Hyperglucagonemia contributes to
hyperglycemia in patients with
type 1 diabetes (T1D); however, novel
therapeutics that block
glucagon action could improve
glycemic control. This phase 2 study evaluated the safety and efficacy of
volagidemab, an antagonistic monoclonal
glucagon receptor (GCGR) antibody, as an adjunct to
insulin therapy in adults with T1D. The primary endpoint was change in daily
insulin use at week 12. Secondary endpoints included changes in
hemoglobin A1c (HbA1c) at week 13, in average daily
blood glucose concentration and time within target range as assessed by continuous
blood glucose monitoring (CGM) and seven-point
glucose profile at week 12, incidence of
hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%,
volagidemab drug concentrations and incidence of anti-
drug antibodies. Eligible participants (n = 79) were randomized to receive weekly
subcutaneous injections of placebo, 35 mg
volagidemab or 70 mg
volagidemab.
Volagidemab produced a reduction in total daily
insulin use at week 12 (35 mg
volagidemab: -7.59 units (U) (95% confidence interval (CI) -11.79, -3.39; P = 0.040 versus placebo); 70 mg
volagidemab: -6.64 U (95% CI -10.99, -2.29; P = 0.084 versus placebo); placebo: -1.27 U (95% CI -5.4, 2.9)) without meeting the prespecified significance level (P < 0.025). At week 13, the placebo-corrected reduction in HbA1c percentage was -0.53 (95% CI -0.89 to -0.17, nominal P = 0.004) in the 35 mg
volagidemab group and -0.49 (95% CI -0.85 to -0.12, nominal P = 0.010) in the 70 mg
volagidemab group. No increase in
hypoglycemia was observed with
volagidemab therapy; however, increases in serum
transaminases,
low-density lipoprotein (
LDL)-cholesterol and blood pressure were observed. Although the primary endpoint did not meet the prespecified significance level, we believe that the observed reduction in HbA1c and tolerable safety profile provide a rationale for further randomized studies to define the long-term efficacy and safety of
volagidemab in patients with T1D.