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An oral, fixed-dose coformulation of sodium phenylbutyrate and ursodoxicoltaurine (ALBRIOZA™; hereafter denoted sodium phenylbutyrate/ursodoxicoltaurine) is being developed by Amylyx Pharmaceuticals for the treatment of neurodegenerative diseases. In June 2022, the coformulation received its first approval with conditions in Canada for the treatment of amyotrophic lateral sclerosis (ALS) in adults. The approval was based on results from the multicentre, phase II CENTAUR trial, in which slowing of ALS progression was demonstrated with sodium phenylbutyrate/ursodoxicoltaurine relative to placebo. This article summarizes the milestones in the development of sodium phenylbutyrate/ursodoxicoltaurine leading to this first approval. [ABSTRACT FROM AUTHOR]

Background: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators improve nutritional status and are of importance in achieving normal growth among younger children with CF. The study was designed to examine CFTR modulator-associated changes in nutrition status, including bile acids and fatty acids after lumacaftor/ivacaftor therapy for 24 weeks., Methods: Children 2 to 5.9 years were recruited from US and Canadian CF Centers. Eligible children were lumacaftor/ivacaftor naïve and approved to initiate therapy. Anthropometrics, diet, energy expenditure, nutrition biomarkers, pancreatic status, serum and fecal calprotectin, serum bile acids and plasma fatty acids were measured. Changes from baseline at 12 and 24 weeks were examined using mixed effects linear regression modeling., Results: Weight-for-age z-score (WAZ) increased at 12 (0.15 ± 0.1, p = 0.01) and 24 weeks (0.23 ± 0.1, p = 0.001) from baseline following modulator therapy. Head circumference-for-age (HCZ) increased at 12 weeks compared to baseline (0.22 ± 0.1, p = 0.03) and subscapular Z score increased from baseline at 24 weeks following therapy (0.33 ± 0.1, p = 0.02). There were no changes in energy expenditure. Serum total bile acids (6.7 ± 2.0, p = 0.001), chenodeoxycholic acid (CDCA) (2.4 ± 1.1, p = 0.001), and cholic acid (CA) (3.5 ± 0.8, p < 0.0001) increased at 24 weeks compared to baseline. Fecal calprotectin decreased at 12 and 24 weeks compared to baseline (-463 ± 310, p = 0.03 and 566 ± 347, p = 0.047). A number of plasma fatty acids changed over the course of 24 weeks of therapy. Noteably, alpha-linolenic acid (ALA) decreased at 12 and 24 weeks (-24 ± 10,p = 0.03 and -18 ± 10, p = 0.02, respectively)., Conclusions: Overall, young children experienced favorable changes in nutritional and growth, with the exception of plasma ALA status in the first 24 weeks of lumacaftor/ivacaftor therapy., Competing Interests: Declaration of competing interest All authors disclose they have no conflicts of interest related to this project and manuscript. The funding sources had no role in study design, analysis or drafting of the manuscript., (Copyright © 2024. Published by Elsevier B.V.)

Background: Highly effective CFTR modulators improve nutritional status and are of particular importance among younger children experiencing rapid growth. This study was designed to examine CFTR modulator associated changes in nutritional and other extrapulmonary outcomes in children 4-24 months of age with ivacaftor treatment over 12 weeks., Methods: Children 4-24 months were recruited from US and Canadian CF Centers. Eligible children were ivacaftor naïve and approved to start therapy. Anthropometrics, diet, sleeping energy expenditure (SEE), nutrition biomarkers, pancreatic status, serum and fecal calprotectin, serum bile acids, plasma fatty acids were measured. Changes from baseline at 6 and 12 weeks were examined using mixed effects linear regression modeling., Results: Fifteen participants enrolled (40% male). Weight-for-age z-scores increased at 6 (p = 0.03) and 12 weeks ivacaftor therapy (p<0.001) compared to baseline. Plasma docosatetraenoic acid (DTA), total saturated fatty acids increased at 6 weeks (p = 0.02) and 12 weeks (p = 0.009). At 12 weeks, serum CO 2 concentration decreased (p = 0.002), serum urea nitrogen increased (p = 0.01) and fecal elastase increased (p = 0.02) compared to baseline. Bile acids, deoxycholic acid increased (p = 0.03) and ursodeoxycholic acid decreased (p = 0.02) after 12 weeks. Plasma total fatty acids, palmitic acid, mead, and docosatetraenoic acid (DTA) increased after 12 weeks (p = 0.02, p = 0.002 and p = 0.04, respectively). Plasma total saturated fatty acids increased at 6 weeks (p = 0.02) and 12 weeks (p = 0.009). Dietary intake (p = 0.04) and percent kcal from protein (p = 0.04) increased after 12 weeks compared to baseline., Conclusions: Overall, younger children experienced favorable changes in nutritional and growth status in the first 12 weeks of ivacaftor therapy., Competing Interests: Declaration of Competing Interest All authors disclose they have no conflicts of interest related to this project and manuscript. The funding sources had no role in study design, analysis or drafting of the manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Background: With increased rates of obesity and insulin resistance in youth, development of postprandial dyslipidemia, an important cardiovascular disease risk factor, is a concern. Glucagon-like peptides (ie, GLP-1 and GLP-2) and bile acids have been shown to regulate dietary fat absorption and postprandial lipids in animal models and humans. We hypothesize that the physiological response of GLPs and bile acids to dietary fat ingestion is impaired in adolescents with obesity and this associates with marked postprandial dyslipidemia and insulin resistance., Methods: In this cross-sectional study, normal weight adolescents and adolescents with obesity underwent a 6-hour oral fat tolerance test. The postprandial lipoprotein phenotype profile was determined using various assays, including nuclear magnetic resonance spectroscopy, to characterize lipoprotein particle number, size, lipid content, and apolipoproteins. GLP-1 and GLP-2 were quantified by electrochemiluminescent immunoassays. Total bile acids were measured by an automated enzymatic cycling colorimetric method and the bile acid profile by mass spectrometry., Results: Adolescents with obesity exhibited fasting and postprandial dyslipidemia, particularly augmented postprandial excursion of large triglyceride-rich lipoproteins. Postprandial GLPs were reduced and inversely correlated with postprandial dyslipidemia and insulin resistance. Postprandial bile acids were also diminished, particularly lithocholic acid, a potent stimulator of GLP-1 secretion., Conclusion: Blunted postprandial GLP and bile acid response to dietary fat ingestion strongly associates with marked postprandial dyslipidemia. Further investigation is needed to assess their potential utility as early biomarkers for postprandial dyslipidemia in adolescents with obesity., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)