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Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial
Nature Medicine
Swansea University Authors:
Kym Carter , Ivy Cheung, Steve Luzio
, Gareth Dunseath
, Hayley Hutchings
, Gail Holland
, Steve Hiles, Greg Fegan
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DOI (Published version): 10.1038/s41591-024-03115-2
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...
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ISSN: | 1078-8956 1546-170X |
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Springer Science and Business Media LLC
2024
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<?xml version="1.0" encoding="utf-8"?><rfc1807 xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xsd="http://www.w3.org/2001/XMLSchema"><bib-version>v2</bib-version><id>67256</id><entry>2024-07-30</entry><title>Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial</title><swanseaauthors><author><sid>1b1870c5c1ec66eed0bf209e50a6ee25</sid><ORCID>0000-0003-0691-6282</ORCID><firstname>Kym</firstname><surname>Carter</surname><name>Kym Carter</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>a9142ffd398f89eff40ada503e315639</sid><firstname>Ivy</firstname><surname>Cheung</surname><name>Ivy Cheung</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>01491e1cd582746a654fad9addf0de16</sid><ORCID>0000-0002-7206-6530</ORCID><firstname>Steve</firstname><surname>Luzio</surname><name>Steve Luzio</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>fccbba9edcaee08a839a3c5cff8cbe19</sid><ORCID>0000-0001-6022-862X</ORCID><firstname>Gareth</firstname><surname>Dunseath</surname><name>Gareth Dunseath</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>bdf5d5f154d339dd92bb25884b7c3652</sid><ORCID>0000-0003-4155-1741</ORCID><firstname>Hayley</firstname><surname>Hutchings</surname><name>Hayley Hutchings</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>b9f3a8bf7478db012c8856b7bbbc7597</sid><ORCID>0000-0002-6924-2521</ORCID><firstname>Gail</firstname><surname>Holland</surname><name>Gail Holland</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>5ecd70f8c0f27219f84a7f297d99b22b</sid><firstname>Steve</firstname><surname>Hiles</surname><name>Steve Hiles</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>a9005418b89918776f3d8895ba42e850</sid><firstname>Greg</firstname><surname>Fegan</surname><name>Greg Fegan</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2024-07-30</date><deptcode>MEDS</deptcode><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).</abstract><type>Journal Article</type><journal>Nature Medicine</journal><volume>0</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>1078-8956</issnPrint><issnElectronic>1546-170X</issnElectronic><keywords/><publishedDay>30</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-07-30</publishedDate><doi>10.1038/s41591-024-03115-2</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>This project (project reference 16/36/01) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, a partnership between the National Institute for Health and Care Research (NIHR) and the Medical Research Council (MRC). The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. Additional funding for mechanistic laboratory tests has been provided by Breakthrough T1D (formerly JDRF (Juvenile Diabetes Research Foundation)) International awards (3-SRA-2018-629-S-B and 4-SRA-2020-882-S-B). The UK Type 1 Diabetes Consortium supported the USTEKID study via grants from Diabetes UK (19/0005951 and 15/0005232) and Breakthrough T1D (formerly JDRF) (3-SRA-2019-774-A-N). S.J.H. is funded by the Diabetes Research and Wellness Foundation Professor David Matthews Non-Clinical Research Fellowship. M.K.L. receives a salary award from the BC Children’s Hospital Research Institute and is a Canada Research Chair in Engineered Immune Tolerance. K.W.H. received a fellowship from the Canadian Institutes for Health Research.