Zhimeng cleared to launch study of ALS therapy CB03-154 in China
Treatment is designed to slow progression by reducing nerve cell overactivity
China’s Center for Drug Evaluation (CDE) has approved a request by Zhimeng Biopharma to launch a Phase 2/3 study of its experimental therapy CB03-154 in people with amyotrophic lateral sclerosis (ALS).
The oral treatment, which is designed to slow disease progression by reducing nerve cell overactivity, is also being investigated in healthy volunteers in two Phase 1 clinical trials in the U.S. (NCT05499260) and Australia (NCT05502549). The findings so far show promising safety and tolerability results. CB03-154 has won orphan drug status for ALS in the U.S., a designation that provides incentives to accelerate the development of candidate therapies for rare diseases, which are those affecting fewer than 200,000 people in the U.S.
“The approval by CDE is another important milestone in Zhimeng’s global clinical development for ALS and other central nervous system diseases,” Huanming Chen, founder and CEO of Zhimeng, said in a company press release. “We believe CB03-154 has the potential to become a first-in-class therapy for ALS.”
In ALS, the nerve cells that control muscles, called motor neurons, become progressively dysfunctional and die, leading to muscle weakness and other symptoms. Several approved treatments can help manage its symptoms and slow disease progression, but there is no cure yet.
Exactly what causes nerve cell damage in ALS isn’t fully understood, but increased neuronal excitability may contribute to it. This means nerve cells become too easily activated, firing signals more often than they should and putting extra stress on motor neurons.
Potassium channel proteins, which regulate the passage of potassium ions, are important modulators of neuronal excitability. However, the only drug that opened potassium channels to reduce excitability was withdrawn from the market due to serious side effects.
Favorable preclinical and safety results
CB03-154 is a newer, or next-generation, drug that’s designed to open the KCNQ2 and KCNQ3 potassium channels in nerve cells. It targets these channels without significantly affecting other types of ion channels, resulting in favorable pharmacological and safety profiles.
Preclinical results show CB03-154 significantly reduced hyperexcitability in cells derived from ALS patients, resulting in neural activity more like in healthy cells. The molecule also eased motor symptoms and significantly prolonged lifespan in a mouse model of ALS. Neural signals traveled more quickly in treated mice, indicating the therapy was protecting nerve cells.
Data from the Phase 1 trial in Australia, where 56 healthy volunteers received one or more oral doses of CB03-154 or a placebo, also showed the therapy was safe and well tolerated at single doses up to 30 mg and multiple 14-day doses up to 20 mg.
The most common adverse events related to treatment were dizziness, sleepiness, and headache. Most were mild, with only one event being moderate in severity. Laboratory tests and heart monitoring showed no unusual results. One participant had a brief period of abnormal brain signals during an electroencephalogram, but this resolved in under a minute. An analysis of the therapy’s pharmacokinetics, that is, the way a drug moves through the body, showed it was absorbed rapidly, reaching a stable concentration in 13 days.
With the newly approved Chinese study, the company hopes to translate these favorable preclinical and safety results to an ALS population. “We hope our dedicated efforts will allow us to bring a safer and more effective medicine to ALS patients worldwide,” Chen said.
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