Methods of using neuregulin 4 compounds

Abstract

The present invention relates to doses and dosing regimens of NRG4 compounds in the treatment of cardiovascular disease (CVD)-related disorders, including heart failure (HF).

Description

[0001] The present invention relates to the field of medicine. More specifically, the present invention relates to methods of using neuregulin 4 compounds to treat cardiovascular disease (CVD) and related disorders, particularly including heart failure (HF).

[0002] There is an unmet medical need for new and improved treatments for HF. HF is a serious disease that is estimated to affect more than 6 million adults in the United States and at least 26 million people worldwide. The prevalence of HF is expected to continue to rise substantially. Currently available therapies are designed to slow disease progression and improve symptoms and rely on hemodynamic changes to reduce the workload of heart failure. These therapies include agents that are used to: (a) reduce heart rate, such as beta blockers and ivabradine; and (b) reduce blood pressure, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and sacubitril / valsartan. and / or (c) treatment or prevention of volume overload, such as diuretics and MRAs and sodium-glucose co-transporter 2 (SGLT2) inhibitors. However, these therapies 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. Given the high unmet medical need, new and better treatments for chronic HF are needed.

[0003] WO2020 / 205840 describes NRG4 compounds for treating or preventing CVD and related conditions, particularly HF with reduced ejection fraction (HFrEF), through mechanisms that may involve cardiac tissue repair. Preferably, the NRG4 compound comprises the following amino acid sequence:

[0004] GGGGSGHEEPCGPSHKSFCLNGGLCYQIPTIPSPFCRCVENYTGARCEKVFL(SEQ ID NO:1)

[0005] Specific dosages and administration regimens for treatment with such compounds are required.

[0006] Thus, the present invention provides a method of treating HFrEF in a patient in need thereof, comprising administering to the patient a dose of 21-560 mg of the NRG4 compound of SEQ ID NO: 1.

[0007] In another aspect, the present invention provides a pump device comprising a dose of 21-560 mg of the NRG4 compound of SEQ ID NO: 1.

[0008] In another aspect, the present invention provides a NRG4 compound of SEQ ID NO: 1 for use in treating HFrEF in a patient at a dose of 21-560 mg.

[0009] Figure 1 :Clinical study protocols in patients with HFrEF.

[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 a dose of 21-560 mg. In one embodiment, the dose is 21-63 mg. In another embodiment, the dose is 21-140 mg. In another embodiment, the dose is 21-189 mg. In another embodiment, the dose is 21-280 mg. In another embodiment, the dose is 21-420 mg. In another embodiment, the dose is 21-560 mg. In another embodiment, the dose is 63-140 mg. In another embodiment, the dose is 63-189 mg. In another embodiment, the dose is 63-280 mg. In another embodiment, the dose is 63-420 mg. In another embodiment, the dose is 63-560 mg. In another embodiment, the dose is 140-189 mg. In another embodiment, the dose is 140-280 mg. In another embodiment, the dose is 140-420 mg. In another embodiment, the dosage is 140-560 mg. In another embodiment, the dosage is 189-280 mg. In another embodiment, the dosage is 189-420 mg. In another embodiment, the dosage is 189-560 mg. In another embodiment, the dosage is 280-420 mg. In another embodiment, the dosage is 280-560 mg. In another embodiment, the dosage is 420-560 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 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.

[0012] 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 1-60 mg. In certain embodiments, the dose is 3-30 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.

[0013] In certain embodiments, the dosage is administered by subcutaneous (SC) infusion within 24-96 hours. In certain embodiments, the dosage is administered by subcutaneous (SC) infusion within 24-48 hours. In certain embodiments, the dosage is administered by subcutaneous (SC) infusion within 24-72 hours. In certain embodiments, the dosage is administered by subcutaneous (SC) infusion within 48-72 hours. In certain embodiments, the dosage is administered by subcutaneous (SC) infusion within 48-96 hours. In certain embodiments, the dosage is administered by subcutaneous (SC) infusion within 72-96 hours.

[0014] In certain embodiments, the dose is administered by SC infusion within about 24 hours. In other embodiments, the dose is administered by SC infusion within about 48 hours. In other embodiments, the dose is administered by SC infusion within about 72 hours. In other embodiments, the dose is administered by SC infusion within about 96 hours.

