Davunetide
Also known as: NAP · AL-108 · NAPVSIPQ
An 8-amino-acid ADNP-derived peptide (NAPVSIPQ) evaluated in multiple neurodegenerative disease trials — the flagship clinical-trial peptide in the synaptogenic / neuroprotective family.
Davunetide (NAP, AL-108) is an ADNP-derived octapeptide evaluated through Phase III for tauopathy indications; positive Phase II in Alzheimer's, failed Phase III in PSP.
Evidence tier: B — clinical evidence (trials or approved use in some jurisdictions)
- Category
- Neurogenesis
- Half-life
- Short plasma half-life; pharmacodynamic effects on microtubule stabilisation persist
Section 1
Overview
Davunetide (NAP) is an eight-amino-acid peptide fragment — NAPVSIPQ — derived from activity-dependent neuroprotective protein (ADNP), an endogenous neuroprotective and neurotrophic protein critical to normal brain development. The peptide fragment retains the neuroprotective activity of the parent protein and produces microtubule-stabilising and neurotrophic effects at pharmacologically-relevant concentrations.
Davunetide's distinctive feature in the research-peptide field is its clinical-trial history. Unlike most cognitive-relevance peptides on this site, Davunetide has been evaluated in multiple Phase II and Phase III human clinical trials — in Alzheimer's disease, in schizophrenia cognitive-symptom research, and most substantively in progressive supranuclear palsy (PSP) via the CONNECT trial. The PSP trial ultimately did not demonstrate clinical efficacy, but the compound's clinical-trial footprint is substantially deeper than that of any other peptide in the synaptogenic/neuroprotective research class.
The compound was developed initially by Allon Therapeutics and subsequently by Coronado Biosciences. The failure of the CONNECT PSP trial in 2012 effectively ended the compound's clinical-development pathway, though continued academic research has explored its mechanism and possible re-positioning for other indications.
Section 2
Discovery & History
- Identified in the late 1990s as an active fragment of activity-dependent neuroprotective protein (ADNP) by the Gozes laboratory at Tel Aviv University, providing the mechanistic scaffold for peptide-based ADNP-mimetic drug development.
- Developed as a therapeutic candidate initially by Allon Therapeutics (Canada) for Alzheimer's disease and other neurodegenerative indications.
- Entered Phase II clinical evaluation in mild cognitive impairment / early Alzheimer's disease in the late 2000s, with results supporting cognitive-endpoint improvement.
- Entered Phase III clinical evaluation in progressive supranuclear palsy (PSP) via the CONNECT trial; the trial results, published in 2014, did not demonstrate clinical efficacy on the primary endpoint and effectively ended the compound's clinical-development trajectory.
- Continued academic research since 2014 has explored possible re-positioning in autism spectrum disorder (given ADNP's role in Helsmoortel-Van der Aa syndrome) and in schizophrenia cognitive symptoms.
Section 3
Mechanism of Action
- 1Microtubule stabilisation via direct binding to tau and interaction with the microtubule end-binding proteins — the principal mechanism identified for Davunetide's neuroprotective effects and the mechanistic link to tauopathy diseases (Alzheimer's, PSP, frontotemporal dementia); the peptide preserves microtubule dynamics under tau-pathology-inducing conditions.
- 2Neurotrophic effects — reported enhancement of neurite outgrowth, dendritic branching, and synaptic protein expression (PSD-95, synaptophysin) in primary neuronal cultures at picomolar-to-nanomolar concentrations, extending the mechanism beyond pure microtubule stabilisation.
- 3Anti-apoptotic effects in stressed neuronal preparations, providing survival support to neurons under injury or degenerative-disease-relevant insult via preservation of mitochondrial membrane integrity and reduced caspase-3 activation.
- 4Anti-oxidative-stress effects — measurable reductions in oxidative damage markers (MDA, 4-HNE, protein carbonylation) and preserved mitochondrial function under experimental stress across multiple neuronal preparation contexts.
- 5Blood-brain-barrier penetration sufficient for CNS activity following subcutaneous or intranasal administration, distinguishing it from many peptides of similar size and providing the practical delivery pathway for CNS-directed research applications.
- 6Reported effects on tau pathology — reduced hyperphosphorylation, improved microtubule dynamics, and reduced tau-aggregate formation in Alzheimer's and PSP model systems; the mechanistic scaffold for the tauopathy-indication clinical evaluation.
- 7Neurodevelopmental effects reflecting ADNP's normal role — plausibly relevant to the autism-spectrum-disorder repositioning research angle given ADNP mutations cause Helsmoortel-Van der Aa syndrome with autism-spectrum features.
- 8Anti-inflammatory effects reported in some preclinical models, adding a neuroinflammation-relevance angle to the primary microtubule-stabilisation mechanism and connecting Davunetide to the broader neuroinflammatory-cognitive-decline research context.
Section 4
Researched Benefits
Findings reported in the published preclinical and clinical literature. Effects in research contexts do not constitute claims of therapeutic benefit in humans.
- 1Microtubule stabilisation providing a distinctive mechanism-of-action targeting the cytoskeletal pathology in tauopathies (Alzheimer's, PSP, FTD) — a mechanistically differentiated research tool.
- 2Cognitive improvement in Phase II mild-cognitive-impairment / early-AD trials — supporting continued research interest despite the PSP trial failure and providing the empirical support for continued academic research.
