Daily Endocrinology Research Analysis
Analyzed 29 papers and selected 3 impactful papers.
Summary
Analyzed 29 papers and selected 3 impactful articles.
Selected Articles
1. Efficacy and safety of inclisiran in adolescents with heterozygous familial hypercholesterolaemia (ORION-16): a two-part, randomised, multicentre clinical trial.
In a two-part, phase 3 RCT of 141 adolescents with HeFH on maximally tolerated statins, inclisiran reduced LDL-C by 27.1% versus 1.4% with placebo at day 330 (between-group difference -28.5%, p<0.0001) and maintained a mean -33.7% reduction at day 720. Safety was favorable with only mild injection site reactions and no treatment-related serious adverse events.
Impact: This is the first rigorous randomized trial demonstrating sustained LDL-C lowering with inclisiran in adolescents with HeFH, filling a key evidence gap in pediatric lipid management with an infrequent dosing regimen.
Clinical Implications: Inclisiran can be considered as an add-on for adolescents with HeFH inadequately controlled on statins ± other agents, offering substantial LDL-C reductions with twice-yearly maintenance dosing and a favorable safety profile.
Key Findings
- At day 330, LDL-C decreased by -27.1% with inclisiran vs 1.4% with placebo; between-group difference -28.5% (95% CI -35.8 to -21.3; p<0.0001).
- Mean LDL-C reduction sustained to day 720 at -33.7% (SD 24.0).
- Safety profile was favorable with mild injection-site reactions and no treatment-related serious adverse events or deaths.
Methodological Strengths
- Multicentre, randomized, double-blind design in Part 1 with objective biochemical endpoint.
- International enrollment across 26 countries and sustained follow-up to 2 years.
Limitations
- Part 2 was open-label and the trial assessed surrogate endpoints (LDL-C) rather than hard cardiovascular outcomes.
- Predominantly White cohort (91%) may limit generalizability; pediatric patients <12 years were not studied.
Future Directions: Prospective studies should evaluate long-term cardiovascular outcomes, adherence/quality-of-life impacts of infrequent dosing, and effectiveness across diverse populations including younger children.
BACKGROUND: Inclisiran, a small interfering RNA targeting hepatic PCSK9, was previously studied in various adult patient populations, but it has not yet been assessed in paediatric patients with heterozygous familial hypercholesterolaemia (HeFH), a genetic disorder characterised by elevated LDL cholesterol. The ORION-16 study aimed to evaluate the efficacy and safety of inclisiran treatment in adolescents with HeFH. METHODS: ORION-16 was a two-part (1-year double-blind, 1-year open-label), randomised, phase 3 trial at 51 sites across 26 countries. In Part 1, adolescents (aged 12 to <18 years) with HeFH and elevated LDL cholesterol on maximally tolerated statin treatment with or without other lipid-lowering therapy were randomly assigned 2:1 (via interactive response technology) to either inclisiran sodium 300 mg subcutaneously or placebo (administered on days 1, 90, and 270); in Part 2, all patients received inclisiran (days 360 [only patients previously assigned to receive placebo], 450, and 630). The primary endpoint was the percentage change in LDL cholesterol from baseline to day 330, assessed in all randomly assigned patients. Safety was assessed in all patients who received at least one dose of study drug. Endpoints in Part 2 were analysed in all patients who entered and received at least one dose of study drug in Part 2. ORION-16 is registered at ClinicalTrials.gov (NCT04652726) and is completed. FINDINGS: Between Feb 17, 2021, and Dec 14, 2022, 141 patients were randomly assigned (93 to inclisiran, 48 to placebo; median age 15·1 years [IQR 13·4-16·8]; 75 [53%] female; 128 [91%] White). In Part 1, the least squares mean percentage change in LDL cholesterol from baseline to day 330 was -27·1% in the inclisiran group and 1·4% in the placebo group, with a between-group difference of -28·5% (95% CI -35·8 to -21·3; p<0·0001). In Part 2, at day 720, a mean percentage change in LDL cholesterol from baseline of -33·7% (SD 24·0) was observed. Inclisiran was well tolerated, with a safety profile comparable to studies in adults. Injection site reactions were more frequent with inclisiran (15 [16%] of 93 patients) than with placebo (three [6%] of 48) in Part 1 (13 [9%] of 139 in Part 2); all were mild and did not lead to study drug discontinuation. There were no treatment-related serious adverse events, and no deaths during the study. INTERPRETATION: In adolescents with HeFH, inclisiran was effective in lowering LDL cholesterol, with sustained efficacy over 2 years, and was well tolerated. These results support inclisiran as a potentially useful addition for the treatment of adolescents with HeFH, providing an infrequent dosing regimen. FUNDING: Novartis Pharma.
