Single-dose Study to Evaluate Safety, Tolerability, and Pharmacodynamics of REMD-477 in Subjects With Type 1 Diabetes Mellitus

This is a randomized, placebo-controlled, double-blind study to evaluate safety, tolerability and pharmacodynamics of REMD-477 in subjects who have Type 1 diabetes and are currently receiving insulin treatment. This proof of concept study will determine whether glucagon receptor blockade using a single dose REMD-477 can improve short-term glucose homeostasis in people with Type 1 diabetes.

The study will be conducted at two sites in the United States, and approximately 20 subjects with type 1 diabetes will be enrolled. Eligible subjects will be admitted to the clinical research unit, to carefully monitor blood glucose; and establish the baseline insulin requirement for maintaining targeted normoglycemia (postabsorptive: 90-120 mg/dL; and postprandial: \<180 mg/dL).

The patients will then be subjected to a hyperglycemic period (250-300 mg/dL) by a stepwise reduction in insulin infusion. After receiving a single SC dose of REMD-477 or matching placebo in a double-blinded fashion, all subjects will be assessed for the post-treatment 24-hour insulin requirement needed to maintain targeted normoglycemia (postabsorptive: 90-120 mg/dL; and postprandial: \<180 mg/dL); and to be monitored closely for safety, tolerability and targeted glycemic control, for a 48-hr period. After the in-patient residency period, subjects will return to the clinic for weekly out-patient safety follow-up visits for 8 weeks.

Eligibility Criteria:
Inclusion Criteria:

* Men and women between the ages of 18 and 60 years old, inclusive, at the time of screening;
* Females of non-child bearing potential must be ≥1 year post-menopausal (confirmed by a serum follicle-stimulating hormone (FSH) levels ≥ 40 IU/mL) or documented as being surgically sterile. Females of child bearing potential must agree to use two methods of contraception;
* Male subjects must be willing to use clinically acceptable method of contraception during the entire study;
* Body mass index between 18.5 and 26.9 kg/m2, inclusive, at screening;
* Diagnosed with Type 1 diabetes for greater than 2 years, based on clinical history or as defined by the current American Diabetes Association (ADA) criteria;
* HbA1c ≥6.0 % but \<9.0 % at screening;
* Fasting C-peptide \<0.2 ng/mL;
* Current use of insulin pump and willing to use continuous glucose monitoring (CGM) system (e.g. DexCom) throughout the entire study;
* ALT and/or AST within \<1.5x ULN at screening;
* Serum amylase and lipase within normal limits at screening;
* Able to provide written informed consent approved by an Institutional Review Board (IRB).

Exclusion Criteria:

* History or evidence of clinically-significant disorder or condition that, in the opinion of the Investigator, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion;
* Significant organ system dysfunction (e.g., clinically significant pulmonary or cardiovascular disease, anemia \[Hemoglobin \<10.0 g/dL\], and renal dysfunction \[eGFR \<90 ml/1.73M2/min\]);
* Any severe symptomatic hypoglycemic event associated with a seizure or requiring help from other people or medical facility in the past 6 months;
* Current or recent (within 1 month of screening) use of diabetes medications other than insulin;
* Use of steroids and/or other prescribed or over-the-counter medications that are known to affect the outcome measures in this study or known to influence glucose metabolism;
* Smokes tobacco;
* Known sensitivity to mammalian-derived drug preparations, recombinant protein-based drugs or to humanized or human antibodies;
* History of illegal drug use or alcohol abuse within the last 6 months or a positive drug urine test result at screening;
* History of pancreatitis, pancreatic neuroendocrine tumors or multiple endocrine neoplasia;
* History of pheochromocytoma, or family history of familial pheochromocytoma;
* Known or suspected susceptibility to infectious disease (eg, taking immunosuppressive agents or has a documented inherited or acquired immunodeficiency);
* Positive for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HbsAg), or hepatitis C antibodies (HepC Ab);
* Participation in an investigational drug or device trial within 30 days of screening or within 5 times the half-life of the investigational agent in the other clinical study, if known, whichever period is longer;
* Blood donor or blood loss \>500 mL within 30 days of Day 1;
* Women who are pregnant or lactating/breastfeeding;
* Regular exercise \>120 min/week within 14 days of Day 1;
* Unable or unwilling to follow the study protocol or who are non-compliant with screening appointments or study visits;
* Family history of multiple endocrine neoplasia.

Other inclusion and exclusion criteria may apply.