ACD856

ACD856 comes from AlzeCure Pharma in Huddinge, Sweden, and is the lead compound of the programme the company calls NeuroRestore [4]. The idea behind it is old. The neurotrophins BDNF and NGF keep synapses and cholinergic neurons working, and their signalling is reduced in Alzheimer's disease and depression, but the proteins themselves make poor drugs: they do not cross into the brain, they are cleared quickly, and injected NGF causes pain [1][2][6]. ACD856 is meant to get the benefit without the protein. It is a positive allosteric modulator of the Trk receptors, a small molecule that amplifies the signal wherever BDNF, NGF or NT-3 is already acting [1][7].

The animal data are consistent and narrow. In mice, a single injection of 0.3–1 mg/kg reversed the memory loss caused by scopolamine or by the NMDA blocker MK-801 in a passive avoidance task. The TrkB antagonist ANA-12 blocked that effect, and a low dose added to a low dose of the cholinesterase inhibitor physostigmine worked where neither did alone [1]. Given before training, just after it, or before the recall test, it reversed the deficit on one measure at all three timings and on a second measure at the first two [1]. It did nothing for memory in healthy young mice [1]. In 18-month-old mice a single 3 mg/kg dose produced only a non-significant improvement when recall was tested a day later, but a clear one when the same animals were retested 11 days on, when they performed like two-month-old mice [1]. After four daily doses the lowest effective dose fell from 0.3 to 0.1 mg/kg, which a half-life of 1.4 hours in mice cannot explain by accumulation [2].

The antidepressant-like data come from one test. In the forced swim test, 1 mg/kg cut immobility in mice from about 305 to 245 seconds after a single dose, against 209 seconds for fluoxetine at 20 mg/kg. The effect was still there after 28 days of daily dosing, and also appeared in Flinders Sensitive Line rats after four days [3]. After five daily doses it lasted up to seven days beyond the last one [2]. The authors themselves note that relying on a single behavioural model is a limitation [3].

In people there are two published phase 1 trials and nothing else. The first combined an intravenous microdose in six men with single oral doses of 1–150 mg in 56 healthy adults; the second gave 10, 30 or 90 mg a day for a week to 24 [4][5]. Both were about safety and pharmacokinetics. The second also took spinal fluid, which showed the drug reaching the central nervous system, and recorded a quantitative EEG, which showed more relative theta power and less fast alpha and beta power in a dose-dependent way [5]. The authors read that as a sign of target engagement and are guarded about it: six people per dose, no active comparator, and alertness during recording not controlled, in a pattern that resembles ordinary relaxation [5].

A phase 1b study of higher repeated doses was reported complete in June 2026, with tolerability and rising blood and spinal-fluid levels described in a press release but no data [8]. No trial in patients with Alzheimer's disease, depression or any other condition has been published.

A modulator, with some agonism in overexpressing cells. In engineered cells that report Trk activation, ACD856 potentiated NGF at TrkA, BDNF at TrkB and NT-3 at TrkC with EC50 values of 0.38, 0.30 and 0.33 µM, pushing the response well above what a saturating dose of the natural ligand achieves [1]. It did not change the concentration of NGF needed for a half-maximal response, so it is not making the ligand bind better [2]. In those cells it also switched TrkA on to about 60% with no NGF present. The authors call the profile a positive allosteric modulator with partial agonism and say the ligand-free activity may be an artefact of heavy receptor overexpression [2].

It appears to act on the inside of the receptor. With full-length TrkA pulled out of cells, 1 µM ACD856 raised the maximum rate of the kinase reaction. It had no effect on the isolated intracellular kinase domain, and surface plasmon resonance found only weak binding to that fragment, with an apparent KD of 177 µM [1]. A photo-crosslinkable analogue labelled full-length TrkA [1]. The developers conclude that the binding site needs the juxtamembrane and transmembrane regions to fold properly, and describe the mechanism as the inverse of the allosteric kinase inhibitors known for TrkA [1][6]. No structure of the drug bound to a receptor has been published.

