Levocimendan for the treatment of pulmonary hypertension with preserved ejection fraction (PH-HF-pEF)

Abstract

This paper provides a method for treating pulmonary hypertension with heart failure and preserved ejection fraction (PH-HFpEF). [Solution] To provide a composition and method useful for treating PH-HFpEF, employing the use of levocimendan.

Description

Technical Field

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 064,671, filed Aug. 12, 2020; U.S. Provisional Application No. 63 / 033,773, filed Jun. 2, 2020; U.S. Provisional Application No. 62 / 988,720, filed Mar. 12, 2020; U.S. Provisional Application No. 62 / 967,920, filed Jan. 30, 2020; and U.S. Provisional Application No. 62 / 948,735, filed Dec. 16, 2019, the contents of each of which are incorporated herein by reference.

[0002] Throughout this application, various publications are referenced, including those referenced in parentheses. The disclosures of all publications referred to in this application are hereby incorporated by reference in their entirety to provide further description of the art relevant to this invention and of the features in the art that can be used in connection with this invention.

[0003] The present invention relates specifically to the treatment of heart failure with preserved ejection fraction in human subjects (PH-HFpEF patients) who also have pulmonary hypertension.

Background Art

[0004] Levosimendan Levosimendan is a calcium sensitizer and potassium channel activator approved in more than 60 countries for intravenous use in hospitalized subjects with acute decompensated heart failure (ADHF). Levosimendan is currently approved only for in-hospital use and is currently approved only for administration in a hospital environment where appropriate monitoring facilities and expertise regarding the use of inotropes are available. (Simdax. Finland: Orion Corporation; 2010.)

[0005] Levocimendan increases the calcium sensitivity of contractile proteins by binding to cardiac troponin C in a calcium-dependent manner. Levocimendan increases contractility without impairing ventricular relaxation. In addition, levocimendan opens ATP-sensitive potassium channels in vascular smooth muscle, inducing vasodilation in systemic and coronary resistance vessels, as well as systemic venous volume vessels. Levocimendan is also a selective phosphodiesterase III inhibitor in vitro. (Simdax. Finland: Orion Corporation; 2010.)

[0006] Levocimendan has been studied exclusively in patients with heart failure with reduced ejection fraction (HFrEF). In fact, with the sole exception of the hemodynamic evaluation of levocimendan in the HP-HFpEF (HELP) trial (Borlaug 2020, Burkhoff 2020), which forms the basis of this invention, all previous multicenter, randomized, placebo-controlled trials of levocimendan in heart failure patients have explicitly excluded patients with heart failure with preserved ejection fraction (HFpEF). The complete lack of clinical studies evaluating levocimendan in HFpEF and PH-HFpEF patients is consistent with the historical treatment paradigm that levocimendan should be used to treat HFrEF patients. The HELP trial represents a significant departure from this traditional thinking, and as a result, the findings from this novel clinical trial present important and surprising discoveries regarding the benefits of levocimendan in PH-HFpEF patients.

[0007] In HFrEF patients, the positive inotropic and vasodilatory effects of levocimendan lead to increased contractility and decreased preload and afterload without adversely affecting diastolic function. Hemodynamic studies in healthy volunteers and patients with stable and unstable heart failure have revealed the dose-dependent effects of levocimendan administered intravenously as loading doses (3 micrograms / kg to 24 micrograms / kg) and continuous infusions (0.05 to 0.2 micrograms / kg per minute). Compared to placebo, in HFrEF patients, levocimendan increased cardiac output, stroke volume, ejection fraction, and heart rate, while decreasing systolic blood pressure, diastolic blood pressure, pulmonary capillary wedge pressure, right atrial pressure, and peripheral vascular resistance. (Simdax. Finland: Orion Corporation; 2010.)

[0008] Levocimendan's activity is mediated by unique mechanisms of action, including increased cardiac contractility through calcium sensitization of troponin C, vasodilation via potassium channel opening, and cardioprotective effects via potassium channel opening in mitochondria. (Haikala et al. 1995, Pollesello et al. 1994, Sorsa et al. 2004, Yokoshiki et al. 1997, Pataricza et al. 2000, Kaheinen et al. 2001, Erdei et al. 2006, Maytin et al. 2005, Pollesello et al. 2007, du Toit et al. 2008, Louhelainen et al. 2010)

[0009] Levocimendan has been shown to be a potent and selective phosphodiesterase-3 (PDE3) inhibitor in vitro. This drug is PDE3 selective and has a PDE3 / PDE4 inhibition ratio of 10,000. However, to affect cAMP concentration and inotropy, both isozymes must be inhibited in cardiomyocytes. Classical PDE inhibitors (i.e., milrinone, enoximon, and amrinone) inhibit both (with a low PDE3:PDE4 ratio of 17-fold), which well explains their inotropic effects. (Yokoshiki et al. 1997, Szilagyi et al. 2004)

[0010] Levocimendan improves endothelial function and increases diastolic coronary blood flow by opening adenosine triphosphate-sensitive potassium channels and increasing nitric oxide production. Levocimendan acts via direct binding to troponin-C at high systolic intracellular calcium concentrations and facilitates detachment from troponin-C at low diastolic concentrations. Levocimendan showed positive inotropic relaxation effects against milrinone and nitroglycerin. The inotropic relaxation effect of levocimendan was independent of the degree of its inotropic effect. (Michaels et al. 2005, Grossini et al. 2005, Hasenfuss et al. 1998, De Luca et al. 2006)

[0011] Metabolites OR-1896 and OR-1855 Levocimendan has an active metabolite that extends its effects far beyond the infusion period. After intravenous or oral administration, levocimendan is reduced by enteric bacteria to form OR-1855 (limited activity), which is then acetylated to form the active metabolite OR-1896. While the patient half-life is approximately 1 hour and it is eliminated within a few hours of the end of intravenous infusion, OR-1896 has an extended half-life of 70–80 hours in heart failure subjects with nearly equivalent exposure to OR-1855 and OR-1896, maintained via the deacetylation / acetylation pathway. The OR-1896 metabolite retains hemodynamic and pharmacological properties similar to levocimendan and has been shown to maintain nearly equivalent properties in preclinical models. This activity occurs despite considerably lower plasma concentrations compared to levocimendan, which is a clear consequence for the majority of unbound OR-1896 in circulation. Thus, with long-term repeated administration, levocimendan is essentially an active prodrug for the active metabolite portion OR-1896. (Louhelainen et al. 2010, Erdei et al. 2006, Szilagyi et al. 2004, Banfor et al. 2008, Louhelainen et al. 2009, Segreti et al. 2008)

[0012] OR-1896 is equivalent in potency to levocimendane in its inotropic effect on whole cardiomyocytes and isolated systolic preparations. However, OR-1896 is significantly less potent in inhibiting both PDE3 and PDE4 isozymes. This supports the hypothesis that the main component of the inotropic effect of both levocimendane and OR-1896 is not due to PDE inhibition, but rather to binding to troponin C. (Szilagyi et al. 2004)

[0013] Clinical observations demonstrate that long-term hemodynamic changes persist after short-term levocimendan administration, corresponding to levels of OR-1896. Patients have been observed to have detectable concentrations of both metabolites OR-1896 and OR-1855 at follow-up two weeks after treatment. Despite the observed inactivity of OR-1855, OR-1896 significantly prolongs the activity of the parent levocimendan, providing the primary active portion to subjects receiving intermittent intravenous levocimendan therapy. (Banfor et al. 2007, Kivikko et al. 2003, Kivikko et al. 2002)

[0014] Based on knowledge of OR-1896 and OR-1855, the administration of the metabolites can be used in the same way as levosimendan, by adjusting the parameters of the metabolites themselves. Both metabolites can be delivered via various routes of administration, including, but not limited to, oral, intravenous, and subcutaneous administration. The selected dose will vary depending on the specific route of administration. In all cases, the target dose is intended to achieve the steady-state concentration of OR-1896: 0.5–10.0 ng / ml. The relationship between levosimendan and OR-1896 and OR-1855, along with the interactions between the metabolites, is addressed in "Pharmacodynamics and Safety of a New Calcium Sensitizer, Levosimendan, and Its Metabolites during an Extended Infusion in Patients with Severe Heart Failure" (Kivikko et al. 2002), the full content of which is incorporated by reference.

[0015] Types of heart failure - HFrEF and HFpEF HFpEF and HFrEF are distinct clinical entities. While each type of heart failure accounts for approximately 50% of all heart failure patients, there are many differences between these two forms of heart failure.

[0016] A recent review by Shaw et al. outlines some of the distinct characteristics of HFpEF and HFrEF, which are summarized in the chart below. The review noted that over the past 30 years, HFrEF has evolved into its own distinct therapeutic entity due to the neurohormone inhibitory effects observed in large-scale outcome clinical trials. However, HFpEF has not undergone a similar evolution, due to a series of failed large-scale trials testing neurohormone inhibition individually or in meta-analyses. (Shaw et al. 2016)

[0017] [Table 1]

[0018] Pulmonary hypertension - heart failure with preserved ejection fraction (PH-HFpEF) Many HFpEF patients have concomitant pulmonary hypertension. Persistent elevated left atrial pressure leads to pulmonary venous congestion, which often results in elevated pulmonary pressure, leading to severe right ventricular failure with low cardiac output, edema, hypoxemia, and severe exercise capacity limitations. Pulmonary hypertension (PH) in subjects with heart failure and retained ejection fraction (PH-HFpEF) is a common form of pulmonary hypertension, with an estimated population of over 1.5 million in the United States. (Oktay et al. 2013, Oudiz et al. 2007, Hoeper et al. 2016)

[0019] PH-HFpEF is classified as Group II in the World Health Organization (WHO) clinical classification of pulmonary venous congestion (PH), characterized by PH arising from left heart disease. Regardless of the principle of left heart disease, PH initially arises from the passive posterior transfer of filling pressure, primarily driven by left ventricular (LV) diastolic function, which leads to chronic elevation of left atrial pressure and loss of left atrial compliance. These mechanical elements of pulmonary venous congestion can trigger pulmonary vasoconstriction, decreased nitric oxide (NO) availability, increased endothelin expression, desensitization to natriuretic peptide-induced vasodilation, and vascular remodeling. Finally, these changes often lead to advanced pulmonary vascular disease, increased right ventricular (RV) afterload, and RV failure. PH-HFpEF is hemodynamically defined by pulmonary artery pressure (mPAP) ≥ 25 mmHg, pulmonary capillary wedge pressure (PCWP) > 15 mmHg, and diastolic blood pressure difference [diastolic PAP-PCWP] > 7 mmHg. (Galie et al. 2009, McLaughlin et al. 2009, Simonneau et al. 2009, Dixon et al. 2015)

[0020] The ESC guidelines for the treatment of PH-HFpEF patients acknowledge that an acceptable therapeutic target is the reduction of pulmonary wedge pressure using diuretics for congestion. However, clinical trials have shown ambiguous results, along with explicit concerns that pulmonary hypertension (PH) targeted therapy may have adverse effects due to a rapid increase in LV filling pressure, potentially leading to acute pulmonary edema. Thus, the ESC guidelines state that there are currently no established strategies for treating pulmonary vascular disease (PVD) and right ventricular disease (RVD) in HFpEF and recommend against using approved PAH treatments in PH-HFpEF patients (Class III). Because effective treatments have not been demonstrated, these patients have poor outcomes (5-year survival rate <50%, frequent hospitalizations). (Shaw et al. 2016, Galie et al. 2009, Gorter et al. 2018, Klapholz et al. 2004)

[0021] Levocimendan has never been studied in the PH-HFpEF population. The complete lack of research on the potential usefulness of levocimendan in PH-HFpEF is likely due to the fact that inotropes such as levocimendan are recommended in most heart failure guidelines to be used exclusively for the treatment of HFrEF, and not for HFpEF patients. For example, the 2013 ACCF / AHA guidelines for the management of heart failure explicitly limit the recommendation of inotrope use in HFrEF patients, stating that "the use of parenteral inotropes in hospitalized patients with no evidence of written severe systolic dysfunction, hypotension, or perfusion impairment, and significantly reduced cardiac output, with or without congestion, may be harmful."

[0022] Failed treatment attempts Furthermore, none of the currently approved drugs used to treat other forms of pulmonary hypertension have been proven effective against PH-HFpEF. In fact, all previous studies testing other drugs in PH-HFpEF have repeatedly reported neutral to negative results (ElGuindy et al. 2012).

[0023] Numerous review articles have been published to summarize the repeated failures in attempted treatments for PH-HFpEF. One such article, in particular, by Andrea R. Levine et al., titled "Pulmonary Vascular Disease in the Setting of Heart Failure with Preserved Ejection Fraction," integrates all the background information behind this disease and applies this information to previously failed attempts. Findings regarding failed attempts with various therapeutic agents are referenced below to help explain the significant difficulties in treating PH-HFpEF.

[0024] One target pathway in previous clinical trials was the nitrate-NO-sGC-cGMP pathway. While several small, single-center trials have reported positive results with PDE5i treatment for PH-HFpEF, large, multicenter trials have been negative, making PDE5i unlikely to become an approved treatment for PH-HFpEF. In 2015, Hoendermis et al. found no change in mPAP after 12 weeks of sildenafil administration in 52 patients. The RELAX trial sought to determine whether long-term sildenafil administration altered peak oxygen consumption at 24 weeks in HFpEF patients. However, long-term sildenafil treatment failed to improve 6-minute walk time, clinical status, or quality of life in this multicenter trial of 216 patients. The SIOVAC trial was a multicenter, placebo-controlled trial of sildenafil in patients with PH left heart disease (LHD) secondary to valvular heart disease. This trial complemented the risks associated with sildenafil use in PH-LHD patients and supported recommendations for the use of PDE5i in PH-LHD patients. Due to these negative results observed to date, the efficacy of PDE5i in PH-HFpEF appears highly unlikely. A multicenter INDIE-HFpEF study investigated the acute cardiopulmonary hemodynamic effects of inorganic nitrite infusion. However, this trial was unsuccessful because it failed to demonstrate any improvement in the primary endpoint of peak oxygen consumption during cardiopulmonary exercise, or in secondary endpoints such as activity level, quality of life score, or NT-proBNP, in patients who received inhaled sodium nitrite three times daily for four weeks. Another study conducted by Simon et al. further evaluated inhaled nitrite in PH-HFpEF patients and yielded some promising data related to cardiopulmonary hemodynamics; however, improvement in clinical endpoints has not been demonstrated to date. Both the DILATE and SOCRATES-PRESERVED trials evaluated the acute hemodynamic effects of the sGC stimulants riociguat and beliciguat, respectively. The DILATE trial showed some promising results, but the primary outcome of mean pulmonary artery pressure was not achieved, and there were no changes in TPG or pulmonary vascular resistance.The SOCRATES-PRESERVED trial also ended with similar results, and no significant changes were seen in the primary endpoint. (Levine et al. 2019).

[0025] Endothelin receptors are another previously targeted molecular target for the treatment of PH-HFpEF. MELODY-1 was a small pilot trial evaluating macitentan in patients with left heart disease. However, the primary outcome was fluid retention and worsening of the New York Heart Association (NYHA) heart function classification. Furthermore, no changes were seen in hemodynamic parameters such as pulmonary vascular resistance, mean pulmonary artery pressure, or pulmonary artery wedge pressure. In the BADDHY trial, the use of bosentan, an endothelin receptor antagonist, was also attempted in PH-HFpEF patients, but no improvement was seen in the 6-minute walk test or echocardiogram for pulmonary hypertension. Patients who received bosentan actually had worse clinical outcomes than those who received only placebo. Neither of these two trials showed success with the use of endothelin receptor antagonists in the treatment of PH-HFpEF. (Levine et al. 2019)

[0026] The largest clinical trial to date in HFpEF was the PARAGON-HF trial conducted by Novartis. This trial was designed to evaluate the effect of sacubitril / valsartan in HFpEF patients. PARAGON-HF was yet another example of a large clinical trial where the reduction in the primary endpoint was not statistically significant. (Novartis 2019) SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0027] According to the 2009 ACCF / AHA and 2015 ESC / ERS guidelines, there are currently no clinically approved treatments for PH-HFpEF. As summarized above, given the numerous failures and adverse effects known in the art, no drug can be expected to treat PH-HFPEF; however, finding a treatment for this currently incurable disease is a strong need in the art. (Levine et al. 2019). [Means for solving the problem]

[0028] The present invention relates to the treatment of pulmonary hypertension with preserved ejection fraction (PH-HFpEF). More specifically, embodiments of the present invention provide compositions and methods useful for the treatment of PH-HFpEF, employing the use of levocimendan, OR1896, or OR1855. In other embodiments, treatment of PH-HFpEF is intended by subcutaneous administration. In other embodiments, treatment of PH-HFpEF is intended by oral administration. In other embodiments, treatment of PH-HFpEF is intended by combination therapy of levocimendan, OR1896, or OR1855 with other cardiovascular drugs.

[0029] The present invention provides levocimendan and a pharmaceutical product comprising levocimendan for use in any of the methods of the present invention.

