Daily Endocrinology Research Analysis
A phase 2 NEJM trial shows the HIF-2α inhibitor belzutifan yields durable tumor control in advanced pheochromocytoma/paraganglioma. Basic research in Science Advances identifies leptin signaling as a cross-organ driver of fibrosis and demonstrates therapeutic efficacy of a leptin-neutralizing antibody in multiple mouse models. A multicenter cohort in Liver International finds guideline-endorsed FIB-4 (± transient elastography) misclassifies many MASLD patients with significant fibrosis, challeng
Summary
A phase 2 NEJM trial shows the HIF-2α inhibitor belzutifan yields durable tumor control in advanced pheochromocytoma/paraganglioma. Basic research in Science Advances identifies leptin signaling as a cross-organ driver of fibrosis and demonstrates therapeutic efficacy of a leptin-neutralizing antibody in multiple mouse models. A multicenter cohort in Liver International finds guideline-endorsed FIB-4 (± transient elastography) misclassifies many MASLD patients with significant fibrosis, challenging current selection for new antifibrotic therapies.
Research Themes
- Targeted therapies for endocrine neoplasms
- Hormone signaling as a driver and target in fibrosis
- Optimizing noninvasive fibrosis stratification in MASLD
Selected Articles
1. Belzutifan for Advanced Pheochromocytoma or Paraganglioma.
In an international phase 2 single-arm trial of 72 patients with advanced PPGL, belzutifan achieved a 26% confirmed objective response and 85% disease control, with median PFS of 22.3 months. Hypertension burden lessened in one-third of treated patients, while grade 3 anemia occurred in 22%.
Impact: This study provides high-quality prospective evidence supporting HIF-2α inhibition in PPGL, a rare endocrine cancer with limited options, and demonstrates durable clinical benefit.
Clinical Implications: Belzutifan may become a targeted option for unresectable/metastatic PPGL, potentially reducing catecholamine-driven hypertension and improving disease control. Patient selection and anemia management are critical.
Key Findings
- Confirmed objective response rate: 26% (95% CI 17–38)
- Disease control rate: 85% (95% CI 74–92)
- Median progression-free survival: 22.3 months (95% CI 13.8 to not reached)
- 32% of patients reduced antihypertensive dose by ≥50% for ≥6 months
- Grade 3 anemia in 22%; treatment-related serious adverse events in 11%
Methodological Strengths
- Blinded independent central review for efficacy endpoints
- International multicenter design with prespecified outcomes
Limitations
- Single-group, nonrandomized design limits causal inference
- High incidence of treatment-related adverse events (notably anemia)
Future Directions: Conduct randomized comparisons versus standard care or MIBG/chemotherapy, identify predictive biomarkers of HIF-2 pathway dependence, and optimize toxicity management strategies.
2. Leptin as a key driver for organ fibrogenesis.
Structural biology reveals how a leptin-neutralizing antibody (hLep3) mimics receptor binding to disrupt signaling. In multiple mouse models (kidney, liver, lung, heart, vasculature), leptin neutralization consistently reduced fibrosis by dampening pro-inflammatory and profibrotic pathways.
Impact: This work positions leptin as a core endocrine driver of multiorgan fibrosis and provides a directly translatable biologic with structural validation, potentially reshaping antifibrotic strategies.
Clinical Implications: Leptin-neutralizing biologics could emerge as a class-wide antifibrotic therapy across organs, but human safety, metabolic consequences (e.g., weight/appetite changes), and dosing windows require careful evaluation.
Key Findings
- X-ray crystal structures of hLep3 in unbound and leptin-bound states elucidate a LEPR-mimicking binding mode.
- Leptin neutralization reduced fibrosis progression in mouse models across kidney, liver, lung, heart, and vessels.
- Mechanistic readouts showed reductions in pro-inflammatory and profibrotic processes upon leptin blockade.
Methodological Strengths
- Integration of structural biology with in vivo efficacy across multiple organ systems
- Consistent mechanistic signaling readouts supporting antifibrotic effects
Limitations
- Preclinical mouse models; human translatability and safety remain untested
- Potential metabolic side effects of leptin blockade not addressed in depth
Future Directions: Advance to first-in-human studies with careful metabolic monitoring; explore combination with standard antifibrotics and define biomarkers of leptin-driven fibrogenesis.
3. Limitations of Guideline-Recommended Risk Stratification in Identifying MASLD Patients for Novel Drug Treatments.
In 458 biopsy-proven MASLD patients, FIB-4 misclassified many with histologically significant fibrosis (≥F2), yielding 43% false positives and 26% false negatives. Sequential FIB-4 plus transient elastography remained suboptimal, challenging current guideline pathways for selecting candidates for new MASLD drugs.
Impact: The study directly interrogates guideline algorithms against biopsy gold standards and reveals substantial misclassification at the decision threshold for new approved therapies.
Clinical Implications: Clinicians should avoid relying on FIB-4 (± transient elastography) alone for treatment eligibility and consider confirmatory testing (e.g., imaging elastography thresholds refinement, serum panels, or biopsy) before initiating F2/F3-indicated therapies.
Key Findings
- In 458 biopsy-proven MASLD patients, FIB-4 showed high misclassification for ≥F2: false positives 43%, false negatives 26%.
- Sequential guideline algorithm (FIB-4 then transient elastography, n=291) remained suboptimal for identifying significant fibrosis.
- Guideline-based stratification risks inappropriate inclusion/exclusion for F2/F3-approved MASLD therapies.
Methodological Strengths
- Biopsy-proven reference standard across a multicenter cohort
- Evaluation of both standalone FIB-4 and sequential guideline algorithm
Limitations
- Abstract lacks detailed performance metrics for transient elastography and thresholds used
- Potential referral/spectrum bias in biopsy-proven cohorts
Future Directions: Develop and externally validate integrated models (e.g., machine learning, combinatorial biomarkers) to minimize misclassification and define cost-effective diagnostic pathways for therapy eligibility.