IM Therapeutics is developing a personalized, orally available small molecule therapeutic for diabetes. This is a milestone for autoimmune diseases and may be the first time diabetes patients can be preselected for a therapeutic based on whether they carry a specific gene.
IM Therapeutics is developing a personalized, orally available small molecule therapeutic for diabetes. This is a milestone for autoimmune diseases and may be the first time diabetes patients can be preselected for a therapeutic based on whether they carry a specific gene.
The pill is designed for patients with the HLA-DQ8 gene. It has the potential to extend diabetes patients’ “honeymoon” when their insulin activity is still reasonably high. Known as IMT-002, the drug molecule may not yet eliminate the need for insulin injections, but developers say it may notably lengthen the time people can go without adjusting insulin doses.
In this approach, human leukocyte antigen (HLA) are key.
“HLA proteins recognize and bind to invading bacteria or viruses and present these to the T cells, activating the immune system to fight infections,” Nandan Padukone, Ph.D., CEO, told BioSpace. “But there also are certain HLA variants that erroneously bind natural peptides. When these peptides are presented to the T cells, autoimmune diseases result.”
Blocking the activity of the DQ8 gene seems to resolve that challenge for certain diseases.
“Imagine HLA as a protein with A and B domains sitting on a cell surface and foreign bodies in its pockets. We believe oral drugs – specifically IMT-002 – can be designed to sit in the erroneous HLA pockets, thus displacing those natural peptides,” Padukone said.
IMT-002 occupies the DQ8 peptide binding groove on the HLA-presenting cells, where it blocks the binding of insulin and the activation of the CD4 T-cells. “When HLA-DQ8 is blocked, the immune system will no longer attack insulin producing beta-cells, thus modifying the disease course to keep patients making their own insulin,” the company explained on its website.
Initially, IM Therapeutics considered L-methyldopa – FDA-approved for hypertension – as a possible DQ8 blocker before focusing on its enantiomer (mirror image), D-methyldopa.
“In comparison to the other drugs we’ve looked at, IMT-002 may be more potent and may stay on target longer,” Peter Gottlieb, M.D., co-founder and CMO, told BioSpace.
It appears to be even safer than L-methyldopa because of its inability to be metabolized. The drug has been granted Orphan Drug Status by the FDA.
Type 1 diabetes and celiac disease are the company’s top two disease targets.
“Neither has an approved therapy yet, so there is high unmet need,” Padukone said.
Lupus, rheumatoid arthritis, multiple sclerosis and other conditions also have underlying HLA factors and may present eventual therapeutic opportunities.
Initially, IM Therapeutics is focusing on diabetes and blocking the action of the DQ8 gene.
“We know that about 60% of type 1 diabetics and 10% of celiac patients carry the DQ8 gene,” Padukone said. “DQ2, our second gene target, is carried by 90% of celiac patients and about 40% of type 1 diabetics.”
Although the therapy holds the hope of one day eliminating the need for insulin injections, the immediate goal is to limit the amount of insulin diabetics need.
“People with diabetes have lost 30% to 70% of their endogenous insulin production capabilities,” Gottlieb said. “When we stabilize insulin production, they go on a therapeutic honeymoon. They don’t have to think much about carbohydrate counts or adjusting insulin doses during that period.”
“After the honeymoon, though, life gets hard,” Gottlieb said. “They have to count their carbohydrate intake and adjust their insulin doses to compensate for fluctuations in insulin production. If we could keep them in the honeymoon period it would be awesome.”
Although other researchers have explored the ideal of regulating the immune system to modulate insulin production, “The idea of using a small molecule to block the action of DQ8 is novel,” Gottlieb said.
The approach is possible now because of advances in technology and science.
“We have very good models of the HLA system. We did in silico modeling, using a library of hundreds of thousands of compounds and millions of orientations to position the molecules into the pockets to find the best blockers,” Gottlieb said.
That in silico work minimized the in vitro experiments needed to identify amenable targets.This methodology is amenable to a platform approach.
“We’re seeing similar sorts of small molecules binding with DQ2 and other HLA genes, so our approach is setting up to be a paradigm to move forward,” Dr. Gottleib added.
“Oral small molecule drugs have an advantage in terms of delivery,” Dr. Padukone said. They also offer flexibility in terms of binding affinity. If a small molecule or antibody binds too tightly it may block the normal immune responses as well as the autoimmune response. IM Therapeutics, therefore, is designing a molecule that “sits in the HLA pocket and binds strongly enough to prevent the autoimmune response while also preserving the normal immune response.”
IM Therapeutics submitted is investigational new drug (IND) application in April for diabetes, received FDA clearance to begin a single-dose escalation study in May, and dosed the first patient soon thereafter. The first study is on track for completion by mid-summer, with final data expected late August. Next, the company plans to launch a Phase Ib multidose trial that incorporates pharmacodynamics.
