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Davunetide

Also known as NAP, AL-108, AL-208, NAPVSIPQ, CP201

Eight-residue ADNP fragment that failed a large phase 2/3 trial in progressive supranuclear palsy.

early-clinical Neuro & cognition research chemical

At a glance

Category
Neuro & cognition
Status
research chemical
Route
intranasal in the clinical programme (30 mg twice daily, two 0.1 ml puffs per nostril, in the PSP trial); intravenous in the AL-208 formulation
Half-life
Short in plasma. Detailed human pharmacokinetics from the Allon programme were not published in full in the peer-reviewed literature; the intranasal route was chosen specifically to deliver peptide to the brain along olfactory and trigeminal pathways rather than to rely on systemic exposure.
Onset
None claimed acutely; the PSP trial measured disease progression over 52 weeks 45
Molecular weight
824.9 g/mol (C36H60N10O12, free peptide; the drug substance was the acetate salt) 10
Sequence
Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln (NAPVSIPQ)

Not approved anywhere. Developed by Allon Therapeutics as AL-108 (intranasal) and AL-208 (intravenous) and taken through a phase 2/3 trial in progressive supranuclear palsy in which 313 patients were randomised across 48 centres in six countries, and which missed both co-primary endpoints 45; Allon's programme did not survive the result. The peptide has since been picked up for a rare-disease indication: it carries US FDA orphan drug and rare paediatric disease designation and EMA orphan drug status for ADNP syndrome, and ExoNavis, which licensed it from Tel Aviv University in 2021, is reported to have begun a phase 3 trial in 97 children with ADNP mutations in October 2024 9. Where it is sold online it is an unapproved research chemical.

Doping status: Not listed by name; as a non-approved substance it falls under the S0 residual category and is prohibited at all times

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Davunetide is an eight-amino-acid fragment (NAPVSIPQ) of activity-dependent neuroprotective protein (ADNP), a protein essential for brain development and identified through work on vasoactive intestinal peptide-dependent glial neuroprotection. NAP is the smallest fragment of ADNP that retains neuroprotective activity in culture at femtomolar concentrations.

The proposed mechanism is microtubule stabilisation. NAP contains an SIP motif that resembles the microtubule end-binding protein interaction motif; it has been reported to bind EB1 and EB3, promote microtubule assembly, and thereby reduce abnormal tau phosphorylation and restore axonal transport. This is a genuinely coherent hypothesis and it is why davunetide was taken into a tauopathy: if tau dysfunction causes microtubule destabilisation, a microtubule stabiliser should help.

The trial result is the test of that hypothesis in humans, and it was negative 4. Either the microtubule mechanism does not operate at achievable brain concentrations in humans, or microtubule stabilisation is not sufficient to alter the course of an established tauopathy, or the intranasal route did not deliver enough peptide. The trial does not distinguish between these, but it does mean that the mechanism has been tested and has not delivered a clinical effect.

What the research shows

Davunetide is the rare compound in this reference that was tested properly - a large, multinational, double-blind, placebo-controlled trial - and failed. That is the headline. The negative phase 2/3 result in progressive supranuclear palsy, published in Lancet Neurology in 2014, is the highest-quality piece of evidence about this peptide, and it shows no benefit 4. A separate randomised trial in schizophrenia also failed to show benefit on its primary outcome 3. Any claim that davunetide is a proven neuroprotective or cognition-enhancing agent is contradicted by the best available data.

Research in humans

The pivotal study randomised 313 patients with progressive supranuclear palsy at 48 centres in Australia, Canada, France, Germany, the UK and the USA to intranasal davunetide 30 mg twice daily or placebo for 52 weeks 4. Neither co-primary endpoint - the PSP Rating Scale and the Schwab and England Activities of Daily Living scale - showed a difference from placebo 4, and the secondary and imaging endpoints did not rescue the result. The authors concluded plainly that davunetide is not an effective treatment for PSP, while noting that the trial demonstrated disease-modification trials in PSP are feasible 4. A separate 12-week randomised trial of AL-108 in schizophrenia (2012) found no significant effect on the cognitive primary endpoint, with a signal on a functional capacity measure that was not confirmatory 3. An earlier phase 2 study in amnestic mild cognitive impairment reported some effect on memory measures, but it was small and never replicated in a phase 3. A 2023 post-hoc reanalysis of the PSP dataset reported a sex-specific signal favouring women 8; a post-hoc subgroup finding in a failed trial is hypothesis-generating only and does not change the conclusion.

Animal and lab research

The preclinical record is broad and largely positive: neuroprotection at femtomolar concentrations in culture, protection against beta-amyloid toxicity, reduced tau hyperphosphorylation and improved cognition in tau and amyloid transgenic mice, protection in models of stroke, head injury and fetal alcohol exposure, and benefit in ADNP-haploinsufficient mice. This is a reminder of how weak preclinical neuroprotection data are as a predictor: a compound with this much positive animal work still failed unambiguously in humans.

