Contemporary Accounts in Drug Discovery and Development. Группа авторов

3.6). In addition, vericiguat could significantly prevent the development of heart hypertrophy. In comparison with the placebo group, the heart/body weight ratio decreased by 8 and 11% under vericiguat treatment in the 3 and 10 mg/kg treatment arm, respectively (Table 3.6). In parallel, the plasma atrial natriuretic peptide (ANP) levels decreased significantly in both vericiguat treatment arms by 45 and 65%, respectively when compared with placebo treatment. (Table 3.6). The L‐NAME‐treated RenTG rats also develop severe kidney damage characterized by a substantial proteinuria. The proteinuria was also significantly and dose‐dependently decreased by 65 and 88% in the 3 and 10 mg/kg vericiguat treatment group, respectively (Table 3.6).

      In summary, these results suggested that vericiguat is a stimulator of sGC and induces a cGMP increase by stimulating sGC NO independently but also in synergy with endogenous NO. Due to this mode of action and pharmacological properties, vericiguat showed pronounced effects on the CV system ex vivo on blood vessels and heart. In addition, vericiguat was effective in vivo in CV disease model. Thus, vericiguat has potential for the treatment of CV diseases and HF [41].

3.6 Clinical Studies

      The clinical development of vericiguat started on the 29th of July 2011 with the first‐in‐human study. Overall, 28 clinical phase 1 trials to evaluate vericiguat, which enrolled more than 650 participants, have been designed, conducted and completed to characterize the safety and pharmacodynamics (PD) in healthy volunteers and HFrEF patients, pharmacokinetics (PK), biopharmaceutical properties, metabolism, and PK and PD drug–drug interaction (DDI) potential, influence of intrinsic factors such as renal and hepatic impairment on vericiguat pharmacokinetics and dynamics in support of the development of vericiguat in HFrEF in combination with other HF therapies. In addition, population‐pharmacokinetic (POP‐PK)/PD analyses and physiologically based pharmacokinetic (PBPK) evaluations have been carried out. All studies were performed according to GCP (Good Clinical Practice) guidelines.

      3.6.1 Safety, PD, PK and PK/PD in Healthy Volunteers

      The safety, tolerability, PD, and PK of vericiguat were investigated in six phase 1, randomized, single/double‐blind studies conducted between July 2011 and May 2017 [42]. The studies included: two single dose escalation studies in Germany and Singapore; three multiple dose escalation studies conducted in Germany, Japan and China and a relative bioavailability and food effect study to characterize the vericiguat immediate release (IR) tablet. All studies comprised a screening, treatment, and follow‐up period.

      Across the vericiguat clinical pharmacology program, vericiguat (IR) tablets administered once daily at doses of 1.25, 5, and 10 mg or 5 mg twice daily up to a treatment period of seven days were well tolerated in healthy volunteers. A single dose of 15 mg administered as an oral solution (fasted) was not well tolerated due to the occurrence of hemodynamic effects (sinus bradycardia, orthostatic hypotension, orthostatic dizziness, and syncope during the standing BP procedure) reported by 3 of the 4 subjects tested at this dose range and prevented further dose escalation in the single rising dose study. However, administration of a single dose of 15 mg vericiguat as an IR tablet (fasted) was safe and well tolerated most likely because the slope of the plasma concentration time curves was less steep as compared with the oral solution. All treatment emergent adverse events (AEs) were of mild or moderate intensity. Within the phase 1 program, no severe or serious AEs occurred. The most common AEs after vericiguat treatment were headache with an incidence of 15.0% (placebo: 5.1%), followed by dyspepsia with 3.8% (placebo: 0%), nasopharyngitis with 3.5% (placebo: 1.7%) and ocular hyperemia with 2.8% (placebo: 1.7%). Overall, the AE profile of vericiguat was predominantly associated with its pharmacodynamic mode of action, (i.e. relaxation of smooth muscle leading to hemodynamic changes and gastrointestinal side effects). Neither AE analysis, nor the laboratory results, vital signs or ECG evaluations identified a safety signal.

      The PD effects of vericiguat were evaluated after single and multiple dose administrations in healthy subjects and are consistent with the mode of action of a sGC stimulator, i.e. relaxation of the smooth muscles in the vasculature leading to changes in hemodynamics. In accordance with the established pharmacological profile of vericiguat as a direct sGC stimulator in preclinical experiments, the expected hemodynamic effects were observed in healthy subjects. Specifically, in healthy subjects, an increase in HR was observed as a compensatory reaction to the BP lowering activity of vericiguat through the baroreflex.

Generally, immediate and direct correlations between vericiguat plasma concentration and PD measures (hemodynamics and vasoactive hormones) were observed (Figure 3.6). Consistent changes in pharmacodynamic parameters were observed at doses of 5 mg vericiguat and higher with an increase in HR, in vasoactive hormones, plasma cGMP and changes in impedance cardiographic parameters (increased stroke volume, cardiac output and cardiac index, decreased systemic vascular resistance). Effects on BP were less consistent and not seen in a dose‐dependent manner. Mostly, slight decreases were observed in systolic BP and in diastolic BP (decreases in the range of 2–3 mmHg), associated with the increase in HR.

Figure 3.6 Relationship between vericiguat PK and (a) HR over one minute, (b) cardiac index, (c) SVR, (d) cGMP, (e) adrenaline and (f) noradrenaline.

In a dedicated QT study in patients with stable coronary artery disease, administration of vericiguat 10 mg at steady‐state did not prolong the QT interval to a clinically relevant extent, i.e. the maximum mean prolongation of the QTcF interval did not exceed 6 ms (upper bound of the 90%CI <10 ms).

      3.6.2 Clinical Pharmacokinetics

Vericiguat shows slightly less than dose proportional, time‐independent PK, with low to moderate variability when administered with food. Vericiguat accumulates in plasma up to 155–171% and reaches pharmacokinetic steady‐state after approximately six days. The mean steady‐state population PK parameters of vericiguat in HF patients are summarized (Table 3.7).

      3.6.2.1 Absorption

      The absolute bioavailability of vericiguat is high (93%) when taken with food. Bioavailability (F) (area under the plasma concentration–time curve, AUC) and peak plasma levels (C _max) of vericiguat administered orally as a crushed tablet in water is comparable with that of a whole tablet.

      3.6.2.2 Effect of Food

      Administration of vericiguat with a high‐fat, high‐calorie meal increases T _max from about one hour (fasted) to about four hours (fed), reduces PK variability, and increases vericiguat exposure by 19% (AUC) and 9% (C _max) for the 5 mg tablet and by 44% (AUC) and 41% (C _max) for the 10 mg tablet as compared with the fasted state. Similar results were obtained when vericiguat was administered with a low‐fat, high‐carbohydrate meal. Based on the results of these studies, vericiguat was recommended to be taken with food in the phase 2 and 3 studies.

      3.6.2.3 Distribution

      The mean steady‐state volume of distribution of vericiguat in healthy subjects is approximately 44 l. Plasma protein binding of vericiguat is about 98%, with serum albumin being the main binding component. Plasma protein binding of vericiguat is not altered by