davunetide intranasal (AL-108) / Endo - LARVOL DELTA

Activity-dependent neuroprotective protein (ADNP) derived peptide NAP prevents musculoskeletal abnormalities in ovariectomized mice. (PubMed, Front Neurosci) - "Thus, the standard diet may have exerted a systemic estrogenic effect that masked the expected physiological phenotypes typically observed in OVX models. Future replication using phytoestrogen-deficient food is required to isolate the specific neuroprotective and musculoskeletal effects of NAP from dietary influence and clarify broader therapeutic benefits."

Journal • Preclinical • Cognitive Disorders • Musculoskeletal Diseases

Dramatic sex differences leading to different brain disease presentation: The requirement for sex-specific medications with ADNP/davunetide as a case study. (PubMed, Front Neuroendocrinol) - "Focusing on the brain-essential gene revealed in our laboratory, activity-dependent neuroprotective protein (ADNP) and its neuroprotective site, the investigational drug davunetide (NAP), we discuss ADNP regulating steroid hormone biosynthesis and sex chromosome genes coupled with sex-dependent shuttling between the nuclei and cytoplasm...ADNP regulation of these sex-specific processes serves as a target for davunetide intervention, toward sex-directed precision medicine, revealing sexually dichotomized neuroprotection against tauopathy risk and progression spanning from coronary artery bypass grafting (CABG) to prodromal Alzheimer's disease, progressive supranuclear palsy (PSP), and schizophrenia, as well as the pediatric ADNP syndrome. Sex-specific intranasal bioavailability of davunetide, regulated by the estrous cycle, provides a mechanistic foundation for these differential outcomes."

Journal • Review • Alzheimer's Disease • CNS Disorders • Movement Disorders • Pediatrics • Progressive Supranuclear Palsy • Psychiatry • Schizophrenia

ADNP Functions During Early Brain Development and Their Relevance to ASD and ADNP Syndrome. (PubMed, Int J Mol Sci) - "This review highlights the functions of full-length ADNP and NAP in early brain development, particularly in neurogenesis and neurite formation during cortical development. We will also discuss the potential of NAP as a therapeutic medication for neurodevelopmental disorders, especially ASD and ADNP syndrome."

Journal • Review • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Mental Retardation • Psychiatry • ADNP • CHD4

Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women. (PubMed, Mol Psychiatry) - "Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound."

Journal • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy • CSF P-tau

Microtubule-stabilizing drugs suppress convulsions in a C. elegans model of CAMSAP disorders. (PubMed, Epilepsy Res) - "We found that animals with genetically disrupted ptrn-1 (the C. elegans homolog of CAMSAP1) exhibited elevated convulsion frequency relative to wild type, and that Epothilone B and Valproic Acid reduced convulsions. We also found that Paclitaxel increased convulsions, and Davunetide produced variable outcomes. These results suggest that pharmacologic microtubule stabilization is a promising strategy for diseases caused by genetic disruption to CAMSAP function."

Journal • CNS Disorders • Epilepsy • Psychiatry

PRE-RECORDED: SEX-DEPENDENT DRUG BIOAVAILABILITY AFFECTS EFFICACY: DAVUNETIDE AS CASE STUDY (ADPD 2026) - "These results underscore the potential for davunetide as a sex-specific therapeutic intervention in the early stages of cognitive decline, with disparate underlying mechanisms in males and females further differentiated at the bioavailability level."

Case study • Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mood Disorders • Movement Disorders • Progressive Supranuclear Palsy

Potential role of MRI to optimize clinical trial design for progressive supranuclear palsy and corticobasal degeneration. (PubMed, J Prev Alzheimers Dis) - "MRI-derived models can identify PSP or CBD with high accuracy, and MRI-based signatures track progression more sensitively than established clinical outcomes. Incorporating these tools into therapeutic trial design could reduce sample sizes and enable more inclusive disease-modifying trials for 4RT."

Journal • Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Biomarkers. (PubMed, Alzheimers Dement) - "Selecting participants with increased diagnostic certainty for PSP and CBD based on baseline MRI, combined with using MRI measures as outcomes could enhance the efficiency of future phase 2 clinical trials for 4R tauopathies. We plan to replicate these results in the Davunetide trial cohort."

Biomarker • Journal • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Systemic davunetide provides sex-specific neuroprotection during Coronary Artery Bypass Grafting (CABG). (PubMed, Transl Psychiatry) - P2 | "These findings, while requiring caution due to the small cohort size, were linked with an apparent protection against brain cell death/disease progression by davunetide (AL-208) neuroprotective effects (neuron-specific enolase - NSE blood content). In men, also for the first time under these circumstances, neuroprotection was coupled to cognitive function increases in the treated group versus placebo, reaching healthy control levels in the Verbal Paired Associates II test, emphasizing the importance of sex-specific brain medicine."

