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.
Nutritional issues in patients with cystic fibrosis (CF)
Children and adolescents with CF frequently have growth failure caused by the combination of malabsorption, increased energy needs, and reduced appetite. Nutrient delivery and correction of maldigestion and malabsorption are essential to achieve normal growth to support optimal pulmonary function and prolong life.
The CF Foundation patient registry has documented substantial improvement in life expectancy of patients with CF in the past 20 years. To a large degree, the longer life achieved by patients with CF can be ascribed to improved treatment of lung disease, pulmonary toilet, potent and tailored antibiotics, dornase alfa (DNase), lung transplantation, and early diagnosis via newborn screening. However, greater emphasis on CF nutrition is considered important to improve longevity and quality of life.
The advent of CF transmembrane conductance regulator (CFTR) modulators has substantially changed the outlook for patients with CF lung disease. Modulator therapy has also altered growth and nutrition statistics and it is likely that they will have an effect on growth and nutrition, but the full impact of these potent drugs is yet to be determined.
Insufficient production of pancreatic enzymes causes malabsorption of fat, protein, and several micronutrients including the vitamins A, D, E, and K. Malabsorption of fat is exacerbated by bile salt abnormalities if there is concurrent intestinal or liver disease. Across all age groups, approximately 90 percent of patients with CF have marked pancreatic insufficiency.
All patients with CF should be screened for pancreatic insufficiency; this is generally done with fecal elastase testing. Those with normal results should be retested annually and more frequently if there is diminished growth, poor weight gain, or abnormal stools to monitor for development of pancreatic insufficiency. Patients with pancreatic insufficiency (as determined by fecal elastase testing or other measure) should be treated with pancreatic enzyme replacement therapy (PERT).
Pancreatic enzymes are extracts of porcine pancreas containing varying amounts of lipase, protease, and amylase. PERT clearly improves fecal fat absorption in most patients with pancreatic insufficiency. This was demonstrated by a double-blind, placebo-controlled trial in pediatric and adult patients with severe pancreatic insufficiency, in which PERT decreased fecal fat excretion (45.4 versus 4.1 g/day) and increased the coefficient of fat absorption, as well as decreased stool frequency. PERT is not indicated for patients with pancreatic sufficiency, as determined by normal fecal elastase or fecal fat testing and no clinical evidence of malabsorption. In particular, patients with one or two CFTR gene mutations known to be associated with pancreatic sufficiency should not be given PERT unless there is clear evidence of fat malabsorption. Since pancreatic insufficiency may develop over time, these patients should be evaluated at every visit for clinical symptoms of fat malabsorption and also monitored with periodic measurements of fecal elastase and fat-soluble vitamins.
Dosing is generally estimated by the patient's weight and adjusted depending on the patient's response and symptoms. Suppression of gastric acid may improve the efficiency of PERT in selected patients, but this practice is based on limited evidence and must be balanced against potential adverse effects of the acid-suppressing medications. Prolonged contact of the enzyme supplements with oral mucosa may cause ulcers and should be avoided. PERT doses should be limited to 2500 lipase units/kg body weight per meal to avoid fibrosing colonopathy.
Nutritional issues in CF are common and are not fully explained by pancreatic insufficiency or overcome by pancreatic enzyme replacement therapy. Although pancreatic dysfunction is the major gastrointestinal contributor to malnutrition in CF, several other factors may contribute to the problem. These include CF-related liver disease (CFLD), bile salt abnormalities, CF-related diabetes mellitus, altered gastrointestinal motility, intestinal dysbiosis, and small bowel bacterial overgrowth. Gastroesophageal reflux, distal intestinal obstructive syndrome, and constipation can also negatively affect nutrition. Early recognition and intensive treatment of undernutrition in patients with CF can minimize the damaging effects of malnutrition on lung disease, longevity, and quality of life.
References:
Baker, R. D., et al. (2023, February 16). Cystic fibrosis: Nutritional issues. UpToDate. Retrieved from uptodate.com/contents/cystic-fibrosis-nutritional-issues?search=cystic%20fibrosis&source=search_result&selectedTitle=6~150&usage_type=default&display_rank=6#H31
Cystic Fibrosis Foundation. 2021 Patient Registry: Annual Data Report. Available at: https://www.cff.org/sites/default/files/2021-11/Patient-Registry-Annual-Data-Report.pdf
Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for pediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2002; 35:246.
Bass R, Brownell JN, Stallings VA. The Impact of Highly Effective CFTR Modulators on Growth and Nutrition Status. Nutrients 2021; 13.
Riordan JR, Rommens JM, Kerem B, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245:1066.
Hayden HS, Eng A, Pope CE, et al. Fecal dysbiosis in infants with cystic fibrosis is associated with early linear growth failure. Nat Med 2020; 26:215.