Davunetide

Cognitive & Mood

Also known as: NAP, AL-108, CP201, NAPVSIPQ, NAP Peptide

Neuroprotective PeptidesResearch phase: Phase 2/3 (failed primary endpoint for PSP)Regulatory: Not approved by any regulatory agency. Phase 2/3 trial for PSP did not meet primary endpoint. Intranasal formulation (AL-108) was studied. Available as research peptide. Ongoing interest for ADNP syndrome (rare genetic disorder).

Mechanism

Davunetide (also called NAP) is an eight-amino-acid peptide derived from activity-dependent neuroprotective protein (ADNP), one of the brain's natural protective proteins. It shields neurons from damage by stabilizing microtubules — the structural highways inside brain cells that transport nutrients and signals. When microtubules break down (as they do in Alzheimer's and other tauopathies), neurons die. Davunetide keeps them intact. It reached Phase 2/3 clinical trials for progressive supranuclear palsy (PSP), a devastating neurodegenerative disease, and showed neuroprotective effects in multiple animal models.

Technical detail

Davunetide (NAPVSIPQ) is a synthetic octapeptide corresponding to an active fragment of ADNP (activity-dependent neuroprotective protein). Primary mechanism: binds tubulin at the taxol-binding site, promoting microtubule assembly, stabilization, and dynamics. This protects against tau-mediated microtubule destabilization — central to tauopathy pathology. Additionally: enhances autophagy-mediated clearance of tau aggregates; inhibits tau hyperphosphorylation via GSK-3β modulation; reduces oxidative stress markers (4-HNE, protein carbonyls); and modulates dendritic spine density and synaptic plasticity. In animal models: improved cognitive function in ADNP haploinsufficient mice, apoE-deficient mice, and multiple AD models. Intranasal administration achieves CNS concentrations within 30 minutes. Phase 2/3 trial for PSP (PMID: 24493463) did not meet primary endpoint (PSPRS score) but showed biomarker signals. Allon Therapeutics and later Coronis Neurosciences continued development.

Evidence

Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.
Boxer AL et al. (2014) — Lancet Neurology — PMID: 24873720
In 313 participants with progressive supranuclear palsy treated for 52 weeks, davunetide failed to improve PSP Rating Scale or Schwab and England ADL scores versus placebo and produced more nasal adverse events, indicating lack of efficacy in PSP.
strong
Effects of davunetide on N-acetylaspartate and choline in dorsolateral prefrontal cortex in patients with schizophrenia.
Jarskog LF et al. (2013) — Neuropsychopharmacology — PMID: 23325325
In an MRS subset of the parent schizophrenia trial, 12 weeks of adjunctive davunetide showed modest increases in DLPFC choline/creatine and a trend toward increased NAA/creatine, supporting a possible neuroprotective biomarker signal despite limited sample size.
moderate
Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia.
Javitt DC et al. (2012) — Schizophrenia Research — PMID: 22169248
In a 12-week multicenter double-blind trial in 63 subjects with schizophrenia, intranasal davunetide was well tolerated and improved UPSA functional capacity versus placebo, but did not significantly improve MATRICS cognition scores or symptom ratings.
moderate

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