RESUMEN
New data suggest that the aggregation of misfolded native proteins initiates and drives the pathogenic cascade that leads to Alzheimer's disease (AD) and other age-related neurodegenerative disorders. We propose a unifying single toxin theory of brain neurodegeneration that identifies new targets and approaches to the development of disease-modifying treatments. An extensive body of genetic evidence suggests soluble aggregates of beta-amyloid (Aß) as the primary neurotoxin in the pathogenesis of AD. New insights from fluid biomarkers, imaging, and clinical studies provide further evidence for the decisive impact of toxic Aß species in the initiation and progression of AD. Understanding the distinct roles of soluble and insoluble amyloid aggregates on AD pathogenesis has been the key missing piece of the Alzheimer's puzzle. Data from clinical trials with anti-amyloid agents and recent advances in the diagnosis of AD demonstrate that the driving insult in biologically defined AD is the neurotoxicity of soluble Aß aggregates, called oligomers and protofibrils, rather than the relatively inert insoluble mature fibrils and amyloid plaques. Amyloid oligomers appear to be the primary factor causing the synaptic impairment, neuronal stress, spreading of tau pathology, and eventual cell death that lead to the clinical syndrome of AD dementia. All other biochemical effects and neurodegenerative changes in the brain that are observed in AD are a response to or a downstream effect of this initial toxic insult by oligomers. Other neurodegenerative disorders follow a similar pattern of pathogenesis, in which normal brain proteins with important biological functions become trapped in the aging brain due to impaired clearance and then misfold and aggregate into neurotoxic species that exhibit prion-like behavior. These aggregates then spread through the brain and cause disease-specific neurodegeneration. Targeting the inhibition of this initial step in neurodegeneration by blocking the misfolding and aggregation of healthy proteins has the potential to slow or arrest disease progression, and if treatment is administered early in the course of AD and other neurodegenerative disorders, it may delay or prevent the onset of clinical symptoms.
Asunto(s)
Enfermedad de Alzheimer , Toxinas Biológicas , Humanos , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Envejecimiento/metabolismo , Toxinas Biológicas/metabolismoRESUMEN
A large body of clinical and nonclinical evidence supports the role of neurotoxic soluble beta amyloid (amyloid, Aß) oligomers as upstream pathogenic drivers of Alzheimer's disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species of Aß provide compelling evidence that inhibition of Aß oligomer toxicity represents an effective approach to slow or stop disease progression: (1) only agents that target soluble Aß oligomers show clinical efficacy in AD patients; (2) clearance of amyloid plaque does not correlate with clinical improvements; (3) agents that predominantly target amyloid monomers or plaque failed to show clinical effects; and (4) in positive trials, efficacy is greater in carriers of the ε4 allele of apolipoprotein E (APOE4), who are known to have higher brain concentrations of Aß oligomers. These trials also show that inhibiting Aß neurotoxicity leads to a reduction in tau pathology, suggesting a pathogenic sequence of events where amyloid toxicity drives an increase in tau formation and deposition. The late-stage agents with positive clinical or biomarker data include four antibodies that engage Aß oligomers (aducanumab, lecanemab, gantenerumab, and donanemab) and ALZ-801, an oral agent that fully blocks the formation of Aß oligomers at the clinical dose.
