Aldosterone synthase inhibitor for treating heart failure

Abstract

Disclosed are methods of using an aldosterone synthase inhibitor of formula (1): for treating, reducing the risk of, or delaying the progression of heart failure related disorders. The invention further relates to methods of using Compound 1 in combination with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

Description

[0001]

[0002] ALDOSTERONE SYNTHASE INHIBITOR FOR TREATING HEART FAILURE

[0003] FIELD OF THE INVENTION

[0004] The invention relates to the use of a certain aldosterone synthase inhibitor for treating, reducing the risk of, or delaying the progression of certain disorders in patients with heart failure. The invention further relates to the use of the aldosterone synthase inhibitor in combination with sodium-glucose cotransporter-2 (SGLT2) inhibitors.

[0005] BACKGROUND

[0006] Heart failure (HF) is a leading cause of morbidity and mortality, associated with poor functional capacity and significantly impaired quality of life, affecting an estimated

[0007] 64 million people worldwide. (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, Lancet 2018;392:1789-1858.. In the United States alone the prevalence is6.7 million in people over the age of 20 and the prevalence is expected to rise to 8.5 million Americans by 2030. (B. Bozkurt et al. Heart failure epidemiology and outcomes statistics: a report of the Heart Failure Society of America. J Card Fail, 2023, 29(10): 1412-1451.) The global number of patients with HF is expected to grow continuously due to advances in therapy for ischemic and valvular heart disease, worsening comorbidity and obesity prevalence, and longer life-expectancy in the population in general. (G. Savarese et al. Global burden of heart failure: a comprehensive and updated review of epidemiology. Cardiovasc Res; 2022;118;3272-3287; and E.J. Benjamin et al. Heart disease and stroke statistics - 2019 update: a report from the American Heart Association. Circulation; 2019;139(10);e56-e528.) Annually, more than 1 million patients are admitted to hospitals with a primary diagnosis of HF, making it the leading cause of hospitalisation among individuals aged 65 and above in western countries. (C.W. Yancy et al. 2013 ACCF / AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation / American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol; 2013; 62(16); el47-e239.) Following a hospitalization for heart failure (HHF) the prognosis is even worse, with 30-day mortality approaching 10%, 1-year mortality about 35%, and 5-year mortality about 75%. (R.K. Cheng et al. Outcomes in patients with heart failure with preserved, borderline, and reduced ejection fraction in the

[0008]

[0009] Medicare population. Am Heart J; 2014; 168(5); 721-730.e3; and K.S. Shah et al. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol; 2017;70(20);2476-2486.) The data support that once an HHF has been needed, the prognosis of HF is poor, irrespective of left ventricular ejection fraction (LVEF).

[0010] Further, while no difference in mortality rate was detected for patients hospitalised for HF based on the ejection fraction at baseline, patients who had been hospitalised for HF had much shorter median life expectancy vs. the overall US population stratified by age, and this data corresponds well with the global population according to The Global Congestive Heart Failure, SWEDE-HF and ASIAN-HF registries, in which the mortality rates remain high without many differences in risk between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF).

[0011] Contemporary therapies for HF include management of risk factors and concomitant diseases, as well as lifestyle interventions, evidence-based medications and device-based therapies. To date, several medication classes, including beta-blockers, ACEi, ARB or ARNi, MRA, and most recently SGLT2 inhibitors (SGLT2i), have shown to provide a morbidity and mortality benefit for patients who have heart failure with reduced ejection fraction (HFrEF). (T.A. McDonagh et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599-3726.) So far only one therapy class, SGLT2i, has convincingly demonstrated to improve outcomes, in patients living with HF, across the full spectrum of LVEF. In 2022, empagliflozin became the first therapy approved to reduce the risk of HHF or CV death in all HF patients, regardless of ejection fraction. In 2023, dapagliflozin received marketing authorisation. Empagliflozin and dapagliflozin have demonstrated a significant reduction in the composite endpoint of CV death and HHF in the population with heart failure with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) and are recommended for the treatment of patients with symptomatic HF across the full spectrum of LVEF (Class IA according to 2023 ESC Guidelines). (T. Shimamoto et al. Clinical impact of turn-up anastomosis in the treatment of type A acute aortic dissection. Asian Cardiovasc Thorac Ann 2023;31(9):759-767.) Similarly, considering the totality of evidence, FDA approved sotagliflozin to reduce the risk of CV death, HHF and urgent heart failure visits in adults with HF with or without diabetes. The indication was granted for the full range of LVEF, based on the SCORED and SOLOIST-WHF trials. (B.

[0012]

[0013] Pitt et al. Effect of sotagliflozin on early mortality and heart failure-related events: a post hoc analysis of SOLOIST-WHF. JACC Heart Fail 2023;l l(8):879-889; and D.L. Bhatt et al.

[0014] Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med

[0015] 2021 ;384(2): 129-139.)

[0016] Regardless of recent treatment advances in the management of HF, the residual risk for cardiovascular death, hospitalisation for heart failure and impaired quality of life remains substantial in patients with HF, which is applicable also to patients with LVEF <40%.

[0017] Accordingly, there is a need for new treatments for heart failure patients.

[0018] BRIEF SUMMARY OF THE INVENTION

[0019] The present invention relates to methods for treating patients with heart failure comprising administering a therapeutically effective amount of an aldosterone synthase inhibitor (“AS inhibitor”) of the invention to a patient in need thereof, optionally in combination with an SLGT2 inhibitor (“the methods of the invention”).

[0020] The AS inhibitor of the invention is a compound having the structure (1) shown below:

[0021]

[0022] (1).

[0023] Compound 1 is a specific aldosterone synthase inhibitor (ASI) that effectively lowers aldosterone plasma concentrations in a dose dependent manner. As used herein, the terms “AS inhibitor of the invention,” “the AS inhibitor,” and “Compound 1” are used interchangeably. Compound 1 is

[0024]

[0025] also known as 2-chloro-4-[(6R)-6,7-dihydro-6-(hydroxymethyl)-6-methyl-4-oxopyrano[3,4-d]imidazol-3(4H)-yl]-benzonitrile, BI 690517 and vicadrostat.

[0026] In another embodiment, the invention relates to a method for treating a patient with heart failure and left ventricular ejection fraction 40% (LVEF <40%), the method comprising administering to the patient a pharmaceutically effective amount of Compound 1, optionally, in combination with an SGLT2 inhibitor.

[0027] In another embodiment, the invention relates to a method for treating a patient with symptomatic chronic heart failure and left ventricular ejection fraction <40% (LVEF <40%), the method comprising administering to the patient a pharmaceutically effective amount of Compound 1, optionally, in combination with an SGLT2 inhibitor.

[0028] In another embodiment, the invention relates to a method for treating a patient with symptomatic chronic heart failure and left ventricular ejection fraction <40% (LVEF <40%), the method comprising administering to the patient a pharmaceutically effective amount of Compound 1, in combination with an SGLT2 inhibitor, as compared to placebo and empagliflozin.

[0029] In one embodiment, the invention relates to a method for reducing the risk of cardiovascular death, hospitalization for heart failure, and / or urgent heart failure visit in a patient, wherein the patient has heart failure and a left ventricular ejection fraction <40%, the method comprising administering to the patient a pharmaceutically effective amount of Compound 1 and, optionally, an SGLT2 inhibitor.

[0030] In one embodiment, the invention relates to a method for reducing the risk to first event of cardiovascular death, hospitalization for heart failure, and / or urgent heart failure visit in a patient, wherein the patient has heart failure and a left ventricular ejection fraction <40%, the method comprising administering to the patient a pharmaceutically effective amount of Compound 1 and, optionally, an SGLT2 inhibitor.

[0031] In one embodiment, the invention relates to any of the embodiments above, where the patient is not taking a mineralcorteroid receptor agonist (MRA).

[0032]

[0033] In one embodiment, the invention relates a method for treating, reducing the risk of, or slowing the progression of:

[0034] experiencing first event of cardiovascular death or hospitalization for heart failure, occurrence of hospitalization for heart failure (first and recurrent),

[0035] the absolute change from baseline in KCCQ-TSS at Week 32 (C.P. Green et al.

[0036] Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol 2000;35(5): 1245-1255.) the time to CV death, and / or

[0037] the time to all-cause mortality in a patient,

[0038] wherein the patient has heart failure and a left ventricular ejection fraction <40%, the method comprising administering to the patient a pharmaceutically effective amount of Compound 1 and, optionally, an SGLT2 inhibitor.

[0039] In another embodiment, the patient is an adult patient.

[0040] In one embodiment, the SLGT inhibitor when used in the methods or uses of the invention is selected from the group consisting of empagliflozin, dapagliflozin, sotagliflozin and canagliflozin.

[0041] In another embodiment, the SLGT inhibitor when used in the methods of uses of the invention is empagliflozin.

[0042] In one embodiment, the amount of the empagliflozin when used in the methods or uses of the invention is from 5 mg to 30 mg, or 10 mg to 25 mg, or 10 mg, or 25 mg.

