Methods of using neuregulin-4 compounds

Abstract

The present invention relates to the dosage and administration regimen of NRG4 compounds in the treatment of cardiovascular disease (CVD)-related conditions including heart failure (HF).

Description

Technical Field

[0001] The present invention relates to the field of medicine. More particularly, the present invention relates to methods of using neuregulin-4 compounds in the treatment of cardiovascular diseases (CVDs) and related conditions, including in particular heart failure (HF).

Background Art

[0002] There is an unmet medical need for new and improved treatments for HF. HF is a serious condition estimated to affect over 6 million adults in the United States and at least 26 million people worldwide. The prevalence of HF is predicted to continue to increase significantly. Currently available treatments are aimed at slowing the progression of the disease and improving symptoms, and rely on hemodynamic changes to reduce the burden on the failing heart. These therapies include (a) drugs intended to lower heart rate, such as beta blockers and ivabradine; (b) drugs intended to lower blood pressure, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and sacubitril / valsartan (ENTRESTO®); and / or (c) drugs intended to treat or prevent volume overload, such as diuretics and MRAs and sodium-glucose cotransporter 2 (SGLT2) inhibitors. However, these treatments do not directly treat the heart and have practical limitations such as the need for dose titration and monitoring for hypotension. Despite improvements in the treatment of chronic HF, morbidity and mortality remain high. Considering the unmet high medical need, new and better treatments for chronic HF are needed.

[0003] WO 2020 / 205840 pamphlet describes NRG4 compounds that are useful in the treatment or prevention of CVD and related conditions, including HF (HFrEF) with reduced ejection fraction, particularly through mechanisms potentially involved in heart tissue repair. The preferred NRG4 compounds described contain the following amino acid sequence. GGGGSGHEEPCGPSHKSFCLNGGLCYQIPTIPSPFCRCVENYTGARCEKVFL (SEQ ID NO: 1)

[0004] Specific dosages and administration regimens are required for treatment with such compounds.

SUMMARY OF THE INVENTION

[0005] Accordingly, the present invention provides a method for treating HFrEF in a patient in need of treatment, the method comprising administering to the patient an NRG4 compound of SEQ ID NO: 1 in a dosage of 21 to 560 mg.

[0006] In another aspect, the present invention provides a pump device comprising an NRG4 compound of SEQ ID NO: 1 in a dosage of 21 to 560 mg.

[0007] In another aspect, the present invention provides an NRG4 compound of SEQ ID NO: 1 for use in the treatment of HFrEF in a patient at a dosage of 21 to 560 mg.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008]

Figure 1

DETAILED DESCRIPTION OF THE INVENTION

[0009] In certain embodiments, the present invention provides a method of treating HFrEF, wherein the NRG4 compound of SEQ ID NO: 1 is administered at a dose of 21 to 560 mg. In one embodiment, the dose is 21 to 63 mg. In another embodiment, the dose is 21 to 140 mg. In another embodiment, the dose is 21 to 189 mg. In another embodiment, the dose is 21 to 280 mg. In another embodiment, the dose is 21 to 420 mg. In another embodiment, the dose is 21 to 560 mg. In another embodiment, the dose is 63 to 140 mg. In another embodiment, the dose is 63 to 189 mg. In another embodiment, the dose is 63 to 280 mg. In another embodiment, the dose is 63 to 420 mg. In another embodiment, the dose is 63 to 560 mg. In another embodiment, the dose is 140 to 189 mg. In another embodiment, the dose is 140 to 280 mg. In another embodiment, the dose is 140 to 420 mg. In another embodiment, the dose is 140 to 560 mg. In another embodiment, the dose is 189 to 280 mg. In another embodiment, the dose is 189 to 420 mg. In another embodiment, the dose is 189 to 560 mg. In another embodiment, the dose is 280 to 420 mg. In another embodiment, the dose is 280 to 560 mg. In another embodiment, the dose is 420 to 560 mg.

[0010] In certain embodiments, the present invention provides a method of treating HFrEF, wherein the NRG4 compound of SEQ ID NO: 1 is administered at doses of about 21 mg, about 63 mg, about 140 mg, about 189 mg, about 280 mg, about 420 mg, and about 560 mg. In one embodiment, the dose is about 21 mg. In another embodiment, the dose is about 63 mg. In another embodiment, the dose is about 140 mg. In another embodiment, the dose is about 189 mg. In another embodiment, the dose is about 280 mg. In another embodiment, the dose is about 420 mg. In another embodiment, the dose is about 560 mg.

[0011] In certain embodiments, the present invention provides a method of treating HFrEF, wherein the NRG4 compound of SEQ ID NO: 1 is administered at a dose of 1 to 60 mg. In certain embodiments, the dose is 3 to 30 mg. In certain embodiments, the dose is selected from the group consisting of about 1 mg, about 3 mg, about 10 mg, about 30 mg, and about 60 mg.

