Research Alliance to Test CMT1A Oral Therapy in Preclinical Studies

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by Patricia Inácio, PhD |

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The Charcot-Marie-Tooth Association (CMTA) and Addex Therapeutics are teaming up to investigate a potential oral therapy for Charcot-Marie-Tooth disease type 1A (CMT1A), in rodent models of the disease.

Established under the association’s Strategy to Accelerate Research (STAR), the collaboration’s goal is to study the benefits of Addex’s proprietary technology — called positive allosteric modulator (PAM) — in targeting the GABAB protein receptor, according to a press release.

CMTA and Addex will work together to assess improvement of key outcomes upon chronic dosing of select PAMs. The outcomes include disease biomarkers, motor function, as well as function and structure of peripheral nerves — which control movement and sensation in the limbs.

“By combining the expertise of both the Charcot-Marie-Tooth Association with our proven track record in the discovery and development of allosteric modulators, we aim to further understand how targeting GABAB with a positive allosteric modulator could benefit patients with CMT1A,” said Tim Dyer, CEO of Addex.

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The results of the collaboration are expected to provide scientific evidence for future investigational new drug application (IND)-enabling studies, which are meant to obtain regulatory clearance to start clinical trials and expected to begin next year.

“As we move towards IND-enabling studies, we look forward to working with the CMTA to build scientific evidence supporting our approach to tackle this tremendous unmet need,” Dyer said.

Preclinical work in a rat model of CMT1A suggests that the GABAB receptors help control the overproduction of peripheral myelin protein 22 (PMP22) in CMT1A.

Overabundance of PMP22 means that the protein is not processed correctly and is less functional, causing problems for the structure and working of myelin — the protective and insulating covering of nerve cell projections. Defective myelin impairs the transmission of electrical signals by nerves, leading to muscle weakness and wasting.

Contrary to traditional therapies, which bind to the receptors’ active site to out-compete activating molecules made by the body, Addex’s PAMs bind to a secondary site, acting to modify receptor response.

Delivered orally, PAMs bind more specifically to their targets and offer a better modulatory control of targeted receptors, according to Addex.

The company expects its approach to spare CMT1A patients the side effects that limit treatment adherence, as in the case of the off-label therapy baclofen, which also targets GABAB receptors.

“We are excited to establish this partnership with Addex Therapeutics as they work to advance their PAMs to treat CMT1A,” said Amy Gray, CEO of CMTA.

CMTA’s STAR connects clinicians and researchers working in CMT with pharmaceutical partners as a way to accelerate treatments and a cure for the disease.

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“Strategic research partnerships with companies like Addex is a central part of our strategy to accelerate the development of treatments for the CMT community,” Gray said.

“Since launching STAR 12 years ago, the CMTA has been able to establish research partnerships with almost 40 pharmaceutical and biotech companies, and leading research labs around the world,” she added. “We share Addex’s enthusiasm and passion for developing life-changing treatments for patients.”