Contemporary Accounts in Drug Discovery and Development. Группа авторов

this strong rationale for cGMP elevation as an effective treatment option for HF, previous attempts by NO donors which also stimulate sGC and cGMP production, and also by PDE5 inhibitors which inhibit degradation of cGMP, mostly failed [13].

      sGC activators which generate cGMP via interaction with the dysfunctional form of sGC, apo‐sGC, have not been explored in chronic HF; however, cinaciguat (BAY 58‐2667) has been characterized in acute HF [13]. Based on promising preclinical results, a phase 2 study in patients with acute decompensated heart failure (ADHF) was initiated. Continuous intravenous infusion of cinaciguat was well tolerated and resulted in an improvement of cardiopulmonary hemodynamics. The subsequent clinical phase 2b program studied the effects of cinaciguat in three randomized, double‐blind, placebo‐controlled studies in ADHF patients; however, the clinical development of cinaciguat was terminated prematurely because of hypotensive events without clear benefit [12].

      Very recently, another cGMP‐elevating principle, sacubitril combined with the angiotensin receptor blocker valsartan, was studied successfully as an oral treatment in HF [14]. The neprilysin inhibitor sacubitril is hypothesized to work via natriuretic peptide elevation and associated stimulation of the particulate guanylate cyclase (pGC) [15–17]. The endopeptidase inhibitor sacubitril may affect other potential downstream effectors such as substance P, and the actual contribution to the improved outcomes in HFrEF of the observed elevation of natriuretic peptide in response to neprilysin inhibition with subsequent cGMP generation via pGC remains open [16]. However, as discussed elsewhere in more detail, since the cellular signaling and biologic effects of pGC‐derived and sGC‐derived cGMP differ [12], stimulation of sGC with vericiguat is likely to act complementarily and may add further efficacy to the remaining high residual event rates still seen in HFrEF even with sacubitril/valsartan treatment [14].

      3.2.1 Persistent High Medical Need in High‐Risk Patients with Chronic HF

A unique population of patients with worsening chronic HF was studied in VICTORIA. All patients were enrolled within a time window of six months after a qualifying previous HF decompensation (defined in the protocol as HF hospitalization or use of IV diuretics for HF [without hospitalization]) [18]. Worsening chronic HF was identified in registries of patients admitted for HF about two decades ago. In order to overcome the misleading distinction between acute and stable chronic HF, the term worsening chronic HF was coined when registry data indicated that the majority of events previously classified as acute decompensated HF events occurred due to exacerbations of chronic HF in more than 70% of patients admitted with acute HF [19, 20]. In these patients, worsening of hemodynamic function and further activation of neurohormones during acute HF syndromes contribute to the progression of HF (Figure 3.3) [21].

To reflect the recurrent nature of worsening HF episodes within the course of the disease, worsening chronic HF denominates the specific population of those patients with HF who had at least one worsening HF event as opposed to those who never required hospitalization. This has important prognostic implications. Even after just one worsening HF event, subsequent clinical event rates of recurrent worsening HF or CV death are substantially higher than in patients without a previous decompensation [22–24]. The independent prognostic value of the previous worsening HF event becomes evident when comparing the clinical characteristics of patients with a previous hospitalization as opposed to those without who were enrolled in the CHARM trial [24]. Subtle differences were seen between these patient groups for several traditionally established risk factors. Patients with a previous HF hospitalization had suffered more frequently with diabetes and atrial fibrillation, were on average in a higher New York Heart Association (NYHA) class, though less often had a previous myocardial infarction. However, the presence or absence of these established factors was less clearly differentiating between populations at different levels of risk than the single attribute of the presence or absence of a previous HF event [24].

Figure 3.3 Recurrent acute events contribute to heart failure progression. With each admission for acute heart failure syndrome, there is a short‐term improvement; however, the patient leaves the hospital with a further decrease in cardiac.

      Source: Reproduced with permission. Copyright© 2005, Elsevier [21].

      As worsening HF events occur despite established treatment for HF, a large residual medical need persists in patients with worsening chronic HF. New therapies are urgently needed to reduce the unacceptably high mortality and morbidity rates in this segment of the overall population of patients with HF at particular risk of future events. The pivotal event‐driven phase 3 trial studied the efficacy of vericiguat in the population of patients with worsening chronic heart failure and EF <45% in order to reduce the residual burden of CV death and HF hospitalization in these patients [18].

Upon the successful completion of phase 2 studies with the sGC stimulator riociguat in patients with pulmonary artery hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), we hypothesized that direct sGC stimulation may also benefit patients in whom pulmonary hypertension was associated with left ventricular dysfunction (Figure 3.4) [25]. Therefore, the LEft ventricular systolic dysfunction associated with Pulmonary Hypertension riociguat Trial (LEPHT) was conducted in parallel with the phase 3 studies PATENT and CHEST in PAH and in CTEPH, respectively. We tested the hypothesis that direct sGC stimulation with riociguat would reduce elevated mean pulmonary artery pressures (PAPs; inclusion criterion: above 25 mmHg) in patients suffering from heart failure with reduced ejection fraction (HFrEF) who were symptomatic despite optimized medical therapy at a stable dose regimen for >30 days before randomization. Although the primary endpoint reduction in PAPmean upon 16 weeks of treatment with riociguat compared with placebo both added to standard of care was not met, consistent dose‐dependent hemodynamic improvements were found in invasive hemodynamic measurements [26]. These included balanced reductions in both systemic and pulmonary resistance, which were associated with significant increases in cardiac index and stroke volume at the highest tested dose regimen, and a parallel decrease in N‐terminal pro–B‐type natriuretic peptide (NT‐proBNP) as marker of cardiac wall stress. Riociguat titration up to 2 mg was well tolerated, and the observed dose‐dependent hemodynamic improvements did not come at the expense of an increase in heart rate (HR) or decreases in blood pressure (BP) at 16 weeks of treatment.

Figure 3.4 sGC stimulator riociguat.

Mechanistically, we postulated that balanced reductions in pulmonary and systemic resistances may facilitate unloading of the dysfunctional left ventricle, improving CV performance and flow without adverse compromise in BP. However, as patients with HFrEF in the LEPHT study were only eligible with elevated PAPmean including both pre‐ and post‐capillary pulmonary hypertension (PH), we considered whether the observed improvements were dependent on reductions in the precapillary component of PH in patients with high baseline pulmonary vascular resistance (PVR), or more generalizable resulting from decongestion addressing the post‐capillary passive PH component that occurs secondary to backward failure of the left ventricle. Subgroup analyses presented at the 18th Annual Scientific Meeting of the HFSA 2014 indicated that riociguat improved pulmonary capillary wedge pressure (PCWP), pulmonary artery compliance (PAC), stroke volume (SV), and quality of life (QoL) to a greater extent in patients with HFrEF, secondary PH, and low baseline PVR than in those with high baseline PVR (Table 3.1 [27]).

      Since the LEPHT study was confined to patients with PH associated with left ventricular dysfunction and did not meet its primary