BACKGROUND Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.)

Catalytic reduction of pyrolyzed biomass is required to remove oxygen and produce transportation fuels, but limited knowledge of how hydrodeoxygenation (HDO) catalysts work stymies the rational design of more efficient and stable catalysts, which in turn limits deployment of biofuels. This work reports results from a novel study utilizing both isotopically labeled phenol (which models the most recalcitrant components of biofuels) with D 2 O and DFT calculations to provide insight into the mechanism of the highly efficient HDO catalyst, Ru/TiO 2 . The data point to the importance of interface sites between Ru nanoparticles and the TiO 2 support and suggest that water acts as a cocatalyst favoring a direct deoxygenation pathway in which the phenolic OH is replaced directly with H to form benzene. Rather than its reducibility, we propose that the amphoteric nature of TiO 2 facilitates H 2 heterolysis to generate an active site water molecule that promotes the catalytic C−O bond scission of phenol. This work has clear implications for efforts to scale-up the hydrogen-efficient conversion of wood waste into transportation fuels and biochemicals.

AimTo investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying.Materials and methodsThis was a randomized, double‐blind, placebo‐controlled, 2‐period, crossover trial. Subjects with obesity (N = 30) received once‐weekly subcutaneous semaglutide, dose‐escalated to 1.0 mg, or placebo. After each 12‐week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed.ResultsSemaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC0‐5h]; estimated treatment difference: glucose −1.34 mmol h/L [−2.42, −0.27]; insulin −921 pmol h/L [−1461, −381]; C‐peptide −1.42 nmol h/L [−2.33, −0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First‐hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC0‐1h; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide‐treated subjects. Overall gastric emptying (AUC0‐5h) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively).ConclusionSemaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first‐hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.

Aim: To assess the effects of oral semaglutide on postprandial glucose and lipid metabolism, and gastric emptying, in subjects with type 2 diabetes (T2D).Materials and Methods: In this randomized, double-blind, single-centre, crossover trial, subjects with T2D received once-daily oral semaglutide (escalated to 14 mg) followed by placebo, or vice versa, over two consecutive 12-week periods. Glucose and lipid metabolism, and gastric emptying (paracetamol absorption) were assessed before and after two types of standardized meals (standard and/or fat-rich) at the end of each treatment period. The primary endpoint was area under the glucose 0-5-h curve (AUC 0-5h ) after the standard breakfast.Results: Fifteen subjects were enrolled (mean age 58.2 years, HbA1c 6.9%, body weight 93.9 kg, diabetes duration 3.1 years; 13 [86.7%] males). Fasting concentrations of glucose were significantly lower, and C-peptide significantly greater, with oral semaglutide versus placebo. Postprandial glucose (AUC 0-5h ) was significantly lower with oral semaglutide versus placebo (estimated treatment ratio, 0.71; 95% CI, 0.63, 0.81; p < .0001); glucose incremental AUC (iAUC 0-5h/5h ) and glucagon AUC 0-5h were also significantly reduced, with similar results after the fat-rich breakfast. Fasting concentrations of triglycerides, very low-density lipoprotein (VLDL) and apolipoprotein B48 (ApoB48) were significantly lower with oral semaglutide versus placebo. AUC 0-8h for triglycerides, VLDL and ApoB48, and triglycerides iAUC 0-8h/8h , were significantly reduced after oral semaglutide versus placebo. During the first postprandial hour, gastric emptying was delayed (a 31% decrease in paracetamol AUC 0-1h ) with oral semaglutide versus placebo. One serious adverse event (acute myocardial infarction) occurred during oral semaglutide treatment. Conclusion:Oral semaglutide significantly improved fasting and postprandial glucose and lipid metabolism, and delayed gastric emptying.

Background and objectivesIn-vitro data suggest that clearance of vilaprisan is mediated by cytochrome P450 3A4 (oxidation) and aldoketoreductases (reduction). To fully understand the elimination and biotransformation pathways of vilaprisan, a selective progesterone receptor modulator, and to quantify the impact of cytochrome P450 3A4 inhibition on the pharmacokinetics of vilaprisan, two clinical studies in healthy postmenopausal women were conducted.MethodsIn study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [14C]-labeled vilaprisan in six subjects. In study 2, pharmacokinetics were determined after single oral administration of 4 mg of vilaprisan without and with concomitant administration of the strong cytochrome P450 3A4 inhibitor itraconazole (200 mg/day) in 14 subjects. In addition, a microtracer dose of vilaprisan was given intravenously to determine absolute bioavailability, clearance, and volume of distribution.ResultsThe dominant single compound in plasma was vilaprisan. No plasma metabolites exceeding 10% of total drug-related area under the concentration–time curve were detected. The absolute oral bioavailability of vilaprisan was ~ 60%. The mean clearance was ~ 7 L/h and the volume of distribution at steady state was ~ 360 L. Excretion occurred primarily via feces (73.5 ± 3.70% of dose; urine: 13.1 ± 1.71%; total recovery: 86.6 ± 2.81%), mostly in a metabolized form. Only small amounts of the parent drug were found in excreta. When vilaprisan was administered together with itraconazole, exposure to vilaprisan was increased 6.2-fold (90% confidence interval 5.4–7.2).ConclusionsVilaprisan is predominantly metabolized in the liver to a complex variety of metabolites, which are mainly excreted with feces. The pivotal role of cytochrome P450 3A4 in the metabolism of vilaprisan was confirmed.Clinical Trial RegistrationEudraCT numbers 2013-000707-16 (mass balance study) and 2014-004929-41 (drug–drug interaction/microtracer study); NCT02456129 (drug–drug interaction/microtracer study).Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0607-4) contains supplementary material, which is available to authorized users.