PwPepwise

Davunetide (NAP)

Brain & Focus

a.k.a. AL-108

ADNP-derived 8-mer

Davunetide, also known as NAP, is a short neuroprotective peptide derived from a naturally occurring brain protein called activity-dependent…

§Dosing at a glance

1 protocol · from the research
What it's forDoseHow oftenHowFor how long
General protocol30 mgTwice dailyIntranasalSprayed into the nose.52 wks

Approximate values pulled from the research — double-check before dosing.

§01Summary

Davunetide, also known as NAP, is a short neuroprotective peptide derived from a naturally occurring brain protein called activity-dependent neuroprotective protein (ADNP). In the body, davunetide appears to support the structural integrity of nerve cells by stabilizing microtubules — the internal scaffolding that keeps neurons healthy and functional — and by reducing abnormal phosphorylation of tau protein, a process associated with several neurodegenerative diseases.1 These properties led to significant scientific interest in davunetide as a potential treatment for conditions where tau dysfunction plays a central role, including progressive supranuclear palsy (PSP), mild cognitive impairment, and other tauopathies.1,11 Delivered as an intranasal spray, davunetide has been evaluated across multiple clinical indications, with the largest trial conducted in patients with PSP.1 Animal research has also suggested davunetide may support corneal barrier repair in diabetic eye disease17 and may partially improve certain behavioral and tau-related changes in Parkinson's disease models.19 More recently, davunetide is being investigated in novel oncology applications, including as a component of engineered CAR-T cell therapies.6 The evidence base for davunetide spans a range of preclinical and clinical contexts, with human trials providing important data on safety and tolerability alongside key insights into the challenges of translating tau-targeting strategies into clinical benefit.

This is the layperson summary. Mechanism, dosing, the evidence base, and the published literature are in the sections below — every claim links to its source.

§02In depth

Davunetide (NAP; sequence: Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln; NAPVSIPQ) is an octapeptide derived from the active domain of activity-dependent neuroprotective protein (ADNP), a zinc-finger transcription factor and chromatin remodeler that is essential for brain development and neuronal survival. ADNP is among the most frequently mutated genes in autism spectrum disorder, and its peptide fragment NAP retains core neuroprotective functions at femtomolar to nanomolar concentrations.

The primary molecular mechanism of davunetide centers on microtubule stabilization. Davunetide interacts with tubulin and microtubule-associated proteins, promoting polymerization and resisting depolymerization. Critically, it reduces hyperphosphorylation of tau protein — a post-translational modification that disrupts tau's normal role in stabilizing axonal microtubules and instead promotes aggregation into neurofibrillary tangles characteristic of tauopathies including PSP, Alzheimer's disease, and corticobasal syndrome.1 In alpha-synuclein overexpressing mouse models, intranasal davunetide significantly reduced p-tau/tau ratios in subcortical regions at 2 µg/day and in the cerebellum at 15 µg/day, confirming dose- and region-dependent tau effects.19 In diabetic corneal epithelial models, davunetide preserved the microtubule-associated proteins EB1 and Tau against VEGF-induced internalization, restoring tight junction proteins occludin and ZO-1 and transepithelial electrical resistance — indicating that the microtubule-stabilizing mechanism operates in non-neuronal epithelia as well.17

The intranasal route of administration is pharmacologically deliberate: nasal delivery allows direct access to the olfactory and trigeminal pathways that connect the nasal mucosa to the brain, bypassing the blood-brain barrier that limits CNS penetration of most systemically administered peptides. This route was consistently used across all clinical trials at doses ranging from 5 mg to 30 mg twice daily.1,2,5 The short peptide length confers relative metabolic stability compared to larger proteins, though specific half-life and systemic bioavailability data are not fully characterized in the available published literature.

