A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes
© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology..
OBJECTIVES: We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia.
METHODS: We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses.
RESULTS: Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A.
CONCLUSION: Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:2 |
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| Enthalten in: |
Immunotherapy advances - 2(2022), 1 vom: 10., Seite ltab022 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Marwaha, Ashish K [VerfasserIn] |
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| Links: |
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| Themen: |
Clinical trial |
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| Anmerkungen: |
Date Revised 03.05.2023 published: Electronic-eCollection ClinicalTrials.gov: NCT02117765 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1093/immadv/ltab022 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM336067305 |
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| 100 | 1 | |a Marwaha, Ashish K |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A phase 1b open-label dose-finding study of ustekinumab in young adults with type 1 diabetes |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Revised 03.05.2023 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a ClinicalTrials.gov: NCT02117765 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Immunology. | ||
| 520 | |a OBJECTIVES: We assessed the safety of ustekinumab (a monoclonal antibody used in psoriasis to target the IL-12 and IL-23 pathways) in a small cohort of recent-onset (<100 days of diagnosis) adults with type 1 diabetes (T1D) by conducting a pilot open-label dose-finding and mechanistic study (NCT02117765) at the University of British Columbia | ||
| 520 | |a METHODS: We sequentially enrolled 20 participants into four subcutaneous dosing cohorts: (i) 45 mg loading weeks 0/4/16, (ii) 45 mg maintenance weeks 0/4/16/28/40, (iii) 90 mg loading weeks 0/4/16, and (iv) 90 mg maintenance weeks 0/4/16/28/40. The primary endpoint was safety as assessed by an independent data and safety monitoring board (DSMB) but we also measured mixed meal tolerance test C-peptide, insulin use/kg, and HbA1c. Immunophenotyping was performed to assess immune cell subsets and islet antigen-specific T cell responses | ||
| 520 | |a RESULTS: Although several adverse events were reported, only two (bacterial vaginosis and hallucinations) were thought to be possibly related to drug administration by the study investigators. At 1 year, the 90 mg maintenance dosing cohort had the smallest mean decline in C-peptide area under the curve (AUC) (0.1 pmol/ml). Immunophenotyping showed that ustekinumab reduced the percentage of circulating Th17, Th1, and Th17.1 cells and proinsulin-specific T cells that secreted IFN-γ and IL-17A | ||
| 520 | |a CONCLUSION: Ustekinumab was deemed safe to progress to efficacy studies by the DSMB at doses used to treat psoriasis in adults with T1D. A 90 mg maintenance dosing schedule reduced proinsulin-specific IFN-γ and IL-17A-producing T cells. Further studies are warranted to determine if ustekinumab can prevent C-peptide AUC decline and induce a clinical response | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a ustekinumab | |
| 700 | 1 | |a Chow, Samuel |e verfasserin |4 aut | |
| 700 | 1 | |a Pesenacker, Anne M |e verfasserin |4 aut | |
| 700 | 1 | |a Cook, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Annika |e verfasserin |4 aut | |
| 700 | 1 | |a Long, S Alice |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Jennie H M |e verfasserin |4 aut | |
| 700 | 1 | |a Ward-Hartstonge, Kirsten A |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Evangelia |e verfasserin |4 aut | |
| 700 | 1 | |a Domingo-Vila, Clara |e verfasserin |4 aut | |
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| 700 | 1 | |a Tree, Timothy I M |e verfasserin |4 aut | |
| 700 | 1 | |a Levings, Megan K |e verfasserin |4 aut | |
| 700 | 1 | |a Elliott, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Tan, Rusung |e verfasserin |4 aut | |
| 700 | 1 | |a Dutz, Jan P |e verfasserin |4 aut | |
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