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Davunetide

Tier 1 · Human trials
Also known as NAP peptide · AL-108 · CP201

Multiple human randomized placebo-controlled trials exist (aMCI n=144, schizophrenia n=63, and the pivotal phase 2/3 PSP trial n=313, plus a phase 1 tauopathy pilot), supporting a Tier 1 designation. However, the strongest and most rigorous trial (PSP) was negative on all pre-specified endpoints; positive signals in aMCI and schizophrenia came from trials that missed primary endpoints or reached significance only on secondary/subgroup measures. Mechanistic support is largely Tier 2 (animal/in vitro). Human pharmacokinetics remain poorly characterized.

Half-life
~1.2 h
Routes
Intranasal
Goals
Cognitive function · Neuroprotection · Neurodegenerative disease research · Tauopathy research
Cost / mg
Not recorded

How it works

Davunetide (NAP) is a short 8-amino-acid piece of a natural brain protein called ADNP (activity-dependent neuroprotective protein). Its main proposed action is to help stabilize microtubules — the internal scaffolding of nerve cells — and to reduce abnormal phosphorylation of the tau protein that, when overloaded, forms toxic tangles seen in diseases like Alzheimer's. By binding to microtubule end-binding proteins and helping tau attach to microtubules, it is proposed to protect neurons from damage, prevent cell death, and support the growth of nerve fibers and synapses. Additional proposed effects include anti-inflammatory activity, antioxidant activity, and reducing protein aggregation.

Overview

Overview

Davunetide (also known as NAP peptide, AL-108, and CP201) is a straight-chain, unmodified synthetic eight-amino-acid peptide with the sequence NAPVSIPQ (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln). It is supplied as the acetate salt (molecular formula C36H60N10O12; CAS 211439-12-2). It has been described as the first neuroprotective peptide in its class, with preclinical evidence for neuroprotective, neurotrophic, and cognitive-protective properties.

Origin and Biology

NAP is derived from activity-dependent neuroprotective protein (ADNP), a 1102-amino-acid protein, and constitutes the smallest active neuroprotective fragment of that parent protein. ADNP is a growth factor released from glia in response to vasoactive intestinal peptide (VIP). It is essential for brain formation and cognitive function, is involved in chromatin remodeling and transcription (interacting with the SWI/SNF complex), and regulates over 400 genes during embryonic development. ADNP is reported to be dysregulated or mutated in Alzheimer's disease, Parkinson's disease, schizophrenia, and autism (estimated prevalence 0.17%), with somatic mutations in Alzheimer's brains correlating with tauopathy, and it is linked to circadian rhythm regulation.

Proposed Mechanism

The primary proposed mechanism is promotion of microtubule stability and reduction of tau phosphorylation/hyperphosphorylation. Davunetide binds microtubule end-binding proteins (EBs) that decorate the plus-tips of growing microtubules, promoting microtubule stability and the tau–microtubule interaction, and preventing microtubule degradation by recruiting tau and EBs. In preclinical models it prevented apoptosis (via PI-3K/Akt and MAPK/MEK1 pathways), promoted neurite outgrowth and synaptogenesis, and protected against amyloid-beta, viruses, oxidative stress, and microtubule toxins (zinc, nocodazole). ADNP knockout is lethal in mice; 50% ADNP reduction produces tau pathology, cognitive dysfunction, and neurodegeneration that NAP partly ameliorates. A theoretical hypothesis holds that NAP's preference for Tau3R over Tau4R may explain efficacy in mixed 3R/4R tauopathies (e.g. prodromal Alzheimer's) but failure in the predominantly 4R tauopathy PSP. One source also characterizes davunetide as a GSK-3 inhibitor.

Clinical Investigation

Davunetide has been studied across roughly 10 clinical trials and was reported to be generally safe and well-tolerated:

  • Amnestic mild cognitive impairment (aMCI): A 12-week phase 2 trial (NCT00422981, n=144) comparing 5 mg once daily, 15 mg twice daily, and placebo suggested potential benefits on attention/working memory, with statistically significant improvement versus placebo at 8 and 16 weeks but not at 12 weeks. A re-analysis reported sex-dependent effects.
  • Schizophrenia: A phase 2 trial (n=63) of 5 mg/day and 30 mg/day over 12 weeks missed its co-primary MCCB cognitive outcome (p=.45) but showed a significant treatment effect on functional capacity (UPSA, p=.048; effect sizes d=.74 at 5 mg, d=.48 at 30 mg) and a reported effect on cortical thickness.
  • Progressive supranuclear palsy (PSP): The pivotal phase 2/3 randomized, double-blind, placebo-controlled trial (Boxer et al., Lancet Neurology 2014; n=313, 30 mg intranasal twice daily for 52 weeks) was negative on all endpoints — no difference on the PSPRS (mean difference 0.49, p=0.72) or the Schwab and England ADL scale — leading to the conclusion that davunetide is not an effective treatment for PSP. Later subgroup/re-analyses controversially claim sex-dependent efficacy (slowing progression in women), but these derive from re-analysis rather than pre-specified outcomes.
  • Tauopathy pilot: A 12-week phase 1 study (NCT01056965, n=12) in FTLD/CBS/PSP collected safety and biomarker data.

