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.
BACKGROUND: Pheochromocytoma and paraganglioma are neoplasms originating in the adrenal medulla and extraadrenal paraganglia, respectively. Most cases of metastatic pheochromocytoma and paraganglioma are driven by dysregulation of the hypoxia-inducible factor 2α (HIF-2α) pathway. Belzutifan is a HIF-2α inhibitor that may provide antitumor activity in patients with advanced pheochromocytoma or paraganglioma. METHODS: We conducted a phase 2, international, single-group trial involving 72 participants with locally advanced or metastatic pheochromocytoma or paraganglioma that was not amenable to surgery or curative-intent treatment. Participants received belzutifan at a dose of 120 mg once daily until the occurrence of progression, unacceptable toxic effects, or withdrawal from the trial. The primary end point was confirmed objective response (complete or partial response) as assessed by blinded independent central review. Secondary and other key end points included the duration of response, disease control, progression-free survival as assessed by blinded independent central review, overall survival, safety, and a reduction from baseline in antihypertensive medication. RESULTS: At a median follow-up of 30.2 months (range, 23.3 to 37.6), the percentage of participants with a confirmed objective response was 26% (95% confidence interval [CI], 17 to 38) and the percentage of participants with disease control was 85% (95% CI, 74 to 92). The median duration of response was 20.4 months (95% CI, 8.3 to not reached), with a median duration of progression-free survival of 22.3 months (95% CI, 13.8 to not reached). Overall survival was 76% at 24 months. Among the 60 participants who were receiving antihypertensive medications, 19 (32%) had a reduction of at least 50% in the total daily dose of at least one antihypertensive medication for at least 6 months after starting treatment with belzutifan. Treatment-related adverse events occurred in 71 participants (99%); anemia of grade 3 was noted in 22% of the participants. Eight participants (11%) had treatment-related serious adverse events. CONCLUSIONS: Belzutifan showed antitumor activity with durable responses in participants with advanced pheochromocytoma or paraganglioma. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-015 ClinicalTrials.gov number, NCT04924075.).
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.
Leptin, a hormone primarily secreted by adipocytes, regulates energy balance and systemic metabolism through its interaction with the leptin receptor (LEPR). Beyond these functions, leptin signaling has been implicated in the pathogenesis of tissue fibrosis. Here, we report the x-ray crystal structures of a leptin-neutralizing antibody (hLep3) in the unbound and leptin-bound states. The interaction of this antibody with leptin mimics the interaction of the LEPR with leptin, providing direct insights into the mechanism by which the antibody disrupts leptin signaling. We furthermore evaluate the therapeutic potential of neutralizing leptin with this antibody across distinct mouse models of fibrosis affecting the kidney, liver, lung, heart, and blood vessels. Leptin neutralization markedly inhibited fibrosis progression in all models. Mechanistically, suppression of leptin activity reduces pro-inflammatory and profibrotic processes, underscoring its therapeutic potential. These findings suggest that leptin signaling plays a vital role in tissue fibrosis and that treatment with a leptin-neutralizing antibody may be a promising therapeutic approach.
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.
Current guidelines recommend FIB-4 and transient elastography for non-invasive risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD). These tests can predict the presence or absence of advanced fibrosis, but their accuracy for identifying significant fibrosis in MASLD patients eligible for novel drug treatments remains unclear. In a multicenter cohort of 458 biopsy-proven MASLD patients, we evaluated the suitability of FIB-4 for identifying MASLD with histologically significant fibrosis (≥ F2). In a subcohort of 291 patients, we further assessed the diagnostic performance of the guideline-based sequential use of FIB-4 and transient elastography. We demonstrate that the recommended risk stratification remains suboptimal for the identification of patients with significant fibrosis, resulting in remarkably high false-positive and false-negative rates for FIB-4 (43% and 26%, respectively). Consequently, guideline-based risk stratification may misclassify a significant proportion of patients, leading to inappropriate treatment decisions regarding novel MASLD therapies approved for F2/F3 fibrosis.