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phase 2Cognitive & Neuro

Davunetide

Also known as: NAP, AL-108, CP201, NAPVSIPQ, Activity-dependent neuroprotective protein-derived peptide

Davunetide (NAP) is an 8-amino acid peptide (NAPVSIPQ) derived from activity-dependent neuroprotective protein (ADNP), one of the most essential proteins for brain development and function. Developed by Allon Therapeutics and later Palatin Technologies (as CP201), it was the first ADNP-derived neuroprotective peptide to reach clinical trials. While it failed Phase II/III for progressive supranuclear palsy (PSP), it showed cognitive benefits in amnestic mild cognitive impairment trials and remains under investigation for ADNP syndrome, a rare genetic neurodevelopmental disorder caused by mutations in the ADNP gene.

3 cited references·5 researched benefits

Quick Answer

Davunetide (NAP/AL-108/CP201) is an 8-amino acid neuroprotective peptide derived from activity-dependent neuroprotective protein (ADNP). It stabilizes microtubules, protects against tau pathology, and promotes neuronal survival. While it failed Phase II/III trials for progressive supranuclear palsy, it showed cognitive improvements in mild cognitive impairment studies and is being investigated for ADNP syndrome. It is administered intranasally and has a well-characterized safety profile from clinical trials.

Key Facts

Mechanism
Davunetide interacts with microtubule-associated proteins, particularly tubulin, to stabilize the microtubule cytoskeleton within neurons. Microtubule stability is critical for axonal transport, synaptic function, and neuronal morphology — all of which are compromised in tauopathies and neurodegenerative diseases. NAP binds to tubulin at a site distinct from taxol and other microtubule-stabilizing drugs, providing a gentler stabilization that preserves dynamic microtubule behavior while preventing pathological destabilization. Additionally, NAP reduces tau hyperphosphorylation (a hallmark of Alzheimer's disease and frontotemporal dementia), protects against oxidative stress, and inhibits caspase-3-mediated apoptosis. The peptide also interacts with the SWI/SNF chromatin remodeling complex through its parent protein ADNP, modulating gene expression patterns essential for neuronal survival and differentiation. NAP has demonstrated neuroprotection at femtomolar concentrations in vitro, making it one of the most potent neuroprotective peptides identified.
Research Status
phase 2
Half-Life
~20–30 minutes (intranasal); effects persist through downstream microtubule stabilization
Molecular Formula
C₃₆H₆₅N₉O₁₂S₁
Primary Use
Cognitive & Neuro
Table of Contents

Benefits

  • Microtubule stabilization — directly stabilizes neuronal microtubules, protecting axonal transport and synaptic structure without the toxicity of conventional microtubule-stabilizing drugs like taxolstrong
  • Cognitive improvement in MCI — Phase II trial in amnestic mild cognitive impairment showed significant improvement in memory scores compared to placebo over 12 weeks of intranasal administrationmoderate
  • Tau pathology reduction — reduces tau hyperphosphorylation and neurofibrillary tangle formation in preclinical models of tauopathymoderate
  • Femtomolar neuroprotective potency — protects neurons from a variety of toxic insults (oxidative stress, excitotoxicity, amyloid-beta) at extremely low concentrations in vitromoderate
  • Favorable safety profile — well-tolerated in multiple clinical trials with no serious drug-related adverse events reported at therapeutic dosesstrong

Dosage Protocols

RouteDosage RangeFrequencyNotes
Intranasal2–15 mg twice dailyTwice dailyPrimary clinical route. The Phase II MCI trial used 5 mg and 15 mg twice daily (AL-108). The PSP trial (AL-108-231) used 30 mg twice daily. Intranasal delivery provides direct nose-to-brain transport bypassing the blood-brain barrier.
Intravenous (AL-208)300 mg single doseSingle dose (surgical neuroprotection setting)IV formulation (AL-208) was tested in a Phase II trial for neuroprotection during coronary artery bypass surgery. This route is not used for chronic cognitive conditions.

Medical disclaimer

Dosage information is provided for educational reference only. Always follow your prescriber's instructions and consult a qualified healthcare provider before starting any peptide protocol.

Side Effects

  • Nasal discomfort — mild nasal irritation, rhinorrhea, or congestion with intranasal administration; the most commonly reported side effect in clinical trialscommon
  • Headache — transient headache reported in some trial participants, generally mildcommon
  • Upper respiratory symptoms — increased incidence of common cold-like symptoms noted in some trials, possibly related to the intranasal routerare
  • Falls (PSP trial) — increased falls were noted in the PSP trial, though this may be related to the underlying disease progression rather than the drugserious

Frequently Asked Questions

Why did Davunetide fail in the PSP clinical trial?
The Phase II/III trial for progressive supranuclear palsy (PSP) failed to meet its primary efficacy endpoints, showing no significant improvement in the PSP Rating Scale or Schwab and England Activities of Daily Living scale. Several factors may explain this: PSP involves severe, widespread neurodegeneration that may be too advanced for a neuroprotective approach; the trial enrolled patients with established disease rather than early-stage; the dose may have been insufficient for the degree of pathology; and PSP involves multiple pathological mechanisms beyond microtubule instability. The failure in PSP does not necessarily predict failure in other conditions — earlier-stage cognitive impairment or the genetically-defined ADNP syndrome may be more responsive.
What is ADNP syndrome and could Davunetide help?
ADNP syndrome (Helsmoortel-Van der Aa syndrome) is a rare neurodevelopmental disorder caused by de novo mutations in the ADNP gene. It affects roughly 1 in 10,000 births and is characterized by intellectual disability, autism spectrum features, delayed motor development, and distinctive facial features. Because Davunetide is derived from ADNP and can partially compensate for ADNP deficiency, it is being investigated as a potential treatment. Palatin Technologies (under the name CP201) is pursuing clinical development for this indication, with the rationale that replacing the missing ADNP-derived neuroprotective activity could improve neurological outcomes in these patients.
How does intranasal delivery get Davunetide into the brain?
Intranasal delivery exploits the unique anatomy of the nasal cavity, where olfactory and trigeminal nerve endings provide direct pathways to the brain. Molecules applied to the nasal mucosa can travel along these neural pathways to reach the brain within minutes, bypassing the blood-brain barrier entirely. This nose-to-brain transport is particularly effective for small peptides like Davunetide. Clinical imaging and biomarker studies have confirmed that intranasally administered NAP reaches the cerebrospinal fluid and brain tissue at pharmacologically relevant concentrations.

References

  1. 1
    NAP (davunetide) — a neuroprotective peptide derived from activity-dependent neuroprotective protein (ADNP): from gene silencing to clinical trial(2003)PubMed ↗
  2. 2
    Davunetide (AL-108) for progressive supranuclear palsy: a Phase 2/3 randomized, double-blind, placebo-controlled trial(2014)PubMed ↗
  3. 3
    Davunetide improves cognition in patients with amnestic mild cognitive impairment: a Phase 2a, randomized, double-blind study(2012)PubMed ↗

Latest Research

Last updated: 2026-02-19