Combination Of Ivacaftor Research Articles

Restoring CFTR function with Orkambi decreases the severity of alcohol-induced acute pancreatitis.

Heavy alcohol intake is one of the most common causes of acute pancreatitis (AP). We have previously shown that ethanol (EtOH) decreases the expression and activity of the cystic fibrosis transmembrane conductance regulator (CFTR), which plays a key role in alcohol-induced AP development. The prescription drug, Orkambi (a combination of ivacaftor and lumacaftor) can correct impaired CFTR function and expression in cystic fibrosis (CF) patients. Thus, the present study aimed to investigate whether Orkambi can mitigate alcohol-induced AP. Intact guinea-pig pancreatic ducts were pre-treated with different concentrations of ethanol (EtOH; 30, 50 and 100mm) for 12h alone or in combination with ivacaftor (VX770) and/or lumacaftor (VX-809), and CFTR expression and activity were evaluated by immunostaining and by the patch clamp technique, respectively. Alcoholic AP was induced in Orkambi-treated guinea-pigs, and standard laboratory and histological parameters were measured. Ivacaftor and lumacaftor alone or in combination dose-dependently restored the apical expression and activity of CFTR after EtOH treatment in vitro. Oral administration of Orkambi reduced the severity of alcohol-induced AP and restored impaired CFTR activity and expression. Orkambi is able to restore the CFTR defect caused by EtOH and decreases the severity of alcohol-induced pancreatitis. This is the first in vivo pre-clinical evidence of Orkambi efficacy in the treatment of alcohol-induced AP. KEY POINTS: Acute pancreatitis is one of the leading causes of hospital admission among gastrointestinal diseases in which the lack of a specific drug therapy plays a crucial role. The cystic fibrosis transmembrane conductance regulator (CFTR) plays an essential role in pancreatic ductal HCO3 - secretion; inappropriate CFTR function, as seen in heavy alcohol consumption, increases the risk of pancreatitis development. CFTR modulators are able to prevent the inhibitory effect of ethanol and reduce pancreatic ductal injury and the severity of alcohol-induced pancreatitis. CFTR modulators present a novel option in the pharmacotherapy of alcohol-induced pancreatitis by enhancing pancreatic functions or preventing recurrence.

Personalized assessment of the effectiveness of targeted drugs for the treatment of cystic fibrosis in a patient with c.264_268delATATT and c.3139+1G>C rare variants of the <i>CFTR</i> gene

BACKGROUND: When new, most often rare CFTR gene variants, are detected in patients with cystic fibrosis, intestinal organoids are used, which allows for the assessment of the residual functional activity of the CFTR channel and the effect of targeted drugs to determine the possibility of further pathogenetic therapy. Clinical trials of the effectiveness of the targeted drugs in patients with rare CFTR variants are expensive, and patient groups are extremely small. A forskolin-induced swelling assay on a patient’s intestinal organoids allows for a personalized approach when studying rare or even single CFTR variants. AIM: To examine the effect of the CFTR potentiator ivacaftor and the combination of ivacaftor with the CFTR correctors lumacaftor, tezacaftor, and elexacaftor on the restoration of CFTR channel functions on a culture of intestinal organoids obtained from a patient with two rare CFTR variants c.264_268delATATT and c.3139+1GC. MATERIALS AND METHODS: To assess the activity of the CFTR channel, the forskolin-induced swelling assay on organoids and intestinal current measurements on rectal biopsy samples method were used. The clinical picture of a patient with the c.264_268delATATT/c.3139+1GC genotype was described. RESULTS: In vitro, the genetic variants c.264_268delATATT and c.3139+1GC lead to a complete loss of the functional CFTR protein, whereas CFTR modulators do not positively affect and do not lead to the restoration of CFTR function, in contrast from F508del/F508del control. The disease severity in a child is consistent with the results of functional tests. CONCLUSION: Both CFTR variants are classified as “severe” and cause a complete loss of chloride channel activity. No effective CFTR modulators were found for the c.264_268delATATT and c.3139+1GC variants; thus, targeted therapy cannot be recommended to the patient.

Воспроизведенная комбинация модуляторов белка CFTR — ивакафтора и лумакафтора. Этические и фармакокинетические аспекты

The lack of effective and affordable therapies for rare diseases is an important ethical issue. One example is cystic fibrosis (CF), a chronic, progressive disease characterized by an impaired function of all exocrine glands. The combination of ivacaftor and lumacaftor (CFTR potentiator and corrector) should lead to a sufficient level of protein on the cell surface and to an increase in its activity, thereby correcting the impaired function. Development of a generic drug containing ivacaftor and lumacaftor as active pharmaceutical substances will increase the availability of this medication and improve patient survival. To study comparative pharmacokinetics and bioequivalence of drugs containing ivacaftor and lumacaftor in healthy volunteers. It was conducted as an open-label, randomized, crossover bioequivalence study involving a single intake of the drug during each period under fed condition in healthy male and female volunteers. The conclusion about bioequivalence was made if 90% confidence interval for primary pharmacokinetic parameters (Cmax, AUC0-t) fell within the accepted bioequivalence limits of 80–125%. According to the results of the study, it was shown that the values of 90% CI of the geometric mean of the main pharmacokinetic parameters for ivacaftor and lumacaftor fall within the acceptance limits for bioequivalence. According to the applied criteria, the drugs are bioequivalent, which makes it possible to recommend the investigational drug to the Ministry of Health of the Russian Federation for obtaining the registration status.