A novel mechanistic application of davunetide is currently under investigation in oncology: a CAR-T cell construct designated CAR20(NAP)-T incorporates the NAP peptide into an anti-CD20 chimeric antigen receptor framework targeting relapsed or refractory B-cell lymphoma.6 This approach may exploit davunetide's cytoskeletal regulatory properties to influence T-cell persistence, trafficking, or reduce CAR-T-associated neurotoxicity — representing a significant mechanistic extension beyond its established neurodegenerative context that is being characterized in a Phase I/IIa trial.6

§04Evidence & efficacy

Evidence base
470Studies
219Human
29Animal

Davunetide's preclinical profile in tau-related models is well-established, with animal studies demonstrating reductions in tau hyperphosphorylation and partial improvements in behavioral endpoints.19 In diabetic corneal models, NAP appears to restore epithelial barrier integrity and support wound healing by preserving microtubule-associated proteins.17

In the most rigorous human evaluation — a randomized, double-blind, placebo-controlled Phase 2/3 trial enrolling 313 patients with progressive supranuclear palsy over 52 weeks — davunetide at 30 mg intranasal twice daily did not demonstrate a measurable benefit on either the PSP Rating Scale or the Schwab and England Activities of Daily Living scale compared to placebo.1 Phase 2 trials in mild cognitive impairment2 and schizophrenia5, and a pilot tauopathy study11, have registered protocols but have not contributed published efficacy outcome data to the peer-reviewed literature. An ongoing Phase I/IIa trial is investigating a novel davunetide-containing CAR-T construct in B-cell lymphoma, with efficacy data anticipated in future reporting.6

Animal model data suggest that dosing regimen design — particularly continuity of administration — may influence the breadth of behavioral benefit achievable, with intermittent dosing showing only partial effects compared to continuous protocols.19

§05Safety

Davunetide has demonstrated a generally acceptable tolerability profile in human trials. The most thoroughly characterized safety data come from the 52-week Phase 2/3 PSP trial, in which 30 mg intranasally twice daily was compared against placebo in 313 participants.1 Serious adverse events occurred at comparable rates between groups (54 in each arm), and deaths were similar (11 davunetide vs. 10 placebo), with no statistically significant safety signal identified.1 Local nasal tolerability events were more frequent in the davunetide arm, including epistaxis (12% vs. 8%), rhinorrhoea (10% vs. 5%), and nasal discomfort (10% vs. less than 1%), reflecting the expected profile of intranasal drug delivery.1 No systemic organ toxicity, serious immunological events, or drug interactions were reported in available clinical summaries.

In animal studies examining intranasal davunetide in Parkinson's disease models, no formal adverse event reporting was included, and the peptide appeared well tolerated at doses of 2–15 µg/day.19 A novel CAR-T cell application incorporating davunetide is in early clinical investigation, with safety as a primary endpoint, though no results are yet available.6

§06History

Davunetide (NAP) was identified in the laboratory of Illana Gozes as the smallest active neuroprotective fragment of activity-dependent neuroprotective protein (ADNP), a gene discovered in the late 1990s. Early research demonstrated that the octapeptide NAPVSIPQ could protect neurons against a range of insults at extraordinarily low concentrations, attributable to its microtubule-stabilizing and tau-modulating properties. These findings established a compelling preclinical rationale for therapeutic development, particularly in neurodegenerative diseases characterized by tau pathology.

Clinical development was advanced primarily by Allon Therapeutics, which progressed davunetide — initially designated AL-108 — through Phase 2 trials in mild cognitive impairment2 and schizophrenia-associated cognitive deficits.5 The compound was subsequently evaluated in a 12-week pilot study in predicted tauopathies11 and ultimately in a pivotal Phase 2/3 randomized controlled trial in progressive supranuclear palsy, enrolling 313 participants across multiple international sites and completing in approximately 2012–2013.1,3 Results published in 2014 demonstrated no statistically significant benefit over placebo on either primary endpoint, leading to discontinuation of the Allon Therapeutics davunetide program.1

Despite this clinical setback, basic and translational research with davunetide has continued. Animal studies have explored its activity in synucleinopathy models19 and diabetic corneal disease.17 Most recently, davunetide has been incorporated into a novel CAR-T cell therapeutic construct in oncology, with a Phase I/IIa trial registered in 2024.6 The compound remains an active subject of research as understanding of ADNP biology and tau-targeting strategies continues to evolve.

§07References