RESUMO
OBJECTIVE: This study tested whether galcanezumab, a humanized monoclonal antibody with efficacy against migraine, was superior to placebo for the treatment of mild or moderate osteoarthritis (OA) knee pain. METHOD: In a multicenter, double-blind, placebo- and celecoxib-controlled trial, patients with moderate to severe OA pain were randomized to placebo; celecoxib 200 mg daily for 16 weeks; or galcanezumab 5, 50, 120, and 300 mg subcutaneously every 4 weeks, twice. The primary outcome was change from baseline at Week 8 in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscore measured by 100 mm visual analog scale (VAS). The trial was considered positive if ≥1 dose of galcanezumab demonstrated ≥95% Bayesian posterior probability of superiority to placebo and ≥50% posterior probability of superiority to placebo by ≥9 mm. A planned interim analysis allowed termination of the study if posterior probability of superiority to placebo by ≥9 mm was ≤5%. Secondary endpoints included WOMAC function subscore and Patient Global Assessment (PGA) of OA. Safety and tolerability were also assessed. RESULTS: The study was terminated after interim analysis suggested inadequate efficacy. Celecoxib significantly reduced WOMAC pain subscore compared with placebo [-12.0 mm; 95% confidence interval (CI) -23 to -2 mm]. None of the galcanezumab arms demonstrated clinically meaningful improvement (range: 1.5 to -5.0 mm) or met the prespecified success criteria. No improvement in any secondary objective was observed. Galcanezumab was well tolerated by OA patients. CONCLUSIONS: This study failed to demonstrate sufficient statistical evidence that galcanezumab was efficacious for treating OA knee pain. STUDY IDENTIFICATION: NCT02192190.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Osteoartrite do Joelho/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Celecoxib/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/complicações , Dor/tratamento farmacológico , Dor/etiologia , Manejo da Dor/métodos , Medição da Dor/métodos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
AIM: To describe the clinical effects of single and multiple doses of a potent, selective, orally administered, small-molecule antagonist of the human glucagon receptor, LY2409021, in healthy subjects and in patients with type 2 diabetes. METHODS: LY2409021 was administered in dose-escalation studies to healthy subjects (n = 23) and patients with type 2 diabetes (n = 9) as single doses (Study 1) and daily to patients with type 2 diabetes (n = 47) for 28 days (Study 2). Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were made after single doses and in patients receiving once-daily doses of LY2409021 (5, 30, 60 or 90 mg) for 28 days. RESULTS: LY2409021 was well tolerated at all dose levels in both studies. Fasting and postprandial glucose were reduced and glucagon levels increased after single and multiple dosing, with reductions in fasting serum glucose of up to â¼1.25 mmol/l on day 28. Serum aminotransferases increased in a dose-dependent manner with multiple dosing and reversed after cessation of dosing. Significant glucose-lowering was observed with LY2409021 at dose levels associated with only minor aminotransferase increases. CONCLUSION: Blockade of glucagon signalling in patients with type 2 diabetes is well tolerated and results in substantial reduction of fasting and postprandial glucose with minimal hypoglycaemia, but with reversible increases in aminotransferases. Inhibition of glucagon signalling by LY2409021 is a promising potential treatment for patients with type 2 diabetes and should be evaluated in longer clinical trials to better evaluate benefits and risks.
Assuntos
Compostos de Bifenilo/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Terapia de Alvo Molecular , Receptores de Glucagon/antagonistas & inibidores , Adulto , Idoso , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/sangue , Compostos de Bifenilo/farmacocinética , Estudos de Coortes , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Glucagon/agonistas , Glucagon/sangue , Glucagon/metabolismo , Hemoglobinas Glicadas/análise , Meia-Vida , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/efeitos adversos , Risco , Método Simples-CegoRESUMO
The objectives of this study were to characterize the pharmacokinetics (PK) of LY2510924, a potent peptide antagonist of the CXCR4 receptor, after subcutaneous administration in patients with advanced cancer forms and quantify LY2510924 stimulatory effects on the mobilization of cells bearing the cluster of differentiation 34 (CD34) as an indirect reflection of the chemokine C-X-C motif ligand 12/CXCR4 axis inhibition. LY2510924 PK were best characterized by a two-compartment model with first-order absorption and dose-dependent clearance predicting steady state after three daily doses and little accumulation (accumulation ratio <1.17). The dynamics of CD34+ cell counts were best characterized with a precursor model with reversible transfer from the precursor to the central compartment and LY2510924-driven stimulation of cell mobilization. Model-based simulations show that once-daily doses of 20 mg LY2510924 produce maximum CD34+ cell response and that peak effect typically occurs after three daily doses and slowly wanes over time.
Assuntos
Modelos Biológicos , Peptídeos Cíclicos/farmacologia , Peptídeos Cíclicos/farmacocinética , Receptores CXCR4/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Contagem de Células Sanguíneas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Peptídeos Cíclicos/sangueRESUMO
LY2878735 is a novel dual serotonin (5-hydroxytryptamine (5-HT)) and norepinephrine (NE) reuptake inhibitor (SNRI) in development for chronic pain indications. In vitro profile suggests a more balanced profile as compared with other SNRI's, which is expected to confer superior clinical efficacy. LY2878735 is metabolized partly by the genetically polymorphic cytochrome P450 (CYP) 2D6 pathway, raising pharmacokinetic (PK) variability concerns. Phase 1 PK and biomarker data were analyzed by pharmacometric methods to characterize the balance between dual-target engagement and adverse effects on heart rate (HR) and blood pressure (BP). A narrow range of plasma LY2878735 levels was associated with an acceptable balance. As compared with poor metabolizers (PM), CYP2D6 extensive metabolizers (EM) have 21- and threefold higher clearance and distribution volume, respectively. Even with a CYP2D6-based dosing paradigm, a superior therapeutic index comparable to duloxetine, a widely used SNRI, was not achievable and LY2878735 development was thus terminated. Model-based approach effectively synthesizes PK-pharmacodynamic (PD) relationships, enabling efficient early development decisions.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e66; doi:10.1038/psp.2013.43; published online 21 August 2013.