Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics, Safety, and Tolerability of a Single Dose of Oral Ivosidenib in Otherwise Healthy Participants.

Ivosidenib, a small-molecule inhibitor of mutant isocitrate dehydrogenase 1, is primarily cleared by hepatic metabolism. This open-label study investigated the impact of hepatic impairment on ivosidenib pharmacokinetics (ClinicalTrials.gov: NCT03282513). Otherwise healthy participants with mild (n = 9) or moderate (n = 8) hepatic impairment (Child-Pugh score) and matched participants with normal hepatic function (n = 16) received 1 oral dose of 500-mg ivosidenib. Mild hepatic impairment had a negligible effect on total ivosidenib plasma exposure, with geometric mean ratios (90% confidence interval [CI]) of 0.933 (0.715-1.22) for maximum concentration (Cmax ) and 0.847 (0.624-1.15) for area under the plasma concentration-time curve (AUC) in participants with mild hepatic impairment versus matched controls. Moderate hepatic impairment reduced total ivosidenib exposure by 28% to 44%, with geometric mean ratios (90%CI) of 0.565 (0.419-0.763) for Cmax and 0.716 (0.479-1.07) for AUC, although the 90%CI for AUC included 1.00. The ivosidenib unbound fraction was concentration dependent and higher in participants with mild/moderate hepatic impairment compared with matched controls. There was no apparent trend to increasing unbound Cmax with increased hepatic impairment severity. A single 500-mg ivosidenib dose was well tolerated, with no serious or severe adverse events and no adverse events leading to discontinuation. We conclude that mild/moderate hepatic impairment did not lead to clinically relevant changes in ivosidenib exposure following a single 500-mg dose.

Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction.

In a cell-free approach to regenerative therapeutics, transient application of paracrine factors in vivo could be used to alter the behavior and fate of progenitor cells to achieve sustained clinical benefits. Here we show that intramyocardial injection of synthetic modified RNA (modRNA) encoding human vascular endothelial growth factor-A (VEGF-A) results in the expansion and directed differentiation of endogenous heart progenitors in a mouse myocardial infarction model. VEGF-A modRNA markedly improved heart function and enhanced long-term survival of recipients. This improvement was in part due to mobilization of epicardial progenitor cells and redirection of their differentiation toward cardiovascular cell types. Direct in vivo comparison with DNA vectors and temporal control with VEGF inhibitors revealed the greatly increased efficacy of pulse-like delivery of VEGF-A. Our results suggest that modRNA is a versatile approach for expressing paracrine factors as cell fate switches to control progenitor cell fate and thereby enhance long-term organ repair.

Tbx1 regulates population, proliferation and cell fate determination of otic epithelial cells.

The T-box transcription factor Tbx1 is required for inner ear morphogenesis. Tbx1 null mutants have a small otocyst that fails to grow and remodel and does not give rise to the vestibular and cochlear apparata. Here we show that Tbx1 expression-driven cell tracing identifies a population of otic epithelial cells that contributes to most of the otocyst. Tbx1 is essential for the contribution of this population to the inner ear. Ablation of Tbx1 after this cell population has established itself in the otocyst, restores marker expression lost in germ line mutants, but causes severe reduction in mitotic activity, cell autonomously. Furthermore, timed cell fate mapping demonstrates that loss of Tbx1 switches the fate of some members of the Tbx1-dependent cell population, from non-neurogenic to neurogenic, an event associated with activation of the Delta-Notch pathway. Finally, tissue-specific ablation of Tbx1 demonstrates that, while the abovementioned phenotypic abnormalities are due to loss of epithelial expression of Tbx1, cochlear morphogenesis requires mesodermal Tbx1 expression. We conclude that the main functions of Tbx1 in the inner ear are to control, cell-autonomously, contribution, size and fate of a large population of otic epithelial cells, and, cell non-autonomously, cochlear morphogenesis.