Caveats. For the PSP trial itself, the limitations are mostly the ordinary ones for a negative trial - one might argue about brain exposure achieved by the intranasal route, about whether PSP is too advanced by the time of diagnosis for a microtubule stabiliser to help, or about the sensitivity of the PSP Rating Scale. None of these makes the result positive. For the compound generally: no published human dose-response, no confirmed CNS target engagement biomarker in patients, and no completed trial of any indication that has met its primary endpoint.

What it is used for

  • Investigated and failed in progressive supranuclear palsy (phase 2/3) 45
  • Investigated in schizophrenia-related cognitive impairment 3 and in amnestic mild cognitive impairment, without a confirmed benefit
  • Under investigation for ADNP syndrome, a rare genetic neurodevelopmental disorder, for which davunetide holds US FDA orphan drug and rare paediatric disease designation and EMA orphan drug status 9 - a rational indication given the peptide's origin, but not yet an established treatment
  • Sold and self-administered as a research chemical for claimed cognitive and neuroprotective effects, contrary to the trial evidence

Dosing

Dose
The dose used in the definitive trial was 30 mg intranasally twice daily. It is worth stating what that number means: it is the dose at which davunetide did not work.
Frequency
twice daily in the PSP trial
Route
intranasal (the formulation used in the clinical programme was a nasal spray); intravenous in the AL-208 formulation
Duration
52 weeks in the PSP trial; 12 weeks in the schizophrenia trial
  • No effective dose has been established for any indication, because no trial has demonstrated efficacy. The 30 mg twice-daily intranasal regimen, two 0.1 ml puffs per nostril for 52 weeks, is simply the dose at which davunetide failed both co-primary endpoints 5.
  • There is no published human dose-response study, so no basis exists for the claim that a higher or lower dose would have worked.
  • Research-chemical vendors sell lyophilised powder for subcutaneous or intranasal use; the subcutaneous route was not used in the clinical programme and has no human data.
  • Doses circulating in user protocols are not derived from any published trial.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Progressive supranuclear palsy (phase 2/3)

published trial

Source: Lancet Neurology, 2014 - 313-patient randomised, double-blind, placebo-controlled trial

52 weeks30 mg twice daily, as an intranasal spray

This is the dose at which davunetide missed both co-primary endpoints, so it is a documented schedule rather than an effective one. The clinical formulation was a nasal spray; the subcutaneous route offered by research-chemical vendors was never used in the programme and has no human data.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
5 mg, 10 mg, 20 mg (lyophilised powder, research chemical)
Solvent
bacteriostatic water (0.9% benzyl alcohol) for multi-day use; sterile water only if used the same session
Storage
Lyophilised powder at -20 °C, protected from light; reconstituted at 2-8 °C and, according to suppliers, used within about 2-4 weeks. These are supplier handling notes, not pharmacopoeia specifications.

Worked example

10 mg vial + 2 ml bacteriostatic water = 5 mg/ml. The clinical trial dose of 30 mg would require 6 ml at that concentration, which is a practical illustration of how far grey-market microdosing sits from the studied regimen.

Let the diluent run down the vial wall, swirl rather than shake, and do not use if cloudy. The clinical product was a formulated nasal spray manufactured to pharmaceutical standards; a self-prepared solution from research-grade powder is not equivalent to it.

This is administered as nasal drops or spray, not by injection, so there is no syringe volume to work out.

Safety

Side effects

  • In the PSP trial davunetide was generally well tolerated; there were 11 deaths on davunetide and 10 on placebo over 52 weeks 5 - the drug failed on efficacy, not on safety
  • Nasal adverse events were genuinely more frequent on davunetide than on placebo in that trial, specifically epistaxis, nasal congestion and rhinorrhoea 5. In the earlier MCI trial headache and nasal irritation were reported 9
  • No signal of serious drug-related toxicity emerged from the clinical programme 45
  • Long-term safety beyond 52 weeks has not been studied, and safety by subcutaneous injection has not been studied at all

Do not use if

  • Hypersensitivity to the peptide or to excipients
  • Pregnancy and breastfeeding - no adequate data
  • Children - not studied outside the ADNP syndrome programme
  • The most important practical point is not a contraindication but a fact: the compound has been tested in a large, well-conducted trial and did not work - negative on primary, secondary and exploratory endpoints alike 459. Use for the claimed neuroprotective indications is not supported by evidence.

Interactions

Not systematically studied. No formal drug-interaction trials have been published. A secondary analysis of concomitant medications in the PSP trial has been reported, but it examined baseline drug use in the trial population rather than pharmacological interaction with davunetide.

Sources