Treatment of chronic heart failure with vericiguat

Abstract

A method of reducing the risk of cardiovascular death in patients with heart failure with reduced ejection fraction without worsening HF comprising treatment with vericiguat.

Description

TREATMENT OF CHRONIC HEART FAILUREFIELD OF THE DISCLOSURE

[0001] The present disclosure concerns reducing the risk of cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF) without worsening heart failure. The present disclosure also concerns reducing the risk of sudden cardiac death in patients with heart failure with reduced ejection fraction (HFrEF) without worsening heart failure. The present disclosure also concerns reducing the risk of death by heart failure in patients with heart failure with reduced ejection fraction (HFrEF) without worsening heart failure. The present disclosure also concerns reducing the risk of all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF) without worsening heart failure.BACKGROUND OF THE DISCLOSURE

[0002] Vericiguat (methyl {4,6-diamino-2-[5-fhroro-l-(2-fluorobenzyl)-lH-pyrazolo[3,4-b] pyridin- 3-yl] pyrimidin-5-yl} carbamate) has been approved in many countries for the treatment of worsening heart failure in certain HFrEF patients. Vericiguat has the following chemical structure:Vericiguat and processes for its preparation and use are disclosed in U.S. Pat. Nos. 8,420,656; 8,921,377; 9,604,948; 9,993,476; 10,736,896; and 11,439,642.

[0003] Vericiguat is a soluble guanylate cyclase (sGC) stimulator. The sGC enzyme is involved in the nitric oxide (NO) signaling pathway. On binding of NO to a prosthetic heme group on sGC, sGC catalyzes synthesis of the second messenger cGMP, which produces vasorelaxation and inhibits smooth muscleproliferation, leukocyte recruitment, and platelet aggregation through a number of downstream mechanisms. Because of these effects, sGC is a therapeutic target in cardiovascular disorders. sGC stimulators bind to the heme -containing (active) form of sGC and stimulate cGMP formation.

[0004] In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) phase 3 clinical trial, vericiguat was shown to reduce the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with worsening HFrEF with either a recent hospitalization within 6 months or outpatient IV diuretic treatment within 3 months of beginning the trial. See Butler et al., 2022; Ezekowitz et al., 2020; Senni et al., ESC Heart Fail 2022. Death from cardiovascular causes occurred in 414 patients (16.4%) in the vericiguat group and in 441 patients (17.5%) in the placebo group (hazard ratio, 0.93; 95% CI, 0.81 to 1.06). Consistent with the high-risk population studied, short term event rates in VICTORIA were high leading to a median follow-up of only 10.8 months in the trial.

[0005] Accordingly, the longer-term impact of vericiguat on cardiovascular mortality was not assessable in VICTORIA. Furthermore, since VICTORIA exclusively included a worsening heart failure population, the effect of vericiguat in more compensated ambulatory patients with HFrEF remains unknown.

[0006] To address this knowledge gap, the VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) phase 3 clinical trial was designed to assess the safety and efficacy of vericiguat on the risk of HHF or cardiovascular death among lower risk patients with HFrEF who have not experienced recent worsening heart failure. There exists a need for improved therapeutics for HFrEF in these patients, and for improved methods of treatment for such patients for HFrEF disease and related conditions.SUMMARY OF THE DISCLOSURE

[0007] According to some aspects, the disclosure concerns a method of reducing the risk of cardiovascular death in a patient, comprising administering to the patient vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein the patient has heart failure and a left ventricular ejection fraction of < 40%, further wherein for at least six months prior to the onset of administration of vericiguat, the patient has not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patient has not received IV diuretics . According to another aspect, the disclosure concerns a method of reducing the risk of cardiovascular death in a population of patients that have heart failure and a left ventricular ejection fraction of < 40%, comprising administering to each patient in the population vericiguat or a pharmaceutically acceptable salt thereof inan amount that is clinically proven effective , wherein for at least six months prior to the onset of administration of vericiguat, the patients have not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patients have not received IV diuretics, wherein as assessed at about 39 to about 43 months after onset of administration of vericiguat the population of patients has a reduction in time to first occurrence of cardiovascular death compared to a control population of patients and wherein the relative reduction in the hazard with vericiguat is 10% to 20% for time to cardiovascular death, and / or wherein the risk reduction in the population corresponds to a hazard ratio (“HR”) of about 0.8 to about 0.9. According to one embodiment of the present disclosure, the risk reduction in the population corresponds to a hazard ratio (“HR”) of about 0.83, with a 95% CI of 0.71 to 0.97. According to one embodiment, the reduction in time to first occurrence of cardiovascular death compared to a control population of patients is assessed 39 months after onset of administration of vericiguat.

[0008] According to another aspect, the disclosure concerns a method of reducing the risk of sudden cardiac death, comprising administering to the patient vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein the patient has heart failure and a left ventricular ejection fraction of < 40%, further wherein for at least six months prior to the onset of administration of vericiguat, the patient has not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patient has not received IV diuretics . According to another aspect, the disclosure concerns a method of reducing the risk of sudden cardiac death in a population of patients that have heart failure and a left ventricular ejection fraction of < 40%, comprising administering to each patient in the population vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein for at least six months prior to the onset of administration of vericiguat, the patients have not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patients have not received IV diuretics, wherein as assessed at about 39 to about 43 months after onset of administration of vericiguat the population of patients has a reduction in time to first occurrence of sudden cardiac death compared to a control population of patients and wherein the risk reduction in the population corresponds to a hazard ratio (“HR”) of about 0.75 with a 95% CI of 0.56 to 0.99.

[0009] According to another aspect, the disclosure concerns a method of reducing the risk of death from heart failure, comprising administering to the patient vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein the patient has heart failure and a left ventricular ejection fraction of < 40%, further wherein for at least six months prior to the onset of administration of vericiguat, the patient has not been hospitalized for heart failure and for at least threemonths prior to the onset of administration of vericiguat the patient has not received IV diuretics . According to another aspect, the disclosure concerns a method of reducing the risk of death from heart failure in a population of patients that have heart failure and a left ventricular ejection fraction of < 40%, comprising administering to each patient in the population vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein for at least six months prior to the onset of administration of vericiguat, the patients have not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patients have not received IV diuretics, wherein as assessed at about 39 to about 43 months after onset of administration of vericiguat the population of patients has a reduction in time to first occurrence of death from heart failure compared to a control population of patients and wherein the risk reduction in the population corresponds to a hazard ratio (“HR”) of about 0.71 with a 95% CI of 0.54 to 0.94.

[0010] According to another aspect, the disclosure concerns a method of reducing the risk of all-cause mortality, comprising administering to the patient vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein the patient has heart failure and a left ventricular ejection fraction of < 40%, further wherein for at least six months prior to the onset of administration of vericiguat, the patient has not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patient has not received IV diuretics. According to another aspect, the disclosure concerns a method of reducing the risk of all-cause mortality in a population of patients that have heart failure and a left ventricular ejection fraction of < 40%, comprising administering to each patient in the population vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein for at least six months prior to the onset of administration of vericiguat, the patients have not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patients have not received IV diuretics, wherein as assessed at about 39 to about 43 months after onset of administration of vericiguat the population of patients has a reduction in time to first occurrence of all-cause mortality compared to a control population of patients and wherein the risk reduction in the population corresponds to a hazard ratio (“HR”) of about 0.84 with a 95% CI of 0.74 to 0.99.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a chart showing the dose of vericiguat given to participants at different time periods during the VICTOR clinical trial.

[0012] FIG. 2 Shows Estimates of the Cumulative Incidence of the Mortality Outcomes in the VICTOR trial. Death from cardiovascular causes (Panel A), death from all cause (Panel B), sudden cardiac death (Panel C), and death related to heart failure (Panel D).Fig. 2A. Death from cardiovascular causes Number of participants at riskCumulative number of events up to the time point:HR 0.83, 95% CI 0.71-0.97; P = 0.02Fig. 2B. Death from all cause. Number of participants at riskCumulative number of events up to the time point:HR 0.84, 95% CI 0.74-0.97; P = 0.02Fig. 2C. Sudden cardiac deathNumber of participants at riskCumulative number of events up to the time point:HR 0.75, 95% CI 0.56-0.99; P = 0.04 Fig. 2D. Death by HF

[0013] The present disclosure is directed to methods to reduce the risk of cardiovascular death by administering vericiguat to patients with HFrEF who have not experienced recent worsening heart failure, including inter alia a therapy that has been proven to be clinically effective in such patients.

[0014] One embodiment of the disclosure is a method of reducing the risk of cardiovascular death in a patient, comprising administering to the patient vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective, wherein the patient has heart failure and a left ventricularej ection fraction (LVEF) of < 40%, further wherein for at least six months prior to the onset of administration of vericiguat, the patient has not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patient has not received IV diuretics.

[0015] One embodiment is the method of reducing the risk of cardiovascular death in a patient, wherein cardiovascular death is sudden death or death from heart failure. One embodiment is the method of reducing the risk of cardiovascular death in a patient, wherein the patient has never been hospitalized for heart failure prior to the onset of administration of vericiguat.

[0016] One embodiment is a method of reducing the risk of cardiovascular death in a population of patients that have heart failure and a left ventricular ejection fraction (LVEF) of < 40%, comprising: administering to each patient in the population vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective; wherein for at least six months prior to the onset of administration of vericiguat, the patients have not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patients have not received IV diuretics; wherein as assessed at about 39 to about 43 months after onset of administration of vericiguat the population of patients has a reduction in time to first occurrence of cardiovascular death compared to a control population of patients, and wherein the hazard ratio for cardiovascular death with the administration of vericiguat compared to the control population of patients is 0.80 to 0.90. In one embodiment, the hazard ratio for cardiovascular death with the administration of vericiguat compared to the control population of patients is 0.83. In one embodiment, the hazard ratio for cardiovascular death with the administration of vericiguat compared to the control population of patients is 0.83, with a 95% Confidence Interval of 0.71-0.97, and p=0.02.

[0017] One embodiment of the disclosure is the method of reducing the risk of cardiovascular death in a patient, wherein the patient has symptomatic chronic heart failure.

