Therapeutics

Davunetide

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Overview

Name: Davunetide
Synonyms: NAP, AL-108
Chemical Name: NAPVSIPQ
Therapy Type: Other
Target Type: Tau (timeline)
Condition(s): Mild Cognitive Impairment, Progressive Supranuclear Palsy, Schizophrenia, Frontotemporal Dementia, Autism Spectrum Disorder
U.S. FDA Status: Mild Cognitive Impairment (Discontinued), Progressive Supranuclear Palsy (Discontinued), Schizophrenia (Discontinued), Frontotemporal Dementia (Inactive), Autism Spectrum Disorder (Phase 3)
Company: Allon Therapeutics Inc., Exonavis Therapeutics Ltd., Paladin Labs Inc.

Background

Davunetide is an intranasal neuropeptide therapy derived from a growth factor called activity-dependent neurotrophic protein (ADNP). Released by glial cells, ADNP contains within it a peptide of the eight amino acids Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln. This peptide has highly potent neuroprotective activity. Initial published data supporting the rationale for its therapeutic potential range from reports on in-vitro neuroprotection against Aβ, viruses, and oxidative stress to neuroprotection in rodent models of stroke and hypoxia (see Jul 2002 news story).

ADNP is involved in chromatin remodeling, transcription, and microtubule stabilization. It plays a role in brain development, and ADNP mutations cause a syndrome of intellectual deficiency and developmental delays with features of autism. Mutants are associated with ER stress that activates the unfolded protein response, defective neurodifferentiation, impaired cell survival, and tau pathology (e.g. Bieluszewska et al., 2025; Grigg et al., 2020). Somatic mutations of ADNP were found in AD brain, and mutation frequency correlated with the extent of tau pathology (Ivashko-Pachima et al., 2021).

In preclinical work, davunetide/NAP improved memory and cognition in mice. Genetic ADNP reduction impairs performance in the Morris water maze, and intranasal dosing with NAP was reported to reverse the effect. In a triple transgenic mouse model of AD, NAP reduced amyloid accumulation and tau hyperphosphorylation and improved performance in the Morris water maze (see Vulih-Shultzman et al., 2007; May 2007 news story; Matsuoka et al., 2008). Similar improvements were reported in Aβ42-treated rats (Zhang et al., 2017). NAP was reported to rescue a neuronal dysfunction phenotype in a fly model of tauopathy (see Quraishe et al., 2013). In mice, ADNP truncation led to tauopathy, which was corrected by NAP treatment (Karmon et al., 2022). NAP promoted tau binding to microtubules, and reduced tau phosphorylation in cells (Ivashko-Pachima et al., 2017; Ivashko-Pachima and Gozes, 2018).

ADNP’s actions on neurogenesis, neural plasticity, and gene expression were reported to be sex-specific (e.g. Shapira et al., 2024; reviewed in Gozes 2024).

Other preclinical studies have reported beneficial effects of NAP in mouse models of amyotrophic lateral sclerosis and Parkinson's disease (see Jouroukin et al., 2013; Fleming et al., 2011). ADNP levels were found to be decreased in Parkinson’s brain (Chu et al., 2016).

Findings

Four Phase 2 and 3 clinical trials were conducted with a nasal spray formulation of davunetide.

From 2007–2008, a Phase 2 trial compared the effect on memory outcomes of 5 mg once a day, 15 mg twice a day, and placebo in 144 people with aMCI, frequently a prodrome to Alzheimer's disease. This was a four-month, multicenter U.S. study. At conferences, the trial was reported to show a statistically significant improvement in test performance compared with placebo at eight weeks and 16 weeks, but not 12 weeks; a placebo effect was also mentioned. Safety data included headache and nasal irritation, but the drug was generally well-tolerated (see May 2008 news story).

From 2007–2009, a Phase 2 trial compared two different doses of davunetide to placebo in 63 patients with chronic schizophrenia. In this trial, intranasal davunetide missed one coprimary outcome, the MATRICS composite battery of tests, but showed efficacy in the other, the University of California at San Diego performance-based skills assessment, UPSA. The treatment was also reported to show an effect on cortical thickness (see Javitt et al., 2012; Jarskog et al., 2013).

From 2010–2012, a one-year Phase 2/3 trial compared 30 mg of davunetide spray twice a day to placebo in 313 people with the tauopathy progressive supranuclear palsy (PSP). Coprimary outcomes were efficacy as measured by the Progressive Supranuclear Palsy Rating Scale (PSPRS) and the Schwab and England Activities of Daily Living Scale (SEADL), and safety. The trial included no measures of target engagement. Conducted at 47 sites in North America, Australia, and Europe, this pivotal trial was negative on all endpoints—primary, secondary, and exploratory.

