Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models.

Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK ß1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK ß1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans.

An Industry Perspective on the 2017 EMA Guideline on First-in-Human and Early Clinical Trials.

The European Medicines Agency (EMA) in 2017 issued a revised guideline on nonclinical and clinical aspects of first-in-human (FIH) and early clinical trials (CTs). External input was solicited during a draft comment phase, and although some industry suggestions were adopted, others were not. We agree that subject safety is of utmost priority, and believe that minimizing risk must be balanced with efficient and informative study designs to bring new medicines to patients.

Current nonclinical testing paradigms in support of safe clinical trials: An IQ Consortium DruSafe perspective.

The transition from nonclinical to First-in-Human (FIH) testing is one of the most challenging steps in drug development. In response to serious outcomes in a recent Phase 1 trial (sponsored by Bial), IQ Consortium/DruSafe member companies reviewed their nonclinical approach to progress small molecules safely to FIH trials. As a common practice, safety evaluation begins with target selection and continues through iterative in silico and in vitro screening to identify molecules with increased probability of acceptable in vivo safety profiles. High attrition routinely occurs during this phase. In vivo exploratory and pivotal FIH-enabling toxicity studies are then conducted to identify molecules with a favorable benefit-risk profile for humans. The recent serious incident has reemphasized the importance of nonclinical testing plans that are customized to the target, the molecule, and the intended clinical plan. Despite the challenges and inherent risks of transitioning from nonclinical to clinical testing, Phase 1 studies have a remarkably good safety record. Given the rapid scientific evolution of safety evaluation, testing paradigms and regulatory guidance must evolve with emerging science. The authors posit that the practices described herein, together with science-based risk assessment and management, support safe FIH trials while advancing development of important new medicines.

Analyzing angular distributions for two-step dissociation mechanisms in velocity map imaging.

Increasingly, velocity map imaging is becoming the method of choice to study photoinduced molecular dissociation processes. This paper introduces an algorithm to analyze the measured net speed, P(vnet), and angular, ß(vnet), distributions of the products from a two-step dissociation mechanism, where the first step but not the second is induced by absorption of linearly polarized laser light. Typically, this might be the photodissociation of a C-X bond (X = halogen or other atom) to produce an atom and a momentum-matched radical that has enough internal energy to subsequently dissociate (without the absorption of an additional photon). It is this second step, the dissociation of the unstable radicals, that one wishes to study, but the measured net velocity of the final products is the vector sum of the velocity imparted to the radical in the primary photodissociation (which is determined by taking data on the momentum-matched atomic cophotofragment) and the additional velocity vector imparted in the subsequent dissociation of the unstable radical. The algorithm allows one to determine, from the forward-convolution fitting of the net velocity distribution, the distribution of velocity vectors imparted in the second step of the mechanism. One can thus deduce the secondary velocity distribution, characterized by a speed distribution P(v1,2°) and an angular distribution I(θ2°), where θ2° is the angle between the dissociating radical's velocity vector and the additional velocity vector imparted to the product detected from the subsequent dissociation of the radical.