[0015] In one embodiment, the dose is 21 mg and the administration period is about 24, about 48, about 72, or about 96 hours. In one embodiment, the dose is about 63 mg and the administration period is about 24, about 48, about 72, or about 96 hours. In one embodiment, the dose is about 140 mg and the administration period is about 24, about 48, about 72, or about 96 hours. In one embodiment, the dose is about 189 mg and the administration period is about 24, about 48, about 72, or about 96 hours. In one embodiment, the dose is about 280 mg and the administration period is about 24, about 48, about 72, or about 96 hours. In one embodiment, the dose is about 420 mg and the administration period is about 24, about 48, about 72, or about 96 hours. In one embodiment, the dose is 560 mg and the administration period is about 24, about 48, about 72, or about 96 hours.

[0016] In certain embodiments, a patient receives a dose of a NRG4 compound about once a month. In certain embodiments, a patient receives a dose of a NRG4 compound about once every two months. In certain embodiments, a patient receives a dose of a NRG4 compound about once every three months. In certain embodiments, a patient receives a dose of a NRG4 compound about once every four months. In certain embodiments, a patient receives a dose of a NRG4 compound about once every five months. In other embodiments, a patient receives a dose of a NRG4 compound about once every six months.

[0017] As used herein, the term "about" is intended to indicate an acceptable degree of error for an indicated amount or quantity given the nature or precision of a measurement. For example, the degree of error may be indicated by the number of significant figures provided for a measurement, as understood in the art, and includes, but is not limited to, a variation of + / -1 in the most accurate significant figure reported for an amount or quantity. Typical exemplary degrees of error are within 20 percent (%) of a given value or range of values, preferably within 10%, and more preferably within 5%. Unless otherwise indicated, numerical quantities given herein are approximate, meaning that the term "about" can be inferred when not expressly stated.

[0018] As used herein, the term "treating" and its variants include inhibiting, slowing, stopping or reversing the progression or severity of an existing symptom or condition. Treatment of heart failure or HFrEF according to the present invention may be reflected in one or more measurements related to heart failure, including, for example, improvement in one or more echocardiographic 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 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 annular 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 reduction in the risk of CV death. In certain embodiments, the method results in a significant reduction in the risk associated with HF in 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 symptom assessment.

[0019] Certain benefits of treatment according to embodiments of the present invention may be achieved after at least about 1 month of treatment. Certain benefits of treatment according to embodiments of the present invention may be achieved after at least about 3 months of treatment. Certain benefits of treatment according to embodiments of the present invention may be achieved after at least about 6 months of treatment. Certain benefits of treatment according to embodiments of the present invention may be achieved after at least about 1 year of treatment.

[0020] In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in an improvement in LVEF. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in an improvement in LVEF of at least about 3%. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in an improvement in LVEF of at least about 5%. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in an improvement in LVEF of at least about 5% after 6 months of treatment. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in an improvement in LVEF of at least about 5% after 1 year of treatment.

[0021] In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in at least about a 5% improvement in LVESV after 1 year of treatment.

[0022] In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in a significant reduction in LVEDV after 1 year of treatment. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in a reduction in LVGLS. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in a reduction in LVGLS of at least about 1%. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in a reduction in LVGLS of at least about 3.5%. In certain embodiments, administration of the NRG4 compound of SEQ ID NO: 1 of the present invention results in a reduction in the risk of CV death and / or HF hospitalization of at least about 15%.

[0023] In certain embodiments, the methods result in a reduction in the risk of total mortality, a reduction in the risk of myocardial infarction (MI), a reduction in the risk of stroke, a reduction in the risk of requiring left ventricular assist device (LVAD) implantation and / or heart transplantation, improvements in heart failure symptoms and physical limitations, and / or improvements in quality of life (QoL).

[0024] In addition, as described above, according to certain embodiments of the present specification, the administration of the NRG4 compound of SEQ ID NO: 1 can improve heart failure-related measurements, such as those described above, without increasing safety risks. Therefore, in a preferred embodiment, the administration of the NRG4 compound of SEQ ID NO: 1 of the present invention does not lead to increased safety risks, such as increased hypotension; worsening renal function; electrolyte imbalance; liver dysfunction; or the incidence of tumors.

[0025] According to the present invention, the administration of the NRG4 compound of SEQ ID NO: 1 is typically parenteral, such as intravenous (IV), subcutaneous (SC) or intraperitoneal (IP). Therefore, 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.