Overall, a signal of clinical effect was observed in aMCI and schizophrenia-associated cognitive impairment, while no benefit was seen in PSP. Investigational repositioning as CP201 for ADNP syndrome (Helsmoortel–Van Der Aa syndrome) is underway — a reported phase 3 trial in 97 children was initiated in October 2024 — but a pivotal efficacy trial has not been completed. One drug database also lists ALS as an active indication (single, lower-tier source). PSP itself is a neurodegenerative atypical parkinsonism (Richardson's syndrome prevalence ~6.5/100,000) with no approved or effective treatment.

The original developer, Allon Therapeutics, became insolvent following the PSP trial failure.

What the research shows

180 findings extracted from the 26 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 35 human trial findings, 3 human study findings, 13 animal findings, 1 in vitro finding and 1 expert opinion finding.

  • human trial360 participants were screened, 313 were randomized and 243 (77.6%) completed the study1

  • human trialDavunetide 30 mg administered intranasally twice daily for 52 weeks showed no group differences in PSPRS compared to placebo1

  • human trialMean 52 week change from baseline PSPRS scores were similar between davunetide (11.3 [9.8, 12.8]) and placebo groups (10.9 [9.1, 13.0])1

  • human trialSEADL showed no group difference (1% [−2, 4%], p = 0.76) change from baseline between davunetide and placebo1

  • human trialThere were no differences in any of the secondary or exploratory endpoints1

  • human trialDavunetide 30 mg twice daily intranasally did not differ from placebo in change from baseline in PSP Rating Scale at 52 weeks2

  • human trialDavunetide 30 mg twice daily intranasally did not differ from placebo in change from baseline in Schwab and England Activities of Daily Living scale at 52 weeks2

  • human trialDavunetide is not an effective treatment for PSP2

Show 45 more findings

  • human trialA signal of clinical effect was observed in amnestic mild cognitive impaired and cognitive impairment associated with schizophrenia patients; however, no clinical benefit was observed in progressive supranuclear palsy patients3

  • human trialData from 10 separate clinical trials of davunetide, investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated, and has shown some signs of clinical efficacy3

  • human trialSecondary objectives include obtaining preliminary data on short-term changes at 12 weeks in clinical, functional and biomarker measurements including CSF tau levels, eye movements, and brain MRI4

  • human trialSecondary outcome measures included PSP Rating Scale, Clinician's Global Impression, Schwab and England Activities of Daily Living scale, MRI brain ventricular volume, RBANS, UPDRS, NPI, GDS, CSF biomarkers (total tau, phosphorylated tau, amyloid beta 1-42), saccadic eye movements, CDR, and FAQ at 12 weeks4

  • human trialClinical studies on NAP (davunetide) administered via intranasal delivery have demonstrated potential efficacy in improving cognitive function5

  • human trialIn the pure tauopathy, progressive supranuclear palsy, NAP (davunetide) significantly slowed disease progression in women in a phase II-III clinical trial5

  • human trialDavunetide shows sex-dependent efficacy in women suffering from progressive supranuclear palsy6

  • human trialIn men, significant dose-dependent cognitive increases were observed compared to women on a test of delayed visual matching to the sample6

  • human trialIn women, high dose davunetide showed significant improvement over matched placebo on digit span test (semantic working memory and attention)6

  • human trialWomen showed a significant low-dose placebo effect on digit span test6

  • human trialIn women, anxiety showed significant correlation with delayed matching to sample performance6

  • human trialClinical trials have suggested potential efficacy of NAP (davunetide, CP201) for improving cognitive performance in amnestic mild cognitive impairment (aMCI)7

  • human trialClinical trials have suggested potential efficacy of NAP for improving functional activities of daily living in schizophrenia patients7

  • human trialNAP was not found to be an effective treatment for progressive supranuclear palsy (PSP) patients though well-tolerated7

  • human trialA 12-week phase 2, randomised placebo-controlled clinical trial of davunetide administered intranasally to 144 individuals with amnestic mild cognitive impairment suggested potential treatment benefits on attention and working memory10

