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INTRODUCTION: The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aß) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aß, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. METHODS: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aß 42/40 ratio (Aß 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. RESULT: The focus of this article is on the innovative design of the study. DISCUSSION: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.
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Doença de Alzheimer , Disfunção Cognitiva , Tauopatias , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Austrália , Tauopatias/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons , Disfunção Cognitiva/metabolismo , Biomarcadores/metabolismo , Proteínas tau/metabolismoRESUMO
INTRODUCTION: Individuals living in rural communities are at heightened risk for Alzheimer's disease and related dementias (ADRD), which parallels other persistent place-based health disparities. Identifying multiple potentially modifiable risk factors specific to rural areas that contribute to ADRD is an essential first step in understanding the complex interplay between various barriers and facilitators. METHODS: An interdisciplinary, international group of ADRD researchers convened to address the overarching question of: "What can be done to begin minimizing the rural health disparities that contribute uniquely to ADRD?" In this state of the science appraisal, we explore what is known about the biological, behavioral, sociocultural, and environmental influences on ADRD disparities in rural settings. RESULTS: A range of individual, interpersonal, and community factors were identified, including strengths of rural residents in facilitating healthy aging lifestyle interventions. DISCUSSION: A location dynamics model and ADRD-focused future directions are offered for guiding rural practitioners, researchers, and policymakers in mitigating rural disparities. HIGHLIGHTS: Rural residents face heightened Alzheimer's disease and related dementia (ADRD) risks and burdens due to health disparities. Defining the unique rural barriers and facilitators to cognitive health yields insight. The strengths and resilience of rural residents can mitigate ADRD-related challenges. A novel "location dynamics" model guides assessment of rural-specific ADRD issues.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/epidemiologia , População Rural , Saúde da População Rural , Fatores de RiscoRESUMO
Between 2018 and 2019, multiple clinical trials ended earlier than planned, resulting in calls to improve communication with and support for participants and their study partners ("dyads"). The multidisciplinary Participant Follow-Up Improvement in Research Studies and Trials (Participant FIRST) Work Group met throughout 2021. Its goals were to identify best practices for communicating with and supporting dyads affected by early trial stoppage. The Participant FIRST Work Group identified 17 key recommendations spanning the pre-trial, mid-trial, and post-trial periods. These focus on prospectively allocating sufficient resources for orderly closeout; developing dyad-centered communication plans; helping dyads build and maintain support networks; and, if a trial stops, informing dyads rapidly. Participants and study partners invest time, effort, and hope in their research participation. The research community should take intentional steps toward better communicating with and supporting participants when clinical trials end early. The Participant FIRST recommendations are a practical guide for embarking on that journey.
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Comunicação , HumanosRESUMO
OBJECTIVES: The German-speaking Myeloma Multicenter Group (GMMG) conducted this trial to investigate efficacy and safety of the three-drug combination bendamustine/prednisone/bortezomib (BPV) as first-line therapy for elderly patients with multiple myeloma (MM). METHODS: Elderly MM patients requiring first-line therapy and not eligible for intensive treatment were enrolled in this phase IIb multicenter study. Patients were treated with BPV regimen for a maximum of nine cycles. RESULTS: Forty-six patients were included in the trial with a median age of 76 years. Nineteen patients had renal impairment at baseline. The ORR was 78.8% for patients treated with 3 and more BPV cycles and 71.1% for all evaluable patients. The median progression-free survival was 25 months, and overall survival at 24 months was 83.3%. The clinical benefit rate including MR was 91.2%. In patients with renal impairment at baseline, a renal response was observed in 11 pts. with complete recovery of the renal function in six patients. The most frequent CTC grade 3/4 AEs experienced by patients were hematological (17.5%) and infectious (9.8%) complications. No new safety signals were observed for the study drugs under investigation. CONCLUSIONS: Bendamustine/prednisone/bortezomib may serve as a first-line regimen for transplant-ineligible elderly MM patients in particular for patients with renal impairment requiring a fast and durable renal response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Biomarcadores Tumorais , Bortezomib/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Prednisona/administração & dosagem , Prognóstico , Intervalo Livre de Progressão , Insuficiência Renal/diagnóstico , Insuficiência Renal/etiologia , Resultado do TratamentoRESUMO
Objective The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model. Methods Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured. Results BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect. Interpretation These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.
