A safety and pharmacodynamics study of temelimab, an antipathogenic human endogenous retrovirus type W envelope monoclonal antibody, in patients with type 1 diabetes.
disease-modifying drug, endogenous retrovirus, human endogenous retroviruses, monoclonal antibody, phase II study, temelimab, type 1 diabetes
Journal
Diabetes, obesity & metabolism
ISSN: 1463-1326
Titre abrégé: Diabetes Obes Metab
Pays: England
ID NLM: 100883645
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
11
11
2019
revised:
14
02
2020
accepted:
17
02
2020
pubmed:
23
2
2020
medline:
25
6
2021
entrez:
21
2
2020
Statut:
ppublish
Résumé
To report the first study of temelimab, a monoclonal antibody neutralizing the pathogenic human endogenous retrovirus type W envelope, in patients with type 1 diabetes (T1D). This double-blind, placebo-controlled, randomized clinical trial recruited adult patients with T1D within 4 years postdiagnosis and remaining C-peptide secretion. Sixty-four patients were randomized (2:1) to monthly temelimab 6 mg/kg or placebo during 24 weeks followed by a 24-week, open-label extension, during which all patients received temelimab. The primary objective was the safety and tolerability of temelimab. The secondary objective was to assess the pharmacodynamics response such as C-peptide levels, insulin use, HbA1c, hypoglycaemia and autoantibodies. Temelimab was well tolerated without any group difference in the frequency or severity of adverse events. Concerning exploratory endpoints, there was no difference in the levels of C-peptide, insulin use or HbA1c between treatment groups at weeks 24 and 48. The frequency of hypoglycaemia events was reduced with temelimab (P = 0.0004) at week 24 and the level of anti-insulin antibodies was lower with temelimab (P < 0.01); the other autoantibodies did not differ between groups. Temelimab appeared safe in patients with T1D. Pharmacodynamics signals (hypoglycaemia and anti-insulin antibodies) under temelimab were observed. Markers of β-cell functions were not modified by treatment. These results need to be further explored in younger patients with T1D with earlier disease onset.
Substances chimiques
Antibodies, Monoclonal
0
Antibodies, Monoclonal, Humanized
0
Hypoglycemic Agents
0
temelimab
T32CR1A69R
Types de publication
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1111-1121Subventions
Organisme : GeNeuro Australia Pty Ltd
Pays : International
Informations de copyright
© 2020 John Wiley & Sons Ltd.
Références
Ehlers MR. Strategies for clinical trials in type 1 diabetes. J Autoimmun. 2016;71:88-96.
Greenbaum C, VanBuecken D, Lord S. Disease-modifying therapies in type 1 diabetes: a look into the future of diabetes practice. Drugs. 2019;79:43-61.
Gomez-TourinoI AS, Eichmann M, Peakman M. T cells in type 1 diabetes: instructors, regulators and effectors: a comprehensive review. J Autoimmun. 2016;66:7-16.
Santoni M, Andrikou K, Sotte V, et al. Toll like receptors and pancreatic diseases: from a pathogenetic mechanism to a therapeutic target. Cancer Treat Rev. 2015;41:569-576.
Levet S, Medina J, Joanou J, et al. An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes. JCI Insight. 2017;2:17. pii: 94387.
Nath A, Küry P, Sciascia do Olival G, et al. First international workshop on human endogenous retroviruses and diseases, HERVs & disease 2015. Mob DNA. 2015;15(6):20.
Rolland A, Jouvin-Marche E, Viret C, Faure M, Perron H, Marche PN. The envelope protein of a human endogenous retrovirus-W family activates innate immunity through CD14/TLR4 and promotes Th1-like responses. J Immunol. 2006;176(12):7636-7644.
Bashratyan R, Regn D, Rahman MJ, et al. Type 1 diabetes pathogenesis is modulated by spontaneous autoimmune responses to endogenous retrovirus antigens in NOD mice. Eur J Immunol. 2017;47(3):575-584.
Curtin F, Perron H, Kromminga A, Porchet H, Lang AB. Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein. MAbs. 2015;7:265-275.
Curtin F, Bernard C, Levet S, et al. A new therapeutic approach for type 1 diabetes: rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody. Diabetes Obes Metab. 2018;20:2075-2084.
Hartung HP, Cree B, Derfuss T, et al. Neuroprotective effects of temelimab in relapsing-remitting multiple sclerosis patients extend to 96 weeks. Stockholm, Sweden: ECTRIMS; 2019.
Perdigoto AL, Preston-Hurlburt P, Clark P, et al. Treatment of type 1 diabetes with teplizumab: clinical and immunological follow-up after 7 years from diagnosis. Diabetologia. 2019;62(4):655-664.
Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36(5):1384-1395.
Porchet H, Vidal V, Kornmann G, Malpass S, Curtin F. A high-dose pharmacokinetic study of a new IgG4 monoclonal antibody Temelimab/GNbAC1 antagonist of an endogenous retroviral protein pHERV-W Env. Clin Ther. 2019;41:1737-1746.
Hagopian W, Ferry RJ Jr, Sherry N, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial. Diabetes. 2013;62:3901-3908.
Keymeulen B, Walter M, Mathieu C, et al. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia. 2010;53:614-623.
Yu L, Herold K, Krause-Steinrauf H, et al. Rituximab selectively suppresses specific islet antibodies. Diabetes. 2011;60:2560-2565.
Atkinson MA, Roep BO, Posgai A, Wheeler DCS, Peakman M. The challenge of modulating β-cell autoimmunity in type 1 diabetes. Lancet Diabetes Endocrinol. 2019;7:52-64.
Shields BM, McDonald TJ, Oram R, et al. C-peptide decline in type 1 diabetes has two phases: an initial exponential fall and a subsequent stable phase. Diabetes Care. 2018;41:1486-1492.
Hartung HP, Curtin F, Schneble HM, et al. GNC-003: an international, double-blind, randomized, placebo-controlled phase IIb trial to assess the efficacy, safety and pharmacokinetics of GNbAC1 in patients with relapsing remitting multiple sclerosis. Paris, France: ECTRIMS Congress; 2017.
De Stefano N, Curtin F, Stubinski B, et al. Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis. Mult Scler. 2010;16:888-892.
Asher M. Anti-CD3 antibody charts out a type 1 diabetes comeback nature reviews. Drug Discovery. 2019;18:573.