[0012] In certain embodiments, the dose is administered by subcutaneous (SC) injection over 24 to 96 hours. In certain embodiments, the dose is administered by subcutaneous (SC) injection over 24 to 48 hours. In certain embodiments, the dose is administered by subcutaneous (SC) injection over 24 to 72 hours. In certain embodiments, the dose is administered by subcutaneous (SC) injection over 48 to 72 hours. In certain embodiments, the dose is administered by subcutaneous (SC) injection over 48 to 96 hours. In certain embodiments, the dose is administered by subcutaneous (SC) injection over 72 to 96 hours.

[0013] In certain embodiments, the dose is administered by SC injection over about 24 hours. In other embodiments, the dose is administered by SC injection over about 48 hours. In other embodiments, the dose is administered by SC injection over about 72 hours. In other embodiments, the dose is administered by SC injection over about 96 hours.

[0014] In one embodiment, the dosage is 21 mg administered over about 24, about 48, about 72, or about 96 hours. In one embodiment, the dosage is about 63 mg administered over about 24, about 48, about 72, or about 96 hours. In one embodiment, the dosage is about 140 mg administered over about 24, about 48, about 72, or about 96 hours. In one embodiment, the dosage is about 189 mg administered over about 24, about 48, about 72, or about 96 hours. In one embodiment, the dosage is about 280 mg administered over about 24, about 48, about 72, or about 96 hours. In one embodiment, the dosage is about 420 mg administered over about 24, about 48, about 72, or about 96 hours. In one embodiment, the dosage is 560 mg administered over about 24, about 48, about 72, or about 96 hours.

[0015] In certain embodiments, the patient is treated with a dosage of the NRG4 compound once about every month. In certain embodiments, the patient is treated with a dosage of the NRG4 compound once about every two months. In certain embodiments, the patient is treated with a dosage of the NRG4 compound once about every three months. In certain embodiments, the patient is treated with a dosage of the NRG4 compound once about every four months. In certain embodiments, the patient is treated with a dosage of the NRG4 compound once about every five months. In other embodiments, the patient is treated with a dosage of the NRG4 compound once about every six months.

[0016] As used herein, the term "about" is intended to refer to the degree of tolerance of the indicated amount or quantity, taking into account the nature or precision of the measurement. For example, the degree of error can be indicated by the number of significant figures provided for the measurement, as understood in the art, and includes, but is not limited to, a variation of ±1 of the most accurate significant figure reported for the amount or quantity. Typically, the exemplary degree of error is within 20 percent (%), preferably within 10%, more preferably within 5% of a given value or range of values. Numerical values presented herein are approximate unless otherwise indicated, and the term "about" means what can be inferred when not explicitly stated.

[0017] As used herein, the terms "treating" or "to treat" include limiting, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder. Treatment of heart failure or HFrEF according to the present invention can be reflected in one or more of various measures related to heart failure, including, for example, improvement of one or more echocardiogram parameters. Examples of such parameters include left atrial volume (LAV); left atrial volume index (LAVI); left ventricular end-diastolic volume (LVEDV); left ventricular end-diastolic volume index (LVEDVI); left ventricular ejection fraction (LVEF); left ventricular end-systolic volume (LVESV); left ventricular end-systolic volume index (LVESVI); left ventricular global circumferential strain (LVGCS); left ventricular global longitudinal strain (LVGLS); left ventricular mass (LVM); left ventricular mass index (LVMI); E wave to A wave ratio (E / A); ratio between early mitral inflow velocity and early mitral annulus diastolic velocity (E / e'); left ventricular outflow tract - velocity time integral (LVOT-VTI); tricuspid regurgitation peak velocity (TRV); and TR velocity gradient, estimated right ventricular systolic pressure. In certain embodiments, the method results in a significant increase in LVEF. In certain embodiments, the method results in a significant decrease in the risk of CV death. In certain embodiments, the method results in a significant decrease in the risk of HF-related during hospitalization. In certain embodiments, the method results in an improvement in the patient's NYHA class assessment. In certain embodiments, the method results in an improvement in the patient's functional and symptomatic assessment.

[0018] Certain benefits of treatment according to embodiments of the present invention can be achieved after at least about 1 month of treatment. Certain benefits of treatment according to embodiments of the present invention can be achieved after at least about 3 months of treatment. Certain benefits of treatment according to embodiments of the present invention can be achieved after at least about 6 months of treatment. Certain benefits of treatment according to embodiments of the present invention can be achieved after at least about 1 year of treatment.

[0019] In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in an improvement in LVEF. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in an improvement of at least about 3% in LVEF. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in an improvement of at least about 5% in LVEF. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in an improvement of at least about 5% in LVEF after 6 months of treatment. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in an improvement of at least about 5% in LVEF after 1 year of treatment.