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Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Transtornos da Cefaleia Secundários/metabolismo , Transtornos da Cefaleia Secundários/prevenção & controle , Doadores de Óxido Nítrico/toxicidade , Estresse Psicológico/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos da Cefaleia Secundários/etiologia , Hiperalgesia/metabolismo , Masculino , Estimulação Luminosa/efeitos adversos , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/complicações , Sumatriptana/toxicidadeRESUMO
AMG 416 (etelcalcetide) is a novel synthetic peptide agonist of the calcium-sensing receptor composed of a linear chain of seven d-amino acids (referred to as the d-amino acid backbone) with a d-cysteine linked to an l-cysteine via a disulfide bond. AMG 416 contains four basic d-arginine residues and is a +4 charged peptide at physiologic pH with a mol. wt. of 1048.3 Da. The pharmacokinetics (PK), disposition, and potential of AMG 416 to cause drug-drug interaction were investigated in nonclinical studies with two single (14)C-labels placed either at a potentially metabolically labile acetyl position or on the d-alanine next to d-cysteine in the interior of the d-amino acid backbone. After i.v. dosing, the PK and disposition of AMG 416 were similar in male and female rats. Radioactivity rapidly distributed to most tissues in rats with intact kidneys, and renal elimination was the predominant clearance pathway. No strain-dependent differences were observed. In bilaterally nephrectomized rats, minimal radioactivity (1.2%) was excreted via nonrenal pathways. Biotransformation occurred primarily via disulfide exchange with endogenous thiol-containing molecules in whole blood rather than metabolism by enzymes, such as proteases or cytochrome P450s; the d-amino acid backbone remained unaltered. A substantial proportion of the plasma radioactivity was covalently conjugated to albumin. AMG 416 presents a low risk for P450 or transporter-mediated drug-drug interactions because it showed no interactions in vitro. These studies demonstrated a (14)C label on either the acetyl or the d-alanine in the d-amino acid backbone would be appropriate for clinical studies.
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Calcimiméticos/farmacocinética , Peptídeos/farmacocinética , Receptores de Detecção de Cálcio/agonistas , Administração Intravenosa , Animais , Biotransformação , Calcimiméticos/administração & dosagem , Calcimiméticos/sangue , Calcimiméticos/toxicidade , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Interações Medicamentosas , Feminino , Células HEK293 , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Estrutura Molecular , Peptídeos/administração & dosagem , Peptídeos/sangue , Peptídeos/toxicidade , Ligação Proteica , Ratos Endogâmicos BN , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismo , Eliminação Renal , Medição de Risco , Albumina Sérica/metabolismo , Relação Estrutura-Atividade , Distribuição Tecidual , TransfecçãoRESUMO
Etelcalcetide is a novel d-amino acid peptide that functions as an allosteric activator of the calcium-sensing receptor and is being developed as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on hemodialysis. To support clinical development and marketing authorization, a comprehensive nonclinical safety package was generated. Primary adverse effects included hypocalcemia, tremoring, and convulsions. Other adverse effects were considered sequelae of stress associated with hypocalcemia. Cardiovascular safety evaluations in the dog revealed an anticipated prolongation of the corrected QT interval that was related to reductions in serum calcium. Etelcalcetide did not affect the human ether-a-go-go gene ion channel current. Etelcalcetide was mutagenic in some strains of Salmonella, however, based on the negative results in 2 in vitro and 2 in vivo mammalian genotoxicity assays, including a 28-day Muta mouse study, etelcalcetide is considered nongenotoxic. Further support for a lack of genotoxicity was provided due to the fact that etelcalcetide was not carcinogenic in a 6-month transgenic rasH2 mouse model or a 2-year study in rats. There were no effects on fertility, embryo-fetal development, and prenatal and postnatal development. All of the adverse effects observed in both rat and dog were considered directly or secondarily related to the pharmacologic activity of etelcalcetide and the expected sequelae associated with dose-related reductions in serum calcium due to suppression of parathyroid hormone secretion. These nonclinical data indicate no safety signal of concern for human risk beyond that associated with hypocalcemia and associated QT prolongation.