[0043] In another embodiment, the amount of empagliflozin when used in the methods or uses of the invention is 10 mg.

[0044] In another embodiment, the amount of Compound 1 administered to the patient according to the methods or uses of the invention is from 0.5 to 30 mg; or from 1 to 25 mg; or from 3 to 20 mg; or 3 mg, or 6 mg, or 10 mg, or 20 mg.

[0045] In another embodiment, the amount of Compound 1 administered to the patient is 3 mg.

[0046] In another embodiment, the amount of Compound 1 administered to the patient is 6 mg.

[0047]

[0048] In another embodiment, the amount of Compound 1 administered to the patient is 10 mg.

[0049] In another embodiment, the amount of Compound 1 administered to the patient is 20 mg.

[0050] In another embodiment, the amount of Compound 1 administered to the patient is 3 mg, and the amount of empagliflozin administered to the patient is 10 mg.

[0051] In another embodiment, the amount of Compound 1 administered to the patient is 10 mg, and the amount of empagliflozin administered to the patient is 10 mg.

[0052] In another embodiment, the amount of Compound 1 administered to the patient is 20 mg, and the amount of empagliflozin administered to the patient is 10 mg.

[0053] In one embodiment, the invention relates methods for treating patients with heart failure and LVEF <40%, comprising administering to the patient a combination of 10 mg of Compound 1 and 10 mg empagliflozin.

[0054] In another embodiment, the invention relates to method for treating patients with heart failure and LVEF<40%, comprising administering a combination of 10 mg of Compound 1 and 10 mg empagliflozin to the patient, wherein the treatment prevents, reduces the risk of, and / or slows the progression of first cardiovascular death, hospitalisation for heart failure and / or urgent heart failure visit in the patient.

[0055] In another embodiment, the invention relates to method for treating patients with heart failure and LVEF <40%, comprising administering a combination of 10 mg of Compound 1 and 10 mg empagliflozin to the patient, wherein the treatment prevents, reduces the risk of, and / or slows the progression of:

[0056] a first event of cardiovascular death or hospitalization for heart failure,

[0057] occurrence of hospitalization for heart failure (first or recurrent),

[0058] the absolute change from baseline in KCCQ-TSS at Week 32,

[0059] the time to CV death, and / or

[0060] the time to all-cause mortality in a patient.

[0061]

[0062] In one embodiment, the combination of Compound 1 and empagliflozin are administered as a free combination.

[0063] In another embodiment, the combination of Compound 1 and empagliflozin are administered as a fixed-dose combination.

[0064] In one embodiment, the patient with heart failure and LVEF <40% is a type 2 diabetes mellitus patient.

[0065] In another embodiment, the patient with heart failure and LVEF <40% is a type 1 diabetes patient.

[0066] DETAILED DESCRIPTION OF THE INVENTION

[0067] Abbreviations:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075] As used herein, the term “heart failure event” or “HFE” is refers to an event of worsening HF that requires augmentation of therapy for HF. For example, the assessment of the participant and treatment augmentation may require HHF or may be undertaken during an ER, urgent care, or other urgent outpatient visit.

[0076] The term “symptomatic chronic heart failure” refers to heart failure classification NYHA, II -IV. (See Table 1.)

[0077] The term “heart failure hospitalization” or “HHF” as used herein means an event that meets all of the following criteria:

[0078] • The participant has a non-elective / unplanned admission to the hospital (e.g. a hospital ward, or a cardiac, coronary, intermediate or intensive care unit) with a primary diagnosis of HF

[0079] • The participant’s length-of-stay in hospital extends for at least 12 hours (or a change in calendar date if the hospital admission and discharge times are unavailable) NOTE: An unplanned visit to an ER or any other urgent care or outpatient setting for a primary diagnosis of HF, without being admitted to the hospital as an inpatient would also be considered

[0080]

[0081] equivalent to meeting the first and second criterion if the duration is at least 12 hours (or a change in calendar date if admission and discharge times are unavailable).

[0082] • The participant exhibits documented new or worsening symptoms due to HF on presentation, including at least one of the following:

[0083] o Dyspnoea (dyspnoea with exertion, dyspnoea at rest, orthopnoea, paroxysmal nocturnal dyspnoea)

[0084] o Decreased exercise tolerance

[0085] o Fatigue

[0086] o Other symptoms of worsened end-organ perfusion or volume overload o At least one physical examination finding OR at least one laboratory criterion as objective evidence of new or worsening HF.

[0087] o Physical examination findings considered to be due to HF include new or worsened:

[0088] ■ Peripheral edema

[0089] ■ Increased abdominal distention or ascites (in the absence of primary hepatic disease)

[0090] ■ Pulmonary rales / crackles / crepitations

[0091] ■ Increased jugular venous pressure and / or hepatojugular reflux

[0092] ■ S3 gallop

[0093] ■ Clinically significant or rapid weight gain thought to be related to fluid retention

[0094] ■ Other physical examination findings (e.g. jaundice)

[0095] o Laboratory criteria of new or worsening HF, if obtained in close temporal relationship of presentation, include:

[0096] ■ Increased BNP or NT-proBNP concentrations consistent with decompensation of HF (in participants with chronically elevated natriuretic peptides, a significant increase should be noted above baseline) ■ Radiological, ultrasonographic or implantable monitor evidence of pulmonary congestion

[0097]

[0098] ■ Non-invasive or implantable diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure, or low cardiac output

[0099] ■ Invasive evidence of new or worsening HF including right heart catheterisation showing elevated pulmonary capillary wedge pressure (pulmonary artery occlusion pressure), elevated central venous pressure, depressed cardiac index, or left heart catheterisation showing elevated left ventricular end-diastolic pressure consistent with decompensation of HF ■ Other laboratory criteria (e.g. elevated transaminases consistent with decompensated HF)

[0100] • Intensification of therapy (significant augmentation of a current therapy for HF, or addition of a new therapy for HF).

[0101] o Significant augmentation in oral diuretic therapy (for example, the doubling of diuretic dose; initiation of maintenance diuretic therapy; or initiation of combination diuretic therapy to relieve congestion)

[0102] o Initiation of i.v. diuretic (a single dose is sufficient)

[0103] o Initiation of an i.v. vasoactive agent (catecholamine, phosphodieaterase-3 inhibitor, other vasopressor, vasodilator)

[0104] o Mechanical or surgical intervention, including:

[0105] ■ Mechanical circulatory support (e.g. intra-aortic balloon pump, ventricular assist device, extracorporeal membrane oxygenation, total artificial heart) ■ Mechanical fluid removal (e.g. ultrafiltration, haemofiltration, or initiation of dialysis for what is felt to be a primary cardiac rather than renal cause)

[0106] As used herein, the term “urgent heart failure visit” or “UHFV” means any visit meeting the above criteria for UHF, but where the duration of stay must be less than 12 hours for a hospitalisation, a visit to an ER or any other urgent care or outpatient setting, and augmentation of oral diuretics is not considered sufficient to fulfil the criterion of intensification of treatment (but might qualify as outpatient oral diuretic intensification, as described below). This means, clinic visits for planned administration of HF therapies or procedures (e.g. intravenous diuretics,

[0107]

[0108] intravenous vasoactive agents, or mechanical fluid removal) do not qualify as urgent Heart Failure Visits.

[0109] “Outpatient oral diuretic intensification for HF” is defined as an event not meeting the above definitions for HHF and Urgent Heart Failure Visit, but meeting the following criteria: new or worsening symptoms due to HF and physical examination finding or laboratory criterion as objective evidence of new or worsening HF and intensification of treatment defined as a significant augmentation of oral diuretics with HF as primary treatment indication in a patient not admitted to the hospital. Significant augmentation in oral diuretic therapy (for example, the doubling of diuretic dose; or initiation of maintenance diuretic therapy; or initiation of combination diuretic therapy to relieve congestion) should be sustained for a period of at least 7 days.

[0110] As used herein, the term “cardiovascular death” or “CV” death means death resulting from an acute MI, sudden cardiac death, death due to HF, death due to stroke, death due to CV procedures, death due to CV haemorrhage, and death due to other CV causes. For the analysis of the primary endpoint, CV death will include death of undetermined cause.

[0111] As used herein, the term “death due to acute myocardial infarction” refers to a death by any CV mechanism (e.g., arrhythmia, sudden death, HF, stroke, pulmonary embolus, peripheral arterial disease) < 30 days after a MI related to the immediate consequences of the MI, such as progressive HF or recalcitrant arrhythmia. There may be assessable mechanisms of CV death during this time period, but for simplicity, if the CV death occurs < 30 days of the MI, it will be considered a death due to MI. Acute MI should be verified to the extent possible by the diagnostic criteria for acute MI or by autopsy findings showing recent MI or recent coronary thrombosis. Death resulting from a procedure to treat a MI (percutaneous coronary intervention, coronary artery bypass graft surgery), or to treat a complication resulting from MI, should also be considered death due to acute MI. Death resulting from an elective coronary procedure to treat myocardial ischemia (i.e. chronic stable angina) or death due to a MI that occurs as a direct consequence of a CV investigation / procedure / operation should be considered as a death due to a CV procedure.

