A Research Study Looking at How NNC0385-0434 Tablets Work to Lower Blood Cholesterol in People With Heart Disease or a High Risk of Heart Disease

Study Overview
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Brief Summary
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This study looks at how well a new medicine, NNC0385-0434, works to lower blood cholesterol levels. Participants will either get NNC0385-0434 as a tablet (a potential new medicine), or placebo as a tablet (a dummy medicine that looks like NNC0385-0434 but has no effect on the body), or evolocumab as an injection (a medicine that doctors can already prescribe). Which treatment participants get is decided by chance. If participants get NNC0385-0434 or placebo participants will need to take 1 tablet every morning. If participants get evolocumab participants will need to take 1 injection every 2 weeks. The study will last for about 22 weeks. About 255 people will participate in the study. Participants will have 9 visits to the clinic and 2 phone calls with the study doctor. Some people will be invited to participate in a sub-study and will have 4 extra visits (13 visits in total). Participants will have blood samples taken at all visits to the clinic (except visit 0). At 4 clinic visits, participants will have an electrocardiogram (ECG). This is a test to check your heart. Women can only take part in the study if they are not able to become pregnant.

Official Title
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Dose Response and Safety of an Oral PCSK9i, NNC0385-0434, in Patients With Established Atherosclerotic Cardiovascular Disease (ASCVD) or ASCVD Risk on Maximally Tolerated Statin Dose and Other Lipid-lowering Therapy Requiring Further LDL-C Reduction

Conditions
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Atherosclerotic Cardiovascular Disease

Intervention / Treatment
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* Drug: NNC0385-0434 A 15 mg
* Drug: NNC0385-0434 A 40 mg
* Other: Placebo I A (for NNC0385-0434 A 15 mg)
* Drug: NNC0385-0434 A 100 mg
* Other: Placebo I A (for NNC0385-0434 A 40 mg)
* Other: Placebo II A (for NNC0385-0434 A 100 mg)
* Drug: Evolocumab 140 mg/mL, Repatha®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females of non-childbearing potential. Established atherosclerotic cardiovascular disease (ASCVD) (criteria a) or ASCVD risk (criteria b): Age 40 years or older at the time of signing informed consent and history of ASCVD Age above 50 years at the time of signing informed consent and with ASCVD risk Serum LDL-C above or equal to 1.8 mmol/L (above or equal to 70 mg/dL) as measured by the central laboratory at screening. Japanese participants: Serum LDL-C above or equal to 2.6 mmol/L (above or equal to 100 mg/dL) for participants of 40 years of age or older and with a history of coronary heart disease, and serum LDL-C above or equal to 3.1 mmol/L (above or equal to 120 mg/dL) for all other Japanese participants Participants must be on maximally tolerated dose of statins. Participants not receiving statin must have documented evidence of intolerance to all doses of at least two different statins. Exclusion Criteria: Treatment with PCSK9i therapy (alirocumab or evolocumab within 90 days prior to screening) or PCSK9 siRNA therapy (inclisiran within 12 months prior to screening). Fasting triglyceride above 4.52 mmol/L (above 400 mg/dL) as measured by the central laboratory at screening. Myocardial infarction, stroke, hospitalization for unstable angina pectoris or transient ischaemic attack within 180 days prior to the day of screening. Renal impairment with eGFR less than 30 ml/min/1.73 m2 as measured by the central laboratory at screening

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral NNC0385-0434 15 mg once-daily (OD)<br>15 mg NNC0385-0434 co-formulated with 500 mg Salcaprozate sodium (SNAC) tablet once daily | Drug: NNC0385-0434 A 15 mg<br>* 15 mg administered as one oral tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces).<br>|
| Placebo Comparator: Oral placebo (NNC0385-0434 15 mg)<br>15 MG placebo administered as tablets (without SNAC) once daily | Other: Placebo I A (for NNC0385-0434 A 15 mg)<br>* Placebo administered as 1 tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces). placebo tablets are sized match to the active arm within dose level<br>|
| Experimental: Oral NNC0385-0434 40 mg OD<br>40 mg study drug co-formulated with 500 mg SNAC tablet once daily | Drug: NNC0385-0434 A 40 mg<br>* 40 mg administered as one oral tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces).<br>|
| Placebo Comparator: Oral placebo (NNC0385-0434 40 mg)<br>placebo administered as tablets (without SNAC) once daily | Other: Placebo I A (for NNC0385-0434 A 40 mg)<br>* Placebo administered as one tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces). placebo tablets are sized match to the active arm within dose level<br>|
| Experimental: Oral NNC0385-0434 100 mg<br>100 mg NNC0385-0434 co-formulated with 500 mg SNAC tablet once daily (51 participants) | Drug: NNC0385-0434 A 100 mg<br>* 100 mg administered as one oral tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces).<br>|
| Placebo Comparator: Oral placebo (NNC0385-0434 100 mg)<br>placebo administered as tablets (without SNAC) once daily | Other: Placebo II A (for NNC0385-0434 A 100 mg)<br>* Placebo administered as one tablet once daily in the morning in a fasting state. The tablet should be taken at least 30 min before the first food, beverage or other oral medications of the day. The tablet can be taken with up to half a glass of water (approximately 120 mL/ 4 fluid ounces). placebo tablets are sized match to the active arm within dose level<br>|
| Active Comparator: Subcutaneous evolocumab 140 mg Q2W<br>140 mg evolocumab Subcutaneous (s.c.) injections every 2 weeks (51 participants). The s.c. evolocumab arm is open-label to limit unnecessary injections | Drug: Evolocumab 140 mg/mL, Repatha®<br>* Every 2 weeks subcutaneous (s.c.) injection of 140 mg into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated. Administered using a pre-filled SureClick® autoinjector (single-use). Dose volume: 1 mL<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in low-density lipoprotein (LDL)-cholesterol | percent | From baseline (week 0) to visit 9 (week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in total cholesterol | Percent | From baseline (week 0) to visit 9 (week 12) | 
| Change in high density lipoprotein (HDL)-cholesterol | percent | From baseline (week 0) to visit 9 (week 12) | 
| Change in very low density lipoprotein (VLDL)-cholesterol | Percent | From baseline (week 0) to visit 9 (week 12) | 
| Change in triglycerides | percent | From baseline (week 0) to visit 9 (week 12) | 
| Change in total Apo B | percent | From baseline (week 0) to visit 9 (week 12) | 
| Change in total Apo CIII | precent | From baseline (week 0) to visit 9 (week 12) | 
| Change in total Lipoprotein(a) ( Lp(a)) | Ratio | From baseline (week 0) to visit 9 (week 12) | 
| Treatment-emergent adverse events | Number of events | From baseline (week 0) to visit 10 (19 weeks + 4 days) |