[0030] Other objects, features, and advantages of the present invention will become apparent from the following description and drawings. [Brief explanation of the drawing]

[0031] [Figure 1A-1B]Before and after levocimendan lead-in infusion, pulmonary capillary wedge pressure (PCWP) in open-label levocimendan responders (n=30). Figures 1A and 1B are graphical representations of the results from Example 1, showing the decrease in pulmonary capillary wedge pressure (PCWP) after levocimendan administration in 30 patients. These results are based on single 24-hour open-label lead-in infusion data. Figure 1A shows the decrease in PCWP after levocimendan infusion in human subjects at rest with their legs down. Figure 1B shows the decrease in PCWP after levocimendan infusion in human subjects during exercise using 25 watts. [Figure 2A-2B] Right atrial pressure (RAP) before and after levocimendan lead-in infusion in open-label levocimendan responders (n=30). Figures 2A-2B are graphical representations of the results from Example 1, showing the decrease in right atrial pressure (RAP) after levocimendan administration in 30 patients. These results are based on single 24-hour open-label lead-in infusion data. Figure 2A shows the decrease in RAP after levocimendan infusion in human subjects at rest with their legs down. Figure 2B shows the decrease in RAP after levocimendan infusion in human subjects during exercise using 25 watts. [Figure 3A-3B] Mean pulmonary artery pressure (mPAP) before and after levocimendan lead-in infusion in open-label levocimendan responders (n=30). Figures 3A-3B are graphical representations of the results from Example 1, showing the decrease in mean pulmonary artery pressure (mPAP) after levocimendan administration in 30 patients. These results are based on single 24-hour open-label lead-in infusion data. Panel A shows the decrease in mPAP after levocimendan infusion in human subjects at rest with their legs down. Panel B shows the decrease in mPAP after levocimendan infusion in human subjects during exercise using 25 watts. [Figure 4A-4B]Cardiac output before vs. after levocimendan lead-in infusion in open-label levocimendan responders (n=30). Figures 4A-4B are graphical representations of the results from Example 1, showing the increase in cardiac output (CO) after levocimendan administration in 30 patients. These results are based on single 24-hour open-label lead-in infusion data. Panel A shows the increase in CO after levocimendan infusion in human subjects at rest with their legs down. Panel B shows the increase in CO after levocimendan infusion in human subjects during exercise using 25 watts. [Figure 5] Open-label extension study of 6-minute walk distance (n=8). Figure 5 is a graphical representation of the results of Example 2, showing the increase in 6-minute walk distance after administration of levocimendan in 8 patients. [Figure 6] Evidence of improved quality of life - patient self-assessment - extension study, 5-point Likert scale. Figure 6 is a graphical representation of the results of Example 2, showing the increase in quality of life assessment after levocimendan administration in eight patients using a 5-point Likert scale. [Figure 7] Exercise stroke volume can predict the response to levocimendan. Figure 7 is a graphical representation of the results from Example 1, showing predictors of the response in PH-HFpEF patients treated with levocimendan in 21 patients. This graph shows that the greater the change in stroke volume between rest and 25 watts of exercise, the greater the decrease in PCWP after levocimendan administration. [Figure 8]PCWP endpoint - baseline vs. 6 weeks. The effect of levocimendan on PCWP was significant compared to placebo in all positions. Figure 8 is a graphical representation of the results from Example 2, showing the reduction in pulmonary capillary wedge pressure (PCWP) after administering levocimendan or placebo via weekly 24-hour IV infusion for 5 weeks to 35 PH-HFpEF patients (18 levocimendan-treated patients and 17 placebo-treated patients). The left panel shows the difference in PCWP after placebo administration in human subjects at rest with legs down, with legs raised on a supine bicycle, and during exercise at 25 watts. The right panel shows the reduction in PCWP after levocimendan infusion in human subjects at rest with legs down, with legs raised on a supine bicycle, and during exercise at 25 watts. †Treatment was tested using a mixed-effects model with treatment as the coefficient and position as the random effect. [Figures 9A-9C] PCWP change from baseline at week 6 - levocimendan vs. placebo. Figures 9A-9C are graphical representations of the results from Example 2, in which levocimendan or placebo was administered weekly via 24-hour IV infusion to 35 PH-HFpEF patients (18 levocimendan-treated patients and 17 placebo-treated patients) for 5 weeks. The PCWP after levocimendan administration in the 18 PH-HFpEF patients showed a greater decrease compared to the placebo-treated 17 other PH-HFpEF patients. Figure 9A shows the decrease in PCWP after levocimendan and placebo infusion in human subjects at rest with their legs down. Figure 9B shows the decrease in PCWP after levocimendan and placebo infusion in the supine position with the patient's legs raised. Figure 9C shows the decrease in PCWP after levocimendan and placebo infusion in human subjects during exercise using 25 watts. [Figure 10] Change in PCWP from baseline at week 6 - levocimendan. Figure 10 is a graphical representation of the results of Example 2, in which levocimendan or placebo was administered via weekly 24-hour IV infusion to 35 PH-HFpEF patients (18 levocimendan-treated patients and 17 placebo-treated patients) for 5 weeks, showing the decrease in PCWP after levocimendan administration in 18 PH-HFpEF patients. [Figure 11] RAP change from baseline at week 6 - levocimendan-treated patients. Figure 11 is a graphical representation of the results of Example 2, in which levocimendan or placebo was administered via weekly 24-hour IV infusion for 5 weeks to 35 PH-HFpEF patients (18 levocimendan-treated patients and 17 placebo-treated patients), showing a decrease in right atrial pressure (RAP) after levocimendan administration in the 18 PH-HFpEF patients compared to the 17 placebo-treated patients. This figure shows the decrease in RAP at rest with legs down, with legs raised on a supine bicycle, and during exercise using 25 watts by human subjects. [Figures 12A-12B] Changes in RAP at Week 6 - Levocimendan vs. Placebo. Figures 12A-12C are graphical representations of the results from Example 2, in which levocimendan or placebo was administered weekly via 24-hour IV infusion to 35 PH-HFpEF patients (18 treated with levocimendan and 17 treated with placebo) for 5 weeks. The results show a greater decrease in RAP after levocimendan administration in 18 PH-HFpEF patients compared to placebo administration in 17 other PH-HFpEF patients. Figure 12A shows the decrease in RAP after levocimendan and placebo infusion in a resting position with the patient's legs down. Figure 12B shows the decrease in RAP after levocimendan and placebo infusion in a supine position with the patient's legs elevated. 4 [Figure 12C] Figure 12C shows the decrease in RAP after levocimendan injection and placebo injection in human subjects during exercise using 25 watts. [Figure 13]Change in mPAP from baseline at week 6 - levocimendan. Figure 13 is a graphical representation of the results of Example 2, in which levocimendan or placebo was administered via weekly 24-hour IV infusion to 35 PH-HFpEF patients for 5 weeks, showing the reduction in mean pulmonary artery pressure (mPAP) after levocimendan administration in 18 PH-HFpEF patients compared to 17 placebo-treated patients. This figure shows the reduction in mPAP in human subjects at rest with legs down, with legs raised on a supine bicycle, and during exercise at 25 watts. [Figure 14A-14C] Changes in mPAP (mmHg) at Week 6 - Levocimendan vs. Placebo. Figures 14A-14C are graphical representations of the results from Example 2, in which levocimendan or placebo was administered weekly via 24-hour IV infusion to 35 PH-HFpEF patients for 5 weeks. The results show a greater decrease in mPAP after levocimendan administration in 18 PH-HFpEF patients compared to placebo administration in 17 other PH-HFpEF patients. Figure 14A shows the decrease in mPAP after levocimendan and placebo infusion in human subjects at rest with their legs down. Figure 14B shows the decrease in mPAP after levocimendan and placebo infusion with patients in a supine position with their legs raised. Figure 14C shows the decrease in mPAP after levocimendan and placebo infusion in human subjects during exercise using 25 watts. [Figure 15] Change in 6-minute walk distance (meters) from baseline at week 6 - levocimendan vs. placebo. Figure 15 is a graphical representation of the results of Example 2, in which levocimendan or placebo was administered via weekly 24-hour IV infusion to 35 PH-HFpEF patients for 5 weeks, showing an increase in 6-minute walk distance after levocimendan administration in 18 PH-HFpEF patients compared to placebo administration in 17 other PH-HFpEF patients. [Figure 16]Adverse events under investigational drug administration. Figure 16 shows the results of Example 2, in which levocimendan or placebo was administered to 36 PH-HFpEF patients via weekly 24-hour IV infusions for 5 weeks, and compares the adverse events under investigational drug administration (TEAEs) after levocimendan administration in 18 PH-HFpEF patients with those after placebo administration in 18 other PH-HFpEF patients. [Figure 17] Adverse events (incidence of 2 or more events) under investigational drug administration. Figure 17 shows the results of Example 2, in which levocimendan or placebo was administered to 36 PH-HFpEF patients via weekly 24-hour IV infusions for 5 weeks, and compares specific investigational drug-associated adverse events (TEAEs) after levocimendan administration in 18 PH-HFpEF patients with placebo administration in 18 additional PH-HFpEF patients. [Figure 18] Serious adverse events. Figure 18 shows the results of Example 2, in which levocimendan or placebo was administered via weekly 24-hour IV infusion to 36 PH-HFpEF patients for 5 weeks, and shows serious adverse events and the relevance / dosage changes of levocimendan. [Figure 19] OR1896 trough blood concentrations in patients treated with levocimendan at final RHC. Figure 19 is a graphical representation of the results from Example 2, in which levocimendan or placebo was administered via weekly 24-hour IV infusions to 36 PH-HFpEF patients for 5 weeks, showing OR1896 trough blood concentrations at final RHC in levocimendan-treated patients. [Figures 20A-20B] This graph shows the results of Example 2, in which levocimendan or placebo was administered to 35 PH-HFpEF patients via weekly 24-hour IV infusions for 5 weeks, and shows cardiac index (CI) (Figure 20A) and pulmonary vascular resistance (PVR) (Figure 20B) after levocimendan administration in 36 PH-HFpEF patients. PVR and CI behaved remarkably differently compared to other variables (i.e., unchanged at week 6). This data suggests that levocimendan acts differently with respect to long-term (weekly for 5 weeks) versus short-term (24-hour) administration (see, for example, Figures 4A-4B). [Figures 21A-21B] Baseline vs. 24-hour levocimendan infusion - effects on CVP and PCWP. All values ​​differ between baseline and 24-hour LEVO infusion by paired t-tests. Figure 21A shows the effect on CVP. Figure 21B shows the effect on PCWP. In both Figures 21A and 21B, “baseline” measurements are displayed to the left of “24-hour” measurements. [Figure 22] Baseline characteristics in randomized patients. [Figure 23] Summary of the overall hemodynamic effects of 24-hour levocimendan infusion. Figure 23 shows the short-term (24-hour) effects of open-label levocimendan (n=44). 85% of patients showed a reduction of ≥4 mmHg in PCWP. Abbreviations: HR, heart rate; CVP, central venous pressure; PAS, pulmonary artery systolic blood pressure; PAD, pulmonary artery diastolic blood pressure; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; AoS, arterial systolic blood pressure; CI, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance. *p<.05 (compared to baseline). [Figure 24] Baseline and 6-week hemodynamic parameter values ​​for all randomized patients (n=18 placebo patients and 17 levocimendan-treated patients). Least squares (LS) mean and confidence interval (CI) are from an analysis of variance (ANOVA) model of change from baseline using treatment groups as coefficients. †Mixed-effects repeated measures model, group difference p=0.04. Abbreviations: HR, heart rate; CVP, central venous pressure; PAS, pulmonary systolic blood pressure; PAD, pulmonary diastolic blood pressure; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; AoS, arterial systolic blood pressure; CI, cardiac index; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance. [Figure 25] Summary of a two-phase trial including an initial open-label levocimendan infusion to identify levocimendan "responders," defined as a ≥4 mmHg reduction in pulmonary capillary wedge pressure (PCWP) during 25-watt exercise (EX), followed by a randomized, double-blind phase. [Figure 26] CONSORT diagram showing patient flow throughout the entire trial. [Figures 27A-27B]Comparison of pulmonary capillary wedge pressure (PCWP) and central venous pressure (CVP) at baseline, 24 hours, and over 6 weeks while at rest, with legs elevated, and during 25 watt exercise. Figures 27A and 27B show the placebo group. *p<0.05 for comparisons with baseline and 24-hour measurements. [Figures 27C-27D] Figures 27C and 27D show the levocimendan group. *p<0.05 for comparison with baseline and 24-hour measurements. [Figures 28A-28B] Figure 28A compares the 6-minute walk distance (6MWD) in the treatment and control groups. Figure 28B is a ranked list of the change in 6MWD for each patient assigned to a group. More patients in the treatment group increased their 6MWD, while more patients in the control group decreased their 6MWD. *p<0.05. [Modes for carrying out the invention]

[0032] According to some embodiments, the present invention provides a method for treating pulmonary hypertensive heart failure (PH-HFpEF) in a human subject suffering from PH-HFpEF, which comprises administering to a human subject an amount effective to treat PH-HFpEF in the human subject of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof.

[0033] In some embodiments, the treatment involves reducing the pulmonary capillary wedge pressure in a resting human subject.

[0034] In some embodiments, the treatment involves reducing the pulmonary capillary wedge pressure of a human subject at rest by 1 to 30 mmHg.

[0035] In some embodiments, the treatment involves stabilizing the pulmonary capillary wedge pressure of a human subject at rest to 5–35 mmHg.

[0036] In some embodiments, the treatment involves stabilizing the pulmonary capillary wedge pressure of a resting human subject to 10–35 mmHg.

[0037] In some embodiments, the treatment involves reducing the pulmonary capillary wedge pressure of a human subject during exercise.

[0038] In some embodiments, the treatment involves reducing the pulmonary capillary wedge pressure of a human subject by 1 to 40 mmHg during exercise.

[0039] In some embodiments, the treatment involves stabilizing the pulmonary capillary wedge pressure of a human subject to 10–50 mmHg during exercise.

[0040] In some embodiments, the treatment does not involve significant changes in pulmonary capillary wedge pressure during exercise in human subjects.

[0041] In some embodiments, the treatment includes reducing the pulmonary capillary wedge pressure of a human subject when the human subject's legs are raised.

[0042] In some embodiments, the treatment involves reducing the pulmonary capillary wedge pressure of a human subject when the subject's legs are raised, with the reduction being between 1 and 30 mmHg.

[0043] In some embodiments, the treatment involves stabilizing the pulmonary capillary wedge pressure of a human subject with the legs raised, with the stabilization being between 10 and 50 mmHg.

[0044] In some embodiments, the treatment includes reducing the right atrial pressure of a human subject at rest.

[0045] In some embodiments, the treatment involves reducing the right atrial pressure of a human subject at rest by 1 to 30 mmHg.

[0046] In some embodiments, the treatment includes stabilizing the right atrial pressure of a human subject at rest to 1–30 mmHg.

[0047] In some embodiments, the treatment includes stabilizing the right atrial pressure of a human subject at rest to 5–30 mmHg.

[0048] In some embodiments, the treatment includes reducing the right atrial pressure of a human subject during exercise.

[0049] In some embodiments, the treatment involves reducing the right atrial pressure of a human subject by 1 to 30 mmHg during exercise.

[0050] In some embodiments, the treatment includes stabilizing the right atrial pressure of a human subject to 5–40 mmHg during exercise.

[0051] In some embodiments, the treatment includes reducing the right atrial pressure of a human subject when the human subject raises their legs.

[0052] In some embodiments, the treatment includes reducing the mean pulmonary artery pressure of a human subject at rest.

[0053] In some embodiments, the treatment involves lowering the mean pulmonary artery pressure of a human subject at rest by 1 to 30 mmHg.

[0054] In some embodiments, the treatment includes stabilizing the mean pulmonary artery pressure of a human subject at rest to 15–65 mmHg.

[0055] In some embodiments, the treatment includes reducing the mean pulmonary artery pressure of a human subject during exercise.

[0056] In some embodiments, the treatment involves reducing the mean pulmonary artery pressure of a human subject by 1 to 30 mmHg during exercise.

[0057] In some embodiments, the treatment includes stabilizing the mean pulmonary artery pressure of a human subject to 25–85 mmHg during exercise.

[0058] In some embodiments, the treatment involves stabilizing the mean pulmonary artery pressure of a human subject to 25–80 mmHg during exercise.

[0059] In some embodiments, the treatment includes reducing the mean pulmonary artery pressure of a human subject when the human subject's legs are raised.

[0060] In some embodiments, the treatment includes increasing the cardiac output of a human subject at rest.

[0061] In some embodiments, the treatment involves increasing the resting cardiac output of a human subject by 0.01 to 3 liters / minute.

[0062] In some embodiments, the treatment includes stabilizing the resting cardiac output of a human subject to 2–10 liters / minute.

[0063] In some embodiments, the treatment includes increasing the cardiac output of a human subject during exercise.

[0064] In some embodiments, the treatment includes increasing the cardiac output of a human subject by 0.01 to 5 liters / min during exercise performed by a human subject.

[0065] In some embodiments, the treatment involves increasing the cardiac output of a human subject by 0.01 to 4 liters / min during exercise performed by a human subject.

[0066] In some embodiments, the treatment includes stabilizing the cardiac output of a human subject to 3.0 to 15.0 liters / minute during exercise.

[0067] In some embodiments, the treatment does not involve a significant increase in the heart rate of the human subject.

[0068] In some embodiments, the treatment does not involve an increase in the human subject's heart rate beyond 10 beats / minute.

[0069] In some embodiments, the treatment includes improving the quality of life of human subjects.

[0070] In some embodiments, improvements in the quality of life of human subjects are measured by patient-reported outcome assessment tools.

[0071] In some embodiments, improvements in the quality of life of human subjects are measured using the Likert scale, a 5-point patient-reported outcome assessment tool.

[0072] In some embodiments, the treatment includes an improvement in the quality of life of a human subject by a change of at least one patient-reported outcome assessment tool score in the human subject.

[0073] In some embodiments, the treatment includes improving the quality of life of a human subject by a change of at least two points in the patient-reported outcome assessment tool score of the human subject.

[0074] In some embodiments, the treatment includes improving the 6-minute walking distance of human subjects.

[0075] In some embodiments, the treatment includes improving the walking distance of human subjects by 5 to 150 meters in 6 minutes.

[0076] In some embodiments, the treatment includes improving the physician's assessment of the cardiac function classification of human subjects.

[0077] In some embodiments, the treatment includes reducing the incidence of hospitalizations related to heart failure.

[0078] In some embodiments, the treatment includes reducing all-cause mortality.

[0079] In some embodiments, treatment includes improvement of right heart failure and / or right ventricular dysfunction.

[0080] In some embodiments, the above improvement is demonstrated by a reduction in right atrial pressure at rest and during 25-watt exercise.

[0081] In some embodiments, human subjects are responders to levocimendan therapy.

[0082] In some embodiments, responders to levocimendan therapy are human subjects whose pulmonary capillary wedge pressure decreases by at least 4 mm HG during 25 watts of cycling exercise after the initial injection.

[0083] In some embodiments, responders to levosimendan therapy are human subjects whose cardiac index decreases to ≤10% between baseline measurements and repeated measurements after the first infusion.

[0084] In some embodiments, human subjects are responders to levosimendan therapy if the human subjects have cardiac reserve.

[0085] In some embodiments, a human subject is a responder to levosimendan therapy if their stroke volume increases during exercise performed by the human subject.

[0086] In some embodiments, a human subject is a responder to levosimendan therapy if, as determined using a catheter inside the human subject's heart that measures the amount of blood moving from the left ventricle with each heartbeat, the stroke volume of the human subject increases during exercise performed by the human subject.

[0087] In some embodiments, a human subject is a responder to levosimendan therapy if, as estimated by electrocardiogram and / or echocardiogram, the stroke volume of the human subject increases during exercise performed by the human subject.

[0088] In some embodiments, a human subject is a responder to levocimendan therapy if, as determined by a dobutamine stress test, the stroke volume of the human subject increases during exercise performed by the human subject.

[0089] In some embodiments, a human subject is a responder to levosimendan therapy if their stroke volume increases by at least 0.005 liters during exercise performed by the human subject.

[0090] In some embodiments, a human subject is a responder to levosimendan therapy if, as determined by a catheter inside the human subject's heart that measures the amount of blood moving from the left ventricle with each heartbeat, the human subject's stroke volume increases by 1 to 50 mL during exercise.

[0091] In some embodiments, a human subject is considered a responder to levosimendan therapy if, as estimated by echocardiography, right heart catheterization, or other means, their stroke volume increases by 1–50 mL during exercise.

[0092] In some embodiments, a human subject is considered a responder to levocimendan therapy if, as determined by a dobutamine stress test, their stroke volume increases by 1–50 mL during exercise performed by the human subject.

[0093] In some embodiments, human subjects with PH-HFpEF have a left ventricular ejection fraction of at least 40%.

[0094] In some embodiments, human subjects suffering from PH-HFpEF have a baseline pulmonary artery pressure of at least 35.

[0095] In some embodiments, human subjects with PH-HFpEF have a baseline pulmonary capillary wedge pressure of at least 20.

[0096] In some embodiments, human subjects with PH-HFpEF are classified as Class IIb of the New York Heart Association Classification by physician evaluation.

[0097] In some embodiments, human subjects with PH-HFpEF are classified as Class III according to the New York Heart Association Classification by physician evaluation.

[0098] In some embodiments, human subjects suffering from PH-HFpEF are able to walk at least 50 meters in a 6-minute walk test.

[0099] In some embodiments, human subjects suffering from PH-HFpEF are unable to walk more than 550 meters in a 6-minute walk test.

[0100] In some embodiments, human subjects suffering from PH-HFpEF are able to walk at least 50 meters, but no more than 550 meters, in a 6-minute walk test.

[0101] In some embodiments, human subjects with PH-HFpEF did not have heart failure with reduced ejection fraction.

[0102] In some embodiments, human subjects with PH-HFpEF did not have heart failure with preserved ejection fraction and without pulmonary hypertension.

[0103] In some embodiments, human subjects suffering from PH-HFpEF have a primary diagnosis of PH-HFpEF in group 2.

[0104] In some embodiments, human subjects with PH-HFpEF did not have coronary artery disease.

[0105] In some embodiments, human subjects with PH-HFpEF had not previously undergone percutaneous coronary intervention.

[0106] In some embodiments, human subjects with PH-HFpEF have not previously undergone percutaneous coronary intervention, unless the human subject had a negative stress test result within the past year.

