No Effect of the Altered Peptide Ligand NBI-6024 on β-Cell Residual Function and Insulin Needs in New-Onset Type 1 Diabetes
Open accessAbstract
OBJECTIVE: This randomized, four-arm, placebo-controlled, dose-ranging phase 2 trial was conducted to determine whether repeated subcutaneous injections of the altered peptide ligand, NBI-6024, designed to inhibit autoreactive T-cells, improves β-cell function in patients with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 188 patients, aged 10–35 years, with recently diagnosed type 1 diabetes were randomly assigned for a treatment consisting of the subcutaneous administration of placebo or 1, 0.5, or 0.1 mg NBI-6024 at baseline, weeks 2 and 4, and then monthly until month 24. Fasting, peak, and area under the curve (AUC) C-peptide concentrations during a 2-h mixed-meal tolerance test were measured at 3-month intervals during treatment. Immune function parameters (islet antibodies and CD4 and CD8 T-cells) were also studied. RESULTS: The mean peak C-peptide concentration at 24 months after study entry showed no significant difference between the groups treated with 0.1 mg (0.59 pmol/ml), 0.5 mg (0.57 pmol/ml), and 1.0 mg NBI-6024 (0.48 pmol/ml) and the placebo group (0.54 pmol/ml). Fasting, stimulated peak, and AUC C-peptide concentrations declined linearly in all groups by ∼60% over the 24-month treatment period. The average daily insulin needs at month 24 were also comparable between the four groups. No treatment-related changes in islet antibodies and T cell numbers were observed. CONCLUSIONS: Treatment with altered peptide ligand NBI-6024 at repeated doses of 0.1, 0.5, or 1.0 mg did not improve or maintain β-cell function.
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After promising phase 1-2 trials in patients with recent-onset type 1 diabetes and detectable endogenous insulin production, phase 3 trials of anti-CD3 antibodies (otelixizumab and teplizumab), and the Diamyd vaccine (GAD-alum immunotherapy) did not meet primary endpoints.
“Disappointingly, after promising phase 1–2 trials in patients with recent-onset type 1 diabetes and detectable endogenous insulin production, phase 3 trials of anti-CD3 antibodies (otelixizumab and teplizumab), and the Diamyd vaccine (GAD-alum immunotherapy) did not meet primary endpoints.135–141”
From Type 1 diabetes (2014) · cites this paper as [135]
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Atkinson, M. A., Eisenbarth, G. S., & Michels, A. W. (2014) · The Lancet · doi:10.1016/s0140-6736(13)60591-7 · Cited by 2,713 · see citing works
Therapeutic Peptides: Current Applications and Future Directions
Wang, L., Wang, N., Zhang, W., Cheng, X., Yan, Z., Shao, G., Wang, X., Wang, R., & Fu, C. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00904-4 · Cited by 2,131 · see citing works
New frontiers in the treatment of type 1 diabetes
Warshauer, J. T., Bluestone, J. A., & Anderson, M. S. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2019.11.017 · Cited by 259 · see citing works
- Authors
- Walter, M., Philotheou, A., Bonnici, F., Ziegler, A.-G., Jimenez, R., & on behalf of the NBI-6024 Study Group
- Affiliations
- Diabetes Research Institute, Forschergruppe Diabetes e.V., Munich, Germany;
- University of Cape Town (ZA)
- Diabetes Clinical Trials Unit, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa, and
- Neurocrine Biosciences (United States) (US)
- Corresponding author
- Ziegler, Anette-G.
- ORCID
- Ziegler, Anette-G.
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2009-08-18
- Volume
- 32
- Issue
- 11
- Pages
- 2036-2040
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC2768201
- OpenAlex
- W2171429103
- Cited by
- 119
- References
- 1
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 9 · 2019: 8 · 2018: 10 · 2017: 2 · 2016: 8 · 2015: 8 · 2014: 6 · 2013: 8 · 2012: 10
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes Care (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Neurocrine Biosciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- altered peptide ligands, type 1 diabetes, beta-cell function, residual beta-cell function, C-peptide, insulin requirement, CD4 and CD8 T cells, subcutaneous immunotherapy, dose-ranging
- MeSH terms
- Adolescent, Adult, C-Peptide, Child, Diabetes Mellitus, Type 1, Electrocardiography, Female, Humans, Hypoglycemic Agents, Insulin, Male, Middle Aged, Peptide Fragments, Placebos, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Patient Selection, Insulin-Secreting Cells, Young Adult
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