Alzheimer Agent ACD856 Shows Promise in Early-Stage Trial

Marta Segerdahl, MD, PhD

AlzeCure has announced new, positive phase 1 results from a trial (NCT05077501) assessing multiple ascending oral doses of its investigational Alzheimer disease (AD) agent ACD856 in healthy individuals. All told, findings showed that the therapy was well tolerated at the tested dose levels (10-90 mg/daily for 7 days), with rapid absorption and dose-dependent exposure in the central nervous system (CNS).^1,2

Published in the Journal of Prevention of Alzheimer’s Disease, the prospective study featured 3 ascending dose cohorts of 8 heathy participants who were randomized to receive either ACD856 (n = 6) or placebo (n = 2) for 7 days of treatment. The main goal of the study was to assess safety and tolerability of the agent, as well as characterize pharmacodynamic effects using quantitative electroencephalography (ECG) as an indicator for central target engagement.

ACD856, a positive allosteric modulator of tropomyosin receptor kinase receptors, was found to be safe, with no serious adverse events (AEs) reported. No dose related trends were observed for AEs, laboratory safety assessments, vital signs, 12-lead ECG, physical examination, or stool. Most of AEs reported were mild in intensity, and 12 events (reported by 10 individuals) were assessed as possibly related to study treatment. Of these, 2 were reported as being of moderate intensity: a transient increase in lipase and amylase in 1 asympomatic individual following the last day of ACD856 treatment.

"The results presented in the article show that ACD856 has a very good profile for further clinical development," Marta Segerdahl, chief medical officer at AlzeCure Pharma, MD, PhD, said in a statement.¹ "With its potential to improve memory functions in a variety of diseases, ACD856 may have a significant role in the treatment of indications where these key functions are impaired, such as Alzheimer's disease, traumatic brain injury and Parkinson's disease."

Over the 7-day treatment period, investigators observed significant dose-dependent changes in qEEG parameters while only observing spurious findings for the placebo group. Changes were most notable in the 90 mg group, and dosing was found to be statistically significantly associated with increased relative theta power and decreased fast alpha and beta power, and an increased theta/beta ratio.

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A cardiac safety analysis concluded that the agent has no or only small effects on the cardiac conduction system of the heart. The largest individuals change in Corrected QT Interval value (22 ms) was observed on day 7 in a patient treated with 30 mg of ACD856. Across all dose groups, the therapy was rapidly absorbed and reached maximum plasma concentrations (Cmax) 30 to 45 minutes after administration both on day 1 and 7. At steady state on Day 7, the geometric mean accumulation ratios ranged between 1.8 and 2.0 for area under the plasma concentration-time curve (AUCtau) and between 1.6 and 1.7 for Cmax. ACD856 exhibited a low volume of distribution (13.42-16.94 L) and a low clearance (0.48-0.63 L/h) with no obvious time dependency.

"The clinical phase I data we have obtained with ACD856 are very promising and the need for new drugs in the Alzheimer's field is great. The results with the substance which support treatment to improve learning and memory abilities as well as depression are clearly positive with regard to partnership and out-licensing discussions and increases interest in the NeuroRestore platform," Martin Jonsson, chief executive officer, AlzeCure Pharma, said in a statement.¹

Blood-brain barrier penetration analyses, examined on day 6, showed dose-dependent increases among ACD856-treated individuals in geometric mean concentration in the cerebrospinal fluid (CSF): 10 mg (3.98 ng/mL), 30 mg (13.8 ng/mL), 90 mg (100 ng/mL). At steady state, the geometric mean ACD856 concentrations in were similar to the estimated unbound average ACD856 plasma concentrations over the dosing interval (mean ratio range, 0.37-1.20).

Overall, investigators concluded that the agent not only passes the blood-brain barrier but also exerts some treatment-associated changes on CNS activity, suggesting that central target engagement was achieved. They noted that the next step in the clinical development of ACD856 is to evaluate its effects in a relevant patient population to see whether it could potentially be an effective treatment option for patients with AD, depression, other psychiatric disorders, and disorders where cognition is impaired.

REFERENCES
1.AlzeCure publishes the positive clinical results from the phase 1 trial of NeuroRestore ACD856 against Alzheimer’s. news release. AlzeCure. August 9, 2023. Accessed August 9, 2023. https://www.biospace.com/article/releases/alzecure-publishes-the-positive-clinical-results-from-the-phase-i-trial-of-neurorestore-acd856-against-alzheimer-s/
2. Onnestam K, Nilsson B, Rother M, et al. Safety, tolerability, pharmacokinetics and qualitative electroencephalography assessment of ACD856, a novel positive allosteric modulator of Trk-receptors following multiple doses in healthy subjects. J Prev Alz Dis. Published online July 12, 2023. doi:10.14283/jpad.2023.89