Daily Endocrinology Research Analysis
Three impactful endocrinology studies stood out today: a global phase 2b trial of an insulin receptor antibody (ersodetug/RZ358) markedly reduced hypoglycemia in congenital hyperinsulinism; a prospective trial of immune checkpoint inhibitors in aggressive pituitary neuroendocrine tumors identified MMR deficiency and temozolomide-induced hypermutation as biomarkers of response; and a nationwide cohort linked impaired glycemic status to higher future risk of acromegaly. These works advance therapy
Summary
Three impactful endocrinology studies stood out today: a global phase 2b trial of an insulin receptor antibody (ersodetug/RZ358) markedly reduced hypoglycemia in congenital hyperinsulinism; a prospective trial of immune checkpoint inhibitors in aggressive pituitary neuroendocrine tumors identified MMR deficiency and temozolomide-induced hypermutation as biomarkers of response; and a nationwide cohort linked impaired glycemic status to higher future risk of acromegaly. These works advance therapy, biomarker-driven oncology, and population-level risk stratification.
Research Themes
- Novel endocrine therapeutics and receptor pharmacology in hypoglycemia disorders
- Biomarker-driven immunotherapy in pituitary neuroendocrine tumors
- Metabolic dysregulation as a risk factor for endocrine neoplasia
Selected Articles
1. Global, multi-center, repeat-dose, phase 2 study of RZ358 (ersodetug), an insulin receptor antibody, for congenital hyperinsulinism.
In a global open-label phase 2b study (n=23), add-on ersodetug produced dose-proportional PK, no dose-limiting toxicities, and marked reductions in hypoglycemia events (median −59%) and time in hypoglycemia (median −54%), with 48–84% event reductions at 6–9 mg/kg. Improvements extended to overnight hypoglycemia, with near-universal response.
Impact: This first-in-class INSR-targeting antibody demonstrates clinically meaningful hypoglycemia reduction in congenital hyperinsulinism, addressing a major unmet need across genotypes.
Clinical Implications: Ersodetug could become a genotype-agnostic therapy for cHI, potentially reducing reliance on pancreatectomy or off-label agents and improving safety of glycemic control, including overnight periods.
Key Findings
- Median reductions from baseline: hypoglycemia events −59% (p<0.001) and time in hypoglycemia −54% (p<0.001) across pooled doses.
- At 6–9 mg/kg, hypoglycemia events decreased by 48%–84% and time in hypoglycemia by 61%–65% (p<0.05).
- Predictable, dose-proportional pharmacokinetics with no deaths, adverse drug reactions, withdrawals, or dose-limiting toxicities.
Methodological Strengths
- Global, multi-center design with standardized CGM and SMBG endpoints
- Clear dose-ranging with pharmacokinetic characterization and consistent efficacy signals
Limitations
- Open-label, nonrandomized design without a control arm
- Short 8-week treatment period limits long-term safety and durability assessment
Future Directions: Randomized controlled trials with longer follow-up to evaluate durability, safety, genotype-specific responses, and combination strategies with existing cHI therapies.
2. Immune Checkpoint Inhibitor Therapy for Aggressive Pituitary Neuroendocrine Tumors.
A prospective phase 2 trial in aggressive PitNETs found no objective responses to ipilimumab+nivolumab but observed tumor shrinkage in 2/9 evaluable patients and demonstrated feasibility and safety. Biomarker analyses implicated mismatch repair deficiency and temozolomide-induced hypermutation as predictors of immune response, with evidence of immunoediting post-therapy.
Impact: This study establishes feasibility of ICI in PitNETs and identifies mechanistically plausible biomarkers (MMRd and temozolomide hypermutation), laying groundwork for precision immunotherapy in endocrine oncology.
Clinical Implications: Patients with aggressive PitNETs harboring MMR deficiency or temozolomide-induced hypermutation may derive benefit from checkpoint blockade; routine biomarker testing could guide referral for ICI.
Key Findings
- No objective responses by iRANO; 2/9 evaluable patients had tumor shrinkage on ipilimumab+nivolumab.
- Mismatch repair deficiency and temozolomide-induced hypermutation associated with immunological response.
- Immunoediting observed post-ICI (loss of MMRd and/or decreased tumor mutational burden).
Methodological Strengths
- Prospective phase 2 design with predefined response criteria (iRANO)
- Integrated translational biomarker analysis including pre/post sequencing
Limitations
- Small, single-center cohort limits statistical power
- No objective responses; clinical benefit signals require confirmation
Future Directions: Multicenter trials enriching for MMRd/temozolomide-hypermutated PitNETs, exploration of combination regimens, and standardized biomarker testing pathways.
3. Association between glycaemic status and the risk of acromegaly: a nationwide population-based cohort study.
In 9.7 million adults followed for a median of 9.2 years, impaired fasting glucose (HR 2.27) and type 2 diabetes (HR 2.45) predicted incident acromegaly versus normal fasting glucose. Risk was elevated across glycemic categories, peaking with poorly controlled T2DM (HR 3.07), and consistent across demographic and lifestyle subgroups.
Impact: This is the first nationwide evidence linking glycemic dysregulation to future acromegaly risk, suggesting metabolic status may aid in earlier case-finding or risk-based vigilance.
Clinical Implications: Patients with IFG or T2DM, especially with poor control, may warrant heightened suspicion for acromegaly when compatible symptoms/signs are present; integrating glycemic status into referral algorithms could reduce diagnostic delay.
Key Findings
- Among 9,707,487 adults, 434 incident acromegaly cases occurred over a median 9.2 years.
- IFG and T2DM increased acromegaly risk vs. normal fasting glucose (HR 2.27 and 2.45).
- Risk stratified by glycemic category: new-onset T2DM (HR 2.18), well-controlled T2DM (HR 2.29), and poorly controlled T2DM with the highest risk (HR 3.07).
Methodological Strengths
- Very large nationwide cohort with long follow-up and robust subgroup consistency
- Granular glycemic categorization using fasting glucose and prescriptions
Limitations
- Observational design susceptible to residual confounding and misclassification
- Case ascertainment likely relies on administrative codes; mechanistic pathways not assessed
Future Directions: Prospective studies integrating biochemical GH/IGF-1 screening in high-risk glycemic groups and mechanistic research into glucose–GH/IGF axis interactions.