[0018] In the context of the present disclosure, pharmaceutically acceptable salts of vericiguat include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Pharmaceutically acceptable salts of the compounds according to the disclosure also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N- methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

[0019] Vericiguat or the pharmaceutically acceptable salts thereof can be employed alone or coadministered with one or more further therapeutically active agents or therapies. “Further therapeutically active agent or therapy” as used herein means, but is not limited to, active agents, medical apparatuses, or therapies that may treat a health condition. In one embodiment, the further therapeutically active agent or therapy is one or more active agents that are used in the standard of care in contemporary guidelines for the disease afflicting the patient. For example, the patient may receive vericiguat or a pharmaceutically acceptable salt thereof in combination with Guideline -directed medical therapy (GDMT) for HFrEF that is reported by the American College of Cardiology / American Heart Association Joint Committee on Clinical Practice Guidelines. The GDMT for HFrEF in 2022 includes four medication classes that are: (1) reninangiotensin system inhibition with angiotensin receptor-neprilysin inhibitor (ARNI, here: Trinatrium[3- (( 1 S,3R)- 1 -biphenyl -4-ylmethyl-3 -ethoxycarbonyl- 1 -butylcarbamoyl)propionate-(S)-3'-methyl-2'- (pentanoyl { 2" -(tetrazol-5 -ylat)biphenyl-4'-ylmethyl } amino)butyrate]hemipentahydrat or LCZ696), angiotensin-converting enzyme inhibitor (ACEI), or angiotensin (II) receptor blocker (ARB) alone; (2) beta-blockers; (3) mineralocorticoid receptor antagonists (MRAs); and (4) sodium-glucose cotransporter-2 inhibitors (SGLT2i). Accordingly, in certain embodiments, vericiguat is co-administered with a further therapeutically active agent or therapy that is a medication from one or more of those four classes of the GDMT. In one embodiment, vericiguat is co-administered with ARNI or, if ARNI is not feasible, with ACEi. In a further embodiment, vericiguat is co-administered with ARB; such as without limitation when the patient is intolerant to ACEi and the use of ARNI is not feasible. In a further embodiment, vericiguat is co-administered with 1 - 3 beta blockers, or 1, 2, or 3 beta blockers. In one embodiment, the patient is administered vericiguat and concomitantly is administered one, two, three, four, or five further therapeutically active agents or therapies. In one embodiment, the further therapeutically active agent or therapy is an SGLT2i or ARNI. In another embodiment, the further therapeutically active agent or therapy is an SGLT2i. In another embodiment, the further therapeutically active agent or therapy is ARNI. In one embodiment an SGLT2i and ARNI are co-administered with vericiguat. In another embodiment, a betablocker, an MRA, ARNI, and an SGLT2i are co-administered with vericiguat.

[0020] A recent meta-analysis on pharmacological treatment of HFrEF by Bart J. van Essen et al. (manuscript submitted) provides an update of a meta-analysis by Tromp et al., 2022. See Tromp et al. Trompshowed that a combination of P-blockers, angiotensin receptor-neprilysin inhibitors (ARNi), mineralocorticoid receptor antagonists (MRA), and sodium -glucose cotransporter 2 inhibitors (SGLT2i) was most effective in reducing all-cause mortality in heart failure with reduced ejection fraction (HFrEF). The recent meta-analysis by Bart J. van Essen updates the treatment benefit by including additional large randomized controlled trials (RCTs) since 2022, including the Vericiguat Global Study in Participants with Chronic Heart Failure (VICTOR) trial. MEDLINE, EMBASE, and Cochrane CENTRAL were searched for RCTs in patients with HFrEF through April 2025. Using frequentist network meta-analysis, hazard ratios (HRs) were estimated for all-cause mortality (primary outcome), cardiovascular death, and the composite of cardiovascular death or heart failure hospitalization (secondary outcomes). Absolute benefits were quantified as life-years gained using BIOSTAT-CHF and ASIAN-HF cohort data. The analysis included 103,754 patients across 89 randomized controlled trials. Relative to placebo, quintuple therapy with ARNi, P-blockers, MRA, SGLT2i, and vericiguat most effectively reduced all -cause mortality (HR 0.35, 95% confidence interval [CI]: 0.27-0.45), followed by quadruple therapy with ARNi, P-blockers, MRA and SGLT2i (0.39, 95% CI: 0.32-0.49). For a representative 70-year-old patient, quadruple therapy (ARNi / p-blockers / MRA / SGLT2i) provided 5.3 additional life-years (95% CI: 2.9-7.7 years) versus no treatment, while quintuple therapy (ARNi / p-blockers / MRA / SGLT2i / vericiguat) provided 6.0 additional life-years (95% CI: 3.7-8.4). A quintuple therapy regimen including ARNi, P-blockers, MRA, SGLT2i, and vericiguat provides the most significant mortality benefit in patients with HFrEF. Quintuple therapy can extend life by an estimated 6 years compared to no treatment.

[0021] In certain embodiments, the SGLT2i is dapagliflozin, canagliflozin, empagliflozin, ertugliflozin, atigliflozin, remogliflozin, or sergliflozin. In certain embodiments, the beta blocker is atenolol, bisoprolol, carvedilol, metoprolol, nebivolol, or propranolol. In certain embodiments, the MRA is spironolactone, eplerenone, or finerenone. In certain embodiments, ARNI is sacubitril / valsartan, such as the Novartis Entresto® (sacubitril / valsartan) tablets. In certain embodiments, ACEi is benazepril; captopril; enalapril; fosinopril; lisinopril; moexipril; perindopril; quinapril; ramipril; or trandolapril. In certain embodiments, ARB is azilsartan medoxomil; candesartan; eprosartan mesylate; irbesartan; losartan potassium; olmesartan; telmisartan; or valsartan.

[0022] Certain embodiments include co-administration of vericiguat with a further therapeutically active agent or therapy that is an implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT).

[0023] In one embodiment of the disclosure, the patient, at the onset of administration of vericiguat, is being treated with SGLT2 inhibitors and one or more further therapeutically active agent or therapy selected from the group consisting of ACEi-ARB, ARNI, MRA, ICD, and CRT.

[0024] In one embodiment of the disclosure, the patient, at the onset of administration of vericiguat, is being treated with ARNI and one or more further therapeutically active agent or therapy selected from the group consisting of ACEi-ARB, MRA, SGLT2i, ICD, and CRT.

[0025] In one embodiment of the disclosure, the patient, at the onset of administration of vericiguat, is being treated with ICD and one or more further therapeutically active agent or therapy selected from the group consisting of ACEi-ARB, ARNI, MRA, SGLT2i, and CRT.

[0026] One embodiment of the disclosure comprises co-administering or providing to the patient vericiguat in combination with a further therapeutically active agent or therapy, wherein the further therapeutically active agent or therapy is selected from the group consisting of beta-blockers; angiotensinconverting enzyme inhibitors (ACEi); angiotensin receptor blockers (ARB); mineralocorticoid receptor antagonists (MRA); angiotensin receptor neprilysin inhibitors (ARNI); sodium glucose co-transporter-2 inhibitors (SGLT2i); an implantable cardioverter defibrillator (ICD); and cardiac re synchronization therapy (CRT); and wherein the further therapeutically active agent or therapy is administered or provided either simultaneously or sequentially with vericiguat. In one embodiment, the further therapeutically active agent or therapy is an SGLT2i or ARNI. In one embodiment, the further therapeutically active agent or therapy is an SGLT2i. In one embodiment, the further therapeutically active agent or therapy is ARNI. In one embodiment, two or more further therapeutically active agents or therapies are co-administered or provided with vericiguat. In one embodiment, SGLT2i and ARNI are co-administered with vericiguat. In one embodiment, a beta-blocker, an MRA, ARNI, and an SGLT2i are co-administered with vericiguat.

[0027] The one or more therapies described herein can be administered to the patient substantially at the same time, or in any order. For instance, vericiguat and ARNI and an SGLT2i can be administered simultaneously, in the same or in separate compositions, or sequentially. Co -administration or concomitant therapy and similar terms is meant to encompass a patient receiving doses of each of the identified medications or therapies without meaning that the individual doses are administered on the same dose schedule. In some embodiments, the first therapy (e.g., ARNI) is continued when the second therapy is introduced, and in other embodiments the first therapy is withdrawn before, after, or at the same time as the second therapy is introduced. In instances of sequential administration, in some embodiments, the second therapy is initiated after a predetermined amount of time after initiation of a first therapy.

[0028] In one aspect of the disclosure, the patient is administered vericiguat, or a pharmaceutically acceptable salt thereof, orally once daily in a starting dose of 2.5 mg or 5.0 mg. In one embodiment, the starting dose of 2.5 mg is doubled approximately every two weeks to reach a target maintenance dose of 10 mg once daily. In another embodiment, the starting dose is 5.0 mg and is doubled approximately two weeks later to reach a maintenance dose of 10 mg daily.

[0029] The term “cardiovascular death” as used herein is defined as death due to diseases of the heart or blood vessels. Classification of a death as a “cardiovascular death” is aimed at capturing the primary cause of death, rather than an intervening cause. Examples of conditions that can cause cardiovascular death include, without limitation, coronary heart disease (CHD), myocardial infarction (MI), sudden cardiac death, death due to HF, death due to stroke, death due to cardiovascular procedures, death due to cardiovascular hemorrhage, and death due to other cardiovascular causes. In one embodiment of the present disclosure, cardiovascular death is sudden cardiac death. In one embodiment, cardiovascular death is death by heart failure.

[0030] The term “heart failure” as used herein is defined as a condition in which the heart cannot pump enough blood to a patient’s body to meet the body’s needs for blood and oxygen. In the context of the present disclosure, the term heart failure also includes more specific or related types of disease, such as acute decompensated heart failure, right heart failure, left heart failure, global failure, ischemic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, idiopathic cardiomyopathy, congenital heart defects, heart valve defects, heart failure associated with heart valve defects, mitral stenosis, mitral insufficiency, aortic stenosis, aortic insufficiency, tricuspid stenosis, tricuspid insufficiency, pulmonary valve stenosis, pulmonary valve insufficiency, combined heart valve defects, myocardial inflammation (myocarditis), chronic myocarditis, acute myocarditis, viral myocarditis, diabetic heart failure, alcoholic cardiomyopathy, cardiac storage disorders, heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Chronic heart failure patients having left ventricular rejection fraction (LVEF) of less than or equal to 40% are included in the patients treated by the present methods.

[0031] The American Heart Association, in collaboration with the American College of Cardiology have identified four stages of HF, labeled as Stage A, B, C, and D. Stage A HF is typically associated with patients that are at risk for HF. Patients who are at risk for heart failure but do not yet have symptoms or structural or functional heart disease would likely have Stage A HF. Risk factors for patients in this stage include, but are not limited to, hypertension, coronary vascular disease, diabetes, obesity, exposure tocardiotoxic agents, genetic variants for cardiomyopathy and family history of cardiomyopathy. Stage B HF is typically associated with patients that do not have current or previous symptoms of HF but do have structural heart disease, increased filling pressures in the heart, or other risk factors. Stage C HF is typically associated with patients that have current or previous symptoms of HF. Stage D HF is typically associated with heart failure symptoms that interfere with a patient’s daily life functions or lead to repeated hospitalizations. In some embodiments, the methods of the present disclosure are applied to a patient or a population of patients having Stage C or Stage D heart failure, as defined by the American Heart Association, at the onset of administration of vericiguat.