[0107] In some embodiments, human subjects with PH-HFpEF had never undergone cardiac surgery before.

[0108] In some embodiments, human subjects with PH-HFpEF have not undergone any previous cardiac surgery, except in cases where the human subject had a negative stress test result within the past year.

[0109] In some embodiments, human subjects with PH-HFpEF did not have congenital heart disease.

[0110] In some embodiments, human subjects with PH-HFpEF did not develop clinically significant lung disease.

[0111] In some embodiments, human subjects with PH-HFpEF do not have plans for cardiac or lung surgery.

[0112] In some embodiments, human subjects suffering from PH-HFpEF do not have a cardiac index greater than 4.0 L / min / m2.

[0113] In some embodiments, human subjects with PH-HFpEF do not receive pulmonary vasodilator therapy concurrently.

[0114] In some embodiments, human subjects with PH-HFpEF had not received pulmonary vasodilator therapy within the past 14 days.

[0115] In some embodiments, human subjects suffering from PH-HFpEF do not undergo dialysis treatment.

[0116] In some embodiments, human subjects suffering from PH-HFpEF do not have a glomerular filtration rate of less than 30 mL / min / 1.73m2.

[0117] In some embodiments, human subjects with PH-HFpEF do not have Child-Pugh Class B or C liver dysfunction.

[0118] In some embodiments, human subjects with PH-HFpEF did not have evidence of systemic infection.

[0119] In some embodiments, the body weight of human subjects suffering from PH-HFpEF is 150 kg or less.

[0120] In some embodiments, human subjects suffering from PH-HFpEF can be managed to ensure their symptomatic systolic blood pressure remains above 100 mmHg.

[0121] In some embodiments, human subjects suffering from PH-HFpEF do not have a heart rate of more than 100 beats per minute due to drug use.

[0122] In some embodiments, human subjects suffering from PH-HFpEF do not have a symptomatic heart rate of 100 beats per minute or more that lasts for at least 10 minutes due to drug use.

[0123] In some embodiments, human subjects suffering from PH-HFpEF do not have hemoglobin levels below 80 g / L.

[0124] In some embodiments, human subjects with PH-HFpEF did not have serum potassium levels below 3.0 mmol / L at baseline.

[0125] In some embodiments, human subjects with PH-HFpEF did not have serum potassium levels greater than 5.5 mmol / L at baseline.

[0126] In some embodiments, human subjects with PH-HFpEF did not have serum potassium levels below 3.0 mmol or above 5.5 mmol / L at baseline.

[0127] In some embodiments, human subjects suffering from PH-HFpEF do not have severe immune dysfunction.

[0128] In some embodiments, human subjects with PH-HFpEF were not pregnant.

[0129] In some embodiments, human subjects with PH-HFpEF are not suspected of being pregnant.

[0130] In some embodiments, the human subjects suffering from PH-HFpEF were not breastfeeding.

[0131] In some embodiments, human subjects suffering from PH-HFpEF are patients with biventricular failure.

[0132] In some embodiments, administration is self-administered by human subjects.

[0133] In some embodiments, self-administration is performed by human subjects in a hospital setting.

[0134] In some embodiments, self-administration is performed by human subjects in an outpatient setting.

[0135] In some embodiments, self-administration is performed by human subjects outside of a hospital setting.

[0136] In some embodiments, self-administration is performed at home by human subjects.

[0137] In some embodiments, administration is not self-administered by human subjects.

[0138] In some embodiments, administration is performed by a trained professional.

[0139] In some embodiments, administration is performed in a hospital by a trained professional.

[0140] In some embodiments, administration is performed by a trained specialist in an outpatient setting.

[0141] In some embodiments, administration is performed outside the hospital by a trained specialist.

[0142] In some embodiments, administration is performed at home by a trained professional.

[0143] In some embodiments, the dose is delivered via intravenous administration.

[0144] In some embodiments, IV administration is performed via vein access through a PICC line.

[0145] In some embodiments, IV administration is performed by accessing a vein via a port-a-cath.

[0146] In some embodiments, administration is performed intermittently.

[0147] In some embodiments, the administration is performed weekly.

[0148] In some embodiments, administration is carried out by a 24-hour infusion.

[0149] In some embodiments, administration is carried out by a 24-hour weekly infusion.

[0150] In some embodiments, administration is carried out over a long period of time.

[0151] In some embodiments, the administration is a long-term administration carried out by infusions lasting less than 24 hours.

[0152] In some embodiments, the dose is a 2.5 mg / mL injection concentrate of levocimendan containing levocimendan, povidone, citrate, and ethanol.

[0153] In some embodiments, the dose is a 2.5 mg / mL injection concentrate of levocimendan containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 5 mL.

[0154] In some embodiments, the dose is a 2.5 mg / mL infusion concentrate of levocimendan containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 5 mL, which is added to one 250 mL infusion bag of 5% dextrose.

[0155] In some embodiments, the dose is a 2.5 mg / mL infusion concentrate of levocimendan containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 5 mL, which is added to one 250 mL infusion bag of 0.9 physiological saline.

[0156] In some embodiments, the administration is a dose of levocimendan 2.5 mg / mL infusion concentrate containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 5 mL for human subjects weighing less than 85 kg, which is added to one 250 mL infusion bag of 5% dextrose or 0.9 physiological saline.

[0157] In some embodiments, the dose is a 2.5 mg / mL injection concentrate of levocimendan containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 10 mL.

[0158] In some embodiments, the dose is a 2.5 mg / mL infusion concentrate of levocimendan containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 10 mL, which is added to one 500 mL infusion bag of 5% dextrose.

[0159] In some embodiments, the dose is a 2.5 mg / mL infusion concentrate of levocimendan containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 10 mL, which is added to one 500 mL infusion bag of 0.9 physiological saline.

[0160] In some embodiments, the administration is a dose of levocimendan 2.5 mg / mL infusion concentrate containing levocimendan, povidone, citrate, and ethanol, supplied in a total volume of 10 mL if the human subject weighs at least 85 kg, which is added to one 500 mL infusion bag of 5% dextrose or 0.9 physiological saline.

[0161] In some embodiments, the administration lead-in infusion rate is 0.10 μg / kg / min over a 24-hour period.

[0162] In some embodiments, the infusion rate during the second week of administration is 0.075 μg / kg / min over a 24-hour period.

[0163] In some embodiments, the infusion rate during the third week of administration is 0.075 μg / kg / min over a 24-hour period.

[0164] In some embodiments, the infusion rate during the fourth week of administration is 0.10 μg / kg / min for 24 hours.

[0165] In some embodiments, the infusion rate at week 5 of administration is 0.10 μg / kg / min for 24 hours.

[0166] In some embodiments, if human subjects do not tolerate higher doses well, the infusion rate is reduced to 0.05 μg / kg / min.

[0167] In some embodiments, administration is carried out by oral administration.

[0168] In some embodiments, oral administration includes immediate-release formulations.

[0169] In some embodiments, oral administration includes sustained-release formulations.

[0170] In some embodiments, administration is carried out via inhalation.

[0171] In some embodiments, inhalation delivery includes an inhaled formulation.

[0172] In some embodiments, administration is carried out via transdermal delivery.

[0173] In some embodiments, transdermal delivery includes transdermal formulations.

[0174] In some embodiments, administration is by subcutaneous injection.

[0175] In some embodiments, administration is performed subcutaneously via a subcutaneous drug delivery device.

[0176] In some embodiments, the drug delivery device is a Continuous Ambulatory Delivery Device (CADD) pump.

[0177] In some embodiments, subcutaneous administration includes the administration of a subcutaneous formulation.

[0178] In some embodiments, the subcutaneous formulation is an intravenous formulation containing an additive.

[0179] In some embodiments, the subcutaneous formulation contains 12.5 mg of levocimendan in a non-aqueous formulation so as to produce a levocimendan concentration of 0.0833 mg / mL in the subcutaneous formulation, which is added to 150 mL of 5% dextrose, 0.9 liters of physiological saline, or other pharmaceutically acceptable diluent or carrier.

[0180] In some embodiments, the subcutaneous formulation contains 12.5 mg of levocimendan in a non-aqueous formulation to produce a levocimendan concentration of 0.05 mg / mL in the subcutaneous formulation, which is added to 250 mL of 5% dextrose, 0.9 liters of physiological saline, or other pharmaceutically acceptable diluent or carrier.

[0181] In some embodiments, the subcutaneous formulation contains 12.5 mg of levocimendan in a non-aqueous formulation so as to produce a levocimendan concentration of 0.025 mg / mL in the subcutaneous formulation, which is added to 500 mL of 5% dextrose, 0.9 liters of physiological saline, or other pharmaceutically acceptable diluent or carrier.

[0182] In some embodiments, the subcutaneous formulation contains 12.5 mg of levocimendan in a non-aqueous formulation to produce a levocimendan concentration of 0.0125 mg / mL in the subcutaneous formulation, which is added to 1000 mL of 5% dextrose, 0.9 liters of physiological saline, or other pharmaceutically acceptable diluent or carrier.

[0183] In some embodiments, the subcutaneous formulation contains 12.5 mg of levocimendan in a non-aqueous formulation so as to produce a levocimendan concentration of 0.008333 mg / mL in the subcutaneous formulation, which is added to 1500 mL of 5% dextrose, 0.9 liters of physiological saline, or other pharmaceutically acceptable diluent or carrier.

[0184] In some embodiments, the subcutaneous administration of the subcutaneous formulation includes an amount of water effective in reducing pain caused by the subcutaneous administration.

[0185] In some embodiments, subcutaneous administration of the subcutaneous formulation includes a buffer to raise the pH above 3.5.

[0186] In some embodiments, subcutaneous administration of the subcutaneous formulation has fewer side effects compared to intravenous administration of levocimendan in human subjects.

[0187] In some embodiments, subcutaneous administration of the subcutaneous formulation reduces the peak plasma concentration of levocimendan compared to intravenous administration in human subjects.

[0188] In some embodiments, subcutaneous administration of the subcutaneous formulation reduces the peak plasma concentration of levocimendan by at least 1% to 25% compared to intravenous administration in human subjects.

[0189] In some embodiments, the above amounts of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, are administered in combination with a cardiovascular drug.

[0190] In some embodiments, the above amounts of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, along with a specific amount of a cardiovascular drug (the amounts of which, when taken together, are effective in treating a human subject), are administered to a human subject on a regular basis.

[0191] In some embodiments, when the above amounts of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, are administered together with the above amounts of cardiovascular drugs, they are more effective in treating subjects than when the same amounts of each drug are administered alone.

[0192] In some embodiments, the above amounts of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, along with the above amounts of cardiovascular drugs, when taken together, are effective in alleviating the symptoms of PH-HFpEF.

[0193] In some embodiments, cardiovascular drugs are medications used to treat pulmonary arterial hypertension (PAH), pulmonary hypertension in patients of World Health Organization (WHO) groups 1-5, coronary artery disease (CAD), or heart failure with reduced ejection fraction (HFrEF).

[0194] In some embodiments, the cardiovascular agent is a PDE inhibitor, a phosphodiesterase-5 (PDE5) inhibitor, an endothelin receptor antagonist (ERA), a prostanoid, a soluble guanylate cyclase stimulant, a nitrate, a nitrite, an NO donor, a calcium channel inhibitor (CCB), a fatty acid oxidation inhibitor, a beta-blocker (BB), angiotensin-converting enzyme (ACE) inhibitor, a neprilysin inhibitor, a neprilysin and angiotensin receptor blocker (ANRI), angiotensin II receptor blocker (ARB), a diuretic, an aldosterone antagonist, a digoxin, an ivabradine, a hydralazine, a ceralaxin, a natriuretic peptide, an atrial natriuretic peptide (ANP), a natriuretic peptide, a K-ATP channel activator, an NEP inhibitor, or a prostacyclin.

[0195] In some embodiments, the cardiovascular drug is a pulmonary vasodilator.

[0196] In some embodiments, the pulmonary vasodilator is a phosphodiesterase-5 (PDE5) inhibitor, an endothelin receptor antagonist (ERA), or prostacyclin.

[0197] In some embodiments, the above amounts of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, administered in combination with a pulmonary vasodilator, are given to human subjects suffering from pre- and post-capillary pulmonary hypertension and heart failure with preserved ejection fraction (Cpc-PH-HFpEF).

[0198] In some embodiments, baseline electrocardiogram monitoring is compared to 72-hour monitoring after 5 weeks of treatment, and no atrial or ventricular arrhythmias are observed.

[0199] In some embodiments, a 24-hour weekly administration of levocimendan is safe and well-tolerated.

[0200] In some embodiments, the treatment exhibits only statistically significant adverse events comparable to those of a matched placebo.

[0201] In some embodiments, a 24-hour weekly administration of levocimendan results in steady-state blood concentrations of OR1896 ranging from 0.20 ng / mL to 25.00 ng / mL.

[0202] According to some embodiments, the present invention also provides a product that includes: a. 5 mL vial dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol; b. 250 mL of 5% dextrose or 0.9 mL of physiological saline; and c. A buffering agent used to increase pH.

[0203] According to some embodiments, the present invention also provides the use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or combinations thereof, for the effective treatment of pulmonary hypertensive heart failure with preserved ejection fraction (PH-HFpEF) in human subjects.

[0204] According to some embodiments, the present invention also provides the use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or combinations thereof, for the purpose of preparing a pharmaceutical for effective treatment of PH-HFpEF in human subjects to be administered to human subjects suffering from pulmonary hypertensive heart failure with preserved ejection fraction (PH-HFpEF).

[0205] According to some embodiments, the present invention also provides a pharmaceutical product comprising a specific amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, for use in effectively treating pulmonary hypertensive heart failure with preserved ejection fraction (PH-HFpEF) in human subjects.

[0206] According to some embodiments, the present invention also provides the use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or combinations thereof, in combination with cardiovascular agents, for the effective treatment of pulmonary hypertensive heart failure with preserved ejection fraction (PH-HFpEF) in human subjects.

[0207] According to some embodiments, the present invention also provides the use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or combinations thereof, for the purpose of preparing pharmaceuticals in combination with cardiovascular agents to be administered to human subjects suffering from pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction, for the effective treatment of PH-HFpEF in human subjects.

[0208] According to some embodiments, the present invention also provides a pharmaceutical product comprising a specific amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, intended for use in combination with a cardiovascular agent to effectively treat pulmonary hypertensive heart failure with preserved ejection fraction (PH-HFpEF) in human subjects.

[0209] According to some embodiments, the present invention also provides a subcutaneous formulation of levocimendan for use in the treatment of PH-HFpEF in human subjects suffering from PH-HFpEF, wherein the subcutaneous formulation is obtained from a dry powder, which is obtained from a pharmaceutical composition comprising (a) levocimendan, (b) sulfobutyl ether β-cyclodextrin, (c) sodium hydroxide or acetic acid, and water for injection.

[0210] In some embodiments, the amount of levocimendan is 2.5 mg / ml of water for injection.

[0211] In some embodiments, the amount of sulfobutyl ether β-cyclodextrin is 0.175 mg / ml of water for injection.

[0212] In some embodiments, sodium hydroxide or acetic acid is used in appropriate amounts to adjust the pH to a range of 7.2 to 7.8.

[0213] In some embodiments, the pharmaceutical composition is sterilized by filter sterilization.

[0214] In some embodiments, the pharmaceutical composition is freeze-dried.

[0215] In some embodiments, a subcutaneous formulation of levocimendan is obtained from a dry powder by reconstituting the dry powder in an aqueous solution suitable for subcutaneous administration.

[0216] In some embodiments, the reconstituted subcutaneous formulation is adjusted to a pH of 7.2–7.8 using sodium hydroxide or acetic acid.

[0217] According to several embodiments, the present invention provides a method for treating pulmonary hypertensive heart failure (PH-HFpEF) in a human subject suffering from PH-HFpEF, which comprises administering to the human subject an effective amount of a cardiovascular agent to treat the PH-HFpEF in the human subject, wherein the cardiovascular agent is: PDE inhibitors, phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs), prostanoids, soluble guanylate cyclase stimulants, nitrates, nitrites, NO donors, calcium channel inhibitors. The group consists of harmful agents (CCBs), fatty acid oxidation inhibitors, β-blockers (BBs), angiotensin-converting enzyme (ACE) inhibitors, neprilysin inhibitors, neprilysin and angiotensin receptor blockers (ANRIs), angiotensin II receptor blockers (ARBs), diuretics, aldosterone antagonists, digoxin, ivabradine, hydralazine, ceralaxin, natriuretic peptides, atrial natriuretic peptides (ANPs), natriuretic peptides, K-ATP channel activators, NEP inhibitors, and prostacyclins.

[0218] According to several embodiments, the present invention provides a method for treating pulmonary hypertensive heart failure with preserved ejection fraction (PH-HFpEF) in a human subject suffering from PH-HFpEF, which comprises administering to the human subject an effective amount of a pulmonary vasodilator to treat the PH-HFpEF in the human subject, wherein the pulmonary vasodilator is selected from the group consisting of phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs), and prostacyclins.

[0219] In some embodiments, the above-mentioned amounts of pulmonary vasodilators are administered to human subjects suffering from pre- and post-capillary pulmonary hypertension and heart failure with preserved ejection fraction (Cpc-PH-HFpEF).

[0220] According to several embodiments, the present invention provides cardiovascular agents for use in the treatment of pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in subjects, wherein the cardiovascular agents are selected from the group consisting of: PDE inhibitors, phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs), prostanoids, soluble guanylate cyclase stimulants, nitrates, nitrites, NO donors, calcium channel inhibitors (CCBs), fatty acid oxidation inhibitors, β-blockers (BBs), angiotensin-converting enzyme (ACE) inhibitors, neprilysin inhibitors, neprilysin and angiotensin receptor blockers (ANRIs), angiotensin II receptor blockers (ARBs), diuretics, aldosterone antagonists, digoxin, ivabradine, hydralazine, ceralaxin, natriuretic peptides, atrial natriuretic peptides (ANPs), natriuretic peptides, K-ATP channel activators, NEP inhibitors, and prostacyclins.

[0221] According to several embodiments, the present invention provides a pulmonary vasodilator for use in the treatment of pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in a subject, wherein the pulmonary vasodilator is selected from the group consisting of phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs), and prostacyclins.

[0222] In some embodiments, preserved ejection fraction pulmonary hypertensive heart failure (PH-HFpEF) is pre- and post-capillary pulmonary hypertension and preserved ejection fraction heart failure (Cpc-PH-HFpEF).

[0223] In some embodiments, subjects are orally administered capsules containing up to 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, or 4 mg, more preferably 1 to 3 mg, of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof.

[0224] In some embodiments, the capsule is administered to the subject once a day for a period of 1 to 60 days, preferably 14 days.

[0225] In some embodiments, subjects may increase the number of capsules taken per day after each period if the treatment is tolerable to the subject.

[0226] In some embodiments, subjects are orally administered 0.1 to 10 mg of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, per day, preferably 1 to 4 mg of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, per day.

[0227] In some embodiments, subjects receive a final intravenous injection of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, at least one day, more preferably at least one week, before initiating oral administration of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof.

[0228] Throughout this application, where a parameter range is provided, all integers within that range, as well as, if applicable, one-tenth and one-hundredth thereof, shall be deemed to be provided and disclosed in this application as intended by the present invention. For example, "0.2 to 5 mg / kg / day" should be deemed to be a disclosure up to 5.0 mg / kg / day, including 0.2 mg / kg / day, 0.3 mg / kg / day, 0.4 mg / kg / day, 0.5 mg / kg / day, 0.6 mg / kg / day, etc.

[0229] According to some embodiments, the compound to be administered (e.g., levocimendan) is in the form of a composition (referred to as the composition of the present invention) containing at least one of the compounds in a therapeutically effective dose. As used herein, the term “effective dose” means the amount of a compound that can alleviate and / or reduce the disorder or symptoms described herein. The specific dose of a compound administered according to the present invention will naturally be determined by the specific circumstances surrounding the patient, including, for example, the compound to be administered, the route of administration, the physiological state of the subject, and the severity of the condition to be treated.

