Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain

Hey, John A.; Kočiš, Petr; Hort, Jakub; Abushakra, Susan; Power, Aidan; Vyhnálek, Martin; Yu, Yongxin; Tolar, Martin

doi:10.1007/s40263-018-0554-0

Cited by 47 publications

(58 citation statements)

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“…Consistent with how these factors interact to impact efficacy, aducanumab's EMERGE phase 3 results showed the strongest clinical benefit and significance only at the highest dose of 10 mg/kg monthly IV infusion, and only after sufficient number of patients reached sustained peak exposure [19]. The 265 mg dose of ALZ-801 administered twice daily as an oral tablet achieved sustained brain exposures in AD patients that are 5-fold higher than the brain concentration required for full inhibition of formation of neurotoxic oligomers [15,16]. The sustained CSF drug levels at this dose explain the clinical efficacy observed in APOE4 carriers in the tramiprosate phase 3 trials [24,31].…”

Section: Pharmacokinetic Propertiesmentioning

confidence: 99%

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

et al. 2020

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The body of evidence suggesting a causative, initiating role of beta amyloid (Aβ) in the pathogenesis of Alzheimer's disease (AD) is substantial. Yet, only a few anti-amyloid agents have shown meaningful efficacy in clinical trials. We evaluated the unifying characteristics of anti-amyloid agents with positive clinical or biomarker effects in long-duration trials and analyzed how pharmacological characteristics determine their clinical product profiles. Four agents with the potential for near term approval fulfill these criteria: the injectable antibodies, aducanumab, gantenerumab, and BAN2401, and a small molecule oral agent, ALZ-801. Aducanumab and BAN2401 showed significant efficacy on both clinical and biomarker outcomes; gantenerumab showed significant biomarker effects, with no clinical efficacy reported to date; and ALZ-801 showed significant clinical effects in the high-risk population of patients homozygous for the ε4 allele of apolipoprotein E gene (APOE4) and a dose-dependent preservation of hippocampal volume. We explored how the pharmacological properties of these agents, namely selectivity for Aβ oligomers, plasma half-life, brain penetration, and time to peak brain exposure, determine their clinical profiles. A crucial characteristic shared by these agents is their ability to engage neurotoxic soluble Aβ oligomers, albeit to various degrees. Aducanumab and gantenerumab partially target oligomers, while mostly clearing insoluble amyloid plaques; BAN2401 preferentially targets soluble protofibrils (large oligomers) over plaques; and ALZ-801 blocks the formation of oligomers without binding to plaques. The degree of selectivity for Aβ oligomers and brain exposure drive the magnitude and onset of clinical efficacy, while the clearance of plaques is associated with vasogenic brain edema. Only the highest doses of aducanumab and BAN2401 show modest efficacy, and higher dosing is limited by increased risk of vasogenic edema, especially in APOE4 carriers. These limitations can be avoided, and efficacy improved by small molecule agents that selectively inhibit the formation or block the toxicity of Aβ oligomers without clearing amyloid plaques. The most advanced selective antioligomer agent is ALZ-801, an optimized oral prodrug of tramiprosate, which demonstrated efficacy in homozygous APOE4/4 AD subjects. ALZ-801 selectively and fully inhibits the formation of Aβ42 oligomers at

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Section: Pharmacokinetic Propertiesmentioning

confidence: 99%

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

et al. 2020

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“…38 In addition, the recently described active metabolite of ALZ-801, 3-SPA, has also shown potent antioligomer activity in vitro and was found to be endogenously present in the human brain. 49 Multiple molecules of tramiprosate and its active metabolite, 3-SPA, interact reversibly with the A 42 monomer at specific sites, preventing its misfolding and stabilizing the monomer in a conformation that prevents its aggregation into A oligomers. 37,49 ALZ-801 has shown favorable pharmaceutical properties in preclinical and clinical studies.…”

Section: Alz-801 Program Provides Effective Test Of Amyloid Hypothesimentioning

confidence: 99%

“…49 Multiple molecules of tramiprosate and its active metabolite, 3-SPA, interact reversibly with the A 42 monomer at specific sites, preventing its misfolding and stabilizing the monomer in a conformation that prevents its aggregation into A oligomers. 37,49 ALZ-801 has shown favorable pharmaceutical properties in preclinical and clinical studies. The ALZ-801 tablet shows consistent oral absorption and sustained plasma and CSF levels, with approximately 40% brain penetration at steady state, which is important to achieve the full inhibition of oligomer formation and clinical efficacy.…”