- 3Neurotrophic effects supporting neuronal survival and connectivity in preclinical models — the mechanism-of-action extension beyond pure microtubule stabilisation.
- 4Clinical-trial-tested safety profile — substantial acute-safety database from multiple Phase II and Phase III human studies with adverse-event profiles not meaningfully different from placebo.
- 5Intranasal administration route documented in clinical evaluation, providing a practical delivery pathway with good compliance characteristics.
- 6Continued research relevance in ADNP-related autism-spectrum research and in schizophrenia cognitive-symptom research, providing continued academic-research applications following the tauopathy-indication clinical-development pathway closure.
- 7Blood-brain-barrier penetration characteristics unusual for a peptide of this size, enabling CNS-directed research applications without invasive administration.
Section 5
Theoretical Dosing & Protocols
| Route | Dosage | Frequency | Duration |
|---|---|---|---|
| Intranasal (research and completed clinical trials) | 5-30 mg per dose in the clinical trial programme | 1-2× daily in clinical trials | 12-24 weeks in the Phase II/III trials |
Note: The clinical-trial programme has ended without regulatory approval. Research-context use should reflect this history.
Section 6
Administration Routes
- Intranasal administration — the primary route in the clinical-trial programme and the practical route for a peptide with good nose-to-brain delivery characteristics.
- Subcutaneous administration in preclinical animal research.
- Intravenous administration in some mechanistic research contexts.
- Oral administration is not viable — the peptide is susceptible to gastrointestinal proteolysis.
Section 7
Safety Profile
Commonly reported
- · Well-tolerated in the completed clinical trials at the doses studied, with adverse-event profiles not meaningfully different from placebo.
- · Occasional mild nasal irritation from the intranasal formulation.
- · Mild transient headache reported at low frequency.
- · No dependence, tolerance, or withdrawal phenomena documented.
Rare / theoretical
- · Long-term chronic-use safety beyond the 6-month trial duration is not characterised.
- · The Phase III PSP trial failure means that efficacy in tauopathy indications is not established, but no safety signals of concern emerged from the trial.
- · Theoretical microtubule-stabilisation-related effects on cell division in high-turnover tissues — no documented clinical concerns but a plausible mechanism-based consideration.
Contraindications
- · Not authorised for human medicinal use in the UK.
- · Pregnancy and lactation — no controlled human data.
- · Active severe nasal pathology — practical route contraindication for the intranasal formulation.
Section 8
UK & EU Regulatory Context
United Kingdom
Not a licensed medicine in the UK.
European Union
Not approved by the EMA. Multiple Phase II/III trials completed without regulatory approval.
Section 9
Clinical Studies Summary
Davunetide in mild cognitive impairment / early Alzheimer's disease (Phase II)
Phase II randomised placebo-controlled trial of intranasal Davunetide in a mild-cognitive-impairment / early Alzheimer's population, reporting cognitive-endpoint improvement over 12 weeks of dosing with modest but statistically significant effect sizes on validated cognitive-assessment batteries. The trial provided the clinical-evidence scaffold that motivated the subsequent Phase III programme in progressive supranuclear palsy.
Davunetide in progressive supranuclear palsy (CONNECT Phase III trial)
The CONNECT Phase III randomised placebo-controlled trial of intranasal Davunetide 30 mg twice daily over 12 months in progressive supranuclear palsy, published in Lancet Neurology in 2014. The trial did not meet its primary endpoint on the PSP Rating Scale despite the promising Phase II AD cognitive-endpoint data, and effectively ended the compound's clinical-development trajectory in tauopathy indications. The failure raised questions about PSP as a trial indication for tau-targeted therapies more broadly.
Davunetide mechanism — microtubule stabilisation and tau interaction
Mechanistic characterisation of Davunetide's microtubule-stabilisation effects, demonstrating direct binding to tau at biophysical resolution, interaction with microtubule end-binding proteins (EB1, EB3), and preserved microtubule dynamics under tau-pathology-inducing conditions in cellular preparations. The mechanistic scaffold for the tauopathy-indication research angle and the molecular-level demonstration of the compound's cytoskeletal-pathway interaction.
Davunetide in schizophrenia cognitive symptoms (exploratory)
Exploratory research on Davunetide effects on cognitive-symptom endpoints in schizophrenia populations, providing a possible repositioning research angle following the PSP trial failure. The results are hypothesis-generating rather than confirmatory but support continued academic research interest in the compound beyond the tauopathy-indication trajectory.
Davunetide in ADNP-related autism-spectrum research
Preclinical and translational research applications of Davunetide in ADNP-mutation-driven autism-spectrum contexts (Helsmoortel-Van der Aa syndrome), providing the mechanistic-connection research angle between ADNP's normal neurodevelopmental role and the potential repositioning of the ADNP-derived peptide in ADNP-loss-of-function conditions. Represents the most active current research application for the compound.
Section 10
Frequently Asked Questions
Section 10a
Practical Research Guidance
Cycle guidance
Reconstitution & storage
UK sourcing notes
Section 11
Sourcing for Laboratory Research
Sourcing Davunetide for laboratory research
Researchers in the United Kingdom and elsewhere typically obtain Davunetide from specialist research-chemical suppliers. Purity, third-party testing, and supplier transparency are the principal differentiators worth evaluating before placing an order. The two suppliers below are commonly referenced in UK research contexts.
Reminder: research peptides are sold strictly for in vitro and preclinical laboratory purposes. Importation or supply for human consumption is not permitted under UK medicines legislation.