Therapeutic Use and Dosage of Lp(a) Disruptor Compounds

Abstract

An oral dose once daily of the Lp(a) disruptor compound (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof, for use in the treatment of cardiovascular disease, elevated Lp(a) levels, individuals with elevated Lp(a) levels at risk of cardiovascular events, and atherosclerotic cardiovascular disease.

Description

[Technical Field]

[0001] This disclosure relates to methods and uses of the Lp(a) disruptor compound (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid, or pharmaceutically acceptable salts thereof, in the treatment of cardiovascular disease, elevated Lp(a) levels, individuals with elevated Lp(a) levels at risk of cardiovascular events, and atherosclerotic cardiovascular disease. It relates in particular to specific doses of Lp(a) disruptor compounds that can be used in the treatment of these conditions. [Background technology]

[0002] There have been remarkable advances in the treatment of cardiovascular disease (CVD). Despite these advances, patients continue to experience cardiovascular events such as angina, myocardial infarction, and stroke, which are fatal if left untreated. Dyslipidemia remains a major risk factor for CVD. Dyslipidemia can be divided into four common risk factors: elevated low-density lipoprotein cholesterol (LDL-c), decreased high-density lipoprotein cholesterol (HDL-c), elevated triglycerides (TG), and elevated lipoprotein(a) (Lp(a)). There are various treatment regimens targeting high LDL-c, low HDL-c, and high triglycerides. There are few treatment options for patients with elevated Lp(a) levels. In some cases, apheresis can be used to filter the blood and remove LDL and Lp(a), however, its effect is temporary and typically needs to be repeated every two weeks. Proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors reduce Lp(a) by about 25%, and niacin reduces Lp(a) moderately, but neither is approved for Lp(a) reduction. There are no approved drug treatments to lower Lp(a) levels. The physiological function of Lp(a) is complex, but elevated Lp(a) plasma levels have been reported to be an independent risk factor for CVD.

[0003] Lp(a) can exhibit both prothrombus-forming and antithrombotic properties, as well as both atherogenic and atherothrombotic properties. Lp(a) inhibits fibrinolysis and can accumulate in the vascular wall, inducing thrombus formation and atherosclerotic lesions. Plasma levels of Lp(a) vary substantially among individuals. Unlike other risk factors, Lp(a) plasma levels are not significantly altered by diet and exercise. Lp(a) plasma levels are primarily determined by genetic predisposition.

[0004] Lp(a) is similar to LDL-c in that it contains an LDL lipid core with an associated apolipoprotein B (apoB), but unlike LDL-c, Lp(a) also contains an intrinsic apolipoprotein (a) (apo(a)) covalently bonded to apoB via a disulfide bond. apo(a) is synthesized in the liver. Aggregations of apo(a) and Lp(a) from LDL particles can occur in hepatocytes, on the cell wall, or in plasma. Inhibition of LDL particle aggregation with apo(a) can lower Lp(a) levels. Additional treatment options are desired for patients with cardiovascular disease, particularly those with dyslipidemia or dyslipidemia. Additional treatment options are needed for patients whose cardiovascular risk is not adequately managed with current standard treatments, such as diet, exercise, and / or the use of one or more medications such as statins, fibrates, or niacin. This invention provides an alternative treatment option for patients suffering from CVD. A pharmaceutically acceptable compound and treatment option are needed to lower plasma Lp(a) levels.

[0005] In particular, there is a need for treatment regimens using optimized doses, and for drug regimens using compounds that effectively reduce Lp(a) plasma levels and associated cardiovascular risk while simultaneously preserving an overall acceptable profile of safety and adverse events, as well as individual tolerability. Specifically, there is a need for doses that reduce an individual's Lp(a) plasma level to less than 125 nmol / L after 12 weeks of treatment, and / or doses that reduce an individual's Lp(a) level to at least 150 nmol / L after 12 weeks of treatment. [Overview of the project] [Means for solving the problem]

[0006] To address this need, this disclosure describes once-daily oral doses of 10 mg to 240 mg of (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid (Compound 1), or a pharmaceutically acceptable salt thereof.

[0007] One embodiment provides a method for treating cardiovascular disease in an individual, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg.

[0008] In another embodiment, a method is provided for treating an individual having elevated Lp(a) levels, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, ranging from 10 mg to 240 mg.

[0009] In another embodiment, a method is provided for treating an individual having elevated Lp(a) levels at risk of cardiovascular events, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, ranging from 10 mg to 240 mg.

[0010] In another embodiment, a method for treating atherosclerotic cardiovascular disease (ASCVD) is provided, comprising orally administering to an individual in need of such treatment a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, ranging from 10 mg to 240 mg.

[0011] In a further embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cardiovascular disease in an individual, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0012] In a further embodiment, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of individuals having elevated Lp(a) levels, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0013] In a further embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of individuals with elevated Lp(a) levels who are at risk of cardiovascular events, wherein the Compound is administered orally in doses of 10 mg to 240 mg once daily.

