Congenital hyperinsulinism (CHI) is a rare genetic disorder of pancreatic beta-cell function characterized by failure to suppress insulin secretion in the presence of hypoglycemia, resulting in brain damage or death if inadequately controlled. Children affected by the most common form of CHI are unresponsive to medical therapy and require a near-total pancreatectomy shortly after birth for intractable hypoglycemia. Preliminary preclinical and clinical data suppor the use of the GLP-1 receptor antagonist, exendin-(9-39) as a novel therapeutic approach. The goal of this proposal is to obtain pharmacodynamics data for assessing the relationship between exendin-(9- 39) exposure and fasting blood glucose. The investigators propose two complimentary approaches to achieve this goal: 1) a clinical trial on the target population, and 2) a trial simulation.
Aim 1 is an open label, placebo-controlled, single dose study to assess the effect, safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous exendin-(9-39) in children with CHI. Sixteen children 6 months of age and older with persistent hypoglycemia due to CHI will receive a six hour infusion of exendin-(9-39) or vehicle during fasting in a cross-over randomized design. The effect of treatment on blood glucose will be examined and pharmacokinetics and safety data will be collected. An exploratory aim will be to assess the immunogenicity of exendin-(9-39). The hypothesis is that exendin-(9-39) will elevate fasting blood glucose in a dose dependent manner and will be sufficiently well tolerated to permit continued clinical investigation.
Aim 2 is a trial simulation to evaluate trial design constructs in an attempt to maximize the likelihood of clinical trial success for subsequent Phase 2/3 trials. The pharmacokinetics and pharmacodynamics data generated will be used for model-based prediction of doses and regimens expected to achieve target clinical endpoints for a future pivotal clinical trial.

Public Health Relevance

Relevance Currently, there are no effective medical therapies for children with congenital hyperinsulinism due to inactivating mutations of the KATP channels and most affected children require pancreatectomy for intractable hypoglycemia. The studies proposed here are important to further the development of exendin-(9-39) for the treatment of congenital hyperinsulinism by providing measurements of effect, safety and PK/PD profile of this peptide.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (S1))
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Children's Hospital of Philadelphia
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Ng, Chee M; Tang, Fei; Seeholzer, Steven H et al. (2018) Population pharmacokinetics of exendin-(9-39) and clinical dose selection in patients with congenital hyperinsulinism. Br J Clin Pharmacol 84:520-532
McGuire, Jennifer L; Barrett, Jeffrey S; Vezina, Heather E et al. (2014) Adjuvant therapies for HIV-associated neurocognitive disorders. Ann Clin Transl Neurol 1:938-52