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

Nature Medicine volume 28, pages 2092–2099 (2022)Cite this article

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A Publisher Correction to this article was published on 17 March 2023

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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. See clinicaltrials.gov registration no. NCT03117998.

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Fig. 1: Patient disposition.
Fig. 2: Daily insulin use.
Fig. 3: HbA1c over time.
Fig. 4: Blood glucose concentrations from seven-point profile.

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Data from these analyses cannot be made publicly available due to the sponsor’s contractual obligations. We encourage researchers or parties interested in collaboration for noncommercial use to apply to the corresponding author. Applications should outline specifically what data they are interested in receiving and how the data will be used. All data shared will be de-identified and will be made available 2 years after the date of publication. A signed data access agreement with the sponsor is required before accessing the shared data. Source data are provided with this paper.

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Acknowledgements

This study was sponsored and funded by REMD Biotherapeutics. REMD Biotherapeutics was directly involved in the design, conduct, analysis and reporting of the study. Research reported in this publication was also supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award number R44DK108305. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Medical writing support, under the direction of the authors, was provided by J. Leonoudakis and was funded by REMD Biotherapeutics in accordance with Good Publication Practice guidelines.

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Authors and Affiliations

  1. Division of Endocrinology, University of California San Diego, La Jolla, CA, USA

    Jeremy Pettus & Schafer C. Boeder

  2. Diablo Clinical Research, Walnut Creek, CA, USA

    Mark P. Christiansen

  3. Clinical Trials of Texas, San Antonio, TX, USA

    Douglas S. Denham

  4. AMCR Institute, Escondido, CA, USA

    Timothy S. Bailey

  5. Barbara Davis Center for Diabetes, University of Colorado Anschutz Campus, Aurora, CO, USA

    Halis K. Akturk & Satish K. Garg

  6. Rainier Clinical Research Center, Renton, WA, USA

    Leslie J. Klaff

  7. Dallas Diabetes Research Center, Dallas, TX, USA

    Julio Rosenstock

  8. Marin Endocrine Care and Research, Greenbrae, CA, USA

    Mickie H. M. Cheng

  9. Atlanta Diabetes Associates, Atlanta, GA, USA

    Bruce W. Bode

  10. REMD Biotherapeutics, Camarillo, CA, USA

    Edgar D. Bautista, Ren Xu, Hai Yan & Dung Thai

  11. Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO and Sansum Diabetes Research Institute, Santa Barbara, CA, USA

    Samuel Klein

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Contributions

All authors contributed to study concept and study supervision. E.D.B, R.X., H.Y. and D.T. were responsible for study administration. J.P., S.C.B., M.P.C., D.S.D., T.S.B., H.K.A., L.J.K., J.R., M.H.M.C., B.W.B., E.D.B., S.K.G. and S.K. provided patients and conducted the investigation. J.P. and D.T. wrote the original draft of the manuscript. All authors critically reviewed the manuscript.

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Correspondence to Jeremy Pettus.

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Competing interests

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 as 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.

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Extended data

Extended Data Fig. 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).

Source data

Extended Data Fig. 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.

Source data

Extended Data Fig. 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).

Source data

Supplementary information

Supplementary Information

Supplementary Tables 1 and 2.

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Source Data Extended Data Fig. 1

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Pettus, J., Boeder, S.C., Christiansen, M.P. et al. Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial. Nat Med 28, 2092–2099 (2022). https://doi.org/10.1038/s41591-022-02011-x

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