A multi- center, randomized, double-blind, placebo-controlled parallel–group, dose-finding study to evaluate efficacy, safety, and tolerability of DII235 in adults with elevated Lipoprotein(a)

The primary objectives of this study are to evaluate the dose-response relationship of DII235 compared to placebo on time averaged percentage change from baseline of lipoprotein(a) in adults with elevated Lp(a) (defined as Lp(a) ≥ 150 nmol/L), and to assess the efficacy of DII235 versus placebo in time averaged percent change from baseline in Lp(a) between Day 60 and Day 360. These objectives are clinically relevant for establishing the optimal dosing strategy and therapeutic efficacy of DII235 in reducing elevated Lp(a) levels, a significant independent risk factor for cardiovascular disease.

The secondary objectives include:

• Evaluation of the efficacy of DII235 versus placebo in time averaged percent change from baseline in Lp(a) between Day 60 and Day 360 (except those covered by the primary objectives) and between Day 240 and Day 360

• Assessment of the proportion of participants achieving Lp(a) < 125 nmol/L for DII235 dose regimens compared to placebo at Day 180 and Day 360

• Assessment of the proportion of participants achieving Lp(a) < 75 nmol/L for DII235 dose regimens compared to placebo at Day 180 and Day 360

• Evaluation of the safety and tolerability of DII235 compared to placebo

This clinical trial enrolled a total of **128 participants** ranging from **18 to 80 years of age**, including both **male and female subjects**. The study population consisted of adults with **elevated lipoprotein(a)**, defined as Lp(a) levels of **150 nmol/L or greater**. Participants were required to have either established **atherosclerotic cardiovascular disease (ASCVD)** and/or **Type 2 diabetes mellitus**. Qualifying cardiovascular conditions included **coronary heart disease** with documented prior **myocardial infarction**, **coronary revascularization** procedures, significant coronary artery stenosis, or elevated **coronary artery calcium scores**; **cerebrovascular disease** with prior **ischemic stroke** or carotid artery disease; or **peripheral arterial disease** with documented amputation, revascularization, or abnormal ankle-brachial index. All participants were maintained on standard of care treatment for ASCVD risk factors according to local guidelines. Those receiving **lipid-lowering therapy**, including **statins**, **ezetimibe**, or **PCSK9 inhibitors**, were required to be on a stable regimen for at least four weeks prior to screening, with no planned changes throughout the treatment period.

This is a multi-center, **randomized**, **double-blind**, **placebo-controlled**, parallel-group, dose-finding **phase 2 clinical trial** designed to evaluate the efficacy, safety, and tolerability of **DII235** in adults with **elevated lipoprotein(a)**. The investigational medicinal product DII235 is a **small interfering RNA (siRNA)** formulated as a **solution for injection** containing the active substance DII235, administered via **subcutaneous injection**. The comparator is **placebo** consisting of sodium chloride and glucose monohydrate solution for injection, also administered subcutaneously. The maximum treatment period is **18 months** for both the investigational product and placebo.

The primary objective is to evaluate the dose-response relationship of DII235 compared to placebo on time-averaged percentage change from baseline of **Lp(a)** in adults with elevated Lp(a) defined as Lp(a) ≥ 150 nmol/L. An additional primary objective is to evaluate the efficacy of DII235 versus placebo in time-averaged percent change from baseline in Lp(a) between Day 60 and Day 360. The **primary endpoints** include time-averaged percent change from baseline in Lp(a) measured between Day 60 and Day 180, and between Day 60 and Day 360.

**Secondary endpoints** include time-averaged percent change from baseline in Lp(a) measured between Day 60 and Day 360 and between Day 240 and Day 360, participant status of achieving Lp(a) less than 125 nmol/L at Day 180 and Day 360, participant status of achieving Lp(a) less than 75 nmol/L at Day 180 and Day 360, and incidence of **adverse events**, safety laboratory parameters, and **vital signs**.