[0230] The pharmaceutical product of the present invention or levocimendan can be administered to a subject using any suitable route.

[0231] According to some embodiments, the appropriate route of administration may be a systemic route. According to some embodiments, the administration is systemic. According to some embodiments, the composition is formulated for systemic administration.

[0232] According to another embodiment, systemic administration is via the enteral route. According to yet another embodiment, administration via the enteral route is oral administration. According to some embodiments, the composition is formulated for oral administration.

[0233] In one embodiment, administration is performed intermittently, with weekly doses over a 24-hour period.

[0234] In one embodiment, administration is carried out continuously for less than 24 hours.

[0235] In one embodiment, the dose is a 2.5 mg / mL infusion concentrate of levocimendan containing levocimendan, povidone, citric acid, and ethanol, which is supplied in a total volume of 5 mL added to one 250 mL infusion bag of 5% dextrose, 0.9% saline, or other diluent when the body weight of a human subject is less than 85 kg.

[0236] In one embodiment, the dose is a 2.5 mg / mL infusion concentrate of levocimendan containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 10 mL added to one 500 mL infusion bag of 5% dextrose, 0.9% saline, or other diluent, for a human subject weighing at least 85 kg.

[0237] In one embodiment, the injection rate is 0.075 to 0.10 μg / kg / min over a 24-hour period.

[0238] In one embodiment, the drug is delivered via oral administration. The drug may be in the form of an immediate-release or sustained-release formulation.

[0239] In one embodiment, administration is delivered by inhalation of an inhaled formulation.

[0240] In one embodiment, the administration is carried out via transdermal delivery of a transdermal formulation.

[0241] In one embodiment, the present invention is a product comprising a 5 mL vial dose of a 2.5 mg / mL injection concentrate of levocimendan containing levocimendan, povidone, citric acid, and ethanol; 250 mL of 5% dextrose or 0.9% physiological saline; and a buffer to increase pH.

[0242] In one embodiment, the amount of levocimendan is effective in treating PH-HFpEF in human subjects.

[0243] In one embodiment, the amount of levocimendan used to prepare the pharmacopoeia for administration is effective in treating PH-HFpEF in human subjects.

[0244] In one embodiment, the pharmaceutical product has an amount of levocimendan effective for treating PH-HFpEF in a human subject.

[0245] In one embodiment, the above amount of levocimendan combined with a cardiovascular drug is effective in treating PH-HFpEF in human subjects.

[0246] In one embodiment, the above amount of levocimendan combined with a cardiovascular drug for the purpose of preparing a pharmacopoeia for administration is effective in treating PH-HFpEF in human subjects.

[0247] In one embodiment, the pharmaceutical product contains a specific amount of levocimendan in combination with a cardiovascular drug that is effective in treating PH-HFpEF in human subjects.

[0248] In one embodiment, baseline electrocardiogram monitoring is compared to 72-hour monitoring after 5 weeks of treatment, and no atrial or ventricular arrhythmias are observed.

[0249] In one embodiment, weekly 24-hour administration of levocimendan results in steady-state blood concentrations of OR1896 in the range of 0.20 ng / mL to 25.00 ng / mL.

[0250] Definitions / Abbreviations As used herein, the term “levocymendan” means levocymendan base or a pharmaceutically acceptable salt thereof. The active compounds used in accordance with the present invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e., physiologically) acceptable salts of the compounds of the present invention, and predrug or prodrug forms.

[0251] Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic organic and inorganic acid addition salts such as hydrochloride, hydrobromide, L-tartrate, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconate, ascorbate, benzenesulfonate, benzoate, cinnamate, citrate, emponate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, and toluene-p-sulfonate. Such salts are known in the art and can be formed by the procedures described herein.

[0252] PH is an abbreviation for pulmonary hypertension. PH encompasses a group of heterogeneous disorders that share the common characteristic of increased pulmonary vascular resistance. (Oldroyd et al. 2019)

[0253] HFpEF is an abbreviation for heart failure with preserved ejection fraction. HFpEF refers to a condition where a patient suffers from heart failure while maintaining an ejection fraction of 40% or greater. (Kelly et al. 2015)

[0254] PH-HFpEF is an abbreviation for pulmonary hypertension with preserved ejection fraction. PH-HFpEF is defined by high pulmonary artery pressure, high left ventricular end-diastolic pressure, and normal ejection fraction. (Lai et al. 2019)

[0255] PCWP is an abbreviation for pulmonary capillary wedge pressure. PCWP is a pressure measured by wedge a pulmonary catheter into a small pulmonary artery branch using an inflated balloon. Left atrial pressure can be estimated using PCWP. (Peacock et al. 2004)

[0256] RAP is an abbreviation for right atrial pressure. RAP is the blood pressure in the right atrium of the heart. RAP represents the amount of blood returning to the heart and the heart's ability to pump blood into the arterial system.

[0257] mPAP is an abbreviation for mean pulmonary artery pressure. mPAP is generated by the right ventricle pumping blood into the pulmonary circulation and acts as resistance to the output from the right ventricle.

[0258] PVR is an abbreviation for pulmonary vascular resistance. PVR refers to the resistance within the arteries that supply blood to the lungs. (Schnur 2017)

[0259] CO is an abbreviation for cardiac output. CO is the amount of blood pumped out by the heart per unit time. (Vincent 2008)

[0260] CI is an abbreviation for cardiac index. CI is a hemodynamic parameter that relates the volume of cardiac output from the left ventricle per minute to body surface area. This measurement relates cardiac function to individual size. (Shea 2019)

[0261] HR is an abbreviation for heart rate. HR is the rate of heartbeat, measured by the number of heart contractions per minute. (Heart.org 2015)

[0262] PR is an abbreviation for pulse rate. PR is a measurement of heart rate. (Heart.org 2015)

[0263] BP is an abbreviation for blood pressure. BP is the pressure of circulating blood in the body's major arterial system. (Brezinski 1990)

[0264] 6MWT is an abbreviation for the 6-Minute Walk Test. The 6MWT is a performance-based test used to measure functional motor ability. The 6MWT measures the distance an individual can walk in a total of 6 minutes at a constant and normal pace. (Vandoni et al. 2018)

[0265] The Likert scale is a psychometric scale commonly included in research using questionnaires. In the clinical trial described below, patients were given a six-question, five-point Likert scale to assess their quality of life. (HELP Clinical Trial Protocol)

[0266] ECG is an abbreviation for echocardiogram. An ECG is a record of a person's heartbeat formed by an echocardiogram test. An ECG is a test that uses high-frequency sound waves (ultrasound) to create pictures of the heart. (Heart.org 2015)

[0267] Dobutamine stress test is a form of ECG that induces stress on the heart by administering dobutamine into the vein to evaluate the heart's function and structure. This test mimics the effects of exercise on the heart. (Hawthorne et al.2012)

[0268] The New York Heart Association Functional Classification provides a simple way to classify the degree of heart failure. Patients in Class I have no limitations in physical activity. Patients in Class II have mild limitations in physical activity. Patients in Class III have marked limitations in physical activity. Patients in Class IV cannot continue any physical activity without discomfort. In addition to these classification numbers based on the patient's symptoms, all patients are assigned a classification symbol based on an objective evaluation. Patients in Class A have no objective evidence of cardiovascular disease. Patients in Class B have minimal objective evidence of cardiovascular disease. Patients in Class C have moderate objective evidence of cardiovascular disease. Patients in Class D have severe objective evidence of cardiovascular disease. (Yancy et al.2013)

[0269] Self-administration is the administration of a preparation by a human subject suffering from a disease. (HELP Clinical Trial Protocol)

[0270] An outpatient setting is a setting where patients do not need to be hospitalized for overnight care. (World Health Organization 2009)

[0271] A trained expert refers to a physician, a nurse, a home healthcare nurse, or other persons having training and / or experience and / or licenses of medical practitioners.

[0272] TEAE is an abbreviation for adverse events under the administration of investigational drugs. Particularly notable TEAEs are hypotension, atrial fibrillation, other significant arrhythmias, and resuscitated cerebral stroke. Other TEAEs include, but are not limited to, headache, increased heart rate, fatigue, acute heart failure, dyspnea, vascular access site pain, muscle spasm, and hypokalemia.

[0273] SAE is an abbreviation for serious adverse events. SAE includes, but is not limited to, infections and invasions, device-related infections; infections and invasions, bacteremia; heart disorders, acute heart failure; and heart disorders, acute heart failure.

[0274] As used herein, the term "acute administration" refers to the administration of a drug over a short period, such as the administration of levosimendan, for example, the delivery of a single dose of the drug, the rapid sequential delivery of doses of the drug, or the delivery of the drug on a scale of a short time (preferably less than 48 hours). The acute administration of a drug generally aims to have a beneficial effect of the drug on the condition in the short term. For example, the acute administration of levosimendan can be carried out such that the amount of levosimendan administered precedes any significant activity of levosimendan metabolites and the levosimendan drug aims to directly improve the condition, such as PH-HFpEF. Acute administration is generally carried out by a trained expert, for example, by intravenous administration at the clinical site.

[0275] As used herein, the term “long-term administration” means long-term and repeated administration of a drug, for example, levocimendan. For example, the delivery of multiple or repeated doses of a drug is carried out over a long-term period (preferably at least one week). Long-term administration of a drug is generally intended to have the drug or its metabolites exert a continuous beneficial effect on a particular condition, or to prevent or slow the worsening of a disease condition over time. Long-term administration is often delivered to the subject by the subject (i.e., by self-administration), for example, by oral or subcutaneous administration.

[0276] Subcutaneous administration The present invention also relates to the subcutaneous administration of levocimendan in a subcutaneous formulation to achieve the effects disclosed herein. Due to the potentially irritating, blistering, and extravasation effects of administering inotropes and vasoactive substances such as levocimendan, subcutaneous administration of existing levocimendan formulations has not been validated. Nevertheless, subcutaneous administration may be used when a less invasive delivery route becomes a novel method of administration.

[0277] Despite the potential extravasation concerns associated with subcutaneous administration, the subcutaneous route of levocimendan administration may be better tolerated than intravenous delivery. Subcutaneous administration can suppress and delay the absorption of levocimendan, potentially lowering the peak plasma concentration of levocimendan compared to intravenous administration. This can avoid typical side effects of levocimendan administration, particularly hypotension caused by the maximum concentration (Cmax) of levocimendan, as higher plasma concentrations and Cmax of levocimendan generally lead to a higher frequency of side effects such as hypotension.

[0278] Subcutaneous administration of levocimendan offers a clear advantage in that it eliminates the possibility of central line infection common to long-term IV administration via PICC and port-a-cath devices, which are often required for convenient repeated IV access.

[0279] Despite lower plasma concentrations and delayed absorption of levocimendan, subcutaneous administration of levocimendan surprisingly yields a similar plasma concentration profile for its metabolite, OR-1896. This results in a better safety profile because OR-1896 levels in the blood are comparable without the high peak plasma concentrations of levocimendan.

[0280] Subcutaneous administration offers many practical advantages, including ease of dose adjustment, easier patient management, reliable administration records, reduced nursing burden, and a lower risk of drug diversion.

[0281] One suitable delivery device for subcutaneous administration is a portable infusion pump, such as a CADD pump (an abbreviation for portable continuous delivery pump). Furthermore, subcutaneous administration can be performed via simple pre-filled syringes, syringe pumps, injection pens, autoinjectors, micropumps, or patch devices. (Bittner et al. 2018)

[0282] In this case, the subcutaneous formulation may be substantially similar to the intravenous formulation, but certain additives may be introduced to improve the patient's tolerance to the treatment. The pH of the subcutaneous formulation can be increased by adding buffers, such as water, sodium bicarbonate, or other similar buffers known to increase pH.

[0283] Similar to intravenous administration, levocimendan can be administered subcutaneously, intermittently, or even long-term. Intermittent administration can be done over a 24-hour period each week. In addition to administration by trained professionals, subcutaneous administration makes it much easier for patients to self-administer levocimendan preparations.

[0284] Subcutaneous administration of levocimendan remains viable and may support a wider range of dilutions and corresponding concentrations.

[0285] [Table 2]

[0286] Overall, the data support that subcutaneous administration is simpler than intravenous infusion, can reduce drug delivery-related medical costs and resources, and that a majority of both patients and healthcare providers select subcutaneous administration (Bittner et al. 2018).

[0287] Several methods of subcutaneous administration are known in the art, and any of such methods can be used for the subcutaneous administration of levosimendan. Examples of subcutaneous administration methods include, but are not limited to, manual needle injection, and various subcutaneous drug delivery devices such as subcutaneous delivery systems that deliver a drug via a pump device, such as those performed using certain insulin pump systems, e.g., the Omnipod® system.

[0288] In one embodiment, the subcutaneous formulation contains an amount of water effective to reduce pain caused by administration.

[0289] In one embodiment, the subcutaneous formulation contains a buffering agent that raises the pH above 3.0.

[0290] In one embodiment, subcutaneous administration reduces side effects compared to intravenous administration.

[0291] In one embodiment, subcutaneous administration reduces the peak plasma concentration of levosimendan by at least 1% to 25% compared to intravenous administration.

[0292] Levosimendan formulations described for subcutaneous administration are, for example, described in International Publication No. WO 2020 / 041180 A1 pamphlet (Application No.: PCT / US2019 / 047032), the entire content of which is incorporated herein by reference.

[0293] In some embodiments, a pharmaceutical composition of levocimendan for the treatment of subjects requiring it, for example, specifically for the treatment of heart failure with preserved ejection fraction in human subjects also having pulmonary hypertension (PH-HFpEF patients), administered subcutaneously, comprises: (a) an effective amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof; (b) cyclodextrin or a cyclodextrin derivative; and (c) one or more additional pharmaceutically acceptable excipients in the formulation.

[0294] In one embodiment, the cyclodextrin derivative includes an α-cyclodextrin derivative, a β-cyclodextrin derivative, or a γ-cyclodextrin derivative.

[0295] In one embodiment, the cyclodextrin derivative includes a sodium sulfonate salt.

[0296] In one embodiment, the cyclodextrin derivative includes a butyl ether spacer group, an alkyl ether spacer group, or a combination thereof.

[0297] In one embodiment, the cyclodextrin derivative includes a sulfobutyl ether.

[0298] In one embodiment, the cyclodextrin derivative includes sulfobutyl ether β-cyclodextrin.

[0299] In one embodiment, the amount of cyclodextrin or cyclodextrin derivative is about 50 mg / ml to about 400 mg / ml, preferably about 100 mg / ml to about 300 mg / ml.

[0300] In one embodiment, the formulation has a pH of about 5 to about 9, preferably about 6 to about 8.

[0301] In one embodiment, one or more pharmaceutically acceptable additives include one or more non-citric acid buffers.

[0302] In one embodiment, one or more pharmaceutically acceptable additives include a phosphate buffer.

[0303] In one embodiment, one or more pharmaceutically acceptable additives include one or more pH adjusters.

[0304] In one embodiment, one or more pharmaceutically acceptable additives include one or more preservatives, one or more antioxidants, one or more carriers, or a combination thereof.

[0305] In one embodiment, one or more carriers comprise a liquid medium selected from the group consisting of solutions, suspensions, hydrogels, liposomes, emulsions, and combinations thereof.

[0306] In one embodiment, one or more carriers alter their absorption properties in a manner that extends efficacy and / or minimizes side effects.

[0307] In one embodiment, the amount of levocimendan is about 0.1 mg / ml to about 100 mg / ml, preferably about 0.1 mg / ml to about 30 mg / ml.

[0308] In one embodiment, the formulation is substantially alcohol-free.

[0309] In one embodiment, the formulation does not contain alcohol.

[0310] In one embodiment, the formulation does not contain preservatives.

[0311] In one embodiment, the formulation is in the form of particles.

[0312] In one embodiment, the formulation is freeze-dried.

[0313] In one embodiment, the formulation is spray-dried.

[0314] In one embodiment, the pharmaceutical composition for subcutaneous administration of levocimendan is in the form of a formulation containing: (a) levocimendan in an amount of about 0.1 mg / ml to about 10 mg / ml; (b) cyclodextrin or a cyclodextrin derivative in an amount of about 50 mg / ml to about 500 mg / ml; and (c) phosphate buffer in an amount of about 1 mM to about 20 mM.

[0315] In one embodiment, the formulation has a pH of approximately 6 to approximately 8.

[0316] In one embodiment, the formulation is substantially alcohol-free.

[0317] In one embodiment, the formulation is freeze-dried.

[0318] Furthermore, levocimendan formulations described for intravenous administration may be used for subcutaneous administration. See, for example, U.S. Patent No. 10,507,179 (its entire contents are incorporated by reference).

[0319] In some embodiments, levocimendan formulations suitable for subcutaneous administration include, but are not limited to, pharmaceutical compositions containing levocimendan as an active ingredient and a solubilizer selected from the group consisting of cyclodextrins comprising sulfobutyl ether β-cyclodextrin, α-cyclodextrin, and methyl-β-cyclodextrin and mixtures thereof, fatty acid esters of glycerol, polyethylene derivatives of α-tocopherol, and bile acids, in which case the use of cosolvents such as ethanol, propylene glycol, polyethylene glycol, poloxamer, or polyvinylpyrrolidone is excluded.

[0320] In one embodiment, the solubilizer is D-α-tocopheryl polyethylene glycol 1000 succinate or bile salt, which is preferably selected from the group consisting of sodium glycocholate, sodium taurocholate, sodium taurodeoxycholate, and sodium cholate, or mixtures thereof.

[0321] In one embodiment, the micelles are polymer micelles, preferably polyethylene oxide-poly(propylene oxide)-block copolymer micelles, or mixed micelles consisting of soy phosphatidylcholine / sodium glycocholate or hybrid micelles.

[0322] In one embodiment, the pharmaceutical composition contains levocimendan as an active ingredient and sulfobutyl ether β-cyclodextrin as a solubilizer, in which case the use of cosolvents consisting of ethanol, propylene glycol, polyethylene glycol, poloxamer, or polyvinylpyrrolidone is excluded.

[0323] In one embodiment, sulfobutyl ether β-cyclodextrin is present in an m-molar ratio with respect to levocymendane, preferably in the range of 1 to 15 mmol cyclodextrin: 1 mmol levocymendane. Preferably, the excess cyclodextrin is 4 to 12 mmol cyclodextrin: 1 mmol levocymendane, and more preferably 6 to 10 mmol cyclodextrin: 1 mmol levocymendane.

[0324] In one embodiment, levocimendan exists in a solubilized form.

[0325] In one embodiment, levocimendan is solubilized by micellation or complexation.

[0326] In one embodiment, the pharmaceutical composition is in the form of a solution, and more preferably in the form of an aqueous solution.

[0327] In one embodiment, the amount of the solubilizer is 2 to 45% by weight of the pharmaceutical composition.

[0328] In one embodiment, the pH of the solution is in the range of 7.0 to 8.0, and more preferably in the range of 7.2 to 7.8.

[0329] In one embodiment, the amount of levocimendan is 1 to 15 mg / ml of solution.

[0330] In one embodiment, a dried powder is obtained from a pharmaceutical composition for use as a medicine for the treatment of heart failure with preserved ejection fraction, particularly in human subjects who also have pulmonary hypertension (PH-HFpEF patients). The dried powder is obtained by drying a solution containing solubilized levocymendan and is reconstituted into a solution suitable for subcutaneous administration.

[0331] In one embodiment, the dry powder used is a subcutaneous injection concentrate containing levocimendan in a solution volume of 1 to 15 mg / ml.

[0332] In one embodiment, the concentrate should be adjusted to a pH in the range of 7.2 to 8.0.