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Peptídeos/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Cálcio/sangue , Cães , Canal de Potássio ERG1/fisiologia , Feminino , Células HEK293 , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hiperparatireoidismo Secundário/tratamento farmacológico , Hipocalcemia/induzido quimicamente , Masculino , Camundongos Transgênicos , Testes de Mutagenicidade , Peptídeos/farmacocinética , Peptídeos/farmacologia , Peptídeos/uso terapêutico , Coelhos , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos , Convulsões/induzido quimicamente , Tremor/induzido quimicamenteRESUMO
AMG 416 is a novel D-amino acid-containing peptide agonist of the calcium-sensing receptor (CaSR) that is being evaluated for the treatment of secondary hyperparathyroidism in chronic kidney disease patients receiving hemodialysis. The principal amino acid residues and their location in the CaSR that accommodate AMG 416 binding and mode of action have not previously been reported. Herein we establish the importance of a pair of cysteine residues, one from AMG 416 and the other from the CaSR at position 482 (Cys482), and correlate the degree of disulfide bond formation between these residues with the pharmacological activity of AMG 416. KP-2067, a form of the CaSR agonist peptide, was included to establish the role of cysteine in vivo and in disulfide exchange. Studies conducted with AMG 416 in pigs showed a complete lack of pharmacodynamic effect and provided a foundation for determining the peptide agonist interaction site within the human CaSR. Inactivity of AMG 416 on the pig CaSR resulted from a naturally occurring mutation encoding tyrosine for cysteine (Cys) at position 482 in the pig CaSR. Replacing Cys482 in the human CaSR with serine or tyrosine ablated AMG 416 activity. Decidedly, a single substitution of cysteine for tyrosine at position 482 in the native pig CaSR provided a complete gain of activity by the peptide agonist. Direct evidence for this disulfide bond formation between the peptide and receptor was demonstrated using a mass spectrometry assay. The extent of disulfide bond formation was found to correlate with the extent of receptor activation. Notwithstanding the covalent basis of this disulfide bond, the observed in vivo pharmacology of AMG 416 showed readily reversible pharmacodynamics.
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Peptídeos/farmacologia , Receptores de Detecção de Cálcio/agonistas , Regulação Alostérica , Animais , Cisteína , Dissulfetos/química , Cães , Células HEK293 , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Detecção de Cálcio/química , Relação Estrutura-Atividade , Suínos , Porco MiniaturaRESUMO
CGRP is an extensively studied neuropeptide that has been implicated in the pathophysiology of migraine. While a number of small molecule antagonists against the CGRP receptor have demonstrated that targeting this pathway is a valid and effective way of treating migraine, off-target hepatoxicity and formulation issues have hampered the development for regulatory approval of any therapeutic in this class. The development of monoclonal antibodies to CGRP or its receptor as therapeutic agents has allowed this pathway to be re-investigated. Herein we review why CGRP is an ideal target for the prevention of migraine and describe four monoclonal antibodies against either CGRP or its receptor that are in clinical development for the treatment of both episodic and chronic migraine. We describe what has been publically disclosed about their clinical trials and future clinical development plans.
