P2‐377: A phase 2, double‐blind, placebo‐controlled study to evaluate the safety, tolerability, and effect on cognitive function of AL‐108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment

Schmechel, Donald E.; Gerard, Gary; Vatakis, Nick G.; Harper, Linda; Ross, Joel; Bari, Mohammed Abdul; Walling, David; Stedman, Mary; Winston, Jaron; Morimoto, Bruce H.; Keith, Julian R.

doi:10.1016/j.jalz.2008.05.1455

Cited by 12 publications

(8 citation statements)

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“…NAP (davunetide) that is currently under clinical development by Allon Therapeutic Inc. has shown cognitive protection in patients suffering from amnestic mild cognitive impairment associated with tauopathy [61], [50]. NAP (davunetide) also improved functional capacity in schizophrenia patients [62] and is being developed for treatment of the tauopathy, progressive supranuclear palsy (PSP).…”

Section: Introductionmentioning

confidence: 99%

Protection Against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects

Shiryaev¹,

Pikman²,

Giladi³

et al. 2011

CPD

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Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and partial deficiency in ADNP results in cognitive deficits coupled with tauopathy and neuronal cell death. Our previous results indicated that a peptide snippet from ADNP, NAPVSIPQ (NAP, generic name, davunetide) can restore in part ADNP deficiencies. NAP interacts with tubulin and this interaction is displaced by the NAP related peptide that is derived from activity-dependent neurotrophic factor (ADNF), SALLRSIPA (SAL) and its all D-amino acid peptide derivative (D-SAL, also known as AL-309). Both NAP and D-SAL were shown to protect neurons against amyloid beta toxicity however the mechanism of protection is still under investigation. In addition, NAP protects against tau hyperphosphorylation associated with ADNP deficiency, in vivo. To investigate whether the mechanism of in vitro neuroprotection relates to the in vivo protection against tauopathy and to draw potential additional parallelism between NAP and D-SAL, we asked if: 1]NAP and D-SAL protect against amyloid beta related tau hyperphosphorylation in vitro; and 2] D-SAL protects against haploinsufficiency in ADNP, inhibiting tauopathy in vivo. Assessment of NAP and D-SAL neuroprotection in primary cortical neuro-glial cultures treated with amyloid beta showed that both peptides reduced toxin-related neuronal damage and protected against tau hyperphosphorylation. In vivo, chronic D-SAL administration protected against tau hyperphosphorylation associated with ADNP deficiency (ADNP+/- mice), showing for the first time protection against deficits in odor discrimination and in social recognition. These studies associate neuroprotection in vivo and in vitro and provide a broad base for future drug development based on NAP and D-SAL against multiple neurodegenerative conditions.

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Section: Introductionmentioning

confidence: 99%

Protection Against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects

Shiryaev¹,

Pikman²,

Giladi³

et al. 2011

CPD

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“…Therapeutic strategies directed toward the NFTs are few and remain unproven. They include inhibition of Tau aggregation with methylene blue (1), passive Tau immunotherapy (2), microtubule stabilization (3), and inhibition of Tau kinases such as glycogen synthase kinase 3␤ (GSK3␤) and cyclin-dependent kinase 5 (CDK5) (4 -6). As a candidate target for tauopathies, CDK5 has the merit of phosphorylating Tau at NFT-associated residues.…”

mentioning

confidence: 99%

Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models*

Zhang

Hernández

Rei

et al. 2013

Journal of Biological Chemistry

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Background: Tau is hyperphosphorylated in the tauopathies. Targeting Tau kinases CDK5 and GSK3␤ represents a potential therapeutic approach. Results: Inhibitors of Tau kinases are neuroprotective, decrease PHF-1 immunoreactivity, and induce recovery of memory by fear conditioning. Conclusion: Diaminothiazoles as CDK5 and GSK3␤ inhibitors improve the tauopathy in mouse models. Significance: Dual kinase inhibition can be critical for efficacy when treating tauopathies.

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“…In a Phase 2, placebo-controlled study, a middle dose of methylene blue known as Rember improved cognitive function in mild-to-moderate AD patients and had evidence of slower progression of the disease [ 70 ]. Davunetide (an octapeptide) and nicotinamide are inhibitors of tau aggregation that showed prevention of cognitive deficit in AD animal models [ 71 ]. Rember is safe and tolerable and it continues in clinical studies but Davunetide failed in clinical trials for AD and other tauopathies (for a review, see http://www.alzforum.org/news/research-news/tau-targeting-drug-davunetide-washes-out-phase-3-trials ).…”

Section: Targets Of Developing Drugs In Ad Pathophysiologymentioning

confidence: 99%

Role of Cerebrospinal Fluid Biomarkers in Clinical Trials for Alzheimer's Disease Modifying Therapies

Kang

Ryoo

Shin

et al. 2014

Korean J Physiol Pharmacol

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Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer's disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Aβ1-42, total tau and p-tau181 levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer's Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the

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P2‐377: A phase 2, double‐blind, placebo‐controlled study to evaluate the safety, tolerability, and effect on cognitive function of AL‐108 after 12 weeks of intranasal administration in subjects with mild cognitive impairment

Cited by 12 publications

References 0 publications

Protection Against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects

Protection Against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects

Diaminothiazoles Modify Tau Phosphorylation and Improve the Tauopathy in Mouse Models*

Role of Cerebrospinal Fluid Biomarkers in Clinical Trials for Alzheimer's Disease Modifying Therapies

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