[0026] In order to control the duration of exposure to optimize and maintain therapeutic efficacy while having sufficient cardiotoxicity margin, parenteral administration of NRG4 compounds is preferably performed by continuous or intermittent infusion. For example, various types of infusion pumps are used to infuse a wide range of drugs, and these pumps can be used to administer the NRG4 compounds of the present invention. Recently, patch pumps have been developed that are smaller than traditional devices and attach directly to the patient's skin, thereby causing minimal interference with the patient's daily activities. Therefore, 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.

[0027] As mentioned above, all HF patients, even those with mild symptoms, face an increased risk of death. Therefore, when used herein, reference to a "patient in need" of treatment for heart failure (HF) can refer to a wide range of individuals with HF, including those with a variety of disease severities as described below. The New York Heart Association (NYHA) has provided a grading scheme for the degree or severity of HF, as summarized in Table 1 below:

[0028]

[0029] Table 1.

[0030] In certain embodiments, the patient in need has NYHA class II-IV heart failure. In certain embodiments, the patient in need has NYHA class II heart failure. In certain embodiments, the patient in need has NYHA class III heart failure. In certain embodiments, the patient in need has NYHA class IV heart failure. In certain embodiments, the patient in need has NYHA class II-III heart failure.

[0031] As described above, existing therapeutic treatment options for heart failure, including current standard treatments, improve symptoms and slow disease progression through hemodynamic mechanisms (e.g., lowering blood pressure, heart rate, and / or plasma volume) to reduce the workload of the failing heart. In contrast, the NRG4 compounds of SEQ ID NO: 1 achieve their effects through a different mechanism of action, namely, selective HER4 binding and the resulting activity, which directly improves cardiomyocyte survival and cell metabolism and promotes myocardial regeneration. Due to these different mechanisms of action, the NRG4 compounds of SEQ ID NO: 1 can be administered on top of existing SoCs without titration or monitoring. Therefore, in certain embodiments, the NRG4 compounds of SEQ ID NO: 1 can be administered in combination with one or more additional heart failure treatments. In certain embodiments, the one or more additional heart failure treatments are selected from: beta blockers, ACE inhibitors, ARBs, MRAs, diuretics, ivabradine, and sacubitril / valsartan In certain embodiments, the NRG4 compound of SEQ ID NO: 1 may be administered in combination with a SGLT2 inhibitor or a sGC activator.

[0032] The NRG4 compound of SEQ ID NO: 1 may also be used to treat other diseases or conditions, including but not limited to heart failure with preserved ejection fraction (HFpEF) and / or other cardiac-related conditions or conditions.

[0033] The present invention is further illustrated by the following examples, which should not be construed as limiting. Example

[0034] Clinical studies in healthy volunteers

[0035] A multicenter, investigator- and participant-blind, randomized, placebo-controlled, single ascending dose study is designed to evaluate the safety and tolerability of a single subcutaneous (SC) dose or intravenous (IV) dose of the NRG4 compound of SEQ ID NO: 1 in healthy participants. Cohorts 1-5 are designed to receive a single SC dose of the NRG4 compound or placebo. Cohort 6 is designed to evaluate a single IV injection of the NRG4 compound. This cohort is designed to evaluate the absolute bioavailability of the NRG4 compound. The doses for each cohort are as follows:

[0036] Cohort 1: 1 mg (6 participants NRG4 compound; 2 participants placebo)

[0037] Cohort 2: 3 mg (6 participants NRG4 compound; 2 participants placebo)

[0038] Cohort 3: 10 mg (6 participants NRG4 compound; 2 participants placebo)

[0039] Cohort 4: 30 mg (6 participants NRG4 compound; 2 participants placebo)

[0040] Cohort 5: 60 mg (6 participants NRG4 compound; 2 participants placebo)

[0041] Cohort 6 (8 participants 3 mg NRG4 compound IV)

[0042] Forty-eight participants, eight men and 40 women, received doses of either NRG4 compound or placebo. The age range of the participants was 25 to 65 years. Stable doses of antihypertensive medications (except beta blockers) and lipid-lowering medications were allowed.

[0043] Study interventions were administered by a single SC injection into the lower abdominal area or by IV bolus via syringe into an indwelling intravenous catheter. The study interventions administered are summarized in Table 2:

[0044]

[0045]

[0046] Table 2. Abbreviations: IV = intravenous; NA = not applicable; SC = subcutaneous. a Reconstitute with Sterile Water for Injection.