[0032] In one embodiment of the disclosure, the patient has Stage C or Stage D heart failure, as defined by the American Heart Association, at the onset of administration of vericiguat.

[0033] Symptoms of HF include but are not limited to dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal dyspnea), persistent cough, wheezing, edema, fatigue, lack of appetite, confusion, impaired thinking, sudden weight changes, chest pain, irregular heartbeat, decreased exercise tolerance, or other symptoms of worsened end-organ perfusion or volume overload.

[0034] The severity of symptoms associated with HF can be classified based on the New York Heart Association (NYHA) Functional Classification. The NYHA Functional Classification has four different classes: Class I, II, III, IV. Class I HF is associated with no limitation of physical activity. Patients with Class I HF should be able to engage in ordinary physical activity without undue fatigue, palpitation or shortness of breath. Class II HF is associated with a slight limitation in physical activity. Patients with Class II HF may be comfortable at rest but will often experience fatigue, palpitation, shortness of breath or chest pain during ordinary physical activity. Class III HF is associated with marked limitation in physical activity. Class III patients may be comfortable at rest, but less ordinary activity may cause fatigue, palpitation, shortness of breath or chest pain. Patients with Class IV HF often experience symptoms of HF at rest, with any physical activity causing further discomfort. In some embodiments, the methods of the present disclosure are applied to a patient or a population of patients having HF categorized in Class II, Class III, or Class IV, as defined by the New York Heart Association’s (NYHA) Functional Classification, at the onset of administration of vericiguat.

[0035] In one embodiment of the disclosure, the patient’s heart failure is categorized in Class II, Class in, or Class IV, as defined by the New York Heart Association’s (NYHA) Functional Classification, at the onset of administration of vericiguat. In one embodiment, the patient’s heart failure is categorized in ClassII, as defined by the New York Heart Association’s (NYHA) Functional Classification, at the onset of administration of vericiguat.

[0036] A patient with “symptomatic HF” as used herein is a patient with current or previous symptoms of heart failure.

[0037] A patient with “symptomatic chronic HF” as used herein is a patient with current or previous symptoms of heart failure that have developed overtime.

[0038] The term “hospitalization for heart failure” (HHF) as used herein is defined as a classification of cardiovascular hospitalization. A HHF is an admission to the hospital where a patient’s length of stay extends for at least 24 hours, and: the patient is admitted to the hospital with a primary diagnosis of HF; the patient exhibits documented new or worsening symptoms due to HF on presentation; the patient has objective evidence of new or worsening HF, consisting of at least two physical examination findings or one physical examination finding and one laboratory or invasively measured criterion; and the patient receives at least one of the following treatments specifically for HF: significant augmentation in oral diuretic therapy, initiation of intravenous diuretic, initiation of an intravenous vasoactive agent, mechanical or surgical intervention (including mechanical circulatory support), and mechanical fluid removal.

[0039] HF endpoints meeting these criteria in the emergency department (<24 hour stay) or an unscheduled office visit may be classified as “urgent HF visits.”

[0040] The term “worsening HF” as used herein is defined as either a recent HHF or a need for urgent intravenous diuretic therapy in an outpatient setting. HF worsening may also be defined as either a HF event that required hospitalization in the last six months or urgent outpatient diuretic use in the last three months.

[0041] Comorbidities are common for patients with HF and may affect the safety and efficacy of therapeutic interventions. Comorbidities are also associated with increased symptom burden and worse prognosis. Exemplary comorbidities for HF include, but are not limited to, anemia and iron deficiency, atrial fibrillation (AF) and atrial flutter, cachexia, chronic obstructive pulmonary disease (COPD), CAD, type 2 diabetes mellitus, hyperkalemia and hypokalemia, renal dysfunction, renal failure, sleep-disordered breathing, and valvular disease. In some embodiments the patient or population of patients has one or more of these comorbidities and is treated with one of the methods described herein.

[0042] As used herein “patient” refers to a mammal, such as a human subject, in some embodiments an adult human subject. In some embodiments the patient is under 65 years of age; in other embodiments the patient is 65 years of age or older.

[0043] In one embodiment of the present disclosure, the patient, measured at the onset of administration of vericiguat, has an elevated N-terminal pro-B-type natriuretic peptide (NTproBNP) level. In other embodiments, the patient has an NTproBNP level from about 600 to about 2500, about 600 to about 2400, about 600 to about 1990, about 600 to about 1300, about 600 to about 1400, about 600 to about 1000, or about 600 to about 6000 pg / mL. In other embodiments, the patient has an NTproBNP level of from 600 to 6000 pg / mL with every integer in between the end units being included within the disclosed range. In another embodiment the patient population has a median NTproBNP of between 1000 and 1400 pg / mL, 1100 and 1400, 1200 and 1400, 1300 and 1500, 1300 and 1400, or 1000 to 1800 pg / mL measured at the onset of administration of vericiguat. In one embodiment of the present disclosure, the patient population has a median NTproBNP of between 800 and 2250 pg / mL

[0044] In certain embodiments, the patient at the onset of administration of vericiguat is in sinus rhythm and has an NTproBNP level between about 600 and about 6000 pg / mL or at the onset of administration of vericiguat the patient is in atrial fibrillation and has NTproBNP level between about 900 and about 6000 pg / mL.

[0045] In embodiments of the present disclosure, the patient, at the onset of administration of vericiguat, has a baseline estimated glomerular filtration rate (eGFR) of from 15 to 30, greater than 30 to 60, or greater than 60mL / min / 1.73m2. In one embodiment, the patient, at the onset of administration of vericiguat, has a baseline eGFR of 68.042 ± 26.301 mL / min / 1 ,73m2or a population of patients has a mean baseline eGFR of 68.042 ± 26.301 mL / min / 1.73m2.

[0046] In one embodiment of the present disclosure, the patient, at the onset of administration of vericiguat, has ischemic heart disease. “Ischemic heart disease” as used herein is defined as a history of one or more of coronary artery disease (CAD), myocardial infract (MI), percutaneous coronary intervention (PCI), and coronary artery bypass graft surgery (CABG).

[0047] In one embodiment of the present disclosure, the patient, at the onset of administration of vericiguat, has atrial fibrillation (AF).

[0048] In one embodiment of the present disclosure, the patient, at the onset of administration of vericiguat, or a population of patients on average has a LVEF of less than or equal to 40%, about 40% to about 35%, about 40% to about 30%, about 40% to about 20%, about 30% to about 20%, about 35% to about 20%, or about 35% to about 30%. In another embodiment, the patient, at the onset of administration of vericiguat, has a baseline LVEF of 40% to 30.42% or less than 30.42%; or a population of patients has a mean baseline LVEF of 30.42% ±8.0%, or a mean baseline LVEF of 30.42%. In one embodiment of the disclosure, the patient, at the onset of administration of vericiguat, has a baseline LVEF of > 31% ± 7.

[0049] In one embodiment, the patient at the onset of administration of vericiguat has one or more of the characteristics selected from an NT-proBNP level of 800-2250 pg / mL, an LVEF of > 31%, NYHA class II.

[0050] As used herein a measurement assessed at “the onset of administration” of vericiguat or another therapy includes at a time within 0-12 months from the onset of administration.

[0051] As used herein the term “effective” as it relates to treatment of an HFrEF patient with an sGC stimulator that is vericiguat refers to reducing the risk of cardiovascular death.

[0052] As used herein the term “clinically proven effective” as it relates to treatment of an HFrEF patient with an sGC stimulator that is vericiguat refers to an effective treatment as defined herein that also is shown to meet standards of statistical rigor as those are understood by one skilled in the art for a clinical trial. For example, clinically proven effective treatment of HFrEF with vericiguat in HFrEF patients having LVEF less than or equal to 40%, and no recent worsening heart failure episode (such as no HHF within 6 months or outpatient IV diuretic use within 3 months before randomization) includes a treatment that was shown in a clinical trial such as one acceptable to the USFDA, to have the results statistically conclusive of the benefit of vericiguat administration over placebo or of vericiguat in combination with a further therapeutically active agent or therapy over placebo. The benefit measured in such a clinical trial may be one or more of these as measured across the population of all patients enrolled in the trial: increased mean or median time before cardiovascular death, and increased mean or median time before all-cause mortality. Other benefits of a clinical trial that are sufficient to show clinical efficacy may be increased time before the first event of eGFR slope and change from baseline in health-related quality of life measures (KCCQ, and EQ-5D-5L). Measures of clinical efficacy may be calculated using any statistical measurement known to those of ordinary skill in the art. For example, the statistical method to determine efficacy may be an analysis of the primary endpoint performed with a one-sided stratified log -rank test to test whether the timeto first event of CV death is prolonged in the vericiguat treatment group compared with placebo. The same approach may be used for the endpoint of time to all-cause mortality.

[0053] Kaplan-Meier estimates of the survival curves and the corresponding 95% Cis may be presented for each intervention group. The hazard ratio and corresponding 95% CI may be estimated based on a Cox proportional hazards model stratified by the stratification factor for randomization. In addition, as a sensitivity analysis the primary endpoint may be analyzed using the 5 -STAR stratified testing approach by Mehrotra and West.

[0054] For patients with HFrEF without worsening heart failure the hazard ratio (“HR”) for an endpoint of cardiovascular death with vericiguat compared to a control may be about 0.80, 0.7-0.8, 0.6-0.8, 0.5-0.9, or about 0.80-0.90, or about 0.7, 0.81, 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89 or 0.9. In one embodiment, the hazard ratio is 0.83, with a 95% CI of 0.71 to 0.97. In one embodiment this HR corresponds to the relative reduction in the hazard with vericiguat being 10% to 20% for time to cardiovascular death.

[0055] As used herein, “hazard ratio” is a measure of how often a particular event happens in one group compared to how often it happens in another group, over time. A hazard ratio of one means that there is no difference in survival between the two groups. A hazard ratio of less than one means that there is a decreased risk in one of the groups.

[0056] These hazard ratios may be obtained from clinical studies involving randomization of over 6,000 patients with HFrEF without worsening heart failure. In other embodiments, the clinical trials and the populations being treated have at least 6,105; at least 5,000; at least 4,000; or at least 3,000 patients or 6,200-5,200 or 6,500-6,000 patients enrolled that form a population from which the hazard ratios may be determined and that have a sufficiently large enrollment to establish to the satisfaction of the US FDA the safety and efficacy of the administration of vericiguat for the methods disclosed herein.EXAMPLESEXAMPLE 1 - DESIGN OF THE VICTOR TRIAL

[0057] The VICTOR Phase 3 clinical trial was designed to assess the efficacy and safety of vericiguat in patients with LVEF <40% without recent worsening HF on a background of current foundational HFrEF therapy. The study design and procedures can be found under https: / / clinicaltrials.gov, study number NCT05093933.

