A Single and Repeat-Dose Study of RZ358 in Patients With Post-Gastric Bypass Hypoglycemia (PGBH): Results of Population Pharmacokinetic (PK) / Pharmacodynamic (PD) Modeling

Abstract

\n PGBH is an uncommon individual risk but nevertheless cumulatively prevalent and important consequence of gastric bypass for the management of obesity. It is characterized by dysregulated hyperinsulinism (HI) and significant postprandial hypoglycemia and is not adequately treated with existing therapies. RZ358 is a human monoclonal antibody which allosterically attenuates the binding and action of insulin at target cell insulin receptors (IR), only during high insulin states. In previous clinical studies in induced (healthy volunteer insulin tolerance test) and intrinsic (congenital) hyperinsulinism, RZ358 showed favorable safety and PK, and glucose normalization without hyperglycemia. Therefore, RZ358 may also be beneficial in treating PGBH. The present study is a Phase 2a, single ascending (3, 6, and 9 mg/kg) and repeat dose (3 mg/kg/week for 4 weeks) study of IV RZ358 in patients with PGBH (n=16 [M:2; F:14]). Serial measurements of plasma RZ358 and biomarkers, and continuous glucose monitoring (CGM) were performed for up to 6 weeks. PK/PD modeling was conducted using NONMEM (v7.3) to describe RZ358 concentrations and exposure response (ER) relationships. Other than gender, baseline characteristics were similar between cohorts. RZ358 was safe and well-tolerated overall, with no discontinuations, deaths, or serious adverse reactions. The observed concentrations were well-described by the developed PK model, with dose-proportional exposures, an estimated effective half-life of ~15 days, and PK that was comparable to that in healthy volunteers and congenital HI. Concentration-dependent increases in insulin of up to 4-fold were observed, due to reduced IR clearance, as supported by unchanged c-peptide levels. Concentration-dependent increases in ketones and free fatty acids were also observed, providing further biomarker evidence of insulin attenuation by RZ358 at target tissues. RZ358 resulted in an apparent saturable ER with a ceiling response at normoglycemic values, showing sustained glucose increases by CGM over several weeks after dosing. Patients with the most pronounced postprandial hypoglycemia at baseline experienced an average ~60% glucose increase (by min/day <70 mg/dL; time in range [70–180 mg/dL]) to near normalization, while those with baseline normoglycemia did not become hyperglycemic. Glucose and biomarker responses were well-described by the ER model as a function of RZ358 concentrations and predicted that target RZ358 concentrations may be achieved with weekly administration of 3 mg/kg, or potentially less frequently at other doses. Consistent with its mechanism, RZ358 increased plasma glucose levels in an exposure-dependent fashion, and only when needed (disease-severity dependent). These properties make it uniquely suited as a potential treatment for heterogenous and variable hyperinsulinemic conditions such as PGBH.