Phase III Trials Set After Potential Type 1 Diabetes Vaccine Shows Promise

[Editor’s note: This post has been updated to clarify that the meta-analysis published in Diabetologia and the Phase IIb trial were separate studies.]

Earlier this fall, Phase IIb topline results of the DIAGNODE-2 trial demonstrated a potential type 1 diabetes vaccine GAD-alum —  an immunomodulating antigen-specific therapy – had a highly significant and clinically relevant effect in genetically defined subgroups of individuals with the disease. Diamyd Medical is supporting the trials and developing the drug candidate as Diamyd.

The topline results from the DIAGNODE-2 trial were preceded by a meta-analysis of previous trials that was published in Diabetologia. The authors of the meta-analysis point out that GAD-alum (recombinant human GAD65 conjugated to aluminum hydroxide) is a pancreatic beta cell protein and GAD65 is one of the most frequent autoantigens associated with type 1 diabetes. However, previous studies looking at GAD-alum’s effects in preserving insulin production have returned inconclusive results. “The aim of this study was to estimate, using individual-level patient data from previous randomized, placebo-controlled trials, whether the efficacy of GAD-specific immunotherapy depends on the presence of the GAD and insulin antibody-associated HLA [Human Leukocyte Antigen] haplotypes DR3-DQ2 and DR4-DQ8,” the authors write. The meta-analysis, based on data from more than 500 individual study participants, indeed showed that the HLA haplotype significantly influences the effect of GAD-alum and that individuals carrying the HLA DR3-DQ2 haplotype receive a highly significant and clinically relevant effect of the therapy.

For the DIAGNODE-2 study, the researchers analyzed data from 103 out of 109 patients, evaluated as part of the topline results for the primary endpoint: preserving beta cell function at 15 months, as measured by meal stimulated C-peptide. Fifty-five of the 103 patients evaluated received active treatment while 48 received placebo treatment. Forty-six patients out of 103 evaluated were positive for the HLA DR3-DQ2 haplotype. Out of the 46 patients, 29 received active treatment and 17 received placebo.

While a limited positive but non-significant treatment effect was observed in the 103 patients evaluated as part of the topline results, a statistically significant (p < 0.01) treatment effect was observed in the predefined subgroup of patients positive for HLA DR3-DQ2. In this subgroup of patients, more than 50% greater preservation of C-peptide was observed in those that received active treatment compared to placebo. Likewise, positive trends in patients positive for HLA DR3-DQ2 were observed for all the important secondary endpoints: change in blood glucose levels as determined by HbA1c, insulin dose, and insulin-adjusted HbA1c compared to placebo-treated patients. No benefit was seen in patients negative for HLA DR3-DQ2.

The researchers concluded that GAD65-specific immunotherapy has a significant effect on C-peptide retention in individuals with recent-onset type 1 diabetes who have the DR3-DQ2 haplotype. Based on these results, Diamyd Medical will pursue the HLA-restricted responder subgroup in an upcoming Phase III program.

“I am overjoyed by the positive results,” says Johnny Ludvigsson, MD, PhD, professor at Linköping University and coordinating investigator of the trial. “What we see now is that the GAD treatment works for nearly half of the patients with type 1 diabetes. It is important that this patient group may soon benefit from an effective, safe, and convenient treatment that does not suppress the immune system, especially now in the era of COVID-19.”

“In my 37 years in type 1 diabetes research, these are some of the most promising results I have seen in terms of the potential for providing benefit to those recently diagnosed with type 1 diabetes,” says Mark Atkinson, PhD, director of the Diabetes Research Institute at the University of Florida and Diamyd Medical Board Member. “These findings emphasize the importance of genetic analysis and personalized medicine in the development of treatments for type 1 diabetes and could explain conflicting results of previous trials in the field.”

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