TRE-515 Appears to Block Immune Cell Attacks in Mouse Study

An experimental oral therapy called TRE-515 significantly reduced disease severity and the growth of the abnormal immune cells that drive multiple sclerosis (MS) in two mouse models of the disease, a study found.

Notably, the efficacy of Trethera Corp.’s potential treatment, administered either in a preventive or therapeutic approach (after symptom onset), was comparable to that reported in animal experiments for some approved MS treatments.

These findings support TRE-515’s therapeutic potential in MS and the further work necessary before it might move into clinical trials.

The study, “Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis,” was published in the journal Immunology.

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In MS, the immune system mistakenly mounts immune responses against myelin, the protective sheath around nerve fibers, leading to neuronal damage. This impairs nerve cell communication and health, resulting in neurodegeneration.

These abnormal immune responses are mainly driven by two types of immune cells: T-cells and B-cells. Whereas T-cells typically promote inflammation and the activation of other immune cells,  B-cells are chiefly responsible for producing antibodies against foreign molecules perceived as threats.

Experimental MS treatment targets T- and B-cell developmental pathway

Currently approved MS therapies target several immune-related mechanisms to slow disease progression. However, “none of them completely blocks disease or disease progression,” and all are associated with side effects that include an increased risk of infections and liver injury, the researchers wrote.

As such, safe and highly effective therapies remain a pressing need.

Previous studies showed that the deoxyribonucleoside salvage pathway is highly activated in T-cells and B-cells and required for their development.

This pathway recycles products of DNA degradation found outside the cell, and it uses them to generate deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. It complements the de novo pathway, which produces dNTPs from simpler molecules.

In addition, the deoxyribonucleoside salvage pathway is increased in T-cells during their activation and in the lymph nodes and spleen — structures where immune cells mature and are stored — of mouse models of autoimmune diseases.

These findings suggest blocking the deoxyribonucleoside salvage pathway may halt the development and growth of the immune cells that drive MS and other autoimmune diseases.

To test this hypothesis, a team led by researchers at the University of California, Los Angeles, evaluated the effects of suppressing this pathway with Trethera’s TRE-515 in two mouse models of MS.

TRE-515 is a first-in-class, orally available small molecule designed to potently suppress deoxycytidine kinase (dCK), an essential enzyme in the deoxyribonucleoside salvage pathway.

The mouse models used both develop an MS-like disease called experimental autoimmune encephalitis (EAE), with disease progression similar to that of patients. These models are induced by exposure to different, small portions of MOG, a myelin component often targeted by the damaging immune responses of MS.

Notably, the MOG35-55 model — the most commonly used — is considered to be B-cell independent, while the MOG1-125 model involves both T- and B-cells, more closely resembling what happens in MS.

Researchers initially showed that deoxyribonucleoside salvage pathway was highly activated in immune structures and in the brain — due to infiltrating immune cells — of both mouse models after the disease’s induction. Treating these mice with TRE-515 resulted in a significant reduction in pathway activation.

TRE-515 eases symptoms in mice when given before or after onset

Notably, daily TRE-515 treatment, initiated one day after disease induction, significantly delayed symptom onset and eased disease severity in both mouse models, compared with untreated mice.

Similar results were seen in the MOG35-55 model when TRE-515 treatment was started at symptom onset. Treated mice showed significantly fewer symptoms overall than untreated mice, with benefits observed from the fifth day of treatment.

In both treatment approaches, the clinical benefits were accompanied by fewer infiltrating immune cells in the brain and spinal cord and lesser demyelination, or myelin loss, compared with no treatment.

These findings indicate TRE-515 “can limit clinical symptoms in EAE models driven by just T cells or by both T and B cells,” and “when treatments are started either at disease induction or when symptoms arise,” the researchers wrote.

TRE-515’s apparent effectiveness, both as a preventive treatment or after symptom onset, in the MOG35-55 mouse model was generally comparable — and in many cases superior — to that reported for some MS therapies tested in this same model and later approved for patient use.

With both preventive and therapeutic use, the exception was glatiramer acetate (sold as Copaxone and available in generic versions), whose efficacy was consistently superior to TRE-515 in the mouse model, the researchers noted.

“The efficacy of a therapy in patients with MS will be surely different than the efficacy of that therapy in the MOG35-55 EAE model for many reasons,” the team wrote. “Nevertheless, these and our studies provide early data to suggest that TRE-515 is similarly efficacious in the [mouse] model to other approved therapies that have reached the clinic.”

Additional experiments showed that TRE-515 blocked the growth of active T- and B-cells and the expansion of MOG-targeting T-cells in the MOG35-55 EAE model. This occurred without affecting the levels of other immune cells, such as inactive T- and B-cells, or of red blood cells.

These findings highlight that “dCK activity is necessary for the development of clinical symptoms” in the MOG35-55 and MOG1-125 mouse models of MS and for MOG-targeting T-cell growth, the researchers wrote.

Suppressing dCK with TRE-515 also limited symptom development in these models, supporting dCK as a “potential new target for treating patients and modulating symptoms in MS,” the team wrote.

“Although it remains to be formally tested, based on the proposed mechanism-of-action of TRE-515 in the EAE model, we would hypothesize that TRE-515 may have efficacy across a wide range of autoimmune diseases and could represent a new type of immunomodulatory drug,” they concluded.

One of the study’s 16 researchers, Kenneth Schultz, MD, is the chairman and CEO of Trethera.

TRE-515 was recently designated an orphan drug for demyelinating optic neuritis, an eye condition that may progress to MS or occur during the disease’s course. The designation is given to help expedite the therapy’s clinical development and regulatory review.