A Phase 1 trial evaluating Samumed’s investigational compound SM07883 for Alzheimer’s disease has dosed its first participant.
The Phase 1 trial (ACTRN12619000327189), taking place in Australia, will assess the safety, tolerability, and pharmacokinetics (the movement of a medicine into, through, and out of the body) of ascending doses of SM07883 in healthy volunteers.
Sequential dose groups of healthy participants will receive a single fixed dose of SM07883 at 5, 10, 15, 30, 60, 120 and 180 mg, followed by a 28-day observation period. Safety evaluations will take place after each dose level.
SM07883 is an oral small-molecule inhibitor that selectively targets and inhibits the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), a protein whose levels are increased in the brains of Alzheimer’s patients and correlate with disease severity.
DYRK1A is important in the development of the nervous system; however, in Alzheimer’s disease, it has been shown to promote the phosphorylation (the addition of a chemical group called phosphate) of the tau protein and the amyloid precursor protein (APP), two hallmarks of Alzheimer’s. APP is the precursor of amyloid beta, whose aggregates in Alzheimer’s cause impaired communication between nerve cells and gradual cognitive decline.
Preclinical data has shown that orally administered SM07883 can protect against cognitive decline in a mouse model of Alzheimer’s disease, reducing amyloid beta and tau protein levels as well as brain inflammation.
The results, “Cognitive Improvement and Protection Against Amyloid and Tau Pathology with SM07883, an Oral DYRK1A Inhibitor, in the 3xTg Mouse Model of Alzheimer’s Disease; Preliminary Results,” were presented during the recent 14th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders in Lisbon, Portugal.
Animals received SM07883 (5mg/kg) or an innocuous substance for six months. Researchers assessed the animals’ cognitive behavior using two tools, the Novel Object Recognition (NOR) memory test and the Y Maze spontaneous alternation — a behavioral test measuring the willingness of rodents to explore new environments.
Additionally, they analyzed brain samples for tau and APP phosphorylation, amyloid beta and tau aggregates and levels of a protein called glial fibrillary acidic protein (GFAP). As a response to neuronal death, the brains of Alzheimer’s patients react by increasing the number of astrocytes, a process called astrogliosis. During this process, the gene coding for GFAP is activated.
Treatment with SM07883 reduced the burden of amyloid plaques and decreased the levels of phosphorylated tau and APP proteins.
SM07883 also lessened neuroinflammation, as shown by lower number of reactive astrocytes and lower GFAP. Moreover, researchers saw a significant decrease in the levels of several pro-inflammatory molecules, such as interleukin (IL)-6, IL-1beta and IL-15, among others.
Importantly, SM07883 protected against cognitive decline.
“The accumulation of anomalous Tau proteins in the grey matter of Alzheimer’s patients’ brains has been strongly linked to the progression of the disease for decades,” Yusuf Yazici, MD, chief medical officer of Samumed, said in a press release.
“In preclinical studies, the observed significant reduction in Tau hyperphosphorylation and aggregation in animals treated with SM07883 compared to controls points to DYRK1A as a potential target for Alzheimer’s disease and reinforces our rationale for proceeding with this Phase 1 study,” he added.
We are sorry that this post was not useful for you!
Let us improve this post!
Tell us how we can improve this post?