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Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/tratamento farmacológico , Animais , Anticorpos Monoclonais/efeitos adversos , Peptídeo Relacionado com Gene de Calcitonina/imunologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Descoberta de Drogas , Humanos , Transtornos de Enxaqueca/imunologia , Transtornos de Enxaqueca/metabolismo , Terapia de Alvo Molecular , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/imunologia , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do TratamentoRESUMO
Calcitonin gene-related peptide (CGRP) is a 37-amino-acid neuropeptide whose involvement in migraine pathophysiology is well established. Originally migraine was believed to be a disease of the vasculature, but research has highlighted this to be a disease of the brain with CGRP playing an important role. While targeting CGRP using small molecule antagonists against the receptor has been effective, long-term use of these agents has not been possible due to safety concerns and/or formulation challenges. Recent advances in therapeutic antibodies have opened up new possibilities for treatment of migraine. TEV-48125 is one of four monoclonal antibodies targeting CGRP or its receptors, currently in development for the preventive treatment of migraine. This article discusses the in vitro and in vivo pharmacology of TEV-48125 as well as highlighting its safety profile through the six Phase 1 studies that have been conducted. Finally, the current state of development and future studies for TEV-48125 will be reviewed.
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Analgésicos/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/prevenção & controle , Analgésicos/farmacologia , Anticorpos Monoclonais/farmacologia , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Humanos , Transtornos de Enxaqueca/tratamento farmacológicoRESUMO
Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.
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Variação Genética , Diester Fosfórico Hidrolases/genética , Adolescente , Adulto , Idoso , Encéfalo/patologia , Mapeamento Encefálico/métodos , Estudos de Coortes , Diagnóstico por Imagem/métodos , Feminino , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Saccharomyces cerevisiae/metabolismo , Córtex Visual/anatomia & histologia , Córtex Visual/patologiaRESUMO
BACKGROUND: The vascular effects of acute calcitonin gene-related peptide (CGRP) inhibition are well described, but the effects of sustained inhibition warrant further exploration in humans. OBJECTIVES: The objective of this article is to assess the effects of sustained CGRP inhibition on blood pressure, heart rate, and ECGs in healthy women ≥ 40 years of age. METHODS: In this double-blind, placebo-controlled study, 31 women (mean age = 56) were randomized to receive placebo or an anti-CGRP monoclonal antibody at doses up to 2000 mg. Participants were confined for seven days and followed for 168 days. Cardiac telemetry was conducted for eight hours after infusion completion. Hemodynamic assessments and ECGs were conducted six times during Day 1 and periodically for three months. RESULTS: No clinically relevant changes in systolic or diastolic blood pressure, heart rate, or ECG parameters (RR, PR, QRS, or QTcF) were observed when comparing baseline vs. post-dose time-points or in-between groups. No significant changes were seen for adjusted QTcF (baseline subtracted and placebo and baseline subtracted). No significant differences or relevant abnormalities were seen when comparing parameters obtained at Tmax vs. any other time-point. CONCLUSION: Sustained CGRP inhibition was not associated with hemodynamic or ECG changes in a population at an increased age risk for cardiovascular events.
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Anticorpos Monoclonais/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Adulto , Idoso , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: LBR-101 is a fully humanized monoclonal antibody that binds to calcitonin gene-related peptide. OBJECTIVE: The objective of this article is to characterize the safety and tolerability of LBR-101 when administered intravenously to healthy volunteers, by presenting the pooled results of the Phase 1 program. METHODS: LBR-101 was administered to 94 subjects, while 45 received placebo. Doses ranged from 0.2 mg to 2000 mg given once (Day 1), as a single IV infusion, or up to 300 mg given twice (Day 1 and Day 14). RESULTS: Subjects receiving placebo reported an average of 1.3 treatment-emerging adverse events vs 1.4 per subject among those receiving any dose of LBR-101, and 1.6 in those receiving 1000 mg or higher. Treatment-related adverse events occurred in 21.2% of subjects receiving LBR-101, compared to 17.7% in those receiving placebo. LBR-101 was not associated with any clinically relevant patterns of change in vital signs, ECG parameters, or laboratory findings. The only serious adverse event consisted of "thoracic aortic aneurysm" in a participant later found to have an unreported history of Ehlers-Danlos syndrome. CONCLUSION: Single IV doses of LBR-101 ranging from 0.2 mg up to 2000 mg and multiple IV doses up to 300 mg were well tolerated. Overt safety concerns have not emerged. A maximally tolerated dose has not been identified.