</funders><projectreference/><lastEdited>2024-08-05T17:05:12.3307276</lastEdited><Created>2024-07-30T12:27:58.2751335</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Health Data Science</level></path><authors><author><firstname>Danijela</firstname><surname>Tatovic</surname><orcid>0000-0002-3879-2686</orcid><order>1</order></author><author><firstname>Ashish</firstname><surname>Marwaha</surname><order>2</order></author><author><firstname>Peter</firstname><surname>Taylor</surname><order>3</order></author><author><firstname>Stephanie J.</firstname><surname>Hanna</surname><orcid>0000-0002-0821-4498</orcid><order>4</order></author><author><firstname>Kym</firstname><surname>Carter</surname><orcid>0000-0003-0691-6282</orcid><order>5</order></author><author><firstname>Ivy</firstname><surname>Cheung</surname><order>6</order></author><author><firstname>Steve</firstname><surname>Luzio</surname><orcid>0000-0002-7206-6530</orcid><order>7</order></author><author><firstname>Gareth</firstname><surname>Dunseath</surname><orcid>0000-0001-6022-862X</orcid><order>8</order></author><author><firstname>Hayley</firstname><surname>Hutchings</surname><orcid>0000-0003-4155-1741</orcid><order>9</order></author><author><firstname>Gail</firstname><surname>Holland</surname><orcid>0000-0002-6924-2521</orcid><order>10</order></author><author><firstname>Steve</firstname><surname>Hiles</surname><order>11</order></author><author><firstname>Greg</firstname><surname>Fegan</surname><order>12</order></author><author><firstname>Evangelia</firstname><surname>Williams</surname><order>13</order></author><author><firstname>Jennie H. 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v2 67256 2024-07-30 Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial 1b1870c5c1ec66eed0bf209e50a6ee25 0000-0003-0691-6282 Kym Carter Kym Carter true false a9142ffd398f89eff40ada503e315639 Ivy Cheung Ivy Cheung true false 01491e1cd582746a654fad9addf0de16 0000-0002-7206-6530 Steve Luzio Steve Luzio true false fccbba9edcaee08a839a3c5cff8cbe19 0000-0001-6022-862X Gareth Dunseath Gareth Dunseath true false bdf5d5f154d339dd92bb25884b7c3652 0000-0003-4155-1741 Hayley Hutchings Hayley Hutchings true false b9f3a8bf7478db012c8856b7bbbc7597 0000-0002-6924-2521 Gail Holland Gail Holland true false 5ecd70f8c0f27219f84a7f297d99b22b Steve Hiles Steve Hiles true false a9005418b89918776f3d8895ba42e850 Greg Fegan Greg Fegan true false 2024-07-30 MEDS 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). Journal Article Nature Medicine 0 Springer Science and Business Media LLC 1078-8956 1546-170X 30 7 2024 2024-07-30 10.1038/s41591-024-03115-2 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee This project (project reference 16/36/01) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, a partnership between the National Institute for Health and Care Research (NIHR) and the Medical Research Council (MRC). The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. Additional funding for mechanistic laboratory tests has been provided by Breakthrough T1D (formerly JDRF (Juvenile Diabetes Research Foundation)) International awards (3-SRA-2018-629-S-B and 4-SRA-2020-882-S-B). The UK Type 1 Diabetes Consortium supported the USTEKID study via grants from Diabetes UK (19/0005951 and 15/0005232) and Breakthrough T1D (formerly JDRF) (3-SRA-2019-774-A-N). S.J.H. is funded by the Diabetes Research and Wellness Foundation Professor David Matthews Non-Clinical Research Fellowship. M.K.L. receives a salary award from the BC Children’s Hospital Research Institute and is a Canada Research Chair in Engineered Immune Tolerance. K.W.H. received a fellowship from the Canadian Institutes for Health Research. 