Merana Tamir

β-cell function in new-onset type 1 diabetes and immunomodulation with a heat-shock protein peptide (DiaPep277): a randomised, double-blind, phase II trial

Summary Background Type 1 diabetes results from autoimmune destruction of insulin-producing pancreaticcells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested � -cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (<6 months) type 1 diabetes.

Treatment of new‐onset type 1 diabetes with peptide DiaPep277® is safe and associated with preserved beta‐cell function: extension of a randomized, double‐blind, phase II trial

Treatment with DiaPep277®, a peptide derived from HSP60, has been shown to preserve beta‐cell function in non‐obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10‐month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements.

Treatment of Recent-Onset Type 1 Diabetic Patients With DiaPep277: Results of a Double-Blind, Placebo-Controlled, Randomized Phase 3 Trial

OBJECTIVE To evaluate safety and efficacy of DiaPep277 in preserving β-cell function in type 1 diabetic patients. RESEARCH DESIGN AND METHODS DIA-AID 1 is a multinational, phase 3, balanced-randomized, double-blind, placebo-controlled, parallel-group clinical study. Newly diagnosed patients (N = 457, aged 16–45 years) were randomized to subcutaneous injections of DiaPep277 or placebo quarterly for 2 years. The primary efficacy end point was the change from baseline in the area under the glucagon-stimulated C-peptide curve. Secondary end points were the change from baseline in mixed-meal stimulated C-peptide secretion and in fasting C-peptide and achieving target HbA1c ≤7% (≤53 mmol/mol). Partial remission (target HbA1c on insulin ≤0.5 units/kg/day) and hypoglycemic event rate were exploratory end points. RESULTS DiaPep277 was safe and well tolerated. Significant preservation of C-peptide secretion was observed in the DiaPep277-treated group compared with the placebo (relative treatment effects of 23.4%, P = 0.037, and 29.2%, P = 0.011, in the modified intent-to-treat [mITT] and per-protocol [PP] populations, respectively). The mixed-meal stimulation failed to distinguish between the groups. There was a trend toward efficacy in fasting C-peptide levels, though not statistically significant. Significantly more DiaPep277-treated than placebo-treated patients maintained target HbA1c (mITT 56% versus 44%, P = 0.03; PP 60% versus 45%, P = 0.0082) and entered partial remission (mITT 38% versus 29%, P = 0.08; PP 42% versus 30%, P = 0.035). DiaPep277 treatment reduced the relative hypoglycemic event risk (mITT by 20%; PP by 28%). CONCLUSIONS DiaPep277 safely contributes to preservation of β-cell function and to improved glycemic control in patients with type 1 diabetes.

DiaPep277 preserves endogenous insulin production by immunomodulation in type 1 diabetes.

Abstract:  DiaPep277 is an immunomodulatory peptide that arrests β cell destruction in mouse models of type 1 diabetes mellitus (T1DM). This article extends an original pilot observation to two studies of 61 patients (age > 16 years), diagnosed with T1DM within 6 months, and with measurable β cell function. Patients were treated with placebo (n= 27) or 1.0 mg DiaPep277 (n= 34). After 13 months, 1.0 mg Dia Pep277 treatment significantly (P= 0.02) preserved β cell function as compared to the control with a trend for reduced HbA1c. This was achieved without an increase in insulin dose in the DiaPep277 group and with excellent safety. DiaPep277‐treated patients also had fewer Th1 DiaPep277‐specific T cells.

Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal

OBJECTIVE Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes. RESEARCH DESIGN AND METHODS A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson’s correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (∆AUC). RESULTS The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74–0.9). However, the correlations between the ∆AUC were much weaker (r = 0.39–0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4–11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose. CONCLUSIONS Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.

Treatment of Recent-Onset Type 1 Diabetic Patients With DiaPep277: Results of a Double-Blind, Placebo-Controlled, Randomized Phase 3 Trial. Diabetes Care 2014;37:1392–1400. DOI: 10.2337/dc13-1391

On behalf of the authors identified below, the corresponding author has formally requested to retract the above-cited article. An accompanying article (1) has also been retracted. The article reports on the DIA-AID 1 trial, which examined the safety and efficacy of DiaPep277 to treat type 1 diabetes. The DIA-AID 1 trial, as noted in the Duality of Interest section, was funded by Andromeda Biotech, Ltd. On 8 September 2014, Hyperion Therapeutics, Inc., which acquired Andromeda Biotech in June 2014, announced that it had chosen to terminate the DiaPep277 program. As stated in the press release …

Retraction Note: Abstracts of the 50th Annual Meeting of the EASD, Vienna 2014. ‘Evaluation of DiaPep277® treatment in type 1 diabetes by integrated analysis’

On behalf of the authors identified below, Itamar Raz, the corresponding author, has formally requested to retract Abstract 453, cited above, which was published in Diabetologia Supplement 1, September 2014—the Abstract Volume of 2014 EASD Annual meeting. The abstract reports on the DIA-AID 1 trial, which examined the safety and efficacy of DiaPep277 to treat type 1 diabetes. The DIA-AID 1 trial was funded by Andromeda Biotech, Ltd. On 8 September 2014, Hyperion Therapeutics, Inc., which acquired Andromeda Biotech in June 2014, announced that it had chosen to terminate the DiaPep277 programme. As stated in the press release issued by Hyperion Therapeutics, ‘The company has uncovered evidence that certain employees of Andromeda Biotech, Ltd ... engaged in serious misconduct, including collusion with a third-party biostatistics firm in Israel to improperly receive un-blinded DIA-AID 1 trial data and to use such data in order to manipulate the analyses to obtain a favorable result’ [1]. The corresponding author writes: ‘In view of the public statements by Hyperion Therapeutics [1] regarding alleged scientific misconduct, we, the authors of this statement, are retracting the above-cited abstract. We wish to emphasize that we were not involved in the assembly of the raw data or the alleged misconduct. ‘The following authors support the decision to retract the article: Itamar Raz, Paolo Pozzilli, Thomas Linn and Francois Bonnici.’ Diabetologia was only able to contact four of the six coauthors who are/were Andromeda Biotech employees—Dana Elias, Merana Tamir, Rachel Eren and Shlomo Dagan. None of these co-authors responded to emails and therefore none of the Andromeda Biotech employees were part of this retraction process.

Evaluation of Long-Term Treatment Effect in a Type 1 Diabetes Intervention Trial: Differences After Stimulation With Glucagon or a Mixed Meal. Diabetes Care 2014;37:1384–1391. DOI: 10.2337/dc13-1392

On behalf of the authors identified below, the corresponding author has formally requested to retract the above-cited article. An accompanying article (1) has also been retracted. The study described in this article uses data from the DIA-AID 1 trial on DiaPep277 to compare treatment effects in patients with type 1 diabetes. The DIA-AID 1 trial, as noted in the Duality of Interest section, was funded by Andromeda Biotech, Ltd. On 8 September 2014, Hyperion Therapeutics, Inc., which acquired Andromeda Biotech in June 2014, announced that it had chosen to terminate the …