Vericiguat clinical pharmacology programme: biopharmaceutical properties and potential intrinsic and extrinsic factor effects

Abstract Introduction The Phase III VICTORIA study (NCT02861534), which evaluated vericiguat vs placebo in patients with worsening chronic heart failure (WCHF) with ejection fraction &amp;lt;45%, demonstrated a significant reduction in the primary composite endpoint of cardiovascular death and HF hospitalisation. Purpose A comprehensive clinical pharmacological programme of 28 Phase I trials in &amp;gt;650 participants was performed to inform use of vericiguat. Methods Biopharmaceutical properties, pharmacokinetics (PK) and the potential for intrinsic factors to influence vericiguat dose administration were investigated. The PK and pharmacodynamic (PD) interaction potential of vericiguat with other drugs was assessed. Results Vericiguat had a mean half-life of approximately 24 h and high bioavailability when taken with food, leading to the recommendation of once daily dosing with food. Due to the multi-pathway metabolism and excretion profile of vericiguat, there was a low risk of PK drug–drug interactions (DDI; Table). No clinically relevant PD DDI were identified between vericiguat and aspirin, warfarin, sacubitril/valsartan or nitrates. There was a relatively minor influence of intrinsic factors on vericiguat PK. Conclusion This clinical pharmacology programme supports use of vericiguat in patients with WCHF who are characterised by multiple comorbidities and polypharmacy. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Funding for this research was provided by Bayer AG, Berlin, Germany and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA </jats:sec

Vericiguat: a QTc interval study in patients with coronary artery disease

Abstract Background Vericiguat is a soluble guanylate cyclase stimulator developed for the treatment of symptomatic chronic heart failure (HF) in adult patients with ejection fraction less than 45% who had a previous decompensation event. Guidelines on QT studies recommend evaluation of investigational drugs at supratherapeutic exposures in healthy volunteers. We anticipated that supratherapeutic doses of vericiguat would decrease blood pressure. We conducted an adjusted QT study using the therapeutic range of vericiguat in patients with coronary artery disease (CAD), who were expected to be more haemodynamically stable with fewer confounders (e.g., on the electrocardiogram) than a HF population. Purpose To assess the effect of vericiguat 10 mg once-daily on placebo-adjusted change from baseline of the Fridericia-corrected QT interval (QTcF) in patients with stable CAD. Methods This was a randomised, Phase Ib, placebo-controlled, double blind, double-dummy, multicentre study (NCT03504982). Test drug was vericiguat once-daily (up-titrated from 2.5 mg to 5 mg and then to 10 mg [treatments A, B, C] at 14-day intervals). The positive control was moxifloxacin 400 mg (single dose on Day 8 or Day 50 with placebo on other days [treatment D]; Figure). Patients were randomised to one of two sequences. We evaluated QTcF interval prolongation potential of vericiguat at increasing doses up to 10 mg, steady state. We investigated the pharmacokinetics, safety and tolerability of vericiguat. A clinically meaningful effect was defined as a QTcF change from baseline &amp;gt;10 ms relative to placebo. Assay sensitivity for moxifloxacin was confirmed by the lower limit of the 90% confidence interval (CI) of the time-matched, baseline-adjusted mean difference to placebo exceeding 5 ms at &amp;gt;1 time point. Results A total of 74 patients (66 males and 8 females) with CAD, mean (standard deviation) age 63.4 (8.0) years, were included. Mean difference between vericiguat and placebo in QTcF change from baseline (≤7 h post-dose) was &amp;lt;6 ms; no upper limit of the 90% CIs crossed the threshold of 10 ms. Lower limits of the two-sided 90% CI of the differences between moxifloxacin and placebo in QTcF change from baseline were &amp;gt;5 ms at 3 of 4 time points (Table). Peak plasma concentration (Cmax) of vericiguat following administration of vericiguat 10 mg was 322 μg/l and median time of maximum concentration (Tmax) was 4.5 h post-dose, in line with concentrations observed following administration of vericiguat 10 mg to patients with HF [1]. For moxifloxacin 400 mg, Cmax was 1960 μg/l and median Tmax was 3 h post-dose, in line with previously reported values [2]. Vericiguat up to 10 mg was generally safe and well tolerated. Conclusion This study supports the assessment that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation. These data contribute to the overall safety profile of vericiguat for the treatment of patients with HF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Funding was provided by Bayer AG, Berlin, Germany, and Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA QTc study design </jats:sec

Polymorphisms in the interleukin 4, interleukin 13, and corresponding receptor genes are not associated with systemic sclerosis and do not influence gene expression

Contains fulltext : 109087.pdf (publisher's version ) (Closed access)OBJECTIVE: Polymorphisms in the genes encoding interleukin 4 (IL4), interleukin 13 (IL13), and their corresponding receptors have been associated with multiple immune-mediated diseases. Our aim was to validate these previous observations in patients with systemic sclerosis (SSc) and scrutinize the effect of the polymorphisms on gene expression in various populations of peripheral blood leukocytes. METHODS: We genotyped a cohort of 2488 patients with SSc and 2246 healthy controls from The Netherlands, Spain, United Kingdom, Italy, Germany, and France. Taqman assays were used to genotype single-nucleotide polymorphisms (SNP) in the following genes: (1) IL4 (-590C>T/rs2243250); (2) IL4 receptor alpha (IL4RA) (Q576R/rs1801275); (3) IL13 (R130Q/rs20541 and -1112C>T/rs1800925); and (4) IL13RA1 (43163G>A/rs6646259). The effect of these polymorphisms on expression of the corresponding genes was assessed using quantitative RT-PCR on RNA derived from peripheral blood B cells, T cells, plasmacytoid dendritic cells, monocytes, and myeloid dendritic cells. We investigated whether these polymorphisms influenced development of pulmonary complications over 15 years in patients with SSc. RESULTS: None of the investigated polymorphisms was associated with SSc or any SSc clinical subtype. We did not observe any effect on transcript levels in the cell subtypes or on development of pulmonary complications. CONCLUSION: Our data showed that polymorphisms in IL4, IL13, and their receptors do not play a role in SSc and do not influence the expression of their corresponding transcript in peripheral blood cells