Daily Endocrinology Research Analysis
Analyzed 29 papers and selected 3 impactful papers.
Summary
Three high-impact studies in endocrinology and metabolic medicine stood out: a pediatric phase 3 RCT showing inclisiran safely and durably lowers LDL-C in adolescents with HeFH; a phase 3 randomized crossover trial demonstrating sepiapterin’s superiority over sapropterin in reducing blood phenylalanine in PKU; and a multinational biopsy-confirmed MASLD analysis defining subgroup-specific performance and cutoffs for non-invasive fibrosis tests. Together, they advance treatment options and sharpen risk stratification across diverse patient populations.
Research Themes
- Pediatric lipid-lowering therapies and adherence-friendly dosing
- Targeted metabolic therapy for inborn errors (PKU)
- Risk stratification in MASLD using non-invasive diagnostics
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, multinational RCT, inclisiran produced a 28.5% greater reduction in LDL-C versus placebo at day 330 in adolescents with HeFH and maintained approximately 33.7% mean reduction at 2 years. The safety profile was favorable with mostly mild injection site reactions and no treatment-related serious adverse events.
Impact: This is the first robust randomized evidence of PCSK9-targeted siRNA therapy in adolescents with HeFH, demonstrating clinically meaningful LDL-C lowering with infrequent dosing. It is poised to inform pediatric lipid management and potentially guideline updates.
Clinical Implications: Inclisiran can be considered as an adjunct to maximally tolerated statin therapy in adolescents with HeFH who require additional LDL-C lowering, offering twice-yearly dosing that may enhance adherence.
Key Findings
- Least-squares mean LDL-C change at day 330: −27.1% (inclisiran) vs 1.4% (placebo); between-group difference −28.5% (95% CI −35.8 to −21.3; p<0.0001).
- Sustained efficacy: mean LDL-C change from baseline −33.7% at day 720 (2 years).
- Safety: Injection site reactions were mild and more frequent with inclisiran; no treatment-related serious adverse events or deaths.
- Global, multicenter pediatric RCT across 26 countries with 141 randomized adolescents.
Methodological Strengths
- Two-part randomized design with a double-blind, placebo-controlled year followed by open-label extension.
- Prespecified primary endpoint with multicenter, multinational enrollment.
Limitations
- Predominantly White population (91%), potentially limiting generalizability.
- Surrogate endpoint (LDL-C) without cardiovascular outcome assessment.
Future Directions: Evaluate long-term cardiovascular outcomes, cost-effectiveness, and effectiveness in more diverse pediatric populations and real-world adherence contexts.
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 first head-to-head phase 3 randomized crossover trial in PKU, sepiapterin reduced blood phenylalanine significantly more than sapropterin (−437 vs −256.6 μmol/L; difference −180.4 μmol/L; p<0.0001) over 4-week treatment periods. Both agents were well tolerated, with no new safety signals.
Impact: Demonstrates superiority of a next-generation BH4 precursor (sepiapterin) over the current standard (sapropterin) with robust randomized evidence, potentially shifting PKU pharmacotherapy.
Clinical Implications: Sepiapterin may be preferred over sapropterin for responsive patients, enabling greater Phe reduction and potential dietary flexibility, pending regulatory availability and long-term outcomes.
Key Findings
- Primary analysis (n=58): sepiapterin reduced blood Phe by −437.0 μmol/L vs −256.6 μmol/L with sapropterin; least-squares mean difference −180.4 μmol/L (95% CI −229.5 to −131.4; p<0.0001).
- High responder rate in Part 1: 81.7% achieved ≥20% Phe reduction and 75.6% achieved ≥30%.
- Randomized 1:1 crossover with 4-week treatment periods and 14-day washout minimized carryover.
- Safety profiles were favorable for both treatments with no new safety signals.
Methodological Strengths
- Randomized crossover active-controlled design enabling within-patient comparison.
- International multicenter phase 3 trial with objective biochemical endpoints.
Limitations
- Open-label design may introduce performance bias despite objective endpoints.
- Short 4-week treatment periods limit assessment of long-term efficacy, diet liberalization, and neurocognitive outcomes.
- Part 2 included sepiapterin responders, potentially limiting generalizability.
Future Directions: Longer blinded trials comparing clinical, dietary, and neurocognitive outcomes; head-to-head cost-effectiveness; and evaluation across broader PKU genotypes and age ranges.
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 across 41 countries, FIB-4, LSM, and Agile-3+ had pooled AUCs of 0.79, 0.83, and 0.86 for advanced fibrosis. FIB-4 performance declined with age and in T2D, while LSM was affected by obesity; subgroup-specific thresholds improved diagnostic balance.
Impact: Provides definitive, globally generalizable evidence for tailoring non-invasive fibrosis assessments in MASLD, addressing age-, T2D-, and BMI-related variability at an unprecedented scale.
Clinical Implications: Use age-adjusted FIB-4 thresholds and BMI-adjusted LSM cutoffs; consider imaging-based/composite tools (LSM, Agile-3+) for more consistent performance across subgroups to reduce misclassification and unnecessary biopsies.
Key Findings
- Pooled AUCs for advanced fibrosis: FIB-4 0.79, LSM 0.83, Agile-3+ 0.86.
- FIB-4 accuracy declined with age (AUC 0.70 in ≥65 vs 0.79 in <65; p<0.0001) and in middle-aged T2D.
- LSM performance was stable across T2D but decreased with obesity, most notably BMI >35.
- Subgroup-specific cutoffs: LSM sensitivity 80% thresholds differed by BMI (e.g., 8.8 kPa lean, 11.0 kPa morbid obesity).
Methodological Strengths
- Very large, multinational cohort with biopsy-confirmed MASLD across 41 countries.
- Direct subgroup analyses with derivation of tailored diagnostic thresholds.
Limitations
- Cross-sectional diagnostic design; lacks prospective outcome validation.
- Potential device and protocol heterogeneity for LSM across centers.
- Residual confounding and spectrum effects may influence subgroup AUCs.
Future Directions: Prospective validation of subgroup-specific cutoffs and integration into clinical pathways to assess impact on biopsy rates, treatment decisions, and 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.