Cystic fibrosis is a devastating genetic disorder involving mutations in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Patients with cystic fibrosis have mutations in both genes that code for the CFTR protein channel. Without a functional CFTR protein channel, anion transport is compromised across multiple organ systems. There are several CFTR modulators which improve the production and function of the CFTR channels. These therapies are effective for patients with two copies of the Phe508del mutated gene. Patients with one copy of the Phe508del mutated gene and another minimal-function mutation do not respond well to standard corrector/potentiator treatment. The objective of this study is to evaluate the safety and efficacy of elexacaftor–tezacaftor–ivacaftor in patients with one Phe508del mutation and one minimal-function mutation.
Four hundred and three participants aged twelve years and older with an FEV1 from 40-90% were enrolled in this phase 3, double-blinded, randomized, placebo-controlled trial. Two hundred participants received the elexacaftor–tezacaftor–ivacaftor treatment regimen, and two hundred three participants received placebo for 24 weeks. Participants were stratified based on FEV1, age, and gender to negate factors that could influence prognosis, and groups were similar at baseline. The primary endpoint was the absolute percent change in FEV1 from baseline to week 4, which is a direct indicator of pulmonary function and disease prognosis. Seventy participants were required to achieve 98% power in detecting a 5.0-point difference in FEV1 at a significance level of 0.044. Secondary endpoints included changes in other disease and quality of life measurements over 24 weeks, such as sweat chloride concentration, Cystic Fibrosis Questionnaire–Revised (CFQ-R), body-mass index (BMI), and pulmonary exacerbations.
Preliminary analysis of the primary endpoint at week 4 showed promising results for the triple therapy combination, and this success was sustained through week 24. The absolute change from baseline comparing the treatment arm to the placebo arm at weeks 4 and 24 was 13.8 (P<0.001) and 14.3 (P<0.001), respectively. This change represents statistically and clinically significant improvement in lung function in all participants in the treatment arm, regardless of mutation type. Participants in the treatment arm experienced lower rates of pulmonary exacerbations. Sweat chloride concentrations, which inversely correlates with CFTR functionality, were lower in the treatment arm as compared to placebo, suggesting more functional CFTR protein is produced. The CFQ-R respiratory domain, BMI, and all other secondary endpoints showed improvement in the treatment arm.
Safety endpoints were similar between treatment arms, with many patients experiencing symptoms common to cystic fibrosis. Adverse events occurred in 93.1% and 96.0% in the treatment and placebo arms, respectively. The majority of events were mild or moderate, with serious events occurring in 13.9% and 20.9% of patients in the treatment and placebo arms, respectively. Other adverse events included rash, elevated transaminases, elevated creatinine kinase, and elevated blood pressure. Two patients, both in the treatment group, withdrew from the study due to rash and portal hypertension. Overall, the safety profile was tolerable and consistent with other CFTR modulators.
Elexacaftor–tezacaftor–ivacaftor demonstrated unprecedented efficacy for cystic fibrosis patients with heterozygous Phe508del and minimal-function mutations. This treatment fulfills a substantial unmet medical need in cystic fibrosis communities with no additional safety signals.
Reference: Middleton PG, Mall MA, Dřevínek P et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019 Nov 7;381(19):1809-1819.
Cystic fibrosis (CF) is a genetic condition characterized by a defect in a protein within the body. Individuals with cystic fibrosis possess a faulty protein that impacts the cells, tissues, and glands responsible for producing mucus and sweat. Under normal circumstances, mucus serves as a protective lubricant for the airways, digestive tract and various other organs and tissues. However, in those with cystic fibrosis, the mucus becomes thick and adhesive. As a result, the buildup of mucus can lead to blockages, tissue damage and susceptibility to infections in the affected organs. Historically, cystic fibrosis has posed a significant threat of mortality in childhood. However, advancements in medical research and technology have led to substantial improvements in survival rates. Currently, there are approximately 40,000 individuals living with cystic fibrosis in the United States and over 100,000 worldwide.