[0058] Abstract

[0059] Aims: The VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial showed that the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent HF worsening remained unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with EF <40% without recent worsening HF on a background of current foundational HFrEF therapy.

[0060] Methods: The primary endpoint for VICTOR was time to first event for the composite of HHF or cardiovascular death. As an event driven trial, at least 1080 primary events were expected, but followup continued until the targeted number of at least 590 cardiovascular deaths had been reached. 6105 participants were be randomized to vericiguat (3053 patients) or placebo (3052 patients). The trial also assessed effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death.

[0061] Conclusion: VICTOR is believed to be the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR added important information to the totality of evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

[0062] Introduction

[0063] Vericiguat, a soluble guanylate cyclase stimulator, is approved in many countries for the treatment of worsening heart failure (HF) with reduced ejection fraction (HFrEF). In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, vericiguat was shown to reduce the risk of hospitalization for heart failure (HHF) or cardiovascular death in patientswith HFrEF and a left ventricular ejection fraction (LVEF) <45%. See Armstrong et al., 2020. Worsening HF was defined as either a recent HHF or a need for urgent intravenous diuretic therapy in the outpatient setting. Consistent with the population studied, short term event rates in VICTORIA were high leading to a median follow-up of only 10.8 months in the trial. With potential for vericiguat related cardioprotection with more prolonged drug exposure, the longer-term impact of vericiguat on cardiovascular mortality was therefore not assessable in VICTORIA. See Butler et al., 2022. In keeping with clinical practice at time of enrollment, baseline use of angiotensin receptor neprilysin inhibitors (ARNI) was modest and use of sodium glucose co-transporter-2 (SGLT2) inhibitors was negligible in VICTORIA. Furthermore, since VICTORIA exclusively included a worsening HF population, the effect of vericiguat in more compensated ambulatory patients with HFrEF remained unknown. This is relevant as analyses from VICTORIA suggested that efficacy was potentially greater among less sick patients. See Ezekowitz et al., 2020; Senni et al., ESC Heart Fail 2022.

[0064] The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to address existing knowledge gaps by assessing the safety and efficacy of vericiguat on the risk of HHF or cardiovascular death among contemporary lower risk patients with HFrEF who have not experienced recent worsening HF. The VICTOR trial assessed the impact of vericiguat in the background of expected higher use of ARNI and SGLT2 inhibitors at baseline, affording the opportunity to assess the value of vericiguat on top of contemporary guideline directed medical therapy (GDMT). The VICTOR trial was therefore well positioned to address the unresolved impact of vericiguat on cardiovascular mortality, while expanding the totality of evidence for vericiguat to cover the entire spectrum of risk in HFrEF.

[0065] Study Design

[0066] VICTOR is a double-blind, placebo-controlled, parallel group, 1: 1 randomized, event-driven trial testing the effects of oral vericiguat at a target dose 10 mg vs placebo in ambulatory patients with HFrEF and no recent worsening HF episode. As an event driven trial, the study was designed to assess the primary endpoint but was also designed to ensure adequate power to assess the impact of vericiguat on cardiovascular deaths. Therefore, the follow-up continued until the targeted number of cardiovascular deaths were reached. A steering committee provided guidance and made recommendations on the operational aspects of the study. In addition, a data monitoring committee monitored unblinded interim data from the study and made recommendations to the executive oversight committee. The target dose and titration regimen for VICTOR were based on data from VICTORIA where vericiguat was well toleratedwith -90% of participants receiving the target dose of 10 mg once daily at 1 year. See Armstrong et al., 2020.

[0067] Eligibility

[0068] The eligibility criteria for VICTOR are shown in Table 1. Consistent with the aim of testing vericiguat in an ambulatory HFrEF population without recent worsening HF, there were important eligibility criteria differences between the VICTOR and VICTORIA trials. To test the chronic effects of vericiguat in an ambulatory HFrEF population, VICTOR excluded patients with a recent event of HF worsening, with HF worsening defined as either a HF event that required hospitalization in the last 6 months or urgent outpatient diuretic use in the last 3 months. Indeed, the higher short-term risks of recurrent HHF or cardiovascular death decreases within the first 6 months after a worsening HF event. See Kimmoun et al., 2021.

[0069] The LVEF inclusion criterion in VICTORIA was <45%, whereas VICTOR limited enrollment to patients with LVEF <40%. See Kondo et al., 2023. This threshold is consistent with the universal definition of HFrEF. See Heidenreich et al., 2022. In VICTORIA, those with baseline N-terminal pro-B- type natriuretic peptide (NTproBNP) levels in the lower three quartiles (<5314 pg / mL) derived the greatest benefit from vericiguat with the benefit attenuating in those in the highest quartile. See Ezekowitz et al.,2020; Senni et al., ESC Heart Fail 2022. Consistent with the study aim of evaluating vericiguat in more compensated patients with HFrEF, participants with NTproBNP >6000pg / ml were excluded. The lower limit NT-proBNP entry criterion was 600 pg / ml in patients with sinus rhythm and 900 pg / ml in those with atrial fibrillation. See McMurray et al., 2014; McMurray et al., 2019. Enrollment of participants with estimated glomerular filtration rate (eGFR) between 15 and 30 mL / min / 1.73 m2was limited to -15% of the total study population.

[0070] Despite exclusion of participants at highest risk for events, it was expected that substantial residual risk would remain in enrolled patients despite contemporary therapy. This risk was evident in trials using broadly similar entry criteria including lower natriuretic peptide inclusion thresholds. The annualized event rate for time to HHF or cardiovascular death in DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitors with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) was 11.4% in the dapagliflozin arm and 10.5% in thesacubitril / valsartan arm, respectively, underscoring the unmet need for novel therapies to decrease this residual risk.

[0071] Randomization and Visits

[0072] After a screening period of up to 30 days, -6000 participants were randomized 1: 1 to receive vericiguat titrated to 10 mg daily or placebo. Randomization was stratified by baseline New York Heart Association class (II vs III / IV). Following a 4-week drug titration period (FIG. 1), participants returned for scheduled visits every 24 weeks until study completion. After end of treatment, all participants had a followup evaluation at day 14 for safety assessment. Blood for genetic analysis was collected after randomization to explore potential genetic variation in treatment response, while blood for exploratory biomarker research was collected both at randomization and 24 weeks.

[0073] Drug Titration

[0074] Participants started with a 2.5 mg oral dose of blinded vericiguat or matching placebo once daily. The dose was titrated to 5 mg vericiguat or matching placebo at the next study visit scheduled at 14±4 days and the second titration to 10 mg vericiguat or matching placebo at the following study visit at 28±4 days after randomization. Dose titration depended on systolic blood pressure and symptoms of hypotension (Table 2). If the participant did not reach the 10 mg dose by 28±4 days after randomization, further evaluation for up-titration occurred at unscheduled and scheduled visits. It was strongly recommended that other GDMT should not be reduced for the purpose of facilitating the maintenance of study intervention dosing.

[0075] Background Therapy

[0076] In contrast to VICTORIA, the VICTOR trial was conducted following the establishment of SGLT2 inhibitors as recommended therapy in HFrEF based on the DAPA-HF and the EMPEROR- REDUCED (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction) trials. See McMurray et al., 2014; Packer et al., 2020. Although the results of PARADIGM-HF demonstrating benefit with ARNI were available during VICTORIA enrollment, the use of ARNI was modest (<20%) at baseline in VICTORIA. See McMurray et al., 2014; Senni et al., Eur J Heart Fail 2022. With recent trials and guideline updates now endorsing ARNI as first line therapy for HFrEF, it is anticipated that a higher baseline use of ARNI in VICTOR will be seen. See Velazquez et al., 2019; Heidenreich et al., 2022. VICTOR is the first large, randomized outcome trial in the modem era of quadruple therapy in HFrEF (Table 4). By recruiting a compensated well treated population with persistent left ventricular dysfunction, high rates of implantable cardioverter defibrillator use were also expected. Since ARNI, SGLT2i and defibrillator therapies all decrease sudden cardiac death rates, cardiovascular death rates may be lower in VICTOR than previous trials. See Rohde et al., 2020. Therefore, VICTOR provided contemporary estimates of residual risk for HHF and cardiovascular death in an ambulatory HFrEF population.

[0077] Endpoints

[0078] The primary hypothesis of the VICTOR trial was that vericiguat is superior to placebo in reducing the risk of HHF and cardiovascular death. The effects of vericiguat on the cardiovascular death alone were assessed. Additional secondary efficacy endpoints included assessing the effect of vericiguat on time to first HHF, time to total (first and recurrent) HHF, time to first HHF or all-cause death, and time to all-cause death (Table 5). Exploratory endpoints included time to the first urgent HF visit or HHF, time to first cardiovascular hospitalization, total number of HHF, eGFR slope, and change in health -related quality of life. Quality of life will be measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), and EuroQol 5-dimension 5-level scores at baseline, week 24, and then every 48 weeks to determine their change from baseline to capture treatment effects on patient reported outcomes.

[0079] Endpoint Adjudication

[0080] All primary and secondary endpoint components were adjudicated by an independent clinical endpoint committee (CEC). This included death, cardiovascular hospitalization (including HHF) and urgent HF visits. Adjudication of all events proceeded in 2 phases utilizing pre-specified endpoint criteria and clinical experience. In phase 1, two independent physician reviewers adjudicated events and in case of agreement that event was considered adjudicated. If there was disagreement between the two reviewers, a phase 2 committee of at least three physicians adjudicated the endpoint by consensus. If consensus could not be reached by phase 2 committee, the adjudicated case described via meeting minutes with consultation between phase 2 reviewers and CEC chair with conclusion documented. HHF utilized pre-specified criteria requiring hospitalization for at least 24 hours with objective evidence of symptoms, physical examination, and laboratory evidence of HF with initiation or intensification of treatment for HF. HF endpoints otherwise meeting these objective criteria in the emergency department (<24 hour stay) or an unscheduled office visit were classified as urgent HF visits.