2024-08-05T17:05:12.3307276 2024-07-30T12:27:58.2751335 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Health Data Science Danijela Tatovic 0000-0002-3879-2686 1 Ashish Marwaha 2 Peter Taylor 3 Stephanie J. Hanna 0000-0002-0821-4498 4 Kym Carter 0000-0003-0691-6282 5 Ivy Cheung 6 Steve Luzio 0000-0002-7206-6530 7 Gareth Dunseath 0000-0001-6022-862X 8 Hayley Hutchings 0000-0003-4155-1741 9 Gail Holland 0000-0002-6924-2521 10 Steve Hiles 11 Greg Fegan 12 Evangelia Williams 13 Jennie H. M. Yang 0000-0001-6171-833x 14 Clara Domingo-Vila 15 Emily Pollock 0000-0002-7297-4205 16 Muntaha Wadud 17 Kirsten Ward-Hartstonge 18 Susie Marques-Jones 19 Jane Bowen-Morris 20 Rachel Stenson 21 Megan K. Levings 0000-0002-0305-5790 22 John W. Gregory 23 Timothy I. M. Tree 24 Colin Dayan 25 Evelien Gevers 26 Shankar Kanumakala 27 Sunil Nair 28 Chris Gardner 29 Michal Ajzensztejn 30 Christina Wei 31 Chris Mouditis 32 Fiona Campbell 33 James Greening 34 Emma Webb 35 Mimi Chen 36 Rakesh Amin 37 Billi White 38 Ambika Shetty 39 Chris Bidder 40 Nicholas Conway 41 Amalia Mayo 42 Eleni Christakou 43 Kamila Sychowska 44 Yasaman Shahrabi 45 Maximilian Robinson 46 Simi Ahmed 47 Jan Dutz 48 Laura Cook 49 (USTEKID Study Group) 50 67256__31011__0e889aa34a5243b5b979b2f9a8124b97.pdf Ustekid nature medicine.pdf 2024-07-30T12:47:13.0259847 Output 5080500 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License. true eng http://creativecommons.org/licenses/by/4.0/ |
title |
Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial |
spellingShingle |
Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial Kym Carter Ivy Cheung Steve Luzio Gareth Dunseath Hayley Hutchings Gail Holland Steve Hiles Greg Fegan |
title_short |
Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial |
title_full |
Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial |
title_fullStr |
Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial |
title_full_unstemmed |
Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial |
title_sort |
Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial |
author_id_str_mv |
1b1870c5c1ec66eed0bf209e50a6ee25 a9142ffd398f89eff40ada503e315639 01491e1cd582746a654fad9addf0de16 fccbba9edcaee08a839a3c5cff8cbe19 bdf5d5f154d339dd92bb25884b7c3652 b9f3a8bf7478db012c8856b7bbbc7597 5ecd70f8c0f27219f84a7f297d99b22b a9005418b89918776f3d8895ba42e850 |
author_id_fullname_str_mv |
1b1870c5c1ec66eed0bf209e50a6ee25_***_Kym Carter a9142ffd398f89eff40ada503e315639_***_Ivy Cheung 01491e1cd582746a654fad9addf0de16_***_Steve Luzio fccbba9edcaee08a839a3c5cff8cbe19_***_Gareth Dunseath bdf5d5f154d339dd92bb25884b7c3652_***_Hayley Hutchings b9f3a8bf7478db012c8856b7bbbc7597_***_Gail Holland 5ecd70f8c0f27219f84a7f297d99b22b_***_Steve Hiles a9005418b89918776f3d8895ba42e850_***_Greg Fegan |
author |
Kym Carter Ivy Cheung Steve Luzio Gareth Dunseath Hayley Hutchings Gail Holland Steve Hiles Greg Fegan |
author2 |
Danijela Tatovic Ashish Marwaha Peter Taylor Stephanie J. Hanna Kym Carter Ivy Cheung Steve Luzio Gareth Dunseath Hayley 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 Evelien Gevers Shankar Kanumakala Sunil Nair Chris Gardner Michal Ajzensztejn Christina Wei Chris Mouditis Fiona Campbell James Greening Emma Webb Mimi Chen Rakesh Amin Billi White Ambika Shetty Chris Bidder Nicholas Conway Amalia Mayo Eleni Christakou Kamila Sychowska Yasaman Shahrabi Maximilian Robinson Simi Ahmed Jan Dutz Laura Cook (USTEKID Study Group) |
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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). |
published_date |
2024-07-30T17:05:11Z |
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1806564234302062592 |
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11.021648 |