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ACD856
Clinical data
Other namesACD-856
Routes of
administration		Oral[1][2]
Drug classTropomyosin receptor kinase TrkA, TrkB, and TrkC positive allosteric modulator[1][3][2][4]
Pharmacokinetic data
Elimination half-life~19 hours[5]

ACD856, or ACD-856, is a tropomyosin receptor kinase TrkA, TrkB, and TrkC positive allosteric modulator which is under development for the treatment of Alzheimer's disease, depressive disorders, sleep disorders, and traumatic brain injuries.[1][3][2][5][6][4] It is taken by mouth.[1][2]

Pharmacology

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The drug potentiates the tropomyosin receptor kinases TrkA, TrkB, and TrkC with EC50Tooltip half-maximal effective concentration values of 382 nM, 295 nM, and ~330 nM, respectively.[2][4] As a positive allosteric modulator of TrkA and TrkB, ACD856 potentiates the effects of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).[6][2][7]

In addition to the tropomyosin receptor kinases, ACD856 is also a similarly potent positive allosteric modulator of certain other receptor tyrosine kinases, including the insulin-like growth factor 1 receptor (IGF1R) and the fibroblast growth factor receptor 1 (FGFR1).[4] However, its efficacies at the IGF1R and FGFR1 were much lower than at the TrkA, TrkB, and TrkC.[4]

In animals, ACD856 has been found to reverse scopolamine- and dizocilpine (MK-801)-induced memory impairment, to improve age-related memory deficits, and to have sustained antidepressant-like activity.[5][2][7][8][4] It has also been reported to possess neuroprotective properties.[5][7]

In humans, the drug has been shown to cross the blood–brain barrier and to induce dose-dependent changes in electroencephalogram parameters.[5][2][9] No significant tolerability or safety concerns have been identified in preclinical research or phase 1 clinical trials.[10] The drug's clinical pharmacokinetics have been characterized and its elimination half-life is approximately 19 hours.[5][11][9]

Chemistry

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The chemical structure of ACD856 has not yet been disclosed as of 2024, but the structure of its predecessor ponazuril (ACD855) is known and both ponazuril and ACD856 have been described as triazinetriones.[5][7]

History

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It was discovered through the use of high-throughput screening of 25,000 compounds.[5][2][4] Toltrazuril and ponazuril (ACD855), two veterinary antiparasitic agents, were identified as possessing Trk-potentiating activity with this screen in 2013.[2][5][4] ACD856 was derived via structural optimization of these compounds.[2][5] In the case of ponazuril, this drug was said to have had too long of an elimination half-life to allow for development for use in humans.[11] ACD856 was first described in the scientific literature by 2021.[4][12]

Clinical trials

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As of May 2024, ACD856 is in phase 1 clinical trials for Alzheimer's disease and is in the preclinical stage of development for depressive disorders, sleep disorders, and traumatic brain injuries.[1][3][2] Two phase 1 trials have been completed.[10] A phase 2 clinical trial for Alzheimer's disease is being planned as of May 2024.[1] The drug is under development by AlzeCure Pharma AB.[1][3][2]

References

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  1. ^ a b c d e f g "ACD 856". AdisInsight. Springer Nature Switzerland AG. 17 May 2024. Retrieved 23 October 2024.
  2. ^ a b c d e f g h i j k l m "ACD856". ALZFORUM. 19 December 2023. Retrieved 23 October 2024.
  3. ^ a b c d "Delving into the Latest Updates on ACD-856 with Synapse". Synapse. 12 October 2024. Retrieved 23 October 2024.
  4. ^ a b c d e f g h i Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, et al. (July 2021). "Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction". Cells. 10 (8): 1871. doi:10.3390/cells10081871. PMC 8391421. PMID 34440640.
  5. ^ a b c d e f g h i j Forsell P, Parrado Fernández C, Nilsson B, Sandin J, Nordvall G, Segerdahl M (July 2024). "Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer's Disease". Pharmaceuticals. 17 (8): 997. doi:10.3390/ph17080997. PMC 11357672. PMID 39204102.
  6. ^ a b Wang D, Lang ZC, Wei SN, Wang W, Zhang H (2 May 2024). "Targeting brain-derived neurotrophic factor in the treatment of neurodegenerative diseases: A review". Neuroprotection. 2 (2). Wiley: 67–78. doi:10.1002/nep3.43. ISSN 2770-7296. ACD856 is an innovative allosteric modulator that positively affects all Trk receptors, amplifying their kinase activity. Subsequently, it potentiates the effect of BDNF or nerve growth factor (NGF) on neuronal survival, function, and plasticity of synapses. The finished phase I study showed that ACD856 passed the blood‐brain barrier and induced dose‐dependent treatment‐related alterations in quantitative electroencephalogram parameters with good safety.141,142
  7. ^ a b c d Parrado Fernandez C, Juric S, Backlund M, Dahlström M, Madjid N, Lidell V, et al. (July 2023). "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". International Journal of Molecular Sciences. 24 (13): 11159. doi:10.3390/ijms241311159. PMC 10342804. PMID 37446337.
  8. ^ Madjid N, Lidell V, Nordvall G, Lindskog M, Ögren SO, Forsell P, et al. (August 2023). "Antidepressant effects of novel positive allosteric modulators of Trk-receptor mediated signaling - a potential therapeutic concept?". Psychopharmacology. 240 (8): 1789–1804. doi:10.1007/s00213-023-06410-x. PMC 10349764. PMID 37394539.
  9. ^ a b Önnestam K, Nilsson B, Rother M, Rein-Hedin E, Bylund J, Anderer P, et al. (2023). "Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects". The Journal of Prevention of Alzheimer's Disease. 10 (4): 778–789. doi:10.14283/jpad.2023.89. PMID 37874100.
  10. ^ a b Nordvall G, Forsell P, Sandin J (October 2022). "Neurotrophin-targeted therapeutics: A gateway to cognition and more?". Drug Discovery Today. 27 (10): 103318. doi:10.1016/j.drudis.2022.07.003. PMID 35850433.
  11. ^ a b Nilsson B, Bylund J, Halldin MM, Rother M, Rein-Hedin E, Önnestam K, et al. (May 2024). "ACD856, a novel positive allosteric modulator of Trk receptors, single ascending doses in healthy subjects: Safety and pharmacokinetics". European Journal of Clinical Pharmacology. 80 (5): 717–727. doi:10.1007/s00228-024-03645-1. PMC 11001683. PMID 38353689.
  12. ^ Nordvall G, Madjid N, Backlund M, Halldin M, Rother M, Nilsson B, et al. (2021). "ACD856: A novel positive allosteric modulator of Trk-signaling in clinical development for the treatment of Alzheimer's disease". Alzheimer's & Dementia. 17 (S9). Wiley. doi:10.1002/alz.057730. ISSN 1552-5260.
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