[0081] Statistical Analysis

[0082] The primary efficacy analysis was performed following the intention to treat principle including all randomized participants using a stratified log-rank test. Testing was performed using a onesided type I error rate of 0.025 for the primary endpoint as well as time to cardiovascular death, time to first HHF, time to all -cause mortality, and time to first HHF or all-cause mortality. The total HHF analysis used the Anderson-Gill method. Time to cardiovascular death or time to first HHF was each tested only if the null hypothesis was rejected for the primary endpoint but was not otherwise be controlled for multiplicity. The other secondary endpoints, addressing time to total HHF, time to first HHF or all-cause mortality, and time to all-cause mortality were controlled for multiplicity using a hierarchical testing approach. The secondary endpoints were tested in order if the null hypothesis of the primary composite endpoint was rejected, stopping at the first endpoint that did not achieve significance at the one-sided alpha level of 0.025. Subgroup analyses for the primary endpoint were performed to evaluate for consistency of treatment effectacross age, sex, race, geographic region, eGFR, New York Heart Association class, baseline ARNI use, SGLT2i use, implanted defibrillator, NTproBNP quartile, and median LVEF. Safety analyses, including descriptive statistics of nonserious adverse events, serious adverse events, and events of clinical interest were included all randomized participants.

[0083] Event Rate Assumption

[0084] The placebo event rates for the primary endpoint and for cardiovascular death for VICTOR were based on data from recent HF trials. In PARADIGM -HF, the incidence of HHF or cardiovascular death was 10.5 and 13.2 per 100 patient-years, and cardiovascular death 6 and 7.5 per 100 patient-years, in the sacubitril / valsartan and enalapril arms, respectively. In DAPA-HF, the incidences for HHF or cardiovascular death were 11.4 and 15.3 per 100 patient-years and for cardiovascular death were 6.5 and 7.9 per 100 patient-years, in the dapagliflozin and placebo arms, respectively. See McMurray et al., 2019. Considering these event rates in the context of exclusion of recent worsening HF and anticipated high use of both ARNI and SGLT2i in VICTOR, the event rate for HHF or cardiovascular death in the placebo arm of VICTOR was estimated to be 11.5 per 100 patient-years and for cardiovascular death 6 per 100 patient- years.

[0085] Sample Size and Power Calculation

[0086] The sample size calculation was based on the above estimated event rates, ensuring adequate power to assess cardiovascular death. Assuming a hazard ratio of 0.80 for the cardiovascular death endpoint and using a one-sided alpha of 0.025, 590 cardiovascular deaths provide 80% power for cardiovascular death conditional on a positive primary endpoint. Based on the planned number of cardiovascular deaths and expected incidence rate in the placebo group of 6.0 cardiovascular deaths per 100 patient-years, a sample size of approximately -6000 participants was expected to yield 590 cardiovascular deaths with about 39 to about 43 months from the time of first participant enrolling until the last participant’s last study contact, and median follow-up of approximately 25 months. It was estimated that -1080 participants experienced a primary composite event at the time of 590 cardiovascular death events assuming a placebo incidence rate of 11.5 events per 100 patient-years and a hazard ratio of 0.80 which provided -95% power for the primary hypothesis.

[0087] Interim Analysis

[0088] A single interim analysis for efficacy is planned when approximately 413 cardiovascular deaths (70% of planned for the trial) are observed. To ensure that the study has accumulated adequate follow-up for safety assessment if stopped for efficacy, the timing of the interim analysis will require a median followup time of at least 10 months. At the interim analysis, the primary hypotheses will be tested. The Hwang, Shih and De Cani alpha-spending function will be used to assess superiority of vericiguat at the interim analysis. With this alpha-spending approach and a percentage of information of 70%, the nominal significance level will be approximately 0.005 (one-sided) at the interim analysis and 0.024 (one-sided) at the final analysis, respectively. This testing approach controls the one-sided alpha between the efficacy interim analysis and final analysis at 0.025. The actual alpha to be spent at the efficacy interim analysis will be determined using the number of observed cardiovascular deaths and the alpha-spending function. Cardiovascular death at the interim analysis will not be tested unless the interim success criterion for the primary endpoint is met. The study can be terminated early for success only if both the primary endpoint and the cardiovascular death endpoint reach the statistical significance level of approximately 0.005 (onesided); otherwise, the study will continue until the prespecified number of 590 cardiovascular deaths have accumulated. If the study can be stopped early for success, the nominal one-sided significance level of approximately 0.005 for the primary endpoint and cardiovascular death will be applied to other secondary endpoints as well.

[0089] Safety

[0090] The adverse event profile in VICTORIA was related to vericiguat’s mechanism of action (nausea, headache) and similar to that reported with other soluble guanylate cyclase stimulators. See Armstrong et al., 2020. These adverse events were generally nonserious and uncommon even in the high- risk VICTORIA population. The effect of vericiguat on systolic blood pressure during the study was ~l-2 mm Hg more mean reduction in participants who received vericiguat. See Armstrong et al., 2020; Lam et al., 2021. Based on the overall safety profile of vericiguat in VICTORIA, and VICTOR studying a more stable HFrEF population, the VICTOR trial has been granted by the US Food and Drug Administration a more streamlined approach to adverse event monitoring by sites. Safety endpoints of clinical interest include adverse events of symptomatic hypotension, anemia and potential drug induced liver injury. Since ARNI therapy has a well-established vasodilatory effect with larger decrease in blood pressure compared to angiotensin converting enzyme inhibitors alone, evaluation of safety in this subgroup was of interest. See Pfeffer et al., 2021; Desai et al., 2019. In VICTORIA there was no clear evidence of increased adverse events, dizziness or hypotension with vericiguat compared to placebo in those on background ARNI therapy; however, VICTOR was expected to have a larger proportion of patients with this therapy. SeeSenni et al., Eur J Heart Fail 2022. Modestly higher proportions of participants with an adverse event of anemia were observed in the vericiguat arm (9.6%) compared with the placebo arm (7.4%) in VICTORIA. See Ezekowitz et al. 2021. Since SGLT2is have been demonstrated to improve anemia in HFrEF through multiple mechanisms, the effect of vericiguat on anemia in this population with anticipated high SGLT2i use was evaluated. See Lorenzo et al., 2023.

[0091] Discussion

[0092] The VICTOR trial has several unique features that provided novel insight. The exclusive focus on patients without recent worsening HF was unique among large outcome trials in HFrEF. Recruited patients were also anticipated to have higher rates of quadruple therapy than prior trials, thereby being more representative of the contemporary epidemiology of HFrEF following the availability of ARNI and SGLT2i. These baseline features were expected to translate into lower cardiovascular death rates reflecting true contemporary residual risk for well -treated ambulatory HFrEF. There was also likely to be an alteration in the traditional composition of cardiovascular death events with anticipated lower sudden cardiac death rates in the setting of excellent background medical and device therapy. Recognizing these factors, VICTOR was designed as an event driven trial where follow-up continued until the target number of cardiovascular death events was achieved. VICTOR therefore provided reliable estimates of the effects of vericiguat on cardiovascular death in current ambulatory patients with HFrEF who continue to have meaningful residual risk.

[0093] VICTOR is believed to be the first large event driven trial in patients with HFrEF with an expected high utilization of both ARNI and SGLT2i. The contemporary HFrEF trials that established ARNI and SGLT2i as foundational therapy included active treatment arms with either no patients on current standard of care with quadruple therapy (PARADIGM-HF) or very low use of quadruple therapy. See Solomon et al., 2019. There is currently uncertainty about expected mortality and HF event rates in a contemporary HFrEF population with high utilization of quadruple therapy; information that is necessary to calibrate residual risk for considering additional and advanced HF therapies, including drugs and devices. In VICTOR, anticipated event rates were modeled for a contemporary stable HFrEF population by combining prior trial estimates, but the actual observed rates in VICTOR provided the most updated estimates of residual risk for ambulatory HFrEF with modem medical therapy. By studying the effect of vericiguat on top of high background utilization of quadruple therapy in an event driven trial, VICTOR was believed to represent the first HFrEF trial attempting to demonstrate incremental efficacy on HF outcomes in what is likely to be the most well treated HFrEF trial cohort to date.

[0094] Another notable feature of VICTOR was the enrollment of an ambulatory HFrEF population with intentional exclusion of those with recent worsening HF. Prior outcome trials have focused either exclusively on patients with recent worsening HF (GALACTIC-HF, VICTORIA), or included subsets with recent hospitalization for HF within 6 months (between 16-31% in PARADIGM -HF, DAPA- HF and EMPEROR REDUCED) (Table 4). See Teerlink et al., 2020; Armstrong et al., 2020; Solomon et al., 2019; McMurray et al., 2019; Packer et al., 2020. Inclusion of such patients enriches for a cohort with high short-term event rates. Although this is appealing from a trial design standpoint to decrease the trial duration, there are potential downsides to this approach. Patients with recent worsening HF have an increased early risk for HHF regardless of treatment. The relatively short duration of follow-up reduces the chance to assess the longer-term effect of novel therapy on mortality. In addition to shorter duration of randomized drug exposure, early events after recent worsening HF are dominated by recurrent worsening HF with HHF events, with proportionally lower cardiovascular death events.

[0095] For reference, there was a median 27-month follow-up in a more general HFrEF cohort in PARADIGM-HF, with an even split between cardiovascular death or first HHF events (Ratio cardiovascular death / HHF 1.05) (Table 4). See Kaul et al., 2023. In contrast, the median follow-up time for randomized drug exposure was 11 months in the exclusively worsening HF cohort in VICTORIA with cardiovascular death events being 41 % lower than HHF events (Ratio cardiovascular death / HHF 0.59). See id. Without focusing on a recent worsening HF population and with adequate median follow-up, both cardiovascular mortality and HHF were clearly reduced with ARNI therapy in PARADIGM-HF. In VICTORIA however, only HHF was clearly reduced with vericiguat, with uncertainty over the effect on cardiovascular death due to the short median follow-up and high rate of early HHF in the exclusively worsening HF population studied. In another worsening HF population from the GALACTIC-HF trial, although there were also high HHF events relative to cardiovascular death (Ratio cardiovascular death / HHF 0.68), the trial was larger with greater planned power to evaluate cardiovascular death compared to VICTORIA. This resulted in a longer 22-month median follow-up in GALACTIC-HF which allowed conclusive determination of the absence of a meaningful effect on cardiovascular death with omecamtiv mecarbil. With enrollment of a stable ambulatory HFrEF population in VICTOR, lower event rates will result in a longer median follow-up, thereby providing definitive evidence for either the presence or absence of a meaningful effect of vericiguat on cardiovascular mortality in HFrEF.

[0096] The longer median drug exposure in VICTOR also addressed the relative risks and benefits in this well treated ambulatory HFrEF cohort with high background ARNI and SGLT2i use. The high use of both ARNI and SGLT2i which each independently decrease sudden cardiac death, along with high ratesof defibrillator use resulted in a shift in mode of cardiovascular death with less expected sudden cardiac death. See Rohde et al., 2020. By being the first large contemporary trial of ambulatory HFrEF patients without recent worsening HF, VICTOR provided the best information on the residual risk of HF events and sudden cardiac death in patients on quadruple therapy, comparatively in patients with and without an implantable defibrillator.