[0014] In a further embodiment, compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the treatment of ASCVD in an individual, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0015] In a further embodiment, the use of compound 1, or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a pharmaceutical product for the treatment of cardiovascular disease in an individual, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0016] In a further embodiment, the use of compound 1, or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicament for the treatment of an individual having elevated Lp(a) levels, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0017] In a further embodiment, the use of compound 1, or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a pharmaceutical for the treatment of individuals having elevated Lp(a) levels who are at risk of cardiovascular events, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0018] In a further aspect, there is provided the use of Compound 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ASCVD in an individual, wherein the compound is orally administered at a once-daily dose of 10 mg to 240 mg.

[0019] In one embodiment, the individual to be treated has an Lp(a) plasma level of 75 nmol / L or more before treatment. In another embodiment, the individual to be treated has an Lp(a) plasma level of 125 nmol / L or more before treatment. In a further embodiment, the individual to be treated has an Lp(a) plasma level of 175 nmol / L or more before treatment.

[0020] In one embodiment, the individual to be treated has an Lp(a) plasma level of 30 mg / dL or more before treatment. In another embodiment, the individual to be treated has an Lp(a) plasma level of 50 mg / dL or more before treatment. In a further embodiment, the individual to be treated has an Lp(a) plasma level of 70 mg / dL or more before treatment.

[0021] In one embodiment, the once-daily dose is 60 mg to 150 mg, preferably 60 mg to 120 mg, more preferably 80 mg to 120 mg. In one embodiment, the once-daily dose is about 120 mg. In one embodiment, the once-daily dose is about 10 mg, about 60 mg, or about 240 mg.

Brief Description of the Drawings

[0022] [Figure 1] Data from Part A-SAD: Arithmetic mean + / − SE percent change compared to placebo Lp(a) concentration for the daily profile on a linear scale. Plasma levels of Lp(a) determined using an assay (RX SERIES LP 3403) available from Randox Laboratories Ltd. [Figure 2]Data from Part B-MAD: Arithmetic mean + / - SE change percentage compared to placebo Lp(a) concentration for daily profile on a linear scale. Plasma levels of Lp(a) determined using an assay (RX SERIES LP 3403) available from Randox Laboratories Ltd. [Figure 3] Data from Phase 2: Least squares mean + / - 1.96 SE change percent compared to baseline for weekly profile. Plasma levels of Lp(a) determined using assay (RX SERIES LP 3403) available from Randox Laboratories Ltd. [Modes for carrying out the invention]

[0023] The Lp(a) disruptor compound (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid is referred to herein as Compound 1. Compound 1 and a method for preparing Compound 1 are disclosed in International Publication No. 2020 / 247429. Compound 1 has the following structure:

[0024] [ka]

[0025] Another name for this compound is (2S,2'S,2”S)-3,3',3”-((nitrilotris(methylene))tris(benzene-3,1-diyl))tris(2-((R)-pyrrolidine-3-yl)propanoic acid).

[0026] The present invention provides a method for treating various conditions, disorders, and diseases, comprising administering an oral dose of 10 mg to 240 mg of Compound 1 or a pharmaceutically acceptable salt thereof once daily. The present invention further provides Compound 1 or a pharmaceutically acceptable salt thereof for use in the treatment of various conditions, disorders, and diseases, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0027] In certain embodiments, the condition, disorder, or disease is selected from cardiovascular disease, elevated Lp(a) levels, and ASCVD. In further embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered to an individual having elevated Lp(a) levels that puts them at risk of cardiovascular events. Individuals at risk of cardiovascular events or who are at risk of cardiovascular events include individuals with coronary artery disease (CAD), individuals with stroke, or individuals with peripheral artery disease or ASCVD risk equivalents (familial hypercholesterolemia or type 2 diabetes).

[0028] The normal range for Lp(a) levels varies depending on the individual's ethnicity, as described in the European Heart Journal (2022) 43, 3925-3946. An elevated Lp(a) level is one that exceeds the normal range for that individual from the perspective of their ethnicity. In certain embodiments, an elevated Lp(a) level refers to an Lp(a) plasma level of 75 nmol / L or higher, 125 nmol / L or higher, or 175 nmol / L or higher. In certain embodiments, an elevated Lp(a) level refers to an Lp(a) plasma level of 30 mg / dL or higher, 50 mg / dL or higher, or 70 mg / dL or higher. Both nmol / L and mg / dL are widely recognized and used units of measurement for Lp(a) plasma levels.

[0029] In one embodiment, a method is provided for treating or preventing coronary artery disease in an individual, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg.

[0030] In one embodiment, a method is provided for preventing cardiovascular death, myocardial infarction, emergency coronary revascularization, all-cause mortality, or ischemic stroke in an individual having elevated Lp(a) levels, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg.

[0031] In one embodiment, a method is provided for treating acute coronary syndrome in an individual, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg.

[0032] In one embodiment, a method is provided for reducing cardiovascular events in individuals having ASCVD and elevated Lp(a) levels, comprising orally administering to individuals in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg.

[0033] In one embodiment, a method is provided for treating cardiovascular disease in an individual, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases by at least 150 nmol / L after 12 weeks of treatment.

[0034] In one embodiment, a method is provided for treating an individual having elevated Lp(a) levels, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg, such that the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases by at least 150 nmol / L after 12 weeks of treatment.

