Inclisiran for Hypercholesterolemia

(SOLVE-LDL-C Trial)

Overseen By Antoinette S Birs, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of California, San Diego

Must be taking: Statins

Must not be taking: Inclisiran

Disqualifiers: Active liver disease, Uncontrolled diabetes, Active malignancy, Recent major CV event, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 12 months

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how well inclisiran, an injectable medication, lowers bad cholesterol (LDL) in individuals who cannot take sufficient statins due to interactions with other medications. It focuses on those with complex health issues, such as diabetes, liver or kidney disease, or those who have undergone a solid-organ transplant and are taking five or more medications. The study includes two groups: one will continue their usual treatment, while the other will add inclisiran. This trial suits individuals with high cholesterol who can only tolerate limited statins and are managing multiple health conditions and medications. As a Phase 4 trial, inclisiran has already received FDA approval and proven effective, and this research aims to understand its benefits for more patients.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, it mentions that participants should be on five or more prescription drugs and on maximally tolerated statin therapy, which can be no statin if you have intolerance. It's best to discuss your specific medications with the trial team.

What is the safety track record for inclisiran?

Research has shown that inclisiran is generally safe and well-tolerated. Some studies have found a higher chance of reactions at the injection site, meaning people might notice some redness or discomfort where the shot is given. However, these reactions are usually mild. Inclisiran has been used in a wide range of patients with high cholesterol and has not shown serious safety issues over time. The FDA's approval of inclisiran for lowering cholesterol in other conditions adds confidence about its safety. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Inclisiran is unique because it uses a novel approach to manage high cholesterol by leveraging RNA interference technology. Unlike standard treatments like statins, which reduce cholesterol by inhibiting an enzyme in the liver, inclisiran works by targeting and degrading specific mRNA involved in cholesterol production. This results in a prolonged effect with just a few doses per year, offering a convenient and potentially more consistent option for patients. Researchers are excited about inclisiran because of its innovative mechanism and the promise of sustained cholesterol reduction with less frequent dosing.

What evidence suggests that inclisiran might be an effective treatment for hypercholesterolemia?

Research has shown that inclisiran effectively lowers LDL cholesterol, often referred to as "bad" cholesterol. One study found that inclisiran reduced LDL cholesterol by about 50% and total cholesterol by more than 13%. Besides improving cholesterol levels, inclisiran has been shown to lower the risk of heart problems, such as heart attacks, by 15%. In this trial, participants in the Inclisiran Arm will receive inclisiran as an add-on therapy to their standard lipid-lowering care. Previous evidence supports inclisiran as a proven option for managing high cholesterol, especially for those who cannot fully benefit from traditional statins due to other medications or health conditions. ^{1 3 4 6 7}

Who Is on the Research Team?

Antoinette Birs, MD

Principal Investigator

University of California, San Diego

Michael Wilkinson, MD

Principal Investigator

University of California, San Diego

Eric D Adler, MD

Principal Investigator

University of California, San Diego

Pam Taub, MD

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

This trial is for adults aged 18-85 with metabolic syndrome or hypercholesterolemia, taking five or more prescription drugs. It's aimed at those who can't fully use statins due to drug interactions, like people with Type II diabetes, liver disease, chronic kidney disease, autoimmune diseases, or organ transplants. Participants should have an elevated risk of heart disease and be willing to receive injections.

Inclusion Criteria

I have signed the consent form.

My LDL is over 90 mg/dL or my non-HDL is over 120 mg/dL.

My heart disease risk score for the next 10 years is 7.5% or higher.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Baseline

Baseline assessments and first dose of inclisiran for the intervention group

1 day

1 visit (in-person)

Treatment

Participants receive inclisiran injections at baseline, 3 months, and 9 months; standard of care continues for all

12 months

3 visits (in-person) for inclisiran group, 5 visits (in-person) for all

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Inclisiran

Trial Overview

The study tests Inclisiran sodium as a subcutaneous injection for lowering bad cholesterol (LDL-C) in patients where other medications interfere with statin use. The trial is open-label and randomized; participants will also continue their standard care while receiving the new treatment.

How Is the Trial Designed?

Group I: Standard of Care, no intervention Active Control 1 Intervention

Patients will continue the standard of care for lipid lowering as deemed appropriate by their medical team, no changes to lipid lowering therapy are permited during the study.

Group II: Inclisiran Arm Active Control 1 Intervention

Patients in the intervention arm will be treated with a subcutaneous injection of inclisiran 284mg for three doses (baseline visit, 3 months, then 9 month visit) as add-on therapy to the standard of care for lipid lowering as determined by their medical team.

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

Inclisiran significantly reduces low-density lipoprotein cholesterol (LDL-C) by approximately 50%, with this reduction sustained for up to 4 years, making it an effective long-term treatment option for managing cholesterol levels.

The treatment is well tolerated, with injection-site reactions being the most common side effect, and it has shown potential for reducing cardiovascular events compared to placebo, suggesting it may be a cost-effective alternative to other therapies like PCSK-9 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclisiran for the Treatment of Hyperlipidemia and for Atherosclerotic Cardiovascular Disease Risk Reduction: A Narrative Review. Cowart, K., Singleton, J., Carris, NW.[2023]

Inclisiran, a cholesterol-lowering therapy administered every 6 months, showed significant reductions in LDL cholesterol levels (up to 51%) in patients with atherosclerotic cardiovascular disease (ASCVD) when used alongside maximum tolerated statins, based on the ORION-10 trial.