[0097] With the unresolved issue of vericiguat’ s effect on mortality in HFrEF after VICTORIA, the VICTOR trial is not only event-driven, but also specifically powered for the cardiovascular death component of the primary endpoint. The trial therefore continued until the planned number of cardiovascular death endpoints have been achieved so that the effect of vericiguat on cardiovascular death can be reliably determined. Inclusion of ambulatory HFrEF patients in VICTOR that were excluded from VICTORIA added valuable information to the totality of evidence of the effects of vericiguat across the spectrum of risk for patients with HFrEF.

[0098] VICTOR was designed and powered to assess for cardiovascular mortality independently. Vericiguat led to a 17% significant reduction in events of cardiovascular death, also translating into a 16% significant reduction in events of death for any cause, with reductions in both sudden cardiac death and death due to HF. Vericiguat reduced HF-related and sudden cardiac deaths in a cohort of patients already receiving the most comprehensive HFrEF evidence -based therapy (GDMT). GDMT in HFrEF included SGLT2 -inhibitors and angiotensin receptor-neprilysin inhibitor (ARNI). This suggests an additive benefit, which is even more relevant when considering the overall trend of declining HF -related and sudden cardiac death rates in HFrEF patients due to cumulative effects of proven therapies, such as [3-blockers, MRAs, sacubitril-valsartan, SGLT2-inhibitors, implantable cardioverter defibrillators, and chronic resynchronization therapy. Vericiguat was well tolerated in the VICTOR study, and the safety profile was consistent with previous clinical trials.EXAMPLE 2 - RESULTS OF THE VICTOR STUDY2. 1 EFFECT OF VERICIGUAT ON HF-RELATED MORTALITY

[0099] The significant reduction on cardiovascular death, also translating into a 16% significant reduction in events of death for any cause, with reductions in both sudden cardiac death and death due to HF by treatment with vericiguat is shown in Tables 6 to 10 and Figure 2. Vericiguat reduced HF-related and sudden cardiac deaths in a cohort of patients already receiving the most comprehensive HFrEFevidence-based therapy (GDMT). GDMT in HFrEF included SGLT2 -inhibitors and angiotensin receptor- neprilysin inhibitor (ARNI).Table 6. Baseline characteristics of cardiovascular death survivors vs non-survivorsaExpanded includes participants who self-identified as Black, or Multi-racial including Black.bMissing values: Survivors = 107, Non-Survivors = 12, total = 119.cLoop diuretic use includes Bumetanide, Etacrynic acid, Furosemide, Furosemide sodium, and Torasemide. CV, cardiovascular; eGFR, estimated glomerular filtration rate; IQR, interquartile range; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation.Table 7. Mortality outcomesTable 8. Cardiovascular mortality and all-cause mortality by baseline medical and device therapyCI = confidence interval, GDMT =, HR = hazard ratio, KM = Kaplan Meier estimate, PY = patient-year,Table 9. Mortality Subgroup Analysis: Time-to Cardiovascular MortalityCI = confidence interval, eGFR = estimated glomerular filtration rate, GDMT = guideline-directed medical therapy, HFH = heart failure hospitalization, HR = hazard ratio, ICD = implantable cardioverter defibrillator, KM = Kaplan Meier estimate, NE = Not Estimable LVEF = left ventricular ejection fraction, PY = patient-year, SGLT2i = sodium-glucose cotransporter 2 inhibitorTable 10. Mortality Subgroup Analysis: Time to All-Cause DeathCI = confidence interval, eGFR = estimated glomerular filtration rate, GDMT = guideline -directed medical therapy, HFH = heart failure hospitalization, HR = hazard ratio, ICD = implantable cardioverter defibrillator, KM = Kaplan Meier estimate, NE = Not Estimable, LVEF = left ventricular ejection fraction, PY = patient-year, SGLT2i = sodium-glucose cotransporter 2 inhibitor2.2 EFFECT OF VERICIGUAT ON WORSENING HEART FAILURE IN COMPENSATED OUTPATIENTS WITH HFrEF: INSIGHTS FROM VICTOR

[0100] Background'. In the VICTOR trial, in a contemporary ambulatory cohort with heart failure and reduced ejection fraction (HFrEF) and no recent hospitalization, the primary outcome of hospitalization for heart failure (HHF) and cardiovascular death was not statistically significantly reduced with vericiguat. Vericiguat reduced risk of mortality but not HHF. In this ambulatory compensated cohort, time to first HHF may underestimate the overall worsening HF burden by failing to consider the high proportion of outpatient worsening HF events.

[0101] Objectives'. To determine the effect of vericiguat on the overall risk of worsening HF by incorporating the entire patient experience of worsening outpatient and inpatient HF episodes.

[0102] Methods'. VICTOR, was a phase 3, double-blind, placebo-controlled trial testing the effect of vericiguat in ambulatory patients with HFrEF who had not experienced recent worsening (defined as HHF admission within 6 months or outpatient intravenous diuretic use within 3 months) and were on a background of high use of contemporary guideline therapy. The primary endpoint was a composite of cardiovascular death or HHF. The current analysis provides detailed effects of vericiguat on overall worsening HF in both the inpatient and outpatient settings, including urgent care visits for intravenous diuretics or outpatient oral diuretic initiation or intensification.

[0103] Results'. A total of 6,105 participants were randomized. Outpatient worsening HF was more common as the first worsening HF event (n=851, 59.3%), compared to HHF (n=507, 35.4%) or urgent HF visits (n=76, 5.3%). Outpatient oral diuretic initiation or intensification was associated with increased mortality [RR 1.69 (95% CI 1.47-1.94), p<0.001]. Overall worsening heart failure occurred in 686 participants (22.5%) in the vericiguat group and 748 participants (24.8%) in the placebo group (HR 0.90; 95% CI 0.81-1.00, p=0.047). The composite of all-cause death and overall worsening HF occurred in 917 participants (30.0%) in the vericiguat group and 1004 participants (32.9%) in the placebo group (HR 0.90, 95% CI 0.82-0.98, p=0.016).

[0104] Conclusions'. In compensated patients with HFrEF on contemporary guideline therapy, outpatient worsening HF was more common than HHF and was associated with higher mortality risk. Exploratory analyses suggested a potential reduction in overall worsening HF events when both inpatient and outpatient settings were considered.

[0105] Introduction

[0106] Despite major advances in pharmacotherapy for heart failure (HF) with reduced ejection fraction (HFrEF) (see McMurray et al., 2019; Packer et al, 2020; Solomon et al., 2019), patients still experience disease progression characterized by discrete episodes of clinical worsening in both the inpatient and outpatient setting, see Greene et al., 2023. With the incremental risk reduction for hospitalization for HF (HHF) and outpatient worsening HF due to contemporary guideline directed medical therapy (GDMT) including angiotensin receptor-neprilysin inhibitors (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) (see Docherty et al., 2020; Okumura et al., 2016), the natural history and residual risk of worsening HF among compensated outpatients with HFrEF on the most contemporary GDMT is not well understood.

[0107] In the VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial (NCT05093933), vericiguat was tested in an exclusively compensated, ambulatory HFrEF population without recent worsening HF (see Reddy et al., 2025), in the context of excellent GDMT use including ARNI and SGLT2i of greater than 50% each, (see Saldarriaga et al., 2025) Vericiguat resulted in lower cardiovascular and all-cause mortality compared to placebo in VICTOR, but there was not a statistically significant reduction in time to first HHF. Given the unique characteristics of patients in VICTOR, related to the low rate of either prior or recent HHF, and the best GDMT background therapy to date as compared to all HFrEF trials, the goals of the present secondary analysis were to describe the broader natural history of progressive HF in this contemporary lower risk HFrEF cohort, and to assess the effect of vericiguat on 1) the total of outpatient and inpatient worsening HF events 2) natriuretic peptide trajectory and 3) overall HF stability.

[0108] Outcomes.

[0109] The primary endpoint of VICTOR was the composite of time to first HHF or cardiovascular death. In the original prespecified analysis only adjudicated HHF was included as a secondary endpoint. All suspected HHF or urgent HF visits requiring intravenous diuretic therapy underwent adjudication by an independent clinical endpoint committee. The adjudication criteria for an urgent HF event in the outpatient setting required administration of intravenous diuretics. Given the known clinical and prognostic importance of oral diuretic intensification in HFrEF (see Docherty et al., 2020; Okumura et al., 2016), we evaluated an exploratory endpoint of expanded overall worsening HF composite endpoint that included time to first HHF, first urgent HF visit requiring intravenous diuretics, or first worsening outpatient HF thatrequired oral diuretic initiation or intensification. Oral diuretic initiation was defined as new initiation of oral loop diuretics or thiazide diuretics after randomization in patients with no baseline use. Oral diuretic intensification was defined as a dose increase after randomization compared with last dose on or before randomization. This time to first event expanded worsening HF endpoint therefore collectively captured clinical progression over the entire spectrum of worsening HF events across both the outpatient and inpatient settings, while accounting for the interdependence between individual worsening HF components by capturing only the first worsening HF event. Since vericiguat resulted in a reduction in mortality in VICTOR, there was a higher competing risk of death in the placebo arm that could potentially bias isolated assessment of the effect of vericiguat on the expanded worsening HF endpoint alone. To formally account for this competing risk of death we additionally evaluated a composite of time to mortality or time to first HHF, first urgent HF visit requiring intravenous diuretics or first worsening outpatient HF that required oral diuretic initiation or intensification. Similar competing risk analysis was also performed using CV death instead of all-cause mortality. As an alternate complementary approach, we also evaluated the use of a win ratio on CV death, HHF, first urgent HF visit and first oral diuretic initiation or intensification in an exploratory analysis. An additional post hoc clinical stability analysis evaluated the time to all-cause death, first HHF, first urgent HF visit requiring intravenous diuretics, first worsening outpatient HF that required oral diuretic initiation or intensification, or first NYHA class worsening. NYHA class was assessed by the investigators at every study visit.