Journal • Cardiovascular • CNS Disorders • Cognitive Disorders • Coronary Artery Disease • Ischemic stroke

The ADNP-Mediated Transcriptome Response to Ketamine Impairs the Cytoskeletal Protein Axis. (PubMed, J Mol Neurosci) - "In this respect, two treatment strategies have been proposed to alleviate symptoms in patients with this syndrome: (1) the ADNP-derived octapeptide investigational drug NAP (davunetide), which enhances ADNP's ability to target cytoskeletal deficits, and (2) subnarcotic levels of ketamine, which are suggested to increase endogenous ADNP mRNA levels. The ketamine-induced cytoskeletal alterations were functionally studied using immunoblotting, showing a disturbed expression of α-tubulin, β-actin, and to a minor extent microtubule-associated protein EB3 in patient-derived lymphoblastoid cells. Ketamine upregulates wild-type ADNP transcript and protein levels in a dose- and time-dependent manner in patient-derived lymphoblastoid cell lines from individuals with Helsmoortel-Van der Aa syndrome, while inducing a transcriptomic response that affects key processes including immune system signaling and cytoskeletal organization."

Journal • ADNP

Intranasal NAP (Davunetide): Neuroprotection and circadian rhythmicity. (PubMed, Adv Drug Deliv Rev) - "Additionally, the complex interactions between ADNP, associated pathways, and circadian regulation and the extensive NAP compensation upon ADNP deficiency attest to further clinical development. Thus, NAP is an example of a reductionist approach in drug delivery, replacing/enhancing the critical large ADNP-related pathways including dysregulated microtubules and tauopathy with a small brain bioavailable investigational drug, davunetide."

Journal • Review • Alzheimer's Disease • CNS Disorders • Movement Disorders • Progressive Supranuclear Palsy

Davunetide promotes structural and functional recovery of the injured spinal cord by promoting autophagy. (PubMed, Neural Regen Res) - "These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms. This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury."

Journal • CNS Disorders • Inflammation • Orthopedics • TFEB

ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation. (PubMed, Mol Psychiatry) - "NAP moderated much of the differential expression caused by p.Tyr718*, accompanied by the down-regulation of neurotoxic, pro-inflammatory and pro-apoptotic genes. Thus, ADNP is a key regulator of sex-dependent neurogenesis that acts by controlling canonical pathways, with NAP compensating for fundamental ADNP deficiencies, striding toward clinical development targeting the ADNP syndrome and related neurodevelopmental/neurodegenerative diseases."

Journal • Alzheimer's Disease • Autism Spectrum Disorder • CNS Disorders • Genetic Disorders • Movement Disorders • Progressive Supranuclear Palsy • ADNP

Davunetide sex-dependently boosts memory in prodromal Alzheimer's disease. (PubMed, Transl Psychiatry) - P2 | "In conclusion, sex-specific prodromal Alzheimer's drug development is encouraged, with davunetide playing a lead initiative role."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mood Disorders • Movement Disorders • Progressive Supranuclear Palsy • Psychiatry

Adnp/davunetide multi-site protection against tauoapthy (Neuroscience 2024) - "Modeling this by CRISPR-Cas9 editing in mice (Biol Psychiatry.2022;92:81), we showed protection by the ADNP fragment, investigational drug, davunetide (NAP)...Furthermore, analyzing clinical trial results, we discovered accelerated disease progression in women suffering from the pure tauopathy progressive supranuclear palsy (PSP), which was partly ameliorated by davunetide treatment (Transl Psychiatry. 2023;13:319) toward new research and development."

Alzheimer's Disease • CNS Disorders • Progressive Supranuclear Palsy • Psychiatry • ADNP • SIRT1

Sex-Specific ADNP/NAP (Davunetide) Regulation of Cocaine-Induced Plasticity. (PubMed, J Mol Neurosci) - "Our results implicate ADNP in cocaine abuse, further placing the ADNP gene as a key regulator in neuropsychiatric disorders. Ketamine/cocaine and NAP treatment may be interchangeable to some degree, implicating an interaction with adjacent zinc finger motifs on ADNP and suggestive of a potential sex-dependent, non-addictive NAP treatment for CUD."

Journal • Addiction (Opioid and Alcohol) • CNS Disorders • Mental Retardation • Psychiatry • ADNP

Integrated ribosome and proteome analyses reveal insights into sevoflurane-induced long-term social behavior and cognitive dysfunctions through ADNP inhibition in neonatal mice. (PubMed, Zool Res) - "Thus, ADNP was identified as a promising therapeutic target for the prevention and treatment of neurodevelopmental toxicity caused by general anesthetics. This study provides important insights into the mechanisms underlying social and cognitive disturbances caused by sevoflurane exposure in neonatal mice and elucidates the regulatory pathways involved."