[0035] In one embodiment, a method is provided for treating an individual with elevated Lp(a) levels who is at risk of cardiovascular events, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases by at least 150 nmol / L after 12 weeks of treatment.

[0036] In one embodiment, a method is provided for treating ASCVD in an individual, comprising orally administering to the individual in need a once-daily dose of compound 1, or a pharmaceutically acceptable salt thereof, in a dose of 10 mg to 240 mg, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases by at least 150 nmol / L after 12 weeks of treatment.

[0037] In one embodiment, a method for treating an individual having elevated Lp(a) levels, i. A step of measuring the individual's Lp(a) plasma level, ii. A method is provided which, if the individual has an Lp(a) plasma level of 175 nmol / L or higher, provides the individual with an oral dose of compound 1 or a pharmaceutically acceptable salt thereof in a once-daily dose of 10 mg to 240 mg.

[0038] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment or prevention of coronary artery disease in an individual, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0039] In one embodiment, Compound 1 or a pharmaceutically acceptable salt thereof is provided for use in the prevention of cardiovascular death, myocardial infarction, emergency coronary revascularization, all-cause mortality, or ischemic stroke in individuals having elevated Lp(a) levels, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0040] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of acute coronary syndrome in an individual, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

[0041] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in reducing cardiovascular events in individuals having ASCVD and elevated Lp(a) levels, the compound being administered orally in once-daily doses of 10 mg to 240 mg.

[0042] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of cardiovascular disease in an individual, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg, and the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases by at least 150 nmol / L after 12 weeks of treatment.

[0043] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of an individual having elevated Lp(a) levels, the compound being administered orally in a once-daily dose of 10 mg to 240 mg, and the individual having an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level is reduced by at least 150 nmol / L after 12 weeks of treatment.

[0044] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of an individual having elevated Lp(a) levels at risk of cardiovascular events, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg, and the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases by at least 150 nmol / L after 12 weeks of treatment.

[0045] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of ASCVD in an individual, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg, and the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment. In a particular embodiment, the individual's Lp(a) plasma level is less than 125 nmol / L after 12 weeks of treatment. In a further embodiment, the individual's Lp(a) level decreases by at least 150 nmol / L after 12 weeks of treatment.

[0046] In one embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of an individual having elevated Lp(a) levels, and the treatment is as follows: i. A step of measuring the individual's Lp(a) plasma level, ii. If the individual has an Lp(a) plasma level of 175 nmol / L or higher, the individual is orally administered a once-daily dose of compound 1 or a pharmaceutically acceptable salt thereof in a dose of 10 mg to 240 mg.

[0047] In one embodiment, the once-daily oral dose is 30 mg to 150 mg, particularly 60 mg to 150 mg, particularly 60 mg to 120 mg, and more specifically 80 mg to 120 mg. In a further embodiment, the once-daily dose is 100 mg to 240 mg, particularly 100 mg to 180 mg.

[0048] In one embodiment, the once-daily oral dose is approximately 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, or 240 mg. In a specific embodiment, the once-daily oral dose is approximately 30 mg. In a specific embodiment, the once-daily oral dose is approximately 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, or 150 mg. In certain embodiments, the once-daily oral dose is approximately 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, or 120 mg. In certain embodiments, the once-daily oral dose is approximately 80 mg, 90 mg, 100 mg, 110 mg, or 120 mg. In certain embodiments, the once-daily oral dose is approximately 80 mg. In certain embodiments, the once-daily oral dose is approximately 100 mg. In certain embodiments, the once-daily oral dose is approximately 120 mg.

[0049] In the therapeutic methods and therapeutic uses disclosed herein, compound 1, or a pharmaceutically acceptable salt thereof, may be administered in the form of a pharmaceutical composition formulated for oral administration. The pharmaceutical composition may be formulated as an oral tablet or capsule, or as an oral liquid. In preferred embodiments, the pharmaceutical composition is formulated as a tablet.

[0050] This specification also provides pharmaceutical compositions comprising a dose of 10 mg to 240 mg of compound 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient, the composition being suitable for oral administration. In one embodiment, the dose is 60 mg to 150 mg, preferably 60 mg to 120 mg, more preferably 80 mg to 120 mg. In a further embodiment, the dose is 100 mg to 240 mg, preferably 100 mg to 180 mg, more preferably about 120 mg. The pharmaceutical composition may be formulated as tablets or capsules for oral administration, or as a liquid for oral administration. In a preferred embodiment, the pharmaceutical composition is formulated as tablets.

[0051] As used herein, “about” means within a statistically significant range of one or more values, such as concentration, length, molecular weight, pH, sequence identity, time frame, temperature, or volume. Such values ​​or ranges may be typically within 20%, more typically within 10%, and even more typically within 5% of a given value or range. The permissible variation encompassed by “about” depends on the particular system in the study and will be readily apparent to those skilled in the art.

[0052] As used herein, “dose” or “dose (plural)” means the amount of a compound administered to an individual at a specific point in time.

[0053] As used herein, “the individual in need of it” means a mammal, such as a human, having a condition, disease, disorder, or symptom in need of treatment or therapy, including, for example, those listed herein. Specifically, the preferred individual to be treated is a human.