  • human trialDavunetide has shown some signs of clinical efficacy11

  • human trialDavunetide at doses of 5 mg and 30 mg showed no significant differences in MCCB change compared to placebo over 12 weeks12

  • human trialEffect-size (d) values were .34 and .21 favoring the 5 and 30 mg doses of davunetide vs. placebo on MCCB12

  • human trialDavunetide showed a significant main effect of treatment on UPSA (p=.048) with between-group effect size (d) values of .74 and .48 favoring the 5 and 30 mg doses, respectively12

  • human trialNo significant effects were observed on the SCoRS or on symptom ratings12

  • human trialIn human clinical trials, NAP has been shown to increase memory scores in patients suffering from amnestic mild cognitive impairment13

  • human trialNAP enhances functional daily behaviors in schizophrenia patients13

  • human trialPhase 2/3 randomized, double-blind, placebo-controlled study evaluated safety and efficacy of davunetide for treatment of Progressive Supranuclear Palsy15

  • human trialPhase 2 trial in 144 people with aMCI comparing 5 mg once a day, 15 mg twice a day, and placebo showed statistically significant improvement in test performance compared with placebo at eight weeks and 16 weeks, but not 12 weeks17

  • human trialPhase 2 trial in 63 patients with chronic schizophrenia comparing two different doses of davunetide to placebo missed one coprimary outcome (MATRICS composite battery) but showed efficacy in the other (UPSA)17

  • human trialPhase 2 trial in 63 schizophrenia patients showed treatment effect on cortical thickness17

  • human trialPhase 2/3 trial in 313 people with progressive supranuclear palsy comparing 30 mg of davunetide spray twice a day to placebo was negative on all endpoints—primary, secondary, and exploratory17

  • human studyNAP (davunetide, CP201) exhibited efficacy in prodromal Alzheimer's disease patients (Tau3R/4R tauopathy)8

  • human studyNAP (davunetide, CP201) did not exhibit efficacy in progressive supranuclear palsy (increased Tau4R tauopathy)8

  • human studyDavunetide failed to improve the clinical outcome of PSP patients in two recent studies9

  • animalIn preclinical studies, NAP shows promise in improving cognitive performance and correcting behavioral deficits in different models5

  • animalNAP and SKIP are neuroprotective and stimulate axonal transport7

  • animalNAP protects against ADNP deficiency, exhibiting neuroprotection, MT interaction and memory protection8

  • animalIn transgenic mice with one or more human MAPT mutations, davunetide ameliorates deposition of hyperphosphorylated, insoluble forms of tau and improves performance on behavioural tests such as the Morris water maze10

  • animalDavunetide has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties11

  • animalStudies in animals suggest that davunetide may protect neurons and may improve cognition in schizophrenia15

  • animalRodent models showed neuroprotection of davunetide in stroke and hypoxia17

  • animalSimilar improvements were reported in Aβ42-treated rats17

  • animalMice lacking ADNP suffer from learning and memory deficiencies, muscle weakness, and communication problems21

  • animalNAP (davunetide), an eight amino acid peptide derived from ADNP partly ameliorated deficits associated with ADNP deficiency22

  • animalNAP (davunetide) protected against tau pathology and MAP6 (stable tubuleonly polypeptide - STOP) pathology in vivo22

  • animalNAP (davunetide) protection against neurodegeneration has been shown to extend to katanin-related microtubule disruption under conditions of tau deficiencies22

  • animalNAP (davunetide) provided potent neuroprotection in a broad range of neurodegenerative models22

  • in vitroNAP has been shown to provide potent neuroprotection, in vitro and in vivo13

  • expert opinionNAP was found to have beneficial effects on the behavioral manifestations associated with neurological/neurodegenerative disorders25

How it works

Based on 1 human trial finding, 8 human study findings, 21 animal findings, 18 in vitro findings, 14 expert opinion findings and 10 theoretical findings.

  • human trialDavunetide is a tauopathy inhibitor6

  • human studyADNP is a 1102-amino-acid activity-dependent neuroprotective protein originally discovered by expression cloning through immunological identification of its 8-amino-acid sequence NAPVSIPQ (NAP)7

  • human studyNAP constitutes the smallest active neuroprotective fragment of ADNP7

  • human studyADNP expression is essential for brain formation and cognitive function7

  • human studyADNP has been found to be mutated in autism with an estimated prevalence of 0.17%7

  • human studySomatic mutations in ADNP found in Alzheimer's disease brains correlating with tauopathy7

  • human studyDavunetide is an inhibitor of glycogen synthase kinase-3 (GSK-3)9

  • human studyAt autopsy, insoluble aggregates of the microtubule-associated protein tau are found in neurons and glia throughout the brain, most prominently in the brainstem, deep cerebellar nuclei, and basal ganglia10