[0047] On Day 1, participants in the first 5 cohorts received a single dose of their assigned treatment (NRG4 compound or placebo), with the last IV cohort receiving NRG4 compound. PK sampling and safety assessments (including AEs, medical assessments, clinical laboratory tests, vital signs, and ECGs) were performed at scheduled times until discharge from the CRU on Day 4. Dose escalation cohorts were initiated only after satisfactory review of safety outcomes through Day 4 for all participants who received NRG4 compound from the previous cohort. Participants returned to the CRU for outpatient visits on Days 7 and 15 for PK, safety, and immunogenicity assessments, as appropriate. Follow-up visits for PK, safety, and immunogenicity monitoring were conducted on Day 29.

[0048] At the follow-up visits and times specified in the protocol, approximately 3 mL of venous blood samples were collected to determine the plasma concentration of the NRG4 compound. Phoenix WinNonlin version 8.1 was used to calculate the PK parameter estimates of the NRG4 compound by standard non-compartmental analysis methods. Absolute bioavailability (F) was calculated as the ratio of the geometric mean of the 3 mg SC AUC to the 3 mg IV AUC. The PK parameters of the SC and IV dosing cohorts were summarized and listed separately. The plasma concentrations of the NRG4 compounds were plotted and summarized. The dose proportionality of the SC dose of the NRG4 compound was evaluated using a power model (with logarithmic dose as the explanatory variable) by log-transformed Cmax, AUC (0-∞) and AUC (0-tlast) to estimate the ratio of dose-standardized geometric means and the corresponding 90% CI. The dose proportionality was evaluated using the estimated ratio of the dose-standardized geometric means of the PK parameters between the highest and lowest doses.

[0049] After a single SC dose, the plasma concentration of the NRG4 compound was characterized by a rapid absorption phase, with a median tmax of 2.0 hours (range: 1.00 to 4.08 hours) in the dose range of 1 to 60 mg, and a mean half-life of 2.20 to 3.21 hours. Within the 1 to 60 mg SC dose range, the geometric means of CL / F, Vz / F, and Vss / F ranged from 4.88 to 6.05 L / h, 19.2 to 24.3 L, and 22.5 to 27.5 L. The variability estimates of AUC(0-∞) and Cmax after SC administration were generally moderate, with geometric mean CV% of 16-35% and 13-37%, respectively. After SC bolus administration of 1 to 60 mg doses, the PK of the NRG4 compound increased approximately proportionally, with AUC(0-∞) slightly above proportional and Cmax slightly less than proportional increases with increasing dose.

[0050] Following IV bolus administration of a 3 mg dose of NRG4 compound, plasma concentrations of NRG4 compound appeared to decrease in a multiphasic manner, 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 was not route-dependent. For the 3 mg IV dose group, the geometric means of CL, Vz, and Vss were 6.01 L / h, 22.0 L, and 13.6 L. The variability of AUC (0-∞) and Cmax after IV administration was estimated to be moderate, with geometric mean CV% of 26% and 38%, respectively.

[0051] Based on AUC(0-∞) and AUC(0-tlast), the geometric mean F of NRG4 compound after SC administration relative to IV administration was 104%, indicating near complete absorption. The calculated F higher than 100% may be due to the SC and IV data being generated from different cohorts with different baseline characteristics.

[0052] Most treatment-emergent adverse events (TEAEs) were clinically insignificant, and no deaths, serious adverse events (SAEs), or discontinuations due to adverse events were reported. Based on the low severity of TEAEs and the lack of SAEs, the NRG4 compound was considered safe and well tolerated when administered as a single bolus SC and IV.

[0053] Safety and PK results support the advancement of this study in patients with HFrEF.

[0054] Clinical studies in patients with HFrEF

[0055] The clinical trial is designed to evaluate the effects of different dose levels and subcutaneous infusion durations on the safety, pharmacokinetics, and pharmacodynamics of the NRG4 compound of SEQ ID NO: 1 in patients with chronic heart failure with reduced ejection fraction (HFrEF). The study is a multicenter, randomized, placebo-controlled, participant and investigator blinded, single ascending dose study in patients with HFrEF. Participants received subcutaneous (SC) infusions of the NRG4 compound of SEQ ID NO: 1 or placebo.