[0020] In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in an improvement of at least about 5% in LVESV after 1 year of treatment.

[0021] In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in a significant decrease in LVEDV after 1 year of treatment. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in a decrease in LVGLS. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in a decrease of at least about 1% in LVGLS. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in a decrease of at least about 3.5% in LVGLS. In certain embodiments, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention results in a decrease of at least about 15% in the risk of CV death and / or HF hospitalization.

[0022] In certain embodiments, the method results in a decrease in the risk of total mortality, a decrease in the risk of myocardial infarction (MI), a decrease in the risk of stroke, a decrease in the risk of the need for left ventricular assist device (LVAD) implantation and / or heart transplantation, an improvement in symptoms and physical limitations of heart failure, and / or an improvement in quality of life (QoL).

[0023] Furthermore, as described above, administration of the NRG4 compound of SEQ ID NO:1 according to certain embodiments with a presentation can provide improvement in heart failure-related measures as described above without increasing safety risks. Thus, in a preferred embodiment, administration of the NRG4 compound of SEQ ID NO:1 according to the present invention does not result in an increased safety risk, such as an increase in hypotension; deterioration of renal function; electrolyte imbalance; liver dysfunction; or tumor development.

[0024] Administration of the NRG4 compound of SEQ ID NO:1 according to the present invention is typically parenteral, for example, intravenous (IV), subcutaneous (SC) or intraperitoneal (IP). Thus, in certain embodiments of the present invention, the NRG4 compound of SEQ ID NO:1 is administered intravenously. In other embodiments of the present invention, the NRG4 compound of SEQ ID NO:1 is administered intraperitoneally. In other embodiments, the NRG4 compound of SEQ ID NO:1 is administered subcutaneously.

[0025] To control the exposure period for optimized sustained efficacy with sufficient margin against cardiotoxicity, parenteral administration of the NRG4 compound is preferably by continuous or intermittent infusion. For example, many types of infusion pumps are used to infuse a wide range of drugs, and such pumps can be used for administration of the NRG4 compound according to the present invention. More recently, patch pumps that are smaller than conventional devices and can be directly attached to the patient's skin have been developed, minimizing interference with the patient's daily activities. Thus, in certain embodiments, the NRG4 compound of SEQ ID NO:1 is administered by an infusion pump or a patch pump. Preferably, the NRG4 compound of SEQ ID NO:1 is administered by a patch pump.

[0026] As noted above, all HF patients, even those with mild symptoms, are at increased risk of death. Thus, as used herein, reference to a patient "in need of" treatment for heart failure (HF) may refer to a broad range of individuals with HF, including those having a broad range of disease severities as described below. The New York Heart Association (NYHA) provides a classification scheme for the degree or severity of HF, as summarized in Table 1 below.

[0027] [Table 1]

[0028] In certain embodiments, the patients in need are in NYHA classes II-IV of heart failure. In certain embodiments, the patients in need are in NYHA class II of heart failure. In certain embodiments, the patients in need are in NYHA class III of heart failure. In certain embodiments, the patients in need are in NYHA class IV of heart failure. In certain embodiments, the patients in need are in NYHA classes II-III of heart failure.

[0029] As described above, existing treatment options for heart failure, including current standard of care, improve symptoms, slow disease progression, and reduce the workload of heart failure through hemodynamic mechanisms, e.g., reduction of blood pressure, heart rate, and / or plasma volume. In contrast, the NRG4 compound of SEQ ID NO:1 achieves its effects through a different mechanism of action, namely, selective HER4 binding and the resulting activity, which directly improves cardiomyocyte survival and cellular metabolism and promotes myocardial regeneration. Due to these different mechanisms of action, the NRG4 compound of SEQ ID NO:1 can be administered on top of existing SoC without titration or monitoring. Thus, in certain embodiments, the NRG4 compound of SEQ ID NO:1 can be administered in combination with one or more additional treatments for heart failure. In certain embodiments, the one or more additional treatments for heart failure are selected from the group consisting of beta blockers, ACE inhibitors, ARBs, MRAs, diuretics, ivabradine, and sacubitril / valsartan (ENTRESTO®). In certain embodiments, the NRG4 compound of SEQ ID NO:1 can be administered in combination with an SGLT2 inhibitor or an sGC activator.

[0030] The NRG4 compound of SEQ ID NO:1 may also be useful for the treatment of other diseases or conditions, including, but not limited to, heart failure with preserved ejection fraction (HFpEF), and / or other heart-related disorders or conditions.

[0031] The present invention will be further illustrated by the following examples, which should not be construed as limiting.