[0112]

[0113] As used herein, the term “sudden cardiac death” refers to a death that occurs unexpectedly, not following an acute MI, and includes the following deaths:

[0114] • Death witnessed and occurring without new or worsening symptoms

[0115] • Death witnessed within 60 minutes of the onset of new or worsening cardiac symptoms, unless the symptoms suggest acute MI

[0116] • Death witnessed and attributed to an identified arrhythmia (e.g., captured on an electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but found on implantable cardioverter-defibrillator review)

[0117] • Death after unsuccessful resuscitation from cardiac arrest (e.g. ICD) unresponsive sudden cardiac death, pulseless electrical activity arrest)

[0118] • Death after successful resuscitation from cardiac arrest and without identification of a specific cardiac or non-cardiac etiology

[0119] • Unwitnessed death in a subject seen alive and clinically stable < 72 hours prior to being found dead without any evidence supporting a specific non-CV cause of death

[0120] As used herein, the term “death due to heart failure” refers to a death in association with clinically worsening symptoms and / or signs of HF regardless of HF etiology. Deaths due to HF can have various etiologies, including single or recurrent Mis, ischemic or non-ischemic cardiomyopathy, hypertension, or valvular disease.

[0121] As used herein, the term “death due to stroke” refers to death after a stroke that is either a direct consequence of the stroke or a complication of the stroke. Acute stroke should be verified to the extent possible by the diagnostic criteria for stroke.

[0122] As used herein, the term “death due to cardiovascular procedures” refers to death caused by the immediate complications of a cardiac procedure.

[0123] As used herein, the term “death due to cardiovascular haemorrhage” refers to death related to haemorrhage such as a non-stroke intracranial haemorrhage, non-procedural or non-traumatic vascular rupture (e.g., aortic aneurysm), or haemorrhage causing cardiac tamponade.

[0124]

[0125] As used herein, the term “death due to other cardiovascular causes” refers to a CV death not included in the above categories but with a specific, known cause (e.g., pulmonary embolism or peripheral arterial disease).

[0126] As used herein, the term, the term “non-cardiovascular death” means as any death with a specific cause that is not thought to be CV in nature such, for examples,

[0127] • Death from pulmonary causes

[0128] • Death from renal causes. Evidence of renal death requires:

[0129] o Evidence of CKD stage 5 (i.e. eGFR<15 mL / min / 1.73m2 [and usually <10 mL / min / 1.73m2] or ESKD); AND

[0130] o Evidence of:

[0131] ■ Conservative management of ESKD: the participant or their representatives had decided that, despite a clinical need, renal replacement therapy [RRT] was not to be provided. This includes progression to ESKD before RRT can be provided; OR

[0132] ■ Withdrawal from RRT: the participant or their representative has chosen to discontinue RRT (e.g. personal choice, intolerant of dialysis therapy); AND

[0133] ■ No evidence that other major pathology led: (a) to death, or (b) to the decision to withdraw from RRT (e.g. cancer or stroke), or (c) made dialysis infeasible. Such deaths should be ascribed to the underlying condition.

[0134] • Death from any of the following causes: gastrointestinal, hepatobiliary, pancreatic, infection (includes sepsis), inflammatory (e.g., Systemic Inflammatory Response Syndrome (SIRS) / Immune(including autoimmune) (may include anaphylaxis from environmental (e.g., food) allergies), haemorrhage that is neither CV bleeding or a stroke, non-CV procedure or surgery, trauma, suicide, non-prescription drug reaction or overdose, prescription drug reaction or overdose (may include anaphylaxis), neurological (non-CV), malignancy, and orther non-CV causes

[0135] As used herein, the term “undetermined cause of death” refers to a death not attributable to one of the above categories of CV death or to a non-CV cause. Occasionally, it may not be possible

[0136]

[0137] to determine exact causality when 2 lethal conditions contribute to death equally. In this circumstance all events not due solely to non-CV causes should be classified as CV-related.

[0138] As used herein, the term “lack of information” when use to describe a cause of death (e.g., the only available information is “participant died”) refers to a death when there is insufficient supporting information or detail to assign the cause of death. Such death is classified as undetermined cause of death.

[0139] Unless otherwise specified, the terms “patient” and “participant” are given the same meaning.

[0140] The terms “treatment” and “treating” comprise therapeutic treatment of patients having already developed said condition. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy.

[0141] The terms “prophylactically treating”, “preventively treating” and “preventing” are used interchangeably and comprise a treatment of patients at risk to develop a condition mentioned hereinbefore.

[0142] GENERAL SYNTHETIC METHODS

[0143] Compound 1 used in the methods of the invention may be prepared by the methods and examples described in WO 2016 / 014736 and U.S. provisional application no. 63 / 553234, filed February 14, 2024.

[0144] Mono-tablets containing Compound 1 or empagliflozin can be made by conventional monotablet formulations. The mono-tablets contain standard pharmaceutical excipients, for example, mannitol, microcrystalline cellulose, copovidone, croscarmellose sodium, magnesium stearate, and a film coating (containing a colorant, hypromellose, macrogol, talc and titanium dioxide). Mono-tablets containing empagliflozin are also commercially available under the tradename JARDIANCE®.

[0145]

[0146] Placebo tablets are developed to mimic the appearance of the tablets containing the ASi inhibitor. The placebo tablets contain standard pharmaceutical excipient, for example, microcrystalline cellulose, mannitol, and magnesium stearate. The coating of the placebo tablet is generally the same as the tablet containing the ASi inhibitor described above.

[0147] Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).

[0148] METHODS OF THERAPEUTIC USE

[0149] Current SOC for HFrEF includes steroidal MRA on top of ACEi, ARB or ARNi, and SGLT2i to decrease mortality. MRA are commonly associated with impaired sexual function, and hyperkalaemia. Such adverse effects often lead to drug discontinuation or dose lowering of the MRA, thereby limiting its therapeutic potential in HF. In addition, MRA can induce a reactive increase in aldosterone synthesis, which may potentially limit the efficacy of MR blockade and enhance MR-independent pathways. Vicadrostat prevents the formation of aldosterone in a dose dependent manner and lowers the level in circulating plasma, and thus may provide an additional therapeutic advantage compared with MRA. (S.M. Weldon et al. Inhibitors of aldosterone synthase. VitamHorm; 2019;109:211-239.)

[0150] EASi-HF Preserved (NCT06424288) is a phase III double-blind, randomised, parallel-group superiority trial to evaluate efficacy and safety of the combined use of oral vicadrostat (Compound 1) and empagliflozin compared with placebo and empagliflozin in participants with symptomatic heart failure (HF: NYHA II-IV) and left ventricular ejection fraction (LVEF) >40%. Patients in the study of the present invention have LVEF<40% or HFrEF. Patients with HFrEF reportedly have a higher mortality rate the HFpEF patients (LVEF>50%) (See P. Li. Et al., “Similarities and Differences Between HFmrEF and HFpEF,” Front. Cardiovasc. Med.

[0151] 2021:8:678614.) Patients with FrEF may be treated with a multitude of evidence-based medications and device-based therapies. To date, several medication classes, including betablockers, ACEi, ARB or ARNi, MRA, and most recently SGLT2 inhibitors (SGLT2i), have shown to provide a morbidity and mortality benefit for patients who have HFrEF. So far only

[0152]

[0153] one therapy class, SGLT2i, is approved for therapy as it has convincingly demonstrated to improve outcomes, in patients living with HF, across the full spectrum of LVEF.

[0154] Compound 1, and the SGLT2 inhibitor when used, may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies. Compound 1 may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition.

[0155] Advantageously, the compounds may then be administered together in a single dosage form. In some embodiments, the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of Compound 1 (w / w) or a combination thereof. The optimum percentage (w / w) of Compound 1 may vary and is within the purview of those skilled in the art. Alternatively, Compound 1 and the conventional therapeutics or other adjuvants may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regimen.

[0156] As mentioned above, each of the dosage forms of Compound 1 and the optional SGLT2 inhibitor may include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art and suitable to the dosage form. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred or dosage forms include tablets and capsules. Dosage levels and requirements for Compound 1 and the optional SGLT2 inhibitor may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. The amount of the empagliflozin when used in the methods or uses of the invention is from 5 mg to 30 mg, or 10 mg to 25 mg, or 10 mg, or 25 mg. The amount of Compound 1 administered to the patient according to the methods or uses of the invention is from 0.5 to 30 mg; or from 1 to 25 mg; or from 3 to 20 mg; or 3 mg, or 10 mg, or 20

[0157]

[0158] mg. In one embodiment, the amount of Compound 1 administered to the patient is 10 mg, and the amount of empagliflozin administered to the patient is 10 mg.

