ACD856

ACD856 is a novel, orally bioavailable triazinetrione compound functioning as a positive allosteric modulator (PAM) of the tropomyosin receptor kinases TrkA, TrkB, and TrkC, the principal signal-transducing receptors for the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), respectively [1, 2]. The compound was identified through a high-throughput screening campaign of approximately 25,000 compounds and structurally optimized from the veterinary antiparasitic triazinetrione scaffold shared by toltrazuril and ponazuril (ACD855), with the critical improvement of a substantially shortened elimination half-life suitable for once-daily human dosing [3, 4]. ACD856 potentiates the tropomyosin receptor kinases with EC50 values of 382 nM (TrkA), 295 nM (TrkB), and approximately 330 nM (TrkC), and exhibits additional positive allosteric modulation of the insulin-like growth factor 1 receptor (IGF1R) and fibroblast growth factor receptor 1 (FGFR1) [1, 5]. The mechanism of action is distinct from orthosteric Trk agonism: ACD856 binds the intracellular kinase domain of Trk receptors and increases the maximal catalytic velocity (Vmax) of the kinase, thereby amplifying endogenous neurotrophin signaling rather than substituting for it [2, 6]. This allosteric mechanism preserves the spatiotemporal specificity of native neurotrophin activity, a property expected to confer a more favorable safety profile than direct agonist approaches that have historically been limited by pain, hyperalgesia, and off-target proliferative effects.

In preclinical pharmacology, ACD856 has demonstrated reversal of scopolamine-induced and dizocilpine (MK-801)-induced memory impairment in passive avoidance and novel object recognition tasks in mice, restoration of age-related memory deficits in 21-month-old mice to the performance level of young animals following single-dose administration, neuroprotection against amyloid-beta(1-42)-induced synaptotoxicity in primary cortical neurons, enhancement of NGF-stimulated neurite outgrowth in PC12 cells, elevation of BDNF protein levels in the brains of aged mice following repeated dosing, and sustained antidepressant-like effects in the forced swim test persisting up to seven days after the last dose [5, 7, 8]. The compound also enhanced mitochondrial ATP production under energy-deprived conditions, increased phosphorylation of TrkB and ERK1/2 in cortical neurons, elevated hippocampal concentrations of serotonin, noradrenaline, and dopamine by in vivo microdialysis, and increased expression of the presynaptic protein SNAP25, collectively indicating a broad neuroprotective and neuroplasticity-promoting pharmacological profile [5, 7].

ACD856 has completed two Phase 1 clinical studies in healthy volunteers. The single ascending dose (SAD) study (1 to 150 mg oral, n = 56) demonstrated rapid absorption (median tmax 0.33 to 1.0 hours), linear dose-proportional pharmacokinetics, near-complete oral bioavailability (approximately 93 percent relative bioavailability), a terminal elimination half-life of approximately 20 hours supporting once-daily dosing, and an acceptable safety profile with no serious adverse events and no dose-related safety signals [9]. The multiple ascending dose (MAD) study (10, 30, and 90 mg daily for seven days, n = 24) confirmed dose-dependent increases in cerebrospinal fluid concentrations (geometric mean 3.98 to 100 ng/mL), CSF-to-unbound-plasma ratios of 0.37 to 1.20 indicating substantial blood-brain barrier penetration, dose-dependent changes on quantitative electroencephalography (increased theta power and theta/beta ratio) consistent with central target engagement, and continued safety and tolerability with no serious adverse events [10, 11]. AlzeCure Pharma has received a EUR 2.5 million grant from the European Innovation Council to conduct a Phase IIa clinical study of ACD856 in Alzheimer's disease, with higher doses to be evaluated based on the favorable Phase 1 safety profile [12]. Additional indications under preclinical investigation include depressive disorders, traumatic brain injury, sleep disorders, and postoperative cognitive dysfunction.