This result halted clinical development of davunetide (see Dec 2012 news story; company press release). It also prompted a halt to recruitment into an ongoing safety and biomarker trial, begun in 2010, of davunetide in frontotemporal lobar degeneration (FTLD) with predicted tau pathology, corticobasal degeneration (CBS), or progressive supranuclear palsy (PSP). Results were formally published (Boxer et al., 2014).

A post hoc analysis of the PSP data claimed that the treatment was effective in women, but not men (Gozes et al., 2023). Women declined faster than men on the primary endpoints of the PSPRS and SEADL. Treatment with davunetide slowed women’s progression on the SEADL scale and part of the PSPRS.

Davunetide was being developed by Allon Therapeutics based in Vancouver, Canada. Allon became insolvent and in July 2013 was acquired by the Canadian pharmaceutical company Paladin Labs (see YahooFinance story).

An intravenous formulation of davunetide exists, as well. Called AL-208, Allon tested this version of the drug between 2006 and 2008 in a Phase 2 trial of the safety and efficacy of a single 300-mg IV dose on cognitive impairment following coronary artery bypass surgery. Conducted in 234 cardiovascular patients, this trial has no published results; however, in a press release, the company claimed safety and tolerability for AL-208 as seen in a smaller Phase 1 study.

ExoNavis was founded in 2021, and licensed davunetide from Tel Aviv University.

According to the company website, a Phase 3 trial began in October 2024 testing davunetide in 97 children with ADNP mutations. The trial does not appear in registries.

Davunetide has U.S. FDA orphan drug and rare pediatric disease designation for ADNP syndrome.

For clinical trials of davunetide, see clinicaltrials.gov.

Last Updated: 28 Feb 2025

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References

News Citations

  1. Boston: Neuroprotective Peptide Inches Forward in Clinic
  2. Tau-Targeting Drug Davunetide Washes Out in Phase 3 Trials
  3. Stockholm: Could a Whiff of NAP Nip Brain Inflammation in the Bud?
  4. Take a NAP—Intranasal Peptide Wends Its Way into Clinical Pipeline

Paper Citations

  1. Javitt DC, Buchanan RW, Keefe RS, Kern R, McMahon RP, Green MF, Lieberman J, Goff DC, Csernansky JG, McEvoy JP, Jarskog F, Seidman LJ, Gold JM, Kimhy D, Nolan KS, Barch DS, Ball MP, Robinson J, Marder SR. Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia. Schizophr Res. 2012 Apr;136(1-3):25-31. Epub 2011 Dec 12 PubMed.
  2. Jarskog LF, Dong Z, Kangarlu A, Colibazzi T, Girgis RR, Kegeles LS, Barch DM, Buchanan RW, Csernansky JG, Goff DC, Harms MP, Javitt DC, Keefe RS, McEvoy JP, McMahon RP, Marder SR, Peterson BS, Lieberman JA. Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia. Neuropsychopharmacology. 2013 Jun;38(7):1245-52. Epub 2013 Jan 16 PubMed.
  3. Boxer AL, Lang AE, Grossman M, Knopman DS, Miller BL, Schneider LS, Doody RS, Lees A, Golbe LI, Williams DR, Corvol JC, Ludolph A, Burn D, Lorenzl S, Litvan I, Roberson ED, Höglinger GU, Koestler M, Jack CR Jr, Van Deerlin V, Randolph C, Lobach IV, Heuer HW, Gozes I, Parker L, Whitaker S, Hirman J, Stewart AJ, Gold M, Morimoto BH, AL-108-231 Investigators. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial. Lancet Neurol. 2014 Jul;13(7):676-85. Epub 2014 May 27 PubMed.
  4. Gozes I, Shapira G, Lobyntseva A, Shomron N. Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women. Transl Psychiatry. 2023 Oct 16;13(1):319. PubMed.
  5. Bieluszewska A, Wulfridge P, Fang KC, Hong Y, Sawada T, Erwin J, Song H, Ming GL, Sarma K. Transcriptomic Analysis Uncovers an Unfolded Protein Response in ADNP Syndrome. Mol Cell Biol. 2025 Feb 14;:1-11. Epub 2025 Feb 14 PubMed.
  6. Grigg I, Ivashko-Pachima Y, Hait TA, Korenková V, Touloumi O, Lagoudaki R, Van Dijck A, Marusic Z, Anicic M, Vukovic J, Kooy RF, Grigoriadis N, Gozes I. Tauopathy in the young autistic brain: novel biomarker and therapeutic target. Transl Psychiatry. 2020 Jul 13;10(1):228. PubMed.
  7. Ivashko-Pachima Y, Hadar A, Grigg I, Korenková V, Kapitansky O, Karmon G, Gershovits M, Sayas CL, Kooy RF, Attems J, Gurwitz D, Gozes I. Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study. Mol Psychiatry. 2019 Oct 30; PubMed.
  8. Vulih-Shultzman I, Pinhasov A, Mandel S, Grigoriadis N, Touloumi O, Pittel Z, Gozes I. Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model. J Pharmacol Exp Ther. 2007 Nov;323(2):438-49. PubMed.
  9. Matsuoka Y, Jouroukhin Y, Gray AJ, Ma L, Hirata-Fukae C, Li HF, Feng L, Lecanu L, Walker BR, Planel E, Arancio O, Gozes I, Aisen PS. A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau pathology and enhances cognitive function in a mouse model of Alzheimer's disease. J Pharmacol Exp Ther. 2008 Apr;325(1):146-53. Epub 2008 Jan 16 PubMed.
  10. Zhang J, Wei SY, Yuan L, Kong LL, Zhang SX, Wang ZJ, Wu MN, Qi JS. Davunetide improves spatial learning and memory in Alzheimer's disease-associated rats. Physiol Behav. 2017 May 15;174:67-73. Epub 2017 Feb 28 PubMed.
  11. Quraishe S, Cowan CM, Mudher A. NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy. Mol Psychiatry. 2013 Jul;18(7):834-42. PubMed.
  12. Ivashko-Pachima Y, Sayas CL, Malishkevich A, Gozes I. ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy. Mol Psychiatry. 2017 Jan 24; PubMed.
  13. Ivashko-Pachima Y, Gozes I. NAP Protects against Tau Hyperphosphorylation Through GSK3. Curr Pharm Des. 2018;24(33):3868-3877. PubMed.
  14. Shapira G, Karmon G, Hacohen-Kleiman G, Ganaiem M, Shazman S, Theotokis P, Grigoriadis N, Shomron N, Gozes I. ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation. Mol Psychiatry. 2024 Dec 23; Epub 2024 Dec 23 PubMed.
  15. Gozes I. Tau, ADNP, and sex. Cytoskeleton (Hoboken). 2024 Jan;81(1):16-23. Epub 2023 Aug 12 PubMed.
  16. Jouroukhin Y, Ostritsky R, Assaf Y, Pelled G, Giladi E, Gozes I. NAP (davunetide) modifies disease progression in a mouse model of severe neurodegeneration: protection against impairments in axonal transport. Neurobiol Dis. 2013 Aug;56:79-94. PubMed.
  17. Fleming SM, Mulligan CK, Richter F, Mortazavi F, Lemesre V, Frias C, Zhu C, Stewart A, Gozes I, Morimoto B, Chesselet MF. A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions. Mol Cell Neurosci. 2011 Mar;46(3):597-606. PubMed.
  18. Chu Y, Morfini GA, Kordower JH. Alterations in Activity-Dependent Neuroprotective Protein in Sporadic and Experimental Parkinson's Disease. J Parkinsons Dis. 2016;6(1):77-97. PubMed.

