RESUMEN
Nonalcoholic steatohepatitis (NASH) is a complex metabolic disease of heterogeneous and multifactorial pathogenesis that may benefit from coordinated multitargeted interventions. Endogenous metabolic modulators (EMMs) encompass a broad set of molecular families, including amino acids and related metabolites and precursors. EMMs often serve as master regulators and signaling agents for metabolic pathways throughout the body and hold the potential to impact a complex metabolic disease like NASH by targeting a multitude of pathologically relevant biologies. Here, we describe a study of a novel EMM composition comprising five amino acids and an amino acid derivative (Leucine, Isoleucine, Valine, Arginine, Glutamine, and N-acetylcysteine [LIVRQNac]) and its systematic evaluation across multiple NASH-relevant primary human cell model systems, including hepatocytes, macrophages, and stellate cells. In these model systems, LIVRQNac consistently and simultaneously impacted biology associated with all three core pathophysiological features of NASH-metabolic, inflammatory, and fibrotic. Importantly, it was observed that while the individual constituent amino acids in LIVRQNac can impact specific NASH-related phenotypes in select cell systems, the complete combination was necessary to impact the range of disease-associated drivers examined. These findings highlight the potential of specific and potent multitargeted amino acid combinations for the treatment of NASH.
Asunto(s)
Técnicas de Cultivo de Célula , Fibrosis/metabolismo , Inflamación/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Alanina Transaminasa/metabolismo , Biomarcadores/metabolismo , Colágeno/química , Hepatocitos/metabolismo , Humanos , Técnicas In Vitro , Hígado/metabolismo , Cirrosis Hepática/patología , Hepatopatías/metabolismo , Macrófagos/metabolismo , Fenotipo , Transducción de SeñalRESUMEN
Multifactorial disease pathophysiology is complex and incompletely addressed by existing targeted pharmacotherapies. Amino acids (AAs) and related metabolites and precursors are a class of endogenous metabolic modulators (EMMs) that have diverse biological functions and, thus, have been explored for decades as potential multifactorial disease treatments. Here, we review the literature on this class of EMMs in disease treatment, with a focus on the emerging clinical studies on AAs and related metabolites and precursors as single- and combination-agents targeted to a single biology. These clinical research insights, in addition to increasing understanding of disease metabolic profiles and combinatorial therapeutic design principles, highlight an opportunity to develop EMM compositions with AAs and related metabolites and precursors to target multifactorial disease biology. EMM compositions are uniquely designed to enable a comprehensive approach, with potential to simultaneously and safely target pathways underlying multifactorial diseases and to regulate biological processes that promote overall health.
RESUMEN
INTRODUCTION: AXA1665 is a novel investigational amino acid (AA) composition specifically designed to impact AA imbalance, ammoniagenesis, and dysregulated anabolic activity associated with cirrhosis. METHODS: This 2-part study examined AXA1665 effects on safety, tolerability, and hepatic/muscle physiology in subjects with Child-Pugh A and B cirrhosis. Part 1 established plasma ammonia and AA concentration baselines with a standardized protein supplement. Part 2 included two 15-day domiciled periods separated by a 14-day washout. In period 1, subjects were randomly distributed to 2 groups: AXA1665 14.7 g t.i.d. (group 1) or control t.i.d. (group 2). In period 2, subjects from group 1 crossed over to control and those in group 2 crossed over to AXA1665 4.9 g t.i.d. All subjects were maintained on standard of care (standardized meals; 30-minute daily, supervised, mandatory physical activity; and daily late-evening snack). RESULTS: In parts 1 and 2, 23 and 17 participants were enrolled, respectively. Dose-dependent increases were observed in plasma concentrations of AXA1665-constituent AAs. Fasted branched-chain AA-to-aromatic AA and valine-to-phenylalanine ratios were both increased (AXA1665 14.7 g t.i.d. control-adjusted change: 44.3% ± 2.7% and 47.2% ± 3.9%, respectively; P < 0.0001). Despite provision of additional nitrogen, mean fasted plasma ammonia concentration at day 15 numerically decreased (-21.1% in AXA1665 14.7 g t.i.d. vs -3.8% in control; P > 0.05). AXA1665 14.7 g t.i.d. produced a leaner body composition and significantly decreased Liver Frailty Index at day 15 vs control (-0.70 ± 0.15 vs -0.14 ± 0.17; P < 0.05). AXA1665 was safe and well tolerated. DISCUSSION: AXA1665 has potential to mitigate core metabolic derangements associated with cirrhosis.
Asunto(s)
Aminoácidos de Cadena Ramificada/administración & dosificación , Drogas en Investigación/administración & dosificación , Cirrosis Hepática/tratamiento farmacológico , Adulto , Anciano , Aminoácidos de Cadena Ramificada/efectos adversos , Aminoácidos de Cadena Ramificada/sangre , Aminoácidos de Cadena Ramificada/metabolismo , Amoníaco/sangre , Amoníaco/metabolismo , Estudios Cruzados , Drogas en Investigación/efectos adversos , Femenino , Humanos , Hígado/metabolismo , Cirrosis Hepática/sangre , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/metabolismo , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Soluciones , Resultado del TratamientoRESUMEN
Declining pharmaceutical industry productivity is well recognized by drug developers, regulatory authorities and patient groups. A key part of the problem is that clinical studies are increasingly expensive, driven by the rising costs of conducting Phase II and III trials. It is therefore crucial to ensure that these phases of drug development are conducted more efficiently and cost-effectively, and that attrition rates are reduced. In this article, we argue that moving from the traditional clinical development approach based on sequential, distinct phases towards a more integrated view that uses adaptive design tools to increase flexibility and maximize the use of accumulated knowledge could have an important role in achieving these goals. Applications and examples of the use of these tools--such as Bayesian methodologies--in early- and late-stage drug development are discussed, as well as the advantages, challenges and barriers to their more widespread implementation.