[0054] As used herein, the term “pharmaceutically acceptable salt” refers to a salt of a compound that is acceptable for clinical and / or veterinary use. Examples of pharmaceutically acceptable salts and general methodologies for preparing them can be found in “Handbook of Pharmaceutical Salts: Properties, Selection and Use” P. Stahl, et al., 2nd Revised Edition, Wiley-VCH, 2011 and SMBerge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, 1977, 66(1), 1-19. Salt formation can be carried out by adding a pharmaceutically acceptable acid to form an acid addition salt, or by adding a pharmaceutically acceptable base to form a base addition salt. Salts may also be formed simultaneously with the deprotection of nitrogen or oxygen, i.e., the removal of a protecting group. Examples, reactions, and conditions for salt formation are known to those skilled in the art.

[0055] As used herein, “to treat,” “treating,” “in order to treat,” etc., mean to suppress, slow, halt, or reduce the progression or severity of an existing condition, disease, disorder, or symptom.

[0056] Plasma levels of Lp(a) can be determined using a commercially available immunoturbidimetric assay, such as the assay available from Randox Laboratories Ltd (RX SERIES LP 3403). Agglutination occurs due to an antigen-antibody reaction between Lp(a) in the sample and anti-Lp(a) antibodies adsorbed to latex particles. This agglutination is detected as a change in absorbance at 700 nm, which is proportional to the concentration of Lp(a) in the sample. [Examples]

[0057] Phase 1 study: Part A - Single Ascending Dose (SAD) and Part B - Multiple Ascending Dose (MAD) Example 1: Part A-SAD Study The study was designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of compound 1 in healthy individuals. The SAD study was a randomized, physician-blinded, placebo-controlled, single-dose, dose-escalation study conducted in healthy individuals.

[0058] The following orally administered doses and placebo were studied: 1 mg, 10 mg, 30 mg, 100 mg, 200 mg, 400 mg, and 800 mg.

[0059] PD analysis: Absolute values ​​and changes from baseline are calculated from the concentrations of the following PD markers: Lp(a), triglycerides, cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, ApoB, plasminogen, high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1, tissue plasminogen activator antigen, and alpha-2 antiplasmin.

[0060] Safety analysis: Safety parameters evaluated during the study included adverse events (AEs), laboratory parameters, physical examination, vital signs, ECG, and body weight.

[0061] PK Analysis: Plasma concentrations of compound 1 were measured before dose and at 1, 2, 4, 6, 8, 12, 24, 48, 72, 168 (day 8), 336 (day 15), 504 (day 22), 1008 (day 43), 1512 (day 64), 2016 (day 85), and 2520 (day 106) hours after dose. PK parameters were determined using plasma concentrations with a standard non-compartmental method in a validated software program (Phoenix WinNonlin Version 8.1). The determined PK parameters were measured using the AUC. 0-∞ CL / F, C max , t1 / 2, and t max Includes.

[0062] Oral administration of compound 1 in single doses ranging from 1 mg to 800 mg to healthy subjects, starting on day 2 of treatment, reduced Lp(a) levels compared to placebo. The greatest reduction in percentage change compared to placebo was observed at the 400 mg compound dose level, and the greatest reduction compared to placebo was approximately 27% on day 4 in healthy subjects. Lp(a) levels returned to baseline by day 8 for the 10 mg dose level. For other dose levels (1 mg, 30 mg, 100 mg, 200 mg, 400 mg, and 800 mg), Lp(a) levels were still reduced on day 15. The percentage change in Lp(a) concentration up to day 15 is shown in Figure 1.

[0063] There was substantial variability among subjects within treatments for the lipoprotein panel (including HDL cholesterol, LDL cholesterol, triglycerides, cholesterol, and ApoB) and other PD biomarkers (hs-CRP, plasminogen, plasminogen activity, plasminogen activator inhibitor-1, tissue plasminogen activator antigen, and alpha-2 antiplasmin), and no recognizable consistent pattern was seen. Considering the wide range of values obtained at each time point and considering the baseline values and the values obtained after dosing, the data appear to show that while numerical changes (either decreases or increases) were observed, there were no dose-dependent changes relative to baseline identified in either compound 1 treatment compared to placebo.

[0064] The SAD study showed that single oral doses of compound 1 at 1 mg, 30 mg, 100 mg, 200 mg, 400 mg, and 800 mg were well tolerated. Most TEAEs were of mild severity. Six moderate TEAEs were reported. Seven drug-related TEAEs were reported. The most frequently reported TEAEs were headache, back pain, and fatigue. There was no clear relationship between dose and the number of TEAEs reported or the number of individuals reporting TEAEs.

[0065]

Table 1

[0066] overview: Compound 1 in single oral doses ranging from 1 mg to 800 mg was safe and generally well-tolerated by healthy individuals. No overall trends or clinically relevant changes were observed in clinical laboratory parameters, vital signs, ECG, physical examination, and body weight. The mean Cmax of Compound 1 was reached between 2 and 6 hours. The mean t1 / 2 after a single oral dose in healthy individuals ranged from 12.1 to 67.0 hours and increased with increasing dose. After single oral doses of Compound 1 in the range of 30 mg to 800 mg, exposure increased with dose, although the results of dose-proportional analysis showed that Cmax was... max and AUC 0-∞ This indicates that the increase was less than dose-proportional. Following a single oral administration of compound 1, a decrease in Lp(a) levels was observed over the course of treatment, with a maximum decrease of approximately 27% compared to placebo after the single dose.

