# US 10,864,198 B2 · Methods of preventing cardiovascular events in residual risk dyslipidemic populations

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- Number: US 10,864,198 B2
- Document ID: US10864198B2
- Status: Granted
- Kind: B2
- Application number: 15/663,784
- Filed: 2017-07-30
- Published: 2018-02-01
- Granted: 2020-12-15
- Earliest claimed: 2016-07-29
- Assignees: Kowa Company, Ltd.
- Applicants: Kowa Company, Ltd.
- Inventors: Ryu Oshima; Gary Gordon
- Web page: https://patentgrep.com/patent/US10864198B2

## CPC

- A61K 31/423: condensed with carbocyclic rings
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/366: having six-membered rings, e.g. delta-lactones
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides pharmacological interventions for the treatment of dyslipidemia, and to the reduction of residual risk of cardiovascular disease and adverse cardiovascular events in patients on intense statin use or with well-controlled LDL-C concentrations. In particular, the invention relates to the use of pemafibrate to prevent cardiovascular events in populations at-risk due to risk factors such as type 2 diabetes mellitus with dyslipidemia in spite of intense statin use or well-controlled LDL-C.

## Claims

### Claim 1

A method of preventing an adverse cardiovascular event in a patient with type 2 diabetes mellitus comprising administering to the patient a therapeutically effective amount of pemafibrate therapy, wherein:
a) prior to commencing the pemafibrate therapy the patient has an LDL-C concentration ≤70 mg/dL and is on stable statin therapy selected from low to high intensity statin therapy;
b) the patient has an HDL-C concentration ≤40 mg/dL prior to commencing the pemafibrate therapy;
c) the patient has a fasting TG concentration ≥200 mg/dL and <500 mg/dL prior to commencing the pemafibrate therapy;
d) the patient continues the statin therapy after commencing the pemafibrate therapy; and
e) the method prevents the cardiovascular event without decreasing LDL-C concentrations in the patient.

### Claim 2 (depends on 1)

The method of claim 1, wherein said patient does not have systemic atherosclerosis and does not have cardiovascular disease.

### Claim 3 (depends on 1)

The method of claim 1, wherein said patient is ≥50 years of age without systemic atherosclerosis if a man, ≥55 years of age without systemic atherosclerosis if a woman, and said method prevents ischemic stroke, hospitalization for unstable angina requiring unplanned coronary revascularization, or cardiovascular death.

### Claim 4 (depends on 1)

The method of claim 1, wherein said patient is at risk for an ischemic stroke, and said method prevents said ischemic stroke, wherein said method is practiced for a therapeutically effective period of time equaling three years.

### Claim 5 (depends on 1)

The method of claim 1, wherein said patient is at risk for coronary revascularization and said method prevents said coronary revascularization, wherein said method is practiced for a therapeutically effective period of time equaling three years.

### Claim 6 (depends on 1)

The method of claim 1, wherein said patient is at risk for cardiovascular death and said method prevents said cardiovascular death, wherein said method is practiced for a therapeutically effective period of time equaling three years.

### Claim 7 (depends on 1)

The method of claim 1, wherein said patient has an HDL-C concentration of >35 mg/dL prior to commencing the pemafibrate therapy.

### Claim 8 (depends on 1)

The method of claim 1, wherein said patient has an age ≥50 years without systemic atherosclerosis if male or ≥55 years without systemic atherosclerosis if female.

### Claim 9 (depends on 1)

The method of claim 1, wherein said stable statin therapy comprises atorvastatin ≥40 mg/day (based on the weight of the free base).

### Claim 10 (depends on 1)

The method of claim 1, wherein said stable statin therapy comprises rosuvastatin ≥20 mg/day (based on the weight of the calcium salt).

### Claim 11 (depends on 1)

The method of claim 1, wherein said stable statin therapy comprises simvastatin ≥40 mg/day (based on the weight of the free base).

### Claim 12 (depends on 1)

The method of claim 1, wherein said stable statin therapy comprises pitavastatin ≥4 mg/d (based on the weight of the free base).

### Claim 13 (depends on 1)

The method of claim 1, wherein the pemafibrate therapy comprises oral administration of 0.4 mg per day of pemafibrate or a pharmaceutically acceptable salt thereof based on the weight of the free base.

### Claim 14 (depends on 1)

The method of claim 1, wherein, for step e), the method prevents the cardiovascular event without decreasing LDL-C concentrations in the patient during the first 12 weeks of pemafibrate administration.

### Claim 15 (depends on 1)

The method of claim 1, wherein said patient has systemic atherosclerosis or cardiovascular disease.

### Claim 16 (depends on 1)

The method of claim 1, wherein the statin therapy is high intensity statin therapy.

### Claim 17 (depends on 1)

The method of claim 1, wherein the statin therapy is high intensity statin therapy and said patient does not have systemic atherosclerosis and does not have cardiovascular disease.

### Claim 18 (depends on 1)

The method of claim 1, wherein the statin therapy is high intensity statin therapy and said patient has systemic atherosclerosis or cardiovascular disease.

### Claim 19 (depends on 1)

The method of claim 1, wherein the statin therapy is low or moderate intensity statin therapy.

### Claim 20 (depends on 1)

The method of claim 1, wherein the statin therapy is low or moderate intensity statin therapy and said patient has systemic atherosclerosis or cardiovascular disease.

### Claim 21 (depends on 1)

The method of claim 1, wherein the statin therapy is low or moderate intensity statin therapy and said patient does not have systemic atherosclerosis and does not have cardiovascular disease.

### Claim 22 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of a lipid lowering therapy selected from ezetimibe, probucol, niacin, cholestyramine, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA).

### Claim 23 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of a cardiovascular drug selected from an angiotensin converting-enzyme inhibitor, an angiotensin-receptor blocker, aspirin, a beta-blocker, a nitrate, and a thiazide diuretic.

### Claim 24 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of ezetimibe or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

### Claim 25 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of a diabetes medication selected from an alpha-glucosidase inhibitor, a biguanide, a dopamine agonist, a DPP-4 inhibitor, a glucagon-like peptide, a meglitinide, a sodium glucose transporter (SGLT) 2 inhibitor, a sulfonylurea, and a thiazolidinedione.

### Claim 26 (depends on 1)

The method of claim 1, further comprising administering a therapeutically effective amount of a diabetes medication targeting a HbA1c concentration of less than 6%.

### Claim 27 (depends on 1)

The method of claim 1, wherein the patient is at risk for rhabdomyolysis as shown by elevated creatinine kinase.

### Claim 28 (depends on 1)

The method of claim 1, wherein the patient has renal insufficiency.

### Claim 29 (depends on 1)

The method of claim 1, wherein the patient has renal failure.