Examples

[0032] Clinical trial in healthy volunteers. To evaluate the safety and tolerability of a single subcutaneous (SC) or intravenous (IV) dose of the NRG4 compound of SEQ ID NO: 1 in healthy participants, a multi-site, investigator-blinded, randomized, placebo-controlled, single ascending dose study is designed. Cohorts 1-5 are intended to receive a single SC dose of the NRG4 compound or placebo. Cohort 6 is used to evaluate a single IV injection of the NRG4 compound. This cohort enables the estimation of the absolute bioavailability of the NRG4 compound. The doses of the cohorts are as follows. ● Cohort 1: 1 mg (6 participants NRG4 compound; 2 participants placebo). ● Cohort 2: 3 mg (6 participants NRG4 compound; 2 participants placebo). ● Cohort 3: 10 mg (6 participants NRG4 compound; 2 participants placebo). ● Cohort 4: 30 mg (6 participants NRG4 compound; 2 participants placebo). ● Cohort 5: 60 mg (6 participants NRG4 compound; 2 participants placebo). ● Cohort 6 (8 participants 3 mg NRG4 compound IV)

[0033] Forty-eight participants received administration of the NRG4 compound or placebo, 8 were male and 40 were female. The age range of the participants was 25 - 65 years. Stable doses of antihypertensive drugs (excluding β-blockers) and lipid-lowering drugs were permitted.

[0034] The study intervention was performed either via a single SC injection into the lower abdominal region or as an IV bolus from a syringe into an indwelling venous catheter. The study interventions performed are summarized in Table 2.

[0035]

Table 2

[0036] On Day 1, participants received a single dose of the assigned treatment (either the NRG4 compound or placebo) for the first five cohorts and the NRG4 compound for the last IV cohort. PK sampling and safety evaluations (including AEs, medical evaluations, clinical laboratory tests, vital signs, and ECG) were conducted at predetermined times up to discharge from the CRU on Day 4. The escalating-dose cohort was initiated only after sufficient consideration of the safety results from all participants who had received the NRG4 compound in prior cohorts up to Day 4. Participants returned to the CRU for outpatient visits on Days 7 and 15 for PK, safety, and immunogenicity evaluations as needed. On Day 29, follow-up visits for PK, safety, and immunogenicity monitoring were conducted.

[0037] At the protocol-specified visits and times, approximately 3 mL of venous blood samples were collected to determine the plasma concentration of the NRG4 compound. PK parameter estimates for the NRG4 compound were calculated by standard non-compartmental analysis using Phoenix WinNonlin Version 8.1. Absolute bioavailability (F) was calculated as the geometric mean ratio of 3 mg SC AUC to 3 mg IV AUC. PK parameters were summarized and listed separately for the SC and IV dosing cohorts. Plasma concentrations of the NRG4 compound were plotted and summarized. Dose proportionality for the SC doses of the NRG4 compound was evaluated using a power model (log-dose serving as the explanatory variable) for log-transformed Cmax, AUC(0-∞), and AUC(0-tlast) to estimate the ratio of dose-normalized geometric means and corresponding 90% CIs. Dose proportionality was evaluated using the estimated ratio of dose-normalized geometric means of PK parameters between the highest and lowest doses.

[0038] After a single SC dose, the plasma concentration profile of the NRG4 compound was characterized by a rapid absorption phase with a median tmax of 2.0 hours (range: 1.00 - 4.08 hours) over the dose range of 1 - 60 mg, and the mean half-life was in the range of 2.20 - 3.21 hours. The geometric mean values of CL / F, Vz / F, and Vss / F were in the ranges of 4.88 - 6.05 L / h, 19.2 - 24.3 L, and 22.5 - 27.5 L, respectively, over the SC dose range of 1 - 60 mg. The variability estimates for AUC(0-∞) and Cmax after SC dosing were generally moderate, with geometric mean CV% of 16 - 35% and 13 - 37%, respectively. After administration of a 1 - 60 mg SC bolus dose, the PK of the NRG4 compound increased almost proportionally, with AUC(0-∞) slightly higher than proportional and Cmax slightly lower than proportional, increasing with increasing dose.

[0039] After administration of a 3 mg IV bolus dose of the NRG4 compound, the plasma concentration of the NRG4 compound appeared to decrease in a multi-phase pattern with a geometric mean t1 / 2 of 2.53 hours, similar to the geometric mean of the 3 mg SC dose (2.45 hours), indicating that elimination is not route-dependent. The geometric mean values of CL, Vz, and Vss for the 3 mg IV dose group were 6.01 L / h, 22.0 L, and 13.6 L, respectively. The variability estimates for AUC(0-∞) and Cmax after IV dosing were moderate, with geometric mean CV% of 26% and 38%, respectively.

[0040] The geometric mean F of the NRG4 compound after SC dosing relative to IV dosing was 104% based on AUC(0-∞) and AUC(0-tlast), suggesting almost complete absorption. The calculated F higher than 100% could be due to SC and IV data generated from separate cohorts with different baseline characteristics.

