Summary

Davunetide (AL-108, NAPVSIPQ) is an eight-amino-acid peptide derived from activity-dependent neuroprotective protein (ADNP). It stabilises neuronal microtubules and has been investigated as a neuroprotective agent for progressive supranuclear palsy (PSP), mild cognitive impairment, and other neurodegenerative conditions. Administered intranasally in clinical trials, davunetide reached Phase 3 but failed to meet its primary efficacy endpoint in PSP. It remains of significant research interest for its microtubule-stabilising mechanism, which is distinct from other neuroprotective peptides.

Overview

Davunetide (also known as AL-108, NAPVSIPQ, or NAP) is an eight-amino-acid peptide (sequence: NAPVSIPQ) derived from activity-dependent neuroprotective protein (ADNP), a protein essential for brain development and neuronal survival. Discovered in the laboratory of Professor Illana Gozes at Tel Aviv University, davunetide has been investigated primarily as a neuroprotective agent for tauopathies — neurodegenerative diseases characterised by abnormal tau protein accumulation — including progressive supranuclear palsy (PSP), frontotemporal dementia, and mild cognitive impairment.

Davunetide is of significant research interest because it targets the microtubule network — the cellular 'skeleton' whose destabilisation underlies tau pathology — through a mechanism distinct from existing approaches. It reached Phase 3 clinical trials, providing substantial human safety data, though it ultimately failed to meet its primary efficacy endpoint.

Mechanism of Action

Davunetide's primary mechanism centres on microtubule stabilisation. The peptide:

  • Binds tubulin: Davunetide interacts with tubulin dimers, the building blocks of microtubules, promoting their polymerisation and stabilising the microtubule network.
  • Counteracts tau dysfunction: In healthy neurons, tau protein stabilises microtubules. In tauopathies, tau detaches from microtubules and forms toxic aggregates. Davunetide's microtubule-stabilising effect is proposed to compensate for this loss of tau function.
  • Neuroprotective signalling: ADNP (the parent protein) is a transcription factor involved in neuronal development and synaptic plasticity. Davunetide, as its active fragment, may activate neuroprotective gene expression cascades.
  • Reduces tau hyperphosphorylation: Preclinical data suggest davunetide reduces the phosphorylation of tau at disease-associated epitopes, potentially decreasing aggregate formation.
  • Synaptic protection: Preclinical studies show preservation of dendritic spine density and synaptic markers under neurotoxic stress.

The peptide is notable for its ability to cross the blood-brain barrier, an uncommon property among peptides, which was demonstrated in preclinical models.

Research Summary

Preclinical evidence

Extensive in vitro and animal model data demonstrated that davunetide protects neurons against a variety of insults including oxidative stress, amyloid-beta toxicity, and excitotoxicity. Mouse models of tauopathy showed improved cognitive performance and reduced tau pathology. (Gozes et al., various publications, 2000–2014)

Phase 2 — Mild Cognitive Impairment (2012)

A double-blind, placebo-controlled Phase 2a trial intranasally administered davunetide to patients with amnestic mild cognitive impairment over 12 weeks. The study reported a favourable safety profile and some cognitive performance signals, though it was not powered for definitive efficacy. (Morimoto et al., 2012)

Phase 2 — Schizophrenia (2010)

A small Phase 2 trial evaluated davunetide (as AL-108) for cognitive impairment in schizophrenia. Results were inconclusive but the peptide was well tolerated. (Jarskog et al., 2013)

Phase 3 — Progressive Supranuclear Palsy (2013)

A pivotal Phase 3 trial (the AL-108-231 study) randomised 313 PSP patients to intranasal davunetide (30 mg twice daily) or placebo for 52 weeks. The trial failed to meet its primary endpoint — change in PSP Rating Scale — and all secondary endpoints. No disease-modifying effect was demonstrated. (Hung et al., presented at AAN 2013; published data, Allon Therapeutics)

This failure led to the discontinuation of davunetide development for PSP by Allon Therapeutics (subsequently acquired by Bioline Rx). However, research into its mechanism and potential applications in other conditions continues in academic settings.

Evidence grading rationale

Graded as moderate because davunetide has completed Phase 3 human trials with robust safety data, but its primary efficacy endpoint was not met. The mechanistic rationale and preclinical data are strong, but clinical translation has not been demonstrated.

Commonly Discussed Protocols

Research use only. No medical advice. The following reflects published clinical-trial designs, not recommendations.

In clinical trials, davunetide was administered via intranasal delivery — a notable feature that distinguishes it from most injectable research peptides.

  • Phase 2 (MCI): 15 mg or 30 mg intranasal, twice daily for 12 weeks.
  • Phase 3 (PSP): 30 mg intranasal, twice daily for 52 weeks.

No standardised research protocol exists outside of clinical-trial contexts. Intranasal administration in a research setting requires specialised delivery devices and formulations not typically available from standard research peptide suppliers. As with all unlicensed peptides, any use outside of approved clinical trials is investigational and not endorsed.

Stacking

Davunetide has not been studied in combination with other peptides in clinical settings. Its intranasal, CNS-targeted mechanism is mechanistically distinct from injectable research peptides. There is no published rationale for combining it with growth-hormone secretagogues, healing peptides, or metabolic peptides.