[0159] Within this invention, it is to be understood that the combinations or combined uses of Compound 1 and SGLT2 inhibitor according to this invention may envisage the simultaneous, sequential or separate administration of the therapeutic components.

[0160] In this context, “combination” or “combined” within the meaning of this invention may include, without being limited, fixed and non-fixed (e.g. free) forms (including kits, or other administration, application or dosage forms) and uses, such as e.g. the simultaneous, sequential or separate use of Compound 1 and SGLT2 inhibitor.

[0161] The combined administration or application of this invention may take place by administering the therapeutic components together, such as e.g. by administering them simultaneously in one single or in two separate formulations. Alternatively, the administration may take place by administering the therapeutic components sequentially, such as e.g. successively in two separate formulations.

[0162] For the combination therapy of this invention, the therapeutic components may be administered separately (which implies that they are formulated separately) or formulated altogether (which implies that they are formulated in the same preparation). Hence, the administration of one element of the combination of the present invention may be prior to, concurrent to, or subsequent to the administration of the other element of the combination.

[0163] In another aspect of the invention, patients may optionally be treated with additional therapeutic agents, according to best possible standard of care (disregarding SGLT2i and MRA) in accordance with applicable HF local / international guidelines, which may in general include (unless contraindicated or not tolerated): An ACE inhibitor, or ARB or ARNi, and a beta-blocker

[0164] In one embodiment, the methods of the invention relate to the methods or uses described herein where Compound 1 and the SGLT2 inhibitor are administered as a fixed dose combination. The fixed-dose combination of the compounds is expected to offer a new class of foundational

[0165]

[0166] therapy with a beneficial efficacy and safety profile. In another embodiment, the SGLT2 inhibitor is empagliflozin.

[0167] In another embodiment, the combination of Compound 1 and the SGLT2 inhibitor may prevent or reduce the risk of hyperkalaemia events as compared to monotherapy with Compound 1. In another embodiment, the SGLT2 inhibitor is empagliflozin.

[0168] Clinical Trial Protocol

[0169] 1. TRIAL OBJECTIVES

[0170] The trial aims to provide substantial evidence for the efficacy and safety of the combination of oral vicadrostat 10 mg and empagliflozin 10 mg compared with placebo and empagliflozin 10 mg on top of standard of care (SOC) in participants with HF and LVEF <40% not taking MRA.

[0171] Table 1 shows the classification of HF by Left Ventricular Ejection Fraction (LVEF).

[0172] Table 1. Classification of HF by Left Ventricular Ejection Fraction (LVEF)

[0173] <

[0174] >

[0175]

[0176] The primary objective is to demonstrate the efficacy of the combination of Compound 1 (10 mg) and empagliflozin (10 mg) as compared to placebo and empagliflozin (10 mg) for the time to first CV death or hospitalisation for heart failure (HHF) in patients with HF and LVEF <40%, based on hazard ratios as described herein.

[0177] Key secondary objectives are to demonstrate the superiority of the combination of vicadrostat 10 mg and empagliflozin 10 mg compared with placebo and empagliflozin 10 mg for the time to first event of CV death or HHF, the total number of HHF (first and recurrent), the absolute change from baseline in KCCQ-TSS at Week 32, the time to CV death, and the time to all-cause mortality.

[0178]

[0179] Other secondary objectives include evaluating the combination of vicadrostat 10 mg and empagliflozin 10 mg compared with placebo and empagliflozin 10 mg for the time to first HHF, time to first occurrence of the composite renal endpoint, as well as the absolute change from baseline in KCCQ-CSS at Week 32, in KCCQ TSS at Week 52, and in KCCQ-OSS at Week 32 and 52. Furthermore, the absolute change from baseline in systolic blood pressure (SBP) at Week 32 in participants with baseline SBP >130 mmHg and absolute change from baseline in diastolic blood pressure (DBP) at Week 32 in participants with baseline DBP >80 mmHg will be assessed.

[0180] All analyses to address primary, key secondary and other secondary objectives will be based on treatment comparisons as randomised, including the effects of any changes of study treatment or concomitant medications until the end of the trial.

[0181] The main endpoints are as follows:

[0182] Primary endpoint

[0183] Time to first event of

[0184] • Cardiovascular (CV) death; or

[0185] • Hospitalisation for heart failure (HHF); or

[0186] • Urgent heart failure (HF) visit

[0187] Key secondary endpoints

[0188] • Time to first event of cardiovascular death or hospitalisation for heart failure

[0189] • Occurrences of hospitalisation for heart failure (first and recurrent)

[0190] • Absolute change from baseline in Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 32

[0191] • Time to cardiovascular death

[0192] • Time to all-cause mortality

[0193] Other secondary endpoints:

[0194] • Time to first hospitalisation for heart failure

[0195] • Time to first occurrence of death from kidney failure, chronic dialysis (defined as dialysis continuing for at least 30 days) or renal transplant or onset of sustained* reduction of

[0196]

[0197] >50% estimated glomerular filtration rate (eGFR) from baseline using the (CKD-EPI)cr equation or onset of sustained* eGFR (CKD-EPI)cr <10 mL / min / 1.73 m2 (composite renal endpoint)

[0198] * "sustained" is either (a) measured at two consecutive visits at least 30 days apart; or (b) measured at the final Follow-up visit or the last scheduled visit before death, loss to follow-up, or withdrawal of consent.

[0199] • Absolute change from baseline in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) at Week 32

[0200] • Absolute change from baseline in Kansas City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 52

[0201] • Absolute change from baseline in Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (KCCQ-OSS) at Week 32

[0202] • Absolute change from baseline in KCCQ-OSS at Week 52

[0203] • Absolute change from baseline in systolic blood pressure (SBP) [mmHg] at Week 32 in participants with baseline SBP >130 mmHg

[0204] • Absolute change from baseline in diastolic blood pressure (DBP) [mmHg] at Week 32 in participants with baseline DBP >80 mmHg

[0205] Further objection and further endpoints

[0206] • Further objectives are to compare the combination of vicadrostat 10 mg and empagliflozin 10 mg with placebo and empagliflozin 10 mg with respect to composite and individual efficacy and safety endpoints as well as biomarker endpoints.

[0207] • The objective of the optional rhythm monitoring substudy is to explore subclinical Afib and Afib burden by use of a rhythm monitoring patch device in a subset of participants

[0208] Further efficacy endpoints

[0209] • Time to first event of CV death, HHF, urgent HF visit or outpatient oral diuretic intensification for HF

[0210] • Time to first “worsening of HF event” defined as time to first event of HHF, urgent HF visit, or outpatient oral diuretic intensification for HF

[0211] • Time to first HHF or urgent HF visit

[0212]

[0213] • Time to first urgent HF visit

[0214] • Time to first outpatient oral diuretic intensification for HF

[0215] • Occurrences of all-cause hospitalisations (first and recurrent)

[0216] • Time to first all-cause hospitalisation

[0217] • Time to first event of all-cause mortality or all-cause hospitalisation

[0218] • Time to first event of all-cause mortality or HHF

[0219] • Time to first MI (fatal or non-fatal)

[0220] • Time to first stroke (fatal or non-fatal)

[0221] • Time to first TIA

[0222] • Time to first stroke (fatal or non-fatal) or TIA

[0223] • Time to first Afib or Aflutter episode in participants without history of AFF (atrial fibrillation and flutter)

[0224] • Time to first event of CV death or non-fatal MI

[0225] • Time to first event of CV death or non-fatal stroke

[0226] • Time to first event of CV death, non-fatal MI, or non-fatal stroke (3 -point MACE) • Time to first event of CV death, HHF, non-fatal MI or non-fatal stroke (4-point MACE) • Time to first event of ventricular tachycardia

[0227] • Time to sudden cardiac death

[0228] • Time to first composite renal endpoint or CV death

[0229] • Time to first composite renal endpoint, HHF or CV death

[0230] • Time to first composite renal endpoint or all-cause hospitalisation

[0231] • Absolute change from baseline in KCCQ-CSS at Week 52

[0232] • Hierarchical composite of all-cause mortality, total number of HHF and KCCQ-TSS change from baseline at Week 32 (analysed by a win ratio)

[0233] • Change in MoCA score from baseline over time

[0234] • Change in NYHA class from baseline to Weeks 32 and 52

[0235] • Health care resource utilisation data

[0236] • Absolute change from baseline in body weight [kg] over time

[0237] • Absolute change from baseline in SBP [mmHg] over time

[0238]

[0239] • Absolute change from baseline in SBP [mmHg] over time in participants with baseline SBP >130 mmHg

[0240] • Absolute change from baseline in DBP [mmHg] over time

[0241] • Absolute change from baseline in DBP [mmHg] over time in participants with baseline DBP >80 mmHg

[0242] • Absolute change from baseline in pulse rate [bpm] over time

[0243] • Time to new onset of diabetes mellitus

[0244] • Relative change in UACR [mg / g] from baseline over time

[0245] • Absolute change from baseline to off-treatment follow-up visit in eGFR [mL / min / 1.73 m2]