Asunto(s)
Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/toxicidad , Progresión de la Enfermedad , Enfermedad de Alzheimer/genética , Animales , Encéfalo/patología , Humanos , Reproducibilidad de los Resultados , SolubilidadRESUMEN
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 (Aß) 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 Aß oligomers, which are implicated as upstream drivers of neurodegeneration by multiple studies. Development of agents that can effectively inhibit Aß 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 Aß 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.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/farmacología , Descubrimiento de Drogas , Humanos , Taurina/análogos & derivados , Taurina/farmacología , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
OBJECTIVE: To characterize clusters of neuropsychiatric symptoms targeted for tracking the disease course in people with dementia, in relation to stage. METHODS: Baseline symptoms from 2922 subjects from two datasets (one clinic based, one online) were aggregated. Common neuropsychiatric symptoms identified by patients/carers as targets of treatment using a dementia SymptomGuide™ were selected. The Global Deterioration Scale was used for clinic staging, and an artificial neural network algorithm, for staging online subjects. Symptom clusters were detected using multiple correspondence analysis and connectivity graph analysis based on relative risk (RR). In a connectivity graph, each pair of nodes (representing symptoms) is connected if their co-occurrence is statistically significant; direction is indicated as positive if RR > 1 and negative otherwise. RESULTS: Neuropsychiatric symptoms were targeted for treatment in 1072 patients (37%). Agitation (37%) and sleep disturbances (28%) were most common symptoms. One cluster (in people with cognitive impairment, no dementia (CIND) or mild dementia) showed significant co-occurrence of anxiety and restlessness; decreased initiative was chiefly seen in isolation. A second cluster (in moderate/severe dementia) was defined by significant co-occurrence of delusions and hallucinations with sleep disturbances; in these subjects, decreased initiative was related to aggression. CONCLUSIONS: Two analytical methods identified neuropsychiatric symptom clusters targeted to track the disease course. In CIND/mild dementia, a profile of decreased initiative distinct from depression suggests possible executive dysfunction. In moderate/severe dementia, targets more reflected psychotic symptoms. Visual data displays allow the relationships between multiple symptoms to be considered simultaneously, which commonly is how they present in patients.
Asunto(s)
Demencia/psicología , Pruebas Neuropsicológicas , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/diagnóstico , Depresión/diagnóstico , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos del Humor/diagnóstico , Inventario de Personalidad , Agitación Psicomotora/diagnóstico , Trastornos del Sueño-Vigilia/diagnósticoRESUMEN
INTRODUCTION: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aß) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD. METHODS: The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aß42/Aß40) and tau pathology (p-tau181) were enrolled, with serial CSF and plasma levels of Aß42 and Aß40 measured over 104 weeks. Longitudinal changes of CSF Aß42, plasma Aß42/Aß40 ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex. RESULTS: A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aß42 level and plasma Aß42/Aß40 ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26). CONCLUSIONS: In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aß oligomer agent with disease modification potential in AD. TRIAL REGISTRY: https://clinicaltrials.gov/study/NCT04693520.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Apolipoproteína E4 , Biomarcadores , Cognición , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Masculino , Anciano , Apolipoproteína E4/genética , Cognición/efectos de los fármacos , Administración Oral , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Persona de Mediana Edad , Proteínas tau/líquido cefalorraquídeoRESUMEN
INTRODUCTION: ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aß) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments. METHODS: The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aß42 and Aß40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test. RESULTS: The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks. CONCLUSIONS: The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aß oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04693520 .
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Apolipoproteína E4 , Biomarcadores , Cognición , Hipocampo , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/diagnóstico por imagen , Anciano , Masculino , Femenino , Apolipoproteína E4/genética , Hipocampo/efectos de los fármacos , Hipocampo/diagnóstico por imagen , Cognición/efectos de los fármacos , Biomarcadores/sangre , Persona de Mediana Edad , Anciano de 80 o más Años , Imagen por Resonancia Magnética , Proteínas tau , Administración Oral , Heterocigoto , Fragmentos de Péptidos/sangreRESUMEN
