-tezacaftor and M5-tezacaftor. M1-tezacaftor has a similar potency to that of tezacaftor and is considered pharmacologically active. M2-tezacaftor is much less pharmacologically active and M5-tezacaftor is not considered pharmacologically active. Ivacaftor has two major circulating metabolites in humans, M1-ivacaftor and M6-ivacaftor. M1-ivacaftor has around one-sixth of the potency of ivacaftor and is considered pharmacologically active. M6-ivacaftor is not considered pharmacologically active.
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.
Emerging pharmacotherapies in cystic fibrosis
Published in Expert Review of Respiratory Medicine, 2018
Oliver J McElvaney, Cedric Gunaratnam, Oisin Fiachra McElvaney, Isha Bagwe, Emer P Reeves, Noel G McElvaney
A recent addition to the CFTR corrector area is tezacaftor (VX-661), which has been approved for use in combination with ivacaftor in PWCF aged 12 years and older who are homozygous for F508del or who have at least one CFTR mutation that is responsive based on in vitro data or clinical evidence. As for lumacaftor, tezacaftor monotherapy has been shown to modestly reduce sweat chloride concentration in randomized, double-blinded, placebo-controlled phase II studies when compared to placebo, without significant increases in FEV1 in either F508del homozygotes or F508del/G551D patients [26,33]. Once again, greater improvement was observed in those receiving combination therapy with ivacaftor, which achieved a mean absolute change in FEV1 of 4.8% versus placebo for homozygotes, and 4.6% in F508del/G551D. The adverse event profile for tezacaftor appears favorable in comparison to placebo.