[0246] • Absolute change from end of treatment to off-treatment follow-up visit in eGFR [mL / min / 1.73 m2]

[0247] • eGFR (CKD-EPI)cr [mL / min / 1.73 m2] slope of change from baseline from Week 12 onwards (on-treatment; chronic eGFR slope)

[0248] • Absolute change from baseline in eGFR [mL / min / 1.73 m2] on-treatment over time

[0249] • Time to first occurrence of death from kidney failure, chronic dialysis (defined as dialysis continuing for at least 30 days) or renal transplant or onset of sustained* reduction of >40% eGFR from baseline using the (CKD-EPI)cr equation or onset of sustained* eGFR (CKD-EPI)cr <10 mL / min / 1.73 m2(composite renal endpoint-40)

[0250] • Time to first occurrence of death from kidney failure, chronic dialysis (defined as dialysis continuing for at least 30 days) or renal transplant or onset of sustained* reduction of >57% eGFR from baseline using the (CKD-EPI)cr equation or onset of sustained* eGFR (CKD-EPI)cr <10 mL / min / 1.73 m2(composite renal endpoint-57)

[0251] *”sustained” is either (a) measured at two consecutive visits at least 30 days apart; or (b) measured at the final Follow-up visit or the last scheduled visit before death, loss to follow-up, or withdrawal of consent.

[0252] Safety objectives

[0253] • Adverse Events of Special Interest (AESIs)

[0254] • Occurrence of clinically relevant hyperkalaemia (as per investigator judgement)

[0255]

[0256] • Occurrence of hyperkalaemia with serum potassium >5.5 mmol / L, or >6.0 mmol / L (based on central laboratory)

[0257] • Occurrence of adverse events (AEs) leading to discontinuation of vicadrostat / placebo matching vicadrostat

[0258] • Occurrence of adverse events (AEs) leading to discontinuation of empagliflozin

[0259] • Absolute change from baseline in potassium [mmol / 1] over time (central laboratory) • Occurrence of acute renal failure (based on narrow SMQ ‘Acute Renal Failure’)

[0260] • Time to first acute kidney injury (based on preferred term)

[0261] Biomarkers

[0262] • Relative change from baseline in NT proBNP to Week 32

[0263] • Relative change from baseline in hsTnT to Week 32

[0264] • Relative change from baseline in aldosterone, cortisol, and precursors over time

[0265] Table 2. Symptom classification based on NYHA functional classifications:

[0266]

[0267] 2. TRIAL DESIGN

[0268] Aspects of the study design are summarized in Table 3 and further described below:

[0269] Table 3. Treatment groups and blinding:

[0270]

[0271]

[0272]

[0273] All treatment groups are to receive best possible SOC for HF and comorbidities (disregarding SGLT2i) apart from treatment with an MRA, which is exclusionary.

[0274] Comparators / background medication:

[0275] The use of treatments for HF will be at the discretion of the investigator and should be consistent with best possible SOC in accordance with applicable HF local / international guidelines. MRA are prohibited medication from 14 days prior to randomisation until the follow-up visit (planned 7 days after permanent discontinuation of Compound 1 or placebo matching Compound 1).

[0276] For participants who discontinue Compound 1 or placebo matching Compound 1 treatment early, MRA is prohibited until 7 days after permanent discontinuation of Compound 1 or placebo matching Compound 1 and the MRA should thereafter be dosed per investigator judgment.

[0277] Empagliflozin will be provided to all participants as part of the study medication. The use of any SGLT2i or combined SGLTli / SGLT2i, in addition to the provided study medication, is prohibited from the day of randomization until their end of study visit (planned 7 days after EoT for treatment completers) or until empagliflozin is discontinued early.

[0278] Randomisation requirement, stratification factors, block size, and ratio:

[0279] Participants will be randomised via IRT to vicadrostat or placebo matching vicadrostat in a 1:1 ratio. Randomisation is stratified by geographical region (North America, Latin America, Europe West / Australia / South Africa, Europe Central and East, Asia). The block size used for the randomisation will be provided in the CTR.

[0280] Sample Size:

[0281] Overall sample size: approx. 4200*

[0282] Sample size for each group (n = 2 groups): approx. 2100 participants per group

[0283]

[0284] * If the accumulated blinded data suggests a slower accrual of first key secondary outcome events over calendar time than was originally projected (see Section 7.5), then the number of participants randomised may be increased up to a maximum of approximately 6000. The number of first key secondary outcome events required (approximately 763 events) is not affected by this consideration.

[0285] Study periods and duration of treatment:

[0286] • Screening period = up to 3 weeks

[0287] • Treatment period = planned treatment continues until projections support that the required number of events for the primary endpoint will be achieved, study close out is announced, and the planned end of study treatment visits have occurred

[0288] • Follow-up period = 1 week after EOT for each participant

[0289] Completion of treatment

[0290] Participants who prematurely discontinue study drug are expected to remain engaged during the post-treatment follow-up period, adhering to all protocol-specified study visits. They should be actively encouraged to continue with their regular study visits and to complete all scheduled assessments.

[0291] End of trial definition

[0292] The end of the trial is defined as last participant, last FU / EoS Visit completed, planned 1 week (+7 days) after scheduled end of treatment.

[0293] Main diagnosis for trial entry

[0294] The main diagnosis for trial entry is HF (NYHA classes II to IV)(Table 1) and LVEF <40%.

[0295] Inclusion criteria

[0296] Eligible participants will have a diagnosis of HF with LVEF < 40% and meet eligibility criteria below.

[0297] 1. At least 18 years old and at least at the legal age of consent in countries where it is greater than 18 years

[0298]

[0299] 2. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial

[0300] 3. Male or female participants. Women of childbearing potential (WOCBP)l must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria and instructions on the duration of their use is provided in Section 4.2.2.3.

[0301] 4. Chronic HF diagnosed at least 3 months before Visit 1, and in NYHA classes II to IV at Visit 1, with LVEF <40% per local reading (obtained by echocardiography, radionuclide ventriculography, invasive angiography, MRI, or CT). A historical LVEF may be used if it was measured within 12 months prior to Visit 1, or the LVEF may be measured after study consent has been obtained and before randomisation at Visit 2 (if several LVEF assessments are available, the most recent one should be considered).

[0302] 5. Elevated NT-proBNP at Visit 1, analysed at the central laboratory2,3

[0303] a. >600 pg / mL (or if hospitalised for heart failure within the previous 12 months, >400 pg / mL) for participants without Afib or Aflutter (Visit 1 ECG2)

[0304] or

[0305] b. >1200 pg / mL for participants with Afib or Aflutter (Visit 1 ECG2)

[0306] (irrespective of history of heart failure hospitalisation)

[0307] 6. Treated according to best possible SOC (disregarding SGLT2i and MRA) in accordance with applicable HF local / international guidelines and judgement of the investigator, which should in general include (unless contraindicated or not tolerated):

[0308] • An ACE inhibitor, or ARB or ARNi; and

[0309] • A beta-blocker; and

[0310] • If considered appropriate by the patient’s treating physician, an SGLT2i

[0311] (prior SGLT2i treatment will be replaced by the study drug at randomisation)

[0312] Additional inclusion criteria apply to the optional rhythm monitoring substudy:

[0313] 1. Willing and able to provide informed consent for substudy participation

[0314] 2. Sinus rhythm on Visit 1 ECG

[0315] Exclusion criteria

[0316]

[0317] 1. Treatment with an MRA (e.g. spironolactone, eplerenone, finerenone) within 14 days prior to Visit 1 or requiring such treatment before randomisation or planned during the trial based on the judgment of the investigator. Treatment with an MRA should not be discontinued with the intention of study enrolment.

[0318] 2. Treatment with amiloride or other potassium-sparing diuretic within 14 days prior to Visit 1 or requiring such treatment before randomisation or planned during the trial based on the judgment of the investigator.