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Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Adolescente , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos , Idoso , Aneurisma da Aorta Torácica/induzido quimicamente , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Síndrome de Ehlers-Danlos/complicações , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: AMG 416 is a novel peptide agonist of the calcium-sensing receptor (CaSR). This report describes the activity of AMG 416 in two different rodent models of uremia, compared in each case to cinacalcet, an approved therapeutic for secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease on dialysis. METHODS: AMG 416 was administered as a single intravenous (IV) bolus in a severe, acute model of renal insufficiency (the "1K1C" model) and plasma parathyroid hormone (PTH) and serum calcium levels were monitored for 24 hours. In a chronic, less severe model of renal dysfunction, the 5/6 nephrectomy (5/6 Nx) model, AMG 416 was administered as a once-daily IV bolus for 28 days. Both studies included a control (vehicle) group and a comparison cinacalcet group (po dosing at 30 mg/kg and 10 mg/kg for the 1K1C and 5/6 Nx studies, respectively). RESULTS: Administration of AMG 416 by IV bolus injection into rats with acute renal dysfunction (1K1C model) resulted in a sustained reduction in plasma PTH from the initial elevated values. Following a single IV bolus (0.5 mg/kg), AMG 416 caused a substantial drop in PTH levels which remained approximately 50% below their initial level at 24 hrs. In the same model, oral treatment with cinacalcet (30 mg/kg) resulted in an acute drop in PTH which almost returned to the starting level by 24 hours after dosing. In the 5/6 Nx chronic uremia model, daily IV dosing of AMG 416 over 4 weeks (1 mg/kg) resulted in a sustained reduction in PTH, with approximately 50% of the initial level observed 48 hours post treatment throughout the study. Cinacalcet treatment (10 mg/kg) in the same model resulted in acutely lowered plasma PTH levels which returned to placebo levels by 24 hours post-dose. Consistent with the reductions in plasma PTH, reductions in serum calcium were observed in both AMG 416- and cinacalcet-treated animals. CONCLUSIONS: As a long-acting CaSR agonist suitable for administration by the IV route, AMG 416 is a potential new therapy for the treatment of CKD patients with SHPT receiving hemodialysis.
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Calcimiméticos/administração & dosagem , Modelos Animais de Doenças , Naftalenos/administração & dosagem , Peptídeos/administração & dosagem , Receptores de Detecção de Cálcio/agonistas , Uremia/tratamento farmacológico , Animais , Cinacalcete , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Resultado do Tratamento , Uremia/fisiopatologiaRESUMO
A novel peptide, AMG 416 (formerly KAI-4169, and with a United States Adopted Name: velcalcetide), has been identified that acts as an agonist of the calcium-sensing receptor (CaSR). This article summarizes the in vitro and in vivo characterization of AMG 416 activity and the potential clinical utility of this novel compound. AMG 416 activates the human CaSR in vitro, acting by a mechanism distinct from that of cinacalcet, the only approved calcimimetic, since it can activate the CaSR both in the presence or the absence of physiologic levels of extracellular calcium. Administration of AMG 416 in vivo into either normal or renally compromised rats results in dose-dependent reductions in parathyroid hormone (PTH) levels and corresponding decreases in serum calcium, regardless of the baseline level of PTH. Treatment of 5/6 nephrectomized rats with AMG 416 resulted in dramatic improvements in their metabolic profile, including lower PTH and serum creatinine levels, reduced amounts of vascular calcification, attenuated parathyroid hyperplasia, and greater expression of the parathyroid gland regulators CaSR, vitamin D receptor, and FGF23 receptor compared with vehicle-treated animals. No drug accumulation was observed under this dosing regimen, and the terminal half-life of AMG 416 was estimated to be 2-4.5 hours. As a long-acting CaSR agonist, AMG 416 is an innovative new therapy for the treatment of hemodialysis patients with secondary hyperparathyroidism.
