Frequency moving to test agents with remyelination potential

FREQ-162 among compounds that might restore myelin sheath in MS patients

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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An illustration of damaged myelin along a nerve cell fiber.

Frequency Therapeutics announced that it is shifting its focus to advancing small molecules that aim to restore myelin, the protective cover around nerve fibers that is damaged and lost with multiple sclerosis (MS).

This decision follows the failure of an investigative treatment for people with acquired hearing loss to meet its primary goal in a Phase 2 clinical trial, and the company is stopping work on that therapy.

A new “target relevant to myelination” and compounds that in animal disease models led to “robust remyelination” have been identified, Frequency reported in a company press release. It plans to launch a clinical trial into the remyelination potential of its agents by June 2024.

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In MS, the immune system erroneously attacks the brain and spinal cord, causing damage to the myelin sheath. This sheath is required for the rapid transmission of signals along the nerve fibers, and its damage can cause a range of disease symptoms, including muscle weakness, loss of sensation, and trouble with coordination and balance.

While myelin repair is possible, the process tends to be faulty in MS, where ongoing inflammation interferes with the generation of myelin-producing cells called oligodendrocytes at regions of damage. It also affects the production of myelin by these cells.

Scientists have been looking for therapies that can improve this process in MS and other diseases marked by demyelination.

“There’s a significant unmet need for therapies that can remyelinate the brain,” Sanjay Magavi, PhD, vice president of myelination research at Frequency, said in a video from the company.

Oligodendrocytes are large cells that arise from immature cells called oligodendrocyte progenitor cells (OPCs). Frequency’s MS program aims to develop small molecules that drive OPCs to turn into oligodendrocytes, helping restore the myelin that’s lost to the disease.

These small molecules are being designed to bind to a newly identified but, for now, undisclosed target. To date, preclinical studies showed a single dose of its lead compound, called FREQ-162, triggered the maturation of progenitor cells into oligodendrocytes in mice.

“The Frequency compound induced a profound increase in oligodendrocyte differentiation,” Magavi said. “A single oral dose of FREQ-162 yielded a 23-fold increase” in new oligodendrocytes compared with untreated mice.  

In a mouse model of demyelination, these new oligodendrocytes were able to”dramatically increase” the production of new myelin. This was observed both in regions of white matter — which are mainly composed of nerve fibers connecting different brain regions — and gray matter — which is mainly made of nerve cell bodies.

“To the best of our knowledge, no one has published a remyelinating agent with this magnitude of effect. The fact that we saw this robust effect after a single dose is promising and suggests we will only need intermittent dosing to induce significant remyelination,” Magavi said.

The company also announced a corporate restructuring and downsizing program to save costs and to support the proposed MS trial.

Frequency established a clinical advisory board late last year to help move its small molecule candidates into testing in MS patients.