[0319] 3. Receiving the following treatments:

[0320] • A direct renin inhibitor (e.g. aliskiren) at Visit 2

[0321] • More than one ACEi, ARB or ARNi used simultaneously at Visit 2

[0322] • Other aldosterone synthase inhibitors, e.g. baxdrostat at Visit 2 or planned during the trial • Systemic mineralocorticoid replacement therapy (e.g. fludrocortisone) at Visit 2

[0323] • In case of acute decompensated HF:

[0324] o i.v. inotrope, i.v. vasodilating drug (e.g. nitrate, nitroprusside), or i.v. natriuretic peptide (e.g. nesiritide, carperitide), or mechanical support (e.g. intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, any ventricular assist device) within 24 hours prior to randomisation

[0325] o i.v. diuretic with a dose that has been increased / intensified within 6 hours prior to randomisation (a stable dose of an i.v. diuretic is not exclusionary) 4. MI, TIA, stroke, coronary artery bypass graft surgery (CABG), heart valve surgery / intervention or any other major surgery (major according to the investigator’s assessment) within 90 days prior to Visit 2, or scheduled for major elective surgery (e.g. hip replacement, CABG)

[0326] 5. Percutaneous coronary intervention (PCI) or any angiography using iodinated contrast agents in the 7 days prior to Visit 2

[0327] 6. Heart transplant recipient, awaiting heart transplant, or currently implanted LVAD 7. Known cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, hypertrophic obstructive cardiomyopathy or known pericardial constriction, or cardiomyopathy with potentially reversible cause such as stress or peripartum cardiomyopathy or cardiomyopathy induced by chemotherapy within 12 months prior to Visit 1 and until Visit 2

[0328]

[0329] 8. Acute inflammatory heart disease, such as acute myocarditis, within 90 days preceding prior to Visit 1 and until Visit 2

[0330] 9. Known severe valvular heart disease (obstructive or regurgitant) except mitral regurgitation secondary to left ventricular dilatation, as per investigator’s judgement, or valvular heart disease scheduled for surgical or invasive procedures at Visit 1, or anticipated invasive treatment during the study

[0331] 10. Atrial fibrillation or Atrial flutter with a resting pulse rate >110 bpm documented by ECG at Visit 2

[0332] 11. Clinically relevant ventricular arrhythmia neither treated medically nor with a device with a defibrillator function at Visit 1 and / or Visit 2

[0333] 12. Unless managed with an implanted pacemaker: symptomatic bradycardia, sick sinus syndrome, Mobitz Type II second-degree AV block, or third-degree heart block

[0334] 13. Implantation of CRT device within 3 months prior to Visit 1 or until Visit 2, or scheduled for a CRT device implantation

[0335] 14. Symptomatic hypotension and / or a SBP <100 mmHg at Visit 1 or Visit 2

[0336] 15. SBP >180 mmHg at Visit 1 or Visit 2. If SBP >150 mmHg and <180 mmHg at Visit 1 , the participant should be receiving at least 3 antihypertensive drugs

[0337] 16. Severe chronic pulmonary disease according to investigator’s judgement, e.g. with known FEV1 <50% or need for home oxygen for pulmonary disease, pulmonary arterial hypertension, Chronic Thromboembolic Pulmonary Hypertension (CTEPH), or chronic obstructive pulmonary disease (COPD) exacerbation requiring i.v. or chronic oral steroids within 3 months prior to Visit 1 or until Visit 2

[0338] 17. Serum potassium3 >5.2 mmol / L measured by the central laboratory at Visit 1 (Note: one reassessment of serum potassium is allowed during screening)

[0339] 18. ALT or AST3 >3x ULN at Visit 1 or known hepatic cirrhosis (Child Pugh C), or other liver disease causing severe impaired liver function, according to investigator’s judgement 19. Impaired renal function, defined as eGFR3 <20 mL / min / 1.73 m2 (CKD-EPI) as determined at Visit 1 by the central laboratory or on renal replacement therapy

[0340] (Note: one reassessment of eGFR is allowed during screening)

[0341] 20. Haemoglobin (Hb)3 <9 g / dL as determined at Visit 1 by the central laboratory

[0342] 21. Known adrenal insufficiency (e.g. Addison disease) or Cushing’s syndrome

[0343]

[0344] 22. History of ketoacidosis within 5 years prior to Visit 1 or until Visit 2

[0345] 23. Gastrointestinal surgery or gastrointestinal disorder that could interfere with trial medication absorption in the investigator’s opinion, e.g. intestinal resection, inflammatory bowel disease, currently active gastritis, pancreatitis

[0346] 24. Type 1 diabetes mellitus, or history of other autoimmune causes of diabetes mellitus (e.g. LADA)

[0347] 25. Any documented active or suspected malignancy or history of malignancy within 5 years prior to Visit 1, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of uterine cervix or low risk prostate cancer (participants with pretreatment PSA <10 ng / mL and biopsy Gleason score of <6 and clinical stage Tic or T2a)

[0348] 26. Presence of any other disease than heart failure with a life expectancy of < 1 year in the investigator’s opinion

[0349] 27. Participants who must or wish to continue the intake of restricted medications (see Table 4) or any drug considered likely to interfere with the safe conduct of the trial

[0350] 28. Currently enrolled in another investigational device or drug trial, or less than 30 days or 5 half-lives of the investigational drug (whichever is longer) since ending another investigational device or drug trial(s) or receiving other investigational treatment(s). Those patients participating in a purely observational trial will not be excluded

[0351] 29. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes them an unreliable trial participant or unlikely to complete the trial

[0352] 30. Women who are pregnant, breastfeeding, or may become pregnant while in the trial 31. Intolerance or known allergy or hypersensitivity to vicadrostat or empagliflozin or other SGLT2 inhibitors and / or any of the excipients (including lactose). A list of ingredients of vicadrostat and empagliflozin and placebo is provided in the ISF

[0353] 32. Any condition not covered by any of the other exclusion criteria, including abnormal laboratory values, which in the investigator’s opinion, might make a participant otherwise vulnerable (e.g. participant in custody by order of an authority or a court) or jeopardise patient safety or compliance with the protocol

[0354] Additional exclusion criteria apply to the optional rhythm monitoring substudy:

[0355] 1. Known allergies, intolerance or hypersensitivities to adhesives or hydrogel

[0356] 2. Cardiac pacemaker, ICD, or CRT device

[0357]

[0358] 3. History of permanent atrial fibrillation or atrial flutter

[0359] Table 4. Restricted medications

[0360]

[0361] treatment stop. No medications are restricted afterwards.

[0362] 2For participants who discontinue vicadrostat / placebo matching vicadrostat treatment early, MRA and potassium-sparing diuretics are prohibited until 7 days after permanent discontinuation of vicadrostat / placebo matching vicadrostat and may thereafter be adjusted per investigator judgment.3For participants who discontinue trial treatment of vicadrostat / placebo matching vicadrostat and empagliflozin early, MRA and potassium-sparing diuretics are prohibited until 7 days after permanent discontinuation of vicadrostat / placebo matching vicadrostat and SGLT2i are prohibited until permanent discontinuation of empagliflozin, respectively, and may thereafter be adjusted per investigator judgement.

[0363] 4Participants should be instructed to take their prescribed SGLT2 or SGLT1 / 2 inhibitor for the last time on the day before randomisation. For empagliflozin, if the dose cannot be reduced from 25 mg to 10 mg, the participant is not considered to be eligible for trial participation.

[0364] 3. TREATMENTS

[0365]

[0366] Table 5 summarizes the investigation product, placebo and empagliflozin used in the clinical trial.

[0367] Table 5.

[0368]

[0369] Selection of doses in the trial and dose modifications:

[0370] During the treatment period, participants will receive either Compound 1 (10 mg) or matching placebo and empagliflozin (10 mg).

[0371] If serum potassium is >5.5 mmol / L, temporary discontinuation of vicadrostat or placebo matching vicadrostat should be considered. All trial participants are to receive best possible SOC on top of trial treatment. MRA are prohibited medications from 14 days prior to the screening visit until the Follow-up / EoS Visit (planned 7 days after the end of treatment for participants regularly completing treatment with vicadrostat or placebo matching vicadrostat) or until 7 days

[0372]

[0373] after permanent discontinuation of vicadrostat or placebo matching vicadrostat, if vicadrostat or placebo matching vicadrostat treatment is discontinued early.

[0374] Method of assigning trial participants to treatment groups

[0375] Randomisation codes will be generated through a validated software and kept blinded to the trial team, sites, and trial participants. Access to the codes will be controlled and documented. An Interactive Response Technology (IRT) system will be used to screen participants, create a participant number, perform treatment assignment, manage initial / re-supply ordering of IMP supplies, and handle emergency unblinding.

[0376] After the assessment of all inclusion and exclusion criteria, each eligible trial participant will be randomised to a treatment group according to a randomisation plan in a 1:1 ratio at Visit 2 via IRT (see Section 7.4).

[0377] Note that the medication number is different from the participant number (the latter is generated during Visit 1 via the IRT system).

[0378] Drug assignment and administration of doses for each trial participant

[0379] At Visit 2 (start of treatment period), participants will be randomly assigned to receive vicadrostat or placebo matching vicadrostat.

[0380] In addition, all participants will receive a study medication kit containing empagliflozin 10 mg.

[0381] From the start of the treatment period participants will be instructed to take both trial medications together once daily with a glass of water. To ensure a dose interval of about 24 hours, both medications should be taken together in the morning at approximately the same time every day. If a dose is missed by more than 12 hours, that dose should be skipped and the next dose should be taken as scheduled. No double doses should be taken. There are no specific requirements regarding timing of doses in relation to meals.

[0382] Participants should be instructed not to take their study medication at home on the days of their study visits at the clinic as participants will be dosed at the site.

[0383]

[0384] During the treatment period, all trial medication will be dispensed at each on-site visit and medication will be administered from the kit dispensed at the current visit.