Show 64 more findings

  • human studyADNP gene carries a pathogenic sequence variant, mostly a mutation resulting in loss of normal functions in Helsmoortel-Van Der Aa syndrome21

  • animalDavunetide (AL-108, NAP) is an eight amino acid peptide that promotes microtubule stability and decreases tau phosphorylation in pre-clinical studies1

  • animalDavunetide has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties3

  • animalDavunetide functions by stabilization of microtubules and inhibiting tau phosphorylation3

  • animalAdnp haploinsufficiency in mice causes age-dependent reduction in cognitive functions coupled with tauopathy-like features7

  • animalADNP deficiency in mice causes pathological Tau hyperphosphorylation and aggregation, correlated with impaired cognitive functions8

  • animalNAP prevents MT degradation by recruitment of Tau and end-binding proteins to MTs and expression of these proteins is required for NAP activity8

  • animalNAP preferentially interacted with Tau3R protein from rat brain extracts8

  • animalNAP protects microtubules from katanin disruption in the face of reduced tau expression13

  • animalNAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate13

  • animalNAP reduced apoptotic neurons through activation of both PI-3K/Akt and MAPK/MEK1 kinases in the white matter13

  • animalIn a triple transgenic mouse model of AD, NAP reduced amyloid accumulation and tau hyperphosphorylation and improved performance in the Morris water maze17

  • animalNAP improved memory and cognition in mice and reversed genetic ADNP reduction impairment17

  • animalNAP was reported to rescue a neuronal dysfunction phenotype in a fly model of tauopathy17

  • animalIn mice, ADNP truncation led to tauopathy, which was corrected by NAP treatment17

  • animalThe ADNP microtubule-interacting fragment NAP (CP201) resolves, in part, ADNP deficiencies and protects against pathogenic sequence variant abnormalities21

  • animalADNP immunoreactivity was shown to occasionally decorate microtubules22

  • animalADNP silencing inhibited neurite outgrowth as measured by microtubule associated protein 2 (MAP2) labeling22

  • animalADNP knockout is lethal22

  • animal50% reduction in ADNP (ADNP haploinsufficiency) resulted in the microtubule associated protein tau pathology coupled to cognitive dysfunction and neurodegeneration22

  • animalNAP (davunetide) provided neurotrophic functions promoting neurite outgrowth as measured by increases in MAP2 immunoreactivity22

  • animalNAP (davunetide) promoted synapse formation by increasing synaptophysin expression22

  • in vitroDavunetide has been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization3

  • in vitroNAP and SKIP directly interact with end-binding proteins (EBs) which decorate plus-tips of growing axonal cytoskeleton-microtubules7

  • in vitroNAP modulates MT-Tau-EBs crosstalk with different protective potency in selected tauopathies based on Tau isoform expression7

  • in vitroNAP induced increased recruitment of human Tau3R to MTs under zinc intoxication, in comparison to Tau4R8

  • in vitroNAP interaction with tubulin (MTs) was inhibited by obstruction of Tau-binding sites on MTs, confirming the requirement of Tau-MT interaction for NAP activity8

  • in vitroIn cell culture, davunetide has potent neuroprotective effects on cell death and microtubule disruption from a variety of toxic insults10

  • in vitroDavunetide prevents apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization11

  • in vitroIn vitro studies showed davunetide/NAP neuroprotection against Aβ, viruses, and oxidative stress17

  • in vitroNAP promoted tau binding to microtubules, and reduced tau phosphorylation in cells17

  • in vitroReduced microtubule content was observed in the ADNP-mutated cell lines18

  • in vitroDisrupting microtubules by zinc or nocodazole intoxication mimicked ADNP mutation phenotypes and resulted in aberrant nuclear-cytoplasmic boundaries, which were rapidly corrected by NAP treatment18

  • in vitroNo NAP effects were noted on ADNP levels18

  • in vitroBoth NAP and ketamine exhibited direct interactions with ADNP, as observed via in silico docking18

  • in vitroNAP rapidly localized to the cytoplasmic and nuclear compartments, ameliorating mutated ADNP-related deficiencies through a microtubule-linked mechanism18

  • in vitroFour peptides (HAPVSIHQ, NYPVSIHQ, NWPVSIWQ, HAPVSIIQ) exhibit MT-stabilizing activity with NWPVSIWQ and HAPVSIIQ being the most active19

  • in vitroNWPVSIWQ and HAPVSIIQ bind to nonpolymeric tubulin19

  • in vitroNAP (davunetide) interacted with microtubules22

  • in vitroNAP (davunetide) protected against microtubule toxicity associated with zinc, nocodazole and oxidative stress in vitro22