[0110] Statistical analysis

[0111] All time-to-event endpoints were performed following the intention -to-treat principle using a stratified log-rank test. Cox-proportional hazards analyses were used to estimate hazard ratios with 95% confidence intervals with unadjusted two-sided nominal p-values calculated based on the log-rank test. Time to first HHF was a prespecified secondary endpoint. Analyses including oral diuretic intensification were exploratory analyses and these analyses were not part of any hierarchical hypothesis testing. The P values and 95% confidence intervals provided for these exploratory analyses therefore do not account for multiplicity of testing. The proportional hazard assumption was tested using the weighted Schoenfeld residuals test across all time-to-first event outcomes with no statistical evidence of violation with lowest P- value of 0.367 across tested endpoints. In addition, numbers needed to treat, and their 95% confidence interval were provided based on the inverse of the difference in annualized absolute risk reductions (per 100-patient years). Subgroup analyses for the HF endpoints were performed to assess consistency of treatment effect across various demographics characteristics (i.e., age >65 vs <65 years; female vs male; geographic region; baseline therapy (i.e., SGLT2i yes / no; ARNI yes / no; baseline loop diuretic yes / no;implantable cardioverter defibrillator yes / no; number of baseline GDMT 0-2 vs 3 vs 4-5); comorbidities (i.e., diabetes, atrial fibrillation, chronic kidney disease, ischemic heart disease, anemia); baseline eGFR (>15-<30 vs 30-<60 vs >60 mL / min / 1.73 m2); baseline mean LVEF (<31 vs >31%); baseline NT-proBNP quartiles, NYHA class (II vs III / IV); and HHF recency prior to randomization (never, 6-12 months, >12 months). The relationship between NT-proBNP as a continuous variable and the efficacy outcome was performed using a restricted cubic spline model as done previously for VICTORIA. Changes in NT-proBNP over time were analysed using a longitudinal analysis of covariance model, with the change from baseline in log transformed value as the dependent variable, including categorical terms for stratification factor, week, treatment group, and the week-by-treatment group interaction, with the log transformed baseline value as a continuous covariate.

[0112] Results

[0113] Trial participants.

[0114] Between November 2021 and December 2023, 6,105 participants were enrolled, see Saldarriaga et al., 2025. A total of 3,053 participants were assigned to vericiguat and 3,052 to placebo. The baseline characteristics of the 6,105 participants randomized are described in Table 3. Consistent with outpatient stability, 47.5% had never been hospitalized for HF prior, 79% had mild symptoms (NYHA class II), and 30.2% of patients did not require loop diuretics at baseline. Background GDMT included a high utilization of beta-blockers (94.4%), mineralocorticoid receptor antagonist (77.8%), renin-angiotensin modulation use (94.3%, including 56.0% ARNI) and SGLT2i (59.1%).

[0115] Worsening heart failure event rates in the placebo arm.

[0116] Despite high use of contemporary GDMT and no recent worsening HF, participants in the placebo arm demonstrated a substantial residual risk with annualized event rates of 12.2% for the composite of CV death and first HHF. When considering worsening HF alone, annualized event rates were 7.6% for time to first HHF, with even higher annualized event rates of 17.2% for the expanded worsening HF endpoint including HHF, urgent HF visits or outpatient worsening requiring oral diuretic initiation or intensification.

[0117] In the placebo arm, oral diuretic initiation or intensification occurred in 7.1% and in 13.4% of participants, respectively. Among all loop diuretic initiation or intensification events in the placebo arm(n=564), 28.2% underwent loop diuretic initiation, 22.0% had a dose increase that was less than a doubling of baseline dose, and 49.8% had at least a doubling of baseline dose.

[0118] Baseline characteristics of patients who experienced worsening HF during follow up.

[0119] Compared to those with no HHF event during study follow-up, those who eventually experienced a HHF event had at baseline more atrial fibrillation, type 2 diabetes, and prior history of HHF, along with lower systolic blood pressure, estimated glomerular filtration rate and LVEF, and higher NT- proBNP and loop diuretic use (Table 12).

[0120] When considering the type of first event in the expanded worsening HF endpoint, first events as inpatient HHF were more likely to be from North America or Eastern Europe, while first events as oral diuretic initiation or intensification were more likely to be from Western Europe, and in participants who have never had a prior HHF or had lower NT-proBNP levels (Table 13). GDMT use and renal function was comparable across groups.

[0121] First expanded worsening heart failure event (Exploratory Analyses)

[0122] When considering the time to first expanded worsening HF event (including HHF and urgent care visits and outpatient worsening HF requiring oral diuretic intensification or initiation), there were 1434 worsening HF events that occurred in 23.5% of participants, compared to 710 inpatient adjudicated HHF events in 11.6% of participants (Table 11). In the whole population, the first event of the expanded worsening HF composite was comprised mostly of outpatient worsening HF (n=851, 59.3%), followed by HHF (n=507, 35.4%) with fewer urgent HF visits (n=76, 5.3%). Overall worsening HF occurred in 686 participants (22.5%) in the vericiguat group and 748 participants (24.5%) in the placebo group (HR 0.90; 95% CI 0.81-1.00, p=0.047).

[0123] The composite of all-cause death and overall worsening HF (HHF, UHF with IV diuretic, oral diuretic intensification or initiation) occurred in 917 participants (30.0%) in the vericiguat group and 1004 participants (32.9%) in the placebo group (HR 0.90, 95% CI 0.82-0.98, p=0.016). The clinical stability composite of all-cause death, overall worsening HF and worsening NYHA functional class occurred in 1022 participants (33.5%) in the vericiguat group and 1113 participants (36.5%) in the placebo group (HR 0.90; 95% CI 0.83-0.98, p=0.016) (Table 11).

[0124] In an additional analysis, the composite endpoint of cardiovascular death, overall HF and worsening NYHA functional class occurred in 968 participants (31.7%) in the vericiguat group and 1055 participants (34.6%) in the placebo group (HR 0.90; 95% CI 0.83, 0.98, p=0.018).

[0125] Exploratory analysis using the win ratio on CV death, HHF, urgent HF visit and oral diuretic initiation or intensification also favoured the vericiguat group (win ratio 1.12 [95% CI 1.02-1.23], p=0.021). Sensitivity analyses restricting oral diuretic intensification to larger dose increases >50% were consistent with the primary results.

[0126] Changes in natriuretic peptide levels

[0127] NT-proBNP trajectory is provided from baseline through week 72, following which there were <30% of participants with available data. NT-proBNP increased over time in both groups among these compensated ambulatory outpatients. However, the longitudinal increase over time was significantly smaller in the vericiguat group compared to placebo (p<0.001 across weeks 24, 48, and 72), with the geometric mean ratios of vericiguat over placebo decreasing from 0.94 (95% CI 0.91-0.97) to 0.90 (95% CI 0.87-0.94) and 0.89 (95% CI 0.84-0.93) across the Weeks (Figure 4). At 72 weeks, the geometric mean ratio (week 72 / baseline) was 0.86 ± 2.29 with vericiguat compared to 1.00 ± 2.37 with placebo which was significantly lower by 11% with vericiguat.

[0128] Relationship between oral diuretic initiation or intensification and outcomes

[0129] When examining the relationship between oral diuretic intensification or initiation and subsequent occurrence of the primary endpoint composite (HHF or CV Death), of the 1,115 participants who had an oral diuretic intensification or initiation, 245 / 1115 (22.0%) experienced the composite event compared to 662 / 4990 (13.3%) forthose who did not have an oral diuretic intensification or initiation event (difference of 8.7 percentage points). This led to participants with oral diuretic intensification or initiation having a RR of 1.66 (95% CI 1.45, 1.89), P<0.001, of experiencing later HHF or CV death compared to those without increased oral diuretic dosing.

[0130] Similar results were observed for all-cause death, where 224 / 1115 (20.1%) who had an oral diuretic intensification or initiation eventually died, compared to 593 / 4990 (11.9%) who did not have on oral diuretic intensification or initiation (difference of 8.2 percentage points), RR 1.69 (95% CI 1.47, 1.94, p<0.001).

[0131] Discussion

[0132] In this exploratory analysis of VICTOR, we provide updated estimates of the risk of worsening HF with contemporary GDMT among compensated, ‘stable’ outpatients with HFrEF, and determine the potential changes associate with vericiguat in overall worsening HF events across the inpatient and outpatient setting. Although the study cohort included the highest trial utilization of GDMT to date with over 50% of patients on SGLT2i and neprilysin inhibitors, nearly 80% on MRAs, and nearly 95% on beta blockers and ACEi / ARBs, there remained a high residual risk for worsening HF reflected by an annualized HHF event rate of 7.6 % in the placebo arm. Notably, traditional time to first HHF endpoint underestimated true overall worsening HF burden in this ambulatory compensated cohort by failing to consider the high proportion of outpatient worsening HF events that represented nearly two -thirds of initial worsening HF events and were prognostically important with subsequent increase in mortality. With these additional outpatient events, the true annualized event rate for overall worsening HF was more than double the time to first HHF rate, at 17.2% in the placebo arm.

[0133] With more outpatient worsening HF events relative to HHF in this well-treated ambulatory HFrEF cohort without recent worsening HF, vericiguat did not reduce time to first HHF, the traditionally utilized clinical trial endpoint in HF trials to evaluate worsening HF. However, when considering the totality of worsening HF episodes across both outpatient and inpatient settings, there was a reduction in the exploratory endpoint of overall worsening HF driven predominantly by fewer episodes of outpatient worsening HF requiring oral diuretic augmentation. Acknowledging the lack of correction for multiplicity of testing, when considering the high burden of these outpatient worsening HF events which are importantly associated with an increased mortality risk, the exploratory analyses of the changes associated with vericiguat in overall worsening HF including objectively measured natriuretic peptides, and in mortality suggest that vericiguat might mitigate progression of worsening HF among compensated ambulatory outpatients with HFrEF.

[0134] Outpatient worsening HF in contemporary patients with ambulatory HFrEF

[0135] Loop diuretics are effective treatments for episodic congestion, and their initiation or intensification generally reflects progression of underlying HF, as evident by the consistent association with poor survival in multiple observational analyses, see Docherty et al., 2020; Skali et al., 2014; Mallick et al., 2016. These data suggest that outpatient diuretic intensification in a blinded trial may serve as a reliable surrogate endpoint of worsening outpatient HF. Of note, in the current analysis of the most well-treated andcompensated ambulatory cohort with HFrEF reported to date, outpatient worsening HF remained the most common worsening HF event and was mitigated by vericiguat. Consistently, vericiguat was associated with favourable changes on clinical stability and NT-proBNP trajectory.

