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EP-4734986-A1 - THERAPEUTIC USES AND DOSES OF LP(A) DISRUPTER COMPOUNDS

EP4734986A1EP 4734986 A1EP4734986 A1EP 4734986A1EP-4734986-A1

Abstract

Once-daily, oral doses of the Lp(a) disrupter compound (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof, to be used in the treatment of cardiovascular disease, elevated Lp(a) levels, individuals with elevated Lp(a) levels at risk for cardiovascular events and atherosclerotic cardiovascular disease.

Inventors

  • URVA, SHWETA

Assignees

  • Eli Lilly and Company

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. 1. A method of treating cardiovascular disease in an individual, the method comprising: orally administering to the individual in need thereof a once-daily dose of between 10 mg and 240 mg of (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof.
  2. 2. The method of claim 1, wherein the individual has elevated Lp(a) plasma levels.
  3. 3. The method of claim 1 or claim 2, wherein the once daily dose is about 120 mg.
  4. 4. The method of claim 1 or claim 2, wherein the once-daily dose is between 60 mg and 150 mg.
  5. 5. The method of claim 4, wherein the once-daily dose is between 60 mg and 120 mg.
  6. 6. The method of claim 5, wherein the once-daily dose is between 80 mg and 120 mg.
  7. 7. A method of treating an individual with elevated Lp(a) levels, the method comprising: orally administering to the individual in need thereof a once-daily dose of between 10 mg and 240 mg of (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof.
  8. 8. The method of claim 7, wherein the individual has an Lp(a) plasma level greater than or equal to 75 nmol/L prior to treatment.
  9. 9. The method of claim 8, wherein the individual has an Lp(a) plasma level greater than or equal to 125 nmol/L prior to treatment.
  10. 10. The method of claim 9, wherein the individual has an Lp(a) plasma level greater than or equal to 175 nmol/L prior to treatment.
  11. 11. The method of any one of claims 7 to 10, wherein the individual is at risk for cardiovascular events.
  12. 12. The method of any one of claims 7 to 11, wherein the once daily dose is about 120 mg.
  13. 13. The method of any one of claims 7 to 11, wherein the once-daily dose is between 60 mg and 150 mg.
  14. 14. The method of claim 13, wherein the once-daily dose is between 60 mg and 120 mg.
  15. 15. The method of claim 14, wherein the once-daily dose is between 80 mg and 120 mg.
  16. 16. A method of treating an individual with elevated Lp(a) levels at risk for cardiovascular events, the method comprising: orally administering to the individual in need thereof a once-daily dose of between 10 mg and 240 mg of (2S)-3-[3-[[bis[[3-[(2S)- 2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)- pyrrolidin-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof.
  17. 17. The method of claim 16, wherein the individual has an Lp(a) plasma level greater than or equal to 75 nmol/L prior to treatment.
  18. 18. The method of claim 17, wherein the individual has an Lp(a) plasma level greater than or equal to 125 nmol/L prior to treatment.
  19. 19. The method of claim 18, wherein the individual has an Lp(a) plasma level greater than or equal to 175 nmol/L prior to treatment.
  20. 20. The method of any one of claims 16 to 19, wherein the once-daily dose is about 120 mg.

Description

Therapeutic Uses and Doses of Lp(a) Disrupter Compounds TECHNICAL FIELD [001] The disclosure relates to therapeutic methods and uses of Lp(a) disrupter compound (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3- yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof, in the treatment of cardiovascular disease, elevated Lp(a) levels, individuals with elevated Lp(a) levels at risk for cardiovascular events and atherosclerotic cardiovascular disease. It especially relates to particular doses of the Lp(a) disrupter compound which can be used in the treatment of these conditions. BACKGROUND [002] There have been significant advances in treating cardiovascular disease (CVD). Despite treatment advances, patients continue to experience cardiovascular disease events such as angina, myocardial infarction, and stroke, which if untreated, lead to death. Lipid disorder or dyslipidemia remains a major risk factor for CVD. Lipid disorders can be divided into four general risk factors: elevated low-density lipoprotein cholesterol (LDL- c), low high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated lipoprotein(a) (Lp(a)). There are a variety of treatment regimens targeting elevated LDL-c, low HDL-c, and elevated triglycerides. There are few treatment options for patients with elevated Lp(a) concentrations. In some cases, apheresis may be used to filter the blood to remove LDL and Lp(a); however, the effects are temporary and typically need to be repeated every two weeks. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce Lp(a) by approximately 25% and niacin produces modest reductions in Lp(a), but neither are approved for Lp(a) reduction. There is no pharmaceutical treatment approved to lower Lp(a) levels. The physiological function of Lp(a) is complex; however, it is reported that elevated Lp(a) plasma level is an independent risk factor for CVD. [003] Lp(a) may exhibit both prothrombotic and antithrombotic properties, atherogenic and atherothrombotic properties. Lp(a) may inhibit fibrinolysis and accumulate in the vascular wall inducing thrombogenesis and atherosclerotic lesions. Plasma levels of Lp(a) vary substantially among individuals. Unlike the other risk factors, Lp(a) plasma levels do not vary significantly with diet and exercise. Lp(a) plasma levels are primarily determined by genetic predisposition. [004] Lp(a) resembles LDL-c in that it includes an LDL lipid core with the attendant apolipoprotein B (apoB), but unlike LDL-c, Lp(a) also contains a unique apolipoprotein(a) (apo(a)) bound covalently to the apoB via a disulfide bond. Apo(a) is synthesized in the liver. The assembly of Lp(a) from apo(a) and LDL particles can occur in hepatocytes, on the cell wall or in plasma. Inhibition of the assembly of the LDL particle with apo(a) may reduce Lp(a) levels. Additional treatment options are desired for patients suffering from cardiovascular diseases and, in particular, patients suffering from lipid disorders or dyslipidemia. There is a need for additional treatment options for patients whose cardiovascular risks are not adequately managed using current standard of care therapies, such as, diet, exercise and/or the use of one or more drugs such as statins, fibrates, and niacin. The present invention offers another treatment option for patients suffering from CVD. There is a need for pharmaceutically acceptable compounds and treatment options to reduce plasma Lp(a) levels. [005] In particular, there is a need for a treatment regimen with optimized doses and dosing regimens with compounds that effectively reduce Lp(a) plasma levels and associated cardiovascular risk, while also preserving an overall acceptable profile of safety and adverse events and tolerability to the individual. In particular, there is a need for doses which reduce the Lp(a) plasma level of an individual to less than 125 nmol/L after 12 weeks of treatment and/or which lower the Lp(a) level of an individual by at least 150 nmol/L after 12 weeks of treatment. SUMMARY OF THE INVENTION [006] To address this need, the disclosure describes once-daily, oral doses of (2S)-3- [3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidin-3-yl]ethyl]phenyl]methyl]amino] methyl]phenyl]-2-[(3R)-pyrrolidin-3-yl]propanoic acid (compound 1), or a pharmaceutically acceptable salt thereof, of between 10 mg and 240 mg. [007] In an aspect, there is provided a method of treating cardiovascular disease in an individual, the method comprising: orally administering to the individual in need thereof a once-daily dose of between 10 mg and 240 mg of compound 1, or a pharmaceutically acceptable salt thereof. [008] In another aspect, there is provided a method of treating an individual with elevated Lp(a) levels, the method comprising: orally administering to the individual in need thereof a once-daily dose of between 10 mg and 240 mg of compound 1, or a