INTRODUCTION: The approved amyloid antibodies for early Alzheimer's disease (AD) carry a boxed warning about the risk of amyloid-related imaging abnormalities (ARIAs) that are highest in apolipoprotein E (APOE) ε4/ε4 homozygotes. ALZ-801/valiltramiprosate, an oral brain-penetrant amyloid beta oligomer inhibitor is being evaluated in APOE ε4/ε4 homozygotes with early AD. METHODS: This Phase 3 randomized, double-blind, placebo-controlled, 78-week study of ALZ-801 administered as 265 mg twice per day tablets, enrolled 50- to 80-year-old homozygotes with Mini-Mental State Examination (MMSE) ≥ 22 and Clinical Dementia Rating-Global Score 0.5 or 1.0. The study is powered to detect a 2.0 to 2.5 drug-placebo difference on the Alzheimer's Disease Assessment Scale 13-item Cognitive subscale primary outcome with 150 subjects/arm. The key secondary outcomes are Clinical Dementia Rating-Sum of Boxes and Instrumental Activities of Daily Living; volumetric magnetic resonance imaging and fluid biomarkers are additional outcomes. RESULTS: The APOLLOE4 Phase 3 trial enrolled 325 subjects with a mean age of 69 years, 51% female, MMSE 25.6, and 65% mild cognitive impairment. Topline results are expected in 2024. DISCUSSION: APOLLOE4 is the first disease-modification AD trial focused on APOE ε4/ε4 homozygotes. Oral ALZ-801 has the potential to be the first effective and safe anti-amyloid treatment for the high-risk APOE ε4/ε4 population. Highlights: The APOLLOE4 Phase 3, placebo-controlled, 78-week study is designed to evaluate the efficacy and safety of ALZ-801 265 mg twice per day in early Alzheimer's disease (AD) subjects with the apolipoprotein E (APOE) ε4/ε4 genotype.The enrolled early AD population (N = 325) has 51% females, a mean age = 69 years, and a mean Mini-Mental State Examination = 25.6, with the majority being mild cognitive impairment subjects, a similar disease stage to the lecanemab Phase 3 AD trial (Clarity AD).The primary outcome is the cognitive Alzheimer's Disease Assessment Scale 13-item Cognitive subscale, with two functional measures as key secondary outcomes (Clinical Dementia Rating-Sum of Boxes, Amsterdam-Instrumental Activities of Daily Living), and with hippocampal volume and fluid biomarkers as additional outcomes.The study is unique in allowing a large number of microhemorrhages or siderosis at baseline magnetic resonance imaging, lesions that indicate concomitant cerebral amyloid angiopathy (CAA).At baseline, 32% of the enrolled population had at least 1 microhemorrhage, 24% had 1 to 4, and 8% had > 4 microhemorrhages; 10% had at least 1 siderosis lesion; with more males than females having microhemorrhages (63% vs. 37%) and siderosis (68% vs. 32%).Study results will become available in the second half of 2024 and, if positive, ALZ-801 may become the first oral drug to demonstrate a favorable benefit/risk profile in APOE ε4/ε4 AD subjects.
RESUMEN
Current research including the basic biology of Alzheimer's disease (AD) provides a foundation to explore whether our current state of knowledge is sufficient to initiate prevention studies and allow us to believe prevention of AD is possible. Current research and recently revised criteria for the diagnosis of AD by the National Institutes on Aging and the Alzheimer's Association suggest a continuum of disease from preclinical asymptomatic to symptomatic Alzheimer's dementia. In light of these revised criteria, the possibility of secondary prevention and even primary prevention is under discussion. The Alzheimer's Association Research Roundtable convened a meeting to discuss the rationale and feasibility of conducting secondary prevention trials in AD.
Asunto(s)
Enfermedad de Alzheimer/prevención & control , Ensayos Clínicos como Asunto , Prevención Secundaria/métodos , HumanosRESUMEN
Frontotemporal degeneration (FTD) encompasses a spectrum of related neurodegenerative disorders with behavioral, language, and motor phenotypes for which there are currently no effective therapies. This is the second of two articles that summarize the presentations and discussions that occurred at two symposia in 2011 sponsored by the Frontotemporal Degeneration Treatment Study Group, a collaborative group of academic and industry researchers that is devoted to developing treatments for FTD. This article discusses the current status of FTD clinical research that is relevant to the conduct of clinical trials, and why FTD research may be an attractive pathway for developing therapies for neurodegenerative disorders. The clinical and molecular features of FTD, including rapid disease progression and relatively pure molecular pathology, suggest that there are advantages to developing drugs for FTD as compared with other dementias. FTD qualifies as orphan indication, providing additional advantages for drug development. Two recent sets of consensus diagnostic criteria will facilitate the identification of patients with FTD, and a variety of neuropsychological, functional, and behavioral scales have been shown to be sensitive to disease progression. Moreover, quantitative neuroimaging measurements demonstrate progressive brain atrophy in FTD at rates that may surpass Alzheimer's disease. Finally, the similarities between FTD and other neurodegenerative diseases with drug development efforts already underway suggest that FTD researchers will be able to draw on this experience to create a road map for FTD drug development. We conclude that FTD research has reached sufficient maturity to pursue clinical development of specific FTD therapies.
