Therapeutics

ACD856

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Overview

Name: ACD856
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: AlzeCure Pharma AB

Background

This small molecule is a positive allosteric modulator of Trk receptors, which mediate the effects of BDNF, NGF, and other neurotrophic factors. ACD856 increases the kinase activity of Trk receptors and enhances the effects of BDNF or NGF on survival, neuronal function, and synaptic plasticity. This is intended to make up for loss of BDNF and NGF signaling that occurs in AD.

This compound is taken orally. It is being developed for Alzheimer’s disease; other potential indications include cognitive impairment due to Parkinson’s disease, traumatic brain injury, or sleep disorders and depression.

AlzeCure Pharma identified positive Trk receptor modulators in a high-throughput, cell-based screen. Top hits included two triazinetriones that are used as veterinary anti-parasitic agents, and these were chemically optimized to yield ACD856. The compound potentiated cellular signaling of TrkA and TrkB receptors with EC50 values of 382 or 295 nM, respectively. It bound the receptor’s intracellular domain, and increased the Vmax of TrkA kinase, suggesting it acts by accelerating the catalytic cycle. ACD856 or the related veterinary drug Ponazuril facilitated LTP in hippocampal slices, and increased levels of brain acetylcholine in awake rats. ACD856 reversed scopolamine-induced memory impairments in rats and mice, and age-related memory decline in mice (Dahlström et al., 2021). The compound improves mitochondrial function and increases BDNF expression in cells, and shows antidepressant activity in mice (Parrado-Fernandez et al., 2023; Madjid et al., 2023).

Findings

From January 2020 to May 2022, AlzeCure evaluated ACD856 in three Phase 1 trials in Sweden. A micro-dosing study gave a single, intravenous infusion of 100 micrograms to six healthy volunteers to estimate bioavailability. This was followed by a single-dose safety, tolerability, and pharmacokinetic study in 56 healthy volunteers. According to results presented at the March 2022 AD/PD Conference in Barcelona, Spain, an oral solution of drug was administered at doses of 1, 3, 10, 20, 40, 75, and 150 mg, with a placebo control. A study of food effects used doses of 20 or 40 mg. The company reported no significant safety findings on vital signs, physical exams, or urinalyses. Adverse events were mostly mild, with headache and nausea the most common. The compound showed rapid absorption, high bioavailability, and dose-dependent exposure. Food reduced absorption but had little effect on overall availability or half-life in plasma (poster).

A multiple-dosing study began in September 2021, with 24 participants taking 10, 30, or 90 mg daily for seven days. Safety evaluations were as for the SAD study, with the addition of measures of anxiety, depression, suicidality, and prolactin levels. According to results presented at the July 2022 AAIC, ACD856 caused no clinically significant changes in most safety parameters, except two participants had elevated lipase or amylase that returned to normal with time. Most adverse events were mild; none were severe. The drug was detected in CSF at 37 to 120 percent of plasma concentrations, increasing with dose (poster). This study included an exploratory analysis of target engagement by quantitative electroencephalography (qEEG) in 12 participants treated with 30 or 90 mg daily. In a presentation at the November 2022 CTAD meeting in Boston, the company claimed ACD856 significantly increased theta power, and the theta/beta ratio compared to baseline or to placebo (poster). These results were published after peer review (Önnestam et al., 2023).

For details, see clinicaltrials.gov.

Last Updated: 19 Dec 2023

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References

Paper Citations

  1. Önnestam K, Nilsson B, Rother M, Rein-Hedin E, Bylund J, Anderer P, Kemethofer M, Halldin MM, Sandin J, Segerdahl M. Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects. J Prev Alzheimers Dis. 2023;10(4):778-789. PubMed.
  2. Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, Sandin J, Winblad B, Eriksdotter M, Forsell P. Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction. Cells. 2021 Jul 23;10(8) PubMed.
  3. Parrado Fernandez C, Juric S, Backlund M, Dahlström M, Madjid N, Lidell V, Rasti A, Sandin J, Nordvall G, Forsell P. Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer's Disease. Int J Mol Sci. 2023 Jul 6;24(13) PubMed.
  4. Madjid N, Lidell V, Nordvall G, Lindskog M, Ögren SO, Forsell P, Sandin J. Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling - a potential therapeutic concept?. Psychopharmacology (Berl). 2023 Aug;240(8):1789-1804. Epub 2023 Jul 3 PubMed.

External Citations

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  4. clinicaltrials.gov

Further Reading

No Available Further Reading