  • expert opinionPSP is tightly linked to tau pathology1

  • expert opinionNAP (davunetide) is a small peptide derived from Activity-Dependent Neuroprotective Protein (ADNP)5

  • expert opinionADNP is a protein essential for brain development and function5

  • expert opinionADNP is associated with tauopathy-related diseases, such as Alzheimer's Disease (AD)5

  • expert opinionADNP is associated with circadian rhythm regulation5

  • expert opinionNAP enhances microtubule stability and prevents tauopathy5

  • expert opinionDavunetide is the drug candidate derived from the active neuroprotective site NAP of activity-dependent neuroprotective protein (ADNP)24

  • expert opinionVasoactive intestinal peptide (VIP) is a regulator of ADNP24

  • expert opinionThere are Tau-ADNP-NAP interactions with sex-dependent differences24

  • expert opinionNAP (davunetide) is an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP)25

  • expert opinionPossible mechanisms of NAP actions include anti-inflammatory effect25

  • expert opinionPossible mechanisms of NAP actions include antioxidant activity25

  • expert opinionPossible mechanisms of NAP actions include inhibition of protein aggregation25

  • expert opinionPossible mechanisms of NAP actions include interaction with microtubules25

  • theoreticalIn preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation2

  • theoreticalDavunetide (AL-108, NAP) is the acetate salt of an eight amino acid peptide (NAPVSIPQ) derived from activity-dependent neuroprotective protein, a growth factor released from glia in response to exposure to vasoactive intestinal peptide10

  • theoreticalNAP (davunetide) is an eight amino acid peptide (NAPVSIPQ)13

  • theoreticalNAP is derived from activity-dependent neuroprotective protein (ADNP)13

  • theoreticalADNP is essential for brain formation, interacting with chromatin associated protein alpha and the chromatin remodeling complex SWI/SNF13

  • theoreticalADNP regulates >400 genes during embryonic development13

  • theoreticalPartial loss in ADNP results in cognitive deficits and pathology of the microtubule associated protein tau (tauopathy)13

  • theoreticalDavunetide mechanism is TAU inhibitors (Microtubule-associated protein tau inhibitors)15

  • theoreticalDavunetide is an intranasal neuropeptide derived from activity-dependent neurotrophic protein (ADNP), containing eight amino acids Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln17

  • theoreticalADNP is involved in chromatin remodeling, transcription, and microtubule stabilization17

Dosing

Based on 6 human trial findings and 1 theoretical finding.

  • human trialDavunetide was administered intranasally twice daily1

  • human trialThe clinical dose of 60 mg/day (30 mg two-times a day) used in a pivotal clinical trial represents a conservative 3.5-fold safety margin when compared to animal toxicity studies3

  • human trialDavunetide (AL-108, NAP) is administered intranasally as a nasal spray at 15 mg twice daily4

  • human trialNAP is administered via intranasal delivery5

  • human trialSample sizes of at least 45-50 subjects/group would be required to obtain significant effects on both MCCB and UPSA12

  • human trialTwelve-week multicenter, double-blind, randomized clinical trial of two doses of davunetide (5 and 30 mg/day intranasally) versus placebo for treatment of cognitive dysfunction in schizophrenia15

  • theoreticalDavunetide is administered as a nasal spray15

How the body handles it

Based on 1 human trial finding, 2 animal findings and 1 in vitro finding.

  • human trialClinical studies on NAP (davunetide) administered via intranasal delivery have demonstrated favorable bioavailability5

  • animalThe estimated terminal elimination half-life of davunetide in plasma was 70.7 ± 34.0 min14

  • animalThe mean residence time of davunetide was 75.5 ± 19.1 min14

  • in vitroNAP rapidly distributed in the cytoplasm and was also seen in the nucleus18

Safety and side effects

Based on 15 human trial findings, 2 human study findings, 3 animal findings and 2 in vitro findings.

