First participant dosed in Phase 1a trial of experimental ALS treatment

Acelot has dosed the first healthy volunteer in a Phase 1a clinical trial testing ACE-2223, its investigational oral treatment candidate designed to target aggregated TDP-43 in people with amyotrophic lateral sclerosis (ALS).

In the vast majority of people with ALS, the TDP-43 protein moves to the wrong place in nerve cells and forms toxic clumps, which is believed to contribute to neurodegeneration. ACE-2223 is designed to specifically bind to and disrupt aggregated TDP-43 and restore the protein’s normal function.

The Phase 1 trial is assessing the safety, tolerability, and pharmacological properties of ACE-2223 in healthy adults. It is currently enrolling up to 96 participants in Australia.

“We are incredibly honored to move this first in class program representing a potentially disease modifying therapy forward for people with ALS,” Katie Planey, PhD, Acelot’s CEO, said in a company press release. “With a robust preclinical data package and our first healthy participant now dosed, our focus is clear — move as quickly as we can toward delivering a new option to patients in need.”

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ALS is marked by the progressive death of motor neurons, the nerve cells that control voluntary movement. While its cause remains largely unknown, several biological processes are thought to contribute to the disease, including changes involving specific proteins.

About 97% of sporadic ALS cases are associated with abnormal TDP-43 pathology. TDP-43 normally resides inside the cell’s nucleus, where it helps regulate the production of several proteins. In ALS, TDP-43 can become mislocalized outside the nucleus and form abnormal aggregates. The loss of functional TDP-43 in the nucleus disrupts the production of certain proteins needed for normal cell function.

ACE-2223 is designed to target these disease-associated, aggregated forms of TDP-43. In preclinical cell models, the treatment was reported to inhibit the formation of new TDP-43 aggregates, break apart existing clumps, and restore more normal TDP-43 function, leading to improved neuronal survival and function, according to Acelot.

In two ALS mouse models, the investigational therapy entered the brain, where it was associated with reductions in TDP-43 aggregation, neuroinflammation, and neurofilament light chain, a marker of nerve fiber damage. Treatment also improved survival and motor function in the models, the company reported.

Initiating this Phase Ia trial for ACE-2223 … moves us closer to demonstrating how disruption of these toxic protein aggregates can fundamentally alter the progression of ALS.

Based on these promising preclinical findings, the company has now launched a first in-human study involving healthy adults.

“Initiating this Phase Ia trial for ACE-2223 … moves us closer to demonstrating how disruption of these toxic protein aggregates can fundamentally alter the progression of ALS,” said Mark Forman, MD, PhD, Acelot’s chief medical officer and chief development officer.

In Part A, participants will receive a single oral dose of ACE-2223 or a placebo. Up to six dose levels of ACE-2223 may be tested, starting at 5 mg.

Part B will begin after safety and pharmacological data from at least the first three Part A dosing groups have been reviewed. It will assess repeated dosing, with participants receiving ACE-2223 or a placebo once or twice daily for seven days. As in Part A, up to six dose levels may be tested.

In both parts, each dosing group will include eight participants, with six receiving ACE-2223 and two receiving the placebo.

The trial’s main goal is to assess the treatment’s safety and tolerability, based on adverse events and clinical and laboratory safety measures. Researchers will also examine pharmacokinetic measures, which refer to how ACE-2223 is absorbed and processed by the body, at different dose levels.