“These two analyses show the robustness of our data and provide a high likelihood of success for the Phase III trial and the therapeutic precision diabetes vaccine Diamyd® ”, says Ulf Hannelius, CEO of Diamyd Medical.
Analysis 1) When restricting the data in the 627-individual meta-analysis set to the same age range and country selection as used in the design of the Phase III trial DIAGNODE-3, the positive treatment effect of Diamyd® in individuals that carry the HLA DR3-DQ2 gene remained intact, showing a positive and highly statistically significant treatment effect both on the preservation of endogenous insulin-producing capacity and on improved blood glucose control in the genetically defined responder group.
Analysis 2) In the original meta-analysis, the analysis model automatically replaced missing values (less than 4% of all data in the data set) with "best-guesses". This is common practice but may in some situations bias the results. Diamyd Medical has made a careful and conservative assessment replacing all missing values with the worst possible values from a Diamyd Medical perspective. When replacing missing data from the meta-analysis by these worst possible data, the effect estimates remained statistically significant and positive, indicating very robust results regarding treatment effect of Diamyd®.
Targeting responders and super-responders in the Phase III trial
As previously communicated, the best effect of the therapeutic diabetes vaccine Diamyd® is seen in individuals that are positive for the HLA DR3-DQ2 gene and simultaneously negative for the HLA DR4-DQ8 gene, the so-called Super-responder group. The Phase III trial, DIAGNODE-3, is designed to formally assess, with high statistical power, the treatment effect in both the full patient population of individuals that carry the DR3-DQ2 gene as well as in the Super-responder subgroup (about half of the full patient population). The Phase III trial will also include a blinded interim analysis that provides an opportunity to re-estimate the sample size when data from a selection of individuals followed for a shorter time have been analysed, further increasing the robustness of the trial by ensuring high power to reach significance in the co-primary endpoints of beta-cell preservation and improved blood glucose control.
About the meta-analyses
The original large-scale meta-analysis, comprising data from three previous placebo controlled clinical trials, was announced in December 2019 and published in Diabetologia in August 2020. The meta-analysis showed that the HLA genotype of the individual significantly influenced the effect of Diamyd®, with individuals carrying the HLA DR3-DQ2 haplotype receiving a highly significant and clinically relevant treatment effect.
The European Phase IIb trial DIAGNODE-2 that was started in 2017 and evaluated the safety and efficacy of intralymphatic injections of Diamyd® in individuals with recent-onset type 1 diabetes was, following the announcement of the meta-analysis results, in December 2019, amended to prespecify individuals with the HLA DR3-DQ2 haplotype as part of the topline analyses. The topline results from DIAGNODE-2 were announced in September 2020 and published in Diabetes Care in May 2021. The trial confirmed the findings from the meta-analysis; the primary endpoint in the full patient population was not reached while a statistically significant treatment effect in the prespecified patient population positive for the HLA DR3-DQ2 haplotype was shown.
The meta-analysis was consequently updated in January 2021 with DIAGNODE-2 data, now encompassing data from 627 individuals with a recent diagnosis of type 1 diabetes. The updated meta-analysis showed, in line with the original meta-analysis and the DIAGNODE-2 results, that the HLA genotype of the individual significantly influenced the effect of Diamyd® treatment both regarding preservation of endogenous insulin producing capacity as well as improved blood glucose control.
About DIAGNODE-3
The Phase III trial DIAGNODE-3, with a planned start date later during 2021 and primary completion end of 2025, is designed to enroll approximately 330 individuals aged 12 to 28, recently diagnosed with type 1 diabetes, who carry the HLA DR3-DQ2 haplotype. This patient population is based on clinical efficacy and safety results from the Phase IIa and Phase IIb trials DIAGNODE-1 and DIAGNODE-2, as well as the large-scale meta-analysis encompassing data from more than 600 individuals from previous Phase II and Phase III trials using Diamyd®. A further stratification for HLA haplotypes will be included in order to evaluate the potential super responder group of individuals who are positive for HLA DR3-DQ2 and negative for HLA DR4-DQ8.
The Phase III trial will be conducted at approximately 50 clinical sites in Europe and the United States. Following a run-in period where all subjects receive vitamin D for one month, subjects will be randomized 2:1 to receive three intralymphatic injections of Diamyd® or matching placebo given one month apart, with a primary efficacy readout at 24 months from baseline. The design provides, based on efficacy data from previous trials on the HLA restricted patient population, a high probability to reach its co-primary endpoint regarding preservation of endogenous insulin producing capacity measured as stimulated C-peptide and improved blood glucose control measured as HbA1c.
About Diamyd Medical
Diamyd Medical develops precision medicine therapies for type 1 diabetes. The diabetes vaccine Diamyd® is an antigen-specific immunotherapy for the preservation of endogenous insulin production. Significant results have been shown in a large genetically predefined patient group in a large-scale meta-analysis as well as in the Company’s European Phase IIb trial DIAGNODE-2, where the diabetes vaccine was administered directly into a lymph node in children and young adults with recently diagnosed type 1 diabetes. Preparations for a confirmatory Phase III trial in the US and Europe are on-going, to start recruting patients later in 2021. A vaccine manufacturing facility is being set up in Umeå for the manufacture of recombinant GAD65, the active ingredient in the therapeutic diabetes vaccine Diamyd®. Diamyd Medical also develops the GABA-based investigational drug Remygen® as a therapy for regeneration of endogenous insulin production and to improve hormonal response to hypoglycaemia. An investigator-initiated Remygen® trial in patients living with type 1 diabetes for more than five years is ongoing at Uppsala University Hospital. Diamyd Medical is one of the major shareholders in the stem cell company NextCell Pharma AB.
Diamyd Medical’s B-share is traded on Nasdaq First North Growth Market under the ticker DMYD B. FNCA Sweden AB is the Company’s Certified Adviser; phone: +46 8-528 00 399, e-mail: info@fnca.se