Pharmacokinetics, Safety, and Efficacy of Ixekizumab in Chinese Patients with Moderate-to-Severe Plaque Psoriasis: A Phase 1, Single- and Multiple-Dose Study.

INTRODUCTION: We evaluated the pharmacokinetics (PK), safety, and efficacy of ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A, in Chinese patients with moderate-to-severe psoriasis. METHODS: In this phase 1, multicenter, open-label study, adults (≥ 18 years) diagnosed with moderate-to-severe plaque psoriasis for ≥ 6 months involving ≥ 10% of their body surface area received ixekizumab 80 mg by subcutaneous injection and were observed for 20 weeks (single-dose phase) and then an initial dose of 160 mg followed by randomization (1:1) to 80 mg ixekizumab every 2 weeks (IXE Q2W) or every 4 weeks (IXE Q4W) for an 8-week treatment period (multiple-dose phase). RESULTS: The median time to maximum observed ixekizumab concentrations occurred 2-4 days after dosing and the geometric mean half-life was 15-16 days, after single (n = 12) and multiple (n = 29) doses. Approximately linear pharmacokinetics were observed between the 80 and 160 mg single doses. Steady-state systemic exposure to ixekizumab during a dosing interval was similar with the IXE Q2W and IXE Q4W regimens, with estimates of 224 µg·day/mL and 213 µg·day/mL for the area under the concentration-time curve from time 0 to 14 days post-dose and 0 to 28 days post-dose, respectively. Safety was consistent with the established safety profile of ixekizumab. At week 12 after multiple doses, the proportions of patients achieving a 75% or 90% improvement in Psoriasis Area and Severity Index score were 100% and 86% for IXE Q2W, respectively, and 93% and 80% for IXE Q4W, respectively. A Static Physician's Global Assessment score of 0 or 1 was achieved in 100% and 87% with IXE Q2W and IXE Q4W, respectively. CONCLUSIONS: The PK of ixekizumab in Chinese patients with moderate-to-severe plaque psoriasis was comparable to findings in global populations. After IXE Q2W or IXE Q4W for 12 weeks, clinically relevant treatment responses and an acceptable safety profile were observed. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03073213).

Somatic MIWI2 Hinders Direct Lineage Reprogramming From Fibroblast to Hepatocyte.

Remodeling of the gene regulatory network in cells is believed to be a prerequisite for their lineage reprogramming. However, its key regulatory factors are not yet elucidated. In this article, we investigate the role of PIWI proteins and provide evidence that one of them, MIWI2, is elicited during transdifferentiation of fibroblasts into hepatocyte-like cells. In coincidence with the peak expression of MIWI2, we identified the appearance of a unique intermediate epigenetic state characterized by a specific Piwi-interacting RNA (piRNA) profile consisting of 219 novel sequences. Knockout of MIWI2 greatly improved the formation of the induced hepatocytes, whereas overexpression of exogenous MIWI2 completely abolished the stimulated effect. A bioinformatics analysis of piRNA interaction network, followed by experimental validation, revealed the Notch signaling pathway as one of the immediate effectors of MIWI2. Altogether, our results show for the first time that temporal expression of MIWI2 contributes negatively to cell plasticity not only in germline, but also in developed cells, such as mouse fibroblasts. Stem Cells 2019;37:803-812.