Storage & Reconstitution

Davunetide in clinical-trial formulations was supplied as an intranasal solution. For bulk research-grade lyophilised material, general peptide storage principles apply:

  • Lyophilised: Store at –20°C in a sealed, desiccated container. Protect from light and moisture.
  • Reconstituted: If solubilised for in vitro research, use sterile water or an appropriate buffer (e.g., PBS). Peptide concentration and stability should be verified for the specific application.
  • Handling: As with all research peptides, use appropriate personal protective equipment and follow institutional laboratory safety protocols.

Note: Clinical formulations were intranasal solutions, not injectable. Research-grade material should not be assumed to be suitable for any route without supplier and protocol guidance.

Blood Work

No specific blood-work monitoring protocol was established for davunetide in clinical trials beyond standard safety panels (liver function, renal function, complete blood count, vital signs). In the Phase 3 PSP trial, cerebrospinal fluid (CSF) biomarkers including total tau and phospho-tau were monitored in a subset of patients, but no consistent biomarker changes were attributed to treatment.

UK Legal Status

Davunetide is an investigational medicinal product that has not received marketing authorisation from the MHRA, EMA, FDA, or any other regulatory body. Development was effectively discontinued after the failed Phase 3 trial in 2013. It is not a licensed medicine in the UK.

As a synthetic peptide potentially available from research chemical suppliers, it falls into the UK grey area: legal to purchase and possess for bona fide research purposes (in vitro or laboratory use), but not licensed for human consumption, medical use, or administration outside of approved clinical trials. The MHRA has not issued specific guidance on davunetide.

Researchers should be aware that importing or supplying unlicensed peptides for human use without appropriate regulatory approvals may constitute an offence under UK medicines legislation.

Vetted UK Vendors

Davunetide is not commonly stocked by mainstream UK peptide vendors, reflecting its intranasal clinical formulation, CNS-focused indication, and the discontinuation of clinical development after Phase 3 failure. Researchers seeking the compound may need to contact specialist research chemical suppliers directly. As always, verify that any supplier provides a certificate of analysis (CoA) confirming peptide content and purity.

No vetted UK vendors currently stock davunetide as a standard catalogue item.

References

  1. Gozes I, Giladi E, Pinhasov A, et al. "Activity-dependent neuroprotective protein: a gene delivery target and a peptide for neuroprotection." Journal of Molecular Neuroscience. 2000;14(1-2):61-68. doi:10.1385/JMN:14:1-2:61
  2. Matsuoka Y, Jouroukhin Y, Gray AJ, et al. "A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau phosphorylation and attenuates mild cognitive impairment in subjects with amnestic mild cognitive impairment." Journal of Alzheimer's Disease. 2008;13(3):261-269. doi:10.3233/JAD-2008-13304
  3. Morimoto BH, Fox AW, Stewart AJ, Gold M. "AL-108, a novel, orally available, cognitive-enhancing agent: a review of preclinical and Phase 1 data." Journal of Molecular Neuroscience. 2012;46(3):540-547. doi:10.1007/s12031-011-9646-5
  4. Jarskog LF, Hamer RM, Bhatt DL, et al. "A randomized controlled trial of davunetide for cognitive impairment in schizophrenia." Schizophrenia Research. 2013;146(1-3):254-258. doi:10.1016/j.schres.2013.02.016
  5. Gozes I. "The ADNP syndrome and CP201 (NAP) potential in Alzheimer's disease." Journal of Alzheimer's Disease. 2018;64(s1):S193-S199. doi:10.3233/JAD-179936
  6. Gozes I, Divinski I. "NAP, a neuroprotective drug candidate, shows activity in animal models and in human neurodegenerative diseases." Journal of Molecular Neuroscience. 2004;24(3):391-396. doi:10.1385/JMN:24:3:391

References

  1. Gozes I, Giladi E, Pinhasov A, et al. "Activity-dependent neuroprotective protein: a gene delivery target and a peptide for neuroprotection." J Mol Neurosci. 2000;14(1-2):61-68. doi:10.1385/JMN:14:1-2:61
  2. Matsuoka Y, Jouroukhin Y, Gray AJ, et al. "A neuronal microtubule-interacting agent, NAPVSIPQ, reduces tau phosphorylation and attenuates mild cognitive impairment in subjects with amnestic mild cognitive impairment." J Alzheimers Dis. 2008;13(3):261-269. doi:10.3233/JAD-2008-13304
  3. Morimoto BH, Fox AW, Stewart AJ, Gold M. "AL-108, a novel, orally available, cognitive-enhancing agent: a review of preclinical and Phase 1 data." J Mol Neurosci. 2012;46(3):540-547. doi:10.1007/s12031-011-9645-5
  4. Jarskog LF, Hamer RM, Bhatt DL, et al. "A randomized controlled trial of davunetide for cognitive impairment in schizophrenia." Schizophr Res. 2013;146(1-3):254-258. doi:10.1016/j.schres.2013.02.016
  5. Gozes I. "The ADNP syndrome and CP201 (NAP) potential in Alzheimer's disease." J Alzheimers Dis. 2018;64(s1):S193-S199. doi:10.3233/JAD-179936
  6. Gozes I, Divinski I. "NAP, a neuroprotective drug candidate, shows activity in animal models and in human neurodegenerative diseases." J Mol Neurosci. 2004;24(3):391-396. doi:10.1385/JMN:24:3:391