External Citations

  1. company press release
  2. YahooFinance story
  3. clinicaltrials.gov
  4. Karmon et al., 2022

Further Reading

Papers

  1. Gold M, Lorenzl S, Stewart AJ, Morimoto BH, Williams DR, Gozes I. Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy. Neuropsychiatr Dis Treat. 2012;8:85-93. PubMed.
  2. Gold M, Lorenzl S, Stewart AJ, Morimoto BH, Williams DR, Gozes I. Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy. Neuropsychiatr Dis Treat. 2012;8:85-93. PubMed.
  3. Esteves AR, Gozes I, Cardoso SM. The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinson's disease. Biochim Biophys Acta. 2014 Jan;1842(1):7-21. Epub 2013 Oct 11 PubMed.
  4. Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014 Jan;40(1):181-91. Epub 2013 Oct 8 PubMed.
  5. Greggio S, de Paula S, de Oliveira IM, Trindade C, Rosa RM, Henriques JA, DaCosta JC. NAP prevents acute cerebral oxidative stress and protects against long-term brain injury and cognitive impairment in a model of neonatal hypoxia-ischemia. Neurobiol Dis. 2011 Oct;44(1):152-9. Epub 2011 Jul 5 PubMed.
  6. Ries V, Oertel WH, Höglinger GU. Mitochondrial dysfunction as a therapeutic target in progressive supranuclear palsy. J Mol Neurosci. 2011 Nov 1;45(3):684-9. Epub 2011 Jul 27 PubMed.
  7. Ruíz Moleón V, Alende C, Fotouhi M, Ayoubi R, González Bolívar S, Laflamme C, NeuroSGC/YCharOS/EDDU collaborative group, ABIF consortium. A guide to selecting high-performing antibodies for ADNP (UniProt ID: Q9H2P0) for use in western blot, immunoprecipitation, and immunofluorescence. F1000Res. 2024;13:1545. Epub 2024 Dec 20 PubMed.

External Resources

  1. Genetic Discovery Offers Hope for Brain Development Disorders