Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

Danijela Tatovic; Ashish Marwaha; Peter Taylor; Stephanie J. Hanna; Kym Carter; W. Y. Cheung; Steve Luzio; Gareth Dunseath; Hayley A. Hutchings; Gail Holland; Steve Hiles; Greg Fegan; Evangelia Williams; Jennie H. M. Yang; Clara Domingo-Vila; Emily Pollock; Muntaha Wadud; Kirsten Ward-Hartstonge; Susie Marques-Jones; Jane Bowen-Morris; Rachel Stenson; Megan K. Levings; John W. Gregory; Timothy I. M. Tree; Colin Dayan

doi:10.1038/s41591-024-03115-2

Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

Danijela Tatovic (Lead / Corresponding author)
, Ashish Marwaha (Lead / Corresponding author)
, Peter Taylor
, Stephanie J. Hanna
, Kym Carter
, W. Y. Cheung
, Steve Luzio
, Gareth Dunseath
, Hayley A. Hutchings
, Gail Holland
, Steve Hiles
, Greg Fegan
, Evangelia Williams
, Jennie H. M. Yang
, Clara Domingo-Vila
, Emily Pollock
, Muntaha Wadud
, Kirsten Ward-Hartstonge
, Susie Marques-Jones
, Jane Bowen-Morris

Rachel Stenson, Megan K. Levings, John W. Gregory, Timothy I. M. Tree, Colin Dayan,

Population Health and Genomics

Research output: Contribution to journal › Article › peer-review

42 Citations (Scopus)

110 Downloads (Pure)

Abstract

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).

Original language	English
Pages (from-to)	2657–2666
Number of pages	10
Journal	Nature Medicine
Volume	30
Issue number	9
Early online date	30 Jul 2024
DOIs	https://doi.org/10.1038/s41591-024-03115-2
Publication status	Published - Sept 2024

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SDG 3 Good Health and Well-being

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Tatovic, D., Marwaha, A., Taylor, P., Hanna, S. J., Carter, K., Cheung, W. Y., Luzio, S., Dunseath, G., Hutchings, H. A., Holland, G., Hiles, S., Fegan, G., Williams, E., Yang, J. H. M., Domingo-Vila, C., Pollock, E., Wadud, M., Ward-Hartstonge, K., Marques-Jones, S. (2024). Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial. Nature Medicine, 30(9), 2657–2666. https://doi.org/10.1038/s41591-024-03115-2

@article{b4de7058bd4046e09af0ba30c289c987,

title = "Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial",

abstract = "Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49\% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).",

author = "Danijela Tatovic and Ashish Marwaha and Peter Taylor and Hanna, \{Stephanie J.\} and Kym Carter and Cheung, \{W. Y.\} and Steve Luzio and Gareth Dunseath and Hutchings, \{Hayley A.\} and Gail Holland and Steve Hiles and Greg Fegan and Evangelia Williams and Yang, \{Jennie H. M.\} and Clara Domingo-Vila and Emily Pollock and Muntaha Wadud and Kirsten Ward-Hartstonge and Susie Marques-Jones and Jane Bowen-Morris and Rachel Stenson and Levings, \{Megan K.\} and Gregory, \{John W.\} and Tree, \{Timothy I. M.\} and Colin Dayan and Evelien Gevers and Shankar Kanumakala and Sunil Nair and Chris Gardner and Michal Ajzensztejn and Christina Wei and Chris Mouditis and Fiona Campbell and James Greening and Emma Webb and Mimi Chen and Rakesh Amin and Billi White and Ambika Shetty and Chris Bidder and Nicholas Conway and Amalia Mayo and Eleni Christakou and Kamila Sychowska and Yasaman Shahrabi and Maximilian Robinson and Simi Ahmed and Jan Dutz and Laura Cook",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = sep,

doi = "10.1038/s41591-024-03115-2",

language = "English",

volume = "30",

pages = "2657–2666",

journal = "Nature Medicine",

issn = "1078-8956",

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Tatovic, D, Marwaha, A, Taylor, P, Hanna, SJ, Carter, K, Cheung, WY, Luzio, S, Dunseath, G, Hutchings, HA, Holland, G, Hiles, S, Fegan, G, Williams, E, Yang, JHM, Domingo-Vila, C, Pollock, E, Wadud, M, Ward-Hartstonge, K, Marques-Jones, S, Bowen-Morris, J, Stenson, R, Levings, MK, Gregory, JW, Tree, TIM, Dayan, C 2024, 'Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial', Nature Medicine, vol. 30, no. 9, pp. 2657–2666. https://doi.org/10.1038/s41591-024-03115-2

TY - JOUR

T1 - Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

AU - Tatovic, Danijela

AU - Marwaha, Ashish

AU - Taylor, Peter

AU - Hanna, Stephanie J.

AU - Carter, Kym

AU - Cheung, W. Y.

AU - Luzio, Steve

AU - Dunseath, Gareth

AU - Hutchings, Hayley A.

AU - Holland, Gail

AU - Hiles, Steve

AU - Fegan, Greg

AU - Williams, Evangelia

AU - Yang, Jennie H. M.

AU - Domingo-Vila, Clara

AU - Pollock, Emily

AU - Wadud, Muntaha

AU - Ward-Hartstonge, Kirsten

AU - Marques-Jones, Susie

AU - Bowen-Morris, Jane

AU - Stenson, Rachel

AU - Levings, Megan K.

AU - Gregory, John W.

AU - Tree, Timothy I. M.

AU - Dayan, Colin

AU - Gevers, Evelien

AU - Kanumakala, Shankar

AU - Nair, Sunil

AU - Gardner, Chris

AU - Ajzensztejn, Michal

AU - Wei, Christina

AU - Mouditis, Chris

AU - Campbell, Fiona

AU - Greening, James

AU - Webb, Emma

AU - Chen, Mimi

AU - Amin, Rakesh

AU - White, Billi

AU - Shetty, Ambika

AU - Bidder, Chris

AU - Conway, Nicholas

AU - Mayo, Amalia

AU - Christakou, Eleni

AU - Sychowska, Kamila

AU - Shahrabi, Yasaman

AU - Robinson, Maximilian

AU - Ahmed, Simi

AU - Dutz, Jan

AU - Cook, Laura

PY - 2024/9

Y1 - 2024/9

N2 - Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).

AB - Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).

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U2 - 10.1038/s41591-024-03115-2

DO - 10.1038/s41591-024-03115-2

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SN - 1078-8956

VL - 30

SP - 2657

EP - 2666

JO - Nature Medicine

JF - Nature Medicine

IS - 9

ER -

Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

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