  • human trialThere were 11 deaths in the davunetide group and ten in the placebo group1

  • human trial54 serious adverse events were reported in the davunetide group2

  • human trial11 deaths occurred in the davunetide group2

  • human trialEpistaxis occurred in 18 of 156 (12%) participants in davunetide group versus 13 of 156 (8%) in placebo group2

  • human trialRhinorrhoea occurred in 15 of 156 (10%) participants in davunetide group versus 8 of 156 (5%) in placebo group2

  • human trialNasal discomfort occurred in 15 of 156 (10%) participants in davunetide group versus 1 of 156 (<1%) in placebo group2

  • human trialDavunetide intranasal is well-tolerated in clinical studies with a duration of up to 52 weeks, with modest adverse events3

  • human trialNasal irritation is the most frequent adverse drug reaction but was typically mild and transient3

Show 14 more findings

  • human trialStudy assessed safety through clinical adverse events, clinical laboratory tests, ECGs, and physical examinations at each visit4

  • human trialClinical studies on NAP (davunetide) administered via intranasal delivery have demonstrated its safety5

  • human trialData from 10 separate clinical trials of davunetide investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated11

  • human trialNo significant side effects or adverse events were observed with davunetide12

  • human trialDavunetide was well tolerated12

  • human trial12 week randomized, double blind, placebo-controlled pilot study of davunetide obtained preliminary safety and tolerability data in patients with frontotemporal lobar degeneration, corticobasal degeneration syndrome, or progressive supranuclear palsy15

  • human trialPhase 2 trial in 144 people with aMCI showed safety data included headache and nasal irritation, but the drug was generally well-tolerated17

  • human studyDavunetide demonstrates safety in preclinical and clinical studies16

  • human studyCP201 has clean toxicology and positive human adult experience21

  • animalNonclinical chronic toxicity studies of intranasal davunetide administration are complete in rat and dog3

  • animalPre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated11

  • animalPre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated11

  • in vitroKetamine, used as a control, was ineffective18

  • in vitroNWPVSIWQ and HAPVSIIQ show safety in viability experiments on HEK cells19

What people use it for

Based on 4 human trial findings, 2 human study findings, 8 expert opinion findings and 3 theoretical findings.

  • human trialPrimary objective is to obtain preliminary safety and tolerability data with davunetide in patients with tauopathies (FTLD, CBS, PSP)4

  • human trialThis is a multicentre, randomised, parallel group, double-blind, placebo-controlled trial testing davunetide as an effective treatment for PSP10

  • human trialDavunetide (AL-108, NAP) is an intranasally administered peptide currently being developed for treatment of Alzheimer's disease and related disorders12

  • human trialdavunetide (NAP) is now being evaluated in a Phase II/III study of the tauopathy, progressive supranuclear palsy (PSP)22

  • human studyADNP is dysregulated in Alzheimer's disease, Parkinson's disease, and schizophrenia7

  • human studyThe most common clinical presentation of PSP, termed Richardson's syndrome, has a prevalence of about 6.5 cases per 100,000 individuals10

  • expert opinionProgressive supranuclear palsy (PSP) is a neurodegenerative cause of atypical parkinsonism for which there are no approved or effective treatments10

  • expert opinionPotential clinical uses of davunetide include neurodegenerative disorders such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD)11

Show 9 more findings

  • expert opinionDavunetide may be used for cognitive impairment in schizophrenia where microtubule structure and function is known to be impaired11

  • expert opinionDavunetide shows promise for neurodevelopmental and tauopathy-related disorders16

  • expert opinionMicrotubule stabilization is an attractive pharmacological strategy to hamper the progress of neurodegenerative diseases19

  • expert opinionCP201 is planned for future clinical trials in Helsmoortel-Van Der Aa syndrome21

  • expert opinionDavunetide (AL-108, NAP) is an intranasally administered peptide23

  • expert opinionDavunetide is currently being developed for treatment of Alzheimer's disease and related conditions23

  • theoreticalNAP replacement therapy ameliorates tauopathy in part13

  • theoreticalDavunetide has active indication for Amyotrophic Lateral Sclerosis15

  • theoreticalDavunetide has inactive indications for Cognitive Dysfunction, Dementia, Mild cognitive disorder15

Other findings

Based on 2 human trial findings, 2 expert opinion findings and 1 theoretical finding.

  • human trialStudy was randomized 2:1 (drug:placebo) with quadruple masking in a 12-week design4

  • human trialCognitive dysfunction is a key predictor of functional disability in schizophrenia12

  • expert opinionDavunetide is a straight-chain, unmodified eight amino acid peptide3

  • expert opinionDavunetide is the first neuroprotective peptide in its class11

  • theoreticalDavunetide is a synthetic peptide15

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Limited evidence

Positive cognitive signals came from trials that missed their primary endpoints

The schizophrenia trial (Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia., Davunetide) missed its co-primary cognitive outcome (MCCB) and only reached significance on a secondary functional measure (UPSA, p=.048). The aMCI trial (Davunetide) showed significant improvement at 8 and 16 weeks but not at 12 weeks. These are small trials (63 and 144 patients) with inconsistent timepoints and endpoints.

