Clinical Trials Cognitive & Nootropic

Davunetide

also known as: NAP, AL-108, AL-208, NAPVSIPQ

NAPVSIPQ, the minimum active fragment of ADNP — an 8-amino-acid neuroprotective peptide studied in Phase 2 (cognition in mild cognitive impairment, schizophrenia) and Phase 3 (progressive supranuclear palsy). The Phase 3 PSP trial failed in 2012; development continues in schizophrenia (Coronis / ATL-104) and ADNP syndrome research.

An octapeptide (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln) corresponding to the minimal neuroprotective fragment of activity-dependent neuroprotective protein (ADNP), discovered by Illana Gozes at Tel Aviv University. Originally advanced intranasally by Allon Therapeutics through a Phase 2b program in amnestic mild cognitive impairment and a Phase 3 program (GN-1058) in progressive supranuclear palsy (PSP) — the Phase 3 PSP trial failed its primary endpoints in late 2012, ending Allon. Assets subsequently licensed to Paladin Labs and more recently Coronis Neurosciences for continued development in schizophrenia and ADNP-syndrome (Helsmoortel-Van der Aa syndrome) indications.

Mechanism of action

The parent protein ADNP binds microtubules via its SxIP motif (Ser-Ile-Pro — residues 5–7 of NAP) and interacts with end-binding proteins EB1/EB3 to stabilize dynamic microtubule plus-ends. NAP inherits this microtubule-stabilizing activity and has been reported to reduce tau hyperphosphorylation, protect against amyloid-β toxicity in vitro and in vivo, and normalize axonal transport deficits in tauopathy models. Mechanism of action is well characterized preclinically and represents a distinct therapeutic rationale from amyloid- or tau-clearance strategies.

Primary uses

Progressive supranuclear palsy (failed Phase 3, 2012)
Amnestic mild cognitive impairment (Phase 2 completed)
Schizophrenia — negative symptoms and cognition (investigational, ATL-104 / Coronis)
ADNP syndrome / Helsmoortel-Van der Aa syndrome (preclinical and translational research)

Typical dosing

15–30 (nasal) mg twice daily (intranasal)

Phase 2 and Phase 3 trial dosing used intranasal davunetide 15 mg twice daily or 30 mg twice daily. No established dose for any approved indication.

Regulatory status

Not FDA-approved. Allon Therapeutics advanced davunetide through Phase 2 in amnestic mild cognitive impairment (2008, met multiple secondary cognition endpoints but not primary) and Phase 3 in progressive supranuclear palsy (GN-1058, 2010–2012; n=313; did not meet co-primary endpoints for PSPRS or SEADL). Allon ceased independent operations after the PSP readout. Davunetide (as ATL-104 / Coronis asset) was reported in 2022–2024 to be under evaluation for cognitive and negative symptoms of schizophrenia, and has been the subject of continued preclinical interest as a candidate for ADNP syndrome.

References

[pubmed] Boxer AL, et al. "Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial." Lancet Neurol, 2014;13:676-685 (GN-1058 Phase 3, failed primary endpoints).
[pubmed] Gozes I, et al. "NAP: research and development of a peptide derived from activity-dependent neuroprotective protein (ADNP)." CNS Drug Rev, 2005;11:353-368.
[pubmed] Morimoto BH, et al. "A double-blind, placebo-controlled, ascending-dose, randomized study to evaluate the safety, tolerability and effects on cognition of AL-108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment." Dement Geriatr Cogn Disord, 2013;35:325-336.

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Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.