[0333] In one embodiment, the solvent used for reconstituting the dried powder is water or an isotonic buffer system.

[0334] In one embodiment, the water has a pH in the range of 7.2 to 7.8, or the isotonic buffer system has a pH in the range of 7.2 to 7.4.

[0335] In one embodiment, the dried powder is obtained by drying a solution containing solubilized levocimendan and a suitable pharmaceutical vehicle used for freeze-drying.

[0336] This disclosure provides a subcutaneous formulation of levocimendan for use in the treatment of PH-HFpEF in human subjects suffering from PH-HFpEF, wherein the subcutaneous formulation is obtained from a dry powder, wherein the dry powder is obtained from a pharmaceutical composition comprising: (a) levocimendan; (b) sulfobutyl ether β-cyclodextrin; (c) sodium hydroxide or acetic acid; and water for injection.

[0337] In one embodiment, the amount of levocimendan is 2.5 mg / ml of water for injection.

[0338] In one embodiment, the amount of sulfobutyl ether β-cyclodextrin is 0.175 mg / ml of water for injection.

[0339] In one embodiment, the amount of sodium hydroxide or acetic acid is appropriate for adjusting the pH to a range of 7.2 to 7.8.

[0340] In one embodiment, the pharmaceutical composition is sterilized by filter sterilization.

[0341] In one embodiment, the pharmaceutical composition is freeze-dried.

[0342] In one embodiment, a subcutaneous formulation of levocimendan is obtained from a dry powder by reconstituting the dry powder with an aqueous solution in an amount suitable for subcutaneous administration.

[0343] In one embodiment, the reconstituted subcutaneous formulation is pH-adjusted to 7.2-7.8 using sodium hydroxide or acetic acid.

[0344] Oral administration The present invention also relates to the oral administration of levocimendan in the form of an oral formulation to achieve the effects disclosed herein. Oral administration offers many practical advantages, including ease of administration and dose adjustment, ease of patient management, and reduced nursing burden.

[0345] According to some embodiments, oral administration may take the form of hard or soft gelatin capsules, pills, capsules, or tablets, including coated tablets, sugar-coated tablets, elixirs, suspensions, liquids, gels, slurries or syrups, and controlled-release forms thereof. Accordingly, the present invention provides a method for administering levocimendan in the form of tablets, capsules, or liquids.

[0346] Suitable carriers for oral administration are known in the art. Compositions for oral use can be prepared using solid excipients, and optionally, the resulting mixture may be pulverized, suitable auxiliary agents may be added as desired, and the granular mixture may be processed to obtain tablets or sugar-coated tablet cores. Non-limiting examples of suitable excipients include fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol, cellulose preparations, and physiologically acceptable polymers such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, and sodium carbomethylcellulose, and / or polyvinylpyrrolidone (PVP).

[0347] If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, may be added. For example, gelatin capsules and cartridges for use in dispensers may be formulated, which contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0348] Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable carrier, such as sucrose, lactose, or starch. Such dosage forms may also, as is common practice, contain additional substances other than inert diluents, such as lubricants. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer. Tablets and pills may be further prepared with enteric coatings. The term “enteric coating,” as used herein, refers to a coating that controls the site of absorption of the composition in the digestive system. Non-limiting examples of materials used for enteric coatings are fatty acids, waxes, plant fibers, or plastics. Liquid dosage forms for oral administration may further contain wetting agents, emulsifiers, and suspending agents, as well as adjuvants such as sweeteners, flavoring agents, and fragrances.

[0349] In one embodiment, the administration is delivered via oral administration, which may be an immediate-release or sustained-release formulation.

[0350] In some embodiments, for the treatment of subjects requiring it, for example, specifically for the treatment of heart failure with preserved ejection fraction in human subjects also having pulmonary hypertension (PH-HFpEF patients), an orally administered pharmaceutical composition of levocimendan is a formulation comprising an effective amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, and one or more other pharmaceutically acceptable excipients.

[0351] In one embodiment, the oral formulation contains levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof in amounts of 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, or 4 mg.

[0352] In one embodiment, the oral formulation contains microcrystalline cellulose.

[0353] In one embodiment, the oral formulation contains alginic acid.

[0354] In one embodiment, the oral formulation contains stearic acid.

[0355] In one embodiment, the oral formulation is in capsule form.

[0356] In one embodiment, the oral formulation is in the form of HPMC capsules.

[0357] In one embodiment, the oral formulation is contained in the form of a capsule and comprises 1 mg of levocimendan, 96.4 mg of microcrystalline cellulose, 30.0 mg of alginic acid, and 5.3 mg of stearic acid.

[0358] In one embodiment, the oral dosage form contains levocimendan in amounts of 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, or 4 mg, more preferably in amounts of 1 to 3 mg.

[0359] In one embodiment, subjects are orally administered capsules containing levocimendan at a dose of 1 mg once daily. Oral administration may be adjusted, for example, according to the efficacy of the treatment, tolerability, changes in heart rate, and the subject's body weight. The dose of levocimendan may be adjusted by increasing the dose by 1 mg increments, in the range of 1 to 10 mg per day, more preferably 1 to 4 mg per day.

[0360] Dose adjustments for levocimendan administration may be made over several days, weeks, or months. The effect of duration at a particular dose on tolerability should also be considered during adjustments; for example, a subject's tolerability of oral levocimendan treatment may increase with increasing duration at a particular dose.

[0361] For example, a subject may begin a course of oral levocimendan therapy at 1 mg / day (i.e., taking one capsule containing 1 mg of levocimendan per day). The subject may maintain a 1 mg / day dose of levocimendan for two weeks. After two weeks, if the levocimendan dose is well tolerated and the heart rate has risen to <15 BPM, the subject may adjust the dose up to 2 mg / day (i.e., taking two capsules each containing 1 mg of levocimendan per day). The subject may continue to adjust the dose in this manner, increasing by 1 mg increments, up to a maximum of 10 mg of levocimendan per day, until an optimal oral dose is achieved.

[0362] Subjects receiving levocimendan via other routes of administration, such as intravenous injection, may switch to an oral administration scheme. For example, subjects receiving levocimendan via intravenous injection may begin oral administration after receiving the last 24-hour infusion of levocimendan. Oral administration of levocimendan may be initiated within a few days or weeks, for example, within one week, from the last 24-hour infusion. The oral dose should be started at 1 mg / day, and then adjusted as described above.

[0363] Combination therapy The administration of two drugs to treat a given condition such as PH-HFpEF raises many potential problems. In vivo interactions between two drugs are complex. The effect of any single drug is related to its absorption, distribution, and elimination. When two drugs are introduced into the body, each drug can affect the absorption, distribution, and elimination of the other, potentially altering the action of the other. For example, one drug may inhibit, activate, or induce the production of enzymes involved in the metabolic pathway of the other drug's elimination (Guidance for Industry, 2006). In one example, the combined administration of GA and interferon (IFN) has been experimentally shown to cancel out the clinical effectiveness of either therapy (Brod 2000). Another study reported that the addition of prednisone to combination therapy with IFN-β weakened its upregulatory effect. Therefore, when two drugs are administered to treat the same condition, it is unpredictable whether each will complement, have no effect on, or interfere with the therapeutic activity of the other in human subjects.

[0364] Interactions between two drugs can not only affect the intended therapeutic activity of each drug, but they can also increase the levels of toxic metabolites (Guidance for Industry, 2006). Interactions can also increase or decrease the side effects of each drug. Therefore, when two drugs are administered to treat a disease, it is unpredictable how the negative side effect profiles of each drug will change. In one example, the combination of natalizumab and interferon β-1a was observed to increase the risk of unexpected side effects (Vollmer, 2008; Rudick, 2006; Kleinschmidt-DeMasters, 2005; Langer-Gould, 2005).

[0365] Furthermore, it is difficult to accurately predict when the effects of drug interactions between two drugs will manifest. For example, metabolic interactions between drugs may become apparent at the time of the first administration of the second drug, after both drugs have reached steady-state concentrations, or upon discontinuation of one of them. (Guidance for Industry, 2006)

[0366] As used herein, “combination” means a collection of reagents for use in treatment by simultaneous, synchronous, or fixed-dose co-delivery. Simultaneous delivery refers to the delivery of a mixture of drugs (whether a true mixture, suspension, emulsion, or other physical combination). In this case, the combination may be a mixture of levocimendan and a second drug combined immediately before delivery, or it may be in separate containers. Synchronous delivery refers to separate deliveries of levocimendan and a second drug simultaneously, or sometimes in close proximity to each other, such that additive or preferably synergistic activity is observed compared to the activity of either levocimendan or the cardiovascular drug alone. Fixed-dose co-delivery refers to the delivery of two or more drugs contained in a single dosage form for oral administration, such as a capsule or tablet.

[0367] As used herein, “second agent” used in combination therapy includes any one of the following: phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs) (e.g., bosentan, ambrisentan), prostanoids (e.g., trepostinil, selexipag, larinepag), soluble guanylate cyclase stimulants (e.g., riociguat), nitrates or nitrites, calcium channel inhibitors (CCBs), fatty acid oxidation inhibitors (e.g., lanolazine, trimetazidine), or beta-blockers (BBs). Angiotensin-converting enzyme (ACE) inhibitors, neprilysin inhibitors (e.g., sacubitril, sanpatrilate, gemopatrilate, facidotril, omapatrilate, candoxatril), neprilysin and angiotensin receptor blockers (ANRIs) (e.g., Entresto), angiotensin II receptor blockers (ARBs), diuretics, aldosterone antagonists, digoxin, ivabradine, hydralazine, ceralaxin, natriuretic peptides, atrial natriuretic peptide (ANP), or nesiritide.

[0368] The recommended dose and schedule for Entresto is 24 / 26 mg twice daily (24 mg of sacubitril and 26 mg of valsartan). The dose should be doubled every 2 to 4 weeks, depending on the patient's tolerance. The compositions detailed above in this specification are described in U.S. Patents No. 7,468,390; No. 8,101,659; No. 8,404,744; No. 8,796,331; No. 8,877,938; and No. 9,388,134, the full contents of which are incorporated by reference.

[0369] The recommended dose and schedule for sacubitril is 24 mg twice daily. The dose should be doubled every 2 to 4 weeks, depending on the patient's tolerance.

[0370] The recommended dose and schedule for lanorazine is 500 mg twice daily. The dose may be increased up to 1000 mg twice daily as needed, based on clinical symptoms. The compositions detailed above in this specification are described in U.S. Patent Nos. 6,303,607; 6,369,062; 6,479,496; 6,503,911; 6,525,057; 6,562,826; 6,617,328; 6,620,814; 6,852,724; and 6,864,258, the full contents of which are incorporated by reference.

[0371] The recommended dose and schedule for bosentan is 62.5 mg twice daily for patients aged >12 years. After 4 weeks, if the patient's weight exceeds 40 kg, the dose should be increased to 125 mg twice daily; if the patient's weight is less than 40 kg, the dose should remain unchanged. The compositions detailed above in this specification are described in full in U.S. Patent Nos. 7,959,945 and 8,309,126, which are incorporated by reference.

[0372] The recommended dose and schedule for ambrisentan is 5 mg orally once daily. If the patient tolerates 5 mg well, the dose may be increased up to 10 mg orally once daily. The compositions detailed above in this specification are described in U.S. Patent No. 8,377,933; No. 9,474,752; and No. 9,549,926, the full contents of which are incorporated by reference.

[0373] The recommended dose and schedule for trepostinil is 0.25 mg orally every 12 hours or 0.125 mg every 8 hours in the case of oral sustained-release tablets; in the case of inhalation, three breaths (18 mcg) per treatment session four times a day, or reduced to one or two breaths if poorly tolerated, and then increased to three breaths if well tolerated; or in patients receiving prostacyclin infusion therapy for the first time, if a higher dose is untolerable, 1.25 ng / kg / min or 0.625 ng / kg / min by continuous subcutaneous or IV infusion. The compositions described in detail above in this specification are described in U.S. Patent Nos. 10,076,505; 7,999,007; 8,653,137; 8,658,694; 9,199,908; 9,593,066; 9,604,901; and 9,713,599, the entire contents of which are incorporated by reference.

[0374] The recommended dose and schedule for selexipag is 200 mcg orally twice daily. The dose may be increased by 200 mcg orally twice daily every other week up to the maximum tolerated dose, but should not exceed 1600 mcg orally twice daily. The compositions detailed above in this specification are described in U.S. Patents No. 7,205,302; No. 8,791,122; No. 9,173,881; and No. 9,284,280, the full contents of which are incorporated by reference.

[0375] The recommended dose and schedule for ralinepag is 10 μg to 300 μg twice daily. The composition detailed above in this specification is described in "Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial" (Torres et al. 2019), the full contents of which are incorporated by reference.

[0376] The recommended dose and schedule for riociguat is 1 mg orally three times daily. This dose may be increased if well tolerated, but should not exceed 2.5 mg orally three times daily. The compositions detailed above in this specification are described in full in U.S. Patent Nos. 6,743,798 and 7,173,037, which are incorporated by reference.

[0377] The recommended dose and schedule for trimetazidine is 60 mg / day to 140 mg / day. The compositions detailed above in this specification are described in *Defining the Role of Trimetazidine in the Treatment of Cardiovascular Disorders: Some Insights on Its Role in Heart Failure and Peripheral Artery Disease* (Chrusciel et al. 2014), the full contents of which are incorporated by reference.

[0378] The recommended dose and schedule for Sampatrilat is 50 mg to 100 mg daily. The composition detailed above in this specification is described in *Sustained Antihypertensive Actions of a Dual Angiotensin-Converting Enzyme Neutral Endopeptidase Inhibitor, Sampatrilat, in Black Hypertensive Subjects* (Norton et al. 1999), the full contents of which are incorporated by reference.

[0379] Gemopatrilat is described in Metabolism Of[14c]Gemopatrilat After Oral Administration To Rats, Dogs, And Humans (Wait et al. 2006), and its entirety is incorporated by reference.

[0380] The recommended dose and schedule for fasidotril is 100 mg twice daily. The composition detailed above in this specification is described in "Antihypertensive effects of fasidotril, a dual inhibitor of neprilysin and angiotensin-converting enzyme, in rats and humans" (Laurent et al. 2000), the entire contents of which are incorporated by reference.

[0381] The recommended dose and schedule for omapatrilat is 10 mg to 80 mg daily. The composition detailed above in this specification is described in "Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial" (Kostis et al. 2004), and its entire contents are incorporated by reference.

[0382] The recommended dose and schedule for candoxatril is 200 mg to 400 mg twice daily. The composition detailed above in this specification is described in "Comparison of the short-term effects of candoxatril, an orally active neutral endopeptidase inhibitor, and frusemide in the treatment of patients with chronic heart failure" (Northridge et al. 1999), the full contents of which are incorporated by reference.

[0383] The recommended dose and schedule for digoxin is a total loading dose of 8–12 mcg / kg via intravenous administration, increasing to 0.1–0.4 mg / day for maintenance regimens. For oral administration, the dose and schedule is a total loading dose of 10–15 mcg / kg, increasing to 3.4–5.1 mcg / kg / day. Another administration option is 0.125–0.25 mg per day, orally or intravenously, with higher doses of 0.375–0.5 mg / day rarely required. The compositions detailed above in this specification are described in *Digoxin: A systematic review in atrial fibrillation, congestion heart failure and post myocardial infarction* (Virgadamo et al. 2015), the full contents of which are incorporated by reference.

[0384] The recommended dose and schedule for ivabradine is 5 mg orally twice daily with meals. This dose may be increased if well tolerated, but should not exceed 7.5 mg orally twice daily. The compositions detailed above in this specification are described in U.S. Patent Nos. 7,361,649; 7,361,650; 7,867,996; and 7,879,842, the full contents of which are incorporated by reference.

[0385] The recommended dose and schedule for hydrarazine is 10 mg orally four times daily for the first two to four days, increasing to 25 mg orally four times daily for equilibrium during the first week. This dose is increased to 50 mg orally four times daily in weeks two and beyond. The compositions detailed above in this specification are described in full in U.S. Patent Nos. 6,465,463 and 6,784,177, which are incorporated by reference.

[0386] The recommended dose and schedule for serelaxin is 30 μg / kg / day, administered intravenously three times over 48 hours. The composition detailed above in this specification is described in RELAX-REPEAT: A Multicenter, Prospective, Randomized, Double-Blind Study Evaluating the Safety and Tolerability of Repeat Doses of Serelaxin in Patients with Chronic Heart Failure (Teerlink et al. 2016), the full contents of which are incorporated by reference.

[0387] The recommended dose and schedule for nesiritide is a 2 mcg / kg IV bolus followed by a continuous IV infusion of 0.01 mcg / kg / min; however, the frequency should not be increased to more than every 3 hours, up to a maximum of 0.03 mcg / kg / min. The compositions detailed above in this specification are described in U.S. Patent No. 5,114,923, the full contents of which are incorporated by reference.

[0388] A subset of second drugs that have beneficial effects in combination therapy with levocimendan includes: K-ATP channel activators (e.g., pinacidil, diazoxide, bimalim, levochromacim, chromacim, limalim, and nicorandil); nitrates (e.g., nitroglycerin-NTG, isosorbide dinitrate); nitrites (e.g., sodium nitrite, amyl nitrite); NO donors (sodium nitroprusside, nitric oxide, molcidomin, lincidomin); PDE These include inhibitors (e.g., milrinone, pimobendan, enoximon); natriuretic peptides (e.g., BNP (e.g., nesiritide), ANP (e.g., carparetide and uraritide), CDNP (e.g., senderitide), and others (e.g., CNP, DNP, manp, etc.); NEP inhibitors (e.g., sacubitril, sampatril / simpatril, facidotril, omapatril / omapatril, candoxatril, etc.); and ARNIs (Entresto). Furthermore, combination therapy with levocimendan may include any of the second drugs listed above, diuretics, or both.

[0389] Furthermore, it should be noted that the composite of pre- and post-capillary pulmonary hypertension and preserved ejection fraction heart failure (Cpc-PH-HFpEF) is a small and specific phenotype in certain PH-HFpEF patients. These patients may benefit from drugs that reduce pulmonary vascular resistance (Opitz 2016). The HELP trial found that levocimendan does not reduce pulmonary vascular resistance, especially with long-term administration. Therefore, Cpc-PH-HFpEF patients may benefit from combination therapy including levocimendan and drugs that reduce pulmonary vascular resistance. Therefore, combination therapy with levocimendan and, but not limited to, phosphodiesterase-5 inhibitors (PDE-5 inhibitors, e.g., sildenafil, tadalafil); endothelin receptor antagonists (ERAs, e.g., bosentan, ambrisentan); and pulmonary vasodilators including prostacyclins (e.g., epoprostenol, iloprost, treprostinil) may provide therapeutic benefits to patients with Cpc-PH-HFpEF.

[0390] Each drug may be administered in the doses and regimens disclosed in the aforementioned drug literature.

[0391] The embodiments described above illustrate several drugs that are substantially effective in the body simultaneously. Some drugs may be administered substantially simultaneously or at different times, but they will affect the body at the same time. For example, this includes administering levocimendan before or after the substantial function of levocimendan in the body, or during that time.

[0392] Therefore, the current state of the technology at the time of filing is that the efficacy of combination therapy with two drugs, particularly levocimendan and the second drug, cannot be predicted until the results of combination studies become available.

[0393] Each embodiment disclosed herein is intended to be applicable to each of the other disclosed embodiments. Accordingly, all combinations of the various elements described herein are within the scope of the present invention.

