Samumed’s SM07883 Can Prevent Tau-Mediated Neuroinflammation, Neurodegeneration in Mice, Study Shows

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by Alice Melão |

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The small molecule inhibitor SM07883, being developed by Samumed, can effectively prevent tau protein toxic accumulation, and tau-mediated neuroinflammation in mice, data from preclinical studies show.

As tau-associated mechanisms are implicated in Alzheimer’s disease, these findings suggest that SM07883 may represent a new strategy for the treatment of this progressive neurodegenerative disorder.

SM07883’s preclinical data was reported in the study “Tau pathology reduction with SM07883, a novel, potent, and selective oral DYRK1A inhibitor: A potential therapeutic for Alzheimer’s disease,” published in the journal Aging Cell.

A hallmark feature of Alzheimer’s is the accumulation of tau protein clumps in the brain. These accumulations are believed to precede the loss of nerve cells, shrinkage of the brain, and cognitive impairment that characterize this disease.

SM07883 was engineered to effectively cross the blood-brain barrier, and specifically block the activity of the tyrosine phosphorylation-regulated kinase 1A (DYRK1A), which is known to mediate deactivation of tau protein.

Researchers note that the blood-brain barrier is a semipermeable membrane that protects the brain against the external environment. But it also is a major barrier for the efficient delivery of certain therapeutics that need to reach the brain and central nervous system.

Studies with different species of rodents showed that SM07883 can be easily absorbed, achieving 92% of estimated bioavailability — the amount of a compound that can enter circulation and has an active effect — only two hours after being given orally. The small molecule also was able to effectively reach mice and rat’s brains, and homogeneously spread through different brain regions.

Importantly, treatment with SM07883 could reduce the activation of tau by 47% compared with placebo-treated mice. In particular, increased amounts of the inhibitor resulted in reduced tau activation.

Additional experiments in mice genetically manipulated to develop tau-mediated disease further revealed that SM07883 not only prevents tau activation, but also the accumulation of its toxic aggregates, or clumps, in the brain.

Analysis of brain and spinal cord samples revealed that SM07883-treated mice had reduced signs of active inflammation compared with placebo-treated animals. This suggests the experimental inhibitor also could prevent tau-mediated neuroinflammation.

Three-month treatment with SM07883 could effectively prevent weight loss, and extend mice lifespan, compared with placebo. Treated mice also showed an improvement of approximately 1.4 points in motor task (wire‐hang test) performance scores.

All together, these findings suggest that “reducing DYRK1A activity may be a viable treatment in diseases such as Alzheimer’s disease,” the researchers said. They said increased DYRK1A enzyme activity may regulate tau clumping and neurodegeneration.

“Patients urgently need a treatment for Alzheimer’s disease. DYRK1A represents an important target to potentially change the course of this devastating disease,” Yusuf Yazici, MD, chief medical officer of Samumed, said in a press release.

“These published data show that treatment with our potentially first-in-class DYRK1A inhibitor significantly reduces effects of pathological tau and neuroinflammation while improving performance on a motor task compared to vehicle in animal models,” he added.

The safety and tolerability of increasing doses of SM07883 are currently being evaluated in a Phase 1 clinical trial (ACTRN12619000327189) in healthy volunteers. The data collected will help define the optimal therapeutic dosage of SM07883 to be further tested in human studies.