Peroxisome proliferator‐activated receptor δ (PPARδ) plays a central role in modulating mitochondrial function in ischemia‐reperfusion injury. ASP1128, a potent and selective modulator of PPARδ, is currently under investigation for treating acute kidney injury. This randomized, first‐in‐human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP1128 administered intravenously in healthy participants. Forty‐nine participants received a single dose of ASP1128 0.3–10 mg (n = 37) or placebo (n = 12) and 53 received daily (7 days) doses of ASP1128 3–100 mg (n = 39) or placebo (n = 14), including a cohort aged ≥65 years (ASP1128 100 mg, n = 3; placebo, n = 2). Treatment‐emergent adverse events occurred in 37.8%, 59.0%, and 33.3%–35.7% of participants in the single ASP1128, multiple ASP1128, and placebo groups, respectively. All were mild in severity, and the frequency of adverse events did not appear to be dose‐related. One participant (multiple ASP1128 3 mg group) withdrew with an infusion site erythema, possibly related to study drug. Exposure was roughly dose‐proportional, and elimination was generally consistent across doses (mean t½ 14.6–17.4 hours in the 10, 30, and 100 mg groups on day 7). There was little accumulation in plasma following multiple dosing; steady state was reached after ∼4 days. ASP1128 treatment led to rapid and dose‐related upregulation of six fatty acid oxidation‐related PPARδ target genes at ≥10 mg, which lasted >24 hours postdose. In conclusion, single and multiple intravenous doses of ASP1128 were generally well tolerated, with dose‐dependent pharmacokinetics and target gene engagement in healthy participants.

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Liver sinusoidal endothelial cells (LSECs), which are specialized endothelial cells that line liver sinusoids, have been reported to participate in a variety of liver functions, such as blood macromolecule clearance and factor VIII production. In addition, LSECs play crucial roles in liver regeneration following acute liver injury, as well as the development and progression of liver diseases or drug-induced hepatotoxicity. However, the molecular mechanisms underlying their roles remain mostly unknown. Therefore, in order to contribute to the clarification of those mechanisms, herein we report on the development of a new immortalized human LSEC (HLSEC) line. To produce this cell line, two immortalized genes were introduced into the primary HLSECs, which eventually resulted in the establishment of the HLSEC/conditionally immortalized, clone-J (HLSEC/ciJ). Consistent with the two-immortalized gene expression, HLSEC/ciJ showed excellent proliferation activity. Additionally, the results of gene expression analyses showed that several LSEC (as well as pan-endothelial) marker mRNAs and proteins were clearly expressed in HLSEC/ciJ. Furthermore, we found that adherence junction proteins were localized at the cell border in the HLSEC/ciJ monolayer, and that the cells exhibited a tube-like structure formation property. Taken together, the results obtained thus far indicate that we have successfully immortalized HLSECs, resulting in creation of HLSEC/ciJ, a cell line that possesses infinite proliferation ability while retaining possession of at least some HLSEC features. We believe that the HLSEC/ciJ have the potential to provide a valuable and unlimited alternative source of HLSECs for use in liver/LSEC physiology/pathophysiology, pharmacology, and toxicology studies.Key words liver sinusoidal endothelial cell; immortalized cell; in vitro liver model; liver Liver sinusoidal endothelial cells (LSECs) are specialized endothelial cells lining a liver sinusoid, which is a type of blood vessels characterized by a lack of distinctive basement membrane and the presence of small open pores, called fenestrae.

Introduction/Aims: ASP0367, or bocidelpar sulfate, is an orally administered small molecule that potently and selectively modulates peroxisome proliferator-activated receptor δ (PPARδ) to address mitochondrial dysfunction occurring in diseases including primary mitochondrial myopathy and Duchenne muscular dystrophy. The objectives of this first-in-human trial were to evaluate the safety/tolerability, pharmacokinetics, and pharmacodynamics of ASP0367 in healthy participants.Methods: In this double-blind phase 1 study, adult participants were randomized to single or multiple ascending oral doses of ASP0367 or placebo. The study duration was 1 and 14 days, respectively. Pharmacokinetic parameters under fed conditions were also evaluated.Results: A total of 64 (single-dose cohort) and 37 (multiple-dose cohort) participants were included in the study. After single doses of 1 to 120 mg, ASP0367 was rapidly absorbed, with median time to maximum plasma concentration (t max ) of 1.50 to 2.24 hours under fasting conditions; ASP0367 concentrations declined in a multiphasic manner after reaching maximum plasma concentration. Under fed conditions, t max was delayed 1.7 hours. After multiple once-daily doses, mean half-life of ASP0367 10 to 75 mg ranged from 14.1 to 17.5 hours; steady state was reached after 4 days. Negligible accumulation was observed after repeated dosing. No participants receiving ASP0367 discontinued treatment, and all treatment-emergent adverse events were mild to moderate in severity; none were considered drug-related. No clinically significant changes were observed on laboratory or electrocardiographic evaluation. Treatment-and dose-dependent upregulation of six PPARδ target genes was observed with single and multiple doses of ASP0367.Discussion: ASP0367, or bocidelpar sulfate, was well tolerated; rapid absorption, roughly dose-proportional bioavailability, and effects on PPARδ target genes were demonstrated in healthy adult participants.Abbreviations: AE, adverse event; AUC, area under the concentration-time curve; AUC24, area under the concentration-time curve over 24 hours; AUCinf, area under the concentration-time curve from time zero to infinity; AUC Ʈ , area under the concentration-time curve from time of dosing to start of next dosing interval; BMI, body mass index;

Advances in biotechnology have enabled us to assay human tissue and cells to a depth and resolution that was never possible before, redefining what we know as the “biomarker”, and how we define a “disease”. This comes along with the shift of focus from a “one-drug-fits-all” to a “personalized approach”, placing the drug development industry in a highly dynamic landscape, having to navigate such disruptive trends. In response to this, innovative clinical trial designs have been key in realizing biomarker-driven drug development. Regulatory approvals of cancer genome sequencing panels and associated targeted therapies has brought personalized medicines to the clinic. Increasing availability of sophisticated biotechnologies such as next-generation sequencing (NGS) has also led to a massive outflux of real-world genomic data. This review summarizes the current state of biomarker-driven drug development and highlights examples showing the utility and importance of the application of real-world data in the process. We also propose that all stakeholders in drug development should (1) be conscious of and efficiently utilize real-world evidence and (2) re-vamp the way the industry approaches drug development in this era of personalized medicines.