[0067] Example 2: Part B-MAD Study The study was designed to evaluate the safety, tolerability, and pharmacokinetics of compound 1 in healthy individuals with elevated Lp(a). The MAD study was a randomized, investigator-blinded, placebo-controlled, multi-stage dose-escalation, single-center study conducted in otherwise healthy individuals with elevated Lp(a) (≥75 nM or 30 mg / dL).

[0068] The following oral doses and placebo were studied: 30 mg, 100 mg, 300 mg, 500 mg, and 800 mg. Individuals received the study dose once daily for 14 days. Individuals stayed in the clinical research unit during the course of treatment. Safety follow-up visits were scheduled for 123 days after the last dose.

[0069] PD analysis: Absolute values ​​and changes from baseline are calculated from the concentrations of the following PD markers: Lp(a), triglycerides, cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, ApoB, plasminogen, high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1, tissue plasminogen activator antigen, and alpha-2 antiplasmin.

[0070] Safety analysis: Safety parameters evaluated during the study included adverse events (AEs), laboratory parameters, physical examination, vital signs, ECG, and body weight.

[0071] PK Analysis: Plasma concentrations of compound 1 were measured at the following time points: pre-dose (0 hours) on day 1, and 1, 2, 4, 6, 8, 12, and 24 hours after dose, pre-dose only on days 5, 8, and 11, pre-dose (0 hours) on day 14, and 1, 2, 4, 6, 8, 12, 24 hours (day 15), 96 hours (day 18), 192 hours (day 22), 360 hours (day 29), 696 hours (day 43), 1200 hours (day 64), 1704 hours (day 85), 2208 hours (day 106), and 2952 hours (day 137). PK parameters were determined using plasma concentrations with a standard non-compartmental method in a validated software program (Phoenix WinNonlin Version 8.1). The determined PK parameters were then used in the AR AUC AUC 0-tau CL / F, C max , t1 / 2, and t max Includes.

[0072] Oral administration of multiple doses of compound 1 in healthy individuals with baseline Lp(a) > 30 mg / dL across a dose range of 30 mg to 800 mg reduced Lp(a) levels compared to placebo, starting on day 2 of treatment. The greatest reduction as a percentage change compared to placebo was observed for compound 1 dose levels of 100 mg to 800 mg, with similar greatest reductions compared to placebo occurring at approximately 62%–65% on day 14 / 15. Lp(a) levels returned to baseline by day 29 for the 30 mg dose level, by day 43 for the 100 mg dose level, and by day 64 for the 300 mg, 500 mg, and 800 mg dose levels. The percentage change in Lp(a) concentration up to day 15 is shown in Figure 2.

[0073] Oral administration of compound 1 in multiple doses ranging from 30 mg to 800 mg, initiated on day 2 of treatment, reduced plasminogen levels compared to placebo. The greatest reduction in plasminogen levels compared to placebo was observed at the 800 mg compound 1 dose level, with the maximum reduction being approximately 14% on day 14. Plasminogen levels returned to baseline by day 22 for the 30 mg dose level, by day 43 for the 100 mg, 300 mg, and 500 mg dose levels, and by day 64 for the 800 mg dose level. Considering the literature on individuals with congenital plasminogen deficiency, the plasminogen changes compared to placebo are not clinically relevant.

[0074] For lipoprotein panels (including HDL cholesterol, LDL cholesterol, triglycerides, cholesterol, and ApoB) and other PD biomarkers (hs-CRP, plasminogen activity, plasminogen activator inhibitor-1, tissue plasminogen activator antigen, and alpha-2 antiplasmin), considerable inter-subject variability was observed within treatment, and a consistent pattern was not recognizable. Considering the wide range of values ​​obtained at each time point, and taking into account baseline and post-dose values, the data appear to indicate that numerical changes (either decrease or increase) were observed, but there were no dose-dependent changes relative to baseline identified in any of the compound 1 treatments compared to placebo.

[0075] The MAD study demonstrates that compound 1 is well-tolerated in multiple oral doses of 30 mg, 100 mg, 300 mg, 500 mg, and 800 mg. Most TEAEs were mild in severity. Three moderate TEAEs were reported. One drug-related TEAE was reported. The most frequently reported TEAEs were headache, diarrhea, abdominal pain, nausea, and fatigue. There was no clear relationship between dose and the number of reported TEAEs or the number of individuals reporting TEAEs.

[0076] [Table 2] qd = once a day, N = number of individuals Unless otherwise specified, data is presented as geometric mean. a t max This is presented as the median.

[0077] [Table 3] qd = once a day, N = number of individuals Unless otherwise specified, data is presented as geometric mean.