[0385] Compound 1 or placebo matching vicadrostat will be dispensed in bottles of 112 tablets and empagliflozin will be dispensed in wallets of 112 tablets. Depending on the frequency of trial drug dispense visits (between 12 to 24 weeks), 1 to 2 packages (including reserve) of vicadrostat or placebo matching vicadrostat and 1 to 2 packages (including reserve) of empagliflozin are dispensed.

[0386] If symptoms or signs suggestive of a cortisol insufficiency are reported whilst on study treatment, an unscheduled visit with early morning sample for local measurement cortisol should be performed.

[0387] Restrictions

[0388] Concomitant medication restrictions are described in Table 5.

[0389] Due to potential interference with laboratory results, participants taking biotin will be asked to discontinue, and to schedule laboratory testing to occur >72 hours after the last biotin intake. This includes biotin (Vitamin B7, Vitamin H, or coenzyme R) >5 mg / day (including food supplements) and is applicable to laboratory testing at screening visits or any other trial visit.

[0390] The following should be used with caution, at the discretion of the investigator on a case by case basis: potassium supplementation, non-steroidal anti-inflammatory drugs (NSAIDs), trimethoprim and trimethoprim / sulfamethoxazole, any other medication known to raise potassium levels and / or cause deterioration in renal function.

[0391] While enrolled in this trial, trial participants must not participate in another investigational drug or device trial or receive other investigational treatment(s).

[0392] Restrictions on diet and lifestyle

[0393] There are no restrictions on diet and lifestyle.

[0394] Contraception requirements

[0395]

[0396] A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Tubal ligation is not a method of permanent sterilisation. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

[0397] Throughout the trial and for a period of at least 7 days after the last dose of IMP, women of childbearing potential must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly.

[0398] 4. ASSESSMENT OF EFFICACY

[0399] Urine albumin creatinine ratio

[0400] Urinary albumin and creatinine measurements are the basis for the calculation of UACR. UACR will be collected at the time required points. Urinary albumin and creatinine will be analysed at a central laboratory using routine validated methods.

[0401] Heart failure events and cardiovascular death

[0402] Investigators will review clinical information pertaining to HF events in relevant source documents and document it in a structured eCRF, and where applicable will provide categorisation based on their clinical judgement and on objective criteria.

[0403] For the mortality component of the primary endpoint, the date of death and cause of death will be required. Investigators will categorise deaths as CV death, non-CV death, or death of undetermined cause, based on available information, clinical judgement, and guidance in the eCRF.

[0404] Investigators will also review clinical information pertaining to hospitalisations.

[0405]

[0406] MI, stroke, and HA events will be collected in the eCRF as reported by the investigator.

[0407] The investigator is responsible for reviewing the endpoints. Investigators are blinded to trial treatment and will receive dedicated training on event review prior to trial initiation.

[0408] Investigators assigned to the trial after initiation will also undergo event review training.

[0409] New York Heart Association Functional Classification

[0410] The NYHA Functional Classification will be used to classify HF severity (see Table 2) (Dolgin M, New York Heart Association. Criteria Committee. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. 1994. p. 253-256.; Table 4). The Investigator should place the participants in one of the four NYHA categories based on the participant’s physical activity limitations.

[0411] Candidates for screening are required to have a NYHA Functional Class of II to IV based on LVEF (see Table 1).

[0412] The classification of participant’s physical activity according to NYHA will be performed at onsite visits as displayed in the SoA. If a visit is designated as an on-site visit but is conducted by phone, the NYHA Functional Classification must still be performed.

[0413] Kansas City Cardiomyopathy Questionnaire

[0414] The KCCQ is a 23 -item self-administered questionnaire designed to evaluate physical limitations, symptoms (frequency, severity, and changes over time), social limitations, self efficacy, and quality of life in patients with HF. Electronic version in the required native language of the participant will be used. If the required language is not available, the participant is not required to complete the questionnaire.

[0415] The questionnaire takes about 5 to 8 minutes to complete and will be distributed according to the SoA.

[0416] The Investigator (or designated site personnel) should ensure that the participant has access to a quiet area at the site where he / she can be left alone to record his / her response in the questionnaire. In instances where a participant cannot give or decide upon a response, no

[0417]

[0418] response should be recorded. The Investigator (or designated site-personnel) should check that all items have been completed by the participant, but the response to each item should not be scrutinised. Instructions to participants are included in the questionnaire.

[0419] Patient Global Impression of Severity (PGI-S)

[0420] PGI-S of Heart Failure Symptoms is a 1-item questionnaire to assess the participant’s impression of symptoms severity, including shortness of breath, fatigue and swelling over the past two weeks over the last two weeks. The PGI-S asks the participant to choose one response that best describes how his / her Heart Failure Symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-point scale:

[0421] • Not at all

[0422] • Mild

[0423] • Moderate

[0424] • Severe

[0425] • Very severe

[0426] Montreal Cognitive Assessment

[0427] The MoCA is a widely used screening assessment for detecting impairment in a participant’s cognitive function, including his / her ability to understand, reason, and remember. The MoCA assesses multiple cognitive domains, including short-term memory, executive function, attention, focus, and more. A paper-based version in the required native language of the participant will be used. Because MoCA is English-specific linguistic, and cultural translations are made to adapt the test in other countries. If the required language is not available, the participant is not required to complete the questionnaire.

[0428] This test is a one-page 30 point test administered in approximately 10 to 12 minutes and will be distributed according to the SoA. Participants will receive appropriate instructions required for completing the MoCA. Sites will be given administration instructions as part of their training.

[0429] Electronic clinical outcome assessment (eCOA) handling

[0430] Administration of eCOAs will be handled according to guidance documents from regulatory authorities and international societies (e.g. International Society for Pharmacoeconomics and

[0431]

[0432] Outcomes Research). The participant is to complete ePRO assessments (KCCQ and PGI-S) using a tablet on his / her own at the frequency specified in the SoA, without being influenced by the investigator or other members of the trial team. The assessments are to be completed by the participant in the same language the participant provided written consent for the trial and without any help from or interpretation / translation by other people.

[0433] Adequately trained and qualified site staff are to be available at any time for general questions and to support the participant, as well as to ensure ePRO completion compliance.

[0434] Whether the participant was able to complete the ePRO assessment himself / herself and the mode of administration will be documented.

[0435] ePRO data will be electronically transferred to the ePRO vendor database. In case the electronic system is unavailable CO As should be captured via paper.

[0436] ASSESSMENT OF SAFETY

[0437] Physical examination

[0438] A complete physical examination will be performed at the time points specified in the SoA. This examination includes, at a minimum, general appearance, neck, lungs, cardiovascular system, abdomen, extremities, and skin. Measurement of height and body weight will be performed at the time points specified in the SoA.

[0439] ASSESSMENT OF BIOMARKER(S)

[0440] Exploratory and probable valid biomarkers

[0441] Probable valid biomarker analyses of established biomarkers of disease activity may include, but not be limited to:

[0442] • Mechanism of action related pharmacodynamic biomarker aldosterone and related corticosteroids such as 11 -deoxycorticosterone, cortisol, 11 -deoxycortisol and corticosterone to confirm selectivity of enzyme inhibition and to evaluate prognostic relevance of aldosterone suppression.

[0443]

[0444] • Pharmacodynamics modulation of efficacy-related, disease activity biomarkers NT- proBNP and hsTnT indicative of heart wall remodeling and myocardial injury, respectively.

[0445] These analyses will be conducted in all participants in selected countries with sampling timepoints indicated in the SoA.

[0446] All biomarker samples can be analysed in a staggered approach, and decisions for further analysis may depend on the results of prior analyses. This may also imply that not all collected samples will be analysed, especially in case of termination of the project / trial or when baseline sample was not collected.

[0447] Should other biomarkers become relevant in the context of the trial and / or based on new information in the scientific literature or early trial analysis, these may also be explored from the available specimens.

[0448] The study samples will be discarded after completion of any investigations, but not later than 2 years after the CTR has been signed. Any leftover samples or derived material from prespecified analyses (e.g. RNA, DNA, and blood) may be used for method development / validation but will be destroyed no later than 2 years after the final trial report has been signed.

[0449] Exploratory and probable valid biomarker analyses will be performed by Boehringer Ingelheim or by a laboratory authorized by Boehringer Ingelheim.

[0450] Detailed instructions on sampling, preparation, processing, and shipment of the samples are provided in the laboratory manual.

[0451] Analytical results for the biomarker analyses will be described in an analytical report.

[0452] 5. STATISTICAL DESIGN

[0453] NULL AND ALTERNATIVE HYPOTHESES

[0454] The primary and key secondary hypotheses will be tested with a hierarchical testing procedure at the two-sided type I error level a=5% in the following order:

[0455] (1)

[0456] 1. HoTime to first event of CV death, HHF or urgent HF (primary endpoint).

[0457]

[0458] 2

[0459] 2. Ho. Time to first event of CV death, or HHF visit (first key secondary endpoint).

