Farnesoid X receptor agonist tropifexor attenuates cholestasis in a randomised trial in patients with primary biliary cholangitis.

Background & Aims: The safety, tolerability, and efficacy of the non-bile acid farnesoid X receptor agonist tropifexor were evaluated in a phase II, double-blind, placebo-controlled study as potential second-line therapy for patients with primary biliary cholangitis (PBC) with an inadequate ursodeoxycholic acid response. Methods: Patients were randomised (2:1) to receive tropifexor (30, 60, 90, or 150 µg) or matched placebo orally once daily for 28 days, with follow-up on Days 56 and 84. Primary endpoints were safety and tolerability of tropifexor and reduction in levels of γ-glutamyl transferase (GGT) and other liver biomarkers. Other objectives included patient-reported outcome measures using the PBC-40 quality-of-life (QoL) and visual analogue scale scores and tropifexor pharmacokinetics. Results: Of 61 enrolled patients, 11, 9, 12, and 8 received 30-, 60-, 90-, and 150-µg tropifexor, respectively, and 21 received placebo; 3 patients discontinued treatment because of adverse events (AEs) in the 150-µg tropifexor group. Pruritus was the most frequent AE in the study (52.5% [tropifexor] vs. 28.6% [placebo]), with most events of mild to moderate severity. Decreases seen in LDL-, HDL-, and total-cholesterol levels at 60-, 90-, and 150 µg doses stabilised after treatment discontinuation. By Day 28, tropifexor caused 26-72% reduction in GGT from baseline at 30- to 150-µg doses (p <0.001 at 60-, 90-, and 150-µg tropifexor vs. placebo). Day 28 QoL scores were comparable between the placebo and tropifexor groups. A dose-dependent increase in plasma tropifexor concentration was observed, with 5- to 5.55-fold increases in AUC0-8h and Cmax between 30- and 150-µg doses. Conclusions: Tropifexor showed improvement in cholestatic markers relative to placebo, predictable pharmacokinetics, and an acceptable safety-tolerability profile, thereby supporting its potential further clinical development for PBC. Lay summary: The bile acid ursodeoxycholic acid (UDCA) is the standard-of-care therapy for primary biliary cholangitis (PBC), but approximately 40% of patients have an inadequate response to this therapy. Tropifexor is a highly potent non-bile acid agonist of the farnesoid X receptor that is under clinical development for various chronic liver diseases. In the current study, in patients with an inadequate response to UDCA, tropifexor was found to be safe and well tolerated, with improved levels of markers of bile duct injury at very low (microgram) doses. Itch of mild to moderate severity was observed in all groups including placebo but was more frequent at the highest tropifexor dose. Clinical Trials Registration: This study is registered at ClinicalTrials.gov (NCT02516605).

A Phase 1 Dose-Escalation Study of the Cardiac Myosin Inhibitor Aficamten in Healthy Participants.

This phase 1, randomized, double-blind, placebo-controlled study of aficamten (formerly CK-3773274) in healthy adults identified a pharmacologically active range of doses and exposures. At doses that were pharmacologically active (single doses of ≤50 mg or daily dosing of ≤10 mg for 14 or 17 days), aficamten appeared to be safe and well tolerated. Adverse events were generally mild and no more frequent than with placebo. Pharmacokinetic assessments showed dose proportionality over the range of single doses administered, and pharmacokinetics were not affected by administration with food or in otherwise healthy individuals with a cytochrome P450 2D6 poor metabolizer phenotype. (A Single and Multiple Ascending Dose Study of CK-3773274 in Health Adult Subjects; NCT03767855).

Unraveling the mystery of efficacy in Chinese medicine formula: New approaches and technologies for research on pharmacodynamic substances.

Traditional Chinese medicine (TCM) is the key to unlock treasures of Chinese civilization. TCM and its compound play a beneficial role in medical activities to cure diseases, especially in major public health events such as novel coronavirus epidemics across the globe. The chemical composition in Chinese medicine formula is complex and diverse, but their effective substances resemble "mystery boxes". Revealing their active ingredients and their mechanisms of action has become focal point and difficulty of research for herbalists. Although the existing research methods are numerous and constantly updated iteratively, there is remain a lack of prospective reviews. Hence, this paper provides a comprehensive account of existing new approaches and technologies based on previous studies with an in vitro to in vivo perspective. In addition, the bottlenecks of studies on Chinese medicine formula effective substances are also revealed. Especially, we look ahead to new perspectives, technologies and applications for its future development. This work reviews based on new perspectives to open horizons for the future research. Consequently, herbal compounding pharmaceutical substances study should carry on the essence of TCM while pursuing innovations in the field.

Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-Function Genotypes: Results of a Randomized Pharmacodynamic Study in a Feasibility Investigation of Rapid Genetic Testing.

The feasibility of rapid genetic testing in patients undergoing percutaneous coronary intervention (PCI) and the comparison of the pharmacodynamic effects of prasugrel versus ticagrelor among carriers of cytochrome P450 2C19 loss-of-function alleles treated with PCI has been poorly explored. Rapid genetic testing using the Spartan assay was shown to be feasible and provides results in a timely fashion in a real-world setting of patients undergoing coronary angiography (n = 781). Among patients (n = 223, 28.5%), carriers of at least 1 loss-of-function allele treated with PCI (n = 65), prasugrel, and ticagrelor achieve similar levels of platelet inhibition. (A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients Undergoing PCI With CYP2C19 Loss-of-function [NCT02065479]).

Pharmacodynamic Effects of Vorapaxar in Patients With and Without Diabetes Mellitus: Results of the OPTIMUS-5 Study.

Vorapaxar reduces thrombotic cardiovascular events at the expense of increased bleeding. However, the differential pharmacodynamic (PD) effects of vorapaxar according to diabetes mellitus (DM) status are unknown. Moreover, although withdrawal of aspirin has emerged as a bleeding reduction strategy, the PD effects of stopping aspirin in patients treated with vorapaxar also are unknown. In this prospective PD investigation, vorapaxar was associated with reduced platelet-mediated thrombogenicity without affecting clot kinetics irrespective of DM status. However, platelet-mediated thrombogenicity increased after aspirin withdrawal, particularly among patients with DM. (Optimizing anti-Platelet Therapy In diabetes MellitUS-5 Study [OPTIMUS-5]; NCT02548650).

Structural simplification: an efficient strategy in lead optimization.

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

A feasibility study prior to an international multicentre paediatric study to assess pharmacokinetic/pharmacodynamic sampling and sample preparation procedures, logistics and bioanalysis.

BACKGROUND: Variability in pre-analytical procedures such as blood sampling, sample preparation and transport can substantially influence bioanalytical results and subsequently impair reliability of data gathered during clinical trials. Especially in vulnerable populations, all efforts should be made to facilitate high-quality data extraction excluding unnecessary or repeated intervention. METHODS: The EU-funded LENA project (Labeling of Enalapril from Neonates up to Adolescents) included a feasibility study in its preparatory procedures prior to first-in-child studies. Derived from a regular study visit, it encompassed all procedures, from sampling of two study-specific drugs and four sensitive humoral parameters to bioanalysis, to evaluate the quality of obtained samples and applicability of logistical and bioanalytical procedures. Drug administration to healthy adults was circumvented by pre-spiking the blood collection tubes with a drug solution. Five clinical sites were evaluated. RESULTS: Clinical teams' preparedness and applicability of required sampling procedures was investigated in 18 volunteers, on-site. 97% of collected pharmacokinetic (PK) samples and 93% of samples for humoral parameters were obtained eligibly. Results met expectations, though one team had to be re-trained and performed a re-run. Planned procedures for sampling, sample preparation, transport and analysis were found to be suitable for being applied within paediatric trials. CONCLUSION: The concept of the presented feasibility study that simultaneously assesses PK/PD sampling, sample preparation, logistics and bioanalysis proved to be a promising tool for trial preparation. It revealed improperly installed processes and bottlenecks that required adjustments prior to start of recruitment. It facilitated high-quality conduct from the first moment of paediatric pivotal studies.

Regulatory considerations for clinical development of cancer vaccines.

Cancer vaccines are aimed at stimulating an immune response to tumor tissue. There is a high level of clinical activity in this rapidly advancing field with over 1,400 trials registered on Clincaltrials.gov. The recent approval of Sipuleucel-T which is the first cancer vaccine approved in the US and EU has encouraged developers in this field. In contrast to more established approaches for treating cancer such as chemotherapy, regulatory guidelines have been developed relatively recently for cancer vaccines. These guidelines advise on general clinical requirements. As there is an increase in innovative strategies with novel products, a 2-way dialog with regulators is recommended on a case-by-case basis to justify the clinical development plan, taking into account specific quality issues related to the product(s) in development. It is important that the rationale, background and justification for the planned development is convincing when interacting with the regulatory authorities, to enable drug developers and regulators to reach agreement.