TY - CHAP
T1 - Proinsulin peptide immunotherapy in type 1 diabetes
T2 - safety data of a first in new-onset type 1 diabetes phase 1b trial
AU - Alhadj Ali, Mohammad
AU - Liu, Yuk-Fun
AU - Stenson, Rachel
AU - Clifford, Graham
AU - Adams, Laura
AU - Powrie, Jake
AU - Kyne, Deirdre
AU - Leech, Nicola
AU - Green, Kate
AU - Andrews, Robert
AU - Peakman, Mark
AU - Dayan, Colin
PY - 2015/9
Y1 - 2015/9
N2 - Background and aims: In Type 1 Diabetes, nonclinical studies have shown that Antigen Specific Therapy (ASI) strategies have been highly effective in disease prevention, and some of them have worked in the much more stringent setting of close to, or at, disease onset. Furthermore, they have demonstrated that the ASI strategies may be effective when the relevant autoantigen is delivered as a short peptide, representing a key target (termed an epitope) of the pathological T lymphocyte response that is characteristic of the disease. Clinical trials of ASI as applied to Type 1 Diabetes have predominantly focused on insulin as the autoantigen, administered by a variety of routes, in the setting of secondary prevention.
Aims and objectives: We aimed to examine the safety of intradermal administration of the naturally processed proinsulin peptide C19-A3 (PPI C19-A3) at a dose of 10μg every 14 days or every 28 days for a total of 12 doses (Group B) and 6 doses (Group C), respectively, to patients with new-onset Type 1 diabetes.
Materials and methods: The trial was a multi-centre, randomised; double-blind, placebo-controlled, 3-arm study of 10μg of PPI C19-A3 peptide administered every 14 or every 28 days, with follow-up for 48 weeks. 27 patients aged 18-45 with new-onset Type 1 Diabetes, HLA-DRB1*0401 genotype, antibody positivity and a stimulated c-peptide level >0.2pmol/ml were recruited to the trial within 100 days of diagnosis. TAll subjects received injections at bi-weekly intervals, and in the case of the placebo group (Group A) (n = 8) this was normal saline only; for the low frequency dosing group (Group C) (n = 10) this was alternate study drug and normal saline only; and for the high frequency dosing group (Group B) (n = 9) this was the study drug on every occasion.
Results: The trial injections have been generally well tolerated and all recruited patients completed the trial follow up with no withdrawal. No events of systemic hypersensitivity (type 1) have been reported in the trial, therefore; it has been shown that administration of Proinsulin peptide was safe. Only 5 serious adverse events (SAEs) were reported and classified as mild or moderate in severity (either unrelated or unlikely related to the randomisation drug). Local trial investigators did not report any SUSAR. More than 75% of adverse events (AEs) have been reported as hypoglycaemic episodes unlikely related to the randomisation drug, however; local skin reaction at the injection site has been reported as an AE that is likely related to the trial drug with no systemic complications.
Conclusion: Proinsulin peptide immunotherapy in the dosing regimen used is well tolerated and free from the risk of systemic hypersensitivity and serious adverse reactions. The safety from hypersensitivity reaction was clearly seen in the repeated dosing up to 12 doses in the same patient. This phase 1 trial will pave the route for future phase 2 trials in new-onset Type 1 Diabetes which aim to examine the effectiveness of Proinsulin peptide immunotherapy on T cell autoimmunity and preservation of β cell function
AB - Background and aims: In Type 1 Diabetes, nonclinical studies have shown that Antigen Specific Therapy (ASI) strategies have been highly effective in disease prevention, and some of them have worked in the much more stringent setting of close to, or at, disease onset. Furthermore, they have demonstrated that the ASI strategies may be effective when the relevant autoantigen is delivered as a short peptide, representing a key target (termed an epitope) of the pathological T lymphocyte response that is characteristic of the disease. Clinical trials of ASI as applied to Type 1 Diabetes have predominantly focused on insulin as the autoantigen, administered by a variety of routes, in the setting of secondary prevention.
Aims and objectives: We aimed to examine the safety of intradermal administration of the naturally processed proinsulin peptide C19-A3 (PPI C19-A3) at a dose of 10μg every 14 days or every 28 days for a total of 12 doses (Group B) and 6 doses (Group C), respectively, to patients with new-onset Type 1 diabetes.
Materials and methods: The trial was a multi-centre, randomised; double-blind, placebo-controlled, 3-arm study of 10μg of PPI C19-A3 peptide administered every 14 or every 28 days, with follow-up for 48 weeks. 27 patients aged 18-45 with new-onset Type 1 Diabetes, HLA-DRB1*0401 genotype, antibody positivity and a stimulated c-peptide level >0.2pmol/ml were recruited to the trial within 100 days of diagnosis. TAll subjects received injections at bi-weekly intervals, and in the case of the placebo group (Group A) (n = 8) this was normal saline only; for the low frequency dosing group (Group C) (n = 10) this was alternate study drug and normal saline only; and for the high frequency dosing group (Group B) (n = 9) this was the study drug on every occasion.
Results: The trial injections have been generally well tolerated and all recruited patients completed the trial follow up with no withdrawal. No events of systemic hypersensitivity (type 1) have been reported in the trial, therefore; it has been shown that administration of Proinsulin peptide was safe. Only 5 serious adverse events (SAEs) were reported and classified as mild or moderate in severity (either unrelated or unlikely related to the randomisation drug). Local trial investigators did not report any SUSAR. More than 75% of adverse events (AEs) have been reported as hypoglycaemic episodes unlikely related to the randomisation drug, however; local skin reaction at the injection site has been reported as an AE that is likely related to the trial drug with no systemic complications.
Conclusion: Proinsulin peptide immunotherapy in the dosing regimen used is well tolerated and free from the risk of systemic hypersensitivity and serious adverse reactions. The safety from hypersensitivity reaction was clearly seen in the repeated dosing up to 12 doses in the same patient. This phase 1 trial will pave the route for future phase 2 trials in new-onset Type 1 Diabetes which aim to examine the effectiveness of Proinsulin peptide immunotherapy on T cell autoimmunity and preservation of β cell function
M3 - Meeting abstract
VL - 58
BT - Diabetologia
ER -
