New tyrosine kinase inhibitor shows potential in MS mouse model

ASH41020, an investigational therapy from Ashvattha Therapeutics, significantly reduced disease severity and exhibited immunomodulatory properties in a mouse model of multiple sclerosis (MS), according to a recent presentation.

Evidence indicated the therapy works by shifting the balance of immune cells called macrophages toward a less inflammatory and more restorative profile.

“We are encouraged by these data as they demonstrate … ASH41020, is a potent tyrosine kinase inhibitor and a macrophage switching nanomedicine with the potential to decrease symptom severity after disease onset, warranting further development as a promising treatment for MS,” Jeff Cleland, PhD, CEO and chairman of Ashvattha, said in a press release.

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The findings were discussed at the 16th International Society of Neuroimmunology Congress, held in Canada Aug. 21-24, in the poster titled  “ASH41020, A Novel Hydroxyl Dendrimer CSF1R Tyrosine Kinase Inhibitor ‘Dendranib’ Nanomedicine, Polarizes Macrophages Toward an Anti-Inflammatory Phenotype and Improves Disease Severity in a Mouse Model of Multiple Sclerosis.”

In MS, the over-activation of immune cells called macrophages and their brain-resident relatives, microglia, leads to the production of inflammatory molecules that damage nerve cells.

Macrophages are thought to exist in two different states. The “M1” state is associated with inflammation and has been linked to MS progression, whereas the “M2” state is thought to be involved in restoring myelin, the substance surrounding nerve cells that’s progressively lost due to autoimmune attacks in MS.

As such, therapeutic approaches to reprogram macrophages toward an anti-inflammatory M2 state could be beneficial for MS patients.

Ashvattha believes ASH41020 could serve that purpose. The molecule was developed using the company’s nanomedicine technology, which aims to deliver therapeutic molecules specifically to areas of active inflammation, while leaving unaffected cells alone. This technology is expected to help develop more targeted and tolerable therapeutics.

Specifically, ASH41020 selectively inhibits colony stimulating factor 1 receptor (CSFR1), a protein important for the survival and growth of microglia and macrophages. Increased levels of this molecule in the brain and spinal fluid of MS patients has been linked with more microglial activation and faster disease progression.

In turn, its inhibition eased disease severity and delayed disease onset in animal models of the disease.

CSFR1 belongs to a class of molecules called tyrosine kinases that facilitate immune cell activation. A range of tyrosine kinase inhibitors are being investigated as potential MS therapies; each has a preference for certain types of immune cells. Examples include evobrutinib, fenebrutinib, tolebrutinib, remibrutinib, and masitinib.

A new type of tyrosine kinase inhibitor called a dendranib

ASH41020 is a new type of tyrosine kinase inhibitor called a dendranib, which is metabolically stable and eliminated intact through the kidneys, according to Ashvattha. In recent presentation, researchers explored the molecule’s potential benefits in MS.

In cell culture conditions favoring an M1 environment, ASH41020 decreased the proportion of M1 macrophages and increased the proportion of M2 cells. Dasatinib and masitinib, two other tyrosine kinase inhibitors, did not have this effect.

In an M2-promoting cellular environment, ASH41020 did not affect the M1 macrophage proportion, but did increase M2 macrophages. Both dasatinib and masitinib increased M1 proportions in this environment.

Consistent with its immune-modulating effects, treatment with the therapy for two weeks after disease onset significantly decreased disease severity in a mouse model of MS.

Effects were dose-dependent

The effects were dose-dependent, meaning that higher doses had the greatest impact on disease severity, and the benefits seen with the highest dose were similar to those observed with Gilenya (fingolimod), an approved MS disease-modifying therapy.

Mice treated with the highest dose of ASH41020 also recovered significantly more body weight than untreated animals, similarly to Gilenya-treated mice.

In turn, dasatinib and masitinib did not show efficacy in the mouse model.

ASH41020 administration increased the percentage of both M1 and M2 macrophages in the mouse model, showing a trend toward higher M2 macrophage proportions with increasing doses.

“These data build on previous studies that show our precision nanomedicine therapeutics selectively target activated cells in regions of inflammation,” Cleland noted.

Ashvattha believes the findings support the immunomodulatory potential of ASH41020 in MS.

“These preclinical studies suggest that ASH41020 could be a potent anti-inflammatory and immunomodulatory agent that warrants further development as a promising treatment for MS patients,” the researchers wrote.