Asunto(s)
Modelos Animales de Enfermedad , Descubrimiento de Drogas , Degeneración Lobar Frontotemporal/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Animales , HumanosRESUMEN
The body of evidence suggesting a causative, initiating role of beta amyloid (Aß) 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 Aß 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 Aß 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 Aß 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 Aß oligomers without clearing amyloid plaques. The most advanced selective anti-oligomer 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 Aß42 oligomers at the clinical dose, without evidence of vasogenic edema, and will be evaluated in a phase 3 trial in homozygous APOE4/4 patients with early AD. In addition to clinical measures, the phase 3 trial will include cerebrospinal fluid, plasma, and imaging biomarkers to gain further insights into the role of soluble Aß oligomers in the pathogenesis of AD and their impact on disease progression.
Asunto(s)
Enfermedad de Alzheimer , Preparaciones Farmacéuticas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides , Anticuerpos Monoclonales Humanizados , Humanos , Taurina/análogos & derivados , Valina/análogos & derivadosRESUMEN
INTRODUCTION: Hippocampal volume (HV) and cortical thickness are commonly used imaging biomarkers in Alzheimer's disease (AD) trials, and may have utility as selection criteria for enrichment strategies. Atrophy rates of these measures, in the high-risk apolipoprotein E (APOE) ε4/ε4 homozygous AD subjects are unknown. METHODS: Data from Alzheimer's Disease Neuroimaging Initiative (ADNI-1) and a tramiprosate trial were analyzed in APOE ε4/ε4 and APOE ε3/ε3 subjects with mild cognitive impairment (MCI) or mild AD. Magnetic resonance imaging (MRI) data were centrally processed using FreeSurfer; total HV and composite average cortical thickness were derived and adjusted for age, head size, and education. Volumetric changes from baseline were assessed using Boundary Shift Integral, and correlated with cognitive changes. RESULTS: APOE ε4/ε4 MCI subjects showed significantly higher % HV atrophy and cortical thinning at 12 months (4.4%, 3.1%, n = 29) compared to APOE ε3/ε3 subjects (2.8%, 1.8%, n = 93) and similarly in mild AD (7.4%, 4.7% n = 21 vs 5.4%, 3.3% n = 29). Differences were all significant at 24 months. Over 24 months, HV atrophy and cortical thinning correlated significantly with Alzheimer's Disease Assessment Scale-Cognitive subscale worsening in APOE ε4/ε4 MCI subjects, but not in mild AD. DISCUSSION: Correlation of volumetric measures to cognitive change in APOE ε4/ε4 subjects with early AD supports their role as efficacy biomarkers. If confirmed in a Phase 3 trial with ALZ-801 (pro-drug of tramiprosate) in APOE ε4/ε4 early AD subjects, it may allow their use as surrogate outcomes in future treatment or prevention trials in AD.