[0041] Most of the treatment emergent adverse events (TEAE) that occurred during treatment were not clinically significant, and no deaths, serious adverse events (SAE), or discontinuations due to adverse events were reported. Based on the low severity of TEAE and the absence of SAE, the NRG4 compound is considered safe and well-tolerated in both single bolus SC and IV dosing.

[0042] The safety and PK results support progression to testing in patients with HFrEF.

[0043] Clinical trial in HFrEF patients The clinical trial is designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of the NRG4 compound of SEQ ID NO: 1 at different dose levels and subcutaneous infusion durations in participants with chronic heart failure HFrEF with reduced ejection fraction. The trial is a multi-site, randomized, placebo-controlled, participant- and treating physician-blinded, single ascending dose study in participants with HFrEF. Participants receive a subcutaneous (SC) injection of either the NRG4 compound of SEQ ID NO: 1 or placebo.

[0044] Approximately 50 participants will be enrolled in the study intervention so that approximately 36 to a maximum of 49 evaluable participants complete the trial.

[0045] The criteria for participants to be eligible include the following: at the time of signing the informed consent, being 18 years of age or older and 75 years of age or younger (20 years of age or older and 75 years of age or younger for Japanese participants); having a body mass index < 40 kg / m2 at screening; having sufficient venous access to enable blood sampling and administration of the test intervention in accordance with the protocol; having chronic stable HF (NYHA class II and III) with HF therapy in accordance with the guidelines for at least 6 months prior to enrollment; not having changed HF therapy in accordance with the optimal guidelines for either medications or medication dosages during the last 1 month prior to screening and during the screening period, and having no plan to change HF therapy in the next 3 months; if treated with oral diuretics, the dosage must have been stable for at least 2 weeks prior to screening and must remain at a stable dosage prior to enrollment; in the historical imaging evaluation performed within 12 months prior to screening, using ECHO, computed tomography angiogram, or cardiac magnetic resonance imaging, and the left ventricular ejection fraction (LVEF) quantitatively measured by ECHO at screening determined by the central ECHO laboratory being less than 40%; having a record of NT-proBNP ≧ 300 pg / mL within the past 6 months prior to screening; having an estimated glomerular filtration rate of 30 mL / min / 1.73 m2 or more at screening.

[0046] Criteria for exclusion from the trial include the following: having had a myocardial infarction, coronary artery bypass graft surgery, revascularization, or other major cardiovascular surgery, stroke, or transient ischemic attack in the last 90 days prior to screening; having acute decompensated HF (worsening HF) requiring IV diuretics, IV inotropes, or IV vasodilators within 12 weeks prior to screening and / or during the screening period up to randomization; having SBP ≥ 180 mmHg at screening; having SBP > 160 mmHg at both screening and randomization; having symptomatic hypotension or SBP < 90 mmHg at screening or randomization. Having a resting heart rate > 90 bpm at screening or randomization; having unstable angina or exercise-induced angina within 30 days prior to screening; having known cardiac amyloidosis, storage diseases (e.g., hemochromatosis, Fabry disease), muscular dystrophy, cardiomyopathy with reversible causes (e.g., stress cardiomyopathy), hypertrophic cardiomyopathy, pericardial constriction, or complex congenital heart disease; having moderate to severe stenosis of the mitral and / or aortic valve, or moderate to severe or greater mitral and / or aortic valve regurgitation as determined by the central echocardiography laboratory on screening ECHO; having left bundle branch block at screening, whether complete or incomplete.In the opinion of the principal investigator, having a history or presence of liver, pancreatic, or biliary tract disorders that could confound safety assessment; having any of the following as determined by the local laboratory during screening: ALT or AST level > 2 times the ULN of the reference range, or ALP level > 1.5 times the ULN of the reference range, or TBL above the ULN of the reference range; having a history of malignant tumor or active malignant tumor at the time of screening; not having received cancer screening according to the American Cancer Society recommendations (Smith et al., 2019) or local Japanese guidelines (MHLW 2016) and medical judgment according to age; having suboptimal ECHO image quality as evaluated by the central laboratory at the time of screening; being listed for heart transplantation and / or implantable assistive artificial heart; having had cardiac resynchronization therapy implanted within 6 months; showing evidence of hepatitis C and / or positive hepatitis C antibody at the time of screening; showing evidence of hepatitis B and / or positive hepatitis B surface antigen at the time of screening; showing evidence of human immunodeficiency virus infection and / or positive human immunodeficiency virus antibody at the time of screening; using myocardial contractility modulation therapy.

[0047] Each of the six cohorts of participants will receive a single, continuous SC injection of either an NRG4 compound or placebo (4 NRG4 compounds: 2 placebos, 5 NRG4 compounds: 3 placebos, or 6 NRG4 compounds: 3 placebos). The planned dose levels for cohorts 1 - 5 are 21, 63, and 140 mg / day (total dose range: 21 - 560 mg) over 24 - 96 hours to investigate the exposure - response range after SC injection at different infusion durations in participants with chronic HFrEF.