[0056] Approximately 50 participants participated in the study intervention, thus approximately 36 to a maximum of 49 evaluable participants completed the study.

[0057] Participant inclusion criteria included the following: age 18–75 years (20–75 years for Japanese participants), inclusive, at the time of signing the informed consent; body mass index <40 kg / m2 at screening; adequate venous access for blood sampling and study interventions according to the protocol; and chronic stable HF (NYHA HF) for at least 6 months before enrollment. Patients were eligible for inclusion in the study if they had HF at baseline or after 12 months of follow-up. The study population was ...

[0058] Exclusion criteria for the study included the following: myocardial infarction, coronary artery bypass graft surgery, revascularization or other major cardiovascular surgery, stroke or transient ischemic attack within 90 days before screening; acute decompensated HF (exacerbation of HF) requiring IV diuretics, IV positive inotropes or IV vasodilators within 12 weeks before screening and / or during the screening period until randomization; SBP ≥ 180 mmHg at screening; SBP > 160 mmHg at screening and randomization; symptomatic hypotension or SBP < 90 mmHg at screening or randomization; resting heart rate > 90 bpm at screening or randomization; unstable angina or exercise-induced angina within 30 days before screening; known cardiac amyloidosis, accumulation disease (e.g., hemochromatosis, Fabry disease, disease), muscular dystrophy, reversible cardiomyopathy (e.g., stress cardiomyopathy), hypertrophic cardiomyopathy, pericardial stenosis, or complex congenital heart disease; any moderate to severe mitral and / or aortic stenosis or moderate to severe or greater mitral and / or aortic regurgitation as determined by the central ECHO laboratory at Screening ECHO; left bundle branch block, complete or incomplete, at Screening; history of or presence of liver, pancreatic, or biliary disease that the investigators believe may affect safety assessments; any of the following conditions as determined by the local laboratory at Screening: ALT or AST levels >2X the ULN of the reference range, or ALP levels >1.5X the ULN of the reference range, or TBL above the ULN of the reference range; history of malignancy or active malignancy at Screening; not treated according to the American Cancer Society (Smith et al., 2019) or local Japanese guidelines (MHLW 2016) recommendations and medical judgment; poor ECHO image quality as assessed by the central laboratory at screening; already listed for heart transplant and / or anticipated / implanted ventricular assist device; already implanted with cardiac resynchronization therapy within 6 months; evidence of hepatitis C and / or positive hepatitis C antibodies at screening; evidence of hepatitis B and / or positive hepatitis B surface antigen at screening; evidence of human immunodeficiency virus infection and / or positive human immunodeficiency virus antibodies at screening; currently using cardiac contractility modulation therapy.

[0059] A total of 6 cohorts of participants each received a single continuous SC infusion of NRG4 compound or placebo (4 cohorts NRG4 compound: 2 cohorts placebo, 5 cohorts NRG4 compound: 3 cohorts placebo, or 6 cohorts NRG4 compound: 3 cohorts placebo. The planned dose levels for cohorts 1 to 5 were 21, 63, and 140 mg / day for 24 to 96 hours (total dose range: 21 to 560 mg) to explore the exposure-response range following SC infusions at different infusion durations in participants with chronic HFrEF.

[0060] The dose level and infusion duration for Cohort 6 were determined after review of safety and available PK and PD data from Cohorts 1 to 4. The total exposure (area under the concentration-time curve [AUC]) for Cohort 6 will not exceed the maximum exposure tested in the previous cohort.

[0061] Because this is a dose-escalation study, data will be continuously evaluated until the highest planned dose of the NRG4 compound is reached. The sponsor and investigators will decide whether to proceed to the next dose level of the NRG4 compound based on safety and tolerability data obtained from at least 6 participants who received the previous dose level during hospitalization. The study design is described in Figure 1 middle.

[0062] Participants were required to attend the following study site visits: a screening visit within 45 days prior to dosing; confirmation of eligibility, randomization, and initiation of hospitalization on Day -1; an inpatient treatment visit on Days 4 to 7; an outpatient visit on Day 15; and 3 follow-up visits on Days 30, 60, and 90.

[0063] On day 1, participants received a continuous SC infusion of either NRG4 compound or placebo. The length of hospital stay depended on the duration of the infusion for each cohort. Participants were discharged from the study site 48 hours after the end of the treatment period.

