1st U.S. Patient Enrolled in Phase 2a Trial Evaluating Vafidemstat for Alzheimer’s

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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BPN14770 Tetra Discovery Partners

A Phase 2a trial testing Oryzon’s investigational therapy vafidemstat for Alzheimer’s disease has enrolled its first patient in the U.S.

The trial (NCT03867253), called ETHERAL-US, is an extension of the European trial (2017-004893-32), currently ongoing at 17 sites in the U.K., France, and Spain. Oryzon is planning to recruit up to 30 patients with mild to moderate Alzheimer’s at multiple sites in the U.S. for an expected total of at least 150 participants, including the European arm.

ETHERAL-US is now recruiting participants in Florida and New Jersey. Information on contacts and locations is available here.

Vafidemstat is an epigenetic therapy, meaning it targets the expression and activity of genes, and is capable of crossing the blood-brain barrier, a highly selective membrane that shields the central nervous system from general blood circulation.

Specifically, vafidemstat inhibits two proteins, lysine-specific histone demethylase (LSD1) and monoamine oxidase B (MAOB), which regulate the expression of several genes by removing the epigenetic marks (methyl groups) that sit on top of the genes and work as “off-switch” signals.

Preclinical studies on a mouse model of Alzheimer’s and accelerated aging showed that vafidemstat restored memory, enhanced sociability, and decreased social avoidance.

“Epigenetics plays a role in a broad range of CNS [central nervous system] disorders. LSD1 is as a fascinating target for different CNS conditions and Oryzon has a unique competitive position,” Carlos Buesa, CEO and founder of Oryzon, said in a press release.

“With ETHERAL-US, the company is starting clinical operations in the U.S. and we expect to expand the clinical trials with vafidemstat in the U.S. to additional CNS indications soon,” he added.

This study is intended to investigate the safety, tolerability, and preliminary efficacy of vafidemstat for treating mild and moderate Alzheimer’s disease.

Participants will be randomly assigned to a placebo or to one of two doses of vafidemstat, a low (0.6 milligrams) or a high (1.2 milligrams) dose. Treatment will last for a total of 24 weeks. The first phase of the trial will be followed by an extension phase where patients previously on placebo can switch to one of the two doses of vafidemstat for 24 weeks. Patients will be randomized according to the severity of their cognitive impairment.

During the trial, researchers will compare the effects of vafidemstat with the placebo on patients’ memory and behavior, as well as changes in the levels of several disease biomarkers in the cerebrospinal fluid, the liquid that surrounds the brain and spinal cord.

A $1.5 million grant from the Alzheimer’s Drug Discovery Foundation is supporting the trial’s expansion to the U.S.

“The AD community is committed more than ever to explore new drugs with novel mechanisms of action for this devastating and difficult-to-treat disease. Vafidemstat’s epigenetic approach is supported by strong preclinical data as well as recent clinical findings in patients suffering other types of CNS disorders, which together has heightened our expectations for potentially promising findings from the ETHERAL trial,” said Michael Ropacki, Oryzon’s vice president of clinical development.

Vafidemstat also has been successfully tested in preclinical models of multiple sclerosis (MS) and is currently  in the SATEEN clinical trial for relapsing-remitting and secondary progressive MS.