[0048] The dose level and infusion duration for cohort 6 will be determined after review of the safety and available PK and PD data from cohorts 1 - 4. The total exposure (area under the concentration - time curve [AUC]) for cohort 6 will not exceed the maximum exposure already tested in the preceding cohorts.

[0049] Due to the nature of the escalating-dose study, data are continuously evaluated until the highest planned dose of the NRG4 compound is reached. The decision to progress to the next dose level of the NRG4 compound is made by the sponsor and the principal investigator based on safety and tolerability data obtained from at least six participants at the previous dose level during hospitalization. This trial design is shown in Figure 1.

[0050] Participants are required to participate in the following visits at the trial site: a screening visit conducted up to 45 days before the maximum dosing; a visit to the facility on Day -1 for eligibility confirmation, randomization, and initiation of hospitalization; a 4- to 7-day inpatient treatment visit; an outpatient visit on Day 15; and three follow-up visits on Days 30, 60, and 90.

[0051] On Day 1, participants receive a continuous SC infusion of either the NRG4 compound or placebo. The length of the hospitalization period depends on the infusion period per cohort. Participants are discharged from the study facility 48 hours after the end of the treatment period.

[0052] Participants are discharged on Day 4 for a 24-hour infusion (Cohort 1); on Day 6 for a 72-hour infusion (Cohorts 2, 3, and 4); and on Day 7 for a 96-hour infusion (Cohort 5).

[0053] The dose, infusion period, and length of hospitalization for Cohort 6 are determined after consideration of safety as well as available PK and PD data from at least Cohorts 1 - 4. The dose level of Cohort 6 does not exceed the maximum exposure already tested in the preceding cohorts.

[0054] Enumerate and summarize all safety data using standard descriptive statistics. The safety parameters to be evaluated include safety laboratory parameters, vital signs, and AEs. Summarize the parameters using descriptive statistics with respect to the observed values and the changes from baseline by treatment group at each time point. Further, aggregate all clinical chemistry, hematology, and urine test data outside the reference range by parameter and treatment group. Summarize the vital signs using descriptive statistics with respect to the observed values and the changes from baseline (day 1, pre-dose) by treatment at each time point. Other parameters to be evaluated include cardiac troponin T and creatine kinase.

[0055] Estimate the pharmacokinetic parameters of the NRG4 compound using standard non-compartmental analysis. The primary parameters for the analysis are Cmax, Css, and AUC. Other non-compartmental parameters such as half-life, CL / F, and apparent volume of distribution can be reported.

[0056] For pharmacodynamics, the primary parameters of echocardiogram analysis include LVEF, left ventricular global longitudinal strain, and other echocardiogram parameters. Summarize the PD data and the AUC of the PD data (both actual values and changes from baseline) using descriptive statistics. The longitudinal linear model analyzes the changes from baseline for LVEF and the AUC of LVEF.

[0057] The exploratory endpoints also include the evaluation of the change in the symptomatic state of the participants after administration of either the NRG4 compound or placebo, including the NYHA class assessment.

[0058] The safety and tolerability evaluations are performed across all dose levels, including the incidence of AEs and the evaluation of vital signs, ECG, and clinical safety clinical trials. The decision to escalate the dose between cohorts is mainly based on the safety and tolerability data from the preceding dose cohort and within the cohort.

[0059] Planned dose levels of 21, 63, and 140 mg / day (total dose range: 21 - 560 mg) over 24 - 96 hours were selected with a focus on optimizing the benefit - risk for participants while ensuring evaluation of the exposure - response relationship after SC injection at different infusion durations in participants with chronic HFrEF. To ensure that the initial cohort has the potential for therapeutic benefit, the starting dose is predicted to achieve approximately 20% of the ED 20 for improvement in LVEF.

[0060] Based on preliminary PK results from single - ascending - dose studies, mean CL / F ranges from 4.9 - 6.05 L / h after a single SC dose of 1 - 30 mg, and t1 / 2 is approximately 2.5 - 3 hours in healthy volunteers. Based on non - clinical PK and efficacy evaluations in male Sprague Dawley rats with myocardial infarction, the NRG4 compound exposure to achieve 50% of the maximum effect on ejection fraction (EAUC 50 ) is approximately 2700 nM·h (14.8 μg·h / mL).

[0061] Table 3 shows the estimated safety margins of the NRG4 compound at doses of 21 mg / day infused over 24 hours and 140 mg / day infused over 96 hours. The predicted therapeutic benefit for patients with HFrEF exceeds any potential risks identified in the non - clinical safety profile.

[0062]

Table 3

[0063] The study facility staff administers either the NRG4 compound or placebo as a continuous SC infusion while the participant is hospitalized (Table 4). The study facility staff assigns the doses according to a randomization scheme provided by the sponsor.