[0064] Participants were discharged from the hospital on day 4 for 24-hour infusion (cohort 1); day 6 for 72-hour infusion (cohorts 2, 3, and 4); and day 7 for 96-hour infusion (cohort 5).

[0065] The dose, infusion duration, and length of hospital stay for Cohort 6 will be determined after reviewing safety and available PK and PD data for at least Cohorts 1 to 4. The dose level for Cohort 6 will not exceed the maximum exposure tested in the previous cohorts.

[0066] All safety data were listed and summarized using standard descriptive statistics. Safety parameters evaluated included safety laboratory parameters, vital signs, and AEs. Descriptive statistics were used to summarize the observed values ​​and changes from baseline for treatment groups at each time point. In addition, all clinical chemistry, hematology, and urinalysis data outside the reference range were tabulated by parameter and treatment group. Descriptive statistics were used to summarize the observed values ​​and changes from baseline (Day 1, pre-dose) for vital signs for each time point for treatment groups. Other parameters evaluated included cardiac troponin T and creatine kinase.

[0067] Pharmacokinetic parameter estimates for NRG4 compounds were calculated using standard non-compartmental analysis methods. The primary parameters used for analysis were Cmax, Css, and AUC. Other non-compartmental parameters such as half-life, CL / F, and apparent volume of distribution may be reported.

[0068] For pharmacodynamics, the main parameters analyzed by echocardiography included LVEF, global left ventricular longitudinal strain, and other echocardiographic parameters. Descriptive statistics were used to summarize the PD data and the AUC of the PD data (actual values ​​and changes from baseline). Longitudinal linear models were used to analyze the changes in LVEF and the AUC of LVEF from baseline.

[0069] Exploratory endpoints also include assessment of changes in participants' symptom status following administration of the NRG4 compound or placebo, including assessment of NYHA class.

[0070] Safety and tolerability were evaluated at all dose levels, including AE incidence and assessment of vital signs, ECG, and clinical safety laboratory tests. The decision to escalate doses between cohorts was primarily based on safety and tolerability data from previous dose cohorts and within cohorts.

[0071] The planned dose levels of 21, 63, and 140 mg / day for 24 to 96 hours (total dose range: 21 to 560 mg) were selected with a focus on optimizing the benefit-risk for participants while ensuring evaluation of the exposure-response relationship following SC infusion at varying infusion durations in participants with chronic HFrEF. To ensure the potential for treatment benefit in the early cohort, the starting dose was predicted to achieve approximately 20% of the ED20 for improvement in LVEF.

[0072] Based on preliminary PK results from a single ascending dose study, in healthy volunteers, after a single SC dose of 1-30 mg, the average CL / F ranged from 4.9-6.05 L / h and the t1 / 2 was approximately 2.5-3 hours. Based on nonclinical PK and efficacy evaluations in male Sprague Dawley rats with myocardial infarction, the maximum effect (EAUC) of 50% ejection fraction was achieved. 50)’s NRG4 compound exposure was approximately 2700 nM·h (14.8 μg·h / mL).

[0073] Estimated margins of safety for NRG4 compounds at doses of 21 mg / day for 24 hours and 140 mg / day for 96 hours are shown in Table 3. For patients with HFrEF, the expected benefits of treatment outweigh any potential risks identified in the nonclinical safety profile.

[0074] Table 3. Safety margins for continuous subcutaneous infusion of NRG4 compounds based on predicted exposure

[0075]

[0076]

[0077] Abbreviations: AUC0-t = area under the concentration-time curve from time zero to the end of infusion; Cave,ss = mean steady-state plasma concentration; F = female; HDT = highest dose tested; LOAEL = least observed adverse effect level; M = male; max = maximum; NOAEL = no observed adverse effect level; non-reproductive NOAEL = no observed adverse effect level for non-reproductive effects (e.g., increased epithelial cell proliferation); PK = pharmacokinetics; SC = subcutaneous. Note: Calculations are based on a human body weight of 70 kg.

[0078] a The plasma PK parameters shown are estimated based on preliminary PK data from healthy participants. The doses shown are the starting dose and the highest recommended clinical dose; b Continuous infusion toxicology study in rats; c Continuous infusion toxicology study in cynomolgus monkeys; d Cave,ss in animals was calculated by dividing the AUC0-99 observed during SC infusion in animals by 99h; Cave,ss in humans was calculated as infusion rate during SC infusion / (CL / F); e Cave,ss multiple = average Cave,ss in animals / predicted average Cave,ss in humans.