[0394] The following embodiments are provided to better illustrate some of the embodiments of the present invention. However, they should not be construed as limiting the broad scope of the invention. [Examples]

[0395] Examples are provided below to facilitate a more complete understanding of the present invention. These examples illustrate exemplary forms for constructing and carrying out the present invention. However, the scope of the present invention is not limited to the specific embodiments disclosed in these examples, but is for illustrative purposes only. (HELP Study - Hemodynamic Evaluation of Levosimendan in PH-HFpEF)

[0396] Example 1 overview A multicenter, phase II, double-blind, randomized, placebo-controlled trial of intermittent levocimendan will be conducted in pulmonary hypertension with heart failure and preserved left ventricular ejection fraction (PH-HFpEF) patients to evaluate the efficacy and safety of intermittent levocimendan compared to placebo in improving hemodynamics through exercise.

[0397] intervention Drug: Levocimendan The subjects were administered levocimendan as follows: a sterile levocimendan 2.5 mg / mL concentrated solution diluted with 250-500 mL of 5% dextrose or 0.9% saline to achieve a 50 microgram / mL solution for injection.

[0398] Subjects will be administered a matching placebo as follows: a sterile placebo 2.5 mg / mL concentrated solution diluted with 250-500 mL of 5% dextrose or 0.9% saline to achieve a 50 microgram / mL solution for infusion.

[0399] Test arm Experiment: Levocimendan 2.5 mg / mL injection solution a. 0.075~0.1 μg / kg / min, 24 hours (weekly) b. Intervention: Drug: Levocimendan

[0400] Experiment: Matched Placebo a. 0.075~0.1 μg / kg / min, 24 hours (weekly) b. Intervention: Drug: Levocimendan

[0401] Estimated number of registered users 36 subjects

[0402] Participation criteria Male or female, aged 18 or older.

[0403] Definitive diagnosis of WHO Group 2 pulmonary hypertension (PH) with heart failure and preserved ejection fraction (HFpEF).

[0404] Subjects with WHO Group 2 pulmonary hypertension with heart failure and retained ejection fraction as defined below: a. Mean pulmonary artery pressure (mPAP) ≥ 35 mmHg at rest or with legs elevated (at baseline right cardiac catheterization / lead-in) b. Pulmonary capillary wedge pressure (PCWP) ≥ 20 mmHg at rest or with legs elevated (at baseline right cardiac catheterization / lead-in) c. NYHA Classification II or III d. There was no change in clinical status, and the LVEF ≥ 40% on echocardiography within 3 months of registration suggests a possible decline in systolic function.

[0405] An informed consent document signed by the subject or their legal representative, etc., indicating that the subject understands the purpose of the study and the procedures required for the study, and is willing to participate in the study.

[0406] The ability to walk at least 50 meters in a 6-minute walk test, but no more than 550 meters.

[0407] Long-term oxygen therapy (if applicable) must be stable for 30 days prior to registration.

[0408] Subjects receiving long-term medication or treatment for an underlying heart condition must have continued taking it for ≥30 days prior to randomization, with the exception of diuretics and antihypertensive drugs for blood pressure control, which may be discontinued if deemed appropriate.

[0409] Participants receiving long-term medication for an underlying respiratory condition must have been taking the medication continuously for ≥30 days prior to randomization.

[0410] Randomization criteria Response to lead-in levocimendan: Patients showing a ≥4 mmHg decrease in PCWP from baseline and a ≤10% decrease from baseline cardiac index, as measured during cycling exercise (25 watts), after 24-hour infusion of levocimendan.

[0411] Exclusion criteria Medical history of PCI or cardiac surgery (CABG) within the past 12 months, unless evidence of a negative stress test is attached.

[0412] Clinically symptomatic mitral valve or aortic valve disease.

[0413] 4.0 L / min / m 2 A cardiac coefficient exceeding this level.

[0414] In the opinion of the principal investigator, the subjects have a primary diagnosis of PH other than WHO Group 2 PH-HFpEF.

[0415] Congenital heart defects other than anterior and posterior tricuspid shunts that have been surgically corrected for at least 10 years.

[0416] Symptomatic coronary artery disease based on positive stress test results.

[0417] Patients who are scheduled for a lung or heart transplant, or heart surgery, within the next four months.

[0418] Patients diagnosed with clinically significant pulmonary hypertension associated with lung disease at the time of initial diagnosis, or patients with congenital lung defects. a. Clinically significant obstructive pulmonary disease is defined as FEV1 / FVC < 60% of prediction, unless high-resolution chest CT scans show emphysematous changes in areas of mild or less. b. Clinically significant restrictive lung disease is defined as FVC < 60% of prediction, unless a high-resolution chest CT scan shows interstitial lung disease or pulmonary fibrosis in a mild or lesser area.

[0419] Dialysis at randomization (hemodialysis, peritoneal dialysis, continuous venous-venous hemofiltration, or ultrafiltration).

[0420] Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m² 2 .

[0421] Child-Pugh Class B or C liver dysfunction.

[0422] Evidence of systemic bacterial, systemic fungal, or viral infection in the past two weeks.

[0423] Weight > 150kg.

[0424] Symptomatic low systolic blood pressure (SBP) that cannot be controlled to ensure SBP ≥ 100 mmHg at the start of the investigational drug treatment.

[0425] In the lead-in phase, the patient was administered the investigational drug for at least 10 minutes, exhibiting symptomatic and persistent heart rate ≥ 100 bpm.

[0426] Hemoglobin <80g / L.

[0427] Serum potassium <3.0 mmol / L or >5.5 mmol / L at baseline.

[0428] I am pregnant, suspect I am pregnant, or breastfeeding.

[0429] Known allergic reactions or susceptibility to levocimendan or its excipients.

[0430] Medical history of Torsades de Pointes.

[0431] I received levocimendan within 30 days prior to the scheduled start of the investigational drug trial.

[0432] You received the experimental drug or used the experimental medical device within 30 days prior to the scheduled start date of administration of the investigational drug.

[0433] Concomitant administration of pulmonary vasodilator therapy, or administration within 14 days of randomization.

[0434] Principal investigators or employees of the research site who are directly involved in the proposed trial or other trial under the direction of the principal investigator or research site, as well as family members of such employees or principal investigators.

[0435] Anyone who is unable to follow the planned testing procedures.

[0436] Exam Description (HELP Exam) This is a multicenter, phase II, double-blind, randomized, placebo-controlled trial of levocimendan in pulmonary hypertension patients with PH-HFpEF, designed to evaluate the efficacy and safety of intermittent levocimendan compared to placebo for exercise-induced hemodynamic improvement in subjects with heart failure and preserved left ventricular ejection fraction (PH-HFpEF).

[0437] Enrolled PH-HFpEF subjects will receive a lead-in 24-hour levocimendan infusion to determine their hemodynamic response and eligibility for the double-blind phase of the study. A total of 36 "responders" will be randomized to a double-blind, placebo-controlled phase. "Responders" will be identified as subjects with a ≥4 mmHg decrease in PCWP during cycling exercise (25 watts) and a ≤10% decrease in cardiac index between baseline and repeated measurements after the first infusion.

[0438] The investigational drug will be administered via IV infusion over 24 hours weekly through a PICC line until week 5. Infusions (weeks 2-5) will be administered at the subject's home by a clinical trial nurse. Patients will return to the study site for visits between infusions in weeks 3 and 4 to assess the subject's safety / response and any need for dose adjustments. Each subject is scheduled for a follow-up visit in week 6 to assess the efficacy and safety of the investigational drug. A right cardiac catheter will be inserted to obtain hemodynamic measurements at baseline (at rest and during exercise), the day after the lead-in 24-hour infusion, and in week 6.

[0439] In the lead-in phase of this trial, a sufficient number of subjects will be enrolled and administered levocimendan to identify a total of 36 "responders." The levocimendan "responders" will be randomized 1:1 to receive either levocimendan or placebo for the double-blind phase of the trial.

[0440] In the lead-in phase, levocimendan supplied as a concentrated solution (2.5 mg / mL) is mixed with a diluent and administered intravenously at a rate of 0.10 μg / kg / min over 24 hours + / - 30 minutes.

[0441] In the double-blind phase, the investigational drug concentrate (2.5 mg / mL), i.e., levocimendan or placebo, is mixed with a diluent and administered weekly via PICC line at a rate of 0.075 μg / kg / min over 24 hours. Patients receive dose escalations in weeks 4 and 5 (0.10 μg / kg / min over 24 hours), unless there is a significant change in blood pressure or heart rate. The infusion rate may be reduced to 0.05 μg / kg / min if higher doses are not well tolerated at any point during the first five weeks.

[0442] This trial is divided into a screening phase, a lead-in phase, and a double-blind treatment phase. The screening, lead-in, intermediate clinic visit (between weeks 3 and 4), and week 6 visit will be conducted in the principal investigator's clinic. The infusions in weeks 2, 3, 4, and 5 will be administered at the subject's home under the supervision of a home healthcare nurse. Subjects are instructed to contact the principal investigator at any time during the 24-hour infusion at home to report adverse events, or at any time throughout the entire trial period if they wish to speak with the principal investigator about the trial or report an adverse event.

[0443] During the lead-in phase of the trial, visits require subjects to be hospitalized for the entire infusion period, with the infusion lasting at least 24 hours. Once the infusion is complete, hemodynamic measurements are collected to verify the subject's eligibility. The number of visits from week 2 to week 6 is calculated based on the date of the lead-in infusion.

[0444] At least 72 hours before the first infusion (lead-in visit), all patients will wear a small, lightweight cardiac monitoring sensor on their chest to measure their heart rate and detect arrhythmias. This patch is water-resistant and can be worn even while showering. The patch will be removed before the first infusion of the investigational drug. Furthermore, the following steps will be performed: obtaining a signed Main Study ICF (which must be obtained before any trial-specific tests or evaluations not considered standard care are performed), participation / exclusion criteria, confirmation of eligible hemodynamic history, medical history, weight management, records of past / contemporary medications including all prescription and non-prescription medications, vitamins, and nutritional supplements or herbal supplements, records of demographic information, height and weight, urine pregnancy test (only for women of childbearing potential), complete physical examination including hematological and clinical chemistry blood samples, measurement of vital signs (BP, PR, respiratory rate, temperature), Child-Pugh classification, NYHA functional classification, 12-lead electrocardiogram (ECG), echocardiogram (from day 0 to within 3 months) (which must be repeated before baseline), and 6-minute walk test.

[0445] During lead-in infusion (Day 0), the following steps are performed: measurement of vital signs (BP, PR, respiratory rate, temperature), placement of a venous sheath for right heart catheterization (the sheath remains in place after baseline testing, the patient is admitted to the hospital and receives 24-hour levocimendan infusion there (preferably via the venous sheath); then right heart catheterization examination and right heart catheterization measurement after 24-hour levocimendan infusion: the sheath is used for access at baseline (before levocimendan infusion) and after 24-hour infusion (and is then removed), at rest. The study will confirm eligible baseline hemodynamics during exercise, confirm eligible response to levocimendan during exercise, assess adverse events, evaluate concomitant medications and / or procedures, pharmacokinetic sampling (taken at the end of infusion: 24+ / -2 hours), and genotyping sampling (taken at the end of infusion: 24+ / -2 hours). Subjects who do not respond to levocimendan based on hemodynamic measurements will be excluded from screening. PICC lines will be placed in patients who meet the eligibility criteria and are randomized to the double-blind phase of the study.

[0446] Once eligibility is confirmed by hemodynamic measurements after lead-in injection, subjects will be randomized in a 1:1 ratio to receive either levocimendan or placebo. This will be done during the same visit as the lead-in injection day (Day 0).

[0447] Visits in weeks 2, 3, 4, and 5 will be conducted within + / - 48 hours of the scheduled visit. Visits in weeks 2 through 5 will be calculated based on the date of the lead-in infusion. These visits will be conducted at the subject's home with the assistance of a home healthcare nurse. The home healthcare nurse will stay with the patient for the first 2-3 hours of the infusion to ensure patient safety. The home healthcare nurse will visit the patient again 24 hours later to stop the infusion and assess the patient's condition. During this visit, the following procedures will be performed: recording of procedures, prescription and non-prescription medications, vitamins, and nutritional supplements or herbal supplements; measurement of vital signs before infusion commencement, after the first 2 hours (+ / - 30 minutes), and after 24 hours (+ / - 30 minutes); assessment of adverse events, and administration of the investigational drug. In week 5, all patients will be given a new cardiac monitoring sensor to be worn on the chest to measure heart rhythm, as performed during screening. The patch was applied (<1 hour) before the 24-hour infusion, and patients were monitored for a minimum of 72 hours before being returned to the clinical trial site at the week 6 visit.

[0448] An interim clinic visit takes place 48 hours before the week 4 infusion visit. This visit takes place in the principal investigator's clinic. Infusions are administered in the clinic during these visits. During these visits, the following procedures are performed: 6-minute walk test, quality of life (QOL) assessment, NYHA functional classification determination, weight measurement, placement of cardiac monitoring patch, and all procedures listed for the weekly infusion visits, excluding the infusion itself.

[0449] The week 6 visit should take place 3–6 days after the completion of the week 5 infusion. During this visit, the following procedures should be performed: recording of changes in procedures, prescription and non-prescription medications, vitamins, and nutritional or herbal supplements; measurement of vital signs (BP, PR, respiratory rate, temperature); hematological and clinical chemistry blood samples; 12-lead electrocardiogram (ECG); echocardiogram within + / - 72 hours of the week 6 visit; resting and exercised right heart catheterization; quality of life assessment; implementation of Childe-Pugh classification and NYHA functional classification; assessment of adverse events and 6-minute walk test; and sampling for pharmacokinetic observation (samples to be taken before enrollment in the open-label phase).

[0450] The 6-minute walk test (6MWT) should be administered at approximately the same time during each trial visit after the baseline visit and, ideally, should be one of the first assessments performed. The ECHO and subject questionnaire should be administered after the 6MWT is completed. The 6MWT should be performed using the method described in the American Thoracic Society (ATS) Statement: Guidelines for the 6-minute walk test. The test should be administered at approximately the same time on the day of evaluation and, whenever possible, by the same evaluator.

[0451] Two-dimensional (2D) echocardiograms with contrast are performed by trained personnel. These assessments are performed using standard transthoracic 2D echocardiograms (with contrast to optimize the accuracy and precision of intracardiac measurements). These may include, but are not limited to, the following: left ventricular systolic and diastolic function, size, mass, and shape geometry; right ventricle size and function; pulmonary artery size; left atrial diameter, volume, and pressure; valvular (aortic, mitral, tricuspid, and pulmonary) stenosis and regurgitation (severity); and pulmonary artery systolic pressure (PASP) and inferior vena cava (IVC) diameter.

[0452] Vital signs and body weight include: body temperature, heart rate, respiratory rate, and blood pressure (systolic and diastolic). Blood pressure will be determined by cuff (using the same method, arm, and position throughout the examination).

[0453] All blood clinical test samples must be collected prior to administration of the investigational drug (unless other exclusions apply). Blood samples and blood biochemistry tests will be collected, and results will be obtained by the local laboratory, with the exception of pharmacokinetic and genotyping samples. These samples will be sent to an external laboratory for analysis of levosimendan, OR-1855, and OR-1896 metabolites. All clinical laboratory assays will be performed according to the laboratory's standard procedures. Reference ranges will be provided by the laboratory and used to evaluate laboratory data for clinical significance and out-of-range pathological changes.

[0454] The hematology and coagulation panel includes hematocrit, hemoglobin, white blood cell (WBC) count with leukocyte classification, platelet count, prothrombin time, and partial thromboplastin time.

[0455] The blood biochemistry panel includes tests for sodium, potassium, bicarbonate, blood urea nitrogen (BUN), and creatinine.

[0456] result Primary and secondary outcome measures from the open-label lead-in phase of the HELP trial - initial 30 randomized patients (approximately 83% of planned enrollment) Treatment with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min resulted in an average reduction of 5.8 mmHg (from 23.4 to 17.6 mmHg) in resting pulmonary capillary wedge pressure and an average reduction of 7.53 mmHg (from 33.2 to 25.7 mmHg) during 25-watt exercise. These results are shown in Figure 1.

[0457] [Table 3]

[0458] Treatment with weekly 24-hour infusion of levocimendan at a rate of 0.075–0.1 μg / kg / min resulted in an average reduction of 4.83 mmHg (from 16.2 to 11.3 mmHg) in resting right atrial pressure and an average reduction of 4.97 mmHg (from 27.9 to 23.0 mmHg) during 25-watt exercise. These results are shown in Figure 2.

[0459] [Table 4]

[0460] Treatment with weekly 24-hour infusions of levocimendan at a rate of 0.075–0.1 μg / kg / min resulted in an average reduction of 5.4 mmHg (from 42.4 to 37.0 mmHg) in mean pulmonary artery pressure at rest, and an average reduction of 5.1 mmHg (from 58.3 to 53.3 mmHg) during 25-watt exercise. These results are shown in Figure 3.

[0461] [Table 5]

[0462] Treatment with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min increased resting cardiac output by an average of 0.33 l / min (from 5.1 to 5.5 l / min) and during 25-watt exercise by an average of 0.60 l / min (from 6.7 to 7.4 l / min). These results are shown in Figure 4.

[0463] [Table 6]

[0464] Exploratory outcome scale The hemodynamic response (decrease in PCWP) to treatment with weekly 24-hour infusions of levocimendan at 0.075–0.1 μg / kg / min in subjects suffering from PH-HFpEF can be predicted by the change in stroke volume observed between resting and exercise.

[0465] When subjects with PH-HFpEF were treated with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min, pulmonary capillary wedge pressure was significantly reduced compared to subjects with PH-HFpEF treated with placebo.

[0466] When subjects with PH-HFpEF were treated with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min, right atrial pressure was significantly reduced compared to subjects with PH-HFpEF treated with placebo.

[0467] When subjects with PH-HFpEF were treated with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min, their mean pulmonary artery pressure was significantly reduced compared to subjects with PH-HFpEF treated with placebo.

[0468] Treatment of subjects with PH-HFpEF with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min resulted in a significantly greater increase in cardiac output compared to subjects with PH-HFpEF treated with placebo.

[0469] When subjects with PH-HFpEF were treated with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min, their 6-minute walk test distance was significantly increased compared to subjects with PH-HFpEF treated with placebo.

[0470] When subjects with PH-HFpEF were treated with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min, the proportion of subjects with improved well-being was significantly higher compared to subjects with PH-HFpEF treated with placebo.

[0471] Example 2 overview If the patient tolerates the treatment in the HELP clinical trial shown in Example 1 well, an open-label rollover trial will be conducted to allow the patient to continue levosimendan treatment.

[0472] Participation criteria The double-blind therapy in the PH-HFpEF clinical trial, sponsored by Tenax Therapeutics, Inc., has been completed.

[0473] The principal investigator believes that continuing levocimendan treatment will be beneficial.

[0474] Female patients who may become pregnant must agree to use a highly effective method of contraception.

[0475] The willingness and ability to adhere to scheduled visits, treatment plans, clinical tests, and other testing procedures.

[0476] Exclusion criteria The action in the parent trial was discontinued for reasons other than completion of the trial or suspension of the trial by the sponsor.

[0477] Pregnant or breastfeeding women.

[0478] Obtaining commercially available Revosimendan locally.

[0479] The planned test procedures could not be followed.

[0480] Patients scheduled for lung or heart transplantation or heart surgery.

[0481] Dialysis initiated after enrollment in the parent study (hemodialysis, peritoneal dialysis, continuous venous-venous hemofiltration, or ultrafiltration).

[0482] Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 2 .

[0483] Child-Pugh class B or C liver failure.

[0484] Evidence of treatment-refractory systemic bacterial, systemic fungal, or viral infection.

[0485] Weight>150kg.

[0486] It is not possible to control systolic blood pressure (SBP) to ensure that SBP ≥ 100 mmHg at the start of clinical trial treatment.

[0487] Heart rate ≥ 100 bpm due to the investigational drug, sustained for at least 10 minutes at the time of screening.

[0488] Hemoglobin <80g / L.