[0064]

Table 4

[0065] The clinical site staff administers continuous SC infusions of the test intervention over the described period using a syringe pump. SC infusions using the syringe pump, extension tubing, and needle are used to conduct the test intervention. SC tissue in the lower abdominal area approximately 5 cm below the umbilicus in the left lower abdomen is used. If the infusion cannot be administered in the left lower abdomen, the infusion may be performed in the right lower abdomen. For infusions longer than 24 hours, new SC infusion sites and lines should be inserted every 24 hours according to the dispensing instructions. The switching of the infusion line every 24 hours is performed as soon as possible and does not exceed 15 minutes. The clinical site staff uses the same type of needle (infusion cannula) for all participants to ensure that the infusion is delivered to a consistent target depth within the SC space.

[0066] To be eligible, participants are receiving background standard care therapy for HF in accordance with the American College of Cardiology Foundation / American Heart Association (ACCF / AHA) guidelines. Standard evidence-based treatments include any of an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), or sacubitril / valsartan in combination with a β-blocker, and, where appropriate, a mineralocorticoid receptor antagonist or SGLT2i unless there are contraindications or intolerance. Most participants also require diuretics to control symptoms and volume overload.

[0067] Participants are continuing a stable dose of medication that allows for the evaluation of the incremental effect of the NRG4 compound.

[0068] The data are continuously evaluated until the maximum planned dose is reached. The decision to proceed to the next dose level is made by the sponsor and the principal investigator based on safety and tolerability data obtained from at least six participants at the previous dose level during hospitalization. Participants are discharged on day 4 for 24-hour infusions, day 6 for 72-hour infusions, and day 7 for 96-hour infusions. Further, for the first dose escalation from cohort 1 to 2, the PK results (C max 、C ss 、and AUC) from cohort 1 are used as supporting data for the dose escalation. For the remaining dose escalations, PK data are considered if available, but such data are not required. The dose escalation in cohort 6 is determined based on safety, PD, and available PK data from at least cohorts 1 - 4.

[0069] Table 5 shows the ECHO measurements at each time point.

[0070]

Table 5

[0071] Samples for the measurement of NT-proBNP are collected for analysis at pre-specified visits and times. NT-proBNP is determined as a PD marker in this study and analyzed in a central laboratory. The results of NT-proBNP pre- and post-dose are blinded for the study sites.

[0072] Biomarker research is conducted to address issues related to drug disposition, target engagement, PD, mechanism of action, and variability in participant responses (including safety), as well as their association with clinical outcomes. Sample collection is incorporated into clinical studies to enable examination of these issues through measurement of biomolecules, including DNA, RNA, proteins, lipids, and other cellular components.

[0073] Serum or plasma samples for non-pharmacogenetic biomarker research are collected at specific time points permitted by local regulations. The samples are used for research on drug targets, disease processes, variable responses to NRG4 compounds, pathways related to chronic HF, mechanism of action of NRG4 compounds, and / or investigative methods, or to validate diagnostic tools or assays (if any) related to chronic HF.

[0074] The incidence of AEs for each treatment is presented by severity and in relation to the investigational drug as recognized by the principal investigator of the clinical trial. AEs reported to have occurred prior to trial registration are distinguished from those reported as new or increased in severity during the trial. The number of treatment-related SAEs is reported.

[0075] All safety data are enumerated and summarized using standard descriptive statistics. The safety parameters evaluated include safety laboratory parameters, vital signs, and AEs. The parameters are summarized using descriptive statistics with respect to the observed values and changes from baseline by treatment group at each time point. Additionally, all clinical chemistry, hematology, and urine test data outside the reference ranges are tabulated by parameter and treatment group. Vital signs are summarized using descriptive statistics with respect to the observed values and changes from baseline (day 1, pre-dose) by treatment at each time point. Other parameters evaluated include cardiac troponin T and creatine kinase.

[0076] The PK parameter estimates of the NRG4 compound are calculated using standard non-compartmental analysis. The primary parameters for the analysis are the Cmax, Css, and AUC of the NRG4 compound. Other non-compartmental parameters such as half-life, CL / F, and apparent volume of distribution can be reported. Descriptive statistics of the PK parameters are provided for each dose level or infusion period. Geometric mean and coefficient of variation of geometry are reported as needed. If the data permit, the power model can be used to evaluate the dose proportionality of the NRG4 compound for AUC, Cmax, and Css in order to estimate the slope of the power model representing the ratio of dose-normalized geometric means.

[0077] The primary parameters for PD analysis by echocardiography include LVEF, LVGLS, and other parameters listed in Table 5 above. PD data and the AUC of PD data (both actual values and changes from baseline) are summarized using descriptive statistics.

[0078] In addition to the AUC of these parameters, the actual value changes from baseline for LVEF, LVGLS, and other PD parameters are summarized for each dose level. The longitudinal model analyzes the changes from baseline for LVEF and the AUC of LVEF.