The trial will enroll male or female participants aged 18 to 80 years inclusive at screening. Principal **inclusion criteria** require signed informed consent prior to participation, Lp(a) ≥ 150 nmol/L at screening measured at the central laboratory, and presence of **atherosclerotic cardiovascular disease (ASCVD)** and/or **Type 2 diabetes mellitus (T2DM)**. Qualifying ASCVD includes **coronary heart disease** such as prior **myocardial infarction** of presumed atherosclerotic origin occurring ≥ 12 weeks prior to screening, prior **coronary revascularization** (PCI or CABG) occurring ≥ 12 weeks prior to screening, angiographic or CT-imaging evidence of coronary atherosclerosis with ≥50% stenosis in at least one major epicardial coronary artery, or **coronary artery calcium (CAC)** score of ≥ 300 AU by computed tomography (or ≥ 100 AU if participant has T2DM). Qualifying **cerebrovascular disease** includes prior **ischemic stroke** occurring ≥ 12 weeks prior to screening confirmed by documented brain imaging (CT or MRI), history of percutaneous or surgical **carotid artery revascularization** occurring ≥ 12 weeks prior to screening, or carotid artery stenosis ≥ 70% or symptomatic carotid artery disease with ≥ 50% stenosis. Qualifying **peripheral arterial disease (PAD)** includes prior non-traumatic amputation of a lower extremity due to peripheral artery disease, history of prior percutaneous or surgical revascularization of iliac, femoral, or popliteal artery, or prior documentation of a resting **ankle-brachial index** ≤ 0.9. Participants must be on standard of care treatment for ASCVD risk factors according to local guidelines. Those receiving **lipid lowering therapy** including **statins**, **ezetimibe**, or **proprotein convertase subtilisin/kexin type 9 (PCSK9)** monoclonal antibody inhibitors must be on a stable regimen for a minimum of 4 weeks prior to screening with no planned changes after screening and expected to remain on a stable regimen through the end of treatment.

The estimated recruitment start date is February 4, 2026, and the estimated end date is September 8, 2028. The overall trial duration encompasses the recruitment period, treatment period of up to 18 months, and follow-up assessments. Participant involvement includes a screening visit to assess eligibility criteria including measurement of Lp(a) at the central laboratory, followed by randomization and initiation of treatment. Study visits occur at specified intervals including Day 60, Day 180, Day 240, and Day 360 for assessment of efficacy endpoints and safety parameters. The end-of-study visit occurs at Day 360 or upon early termination. Conditions that may lead to early termination from the study include participant withdrawal of consent, safety concerns as determined by the investigator, protocol violations, or administrative reasons.

**DII235** is the experimental medicinal product in this clinical trial, formulated as a **solution for injection** and administered via **subcutaneous injection**. The active substance is DII235, also known by the synonym BW-20829, which is classified as a **small interfering RNA (siRNA)** of nucleic acid origin. The sponsor product code for this investigational product is DII235, manufactured by NOVARTIS PHARMA AG. The dosage is expressed in milligrams, though specific dose amounts are to be determined as part of the dose-finding objectives of this study. The maximum treatment period for DII235 administration is **18 months**. The study is designed as a multi-center, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the dose-response relationship and efficacy of DII235 in reducing **Lipoprotein(a)** levels in adults with elevated Lp(a) defined as ≥ 150 nmol/L.

The **placebo** comparator consists of a solution containing **sodium chloride** and **glucose monohydrate**, both of chemical origin. This placebo product is formulated as a solution for injection and is administered via subcutaneous injection, matching the route of administration of the experimental treatment. The maximum daily dose amount is 2 milliliters, with a maximum total dose amount of 6 milliliters over the treatment period. The placebo treatment duration also extends to a maximum of 18 months, corresponding to the experimental treatment period. This product has been relabeled for clinical use and carries the ATC code B05CB01. The placebo formulation is designed to maintain the double-blind nature of the study while providing an appropriate control for evaluating the efficacy, safety, and tolerability of DII235 in the target patient population.

Efficacy will be assessed through measurement of lipoprotein(a) levels at specified timepoints throughout the study. The primary efficacy endpoints are the time averaged percent change from baseline in Lp(a) measured between Day 60 and Day 180, and the time averaged percent change from baseline in Lp(a) measured between Day 60 and Day 360. Secondary efficacy endpoints include the time averaged percent change from baseline in Lp(a) measured between Day 60 and Day 360 and between Day 240 and Day 360. Additional secondary endpoints evaluate the participant's status of achieving Lp(a) levels below 125 nmol/L at Day 180 and Day 360, as well as achieving Lp(a) levels below 75 nmol/L at Day 180 and Day 360. Lp(a) measurements will be performed at the central laboratory to ensure standardization of results across study sites.