BREN-02, Potential Restorative ALS Therapy, Named Orphan Drug by FDA

BREN-02, a lab-made form of the human protein engrailed 1 (EN1), has been designated an orphan drug by the U.S. Food and Drug Administration (FDA) as a potential treatment of amyotrophic lateral sclerosis (ALS), its developer, BrainEver, announced in a press release.

Orphan drug status is granted to stimulate the development of therapies aiming to prevent, diagnose, or treat disorders affecting fewer than 200,000 people in the U.S., which might not be otherwise profitable without government assistance.

This designation will allow the company to benefit from specific measures, including exemption from certain FDA application fees, trial protocol assistance, and seven years of exclusive marketing if BREN-02 is approved to treat ALS.

In ALS, nerve cells that control voluntary muscle movements (motor neurons) degenerate and die, leading to progressive muscle weakness and paralysis. 

The death of upper motor neurons, which send messages from the brain to the spinal cord, generally causes spasticity (muscle tightness), whereas the degeneration of lower neurons, which connects the spinal cord to muscles, leads to muscle weakness, atrophy (shrinkage), and twitching.

EN1 is part of a family of proteins — called homeoproteins — that control gene activity and are essential during embryonic and postnatal development. In particular, EN1 helps regulate the development of the cerebellum — the area of the brain responsible for coordinating voluntary movements. But is also needed to maintain certain neurons in adults, including lower motor neurons.

Recent studies have shown that protein EN1 plays a vital role in the survival and maintenance of lower motor neurons that supply nerves to skeletal muscles. Animal models deficient in EN1 developed muscle weakness, abnormal spinal function, and a loss of nerves at the neuromuscular junction (where nerves and muscles communicate), followed by motor neuron degeneration.

A unique property of homeoproteins is their ability to penetrate cells. As such, they do not need special transportation systems to reach the target cells, nor do they require a viral delivery vector.

In preclinical models, a single injection of BREN-02, a lab-made (recombinant) formulation of the EN1 protein (known as rhEN1), into the spinal canal of the lumbar (lower) region prevented the death of motor neurons and improved muscle function. These protective effects were long-lasting, being sustained for at least two months. 

“In ALS, motor neurons degenerate and die, leading to progressive muscle paralysis that includes respiratory muscles,” said Alain Prochiantz, PhD, a neurobiologist at the Collège de France and co-founder of BrainEver. “In preclinical studies, we have observed that the intrathecal lumbar administration of rhEN1, in the early symptomatic stages, restores muscle function and prevents motor neuron death.”

Subject to positive preclinical toxicity data, followed by a regulatory review, BREN-02 is expected to enter clinical testing in ALS patients in the second half of 2021.