Selectivity is partial. ACD856 also potentiated the IGF-1 receptor and FGF receptor 1 at similar concentrations, though to a much lower ceiling [1]. No wider off-target panel has been published.

Downstream it looks like BDNF. In mouse cortical neurons it raised phosphorylated ERK1/2 in neurites without added BDNF, increased BDNF protein by about 30%, kept ATP levels up when glucose and pyruvate were withdrawn, and largely prevented the loss of the synaptic protein SNAP25 caused by four days of amyloid-β 1-42 [2]. In PC12 cells it lengthened and multiplied the neurites grown in response to NGF [2]. The predecessor compound ACD855 made a weak stimulus produce lasting long-term potentiation in rat hippocampal slices, as BDNF does; that experiment was not reported for ACD856 itself [1].

In animals the BDNF rise depends on the animal. Brain BDNF went up in 21-month-old mice after four weeks at 5 mg/kg a day but not in young mice after five days at 3 mg/kg, even though the young mice showed the forced-swim effect [2]. That fits the behavioural picture of a drug that restores impaired function more than it enhances normal function [1].

Monoamines move too. A 10 mg/kg dose in rats raised hippocampal serotonin, noradrenaline and dopamine for under two hours, with no change in acetylcholine or glutamate [3]. A sister compound's forced-swim effect was blocked by ANA-12 and added to sub-threshold doses of fluoxetine and ketamine, although the statistical test for a true interaction was not significant; those experiments were not run with ACD856 [3].

The structure is not public. ACD856 is described only as a triazinetrione derivative, optimised from the veterinary antiparasitic drug ponazuril (toltrazuril sulfone), and the developer's own 2024 review lists the undisclosed structure as a limitation, pointing readers to its patent applications [1][6]. PubChem has no record under the name, so this entry carries no formula or structure image. The mouse pharmacokinetic paper reports paired molar and mass concentrations (3,550 nM as 1,375 ng/mL) that work out to a molecular weight of about 387 [2].

The two published trials used an oral solution at 2 mg/mL [4][5]. The food-effect comparison was run with that solution in four people, and the authors say it will need repeating once a final formulation exists [4].

Short-term tolerability in healthy adults was good; nothing longer has been published. Across the single-dose trial, 31 of 56 participants reported 62 adverse events, with no pattern by dose and no serious events [4]. Twenty-four events in 13 people were judged possibly related, all in people on ACD856. Headache was the commonest, in eight people, all on 1–40 mg, with none at 75 or 150 mg or on placebo [4]. In the seven-day trial 22 of 24 participants reported an event, most of them mild. Headache again led, and seven of the 15 episodes were attributed to the lumbar puncture [5].

Two laboratory findings were recorded. One man in the microdose study, a weightlifter who trained against the protocol, had a transient rise in liver enzymes five days after 0.1 mg; the authors later attributed it to exercise, and no liver signal appeared at the far higher doses given afterwards [4]. One participant had a symptomless rise in lipase and amylase after the last dose of the seven-day course that resolved within 24 hours and was judged possibly related [5]. ECG analysis found no systematic change in QT interval, and anxiety, depression and suicidality questionnaires did not move [5].

The class-specific worries have not shown up. Earlier attempts to stimulate NGF or BDNF signalling in people produced looser and more frequent stools, reduced appetite and weight loss, muscle aches and raised eosinophils, and injected NGF caused pain [4][6]. Both trials therefore tracked stool frequency, which did not change, and the developer reports no pain or allodynia in the clinical studies [2][4][5]. The first Trk receptor was discovered as a kinase with transforming activity [2], and no carcinogenicity study of ACD856 has been published.

Preclinical toxicology is reported in summary only: 28-day studies in rats and minipigs with no findings at the highest doses, and genotoxicity and safety pharmacology described as done to regulatory standards [4].