Daily Endocrinology Research Analysis

BACKGROUND: Congenital hyperinsulinism (cHI) is a rare, primarily pediatric disease characterized by dysregulated insulin secretion resulting in severe, persistent hypoglycemia, frequently leading to lifelong neurologic impairments. The safety, pharmacokinetics, and glycemic efficacy of ersodetug, a fully human monoclonal antibody that allosterically and reversibly binds the insulin receptor (INSR) and reduces excess insulin action, are being evaluated for the treatment of cHI-related hypoglycemia. METHODS: A global, open-label, phase 2b study (ClinicalTrials.gov: NCT04538989) was conducted in 23 patients with cHI with persistent hypoglycemia on standard-of-care (SOC) therapies. Eligible participants (age ≥2 years) received add-on ersodetug at dose levels between 3 and 9 mg/kg intravenously (i.v.) bi-weekly for 8 weeks in 4 sequential dose cohorts. FINDINGS: Enrolled participants (average age = 6.7 years) on SOC (87% medications; 17% previous pancreatectomy) experienced 13 events/week and 23% time in hypoglycemia at baseline. Ersodetug resulted in predictable, dose-proportional pharmacokinetics. No deaths, adverse drug reactions, study withdrawals, or dose-limiting toxicities occurred. Hypoglycemia (<70 mg/dL) events (self-monitored blood glucose) and time (continuous glucose monitoring) improved from baseline by medians of 59% (p < 0.001) and 54% (p < 0.001), respectively, across pooled dose levels and by 48%-84% (events) and 61%-65% (time) at doses of 6 or 9 mg/kg (p < 0.05) with a nearly universal individual patient response rate. Additional hypoglycemia metrics, including overnight hypoglycemia, similarly improved. CONCLUSION: Ersodetug was generally well tolerated and significantly improved hypoglycemia in participants with cHI. Ersodetug represents a novel INSR-targeted mechanism of action with the potential to be an effective therapy for all forms of cHI, alone or in combination with other therapies. FUNDING: Rezolute, Inc. (Redwood City, CA), provided funds.

CONTEXT: Pituitary neuroendocrine tumors (PitNETs) that progress following surgery and radiotherapy are in need of additional treatment options. Responses to immune checkpoint inhibitors (ICIs) have been described; however, the feasibility of ICI therapy and biomarkers of response have not been formally assessed. OBJECTIVE: To evaluate the activity of ICI as a treatment for PitNETs. METHODS: We performed a single-center, prospective, phase 2 trial investigating the activity of ipilimumab and nivolumab in patients with PitNETs. The primary endpoint was objective response using the iRANO response criteria. We then explored genetic biomarkers of response to ICIs in 13 patients with PitNETs who were treated with ICIs, on or outside of the trial. RESULTS: Ten patients with a PitNET were enrolled, including 5 corticotroph, 4 lactotroph, and 1 somatotroph tumor, of which 9/10 (4 metastatic and 5 nonmetastatic) patients were evaluable for the primary endpoint. While no objective responses were observed, tumor shrinkage was seen in 2/9 patients. In a biomarker discovery cohort, comprising 7 tumors treated on trial and 6 tumors treated off trial, temozolomide hypermutation, and mismatch repair deficiency (MMRd) were associated with immunological response. In 3 tumors sequenced pre- and post-ICI treatment, we identified evidence of immunoediting, characterized by loss of MMRd and/or a decrease in tumor mutational burden. CONCLUSION: This study demonstrates the safety and feasibility of ICI treatment in aggressive PitNETs. We also identified MMRd and temozolomide hypermutation as potential biomarkers of response to ICI. Overall, our data suggest that ICIs might provide an additional treatment option for PitNET; this should be evaluated more broadly in future studies.

OBJECTIVES: Although evidence suggests that the overall prevalence of type 2 diabetes mellitus (T2DM) was already higher in the acromegaly group than in the general population several years before diagnosis, the effect of glycaemic status on the risk of developing acromegaly remains unclear. DESIGN: Retrospective cohort study. SETTING: Data were obtained from the National Health Insurance Services in Korea. Baseline glycaemic status was defined based on fasting plasma glucose levels and prescription records, and it was classified into three categories: normal fasting glucose (NFG), impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM) or five categories: NFG, IFG, new-onset T2DM, well-controlled T2DM and poorly controlled T2DM. PARTICIPANTS: A total of 9 707 487 adults without acromegaly participated in the national health screening programme in 2009 and were followed up until 2019. PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcome of interest was the diagnosis of incident acromegaly. RESULTS: Over a median follow-up period of 9.2 years, 434 people (4.5 cases per 100 000 people) developed acromegaly at least 1 year after enrolment. Participants with IFG and T2DM exhibited an increased risk of acromegaly, with hazard ratios (HR) of 2.27 (95% CI 1.84 to 2.80) and 2.45 (95% CI 1.78 to 3.39), respectively, compared with those with NFG. When participants were categorised into five glycaemic status groups, an increased risk of acromegaly was observed in those with new-onset T2DM (HR 2.18, 95% CI 1.38 to 3.43) and well-controlled T2DM (HR 2.29, 95% CI 1.28 to 4.09), similar to individuals with IFG, with the highest risk found in individuals with poorly controlled T2DM (HR 3.07, 95% CI 1.88 to 5.01). These associations are persistent across various subgroups, regardless of age, sex, lifestyle factors and the presence of comorbidities. CONCLUSIONS: The results of this study supported that alterations in glucose metabolism, including IFG and T2DM, are associated with an increased risk of acromegaly.