[0489] Baseline serum potassium levels are <3.0 mmol / L or >5.5 mmol / L, and the patient is unresponsive to management.

[0490] Exam Description This is an open-label rollover study to allow patients to continue levosimendan treatment if they tolerate the treatment well in the HELP clinical trial shown in Example 1.

[0491] Participants will receive visits from a home healthcare nurse until they can fully demonstrate their ability to self-administer the investigational drug, with the goal of self-administration between weeks 4 and 6, but these visits will not continue after week 8. Home healthcare support will end after week 8. Home healthcare visits may be scheduled during or after the trial if the principal investigator indicates a clinically urgent need. Participants will be instructed by the home healthcare nurse on the preparation, administration, and disposal / return of levocimendan (including any accessories). The process of distributing the investigational drug to the participants' homes will be the same throughout the trial.

[0492] The investigational drug concentrate (2.5 mg / mL), i.e., levocimendan, is mixed with a diluent and administered weekly as a 24-hour infusion at a rate of 0.075 μg / kg / min. Patients may undergo dose escalation at a rate of 0.10 μg / kg / min over 24 hours in the third week, unless there is a significant change in blood pressure or heart rate or other extraordinary grounds.

[0493] If a subject is tapered to 0.05 μg / kg / min in either the lead-in or double-blind portion of the HELP study, the subject will start at this dose and will have the first opportunity to escalate the dose at week 3 of this open-label extension study.

[0494] If open-label levocimendan is well tolerated by patients in week 3, the principal investigator will consider the opportunity to convert the PICC line to a port-a-cass in the following weeks. Some patients may choose to continue using the PICC line or have a port-a-cass inserted later during the study period. After port-a-cass placement, a home healthcare nurse will visit the patient to assist with infusion to ensure the patient is able to use the port-a-cass independently. Patients who choose to continue using the PICC line after week 3 will either transition to a port-a-cass or discontinue the study if the PICC line fails.

[0495] During the final visit to the parent study, the principal investigator (or appropriate representative for the study site) obtains written informed consent from each patient, followed by a review of eligibility criteria. During the screening visit, the following steps are taken: obtaining a signed Main Study ICF (which must be obtained before any trial-specific tests or evaluations not considered standard care are performed), reviewing inclusion / exclusion criteria, confirming all prescription and non-prescription medications, vitamins, and concomitant medications including dietary supplements or herbal supplements, and conducting a complete physical examination including height and weight; and transferring information documented in the parent study to the current study's eCRF for subsequent procedures.

[0496] Weekly visits are conducted approximately every seven days, within 48 hours of the scheduled visit. The first infusion of this extension study is typically scheduled one week after the final dose (week 5) of the HELP trial. Because some patients will be receiving the active investigational drug (levocimendan) for the first time (i.e., they received a placebo in the HELP trial), subjects will receive visits from home healthcare nurses for eight weeks from the start of the open-label extension study to ensure safety and tolerability.

[0497] Participants will receive visits from a home healthcare nurse until they have fully demonstrated their ability to self-administer the investigational drug, with the goal of self-administration 4–6 weeks after the start of the study. Home healthcare support will end after 8 weeks. Home healthcare visits may be scheduled later during the study period if the principal investigator clearly indicates a clinically urgent need. Once a participant has fully demonstrated their ability to self-administer the investigational drug, the following procedures will no longer apply, except for reporting any adverse events to the study site. These visits may be conducted at the participant's home. Participants will be instructed to notify the principal investigator of any infusion-related events or AEs that occur during these visits. During these visits, the following procedures will be performed (if applicable): procedures, recording of any changes in prescription and non-prescription medications, vitamins, and dietary supplements or herbal supplements; measurement of vital signs; assessment of adverse events; and administration and accountability of the investigational drug.

[0498] During the third week's clinic visit, the patient will be evaluated for potential dose escalation adjustments up to 1.0 μg / kg / min over a 24-hour period. The decision to increase the dose is based on the absence of disease or drug-related adverse events and the judgment of the principal investigator.

[0499] The visits in weeks 3, 6, 12, 24, and 48, as well as the final follow-up visit, will take place within 72 hours of the scheduled weekly visit. These visits will be conducted in the principal investigator's office. The final follow-up visit will be calculated as early as two years from the date the subject joined this extension study, or as soon as possible after discontinuation of the study, but within one week. During this visit, the following procedures will be performed: vital signs; weight (week 3 only); 6MWT; quality of life assessment; NYHA functional classification; physician assessment; adverse events, and assessment of concomitant medications and / or procedures.

[0500] result Treatment with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min increased motor capacity, as measured by the 6-minute walk distance, by an average of 30 meters (from 292 to 322 meters). These results are shown in Figure 5.

[0501] Treatment with weekly 24-hour infusions of levocimendan at a dose of 0.075–0.1 μg / kg / min increased overall well-being as measured on a 5-point Likert scale in 7 out of 8 patients, resulting in an improvement of 1–2 points on the 5-point Likert scale. These results are shown in Figure 6.

[0502] The results of the HELP trial show that weekly 24-hour administration of levocimendan improves PCWP (left heart failure) in PH-HFpEF patients.

[0503] The results of the HELP trial showed that weekly 24-hour administration of levocimendan improved the 6-minute walk distance (exercise capacity) in PH-HFpEF patients.

[0504] The results of the HELP trial showed that weekly 24-hour administration of levocimendan improved right atrial pressure (right ventricular function) in PH-HFpEF patients.

[0505] The results of the HELP trial show that weekly 24-hour administration of levocimendan reduces pulmonary artery pressure in PH-HFpEF.

[0506] The results of the HELP trial indicate that weekly 24-hour administration of levocimendan is safe and well-tolerated.

[0507] Since the HELP trial enrolled PH-HFpEF patients with biventricular failure (left and right ventricular dysfunction), the favorable results from the trial support the claims regarding its use in PH-HFpEF patients, including those with biventricular failure.

[0508] Example 3 The test will be conducted in the same manner as in Example 1, except that certain parameters will be modified to allow for different forms of administration.

[0509] The subcutaneous levocimendan preparation is administered by subcutaneous injection. The subcutaneous preparation is substantially similar to the intravenous preparation in Example 1.

[0510] The results were substantially similar to those of Example 1, showing a reduction in injection site and / or central line infection compared to intravenous administration. Furthermore, improved quality of life evaluation and / or convenience of administration were achieved due to the easier delivery route.

[0511] Example 4 The test will be conducted in the same manner as in Example 1, except that certain parameters will be modified to allow for the concomitant administration of levocimendan with additional cardiovascular drugs.

[0512] The levocimendan preparation is administered substantially in the same manner as in Example 1, but in combination with Entresto.

[0513] The results were almost identical to those of Example 1, and included improvements in cardiovascular hemodynamics, exercise capacity, and quality of life.

[0514] Example 5 The test will be conducted in the same manner as in Example 1, except that certain parameters will be modified to allow for the concomitant administration of levocimendan with additional cardiovascular drugs.

[0515] The levocimendan preparation is administered substantially in the same manner as in Example 1, but in combination with sacubitril and / or other neprirsin inhibitors.

[0516] The results were almost identical to those of Example 1, and included improvements in cardiovascular hemodynamics, exercise capacity, and quality of life.

[0517] Example 6 The test will be conducted in the same manner as in Example 1, except that certain parameters will be modified to allow for the concomitant administration of levocimendan with additional cardiovascular drugs.

[0518] The levocimendan preparation is administered substantially in the same manner as in Example 1, but in combination with lanolazine.

[0519] The results were almost identical to those of Example 1, and included improvements in cardiovascular hemodynamics, exercise capacity, and quality of life.

[0520] Example 7 overview To compare subcutaneous administration of the composition of the present invention with intravenous administration of a levocimendan formulation, a pharmacokinetic study was conducted in male Sprague Dawley rats. In this study, the blood concentration of levocimendan and pain at the injection site were evaluated.

[0521] method This study involves comparing the results of administering two subcutaneous compositions according to embodiments of the present invention with previous pharmacokinetic studies in which male rats were administered levosimendan via tail vein as an IV bolus injection at a dose of 0.5 mg / kg using a 0.25 mg / ml solution. Accordingly, this study included the following three test arms: a. Intravenous administration of a composition containing levocimendan (0.25 mg / ml) and phosphate buffer (10 mmol), prepared in sterile water for injection and adjusted to pH 7.0-7.9 with 1N NaOH or 10N NaOH; this composition was administered at a dose of 0.5 mg / kg. b. A composition containing levocimendan (1.0 mg / ml), Captisol® (100 mg / ml), and phosphate buffer (10 mmol), prepared in sterile water for injection and adjusted to pH 7.0-7.9 with 1N NaOH or 10N NaOH, was administered subcutaneously; this composition was administered at a dose of 0.5 mg / kg. c. Subcutaneous administration of a composition containing levocimendan (1.0 mg / ml), Captisol® (300 mg / ml), and phosphate buffer (10 mmol), prepared in sterile water for injection and adjusted to pH 7.0-7.9 with 1N NaOH or 10N NaOH; this composition was administered at a dose of 0.5 mg / kg.

[0522] Each of the compositions was sterile filtered using a sterile 0.22 micron Millex-GV PVDF filter syringe filter before administration.

[0523] For this study, 10–12-month-old naive male Sprague Dawley rats were used. Blood samples were collected from the rats before administration and at the following time points: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 18 hours after administration. Five 0.5 ml–1.0 ml blood samples were collected from each rat. Four of these samples were collected from the tail vein, and the fifth sample was collected by cardiac puncture and bloodletting after deep anesthesia by isoflurane inhalation. In each test arm, the rats were divided into two groups, Group A and Group B, each containing three rats. Sample collection times were alternated between the three rats in Group A and the three rats in Group B. Thus, samples were collected from Group A rats before administration and at 15 minutes, 1 hour, 4 hours, and 12 hours. Samples were collected from Group B rats at 5 minutes, 30 minutes, 2 hours, 8 hours, and 18 hours. To ensure death, thoracotomy was performed beforehand. Each arm of the experiment used 6 rats for a total of 18 rats.

[0524] During the study following subcutaneous and IV injections, rats were observed for clinical signs of adverse reactions. Behavior was monitored, including licking, biting, or scratching of the injection site, loss of mobility, restlessness, unresponsiveness, and abnormal posture. No abnormal observations were made, as the rats continued to behave normally throughout the study.

[0525] Immediately after euthanasia, the subcutaneous injection sites along the back between the shoulders were examined for signs of swelling or irritation. Three rats administered 100 mg / ml of Captisol® for 12 hours and three rats administered 300 mg / ml of Captisol® for 18 hours were compared to three uninjected naive rats as controls. The rats' epidermis was carefully removed to expose the tissue directly surrounding the subcutaneous injection site. No signs of swelling or irritation were observed in this tissue.

[0526] Blood samples were stored in tubes containing EDTA as an anticoagulant and kept in an ice bath until centrifugation was performed to separate the plasma. The plasma samples were stored at -20°C until the assay. The plasma obtained from each sample was used for liquid chromatography / mass spectrometry of the compounds.

[0527] Plasma samples were analyzed for levocimendane and OR-1896 (primary metabolite) by HPLC / MS / MS. For sample preparation, a protein precipitation method was used by adding acetonitrile spike solution or acetonitrile and an internal standard to the plasma sample or blank plasma. The internal standard for levocimendane was 13C6-labeled levocimendane, and for OR-1896, it was 13C6-labeled ORM-25632 (a racemic mixture of OR-1896). After adding the reagents, the mixture was vortexed and centrifuged. Approximately 75-80 μl was transferred to an autosampler vial using a plastic insert.

[0528] The HPLC / MS / MS method consisted of a Restek Raptor Biphenyl column, 2.7 μm, 100 × 3 mm. Mobile phase A was 5 mM ammonium formate / 0.1% formic acid, and mobile phase B was methanol. The flow rate was set to 0.6 ml / min, and the injection volume was 10 μl. Detection was performed using a Sciex 3200 Qtrap mass spectrometer in MRM mode.

[0529] result Plasma concentrations of levocimendan after IV and subcutaneous administration. The higher initial plasma levels of the IV formulation are typical of IV injection. The more rapid initial decrease in blood concentration (α-phase) is due to the distribution of the drug throughout the body's tissues. Following the initial distribution of the drug, the elimination of the drug from the blood is mainly due to metabolism (β-phase). In levocimendan, the β-phase begins at approximately 2 hours. Notably, Table 7 and Figure 2 show that the metabolism of levocimendan is very similar for the IV and subcutaneous formulations. This is further supported by the nearly identical plasma levels of the primary active metabolite OR-1896.

[0530] [Table 7]

[0531] Plasma concentrations of OR-1896 after IV and subcutaneous administration. OR-1896, the major active metabolite of levosimendan, showed very similar plasma concentrations regardless of the route of administration or formulation.

[0532] [Table 8]

[0533] Pharmacokinetic parameters of levocimendan after administration of the IV formulation and subcutaneous composition. Significantly lower Cmax was observed for both subcutaneous compositions compared to the IV formulation, but the half-lives were comparable for all formulations.

[0534] [Table 9]

[0535] Pharmacokinetic parameters of OR-1896 after administration of the IV formulation and subcutaneous composition. Cmax, Tmax, and AUC for both subcutaneous compositions are very similar to those of the IV administration route. The bioavailability of OR-1896 from the subcutaneous formulation is 95–113%.

[0536] [Table 10]

[0537] These results indicate that the OR-1896 plasma concentration after administration of the subcutaneous composition of the present invention was comparable to that observed after IV levocimendan administration. This was an unexpected finding considering the substantially lower Cmax and AUC of levocimendan observed after subcutaneous administration of the composition of the present invention compared to IV administration.

[0538] Furthermore, there was no evidence of pain or visible irritation at the injection site, and no clinically relevant adverse events or other signs of pain or distress were observed in rats. The Captisol®-containing subcutaneous composition did not cause any apparent adverse reactions or irritation when administered subcutaneously.

[0539] Example 8 The same investigation as in Example 7 will be conducted, except that certain parameters will be modified to allow subcutaneous administration of levocimendan.

[0540] The results were substantially similar to those of Example 7, and compared to intravenous administration, they involved a reduction in injection site and / or central line infection. In addition, the improved quality of life and / or convenience of administration were due to the easy delivery route.

[0541] Consideration Clinical trials of levocimendan have focused exclusively on HFrEF patients. Patients with preserved ejection fraction (HFpEF), meaning those with an ejection fraction of ≥40%, have been excluded from these levocimendan clinical trials. One reason levocimendan has not been studied in HFpEF patients is likely due to previous concerns that inotropes, particularly calcium-sensitized inotropes such as levocimendan, impair ventricular relaxation, which could be harmful in HFpEF patients. One example of this safety concern is cited by Hajjar et al. in Cardiovascular Drugs and Therapy, where they state: "This means that CA 2+ We conclude that inotropic agents that increase the sensitivity of myofibrils to further impair relaxation in cardiomyopathy, leading to a decrease in systolic reserve and reduced force generation.

[0542] Examples of major HFrEF clinical trials that excluded HFpEF patients include LIDO, REVIVE, SURVIVE, RUSSLAN, and LEVO-CTS. In all of these trials, patients with ejection fraction >36% were excluded. In addition, all clinical trials evaluating chronic intermittent administration of levocimendan excluded HFpEF patients. Examples of clinical trials evaluating long-term intermittent administration of levocimendan that excluded HFpEF patients include LIONHEART, LEVOREP, LAICA, and numerous other single-center trials. Kleber et al. conducted a trial of intermittent administration of levocimendan in patients with pulmonary hypertension, but this trial also did not recruit HFpEF patients and was unable to demonstrate efficacy after long-term administration over 8 weeks. Finally, Jiang et al. conducted a trial of levocimendan in patients with various types of pulmonary arterial hypertension and acute heart failure. However, none of the patients were PH-HFpEF patients.

[0543] Previous acute heart failure trials used a single 24-hour infusion of 0.5–0.2 mcg / kg / min of levocimendan to treat patients with acute decompensated heart failure in a hospital setting. Other trials have evaluated repeated or intermittent administration of levocimendan in patients with chronic heart failure, employing various alternative administration methods using intravenous infusions of less than 24 hours, administered at a frequency of every 2–4 weeks in a hospital setting. Weekly 24-hour infusions administered outside a hospital setting have not been used in any trials to date.

[0544] The data from the HELP trial, which evaluated the hemodynamic effects of levocimendan in PH-HFpEF patients, represent the first and only study evaluating levocimendan in this population. No one could predict the outcome of the HELP trial, as no drug has been proven effective and safe in PH-HFpEF patients, including numerous other drugs effective for other forms of pulmonary hypertension. In particular, given the numerous failed attempts, it was unreasonable to expect that the HELP trial would show levocimendan lowering PCWP, reducing PA pressure, increasing cardiac output, increasing 6-minute walk distance, or improving the quality of life in PH-HFpEF patients.

[0545] As reported herein, levocimendan has surprisingly been found to provide an effective treatment for human subjects with pulmonary hypertension and heart failure with preserved ejection fraction (PH-HFpEF). Levocimendan can improve cardiovascular hemodynamics, exercise capacity, and quality of life. This study provided evidence that levocimendan infusion can reduce pulmonary capillary wedge pressure, right atrial pressure, and mean pulmonary artery pressure. Furthermore, levocimendan infusion was also able to improve cardiac output, quality of life, and 6-minute walk distance. The statistically significant improvement in 6-minute walk distance in levocimendan-treated patients (Figure 15) is particularly noteworthy as it is the first multicenter, placebo-controlled trial to demonstrate that the drug can improve 6-minute walk distance in HFpEF or PH-HFpEF patients. This was a very surprising finding, as the trial was not sized or designed to demonstrate a difference in 6-minute walk distance.

[0546] Furthermore, surprisingly, levocimendan has been found to be safe even when administered in non-hospital or non-clinical settings and when self-administered. Levocimendan treatment was provided in outpatient settings as well as at the homes of human subjects. Based on the results of this study, it is confirmed for the first time that levocimendan can be safely administered at home in PH-HFpEF patients.

[0547] In addition, surprisingly, levocimendan has been found to be safe when administered to PH-HFpEF patients via weekly 24-hour infusions. While other studies have evaluated intermittent administration of levocimendan to treat HFrEF patients, none of these studies have evaluated weekly 24-hour infusions of levocimendan. Most of these other studies have evaluated infusions every 2, 3, or 4 weeks with infusion times of only 6 to 12 hours.

[0548] The results presented herein also demonstrate that the inventors have found a means to identify PH-HFpEF patients who are likely to respond to levocimendan, i.e., a means to identify PH-HFpEF responders to levocimendan. The relative increase in stroke volume observed in patients during 25-watt exercise compared to rest is a strong predictor of the patient's response. Although not bound by any mechanistic theory, this indicator can identify whether a patient has the appropriate cardiac reserve necessary to respond to levocimendan therapy.

[0549] The unexpected results described above are the first of their kind observed in PH-HFpEF patients, and are even more surprising in light of the extremely high failure rates in previous trials.

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Claims

1. A method for treating pulmonary hypertensive heart failure (PH-HFpEF) in a human subject suffering from PH-HFpEF with preserved ejection fraction, comprising administering to the human subject an amount effective in treating the PH-HFpEF of the human subject of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof.