Journal • Preclinical • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • DLG4 • SYP

Longitudinal Genotype-Phenotype (Vineland Questionnaire) Characterization of 15 ADNP Syndrome Cases Highlights Mutated Protein Length and Structural Characteristics Correlation with Communicative Abilities Accentuated in Males. (PubMed, J Mol Neurosci) - "Additionally, correlations were discovered between the two previously described epi-genetic signatures in ADNP emphasizing aberrant acquisition of motor behaviors, with truncating mutations around the nuclear localization signal being mostly affected. Finally, all individuals seem to acquire an age equivalent of 1-6 years, requiring disease modification treatment, such as the ADNP-derived drug candidate, NAP (davunetide), which has recently shown efficacy in women suffering from the neurodegenerative disorder, progressive supranuclear palsy (PSP), a late-onset tauopathy."

Journal • CNS Disorders • Developmental Disorders • Movement Disorders • Progressive Supranuclear Palsy • ADNP

Microtubule stabilising peptides: new paradigm towards management of neuronal disorders. (PubMed, RSC Med Chem) - "Therefore, a systematic updated review on MT stabilising peptides may shed light on many hidden aspects and enable researchers to develop new therapies for diseases related to the CNS. In this review we have summarised the recent examples of peptides as MSAs."

Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Huntington's Disease • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

Unexpected gender differences in progressive supranuclear palsy reveal efficacy for davunetide in women. (PubMed, Transl Psychiatry) - "Female-specific davunetide-mediated protection of ventricular volume corresponded to clinical efficacy. Together with the significantly slower disease progression seen in men, the results reveal sex-based drug efficacy differences, demonstrating the neuroprotective and disease-modifying impact of davunetide treatment for female PSP patients."

Journal • CNS Disorders • Depression • Geriatric Disorders • Movement Disorders • Progressive Supranuclear Palsy • Psychiatry • Vascular Neurology

NAP (Davunetide): The Neuroprotective ADNP Drug Candidate Penetrates Cell Nuclei Explaining Pleiotropic Mechanisms. (PubMed, Cells) - "Ketamine, used as a control, was ineffective, but both NAP and ketamine exhibited direct interactions with ADNP, as observed via in silico docking. (4) Through a microtubule-linked mechanism, NAP rapidly localized to the cytoplasmic and nuclear compartments, ameliorating mutated ADNP-related deficiencies. These novel findings explain previously published gene expression results and broaden NAP (davunetide) utilization in research and clinical development."

Journal • CNS Tumor • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor • ADNP

Tau, ADNP, and sex. (PubMed, Cytoskeleton (Hoboken)) - "I then moved to the original discovery of ADNP and its active neuroprotective site, NAP, drug candidate, davunetide. Tau-ADNP-NAP interactions were then explained with emphasis on sex and future translational medicine."

Journal

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development. (PubMed, Cells) - "However, targeted nose-to-brain, or intranasal (IN), approaches have begun to emerge that allow CNS-specific delivery of therapeutics via the trigeminal and olfactory nerve pathways, laying the foundation for improved alternatives to systemic drug delivery. Here we review a dozen promising IN peptide therapeutics in preclinical and clinical development for neurodegenerative (Alzheimer's, Parkinson's), neuropsychiatric (depression, PTSD, schizophrenia), and neurodevelopmental disorders (autism), with insulin, NAP (davunetide), IGF-1, PACAP, NPY, oxytocin, and GLP-1 agonists prominent among them."

Journal • Review • Alzheimer's Disease • Autism Spectrum Disorder • Cardiovascular • CNS Disorders • Depression • Developmental Disorders • Genetic Disorders • Mental Retardation • Movement Disorders • Parkinson's Disease • Post-traumatic Stress Disorder • Psychiatry • Schizophrenia • Vascular Neurology • ADCYAP1 • IGF1

Distinct Impairments Characterizing Different ADNP Mutants Reveal Aberrant Cytoplasmic-Nuclear Crosstalk. (PubMed, Cells) - "Reduced nuclear/cytoplasmic boundaries were observed in the p.Tyr718* ADNP-mutant line, with this malformation being corrected by the ADNP-derived fragment drug candidate NAP. (4) Distinct impairments characterize different ADNP mutants and reveal aberrant cytoplasmic-nuclear crosstalk."

Journal • Alzheimer's Disease • CNS Disorders • CNS Tumor • Neuroblastoma • Oncology • Solid Tumor

Rational Discovery of Microtubule-Stabilizing Peptides. (PubMed, J Chem Inf Model) - "FASTA sequences for ∼1000 peptides were crafted from single and double mutants of davunetide (NAP) and docked against the Taxol (TX) site on an octameric MT model representing a portion of the MT wall. Tryptophan quenching assays verified that P43 and P52 bind to nonpolymeric tubulin, whereas viability experiments on HEK cells confirmed their safety to pursue future pharmacological studies. The results herein presented are valuable to making progress in the rational design of MT-stabilizing peptides."

Journal • CNS Disorders