As briefly mentioned, cystic fibrosis is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes the CFTR protein. Individuals who inherit two mutated copies of the CFTR gene (one from each parent) will develop cystic fibrosis. In those with a mutated CFTR gene, the function of a protein responsible for regulating salt movement in and out of the cells is altered. Consequently, this leads to the production of thick and sticky mucus and an increase in salt levels in sweat. The abnormal, thick mucus causes blockages and damage to the lungs, digestive system and other organs. Furthermore, under normal circumstances, mucus coats hairlike structures called cilia in the airway of the lungs. These cilia aid in sweeping mucus particles upward toward the nose and mouth for elimination from the body. However, this process is also disrupted in those with cystic fibrosis. The manifestation of symptoms in individuals with cystic fibrosis varies. Symptoms are often contingent upon the organs affected and the severity of the condition. While some individuals may exhibit minimal or no symptoms, others may endure more severe symptoms or face life-threatening complications. Symptoms may fluctuate in intensity over time, with periods of improvement and exacerbation. Most prevalently, cystic fibrosis affects the lungs. Therefore, one of the most telling signs of cystic fibrosis include wheezing and a cough that may produce mucus or blood. However, other symptoms include but are not limited to clubbing of fingers and toes, fever, jaundice, low BMI, pancreatitis, salty skin, and delayed puberty.
Treatment for the management of cystic fibrosis treatment often includes management of symptoms of the disease. CFTR modulators are one of the most common drugs of choice in this condition. These modulators enhance the functionality of defective CFTR proteins, thereby aiding lung function and mitigating the risk of lung-related issues or other complications. The selection of a CFTR modulator medication depends upon the specific CFTR gene mutation present in an individual. Prior to initiating therapy, the healthcare provider will often conduct genetic testing to assess the likelihood of therapeutic efficacy. Currently, there are several CFTR modulator therapies that have been approved for use in the treatment of cystic fibrosis. One of the most common drugs is a triple combination therapy with elexacaftor-tezacaftor-ivacaftor, which also happens to be the first approved treatment and may help up to 90% of people with cystic fibrosis. At present, it is approved for the use in individuals who are at least 2 years of age, encompassing both adults and children, who possess specific CFTR gene mutations.
Another drug currently being tested in randomized controlled trials for use in the treatment of cystic fibrosis is vanzacaftor-tezacaftor-deutivacaftor (VTD). Since Trikafta has already demonstrated safety and efficacy in individuals with cystic fibrosis, the objective of this study was to discover a new combination of CFTR modulators that could enhance CFTR-mediated chloride transport even more, potentially allowing for once-daily administration. Two phase 2 clinical trials have already been conducted, evaluating the safety and efficacy of this once-daily combination. The first trial consisted of a randomized, double-blind, active-controlled study comparing deutivacaftor monotherapy with ivacaftor monotherapy. Following the 4-week monotherapy period, participants were then randomly assigned to ivacaftor 150 mg every 12 hours, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. Part two of the trial consisted of a randomized, double-blind, controlled, proof-of-concept study involving participants with cystic fibrosis and were randomized in a 1:2:2:1 ratio to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor/deutivacaftor or a triple placebo for 4 weeks. The primary endpoints for both part 1 and 2 were safety and tolerability and the absolute change in ppFEV1 from baseline to day 29. In part two of the study, participants treated with vanzacaftor (5 mg)–tezacaftor–deutivacaftor, vanzacaftor (10 mg)–tezacaftor–deutivacaftor, vanzacaftor (20 mg)–tezacaftor–deutivacaftor, and placebo exhibited mean changes relative to baseline at day 29 in ppFEV1 of 4.6 percentage points (−1.3 to 10.6), 14.2 percentage points (10.0 to 18.4), 9.8 percentage points (5.7 to 13.8), and 1.9 percentage points (−4.1 to 8.0), respectively. Additionally, the sweat chloride concentration changes were −42.8 mmol/L (–51.7 to –34.0), −45.8 mmol/L (95% CI –51.9 to –39.7), −49.5 mmol/L (–55.9 to –43.1), and 2.3 mmol/L (−7.0 to 11.6), respectively. Thus, these results support the idea that once-daily administration of vanzacaftor-tezacaftor-deutivacaftor demonstrated safety and good tolerability while enhancing lung function, alleviating respiratory symptoms and enhancing CFTR function. These findings also encourage further exploration of this triple therapy in phase 3 clinical trials.
Resources:
Uluer A, MacGregor G, Azevedo P, Indihar V, Keating C, Mall M. Safety and efficacy of vanzacaftor–tezacaftor–deutivacaftor in adults with cystic fibrosis: randomised, double-blind, controlled, phase 2 trials. The Lancet . February 23, 2023. Accessed May 3, 2024. https://www.thelancet.com/article/S2213-2600(22)00504-5/fulltext.
Savant A, Lyman B, Bojanowski C, et al. Cystic Fibrosis. 2001 Mar 26 [Updated 2023 Mar 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1250/
What is cystic fibrosis? National Heart Lung and Blood Institute. November 21, 2023. Accessed May 2, 2024. https://www.nhlbi.nih.gov/health/cystic-fibrosis.