Limited evidence

The tau isoform hypothesis for PSP failure is theoretical

The proposal that 3R/4R tau isoform preference explains efficacy in Alzheimer's but failure in PSP (Davunetide: Mechanism, Status, Dose Reference & Half-Life, Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy., NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies.) is a mechanistic/theoretical hypothesis supported by in vitro and preclinical data, not by a prospective clinical test.

Single source

ADNP-syndrome phase 3 in children is early-stage and from a lower-tier source

The reported ExoNavis phase 3 trial in 97 children with ADNP mutations (October 2024) comes from a tier-3 web source (Davunetide Dosing Protocols and Administration | Peptide Protocol Wiki); Davunetide: Mechanism, Status, Dose Reference & Half-Life and The ADNP Syndrome and CP201 (NAP) Potential and Hope. note the ADNP-syndrome repositioning (CP201) still lacks a completed pivotal efficacy trial.

Using it with other compounds

Check a stack
  • SemaxComplementary

    No documented conflict

    Both are short neuroactive peptides aimed at cognitive protection through non-overlapping mechanisms: davunetide stabilizes microtubules and lowers tau phosphorylation, whereas semax drives BDNF/NGF-TrkB neurotrophin signaling. Together they address structural stability and growth-factor support.

    Tier 4Theoretical — not established

    Shares anti inflammatory

  • P21Same downstream effect

    May be complementary

    Both peptides converge on reducing tau hyperphosphorylation, but by different routes: davunetide stabilizes microtubules and dampens GSK-3 activity directly, while P21 raises BDNF and inactivates GSK-3beta via the Akt pathway. They arrive at the same anti-tau, pro-synaptic endpoint from different starting points, which is why they are complementary rather than redundant.

    Tier 4Theoretical — not established

    Shares mTOR PI3K

  • NoopeptComplementary

    No documented conflict

    Both offer neuroprotection and cognitive support via different routes — davunetide through microtubule/tau stabilization, noopept through TrkB/BDNF activation and protection against glutamate excitotoxicity. The mechanisms are distinct and potentially additive for neuronal resilience.

    Tier 4Theoretical — not established

    Shares anti inflammatory

  • HumaninComplementary

    No documented conflict

    Both are reported neuroprotective, anti-apoptotic peptides that recruit PI-3K/Akt survival signaling, but davunetide works by stabilizing microtubules and lowering tau phosphorylation while humanin works through mitochondrial/cytokine-receptor cytoprotection. Different molecular handles converging on neuronal survival.

    Tier 4Theoretical — not established

    Shares anti inflammatory · mTOR PI3K

  • DihexaComplementary

    May be complementary

    Davunetide stabilizes microtubules and promotes neurite outgrowth/synapse formation via PI-3K/Akt, a structural complement to Dihexa's HGF/c-Met-driven spine formation. Two different mechanisms both supporting neuronal architecture and plasticity.

    Tier 4Theoretical — not established

    Shares mTOR PI3K · anti inflammatory

  • CerebrolysinComplementary

    May be complementary

    Both act on tau hyperphosphorylation and neuroprotection through PI3K/Akt–GSK3 signaling, but Davunetide works primarily by stabilizing microtubules while Cerebrolysin works via neurotrophic mimicry. Different molecular handles on the same neurodegenerative target make them complementary. Combination data are preclinical/anecdotal.

    Tier 4Theoretical — not established

    Shares anti inflammatory · mTOR PI3K

  • CortexinComplementary

    No documented conflict

    Davunetide stabilizes microtubules and reduces tau pathology while adding anti-apoptotic, anti-inflammatory and neurotrophic protection; Cortexin brings anti-excitotoxic, antioxidant and caspase-8 anti-apoptotic support. Different molecular targets converging on neuronal survival, so they complement rather than duplicate each other.

    Tier 4Theoretical — not established

    Shares anti inflammatory

Safety and side effects

Safety and Tolerability

Across clinical studies of up to 52 weeks in duration, intranasal davunetide was reported to be generally safe and well-tolerated, with modest adverse events. The most frequent adverse drug reaction is nasal irritation, which was typically mild and transient.

Trial-specific findings

  • PSP trial (n=313): Nasal adverse events were more frequent with davunetide than placebo — epistaxis 18/156 (12%) vs 13/156 (8%), rhinorrhoea 15/156 (10%) vs 8/156 (5%), and nasal discomfort 15/156 (10%) vs 1/156 (<1%). There were 11 deaths in the davunetide group and 10 in the placebo group, with 54 serious adverse events reported in each group (i.e. balanced between arms).
  • Schizophrenia trial (n=63): No significant side effects or adverse events were observed; davunetide was well tolerated.

