Assessment of Multiple Dose Administration ofGlucagon Receptor Blocker REMD477 in Type 1 Diabetes

ABSTRACT Insulin remains the mainstay treatment for type 1 diabetes mellitus (T1D); however, it is associated with chronic iatrogenic hyperinsulinemia and life-threatening hypoglycemia events. Long term insulin treatment is also associated with secondary hyperlipidemia, and a higher incidence of cardiovascular complications, which tend to be more severe. Indeed, death due to cardiovascular complications is three-fold higher among insulin- treated T1D patients than in the general public. There exists a critical need for a safe, effective add-on therapy that reduces daily insulin requirements and, in turn, minimizes complications of chronic hyperinsulinemia. Hyperglycemia in T1D is not only caused by deficient pancreatic β-cell, but also by exaggerated glucagon activity. Under normal circumstances, β-cells secrete insulin that locally supresses glucagon release from nearby α-cells. However, since patients with T1D lack intra-islet insulin, α-cells activity and glucagon secretion are unrestrained and unopposed. Exogenous insulin administration is unable to affect this local feedback mechanism. Consequently, glucagon receptor (GCGR) blockade has become an intriguing therapeutic target to treat T1D. REMD-477 is a fully human, high affinity, glucagon receptor (GCGR) antibody that blocks the hepatic GCGR and reduces hepatic glucose and ketone production. REMD-477 exhibited a benign safety profile in animals and in healthy volunteers in a first-in- human study. In Phase I of a recently completed Fast Track, we showed the glucose-lowering effects of REMD-477 in three animal models of diabetes. In Phase II of the Fast Track, we demonstrated the safety and efficacy of a single dose of REMD-477 in a small clinical study. Based on these promising preclinical and clinical results, the current Phase IIB SBIR effort will determine whether multiple doses of REMD-477 can safely and effectively reduce insulin requirements in patients with T1D. In this randomized, double-blind, vehicle-controlled, Phase 2 clinical trial, we explore whether 12 weeks treatment with REMD-477 can lower daily/average insulin use, 24h blood glucose concentration, HgbA1c, and hypoglycemic events. We will also assess the effect of REMD-477 on alpha- and beta-cell function by assessing glucagon and active and total glucagon-like peptide 1 (GLP-1), and c-peptide, respectively. We will also study intrahepatic lipid content, body weight, and quality of life measures. REMD-477 is being developed as an add-on therapy for T1DM, to substantially (andgt;50%) reduce insulin daily doses, leading to better glucose control, fewer and milder complications, and an improved quality of life.People with type 1 diabetes mellitus (T1D) rely heavily on multiple daily insulin injections, which often leads to secondary hyperinsulinemia, and increased incidence and severity of cardiovascular events and life-threatening hypoglycemia. The goal of this research is to test the safety and efficacy of multiple doses of REMD-477, a fully human glucagon receptor antibody with a benign safety profile that can robustly lower glucose levels by suppressing hepatic glucose output, in patients with T1D. If successful, REMD-477 will reduce insulin requirements in patients with T1D and the sequelae of chronic hyperinsulinemia.