2. Efficacy and safety of sepiapterin versus sapropterin in patients with phenylketonuria: Results from the Phase 3, randomized, crossover, open-label, active-controlled AMPLIPHY trial.
In the AMPLIPHY phase 3 randomized crossover trial in PKU, sepiapterin achieved a greater reduction in blood phenylalanine than sapropterin (least-squares mean difference -180.4 μmol/L; p<0.0001), corresponding to a 70% relative advantage. Both treatments were well tolerated without new safety signals.
Impact: This head-to-head phase 3 trial provides definitive comparative efficacy data, positioning sepiapterin as a potentially superior BH4 pathway therapy for PKU responders.
Clinical Implications: For PKU patients who respond to BH4 pathway modulation, sepiapterin may deliver greater Phe lowering than sapropterin; implementation will require consideration of responder enrichment and real-world monitoring of diet, neurocognition, and safety.
Key Findings
- Sepiapterin reduced blood Phe by -437.0 μmol/L vs -256.6 μmol/L with sapropterin; difference -180.4 μmol/L (95% CI -229.5 to -131.4; p<0.0001).
- Responder enrichment in Part 1: 81.7% achieved ≥20% Phe reduction; 75.6% achieved ≥30%.
- Both treatments were well tolerated with no new safety signals across children and adults.
Methodological Strengths
- Randomized crossover design with objective biochemical endpoint and active comparator.
- International, phase 3 framework enhances external validity within responder population.
Limitations
- Open-label design may introduce expectation bias; treatment periods were short (4 weeks) and focused on biochemical endpoints.
- Responder-enriched population limits generalizability to all PKU patients; potential carryover effects despite 14-day washout cannot be fully excluded.
Future Directions: Evaluate long-term clinical outcomes (neurocognition, dietary liberalization), durability of response, and head-to-head cost-effectiveness, alongside broader eligibility beyond responder-enriched cohorts.
AIM: AMPLIPHY is the first Phase 3 study comparing sepiapterin versus sapropterin in children and adults with phenylketonuria (PKU). METHODS: AMPLIPHY was an international, Phase 3, two-part, open-label study in participants with PKU aged ≥2 years. Participants responsive to sepiapterin (60 mg/kg/day) in Part 1 (≥20% reduction in blood phenylalanine [Phe]) entered Part 2, a crossover treatment period, and were randomized 1:1 to alternative treatment sequences of sepiapterin (60 mg/kg/day, licensed dosage) and sapropterin (20 mg/kg/day, maximum licensed dosage) for 4 weeks each, with a 14-day washout between treatments. The primary endpoint was mean change in blood Phe from baseline to Weeks 3-4 of each treatment period (Part 2). RESULTS: Of 82 participants enrolled, 67 (81.7%) and 62 (75.6%) had reductions in blood Phe ≥20% and ≥ 30%, respectively, in Part 1. Sixty-two participants were randomized in Part 2 (mean [SD] age, 15.8 [10.8] years). In the primary analysis set (≥30% reduction in blood Phe in Part 1, n = 58), mean (SD) baseline blood Phe before sepiapterin and sapropterin treatment was 725.8 (302.1) and 790.4 (370.0) μmol/L, respectively. Least-squares mean (SE) reduction in blood Phe from baseline was -437.0 (28.0) and - 256.6 (28.2) μmol/L, respectively, representing a least-squares mean difference of -180.4 μmol/L (95% CI: -229.5, -131.4; p < 0.0001) and a relative 70% greater reduction with sepiapterin versus sapropterin. Both treatments were well tolerated, with safety profiles consistent with previous reports. CONCLUSIONS: Sepiapterin was superior to the highest approved dose of sapropterin in lowering blood Phe. No new safety signals were observed. The trial was registered in the UK Clinical Study Registry, ISRCTN, on January 29, 2024 (ID number, ISRCTN79102999; https://www.isrctn.com/ISRCTN79102999).