Preclinical toxicology

Chronic toxicity studies of intranasal davunetide are complete in rat and dog, and toxicology at the maximum feasible dose provides strong evidence of good tolerability. The PSP clinical dose of 60 mg/day (30 mg twice daily) represented a conservative ~3.5-fold safety margin relative to animal toxicity studies. CP201 has been described as having 'clean toxicology' and positive human adult experience.

Note: This is an investigational research peptide. Davunetide is not an approved therapy; its pivotal PSP trial was negative on all endpoints, and human pharmacokinetics remain poorly characterized.

Reconstitution and handling

Formulation and Administration

No dose has been established for this compound. No regulatory label exists for it, so the figures below are what sources report — not guidance.

Davunetide is administered intranasally as a nasal spray. In clinical trials it was formulated as a ready-to-use intranasal spray solution — that is, it was delivered as a liquid spray rather than requiring end-user reconstitution of a lyophilized powder. Intranasal delivery is proposed to provide direct CNS access via the olfactory and trigeminal nerve pathways, and clinical studies reported favorable bioavailability (without specific human PK parameters being characterized).

Dosing Regimens Used in Trials

  • aMCI: 5 mg once daily and 15 mg twice daily (intranasal).
  • Schizophrenia: 5 mg/day and 30 mg/day (intranasal).
  • Tauopathy pilot: 15 mg twice daily (intranasal).
  • PSP (pivotal phase 2/3): 30 mg twice daily = 60 mg/day (intranasal), for 52 weeks.

The 60 mg/day PSP dose represented a conservative ~3.5-fold safety margin versus animal toxicity data. In the schizophrenia trial, authors estimated that at least 45–50 subjects per group would be needed to detect significant effects on both the MCCB and UPSA endpoints.

Storage

Research material is reported to be stored lyophilized at −20 °C, while the finished nasal spray is stored at controlled room temperature(vendor claim).

These figures are reported from research and clinical-trial contexts for informational purposes and do not constitute dosing guidance.

Sources

Ordered by evidence quality — the strongest first.

  1. Davunetide for Progressive Supranuclear Palsy: a multicenter, randomized, double-blind, placebo controlled trial(opens in a new tab)
    Tier 1Web · pmc.ncbi.nlm.nih.gov
  2. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial(opens in a new tab)
    Tier 1Web · pubmed.ncbi.nlm.nih.gov
  3. Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases: Expert Review of Clinical Pharmacology: Vol 6, No 5(opens in a new tab)
    Tier 1Web · tandfonline.com
  4. Study Details | NCT01056965 | Davunetide (AL-108) in ...(opens in a new tab)
    Tier 1Web · clinicaltrials.gov
  5. Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  6. Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  7. Activity-dependent neuroprotective protein (ADNP)-end-binding protein (EB) interactions regulate microtubule dynamics toward protection against tauopathy.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  8. NAP (davunetide) preferential interaction with dynamic 3-repeat Tau explains differential protection in selected tauopathies.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2019
  9. Interventions in progressive supranuclear palsy.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2016
  10. Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial - ScienceDirect(opens in a new tab)
    Tier 1Web · sciencedirect.com · 2014
  11. Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2013
  12. Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2012
  13. NAP (davunetide) provides functional and structural neuroprotection.(opens in a new tab)
    Tier 1PubMed · pubmed.ncbi.nlm.nih.gov · 2011
  14. Davunetide(opens in a new tab)
    Tier 2Web · researchgate.net
  15. Davunetide - Drug Targets, Indications, Patents - Synapse(opens in a new tab)
    Tier 2Web · synapse.patsnap.com
  16. Intranasal NAP (Davunetide): Neuroprotection and circadian ...(opens in a new tab)
    Tier 2Web · sciencedirect.com
  17. Davunetide(opens in a new tab)
    Tier 2Web · alzforum.org · 2025
  18. NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  19. Rational Discovery of Microtubule-Stabilizing Peptides.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  20. Deciphering the Enigma: NAP (CP201) the Active ADNP Drug Candidate Enters Cells by Dynamin-Associated Endocytosis.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  21. The ADNP Syndrome and CP201 (NAP) Potential and Hope.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  22. Microtubules (tau) as an emerging therapeutic target: NAP (davunetide).(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2011
  23. Schizophrenia Research - CDN(opens in a new tab)
    Tier 3Web · bpb-us-e2.wpmucdn.com
  24. Tau, ADNP, and sex.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  25. Davunetide: Peptide therapeutic in neurological disorders.(opens in a new tab)
    Tier 3PubMed · pubmed.ncbi.nlm.nih.gov · 2014
  26. Alzheimer’s Disease Clinical Trials (Section 3) - Alzheimer's Disease Drug Development(opens in a new tab)
    Tier 4Web · cambridge.org

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