RESUMEN
BACKGROUND: ALZ-801 is an oral, small-molecule inhibitor of beta amyloid (Aß) oligomer formation in clinical development for Alzheimer's disease (AD). ALZ-801 is a prodrug of tramiprosate with improved pharmacokinetic properties and gastrointestinal tolerability. During clinical studies, we discovered that the primary metabolite of tramiprosate and its prodrug ALZ-801, 3-sulfopropanoic acid (3-SPA), is an endogenous molecule in the human brain and present in the cerebrospinal fluid (CSF) of patients with AD and other neurodegenerative brain diseases. OBJECTIVE: The objectives of this research were to (1) identify and confirm the presence of 3-SPA in CSF samples from elderly, drug-naïve patients with memory deficits; (2) quantify the levels of 3-SPA in the CSF of patients with AD from tramiprosate phase III North American (NA) trial; (3) evaluate the in vitro anti-Aß42 oligomer activity of 3-SPA; and (4) characterize the pharmacokinetics and brain-penetration properties of 3-SPA. METHODS: Lumbar CSF samples from 64 drug-naïve patients with cognitive deficits (Mini-Mental State Examination [MMSE] score range 15-30) and six patients with AD treated with tramiprosate 150 mg twice daily in the phase III trial, at week 78, were analyzed. We used liquid chromatography-tandem mass spectrometry to confirm the structural molecular identity of endogenous 3-SPA with a 3-SPA reference standard and ion-mobility spectrometry-mass spectrometry with molecular dynamics to characterize interactions of 3-SPA with Aß42 monomers, and the resultant conformational alterations. Rat studies using oral (30 mg/kg) and intravenous (10 mg/kg) doses were conducted to characterize the pharmacokinetic properties and brain penetration of 3-SPA. RESULTS: We confirmed the presence of 3-SPA in the CSF of drug-naïve patients with cognitive deficits (mean concentration 11.7 ± 4.3 nM). The mean concentration of 3-SPA in patients with AD treated with tramiprosate was 135 ± 51 nM. In vitro studies revealed a multi-ligand interaction of 3-SPA with monomeric Aß42 that inhibits the aggregation of Aß42 into small oligomers. Comparisons of the molecular interactions of tramiprosate and 3-SPA with Aß42 are also presented. Furthermore, in rat preclinical studies, 3-SPA displayed 100% oral bioavailability and 25% brain penetration, indicating that the metabolite is well absorbed and crosses the blood-brain barrier. CONCLUSIONS: We confirmed the endogenous presence of 3-SPA, the major metabolite of tramiprosate, in the CSF of drug-naïve elderly patients with memory deficits due to AD and a variety of other neurodegenerative disorders. The levels of 3-SPA were up to 12.6-fold greater in patients with AD receiving tramiprosate than in drug-naïve patients. In addition, we showed that 3-SPA has potent anti-Aß oligomer activity, inhibiting aggregation of Aß42 into small oligomers with efficacy comparable to that of tramiprosate. 3-SPA displays excellent oral availability and brain penetration in rats, suggesting that the higher CSF concentrations of 3-SPA in the human brain after oral administration of ALZ-801 or tramiprosate (and subsequent conversion to 3-SPA) result from the penetration of the metabolite into the central nervous system. These data suggest that 3-SPA is an endogenous agent with potential activity stabilizing the conformational flexibility of Aß monomers that, in turn, inhibit Aß misfolding and formation of soluble toxic Aß oligomers in humans, thereby preventing the initial pathogenic step in the progression of AD. Clinical improvements observed in patients with AD carrying the ε4 allele of the apolipoprotein E gene in tramiprosate phase III studies may in part be explained by the therapeutic effects of excess levels of the metabolite in the brains of these patients. The potential protective role of 3-SPA in AD pathogenesis, as well as its therapeutic role in AD and other neurodegenerative disorders, warrants further investigation.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Fragmentos de Péptidos/metabolismo , Taurina/análogos & derivados , Valina/análogos & derivados , Anciano , Enfermedad de Alzheimer/complicaciones , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Cromatografía Liquida , Trastornos del Conocimiento/líquido cefalorraquídeo , Trastornos del Conocimiento/etiología , Simulación por Computador , Vías de Administración de Medicamentos , Femenino , Humanos , Masculino , Escala del Estado Mental , Persona de Mediana Edad , Modelos Químicos , Dinámicas no Lineales , Profármacos/química , Profármacos/uso terapéutico , Propionatos/líquido cefalorraquídeo , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem , Taurina/líquido cefalorraquídeo , Taurina/química , Taurina/uso terapéutico , Valina/química , Valina/uso terapéuticoRESUMEN