[0078] overview: Compound 1, administered in multiple oral doses ranging from 30 mg to 800 mg, was safe and generally well-tolerated by healthy individuals. No overall trends or clinically relevant changes were observed in clinical laboratory parameters, vital signs, ECG, physical examination, and body weight. The mean C1 of Compound 1 was [value missing]. max The exposure time reached 2 to 6 hours. In healthy individuals with baseline Lp(a) > 30 mg / dL, the mean t1 / 2 after multiple oral doses ranged from 70.9 hours to 414 hours, increasing with increasing dose. After multiple oral doses of compound 1 in the range of 30 mg to 800 mg, exposure increased with dose, but the results of dose-proportional analysis showed that C max AUC 0-∞ , and AUC 0-tau This indicates that the increase was smaller than dose-proportional. With 30-800 mg once daily dosing for 14 days, there was no associated accumulation of compound 1 (AR in the range of 0.95-1.41). AUC Following multiple oral administrations of compound 1, a decrease in Lp(a) levels was observed throughout the course of treatment, with the greatest decrease being approximately 62%–65% after 14 days of multiple doses compared to placebo.

[0079] Example 3: Phase 2 Study The objective of this study is to investigate the effects of various oral doses of compound 1 over 3 months on Lp(a) levels and safety in a larger group of participants with elevated Lp(a) and a high risk of cardiovascular events. This is a parallel, double-blind, placebo-controlled trial. Individuals will be assigned to one of the following arms: • Arm A: 10 mg of compound 1 • Arm B: 60 mg of compound 1 • Arm C: 240 mg of compound 1 Arm D: Placebo

[0080] The dosage is once daily orally for 12 weeks.

[0081] Inclusion criteria: age 1. Participants must be at least 40 years old at the time they sign the informed consent form.

[0082] Participant types and disease characteristics 2. Participants with Lp(a) ≥ 175 nmol / L measured in the central laboratory on visit 1. 3. High risk of cardiovascular events as defined by recorded coronary artery disease (CAD), stroke, or peripheral artery disease or atherosclerotic cardiovascular disease (ASCVD) risk equivalents (familial hypercholesterolemia or type 2 diabetes). • CAD records should include at least one of the following: a. Angiographic evidence of ≥50% stenosis in one or more major epicardial coronary arteries b. Agatestone score for coronary artery calcification on computerized tomography (CT) scans with a score of ≥300 c. A history of myocardial infarction recorded by a positive enzyme, and either symptoms of myocardial ischemia or electrocardiogram (ECG) changes (Thygesen et al. 2012). d. History of coronary artery revascularization e. Evidence of myocardial ischemia in exercise tests or imaging studies. • Stroke (an acute episode of focal brain, spinal cord, or visual impairment caused by infarction of central nervous system tissue) recordings should include CT scans, magnetic resonance imaging, or other visualization methods. Transient ischemic attacks or embolic strokes (not of atherosclerotic origin) are not eligible events. • Peripheral artery disease records should include intermittent claudication with an ankle-brachial index ≤0.90 and / or limb amputation or revascularization due to lower limb ischemia. Obstructive thromboangiitis is not an eligible event. 4. Participants receiving the following medications in accordance with local practice must have been receiving a stable regimen for at least four weeks prior to their first hospital visit and are expected to continue receiving a stable regimen until the end of the post-treatment follow-up period. a. Lipid-lowering agents (e.g., statins, ezetimibe, PCSK9 inhibitors, prescription-dose niacin, fibrates, fish oil, or other products containing omega-3 fatty acids, including over-the-counter (OTC) preparations) b. Testosterone, estrogen, anti-estrogen, progestin, selective estrogen receptor modulator, or growth hormone

[0083] body weight 5. It has a body mass index in the range of 18.5 to 40 kg / m2, including both ends.

[0084] Gender and contraception / barrier requirements 6. Male and / or female a. Men who agree to use a highly effective or effective method of contraception may participate in this study. b. Women of childbearing potential (WOCBP) and women not of childbearing potential (WNOCBP) who agree to use a highly effective or effective method of contraception may participate in this study.

[0085] The use of contraceptives by participants should be consistent with local regulations regarding contraception for those participating in clinical research.

[0086] Informed consent 7. A signed informed consent can be submitted.

[0087] Other incorporations 8. The principal investigator states that he is willing to take four 12mm round, concave tablets of the research drug daily for 12 weeks, is capable of doing so, is willing to be reliable and able to manage the situation throughout the study period, and is willing to follow the study procedures.