[0136] Recognizing the limitations inherent to cross-trial comparisons, it is notable that outpatient worsening appears to be progressively increasing across modem trials of patients with HFrEF which was only 23% of first HF events in PARADIGM-HF with ARNI use, increased to 44% in DAPA-HF and EMPEROR-Reduced with SGLTi use, and was now 59% in VICTOR with both ARNI and SGLT2i use (Central Illustration), see Docherty et al., 2020; Okumura et al., 2016. While the reasons for these potential changes require further study, these may be indicative a practice shift among contemporary patients on excellent GDMT, many of whom have never experienced a prior HHF. This was the case in the VICTOR trial participants who received the best GDMT reported in all recent HFrEF trials, with almost 30% not on diuretic therapy at baseline and where 79% were in class II NYHA at randomization. Randomized trials with hemodynamic monitoring have also proven that effective outpatient diuretic titration can prevent HHF in patients with HFrEF, effectively shifting worsening HF events from the inpatient to outpatient setting. Patients on multiple disease modifying drugs may have improved hemodynamic resiliency to paroxysms of volume overload that may allow effective treatment as an outpatient, whereas similar episodes of congestion in historical trials would have required hospitalization and counted as a HHF event. The clinical threshold for admitting a patient experiencing a worsening HF episode may be higher in patients who never experienced a prior HHF and may vary across health care systems being highest in low- and mediumincome countries, where a large proportion of participants were enrolled in VICTOR. Finally, VICTOR is also the first HFrEF trial entirely conducted after the COVID pandemic, which may have increased the clinical threshold for HHF, shifting the usual care towards more outpatient management, Regardless of the reason, this shift in worsening HF events from the inpatient to outpatient setting may result in an underestimation of true worsening HF burden in a trial setting where only HF hospitalization events are counted to quantify worsening HF. Failing to consider these prognostically important outpatient worsening HF episodes may then provide incomplete conclusions on treatment effects in blinded, randomized contemporary trials.

[0137] Worsening HF across the spectrum of HFrEF

[0138] In the present VICTOR analysis in a compensated ambulatory HFrEF cohort without recent worsening, vericiguat did not meaningfully lower the risk of the traditional inpatient HHF (HR 0.95; 95 %CI 0.82-1.10, 710 events) with an annualized placebo HHF rate of 7.6%. In contrast, in the VICTORIA(Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, which enrolled only patients with a recent worsening HHF episode, the annualized placebo event rate of the traditional HHF outcome was 29.1%, more than three -fold higher than in VICTOR, and there was a modest 10% reduction in risk of HHF (HR 0.90; 95%CI 0.81-1.00, 1438 events), see Armstrong et al., 2020.

[0139] With all the considerations above of a shift in worsening HF events to the outpatient setting in VICTOR, the current analysis provides a potential explanation for the apparent discordant findings on HHF in VICTOR compared to VICTORIA. These results, taken in the context of findings from VICTORIA, suggest that vericiguat may exert greater effects on HHF among those at highest short-term risk for recurrent HHF such as those with recent worsening HF and HHF as in VICTORIA, and potentially the subgroup from VICTOR who had relatively recent HHF 6-12 months prior to randomization. Among the overall cohort of well-compensated patients on excellent contemporary GDMT included in VICTOR, and where nearly half had never been hospitalized for HF, there may be a reduction in worsening HF primarily in the outpatient setting. Combined with the favourable changes in mortality and in the objectively measured NT- proBNP levels associated with vericiguat in VICTOR, these data suggest that vericiguat might have a potential role in addressing the high residual risk of worsening HF in compensated ambulatory patients with HFrEF receiving contemporary GDMT.Table 11. Primary and Composite OutcomesTable 12. Baseline characteristics of participants with and without HF Hospitalization events in the VICTOR TrialTable 13. Baseline characteristics of HF Hospitalization, Urgent Heart Failure Visit (UHF), or OralDiuretic Intensification or Initiation (ODI) as First Events versus No-Events enrolled in the VICTOR TrialTable 14. Shift in proportion of first HF events due to hospitalization for HF as compared to outpatient worsening or urgent HF visits.Percentage of first expanded HF events that were hospitalization for HF, outpatient worsening or urgent visits presented across PARADIGM HF, DAPA-HF, EMPEROR-Reduced and VICTOR. P values obtained by Chi-square analysis. Data from PARADIGM-HF and DAPA-HF obtained from Okumura et al., 2016 and Docherty et al., 2020, respectively. Data from EMPEROR-Reduced obtained from individual patient data.pO.0001

[0140] Numerous modifications to the present disclosure will be apparent to those skilled in the art in view of the foregoing description. Accordingly, this description is to be construed as illustrative only and is presented for the purpose of enabling those skilled in the art to make and use the disclosure. The exclusive rights to all modifications which come within the scope of the appended claims are reserved. All patents and documents referenced herein are hereby incorporated herein in their entireties by reference.

[0141] References

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Claims

WHAT IS CLAIMED IS:

1. A method of reducing the risk of cardiovascular death in a patient, comprising administering to the patient vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective; wherein the patient has heart failure and a left ventricular ejection fraction (LVEF) of < 40%, further wherein for at least six months prior to the onset of administration of vericiguat, the patient has not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patient has not received IV diuretics.

2. The method of claim 1, wherein cardiovascular death is sudden death or death from heart failure.

3. The method of claim 1 or 2, wherein the patient has been hospitalized for heart failure at least six months prior to the onset of administration of vericiguat.

4. The method of claims 1 or 2, wherein the patient has never been hospitalized for heart failure prior to the onset of administration of vericiguat.

5. The method of any one of claims 1 to 4, wherein the patient has symptomatic chronic heart failure.

6. The method of any one of claims 1 to 5, wherein the patient has Stage C or Stage D heart failure, as defined by the American Heart Association, at the onset of administration of vericiguat.

7. The method of any one of claims 1 to 5, wherein the patient’s heart failure is categorized in Class II, Class III, or Class IV, as defined by the New York Heart Association’s (NYHA) Functional Classification, at the onset of administration of vericiguat.

8. The method of any one of claims 1 to 5 and 7, wherein the patient’s heart failure is categorized in Class II, as defined by the New York Heart Association’s (NYHA) Functional Classification, at the onset of administration of vericiguat.

9. The method of any one of claims 1 to 8, wherein the patient at the onset of administration of vericiguat has an N-terminal pro-B-type natriuretic peptide (NTproBNP) level from about 600 to about 2500, about 600 to about 2400, about 600 to about 1990, about 600 to about 1300, about 600 to about 1400, about 600 to about 1000, or about 600 to about 6000 pg / mL.

10. The method of any one of claims 1 to 9, wherein(1) at the onset of administration of vericiguat the patient is in sinus rhythm and has an N- terminal pro-B-type natriuretic peptide (NTproBNP) level between about 600 and about 6000 pg / mL or(2) at the onset of administration of vericiguat the patient is in atrial fibrillation and has NTproBNP level between about 900 and about 6000 pg / mL.

11. The method of any one of claims 1 to 10, wherein the patient at the onset of administration of vericiguat has one or more of the characteristics selected from- an NT-proBNP level of 800-2250 pg / mL;- an LVEF of > 31%; and- NYHA class II.

12. The method of any one of claims 1 to 11, comprising co-administering or providing to the patient vericiguat in combination with a further therapeutically active agent or therapy, wherein the further therapeutically active agent or therapy is selected from the group consisting of betablockers; angiotensin-converting enzyme inhibitors (ACEi); angiotensin receptor blockers (ARB); mineralocorticoid receptor antagonists (MRA); angiotensin receptor neprilysin inhibitors (ARNI); sodium glucose co-transporter-2 inhibitors (SGLT2i); an implantable cardioverter defibrillator (ICD); and cardiac resynchronization therapy (CRT); and wherein the further therapeutically active agent or therapy is administered or provided either simultaneously or sequentially with vericiguat.

13. The method of claim 12, wherein the further therapeutically active agent or therapy is an SGLT2i or ARNI.

14. The method of claims 12 or 13, wherein the further therapeutically active agent or therapy is an SGLT2i.

15. The method of claims 12 or 13, wherein the further therapeutically active agent or therapy is ARNI.

16. The method of any one of claims 12 to 15, wherein two or more further therapeutically active agents or therapies are co-administered or provided with vericiguat.

17. The method of claim 12, 13, or 16, wherein SGLT2i and ARNI are co-administered with vericiguat.

18. The method of claim 12 or 16, wherein a beta-blocker, an MRA, ARNI, and an SGLT2i are coadministered with vericiguat.

19. A method of reducing the risk of cardiovascular death in a population of patients that have heart failure and a left ventricular ejection fraction (LVEF) of < 40%, comprising: administering to each patient in the population vericiguat or a pharmaceutically acceptable salt thereof in an amount that is clinically proven effective; wherein for at least six months prior to the onset of administration of vericiguat, the patients have not been hospitalized for heart failure and for at least three months prior to the onset of administration of vericiguat the patients have not received IV diuretics; wherein as assessed at about 39 to about 43 months after onset of administration of vericiguat the population of patients has a reduction in time to first occurrence of cardiovascular death compared to a control population of patients, and wherein the hazard ratio for cardiovascular death with the administration of vericiguat compared to the control population of patients is 0.80 to 0.90.

20. The method of claim 19, wherein the hazard ratio for cardiovascular death with the administration of vericiguat compared to the control population of patients is 0.83.

21. The method of claim 20, wherein each patient at the onset of administration of vericiguat has an N-terminal pro-B-type natriuretic peptide (NTproBNP) level from about 600 to about 2500, about 600 to about 2400, about 600 to about 1990, about 600 to about 1300, about 600 to about 1400, about 600 to about 1000, or about 600 to about 6000 pg / mL.

22. The method of any one of claims 19 to 21, wherein the patient at the onset of administration of vericiguat has one or more of the characteristics selected from- an NT-proBNP level of 800-2250 pg / mL;- an LVEF of> 31%; and- NYHA class II.

23. The method of any one of claims 19 to 22, further comprising co-administering or providing to the patients vericiguat in combination with a further therapeutically active agent or therapy, wherein the further therapeutically active agent or therapy is selected from the group consisting of beta-blockers; angiotensin-converting enzyme inhibitors (ACEi); angiotensin receptor blockers (ARB); mineralocorticoid receptor antagonists (MRA); angiotensin receptor neprilysin inhibitors (ARNI); sodium glucose co-transporter-2 inhibitors (SGLT2i); an implantable cardioverter defibrillator (ICD); and cardiac resynchronization therapy (CRT); and wherein the further therapeutically active agent or therapy is administered or provided either simultaneously or sequentially with vericiguat.

24. The method of claim 23, wherein the further therapeutically active agent or therapy is an SGLT2i or ARNI.

25. The method of claims 23 or 24, wherein the further therapeutically active agent or therapy is an SGLT2i.

26. The method of claims 23 or 24, wherein the further therapeutically active agent or therapy is ARNI.

27. The method of claim 23 to 26, wherein two or more further therapeutically active agents or therapies are co-administered or provided with vericiguat.

28. The method of any one of claims 23, 24, or 27, wherein SGLT2i and ARNI are co-administered with vericiguat.

29. The method of claims 23 or 27, wherein a beta-blocker, an MRA, ARNI, and an SGLT2i are coadministered with vericiguat.

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