Methyldopa mechanism

BROOMFIELD, Colo.—Type 1 diabetes (T1D), a polygenetic disorder, affects the insulin producing beta-cells in the pancreas. A group of researchers believes that more specific and personalized therapies are needed for disease prevention, and that blocking disease-relevant MHC class II antigen presentation will demonstrate a novel pathway for preventing type 1 diabetes.

The human HLA-DQ8 gene is the most significant factor in predisposing an individual to acquire T1D. The DQ8 gene is present in 50 to 60 percent of T1D patients. DQ8’s protein product (a major histocompatibility class II molecule) abnormally binds and presents particular autoantigen peptides to autoreactive T cells. In T1D, the immune system abnormally recognizes insulin as a foreign peptide. Over time, it attacks and destroys insulin-producing beta-cells in the pancreas, effectively eliminating the body’s ability to produce this important hormone.

Dr. Aaron Michels, chief scientific officer and co-founder of IM Therapeutics; co-founder Dr. Peter Gottlieb of the Barbara Davis Center for Diabetes at the University of Colorado, Denver; and their collaborators hypothesized that blocking DQ8 antigen presentation with a small molecule could provide therapeutic benefit by preventing recognition of self-peptides by the immune system’s pathogenic T cells.

Michels recently presented a novel approach to blocking the autoimmunity in T1D at the American Diabetes Association 78^th Scientific Sessions. His talk, “From Mechanism to Clinical Trial—Methyldopa for Type 1 Diabetes Prevention,” explored how the group successfully elucidated the mechanism of action and basic science behind the activity of methyldopa (MDOPA) as an innovative small-molecule approach to block the autoimmune response in T1D.

He also discussed results from a Phase 1b clinical trial in patients with recent-onset T1D, in which MDOPA showed a strong signal for efficacy. The results were published earlier this year in the Journal of Clinical Investigation in a paper titled “Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes.”

Michels’ presentation described the discovery process that identified MDOPA as a selective binding pair for DQ8, and the preclinical validation of this binding mechanism’s ability to block diabetes-specific T cells activated by DQ8. A small molecule of similar structure delayed diabetes onset in the non-obese diabetic mouse model of spontaneous autoimmune diabetes. Researchers used a rational structure-based approach to evaluate the drug receptiveness of pockets in the antigen-binding cleft of the T1D risk associated HLA-DQ8 molecule. MDOPA, currently approved by the FDA for the treatment of hypertension, was predicted to bind this pocket, with binding validated in vitro and in an animal model.

Preclinical findings were translated to human T1D in a single-arm, open-label Phase 1b dose-escalation study, in which MDOPA treatment was evaluated for safety and signals of efficacy to block DQ8. Study results demonstrated that DQ8 presentation was inhibited compared to baseline levels, with 17 of 20 patients showing a response. A subset of patients had reduced inflammatory T cell responses toward insulin, and MDOPA had no serious adverse events.

According to Michels, “Once beta-cell function is lost, T1D patients will be forever dependent on an external source of insulin. A drug that prevents the pathologic immune activity, like the one described in today’s presentation, could save beta-cell function early on and help these patients avoid a lifetime of injections and the risks associated with diabetes. In our study we show a new approach for treating autoimmune diseases, using MDOPA, which specifically blocked DQ8 in recent-onset patients with T1D and reduced inflammatory T cell responses toward insulin.”

As Gottlieb explained, “These results further validate the importance of HLA molecules as drug targets for autoimmune diseases, and the ability of a small-molecule inhibitor approach to potentially mitigate the progression of disease. Our lead candidate in development, IMT-002, is being developed to maintain the benefits that MDOPA has in T1D, such as specific binding to the peptide binding groove of DQ8 to block pathogenic function, while avoiding side effects such as lowering blood pressure.”

IMT-002 (D-methyldopa), which has been granted Orphan Drug status by the U.S. Food and Drug Administration, is an oral small-molecule drug being developed to treat T1D in patients with the HLA-DQ8 gene. IMT-002 occupies the peptide binding groove of DQ8 on the surface of antigen-presenting cells. When HLA-DQ8 function is inhibited, the immune system will no longer attack insulin-producing beta cells, thus creating the potential for at-risk or early-stage patients to maintain normal insulin production.

“We are extending the discovery process to celiac disease by targeting HLA-DQ2, which is highly prevalent in Celiac patients,” Gottlieb added.

Michels concluded, “HLA-DQ8 is remarkably amenable to small-molecule targeting. Methyldopa blocks self-antigen specific DQ8 activation of T cells. Identifying MHC class II allele-specific drugs has broad applicability to treating autoimmunity.”