2. Academic Validation
  3. Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial

Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial

  • Nat Med. 2022 Oct;28(10):2092-2099. doi: 10.1038/s41591-022-02011-x.
Jeremy Pettus 1,  Schafer C Boeder 2,  Mark P Christiansen 3,  Douglas S Denham 4,  Timothy S Bailey 5,  Halis K Akturk 6,  Leslie J Klaff 7,  Julio Rosenstock 8,  Mickie H M Cheng 9,  Bruce W Bode 10,  Edgar D Bautista 11,  Ren Xu 11,  Hai Yan 11,  Dung Thai 11,  Satish K Garg 6,  Samuel Klein 12
Affiliations

Affiliations

  • 1 Division of Endocrinology, University of California San Diego, La Jolla, CA, USA. [email protected].
  • 2 Division of Endocrinology, University of California San Diego, La Jolla, CA, USA.
  • 3 Diablo Clinical Research, Walnut Creek, CA, USA.
  • 4 Clinical Trials of Texas, San Antonio, TX, USA.
  • 5 AMCR Institute, Escondido, CA, USA.
  • 6 Barbara Davis Center for Diabetes, University of Colorado Anschutz Campus, Aurora, CO, USA.
  • 7 Rainier Clinical Research Center, Renton, WA, USA.
  • 8 Dallas Diabetes Research Center, Dallas, TX, USA.
  • 9 Marin Endocrine Care and Research, Greenbrae, CA, USA.
  • 10 Atlanta Diabetes Associates, Atlanta, GA, USA.
  • 11 REMD Biotherapeutics, Camarillo, CA, USA.
  • 12 Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO and Sansum Diabetes Research Institute, Santa Barbara, CA, USA.
PMID: 36192552 DOI: 10.1038/s41591-022-02011-x
Abstract

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.

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