Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects: A randomized, double-blind, crossover study.

NDI-010976, an allosteric inhibitor of acetyl-coenzyme A carboxylases (ACC) ACC1 and ACC2, reduces hepatic de novo lipogenesis (DNL) and favorably affects steatosis, inflammation, and fibrosis in animal models of fatty liver disease. This study was a randomized, double-blind, placebo-controlled, crossover trial evaluating the pharmacodynamic effects of a single oral dose of NDI-010976 on hepatic DNL in overweight and/or obese but otherwise healthy adult male subjects. Subjects were randomized to receive either NDI-010976 (20, 50, or 200 mg) or matching placebo in period 1, followed by the alternate treatment in period 2; and hepatic lipogenesis was stimulated with oral fructose administration. Fractional DNL was quantified by infusing a stable isotope tracer, [1-13 C]acetate, and monitoring 13 C incorporation into palmitate of circulating very low-density lipoprotein triglyceride. Single-dose administration of NDI-010976 was well tolerated at doses up to and including 200 mg. Fructose administration over a 10-hour period stimulated hepatic fractional DNL an average of 30.9 ± 6.7% (mean ± standard deviation) above fasting DNL values in placebo-treated subjects. Subjects administered single doses of NDI-010976 at 20, 50, or 200 mg had significant inhibition of DNL compared to placebo (mean inhibition relative to placebo was 70%, 85%, and 104%, respectively). An inverse relationship between fractional DNL and NDI-010976 exposure was observed with >90% inhibition of fractional DNL associated with plasma concentrations of NDI-010976 >4 ng/mL. CONCLUSION: ACC inhibition with a single dose of NDI-010976 is well tolerated and results in a profound dose-dependent inhibition of hepatic DNL in overweight adult male subjects. Therefore, NDI-010976 could contribute considerable value to the treatment algorithm of metabolic disorders characterized by dysregulated fatty acid metabolism, including nonalcoholic steatohepatitis. (Hepatology 2017;66:324-334).

The pharmacokinetics, pharmacodynamics and tolerability of PUR0200, a novel tiotropium formulation, in chronic obstructive pulmonary disease.

AIMS: PUR0200 is a tiotropium bromide formulation engineered with the iSPERSE dry powder delivery technology. PUR0200 is being developed as a bioequivalent alternative to tiotropium bromide, delivered using Spiriva® HandiHaler® (HH). We investigated the bronchodilator effects, pharmacokinetics and safety of PUR0200 in patients with chronic obstructive pulmonary disease (COPD). METHODS: This was a randomized, placebo-controlled, crossover study using different PUR0200 doses and the comparator tiotropium HH. In vitro aerodynamic particle size distribution (aPSD) characterization of PUR0200 and tiotropium HH are presented. The main endpoints included forced expiratory volume in 1 s (FEV1 ) trough and (0-24 h) and pharmacokinetic parameters. RESULTS: The increased fine-particle fraction of PUR0200 demonstrated by testing using the next-generation impactor increased the proportion of drug available for lung deposition compared with the tiotropium HH. There was a numerical dose-response effect for PUR0200 on FEV1 , with 3 µg demonstrating a lower effect than higher doses. The placebo-adjusted mean (95% confidence interval) increases from baseline at 24 h postdose were 150 ml (100-200), 210 ml (160-270) and 200 ml (140-250) for 3 µg, 6 µg and 9 µg doses of PUR0200, respectively. Tiotropium HH (18 µg) caused a mean 169 ml (standard deviation 157ml) improvement in trough FEV1 , which was not significantly different to the PUR0200 effects at any of the tested doses. CONCLUSIONS: PUR0200 treatment caused bronchodilation in COPD patients that was similar in magnitude to that caused by tiotropium HH. This enabled a similar clinical effect on lung function to be achieved with PUR0200 using a lower metered dose of tiotropium compared with tiotropium HH.

Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist.

UNLABELLED: CPG 10101 (ACTILON) is a novel potent and selective unmethylated cytidine-phosphate-guanosine (CpG)-containing oligodeoxynucleotide agonist of Toll-like receptor 9 (TLR9) being developed for the treatment of chronic infections such as HCV. OBJECTIVES AND METHODS: In this randomized, double-blind, placebo-controlled Phase I study in 48 normal volunteers, we investigated the safety, pharmacokinetic parameters and immune effects of subcutaneous administration of CPG 10101. Five sequential escalating doses from 0.25 to 20 mg were administered twice, 14 days apart. In addition, a 4 mg dose was administered twice weekly for four weeks. RESULTS: A maximum tolerated dose was not reached and the adverse event profile was consistent with the known immunostimulatory effects of TLR9 agonists, mostly consisting of injection site reactions or flu-like symptoms that were generally mild in intensity. CPG 10101 induced interferons, cytokines and chemokines in a pattern consistent with the biology of TLR9. The most sensitive marker was IP-10/CXCL10, whose induction was detected in some subjects even at the 0.25 mg dose. Some cytokines showed transient circulating levels, while the levels of others such as the antiviral cytokine 2',5'-oligoadenylate synthetase were sustained for several days. CONCLUSION: This study warrants further investigation of CPG 10101 for the treatment of chronic infections such as HCV.

Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor.

BACKGROUND: Hereditary angioedema (HAE) is a rare, autosomal-dominant disorder caused by C1 inhibitor gene mutation. Patients with HAE experience intermittent attacks of edema affecting the oropharynx, abdomen, gastrointestinal tract, and limbs. C1 inhibitor is the primary endogenous inhibitor of the kallikrein-kinin (contact) cascade. Unregulated kallikrein activation generates bradykinin, the likely mediator of the swelling and pain characterizing HAE attacks. Ecallantide, a novel, recombinant protein, potently inhibits kallikrein. This is the first placebo-controlled assessment in human beings of a therapeutic intervention to improve symptoms of HAE attacks under the hypothesis that the contact cascade is the putative pathway responsible for HAE pathology. OBJECTIVE: To determine the safety and efficacy of ecallantide in patients with HAE. METHODS: This double-blind, placebo-controlled, ascending-dose study assessed efficacy and tolerability of ecallantide (5, 10, 20, or 40 mg/m(2) intravenously) in individuals experiencing acute HAE attacks (N = 49). Twelve patients were assigned to each dose level: 10 to ecallantide and 2 to placebo, per cohort. RESULTS: Ecallantide treatment ameliorated the symptoms of HAE attacks: 72.5% (29/40) of patients treated with ecallantide versus 25.0% (2/8) of placebo patients reported significant improvement in symptoms within 4 hours (P = .0169). Ecallantide was well tolerated at all doses. CONCLUSION: Ecallantide, a potent, specific inhibitor of plasma kallikrein, significantly improved HAE symptoms over placebo. The trial provides strong support for the role of the kallikrein-kinin cascade and its end product, bradykinin, in the pathophysiology of HAE. Further clinical trials are underway. CLINICAL IMPLICATIONS: Ecallantide is a promising new therapy for HAE attacks.