BACKGROUND: Botulinum neurotoxins, which are widely used commercially for therapeutic and cosmetic applications, have historically belonged to serotypes A and B. Serotype E has a distinct profile with a faster onset and shorter duration of effect. EB-001 is a proprietary formulation of serotype E in development for aesthetic (cosmetic) and therapeutic uses. METHODS: This first-in-human, randomized, double-blinded, placebo-controlled, ascending-dose cohort study enrolled 42 subjects who received EB-001 (n = 35) or placebo (n = 7). The efficacy primary outcome was the proportion of subjects with a two-grade investigator-rated improvement in glabellar frown line severity at maximum frown. Safety evaluations included adverse events, laboratory tests, and physical examinations. RESULTS: A two-grade investigator-rated response was observed starting in the third cohort (EB-001), with increased rates observed at higher doses. Onset of clinical effect was within 24 hours, with a duration ranging between 14 and 30 days for the highest doses. Adverse event incidence was low, with the most common being mild to moderate headache. There were no serious adverse events or ptosis, and there were no clinically significant changes in other safety assessments. CONCLUSIONS: In this clinical study in glabellar frown lines, EB-001 showed favorable safety, tolerability, and dose-dependent efficacy, with an 80 percent response rate at the highest dose. The maximum clinical effect of EB-001 was seen within 24 hours and lasted between 14 and 30 days. This differentiated EB-001 profile supports its development for aesthetic and therapeutic applications where fast onset and short duration of effect are desirable. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.
Asunto(s)
Toxinas Botulínicas/administración & dosificación , Frente , Fármacos Neuromusculares/administración & dosificación , Envejecimiento de la Piel/efectos de los fármacos , Adolescente , Adulto , Toxinas Botulínicas/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Persona de Mediana Edad , Fármacos Neuromusculares/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Page 856: Fig. 6 was an incorrect duplication of Fig. 5. The correct figure is given below.
RESUMEN
BACKGROUND: ALZ-801 is an orally available, valine-conjugated prodrug of tramiprosate. Tramiprosate, the active agent, is a small-molecule ß-amyloid (Aß) anti-oligomer and aggregation inhibitor that was evaluated extensively in preclinical and clinical investigations for the treatment of Alzheimer's disease (AD). Tramiprosate has been found to inhibit ß-amyloid oligomer formation by a multi-ligand enveloping mechanism of action that stabilizes Aß42 monomers, resulting in the inhibition of formation of oligomers and subsequent aggregation. Although promising as an AD treatment, tramiprosate exhibited two limiting deficiencies: high intersubject pharmacokinetic (PK) variability likely due to extensive gastrointestinal metabolism, and mild-to-moderate incidence of nausea and vomiting. To address these, we developed an optimized prodrug, ALZ-801, which retains the favorable efficacy attributes of tramiprosate while improving oral PK variability and gastrointestinal tolerability. In this study, we summarize the phase I bridging program to evaluate the safety, tolerability and PK for ALZ-801 after single and multiple rising dose administration in healthy volunteers. METHODS: Randomized, placebo-controlled, phase I studies in 127 healthy male and female adult and elderly volunteers included [1] a single ascending dose (SAD) study; [2] a 14-day multiple ascending dose (MAD) study; and [3] a single-dose tablet food-effect study. This program was conducted with both a loose-filled capsule and an immediate-release tablet formulation, under both fasted and fed conditions. Safety and tolerability were assessed, and plasma and urine were collected for liquid chromatography-mass spectrometry (LC-MS) determination and non-compartmental PK analysis. In addition, we defined the target dose of ALZ-801 that delivers a steady-state plasma area under the curve (AUC) exposure of tramiprosate equivalent to that studied in the tramiprosate phase III study. RESULTS: ALZ-801 was well