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Clinical Trial
. 2022 Oct;28(10):2092-2099.
doi: 10.1038/s41591-022-02011-x. Epub 2022 Oct 3.

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

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
Clinical Trial

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

Jeremy Pettus et al. Nat Med. 2022 Oct.

Erratum in

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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Conflict of interest statement

Competing Interests Statement

J.P. served as an advisor to Novo Nordisk and Sanofi; and served as a consultant to Diasome Pharmaceuticals, Insulet Corporation, Lilly Diabetes, MannKind Corporation, and Tandem Diabetes Care. S.C.B. served as a consultant to Cecelia Health; and received research support from Dexcom. M.P.C. received research support from Abbott Diabetes, Biolinq, Dexcom, Eli Lilly and Company, Medtronic, Merck & Co., Novo Nordisk A/S, Pfizer, and Viacyte. T.S.B. served as a consultant to Abbott, Lifescan, Mannkind, Medtronic, Novo, and Sanofi; received research support from Abbott Diabetes, Abbott Rapid Diagnostics, Biolinq, Capillary Biomedical, Dexcom, Eli Lilly, Kowa, Lexicon, Livongo, Mannkind, Medtronic, Novo Nordisk, REMD, Sanofi, Sanvita, Senseonics, Viacyte, vTv Therapeutics, and Zealand Pharma; and served a speaker for BD, Medtronic, and Sanofi. H.K.A. served as a consultant to the American Diabetes Association; received research support from Dexcom, Eli Lilly and Company, IM Therapeutics, MannKind Corporation, REMD Biotherapeutics, and Senseonics; and served as a speaker for the American Diabetes Association. L.J.K. received research support from Abbott Diabetes, Dong-A ST Co. Ltd., Gan & Lee Pharmaceuticals, Lexicon Pharmaceuticals, Lilly Diabetes, Medtronic, Novo Nordisk, Oramed Pharmaceuticals, Pfizer, and REMD Biotherapeutics. J.R. served as a board member for Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Eli Lilly and Company, Intarcia Therapeutics, Novo Nordisk, Oramed Pharmaceuticals, and Sanofi; and served as a consultant to Applied Therapeutics, Boehringer Ingelheim Pharmaceuticals, Eli Lilly and Company, Intarcia Therapeutics, and Novo Nordisk. B.W.B. served as an advisor to Eli Lilly and Company; served as a consultant to Bigfoot Biomedical, Companion Medical, Lexicon Pharmaceuticals, Medtronic, Novo Nordisk, and Zealand Pharma A/S; received research support from Abvance Therapeutics, Dexcom, Diasome Pharmaceuticals, Dompe, Eli Lilly and Company, Eyenuk, Insulet Corporation, Jaeb Center for Health Research, Medtronic, Nova Biomedical, Novo Nordisk, Provention Bio, REMD Biotherapeutics, Sanofi, Senseonics, Viacyte, vTv Therapeutics, and Xeris Pharmaceuticals; served as a speaker for AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Eli Lilly and Company, MannKind Corporation, Medtronic, Novo Nordisk, and Sanofi; and is a stock/shareholder in AgaMatrix, Aseko, and Glytec, LLC. E.D.B. served as a consultant to REMD Biotherapeutics. R.X. and H.Y. served as board members for REMD Biotherapeutics. D.T. is an employee for REMD Biotherapeutics. S.K.G. served as an advisor to Eli Lilly and Company, Medtronic, Novo Nordisk, and Zealand Pharma A/S; and received research support from Dexcom, Eli Lilly and Company, and Medtronic. S.K. served as an advisor to Altimmune, Janssen, and ProSciento; and received research support from Janssen Research & Development, LLC. D.S.D. and M.G.M.C have no competing interests to disclose.

Figures

Extended Data Figure 1.
Extended Data Figure 1.. Blood glucose concentrations from continuous glucose monitoring
Blood glucose concentration data from available continuous glucose monitoring data are presented as least square means with error bars representing 95% confidence intervals for participants treated with placebo (n=27), 35 mg volagidemab (n=26), or 70 mg volagidemab (n=25). Change in a, average daily glucose; b, percent of samples in target range (70–180 mg/dL); c, percent of samples below target range (<70 mg/dL); d, percent of samples below target range (<55 mg/dL); e, percent samples above target range (>180 mg/dL).
Extended Data Figure 2.
Extended Data Figure 2.. Proportion of patients who reached target hemoglobin A1c ≤7.0
The proportion of patients who reached a target HbA1c level of ≤7.0 are presented for participants treated with placebo (n=27), 35 mg volagidemab (n=26), or 70 mg volagidemab (n=25). Error bars represent 95% confidence intervals.
Extended Data Figure 3.
Extended Data Figure 3.. Adverse events of special interest
Adverse event data are presented as arithmetic means with error bars representing 95% confidence intervals for participants treated with placebo (n=27), 35 mg volagidemab (n=26), or 70 mg volagidemab (n=26). Change in a, serum alanine aminotransferase (ALT); b, serum aspartate aminotransferase (AST); c, low-density lipoprotein (LDL) cholesterol; d, systolic blood pressure (SBP); and e, diastolic blood pressure (DBP).
Figure 1.
Figure 1.. Patient disposition
Figure 2.
Figure 2.. Daily insulin use
Daily insulin use data are presented as change or percent change from baseline in least square means with error bars representing 95% confidence intervals for participants treated with placebo (n=27), 35 mg volagidemab (n=26), or 70 mg volagidemab (n=25). a, Change in average daily total; b, percent change in average daily total; c, percent change basal and; d, percent change bolus insulin dose.
Figure 3.
Figure 3.. Hemoglobin A1c over time
Percent HbA1c data are presented as change from baseline in least square means with error bars representing 95% confidence intervals for participants treated with placebo (n=27), 35 mg volagidemab (n=26), or 70 mg volagidemab (n=25).Two-sided p-values are indicated for differences at Week 13, as assessed by a repeated measures analysis of covariance (ANCOVA) test.
Figure 4.
Figure 4.. Blood glucose concentrations from 7-point profile
Blood glucose concentration data from 7-point profiles are presented as change from baseline in least square means with error bars representing 95% confidence intervals for participants treated with placebo (n=27), 35 mg volagidemab (n=26), or 70 mg volagidemab (n=25).Change in a, average daily glucose; b, percent of samples in target range (70–180 mg/dL); c, percent of samples below target range (<70 mg/dL); d, percent of samples below target range (<55 mg/dL); e, percent samples above target range (>180 mg/dL).
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Comment in

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