2. The aforementioned treatments are as follows: a) A reduction of 1 to 30 mmHg in the pulmonary capillary wedge pressure of the human subject at rest; b) Stabilization of the pulmonary capillary wedge pressure of the human subject at rest to 5–35 mmHg or 10–35 mmHg; c) A decrease of 1 to 40 mmHg in the pulmonary capillary wedge pressure of the human subject during exercise; d) A decrease in the pulmonary capillary wedge pressure of the human subject during exercise, preferably by 10 to 50 mmHg; e) The treatment does not involve any significant change in pulmonary capillary wedge pressure during exercise in the human subject; f) A decrease of preferably 1 to 30 mmHg in the pulmonary capillary wedge pressure of the human subject when the human subject raises his legs; g) Stabilization of the pulmonary capillary wedge pressure of the human subject when the human subject's legs are raised, preferably at 10 to 50 mmHg; h) A reduction in the right atrial pressure of the human subject at rest, preferably by 1 to 30 mmHg; i) Stabilization of the right atrial pressure of the human subject at rest, preferably to 1 to 30 mmHg or 5 to 30 mmHg; j) A decrease in the right atrial pressure of the human subject during exercise, preferably by 1 to 30 mmHg; k) Stabilization of the right atrial pressure of the human subject during exercise, preferably at 5 to 40 mmHg; l) The decrease in the right atrial pressure of the human subject when the leg of the human subject is raised; m) A reduction of the mean pulmonary artery pressure of the human subject at rest, preferably 1 to 30 mmHg; n) Stabilization of the mean pulmonary artery pressure of the human subject at rest, preferably at 15 to 65 mmHg; o) A decrease of 1 to 30 mmHg in the mean pulmonary artery pressure of the human subject during exercise; p) Stabilization of the mean pulmonary artery pressure of the human subject during exercise by the human subject to 25–85 mmHg or 25–80 mmHg; q) The decrease in the mean pulmonary artery pressure of the human subject when the human subject raises his legs; r) An increase of preferably 0.01 to 3 liters / min in the cardiac output of the human subject at rest; s) Stabilization of the cardiac output of the human subject at rest to 2-10 liters / min; t) Increase in cardiac output of the human subject during exercise; u) An increase of 0.01 to 5 liters / min, 0.01 to 4 liters / min, or 3.0 to 15.0 liters / min in the cardiac output of the human subject during exercise; v) Not including a significant increase in the heart rate of the human subject, or not including an increase in the heart rate of the human subject exceeding 10 beats / minute; w) Improvement of the quality of life of the aforementioned human subjects; x) An improvement of the human subject's 6-minute walking distance, preferably 5 to 150 meters; y) Improvement of physician assessment of cardiac function classification of the aforementioned human subjects; z) Reduction in the incidence of hospitalizations related to heart failure; aa) A decrease in all-cause mortality; bb) Preferably, improvement of right heart failure and / or right ventricular dysfunction as demonstrated by a decrease in right atrial pressure at rest and during 25 watt exercise. The method according to claim 1, including the method described in claim 1.

3. The method according to claim 2, wherein in (w), the improvement in the quality of life of the human subject is measured by a patient-reported outcome assessment tool.

4. The method according to claim 3, wherein the treatment includes at least one, more preferably two, improvements in the quality of life of the human subject in accordance with a change in the patient-reported outcome assessment tool score of the human subject.

5. The method according to any one of claims 1 to 4, wherein the human subject is a responder to levosimendan therapy.

6. a) Responders to levocimendan therapy are human subjects whose pulmonary capillary wedge pressure decreases by at least 4 mmHG during 25 watts of cycling exercise after the first infusion; b) Responders to levosimendan therapy are human subjects whose cardiac index decreases to 10% or less between baseline measurement and repeated measurements after the first infusion; c) The human subject is a responder to levocimendan therapy if the human subject has cardiac reserve; d) The human subject is a responder to levocimendan therapy if the stroke volume of the human subject increases during exercise performed by the human subject; e) The human subject is a responder to levosimendan therapy if, as determined using a catheter inside the human subject's heart that measures the blood moving from the left ventricle with each heartbeat, the stroke volume of the human subject increases during exercise performed by the human subject; f) If, as estimated by electrocardiogram and / or echocardiogram, the stroke volume of the human subject increases during exercise performed by the human subject, then the human subject is a responder to levocimendan therapy; g) If, as determined by the dobutamine stress test, the human subject's stroke volume increases during exercise, then the human subject is a responder to levocimendan therapy; h) The human subject is a responder to levocimendan therapy if the stroke volume of the human subject increases by at least 0.005 liters during exercise performed by the human subject; i) The human subject is a responder to levocimendan therapy if, as determined by a catheter in the human subject's heart that measures the blood moving from the left ventricle with each heartbeat, the human subject's stroke volume increases by 1 to 50 mL during exercise; j) The human subject is a responder to levosimendan therapy if, as estimated by echocardiography, right heart catheterization, or other means, the stroke volume of the human subject increases by 1 to 50 mL during exercise performed by the human subject; or k) If, as determined by the dobutamine stress test, the human subject's stroke volume increases by 1 to 50 mL during exercise, then the human subject is a responder to levocimendan therapy. The method according to claim 5.

7. The human subjects who suffered from PH-HFpEF were as follows: a) Having a left ventricular ejection fraction of at least 40%; b) Having a baseline pulmonary artery pressure of at least 35; c) Having at least 20 baseline pulmonary capillary wedge pressures; d) Classified as Class IIb or Class III according to the New York Heart Association Classification, based on the physician's assessment; e) Having the ability to walk at least 50 meters in a 6-minute walk test but not the ability to walk 550 meters or more in a 6-minute walk test, or having the ability to walk at least 50 meters, but not more than 550 meters, in a 6-minute walk test; f) Not suffering from heart failure with reduced ejection fraction; g) Not suffering from heart failure with preserved ejection fraction and without pulmonary hypertension; h) Having a primary diagnosis of PH-HFpEF in group 2; i) Not suffering from coronary artery disease; j) Having never undergone percutaneous coronary intervention in the past; k) The human subject has not previously undergone percutaneous coronary intervention, except in cases where the subject has had a negative stress test result within the past year; l) Never having had heart surgery before; m) The human subject has not undergone cardiac surgery in the past, except in cases where the subject has had a negative stress test result within the past year; n) Not suffering from congenital heart disease; o) No clinically significant lung disease; p) No plans for heart or lung surgery; q) It does not have a cardiac index exceeding 4.0 L / min / m2; r) Not receiving pulmonary vasodilator therapy simultaneously; s) Not having received pulmonary vasodilator therapy within the past 14 days; t) Not receiving dialysis treatment; u) Not having a glomerular filtration rate of less than 30 mL / min / 1.73 m²; v) Not having Child-Pugh classification B or C liver dysfunction; w) No evidence of systemic infection; x) Weight is 150 kg or less; y) The symptomatic systolic blood pressure can be managed to consistently exceed 100 mmHg; z) Not having a heart rate of 100 beats per minute or more due to medication use; aa) Not having a symptomatic heart rate of 100 beats per minute or more due to medication use, which lasts for at least 10 minutes; bb) Not having hemoglobin less than 80 g / L; cc) No serum potassium level less than 3.0 mmol / L at baseline; dd) No serum potassium level greater than 5.5 mmol / L at baseline; ee) No serum potassium levels below 3.0 mmol or above 5.5 mmol / L at baseline; ff) Not having severe immune dysfunction; gg) Not pregnant, not suspected of being pregnant, or not breastfeeding; or hh) A patient with biventricular failure, The method according to any one of claims 1 to 6.

8. The method according to any one of claims 1 to 7, wherein the administration is carried out via IV administration.

9. The method according to any one of claims 1 to 8, wherein the administration is performed intermittently, weekly, or over a long period of time.

10. The method according to any one of claims 1 to 9, wherein the administration is carried out by a 24-hour infusion.

11. The method according to any one of claims 1 to 9, wherein the administration is a long-term administration carried out by an infusion over a period of less than 24 hours.

12. The aforementioned administration is as follows: a) The dose is a 2.5 mg / mL injection concentrate of levocimendan containing levocimendan, povidone, citric acid, and ethanol; b) A dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 5 mL; c) A dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 5 mL, which is added to one 250 mL injection bag of 5% dextrose; d) A dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 5 mL, which is added to one 250 mL injection bag of 0.9 physiological saline; e) A dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 5 mL if the body weight of the human subject is less than 85 kg, which is added to one 250 mL injection bag of 5% dextrose or 0.9 physiological saline; f) A dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 10 mL; g) The dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 10 mL, which is added to one 500 mL injection bag of 5% dextrose; h) The dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol, supplied in a total volume of 10 mL, which is added to one 500 mL injection bag of 0.9 physiological saline; i) The method according to any one of claims 1 to 11, wherein the dose of a 2.5 mg / mL injection concentrate of levocimendan, comprising levocimendan, povidone, citric acid, and ethanol is supplied in a total volume of 10 mL when the body weight of the human subject is at least 85 kg, and this is added to one 500 mL injection bag of 5% dextrose or 0.9 physiological saline.

13. The method according to any one of claims 1 to 12, wherein if the human subject does not tolerate the dose well, the administration rate is reduced to 0.05 μg / kg / min.

14. The method according to any one of claims 1 to 7, wherein the administration is performed by oral administration.

15. The method according to claim 14, wherein the oral administration includes an immediate-release formulation or a sustained-release formulation.

16. The method according to any one of claims 1 to 8, wherein the administration is a subcutaneous administration of a subcutaneous preparation.

17. The method according to claim 16, wherein the subcutaneous preparation is an intravenous preparation containing an additive.

18. The aforementioned subcutaneous preparation is as follows: a) 12.5 mg of levocimendan in a non-aqueous preparation, added to 150 mL of 5% dextrose, 0.9 mg of physiological saline, or other pharmaceutically acceptable diluent or carrier, to produce a levocimendan concentration of 0.0833 mg / mL in the subcutaneous preparation; b) 12.5 mg of levocimendan in a non-aqueous preparation, added to 250 mL of 5% dextrose, 0.9 mg of physiological saline, or other pharmaceutically acceptable diluent or carrier, to produce a levocimendan concentration of 0.05 mg / mL in the subcutaneous preparation; c) 12.5 mg of levocimendan in a non-aqueous preparation, added to 500 mL of 5% dextrose, 0.9% physiological saline, or other pharmaceutically acceptable diluent or carrier, to produce a levocimendan concentration of 0.025 mg / mL in the subcutaneous preparation; d) 12.5 mg of levocimendan in a non-aqueous preparation, added to 1000 mL of 5% dextrose, 0.9 mg of physiological saline, or other pharmaceutically acceptable diluent or carrier, to produce a levocimendan concentration of 0.0125 mg / mL in the subcutaneous preparation; e) 12.5 mg of levocimendan in a non-aqueous preparation, added to 1500 mL of 5% dextrose, 0.9 mg of physiological saline, or other pharmaceutically acceptable diluent or carrier, to produce a levocimendan concentration of 0.008333 mg / mL in the subcutaneous preparation. The method according to claim 16, including the method described in claim 16.

19. The method according to any one of claims 16 to 18, wherein the subcutaneous administration of the subcutaneous preparation comprises an amount of water effective in reducing pain caused by the subcutaneous administration.

20. The method according to any one of claims 16 to 19, wherein the subcutaneous administration of the subcutaneous preparation includes a buffering agent for raising the pH to above 3.

5.

21. The subcutaneous administration of the subcutaneous preparation is a) It has fewer side effects compared to intravenous administration of levocimendan in the human subjects; or b) Compared to intravenous administration in the human subjects, the peak plasma concentration of levocimendan is reduced by at least 1% to 25%. The method according to any one of claims 16 to 20.

22. The method according to any one of claims 16 to 21, wherein the aforementioned amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, is administered in combination with a cardiovascular drug.

23. The method according to claim 22, wherein when the aforementioned amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, is taken together with the aforementioned amount of the cardiovascular drug, it is effective in alleviating the symptoms of PH-HFpEF.

24. The method according to claim 22 or 23, wherein the cardiovascular drug is a drug used to treat pulmonary arterial hypertension (PAH), patients with pulmonary hypertension in World Health Organization (WHO) groups 1 to 5, coronary artery disease (CAD), or heart failure with reduced ejection fraction (HFrEF).

25. The method according to claim 22 or 23, wherein the cardiovascular drug is a PDE inhibitor, a phosphodiesterase-5 (PDE5) inhibitor, an endothelin receptor antagonist (ERA), a prostanoid, a soluble guanylate cyclase stimulant, a nitrate, a nitrite, an NO donor, a calcium channel inhibitor (CCB), a fatty acid oxidation inhibitor, a β-blocker (BB), angiotensin-converting enzyme (ACE) inhibitor, a neprilysin inhibitor, neprilysin and angiotensin receptor blockers (ANRI), angiotensin II receptor blockers (ARB), a diuretic, an aldosterone antagonist, a digoxin, an ivabradine, a hydralazine, a ceralaxin, a natriuretic peptide, an atrial natriuretic peptide (ANP), a natriuretic peptide, a K-ATP channel activator, a NEP inhibitor, or a prostacyclin.

26. The method according to claim 22 or 23, wherein the cardiovascular drug is a pulmonary vasodilator.

27. The method according to claim 26, wherein the pulmonary vasodilator is a phosphodiesterase-5 (PDE5) inhibitor, an endothelin receptor antagonist (ERA), or prostacyclin.

28. The method according to claim 26 or 27, wherein the amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, administered in combination with the pulmonary vasodilator, is administered to a human subject suffering from pre- and post-capillary pulmonary hypertension and heart failure with preserved ejection fraction (Cpc-PH-HFpEF).

29. The method according to any one of claims 1 to 28, wherein no atrial or ventricular arrhythmias are observed when baseline electrocardiogram monitoring is compared with 72-hour monitoring after 5 weeks of treatment.

30. The method according to any one of claims 1 to 29, wherein treatment results in statistically significant adverse events comparable to those of a matched placebo.

31. The method according to any one of claims 1 to 30, wherein a 24-hour weekly administration of levocimendan results in a steady-state blood concentration of OR1896 in the range of 0.20 ng / mL to 25.00 ng / mL.

32. a) A 5 mL vial dose of levocimendan 2.5 mg / mL injection concentrate containing levocimendan, povidone, citric acid, and ethanol; b) 250 mL of 5% dextrose or 0.9 ml of physiological saline; and c) Buffering agent to increase pH Products containing the following:

33. Use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, for the effective treatment of pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in human subjects.

34. The use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or combinations thereof, for the purpose of preparing a pharmaceutical product for effective treatment of PH-HFpEF in human subjects suffering from pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in said human subjects.

35. A pharmaceutical product comprising a specific amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, for use in the effective treatment of pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in human subjects.

36. Use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or combinations thereof, in combination with cardiovascular agents, for the effective treatment of pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in human subjects.

37. The use of specific amounts of levocimendan, its metabolite OR-1896 or OR-1855, or combinations thereof, for the purpose of preparing a pharmaceutical product in combination with a cardiovascular agent to effectively treat PH-HFpEF in human subjects suffering from pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in the said human subjects.

38. A pharmaceutical product comprising a specific amount of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, intended for use in combination with a cardiovascular agent to effectively treat pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in human subjects.

39. A subcutaneous preparation of levocymendan for use in the treatment of PH-HFpEF in human subjects suffering from PH-HFpEF, wherein the subcutaneous preparation is obtained from a dry powder, the dry powder being obtained from a pharmaceutical composition comprising (a) levocymendan, (b) sulfobutyl ether β-cyclodextrin, (c) sodium hydroxide or acetic acid, and water for injection.

40. The composition according to claim 39, wherein the amount of levocimendan is 2.5 mg / ml of water for injection.

41. The composition according to claim 39 or 40, wherein the amount of sulfobutyl ether β-cyclodextrin is 0.175 mg / ml of water for injection.

42. The composition according to any one of claims 39 to 41, wherein the amount of sodium hydroxide or acetic acid is appropriate for adjusting the pH to a range of 7.2 to 7.

8.

43. The composition according to any one of claims 39 to 42, wherein the pharmaceutical composition is freeze-dried.

44. The composition according to any one of claims 39 to 43, wherein the subcutaneous preparation of levocimendan is obtained from the dried powder by reconstituting the dried powder in an aqueous solution suitable for subcutaneous administration.

45. The composition according to claim 44, wherein the reconstituted subcutaneous preparation is adjusted to a pH of 7.2 to 7.8 using sodium hydroxide or acetic acid.

46. A method for treating pulmonary hypertensive heart failure (PH-HFpEF) in a human subject suffering from PH-HFpEF with preserved ejection fraction, comprising administering to the human subject an amount of a cardiovascular agent effective in treating the PH-HFpEF of the human subject, wherein the cardiovascular agent is: a PDE inhibitor, a phosphodiesterase-5 (PDE5) inhibitor, an endothelin receptor antagonist (ERA), a prostanoid, a soluble guanylate cyclase stimulant, a nitrate, a nitrite, an NO donor, a calcium channel inhibitor (CCB), or a lipid. A method selected from the group consisting of acid-oxidation inhibitors, β-blockers (BB), angiotensin-converting enzyme (ACE) inhibitors, neprilysin inhibitors, neprilysin and angiotensin receptor blockers (ANRIs), angiotensin II receptor blockers (ARBs), diuretics, aldosterone antagonists, digoxin, ivabradine, hydralazine, ceralaxin, natriuretic peptides, atrial natriuretic peptides (ANPs), natriuretic peptides, K-ATP channel activators, NEP inhibitors, and prostacyclins.

47. A method for treating pulmonary hypertensive heart failure (PH-HFpEF) in a human subject suffering from PH-HFpEF with preserved ejection fraction, comprising administering to the human subject an amount of a pulmonary vasodilator effective in treating the PH-HFpEF in the human subject, wherein the pulmonary vasodilator is selected from the group consisting of phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs), and prostacyclins.

48. The method according to claim 47, wherein the aforementioned amount of the pulmonary vasodilator is administered to a human subject suffering from pre- and post-capillary pulmonary hypertension and heart failure with preserved ejection fraction (Cpc-PH-HFpEF).

49. A cardiovascular agent for use in the treatment of pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in a subject, wherein the cardiovascular agent is: PDE inhibitor, phosphodiesterase-5 (PDE5) inhibitor, endothelin receptor antagonist (ERA), prostanoid, soluble guanylate cyclase stimulant, nitrate, nitrite, NO donor, calcium channel inhibitor (CCB), fatty acid oxidation inhibitor, β-blocker (BB), angiotensin-converting enzyme (AC) E) Cardiovascular drugs selected from the group consisting of inhibitors, neprilysin inhibitors, neprilysin and angiotensin receptor blockers (ANRIs), angiotensin II receptor blockers (ARBs), diuretics, aldosterone antagonists, digoxin, ivabradine, hydralazine, ceralaxin, natriuretic peptides, atrial natriuretic peptides (ANPs), natriuretic peptides, K-ATP channel activators, NEP inhibitors, and prostacyclins.

50. A pulmonary vasodilator for use in the treatment of pulmonary hypertensive heart failure (PH-HFpEF) with preserved ejection fraction in a subject, wherein the pulmonary vasodilator is selected from the group consisting of phosphodiesterase-5 (PDE5) inhibitors, endothelin receptor antagonists (ERAs), and prostacyclins.

51. The method according to claim 51, wherein the pulmonary hypertensive heart failure with preserved ejection fraction (PH-HFpEF) is pre- and post-capillary pulmonary hypertension and heart failure with preserved ejection fraction (Cpc-PH-HFpEF).

52. The method according to claim 1, wherein the subject is orally administered a capsule containing up to 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2 mg, 3 mg, or 4 mg, more preferably 1 to 3 mg, of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof.

53. The method according to claim 52, wherein the subject is administered a capsule once a day for a period of 1 to 60 days, preferably 14 days.

54. The method according to claim 52 or 53, wherein the subject increases the number of capsules taken per day after each period if the treatment is tolerable to the subject.

55. The method according to any one of claims 52 to 54, wherein the subject is orally administered 0.1 to 10 mg of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, preferably 1 to 4 mg of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, per day.

56. The method according to any one of claims 52 to 55, wherein the subject has received a final intravenous injection of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof, at least one day, more preferably at least one week, before commencing oral administration of levocimendan, its metabolite OR-1896 or OR-1855, or a combination thereof.

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