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Hiperparatireoidismo Secundário/tratamento farmacológico , Peptídeos/uso terapêutico , Receptores de Detecção de Cálcio/agonistas , Animais , Feminino , Fator de Crescimento de Fibroblastos 23 , Células HEK293 , Humanos , Hiperparatireoidismo Secundário/etiologia , Hiperparatireoidismo Secundário/metabolismo , Rim/fisiopatologia , Masculino , Nefrectomia , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/sangue , Peptídeos/farmacocinética , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Diálise Renal/efeitos adversos , Distribuição Tecidual , Uremia/tratamento farmacológico , Uremia/etiologiaRESUMO
Calcitonin gene-related peptide (CGRP) is a ubiquitous neuropeptide found at the very centers of the migraine process, both centrally and peripherally. It has been under careful study for approximately 25 years. Several CGRP-receptor antagonists are being evaluated for acute treatment of episodic migraine. Three monoclonal antibodies are being studied for prevention of episodic migraine, and 1 monoclonal antibody is being studied for prevention of chronic migraine. In this review, we discuss the role of CGRP in normal physiology and the consequences of CGRP inhibition for human homeostasis. We then review the current state of development for CGRP-receptor antagonists and CGRP monoclonal antibodies. We close by speculating on the potential clinical role of CGRP antagonism in the acute and preventive treatment of episodic and chronic migraine.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Compreensão , Transtornos de Enxaqueca/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Ensaios Clínicos como Assunto/tendências , Humanos , Transtornos de Enxaqueca/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismoRESUMO
Slowing the progression of Alzheimer disease (AD) might be the greatest unmet medical need of our time. Although one AD therapeutic has received a controversial accelerated approval from the FDA, more effective and accessible therapies are urgently needed. Consensus is growing that for meaningful disease modification in AD, therapeutic intervention must be initiated at very early (preclinical or prodromal) stages of the disease. Although the methods for such early-stage clinical trials have been developed, identification and recruitment of the required asymptomatic or minimally symptomatic study participants takes many years and requires substantial funds. As an example, in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Trial (the first phase III trial to be performed in preclinical AD), 3.5 years and more than 5,900 screens were required to recruit and randomize 1,169 participants. A new clinical trials infrastructure is required to increase the efficiency of recruitment and accelerate therapeutic progress. Collaborations in North America, Europe and Asia are now addressing this need by establishing trial-ready cohorts of individuals with preclinical and prodromal AD. These collaborations are employing innovative methods to engage the target population, assess risk of brain amyloid accumulation, select participants for biomarker studies and determine eligibility for trials. In the future, these programmes could provide effective tools for pursuing the primary prevention of AD. Here, we review the lessons learned from the AD trial-ready cohorts that have been established to date, with the aim of informing ongoing and future efforts towards efficient, cost-effective trial recruitment.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/terapia , Biomarcadores , Encéfalo , Humanos , Estudos Longitudinais , Sintomas ProdrômicosRESUMO
BACKGROUND: Study participants, patients, and care partners are key stakeholders in research and have asked for greater inclusion in the dissemination of scientific learning. However, the participation of general audiences in scientific conferences dedicated to Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) is not widely supported or studied. OBJECTIVE: Our objectives were to evaluate the interest, level of engagement, and impact of including general audiences in a virtual dementia conference. METHODS: A diverse group of lay participants, identified via community-based health advocacy groups and research centers, were invited to attend the 2021 Alzheimer's Association International Conference (AAIC), with optional small-group discussions. Participants received complimentary access to all scientific sessions and were supported via navigation tips, recommended sessions, and a glossary of frequently used terms and acronyms. RESULTS: Lay participants demonstrated a high level of engagement, even among those that were research-naïve, attending virtual sessions for an average of 11.7 hours across the five days and recommending a variety of sessions to each other on topics extending from prevention of dementia to new therapies and care. Most participants said they would attend the conference again and rated the quality of interaction as high, while requesting more opportunities to engage directly with researchers. CONCLUSION: General audiences, in particular research participants, are advocating for greater participation in scientific conferences. This program can serve as a model to accomplish inclusion; thereby acknowledging their invaluable contribution to science.