RESUMO
Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l-1 (95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.
Assuntos
Ácidos Cólicos/administração & dosagem , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estearoil-CoA Dessaturase/genética , Alanina Transaminase , Biópsia , Ácidos Cólicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Triglicerídeos/metabolismoRESUMO
Laquinimod, is a potential oral immunomodulatory drug, for relapsing-remitting multiple sclerosis (RRMS). We analyzed the blood-transcriptional changes in RRMS patients (who participated in the ALLEGRO clinical trial) at one and six months after laquinimod treatment using gene expression microarrays. The molecular effects of laquinimod were enhanced by duration of treatment and showed down-regulation of inflammatory responses mainly via TGFb signaling, and of pro-inflammatory cytokines as well as of cellular movement, including adhesion, migration and leukocyte extravasation signaling. Our results demonstrate that laquinimod suppresses inflammation through down-regulation of inflammatory cytokines and arrest of leukocyte extravasation and thereby could attenuate disease activity in RRMS patients.
Assuntos
Citocinas/biossíntese , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Quinolonas/farmacologia , Adulto , Adesão Celular/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/genética , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Inflamação , Masculino , Esclerose Múltipla Recidivante-Remitente/imunologia , NF-kappa B/metabolismo , Quinolonas/uso terapêutico , RNA Mensageiro/sangue , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/genéticaRESUMO
Glatiramer acetate (GA) is an immunomodulator approved for therapy of relapsing-remitting multiple sclerosis (RRMS), but recent findings indicate that it may also have additional, neurotrophic effects. Here, we found that supernatants from human GA-reactive T lymphocytes potentiated oligodendrocyte numbers in rodent and human oligodendrocyte progenitor (OPC) cultures. Effects of Th2-polarized lines were stronger than Th1-polarized cells. Microarray and ELISA analyses revealed that neurotrophic factors induced in Th2- and Th1-polarized GA-reactive lines included IGF-2 and BMP-7 respectively, and functional studies confirmed IGF-2 as trophic for OPCs. Our results support the concept that GA therapy may result in supportive effects on oligodendrocytes in RRMS patients.