[0088] Exclusion criteria Medical condition 9. In the opinion of the principal investigator, the participant has a history or presence of any underlying medical condition or surgical, physical, medical, or mental condition that could potentially affect participant safety within the study, or would interfere with participation in or completion of the study, or with the interpretation of data. 10. Within three months prior to the first hospital visit, the patient experienced any of the following or other events indicating an unstable medical condition in the opinion of the attending physician: a.Major surgery b. Revascularization of coronary arteries, carotid arteries, or peripheral arteries c. Stroke or transient ischemic attack d. Myocardial infarction or unstable angina e. Acute limb ischemia. 11. Having uncontrolled type 1 or type 2 diabetes mellitus defined as an episode of ketoacidosis or hyperosmolarity requiring hospitalization within the six months prior to the first visit, or having hemoglobin A1c (HbA1c) ≥ 8% on the first visit. 12. The patient has uncontrolled hypertension with a resting blood pressure of systolic ≥ 160 mmHg and / or diastolic ≥ 100 mmHg on first visit, and repeated measurements are permitted. 13. New York Health Association Class III or IV heart failure or last known left ventricular ejection fraction <30%. 14. Active or acute infection requiring systemic antiviral or antimicrobial therapy that has not been completed two days prior to hospital visit. 15. Malignant disease within the past five years, excluding basal cell carcinoma or squamous cell carcinoma of the skin or cervical intraepithelial neoplasia that has been successfully treated. 16. In the opinion of the responsible physician, a recent history of drug or alcohol abuse, or current drug or alcohol abuse. 17. Having two or more clinically significant or severe drug allergies or severe post-treatment hypersensitivity reactions, including but not limited to the following: a. Erythema multiforme severe type b. Linear immunoglobulin A skin disease c. Toxic epidermal necrolysis d.Exfoliative dermatitis. 18. Hypersensitivity to either the active substance or the excipient. 19. Currently, the individual has an infection caused by hepatitis B virus (HBV), i.e., is positive for hepatitis B surface antigen (HBsAg) and / or is PCR positive for HBV deoxyribonucleic acid (DNA). 20. Currently, the individual has an infection caused by the hepatitis C virus (HCV), meaning they are positive for HCV ribonucleic acid (RNA). 21. Has human immunodeficiency virus (HIV) infection.

[0089] Previous / Combination Therapy 22. Lipoprotein apheresis planned within three months of the first hospital visit or during the study. 23. Treatment with another research drug, biological agent, or device within one month of the first visit, or within five half-lives of the research drug, whichever is longer. 24. Treatment with any research oligonucleotide or siRNA within 9 months of the first visit to the clinic.

[0090] Previous / Current Clinical Research Experience 25. You are currently enrolled in any other clinical research, including any other type of medical research, or any investigational product that is deemed scientifically or medically incompatible with this study.

[0091] Diagnostic evaluation 26. Clinically significant abnormalities in screening test values ​​that make it inappropriate to include a participant in the opinion of the principal investigator. 27. Any of the following abnormalities: a. Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m² b. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3.0 × upper limit of normal (ULN) c. Excluding participants with bilirubin > 1.5 × ULN and those diagnosed with Gilbert's syndrome.

[0092] Other exclusions 28. You are a Lilly employee or an employee of any third party involved in research that requires the exclusion of employees. 29. Personnel of the research facility directly involved in this study and / or their immediate family members. Immediate family members are defined as spouses, parents, children, or siblings, whether biological or legally adopted. 30. Pregnant, or planning to become pregnant or breastfeed during the study. 31. The responsible physician's judgment indicates that the patient has a strong suicidal tendency and therefore is considered to be at very high risk of suicide.

[0093] Optional pre-screening: The study includes an optional pre-screening visit as a simple method for facilities to determine whether participants meet the Lp(a) criteria, as assessed by central laboratory evaluation, before the full screening activity is initiated at visit 1. The pre-screening visit should be completed if a participant has not previously measured or does not know their Lp(a) level.

[0094] screening: Screening visit within 3 weeks prior to the first dose (Visit 1). Participants with an insufficiently high Lp(a) at Visit 1 will likely not be eligible for enrollment.

[0095] Treatment period: All procedures (screening and baseline) must be completed before the first dose. Then, blood samples should be collected and clinically observed at 1, 2, 4, 8, and 12 weeks.

[0096] After treatment: A follow-up visit is scheduled approximately four weeks after the final dose.

[0097] The percentage change in Lp(a) and the absolute decrease in Lp(a) were measured from baseline to week 12. The percentage change from baseline to week 12 was also measured for other cardiovascular biomarkers, ApoB and hsCRP. Lipid profiles in response to compound 1 administration were measured. Lipid profiles included measurements of LDL, total cholesterol, HDL, and triglycerides. Blood samples were collected at designated visits and times to determine the plasma concentration of compound 1, which was used to determine key PK parameters.

[0098] [Table 4] Abbreviations: CFB = Change from baseline, CI = Confidence interval, LSM = Least squares mean, N = Number of participants in the analysis population with baseline and post-baseline values ​​at a specified time, PBO = Placebo, SE = Standard error.

[0099] [Table 5] Abbreviations: CFB = Change from baseline, CI = Confidence interval, LSM = Least squares mean, N = Number of participants in the analysis population with baseline and post-baseline values ​​at a specified time, PBO = Placebo, SE = Standard error.

[0100] Safety results: Compound 1 was safe and well-tolerated in a patient population at high risk of cardiovascular events, with no identified safety issues. Serious adverse events (SAEs) and treatment-emergent adverse events (TEAEs) were balanced across the groups. There was no evidence of increased risk of bleeding or diabetes. Discontinuation of the study drug due to adverse events included one placebo patient and six patients from the 240 mg group. All discontinuations were single cases across various standards of care (SOCs) and did not follow any pattern.

