Search

JP-2026076166-A - Levocimendan for the treatment of pulmonary hypertension with preserved ejection fraction heart failure (PH-HF-pEF)

JP2026076166AJP 2026076166 AJP2026076166 AJP 2026076166AJP-2026076166-A

Abstract

[Problem] To provide a method for treating pulmonary hypertension with heart failure while preserving ejection fraction (PH-HFpEF). [Solution] To provide a composition and method useful for treating PH-HFpEF, employing the use of levocimendan. [Selection Diagram] Figure 1A-1B

Inventors

  • スチュアート・リッチ
  • ダグラス・ランドール
  • ダグラス・ハイ

Assignees

  • テナックス・セラピューティクス，インコーポレイテッド

Dates

Publication Date
20260511
Application Date
20251225
Priority Date
20191216

Claims (20)

  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 in the said human subject: 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) The method according to claim 1, preferably comprising 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.
  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 comprises at least one, more preferably two, improvements in the quality of life of the human subject, according to 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 levocimendan 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 levocimendan 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) The human subject is a responder to levocimendan therapy if, as determined by a dobutamine stress test, the stroke volume of the human subject increases by 1 to 50 mL during exercise performed by the human subject. 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 performed by infusion over 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 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) The method according to claim 16, comprising 12.5 mg of levocimendan in a non-aqueous preparation, which is 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.
  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 the 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 above 3.5.

Description

This application claims the benefits of U.S. Provisional Application No. 63/064,671 filed on 12 August 2020, No. 63/033,773 filed on 2 June 2020, No. 62/988,720 filed on 12 March 2020, No. 62/967,920 filed on 30 January 2020, and No. 62/948,735 filed on 16 December 2019, the contents of which are incorporated herein by reference. Throughout this application, various publications are referenced, including those referenced in parentheses. The disclosures of all publications mentioned herein are incorporated by reference in their entirety to provide a further description of the technology to which the invention relates and the features in the art that can be used in the invention. This invention specifically relates to the treatment of heart failure with preserved ejection fraction in human subjects (PH-HFpEF patients) who also have pulmonary hypertension. Levocimendan is a calcium sensitizer and potassium channel activator approved in over 60 countries for intravenous use in hospitalized patients with acute decompensated heart failure (ADHF). Currently, levocimendan is approved for in-hospital use only, and is only approved for administration in a hospital setting where appropriate monitoring facilities and expertise regarding the use of inotropes are available. (Simdax. Finland: Orion Corporation; 2010.) 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.) 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 explicitly excluded patients 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 for the treatment of 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. 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/min). 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.) The activity of levocimendan 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, Haikala et al. 1995, Pollesello et al. 1994, Sorsa et al. 2004, Yokoshiki et al. 1997, Pataricza et al. 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) Levocimendan has been demonstrated in vitro as a potent and selective phosphodiesterase-3 (PDE3) inhibitor. 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 fully explains their inotropic effects. (Yokoshiki et al. 1997, Szilagyi et al. 2004) 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 tropo