A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus

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Abstract

Background: The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1β (IL-1β) represent potential therapeutic targets for disease modifying therapy. Objective: We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. Subjects and methods: Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. Results: There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged “possibly related” to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P =.01 by paired t test) during 6 months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P =.05), but there was not a significant change in daily insulin dose (0.41 ± 0.23 to 0.47 ± 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 ± 1.8 to 9.0 ± 1.5). Subjects in “remission,” defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. Conclusions: Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function.

Original languageEnglish (US)
Pages (from-to)788-793
Number of pages6
JournalPediatric Diabetes
Volume19
Issue number4
DOIs
StatePublished - Jun 1 2018

Fingerprint

Type 1 Diabetes Mellitus
Anti-Inflammatory Agents
Hemoglobins
Insulin
Cytokines
Therapeutics
C-Peptide
Interleukin-1
Meals
Immune System
Leukocytes
rilonacept
Incidence
Infection
Pharmaceutical Preparations
Genes

Keywords

  • cytokine
  • gene expression
  • immunomodulation
  • innate immunity
  • interleukin-1β

ASJC Scopus subject areas

  • Internal Medicine
  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism

Cite this

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title = "A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus",
abstract = "Background: The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1β (IL-1β) represent potential therapeutic targets for disease modifying therapy. Objective: We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. Subjects and methods: Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. Results: There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged “possibly related” to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P =.01 by paired t test) during 6 months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P =.05), but there was not a significant change in daily insulin dose (0.41 ± 0.23 to 0.47 ± 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 ± 1.8 to 9.0 ± 1.5). Subjects in “remission,” defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. Conclusions: Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function.",
keywords = "cytokine, gene expression, immunomodulation, innate immunity, interleukin-1β",
author = "White, {Perrin C.} and Soumya Adhikari and Grishman, {Ellen K.} and Sumpter, {Kathryn M.}",
year = "2018",
month = "6",
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doi = "10.1111/pedi.12634",
language = "English (US)",
volume = "19",
pages = "788--793",
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T1 - A phase I study of anti-inflammatory therapy with rilonacept in adolescents and adults with type 1 diabetes mellitus

AU - White, Perrin C.

AU - Adhikari, Soumya

AU - Grishman, Ellen K.

AU - Sumpter, Kathryn M.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1β (IL-1β) represent potential therapeutic targets for disease modifying therapy. Objective: We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. Subjects and methods: Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. Results: There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged “possibly related” to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P =.01 by paired t test) during 6 months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P =.05), but there was not a significant change in daily insulin dose (0.41 ± 0.23 to 0.47 ± 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 ± 1.8 to 9.0 ± 1.5). Subjects in “remission,” defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. Conclusions: Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function.

AB - Background: The innate immune system may be activated around the time of diagnosis of type 1 diabetes (T1D). Components of this system, including cytokines such as interleukin-1β (IL-1β) represent potential therapeutic targets for disease modifying therapy. Objective: We conducted a phase 1 trial of rilonacept, an IL-1 cytokine trap, in patients with T1D. Subjects and methods: Thirteen T1D patients (10 males) with median age (interquartile range, IQR) of 17 years (16-18), a median (IQR) of 5 months (5-7) since diagnosis. Rilonacept was administered subcutaneously for 26 weeks. Incidence of infections was the primary end-point. Results: There were 85 adverse events; 13 were Grade 2, of which 9 (8 infectious) were judged “possibly related” to the drug. The mean (SD) C-peptide on 2-hour mixed meal tolerance tests decreased from 0.87 (0.42) to 0.59 (0.29) ng/mL (P =.01 by paired t test) during 6 months on treatment. Hemoglobin A1c (HbA1c) increased from 6.8 (1.1) to 7.3 (1.1) (P =.05), but there was not a significant change in daily insulin dose (0.41 ± 0.23 to 0.47 ± 0.18), or in insulin dose-adjusted HbA1c (IDAA1c, 8.4 ± 1.8 to 9.0 ± 1.5). Subjects in “remission,” defined as HbA1c <6.5 and a total daily insulin dose <0.5 units/kg/24 h, decreased from 5 to 4. There were no significantly differentially expressed genes in peripheral blood leukocytes before and after rilonacept. Conclusions: Rilonacept treatment for 6 months is well-tolerated in individuals with T1D of recent onset, but is unlikely to be efficacious as a single agent in preserving beta cell function.

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