tolerated and there were no severe or serious adverse events (AEs) or laboratory findings. The most common AEs were transient mild nausea and some instances of vomiting, which were not dose-related and showed development of tolerance after continued use. ALZ-801 produced dose-dependent maximum plasma concentration (C max) and AUC exposures of tramiprosate, which were equivalent to that after oral tramiprosate, but with a substantially reduced intersubject variability and a longer elimination half-life. Administration of ALZ-801 with food markedly reduced the incidence of gastrointestinal symptoms compared with the fasted state, without affecting plasma tramiprosate exposure. An immediate-release tablet formulation of ALZ-801 displayed plasma exposure and low variability similar to the loose-filled capsule. ALZ-801 also showed excellent dose-proportionality without accumulation or decrease in plasma exposure of tramiprosate over 14 days. Based on these data, 265 mg of ALZ-801 twice daily was found to achieve a steady-state AUC exposure of tramiprosate equivalent to 150 mg twice daily of oral tramiprosate in the previous phase III trials. CONCLUSIONS: ALZ-801, when administered in capsule and tablet forms, showed excellent oral safety and tolerability in healthy adults and elderly volunteers, with significantly improved PK characteristics over oral tramiprosate. A clinical dose of ALZ-801 (265 mg twice daily) was established that achieves the AUC exposure of 150 mg of tramiprosate twice daily, which showed positive cognitive and functional improvements in apolipoprotein E4/4 homozygous AD patients. These bridging data support the phase III development of ALZ-801in patients with AD.
Asunto(s)
Profármacos/efectos adversos , Profármacos/farmacocinética , Taurina/análogos & derivados , Valina/análogos & derivados , Administración Oral , Adulto , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Área Bajo la Curva , Cápsulas , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Profármacos/administración & dosificación , Comprimidos , Taurina/administración & dosificación , Taurina/efectos adversos , Taurina/farmacocinética , Valina/administración & dosificación , Valina/efectos adversos , Valina/farmacocinética , Adulto JovenRESUMEN
BACKGROUND: ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer's disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. OBJECTIVE: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2â:â1:1 ratio to receive ELND005 at either 250âmg twice daily (BID) or 250âmg once daily (QD) or matching placebo for 4 weeks. RESULTS: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. CONCLUSION: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.
Asunto(s)
Síndrome de Down/tratamiento farmacológico , Inositol/administración & dosificación , Administración Oral , Adolescente , Adulto , Trastornos del Conocimiento/etiología , Método Doble Ciego , Síndrome de Down/complicaciones , Síndrome de Down/diagnóstico por imagen , Electrocardiografía , Femenino , Humanos , Inositol/farmacocinética , Imagen por Resonancia Magnética , Masculino , Trastornos Mentales/etiología , Estudios Prospectivos , Escalas de Valoración Psiquiátrica , Resultado del Tratamiento , Adulto JovenRESUMEN
ELND005 (scyllo-inositol), an endogenous inositol stereoisomer, is being investigated as an oral treatment for Alzheimer's disease (AD). Pharmacokinetics of ELND005 in plasma, cerebrospinal fluid (CSF), and brain was characterized in healthy young subjects. Eight men received 2000 mg ELND005 every 12 hours for 10 days. Plasma and CSF samples were collected at predetermined time points; ELND005 and amyloid-beta (Aß) fragments were measured by validated bioanalytical methods. Brain ELND005 levels, estimated by (1) H Magnetic Resonance Spectroscopy (MRS) scans were obtained from gray/white matter voxels at baseline and Day 8. ELND005 was well-tolerated during the study. During the apparent steady state, ELND005 plasma levels rapidly peaked at 39.8 µg/mL and decreased to an average trough concentration of 10.6 µg/mL at the end of the 12-hour dosing regimen. In contrast, CSF drug levels slowly peaked at 13.7 µg/mL and remained near the same level with average trough concentrations of 12.4 µg/mL. At Day 8, Brain ELND005 concentrations increased by 58-76% compared to baseline levels. The CSF concentrations achieved in this study were similar to those associated with efficacy in transgenic models of AD. No changes were detected in plasma and CSF levels of Aß fragments.