[0079] Study site personnel administered NRG4 compounds or placebo as a continuous SC infusion while participants were hospitalized (Table 4). Study site personnel assigned doses according to the randomization scheme provided by the sponsor.

[0080] Table 4. Treatments Administered

[0081]

[0082]

[0083] Abbreviations: mg = milligram; mL = milliliter; NA = not applicable; SC = subcutaneous.

[0084] a Reconstitute with antibacterial water for injection; b Details on flow rate, concentration, total infusion volume, and other dosing instructions will be provided in the pharmacy leaflet; c A single dose may require a multiple-dose formulation.

[0085] Study site personnel used a syringe pump to provide continuous subcutaneous infusion of the study intervention for the specified time. SC infusion using a syringe pump, extension tubing, and needle was used for the administration of the study intervention. SC tissue in the lower abdominal area approximately 5 cm from the umbilicus in the left lower quadrant was used. If the infusion cannot be performed in the left lower quadrant, the infusion can be performed in the right lower quadrant. For infusions greater than 24 hours, a new SC infusion site and line were inserted every 24 hours according to the pharmacy instructions. Changes to infusion lines every 24 hours should be performed as quickly as possible and take no longer than 15 minutes. Study site personnel used the same type of needle (infusion cannula) for all participants to ensure that the infusion was delivered to a consistent target depth in the SC space.

[0086] To be eligible, participants had to be receiving standard therapy for HF treatment according to the American College of Cardiology Foundation / American Heart Association (ACCF / AHA) guidelines. Standard evidence-based therapy included angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or sacubitril / valsartan in combination with a beta-blocker, and appropriate use of a mineralocorticoid receptor antagonist or SGLT2i unless contraindicated or intolerant. Most participants also required a diuretic to control symptoms and volume overload.

[0087] Participants remained on a stable dose of medication, which allowed for evaluation of the incremental effects of the NRG4 compound.

[0088] Data were evaluated on an ongoing basis until the highest planned dose was reached. The sponsor and investigators made decisions about whether to proceed to the next dose level based on safety and tolerability data obtained from at least 6 participants who received the previous dose level during hospitalization. Participants were discharged on day 4 for a 24-hour infusion, day 6 for a 72-hour infusion, and day 7 for a 96-hour infusion. In addition, for the first dose escalation in Cohorts 1 and 2, PK results from Cohort 1 (C max ,C ssThe dose escalation of cohort 6 was determined based on the safety, PD and available PK data of cohorts 1 to 4 at least.

[0089] Table 5 shows the ECHO measurements at each time point.

[0090]

[0091] Abbreviations: CO = cardiac output; E / A = E-wave to A-wave ratio; E / e′ = ratio between early mitral inflow velocity and early mitral annular diastolic velocity; LAV = left atrial volume; LAVI = left atrial volume index; LV = left ventricle (le / mular); LVEDV = left ventricular end-diastolic volume; LVEDVI = left ventricular end-diastolic volume index; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; LVESVI = left ventricular end-systolic volume index; LVGCS = left ventricular global circumferential strain; LVGLS = left ventricular global longitudinal strain; LVM = left ventricular mass; LVMI = left ventricular mass index; LVOT = left ventricular outflow tract; VTI = velocity time integral.

[0092] At prespecified visits and times, samples for measurement of NT-proBNP were collected for analysis. NT-proBNP was determined as a PD marker in this study and was analyzed in a central laboratory. NT-proBNP results from before dosing were not disclosed to the study sites.

[0093] Biomarker studies are conducted to address questions related to drug distribution, target engagement, PD, mechanism of action, and variability in participant response, including safety and clinical outcomes. Sample collection is incorporated into clinical studies to enable examination of these questions by measuring biomolecules including DNA, RNA, proteins, lipids, and other cellular components.

[0094] Serum or plasma samples for non-pharmacogenetic biomarker studies were collected at designated times, as permitted by local regulations. Samples were used to study drug targets, disease processes, differential responses to NRG4 compounds, pathways associated with chronic HF, mechanisms of action of NRG4 compounds, and / or research methods, or to validate diagnostic tools or assays associated with chronic HF.

[0095] The incidence of AEs for each treatment is presented by severity and relationship to the study product as considered by the investigator. AEs reported prior to study enrollment are distinguished from new AEs or AEs of increased severity reported during the study. The number of SAEs related to the study product is reported.