3. Diagnostic Accuracy of Non-Invasive Tests for MASLD Across Age, Type 2 Diabetes, and Obesity Subgroups: A Multinational Study.
In 18,759 biopsy-confirmed MASLD patients from 41 countries, Agile-3+ (AUC 0.86) and LSM (AUC 0.83) outperformed FIB-4 (AUC 0.79), whose accuracy declined with age and T2D. Subgroup-specific thresholds, including BMI-adjusted LSM cutoffs (e.g., 8.8 kPa in lean vs 11.0 kPa in morbid obesity), can improve advanced fibrosis detection.
Impact: This unprecedented, biopsy-anchored multinational analysis provides actionable, subgroup-specific thresholds for widely used NITs, addressing known heterogeneity and informing precision risk stratification in MASLD.
Clinical Implications: Adopt age-adjusted FIB-4 thresholds and BMI-adjusted LSM cutoffs; use imaging-based or composite NITs (LSM, Agile-3+) preferentially in older adults, those with T2D, and patients with obesity to maintain diagnostic accuracy.
Key Findings
- Pooled AUCs for advanced fibrosis: FIB-4 0.79, LSM 0.83, Agile-3+ 0.86.
- FIB-4 accuracy declined in adults ≥65 years (AUC 0.70) and in middle-aged patients with T2D.
- BMI-specific LSM cutoffs (sensitivity 80%): 8.8 kPa (lean), 9.0 (overweight), 9.6 (obesity), 11.0 (morbid obesity).
Methodological Strengths
- Very large, multinational cohort with biopsy-confirmed reference standard.
- Systematic subgroup analyses and derivation of tailored diagnostic thresholds.
Limitations
- Cross-sectional diagnostic design without prospective validation of clinical outcomes.
- Potential selection and spectrum biases inherent in biopsy-based cohorts; external validation of derived cutoffs is needed.
Future Directions: Prospectively validate subgroup-specific thresholds in diverse care settings and assess impact on referral pathways, cost-effectiveness, and patient outcomes.
BACKGROUND & AIMS: Non-invasive tests (NITs) are widely used to risk-stratify patients with metabolic dysfunction-associated steatotic liver disease (MASLD); however, their performance may vary according to patient characteristics. We evaluated the accuracy of NITs in a large, multinational MASLD cohort across select subpopulations. METHODS: We analyzed 18,759 adults with biopsy-confirmed MASLD from 41 countries. NITs included FIB-4, liver stiffness measurement (LSM), and Agile-3+. Diagnostic performance for advanced fibrosis (F3-F4) was measured using AUCs across subgroups defined by age, sex, type 2 diabetes (T2D), obesity, and alcohol use. Subgroup-specific cutoffs were derived. RESULTS: Advanced fibrosis was present in 37% of patients. Pooled AUCs were 0.79 for FIB-4, 0.83 for LSM, and 0.86 for Agile-3+. FIB-4 accuracy declined with age (AUC 0.70 in ≥65 years vs. 0.79 in <65 years, p<0.0001) and in middle-aged patients with T2D. The LSM performance remained stable across T2D status but was moderately reduced in patients with obesity and, more profoundly, morbid obesity (BMI >35). Sex and alcohol use had minimal impact on AUCs. Age- and T2D-specific FIB-4 cutoffs varied substantially to maintain predefined accuracy (sensitivity or specificity). The cutoffs for LSM also differed based on patients' BMI, with lower diagnostic cutoffs for advanced fibrosis required in non-obese MASLD (sensitivity 80%: 8.8 kPa in lean, 9.0 kPa overweight, 9.6 kPa in obesity, 11.0 kPa in morbid obesity). CONCLUSIONS: Accuracy of non-invasive tests for advanced fibrosis in MASLD is influenced by age, T2D, and obesity. Age-adjusted FIB-4 thresholds may enhance risk stratification. Imaging-based and composite NITs (LSM and Agile-3+) provide more consistent performance across MASLD subpopulations.