[0460] 3. Benjamini-Hochberg procedure for the following two endpoints:

[0461] a. Ho. Occurrences (first and recurrent) of HHF (second key secondary endpoint) b. HQ4'1: Absolute change from baseline in KCCQ-TSS at Week 32 (third key secondary endpoint)

[0462] 4. : Time to event of CV death (fourth key secondary endpoint)

[0463]

[0464] Time to event of all-cause mortality (fifth key secondary endpoint)

[0465] If the null hypothesis (Ho) of step 1 is rejected, a benefit is concluded in the primary endpoint, then the first key secondary endpoint will also be tested in step 2. If the null hypothesis of step 2 2 (3 (HQ ) is subsequently rejected, then both the null hypotheses of the second key secondary (Ho) endpoint and of the third key secondary endpoint

[0466]

[0467] will be tested simultaneously (following a Benjamini-Hochberg procedure) as part of step 3.

[0468] If both null hypothesis of step 3 (H^1

[0469]

[0470] will be rejected , then the fourth key secondary endpoint will be tested in step 4. If the null hypothesis of step 4

[0471]

[0472] is subsequently rejected, then the fifth key secondary endpoint will be tested in step 5

[0473]

[0474] At any stage, when the corresponding null hypothesis is not rejected then all subsequent testing will be considered as exploratory.

[0475] The primary null hypothesis (Ho) to be tested is as follows:

[0476] Null hypothesis (Ho): The hazard ratio (of time to first event of CV death, HHF or urgent HF visit) between Compound 1 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD equals 1.

[0477] Alternative hypothesis (H ): The hazard ratio (of time to first event of CV , HHF or urgent HF visit) between Compound 1 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is not equal 1.

[0478]

[0479] The primary endpoint will be tested for superiority, and superiority will be declared if the hazard ratio between Compound 1 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is significantly less than 1 at the two-sided type I error level a=4.99%.

[0480] The first key secondary hypothesis (Ho) to be tested is as follows:

[0481] 2

[0482] Null hypothesis (Ho): The hazard ratio (of time to first event of CV death or HHF) between Compound 1 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD equals 1.

[0483] Alternative hypothesis (H^ ): The hazard ratio (of time to first event of CV death or HHF) between Compound 1 10 mg+ empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is not equal 1.

[0484] The first key secondary endpoint will be tested for superiority, and superiority will be declared if the hazard ratio between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is significantly less than 1, at the two-sided Type I error level a=0.1% at interim or respectively a=4.99% at final analysis.

[0485] The second key secondary null hypothesis (Ho) to be tested is as follows:

[0486] 3

[0487] Null hypothesis (Ho): The hazard ratio for the comparison (of first and recurrent HHF) between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD equals 1

[0488] 3

[0489] Alternative hypothesis (H ): The hazard ratio for the comparison (of first and recurrent HHF) between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is not equal 1

[0490] (4)

[0491] The third key secondary null hypothesis (HQ ) to be tested is as follows:

[0492] Null hypothesis

[0493]

[0494] The difference in mean change (from baseline) in KCCQ-TSS at Week 32 between vicadrostat 10 mg+ empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is equal to 0

[0495] Alternative hypothesis (H}): The difference in mean change (from baseline) in KCCQ- TSS at Week 32 between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is not equal to 0

[0496]

[0497] 2

[0498] The second and third key secondary null endpoint will be tested for superiority if Hocan be rejected.

[0499]

[0500] will be rejected if both p-values are < a. If one p-value is > a, then the other null hypothesis will be rejected if the p-value is < a / 2, following the Benjamini -Hochberg procedure. Superiority will be declared if the null hypothesis can be rejected in favour of the alternative hypothesis and if the difference in the effect favours the active treatment group (that is, for HQr3>a hazard ratio less than 1, and for HQr4>, a mean difference greater than 0).

[0501] The fourth key secondary null hypothesis

[0502]

[0503] to be tested is as follows:

[0504] Null hypothesis

[0505]

[0506] The hazard ratio (of time to CV death) between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD equals 1 Alternative hypothesis

[0507]

[0508] The hazard ratio (of time to CV death) between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is not equal 1 The fourth key secondary endpoint will be tested for superiority, and superiority will be declared if the hazard ratio between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is significantly less than 1, at the two-sided type I error level 0.1% at interim or respectively a=4.99% at final analysis.

[0509] The fifth key secondary null hypothesis

[0510]

[0511] to be tested is as follows:

[0512] Null hypothesis (HQ6'>): The hazard ratio (of time to all-cause mortality) between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD equals 1

[0513] Alternative hypothesis

[0514]

[0515] The hazard ratio (of time to all-cause mortality) between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is not equal 1

[0516] The fifth key secondary endpoint will be tested for superiority, and superiority will be declared if the hazard ratio between vicadrostat 10 mg + empagliflozin 10 mg QD and placebo + empagliflozin 10 mg QD is significantly less than 1, at the two-sided type I error level a=0.1% at interim or respectively a=4.99% at final analysis.

[0517] PLANNED ANALYSES

[0518] General considerations

[0519]

[0520] Participants will be analyzed according to their randomised treatment including all participants randomised (intention-to-treat principle, ITT). For time to event and count endpoints, participants who do not have an event will be censored at the last day the participant was known to be free of the event, except other intercurrent events occur which may result in earlier censoring as specified below.

[0521] Analysis sets:

[0522] • Randomised Set (RS): the RS includes all randomised patients. The primary efficacy analysis will be based on the RS.

[0523] • Treated Set (TS): the TS includes all randomised patients who received at least one dose of trial treatment. If not stated otherwise, safety analyses will be based on this analysis set.

[0524] Definition of baseline in general, unless otherwise specified in the TS AP, is the last non missing measurement on or prior to the date of first dose of study treatment and will be used as baseline for efficacy and safety variables.

[0525] For the definition of on-treatment for the purposes of on-treatment safety analyses, an assessment (or AE start date) will be considered “on-treatment” if the assessment date (or AE start date) is between the date of first dose and 7 days after the date of last trial medication intake.

[0526] Further details will be provided in the TSAP.

[0527] Adherence to the protocol will be assessed by the trial team. Important protocol deviations (IPD) categories will be defined in the IPD specification file. Identification of participants with IPDs will be confirmed prior to unblinding of the trial team. Summaries of participants with IPDs will be presented in the CTR. Any exclusions from the analysis sets will be decided and documented prior to unblinding of the trial team.

Claims

ClaimsWhat is claimed is:

1. A method for reducing the risk of cardiovascular death, hospitalization for heart failure, and / or urgent heart failure visit in a patient with heart failure and left ventricular ejection fraction <40%, the method comprising administering to the patient a pharmaceutically effective amount of Compound 1:optionally in combination with an SGLT2 inhibitor.

2. Use of Compound 1:optionally in combination with an SGLT2 inhibitor, for reducing the risk of cardiovascular death, hospitalization for heart failure, and / or urgent heart failure visit in a patient, wherein the patient has heart failure and a left ventricular ejection fraction <40%.

3. Use of Compound 1:optionally in combination with an SGLT2 inhibitor, for the preparation of a medicament for treating a patient with heart failure and a left ventricular ejection fraction <40%, wherein the treatment reduces the risk of cardiovascular death, hospitalization for heart failure, and / or urgent heart failure visit in the patient.

4. The method or use according to any one of claims 1 to 3, wherein the heart failure is chronic heart failure, symptomatic heart failure or urgent heart failure.

5. The method or use according to any one of claims 1 to 4, wherein the patient is an adult patient.

6. The method or use according to any one of claims 1 to 5, wherein Compound 1 is used in combination with an SGLT2 inhibitor, wherein the SLGT2 inhibitor is selected from the group consisting of empagliflozin, dapagliflozin, sotagliflozin and canagliflozin.

7. The method or use according to claim 6, wherein the SGLT2 inhibitor is empagliflozin.

8. The method or use according to claim 7, wherein Compound 1 is administered in an amount of 3 mg, or 6 mg, or 10 mg, or 20 mg; and empagliflozin is administered in an amount of 10 mg or 25 mg.

9. The method or use according to claim 8, wherein Compound 1 is administered in an amount of 10 mg; and empagliflozin is administered in an amount of 10 mg.

10. The method or use according to any one of claims 6 to 9, wherein Compound 1 is administered once daily and empagliflozin is administered once daily.

11. The method or use according to any one of claims 1 to 10, wherein the treatment or use prevents, reduces the risk of, and / or slows the progression of:a first event of cardiovascular death or hospitalization for heart failure,occurrence of hospitalization for heart failure (first or recurrent),the absolute change from baseline in KCCQ-TSS at Week 32,the time to CV death, and / orthe time to all-cause mortality in a patient.

12. The method or use according to any one of claims 1 to 11, wherein the patient is a type 2 diabetes mellitus patient.

13. The method or use according to any one of claims 1 to 11, wherein the patient is a type 1 diabetes patient.

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