[0079] An exploratory graphical PK / PD analysis of the serum exposure of the NRG4 compound with respect to the change in LVEF from baseline can be performed. If the data are sufficient, PK / PD and exposure-response models can be investigated to characterize the relationship between the NRG4 compound concentration and the changes in other biomarkers or outcome measurements.

Claims

**Claim 1** A method for treating heart failure with reduced ejection fraction (HFrEF) in a patient in need of treatment, the method comprising administering to the patient an NRG4 compound of SEQ ID NO: 1 in a dose of 21 to 560 mg. **Claim 2** The method of claim 1, wherein the dose is selected from the group consisting of about 21 mg, about 63 mg, about 140 mg, about 189 mg, about 280 mg, about 420 mg, and about 560 mg. **Claim 3** The method of claim 1 or 2, wherein the dose is administered by subcutaneous (SC) injection over 24 to 96 hours. **Claim 4** The method according to any one of claims 1 to 3, wherein the dose is about 280 mg administered over about 48 hours. **Claim 5** The method according to any one of claims 1 to 3, wherein the dose is about 420 mg administered over about 72 hours. **Claim 6** The method according to any one of claims 1 to 3, wherein the dose is about 560 mg administered over about 96 hours. **Claim 7** The method according to any one of claims 1 to 6, wherein the patient is treated once every about three months with the dose of the NRG4 compound. **Claim 8** The method according to any one of claims 1 to 6, wherein the patient is treated once every about six months with the dose of the NRG4 compound. **Claim 9** The method according to any one of claims 1 to 8, wherein the NRG4 compound is administered using a pump device. **Claim 10** The method of claim 9, wherein the pump is a syringe pump or a patch pump. **Claim 11** The method, which results in improvement of one or more echocardiogram parameters selected from the group consisting of left atrial volume (LAV); left atrial volume index (LAVI); left ventricular end-diastolic volume (LVEDV); left ventricular end-diastolic volume index (LVEDVI); left ventricular ejection fraction (LVEF); left ventricular end-systolic volume (LVESV); left ventricular end-systolic volume index (LVESVI); left ventricular global circumferential strain (LVGCS); left ventricular global longitudinal strain (LVGLS); left ventricular mass (LVM); left ventricular mass index (LVMI); E wave to A wave ratio (E / A); ratio between early mitral inflow velocity and early mitral annulus diastolic velocity (E / e'); left ventricular outflow tract - velocity time integral (LVOT-VTI); tricuspid regurgitation peak velocity (TRV); and TR velocity gradient, estimated right ventricular systolic pressure. **Claim 12** The method according to any one of claims 1 to 11, wherein the method results in a significant increase in LVEF.

13. The method according to any one of claims 1 to 12, wherein the method results in a significant reduction in the risk of CV death.

14. The method according to any one of claims 1 to 13, wherein the method results in a significant reduction in the HF-related risk in hospitalization.

15. The method according to any one of claims 1 to 14, wherein the patient has NYHA II or III heart failure.

16. The method according to any one of claims 1 to 15, wherein the method results in an improvement in the NYHA class evaluation of the patient.

17. A pump device comprising an NRG4 compound of SEQ ID NO: 1 in a dose of 21 to 560 mg.

18. The pump device according to claim 17, wherein the dose is selected from the group consisting of about 21 mg, about 63 mg, about 140 mg, about 189 mg, about 280 mg, about 420 mg, and about 560 mg.

19. An NRG4 compound of SEQ ID NO: 1 for use in the treatment of HFrEF in a patient at a dose of 21 to 560 mg.

20. The NRG4 compound for use according to claim 19, wherein the dose is selected from the group consisting of 21 mg, 63 mg, 140 mg, 280 mg, 420 mg, and 560 mg.

21. The NRG4 compound for use according to any one of claims 19 or 20, wherein the dose is administered by subcutaneous (SC) injection over 24 to 96 hours.

22. The NRG4 compound for use according to any one of claims 19 to 21, wherein the dose is 280 mg administered over 48 hours.

23. The NRG4 compound for use according to any one of claims 19 to 21, wherein the dose is 420 mg administered over 72 hours.

24. The NRG4 compound for use according to any one of claims 19 to 21, wherein the dose is 560 mg administered over 96 hours.

25. The NRG4 compound of the dose according to any one of claims 19 to 24, wherein the NRG4 compound of the dose is administered once every three months.

26. The NRG4 compound of the dose according to any one of claims 19 to 24, wherein the NRG4 compound of the dose is administered once every six months.

27. The NRG4 compound for use according to any one of claims 19 to 26, wherein the NRG4 compound is administered using a pump device.

28. The NRG4 compound for use according to claim 27, wherein the pump is a syringe pump or a patch pump.

29. The NRG4 compound for use according to any one of claims 19 to 28, wherein the patient has NYHA II or III heart failure.

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