No effect of the altered peptide ligand NBI-6024 on beta-cell residual function and insulin needs in new-onset type 1 diabetes.
OBJECTIVE
This randomized, four-arm, placebo-controlled, dose-ranging phase 2 trial was conducted to determine whether repeated subcutaneous injections of the altered peptide ligand, NBI-6024, designed to inhibit autoreactive T-cells, improves beta-cell function in patients with recently diagnosed type 1 diabetes.


METHODS
A total of 188 patients, aged 10-35 years, with recently diagnosed type 1 diabetes were randomly assigned for a treatment consisting of the subcutaneous administration of placebo or 1, 0.5, or 0.1 mg NBI-6024 at baseline, weeks 2 and 4, and then monthly until month 24. Fasting, peak, and area under the curve (AUC) C-peptide concentrations during a 2-h mixed-meal tolerance test were measured at 3-month intervals during treatment. Immune function parameters (islet antibodies and CD4 and CD8 T-cells) were also studied.


RESULTS
The mean peak C-peptide concentration at 24 months after study entry showed no significant difference between the groups treated with 0.1 mg (0.59 pmol/ml), 0.5 mg (0.57 pmol/ml), and 1.0 mg NBI-6024 (0.48 pmol/ml) and the placebo group (0.54 pmol/ml). Fasting, stimulated peak, and AUC C-peptide concentrations declined linearly in all groups by approximately 60% over the 24-month treatment period. The average daily insulin needs at month 24 were also comparable between the four groups. No treatment-related changes in islet antibodies and T cell numbers were observed.


CONCLUSIONS
Treatment with altered peptide ligand NBI-6024 at repeated doses of 0.1, 0.5, or 1.0 mg did not improve or maintain beta-cell function.
Walter
Markus
M
Diabetes Research Institute, Forschergruppe Diabetes e.V., Munich, Germany.
Philotheou
Areti
A
Bonnici
François
F
Ziegler
Anette-G
AG
Jimenez
Roland
R
D000293:Adolescent; D000328:Adult; D002096:C-Peptide / Q000097:blood*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D010446:Peptide Fragments / Q000494:pharmacology / Q000627:therapeutic use*; D010919:Placebos; D055815:Young Adult
D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; C460599:NBI6024; D010446:Peptide Fragments; D010919:Placebos
N Engl J Med. 1986 May 22;314(21):1360-8
3517648
Scand J Immunol. 2006 Jan;63(1):59-69
16398702
IDrugs. 2002 Dec;5(12):1162-7
12800057
Science. 1984 Mar 30;223(4643):1362-7
6367043
N Engl J Med. 2008 Oct 30;359(18):1909-20
18843118
J Autoimmun. 1999 Sep;13(2):267-82
10479395
N Engl J Med. 2005 Jun 23;352(25):2598-608
15972866
Diabetes. 2002 Jul;51(7):2126-34
12086942
J Autoimmun. 1994 Dec;7(6):833-43
7888039
J Immunol. 1999 Nov 15;163(10):5708-14
10553102