[0101] overview: The compounds lowered Lp(a) in a dose-response manner. At a dose of 240 mg, compound 1 showed a 69% reduction at week 12. The reduction in Lp(a) plateaued at doses of 60 mg to 240 mg. Compound 1 was safe and well-tolerated, with no identified safety issues, in a patient population at high risk of cardiovascular events. Phase 2 data indicate that doses in the range of 10 mg to 240 mg are effective and safe.

Claims

1. A method for treating cardiovascular disease in an individual, the method comprising orally administering to the individual in need of such treatment a once-daily dose of 10 mg to 240 mg of (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the individual has an elevated Lp(a) plasma level.

3. The method according to claim 1 or 2, wherein the once-daily dose is approximately 120 mg.

4. The method according to claim 1 or 2, wherein the once-daily dose is 60 mg to 150 mg.

5. The method according to claim 4, wherein the once-daily dose is 60 mg to 120 mg.

6. The method according to claim 5, wherein the once-daily dose is 80 mg to 120 mg.

7. A method for treating an individual having elevated Lp(a) levels, the method comprising orally administering to the individual in need 10 mg to 240 mg once daily dose of (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]aminomethyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7, wherein the individual has an Lp(a) plasma level of 75 nmol / L or higher before treatment.

9. The method according to claim 8, wherein the individual has an Lp(a) plasma level of 125 nmol / L or higher before treatment.

10. The method according to claim 9, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment.

11. The method according to any one of claims 7 to 10, wherein the individual is at risk of a cardiovascular event.

12. The method according to any one of claims 7 to 11, wherein the once-daily dose is approximately 120 mg.

13. The method according to any one of claims 7 to 11, wherein the once-daily dose is 60 mg to 150 mg.

14. The method according to claim 13, wherein the once-daily dose is 60 mg to 120 mg.

15. The method according to claim 14, wherein the once-daily dose is 80 mg to 120 mg.

16. A method for treating an individual having elevated Lp(a) levels at risk of cardiovascular events, the method comprising orally administering to the individual in need 10 mg to 240 mg once daily dose of (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid or a pharmaceutically acceptable salt thereof.

17. The method according to claim 16, wherein the individual has an Lp(a) plasma level of 75 nmol / L or higher before treatment.

18. The method according to claim 17, wherein the individual has an Lp(a) plasma level of 125 nmol / L or higher before treatment.

19. The method according to claim 18, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher before treatment.

20. The method according to any one of claims 16 to 19, wherein the once-daily dose is approximately 120 mg.

21. The method according to any one of claims 16 to 19, wherein the once-daily dose is 60 mg to 150 mg.

22. The method according to claim 21, wherein the once-daily dose is 60 mg to 120 mg.

23. The method according to claim 22, wherein the once-daily dose is 80 mg to 120 mg.

24. A method for treating atherosclerotic cardiovascular disease in an individual, the method comprising orally administering to the individual in need of such treatment a once-daily dose of 10 mg to 240 mg of (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid or a pharmaceutically acceptable salt thereof.

25. The method according to claim 24, wherein the individual has an elevated Lp(a) plasma level.

26. The method according to claim 24 or 25, wherein the once-daily dose is approximately 120 mg.

27. The method according to claim 24 or 25, wherein the once-daily dose is 60 mg to 150 mg.

28. The method according to claim 27, wherein the once-daily dose is 60 mg to 120 mg.

29. The method according to claim 28, wherein the once-daily dose is 80 mg to 120 mg.

30. A compound for use in the treatment of cardiovascular disease in an individual, wherein the compound is (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

31. A compound for use in the treatment of individuals having elevated Lp(a) levels, wherein the compound is (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

32. A compound, for use in the treatment of individuals with elevated Lp(a) levels at risk of cardiovascular events, which is (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof, wherein the compound is administered orally in a once-daily dose of 10 mg to 240 mg.

33. A compound for use in the treatment of atherosclerotic cardiovascular disease in individuals, wherein the compound is (2S)-3-[3-[[bis[[3-[(2S)-2-carboxy-2-[(3R)-pyrrolidine-3-yl]ethyl]phenyl]methyl]amino]methyl]phenyl]-2-[(3R)-pyrrolidine-3-yl]propanoic acid, or a pharmaceutically acceptable salt thereof, wherein the compound is administered orally in a dose of 10 mg to 240 mg once daily.

34. A compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 30 to 33, wherein the individual has an Lp(a) plasma level of 75 nmol / L or higher prior to treatment.

35. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 34, wherein the individual has an Lp(a) plasma level of 125 nmol / L or higher before treatment.

36. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 35, wherein the individual has an Lp(a) plasma level of 175 nmol / L or higher prior to treatment.

37. A compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 30 to 36, wherein the once-daily dose is approximately 120 mg.

38. A compound or a pharmaceutically acceptable salt thereof for use according to any one of claims 30 to 36, wherein the once-daily dose is 60 mg to 150 mg.

39. A compound or a pharmaceutically acceptable salt thereof for use according to claim 38, wherein the once-daily dose is 60 mg to 120 mg.

40. A compound or a pharmaceutically acceptable salt thereof for use according to claim 39, wherein the once-daily dose is 80 mg to 120 mg.

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