Using generic drug elexacaftor/tezacaftor/ivacaftor+ ivacaftor in patients with cystic fidosis in routine clinical practice

Cystic fibrosis (CF) is a multisystem disease of exocrine glands with a progressive course. In recent years, targeted (pathogenetic) treatment aimed at correcting the function of the chloride channel has come to the fore in addition to the symptomatic therapy. The greatest effectiveness was demonstrated with the use of the triple combination of the drug elexacaftor (ELX) / tezacaftor (TEZ) / ivacaftor (IVA) + IVA – Trikafta® (Vertex Pharmaceuticals, USA) that has become the “gold standard” of targeted therapy. Currently, there is virtually no information about the effectiveness and safety of the generic products. The aim of the study was to evaluate the efficacy and safety of the generic drug ELX/TEZ/IVA+IVA (Trilexa®) (Tutor S.A.S.I.F.I.A., Buenos Aires, Argentina) in adult patients with CF in real clinical practice.Methods. The 6-month study included patients (n = 11) aged 18 to 46 years with a diagnosis of CF who were prescribed pathogenetic treatment with ELX/TEZ/IVA+IVA. Their external respiration function (forced vital capacity, forced expiratory volume in 1 second), conductivity of sweat fluid electrolytes (sweat test), anthropometric and other clinical and functional data were analyzed. Results. This study demonstrated pronounced positive effects in relation to indicators of respiratory function, sweat test, and nutritional status. The ELX/TEZ/IVA+IVA treatment was well tolerated, with clinical improvement in the form of a decrease in cough intensity, sputum volume, improvement in daily exercise tolerance, height, and body weight. No serious adverse events were recorded and none of the patients discontinued treatment due to adverse reactions.Conclusion. Obvious clinical and functional positive dynamics and safety over 6 months were demonstrated with ELX/TEZ/IVA+IVA combination.

EPS3.01 Analysis of synthetic derivatives with reduced lipophilicity as candidate potentiators towards better treatment alternatives for cystic fibrosis

Objectives: KALYDECO (ivacaftor/VX-770), a potentiator that enhances channel gating of wild-type cystic fibrosis transmembrane conductance regulator (CFTR) protein and certain CFTR gating mutants was first approved to treat Cystic Fibrosis (CF). Thereafter, Orkambi, a combination of ivacaftor and the trafficking corrector lumacaftor was approved for patients with homozygous F508del mutation. Unfortunately, ORKAMBI mediates modest and variable clinical responses which relates to a negative impact of VX-770 on the metabolic stability of F508del-CFTR. VX-770 was also shown to exert a negative effect on the stability of other membrane solute carriers. The destabilizing effect of VX-770 also correlated with its predicted lipophilicity, suggesting the need for discovery and optimization of efficacious potentiators to maximize the clinical benefit in CF.

Impact of highly effective CFTR modulator therapy on digital clubbing in patients with cystic fibrosis

BackgroundThe association of certain disease processes with digital clubbing is well documented. Digital clubbing is often reversible after successful treatment of the underlying pathology, for example, after lung transplantation in patients with cystic fibrosis (CF). We examined the effect of highly effective Cystic Fibrosis Transmembrane Regulator (CFTR) modulators, defined for the purposes of this study as ivacaftor or the combination of ivacaftor, tezacaftor, and elexacaftor (ETI), on digital clubbing. Materials and MethodsClubbing index was measured on plaster of Paris casts of right index fingers obtained from 15 patients with cystic fibrosis, before and after initiation of CFTR modulator therapy. Similar measurements were made on casts for 9 cystic fibrosis patients who underwent lung transplantation. Measurements were made on the most recent casts available before treatment and the first cast available at least 3 months after initiation of treatment. The Wilcoxon signed-rank text was used to detect any significant difference in the pre- and post-treatment casts for each individual. ResultsA significant decrease in the clubbing index was found after both lung transplantation and treatment with highly effective CFTR modulator therapy. ConclusionsThese results add to the body of evidence demonstrating the efficacy of highly effective CFTR modulator therapy, the first agents that act directly at the dysfunctional chloride channel responsible for CF. By demonstrating that CFTR modulator therapy is capable of reversing digital clubbing, this study suggests a beneficial effect on lung pathology aside from air flow and gas transfer.

WS01.4 VX-661 in combination with ivacaftor in patients with cystic fibrosis and the F508del-CFTR mutation

Background The F508del and G551D mutations affect CFTR in different ways. VX-661 increases the quantity of functional F508del-CFTR at the cell surface, and ivacaftor (IVA) increases CFTR gating; effects are additive in vitro. Methods This randomized, double-blind, placebo-controlled, multi-cohort, phase 2 study evaluated escalating doses of VX-661 alone and in combination with IVA (150 mg q12h) in F508del/F508del patients, or the addition of VX-661 (100 mg qd) to F508del/G551D patients on prescribed IVA. Primary outcomes were safety and change in sweat chloride through Day 28. Percent predicted FEV 1 (ppFEV 1 ) was a secondary endpoint. Results The reported cohorts included 128 patients homozygous for F508del and 18 with F508del/G551D . In patients homozygous for F508del, at Day 28, VX-661 monotherapy resulted in reductions in sweat chloride but non-significant increases in ppFEV 1 , whereas VX-661/IVA decreased sweat chloride 5.7 mmol/L ( P 1 4.8 absolute points (P = 0.01 vs placebo; n=15). In F508del/G551D patients, through Day 28, VX-661/IVA led to a mean reduction in sweat chloride of 7.0 mmol/L ( P = 0.053; n=13) and significant within-group changes in absolute ppFEV 1 (4.6 points, P = 0.012; n=14). The overall incidence of AEs in VX-661/IVA-treated patients was similar across treatment groups and was comparable to placebo; the most common events were pulmonary exacerbation, cough, headache, nausea, and increased sputum. Conclusion These data show that the VX-661/IVA combination may benefit patients with CF who are homozygous for F508del and may enhance the benefit of IVA in CF patients with F508del/G551D.