Section: Alz-801 Program Provides Effective Test Of Amyloid Hypothesimentioning

confidence: 99%

“…The ALZ-801 tablet shows consistent oral absorption and sustained plasma and CSF levels, with approximately 40% brain penetration at steady state, which is important to achieve the full inhibition of oligomer formation and clinical efficacy. 37,39,49 Favorable long-term safety of ALZ-801 has been established in more than 1600 patients with AD treated with tramiprosate for up to 1.5 years and in 400 patients treated for up to 2.5 years. 32,33 The main adverse events were mild to moderate nausea and vomiting.…”

Section: Alz-801 Program Provides Effective Test Of Amyloid Hypothesimentioning

confidence: 99%

“…These CSF drug levels of ALZ-801/tramiprosate are several times higher than the concentrations needed for the full inhibition of A oligomer formation in the in vitro assay. 37,49 The extrapolation from in vitro to human studies regarding CSF concentrations of ALZ-801 necessary for full inhibition of formation of A oligomers will be evaluated in the phase 3 study using currently available A oligomer CSF assays, as well as future improved techniques as they become available.…”

Section: Alz-801 Program Provides Effective Test Of Amyloid Hypothesimentioning

confidence: 99%

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The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis

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Development of disease-modifying treatments for Alzheimer's disease (AD) has been challenging, with no drugs approved to date. The failures of several amyloid-targeted programs have led many to dismiss the amyloid beta (A) hypothesis of AD. An antiamyloid antibody aducanumab recently showed modest but significant efficacy in a phase 3 trial, providing important validation of amyloid as a therapeutic target. However, the inconsistent results observed with aducanumab may be explained by the limited brain penetration and lack of selectivity for the soluble A oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit A oligomer formation or block their toxicity is therefore warranted. An ideal drug would cross the blood-brain barrier efficiently and achieve sustained brain levels that can continuously prevent oligomer formation or inhibit their toxicity. A late-stage candidate with these attributes is ALZ-801, an oral drug with a favorable safety profile and high brain penetration that can robustly inhibit A oligomer formation. An upcoming phase 3 trial with ALZ-801 in APOE4/4 homozygous patients with early AD will effectively test this amyloid oligomer hypothesis.

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Using mass spectrometry‐based methods to understand amyloid formation and inhibition of alpha‐synuclein and amyloid beta

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Amyloid fibrils, insoluble β‐sheets structures that arise from protein misfolding, are associated with several neurodegenerative disorders. Many small molecules have been investigated to prevent amyloid fibrils from forming; however, there are currently no therapeutics to combat these diseases. Mass spectrometry (MS) is proving to be effective for studying the high order structure (HOS) of aggregating proteins and for determining structural changes accompanying protein–inhibitor interactions. When combined with native MS (nMS), gas‐phase ion mobility, protein footprinting, and chemical cross‐linking, MS can afford regional and sometimes amino acid spatial resolution of the aggregating protein. The spatial resolution is greater than typical low‐resolution spectroscopic, calorimetric, and the traditional ThT fluorescence methods used in amyloid research today. High‐resolution approaches can struggle when investigating protein aggregation, as the proteins exist as complex oligomeric mixtures of many sizes and several conformations or polymorphs. Thus, MS is positioned to complement both high‐ and low‐resolution approaches to studying amyloid fibril formation and protein–inhibitor interactions. This review covers basics in MS paired with ion mobility, continuous hydrogen‐deuterium exchange (continuous HDX), pulsed hydrogen‐deuterium exchange (pulsed HDX), fast photochemical oxidation of proteins (FPOP) and other irreversible labeling methods, and chemical cross‐linking. We then review the applications of these approaches to studying amyloid‐prone proteins with a focus on amyloid beta and alpha‐synuclein. Another focus is the determination of protein–inhibitor interactions. The expectation is that MS will bring new insights to amyloid formation and thereby play an important role to prevent their formation.

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Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain

Cited by 47 publications

References 24 publications

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

Aducanumab, gantenerumab, BAN2401, and ALZ-801—the first wave of amyloid-targeting drugs for Alzheimer’s disease with potential for near term approval

The path forward in Alzheimer's disease therapeutics: Reevaluating the amyloid cascade hypothesis

Using mass spectrometry‐based methods to understand amyloid formation and inhibition of alpha‐synuclein and amyloid beta

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