[0096] All safety data were listed and summarized using standard descriptive statistics. Safety parameters evaluated included safety laboratory parameters, vital signs, and AEs. Descriptive statistics were used to summarize the observed values ​​and changes from baseline for treatment groups at each time point. In addition, all clinical chemistry, hematology, and urinalysis data outside the reference range were tabulated by parameter and treatment group. Descriptive statistics were used to summarize the observed values ​​and changes from baseline (Day 1, pre-dose) for vital signs for each time point for treatment groups. Other parameters evaluated included cardiac troponin T and creatine kinase.

[0097] PK parameter estimates for NRG4 compounds were calculated using standard non-compartmental analysis methods. The main parameters used for analysis were Cmax, Css, and AUC of NRG4 compounds. Other non-compartmental parameters such as half-life, CL / F, and apparent volume of distribution may be reported. Descriptive statistics for PK parameters were provided for each dose level or infusion duration. Geometric means and geometric coefficients of variation were reported where appropriate. Where data permitted, a power model was used to assess the dose proportionality of NRG4 compounds using AUC, Cmax, and Css to estimate the slope of the power model, which represents the ratio of the dose-normalized geometric means.

[0098] The main parameters for PD analysis by echocardiography included LVEF, LVGLS, and other parameters listed above in Table 5. Descriptive statistics were used to summarize the PD data and the AUC of the PD data (actual values ​​and changes from baseline).

[0099] The actual changes from baseline in LVEF, LVGLS, and other PD parameters and the AUCs of these parameters were summarized for each dose level. Longitudinal linear models were used to analyze the changes from baseline in LVEF and AUCs of LVEF.

[0100] Exploratory graphical PK / PD analyses relating serum exposure of NRG4 compounds to changes from baseline in LVEF can be performed. If data are sufficient, PK / PD and exposure-response models can be explored to characterize the relationship between NRG4 compound concentrations and changes in other biomarkers or outcome measures.

Claims

1. A method of treating heart failure with reduced ejection fraction (HFrEF) in a patient in need thereof, comprising administering to the patient a dose of 21-560 mg of a NRG4 compound of SEQ ID NO:

1.

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.

3. The method of claim 1 or 2, wherein the dose is administered by subcutaneous (SC) infusion over 24-96 hours.

4. The method of any one of claims 1-3, wherein the dose is about 280 mg administered over about 48 hours.

5. The method of any one of claims 1-3, wherein the dose is about 420 mg administered over about 72 hours.

6. The method of any one of claims 1-3, wherein the dose is about 560 mg administered over about 96 hours.

7. The method of any one of claims 1-6, wherein the patient is treated with a dose of the NRG4 compound approximately once every 3 months.

8. The method of any one of claims 1-6, wherein the patient is treated with a dose of the NRG4 compound approximately once every 6 months.

9. The method of any one of claims 1-8, wherein the NRG4 compound is administered with a pump device.

10. The method of claim 9, wherein the pump is a syringe pump or a patch pump.

11. A method according to any one of claims 1-10, wherein the method results in an improvement in one or more echocardiographic parameters selected from the following: 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 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); the ratio between the early mitral inflow velocity and the early diastolic velocity of the mitral annulus (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.

12. The method according to any one of claims 1-11, wherein the method results in a significant increase in LVEF.

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

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

15. The method of any one of claims 1-14, wherein the patient suffers from NYHA II or III heart failure.

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

17. A pump device comprising a dose of 21-560 mg of the NRG4 compound of SEQ ID NO:

1.

18. The pump device of 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. A NRG4 compound of SEQ ID NO: 1 for use in treating HFrEF in a patient at a dose of 21-560 mg.

20. The NRG4 compound for use according to claim 19, wherein the dosage 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 claim 19 or 20, wherein the dose is administered by subcutaneous (SC) infusion over 24-96 hours.

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

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

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

25. The NRG4 compound for use according to any one of claims 19-24, wherein the dosage of the NRG4 compound is administered once every 3 months.

26. The NRG4 compound for use according to any one of claims 19-24, wherein the dosage of the NRG4 compound is administered once every 6 months.

27. The NRG4 compound for use according to any one of claims 19-26, wherein the NRG4 compound is administered with 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 19-28, wherein the patient suffers from NYHA II or III heart failure.

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