The study determined that inclisiran is cost-effective at an annual price below $9,000, with a 100% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost Effectiveness of Inclisiran in Atherosclerotic Cardiovascular Patients with Elevated Low-Density Lipoprotein Cholesterol Despite Statin Use: A Threshold Analysis. Desai, NR., Campbell, C., Electricwala, B., et al.[2023]

Inclisiran, a novel treatment for lowering LDL cholesterol, was evaluated in two phase 3 trials involving a significant number of patients, demonstrating its efficacy in reducing LDL levels over time.

The results indicated that inclisiran effectively lowered LDL cholesterol levels compared to placebo, suggesting it could be a valuable option for patients struggling with high cholesterol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In patients with ASCVD and elevated LDL-C with maximal statin therapy, inclisiran reduced LDL-C levels at 18 months. Clark, J., Montori, V.[2020]

Inclisiran, a first-in-class siRNA therapy, has been shown to effectively lower low-density lipoprotein cholesterol (LDL-C) by approximately 50% in patients with atherosclerotic cardiovascular disease and those at high risk, including those with familial hypercholesterolemia.

The ongoing Phase III trials will further evaluate the long-term safety and effectiveness of inclisiran, as well as its impact on cardiovascular outcomes, particularly in patients with homozygous familial hypercholesterolemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical implications and outcomes of the ORION Phase III trials. Brandts, J., Ray, KK.[2022]

Inclisiran significantly reduces low-density lipoprotein cholesterol (LDLc) levels, with an average reduction of 60.6 mg/dl, based on a meta-analysis of 57,431 patients, including 1,592 treated with Inclisiran.

The treatment with Inclisiran is associated with a reduction in major cardiovascular events (MACE), aligning with findings from trials involving other PCSK9 inhibitors, suggesting its potential effectiveness in preventing cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimation of the major cardiovascular events prevention with Inclisiran. Cordero, A., Santos-Gallego, CG., Fácila, L., et al.[2022]

Inclisiran, a new drug for lowering LDL cholesterol, was found to have a nonsignificant incidence of serious adverse events in a systematic review of 8 clinical trials involving 4981 patients, suggesting it is generally safe.

The analysis indicated that while there were no significant safety concerns overall, specific adverse events like product issues and endocrine disorders were noted, warranting further investigation in larger ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Serious adverse events of Inclisiran in patients with hypercholesterolemia, a meta analysis of ORION trials. Jawwad, M., Riaz, M., Mehtab, M., et al.[2023]

Inclisiran is a promising new treatment for lowering LDL cholesterol in adolescents with familial hypercholesterolemia, with ongoing studies (ORION-13 and ORION-16) assessing its efficacy and safety in this population.

These trials involve approximately 162 adolescents (12 with homozygous and 150 with heterozygous familial hypercholesterolemia) and aim to evaluate LDL-C reduction over a year, potentially providing a valuable option for those with limited treatment choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia. Reijman, MD., Schweizer, A., Peterson, ALH., et al.[2022]

Inclisiran is an effective treatment for dyslipidemia, significantly lowering LDL cholesterol (LDL-C) levels through a novel mechanism that silences the PCSK9 gene, as demonstrated in clinical trials from the ORION program.

The safety profile of inclisiran is favorable, with adverse events similar to placebo, although injection-site reactions were more common; this suggests it is a well-tolerated option for patients compared to other PCSK9 therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia. Banerjee, Y., Pantea Stoian, A., Cicero, AFG., et al.[2022]

Inclisiran has demonstrated favorable efficacy in lowering LDL cholesterol and PSCK9 levels across eight clinical trials, indicating its effectiveness as a lipid-lowering drug.

The safety profile of inclisiran is positive, with no severe adverse effects or fatalities reported, suggesting it is a safe option for patients needing cholesterol management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can Clinicians Start Prescribing Inclisiran for Hypercholesterolemia Today? A Review of Clinical Studies for Internal Medicine Physicians and Endocrinologists. Jahangir, A., Sahra, S., Krzyzak, M.[2021]

Inclisiran is a novel therapy for hyperlipidemia that effectively lowers LDL cholesterol levels by blocking the production of PCSK-9, leading to increased LDL receptor expression in the liver.

It offers the convenience of infrequent dosing (twice a year) and has a safety profile similar to placebo, making it a promising option for patients who struggle with medication adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclisiran for the Treatment of Cardiovascular Disease: A Short Review on the Emerging Data and Therapeutic Potential. Kosmas, CE., Muñoz Estrella, A., Skavdis, A., et al.[2020]

Inclisiran is a novel therapy that effectively lowers low-density lipoprotein cholesterol (LDL-C) through a twice-yearly subcutaneous injection, working by inhibiting the PCSK9 gene, which leads to increased LDL receptor recycling.

In clinical trials, inclisiran demonstrated similar efficacy in reducing LDL-C compared to existing treatments, with a safety profile comparable to placebo, although more data is needed on its long-term safety and impact on cardiovascular outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inclisiran: A First-in-Class siRNA Therapy for Lowering Low-Density Lipoprotein Cholesterol. Samuel, E., Watford, M., Egolum, UO., et al.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11907238/

Safety and Efficacy of Inclisiran in Hyperlipidemia

Our pooled analysis demonstrated that inclisiran was associated with a significant decline in the % of LDL‐C levels (MD = −50.42, 95% CI: −56.15 ...

2.

thelancet.com

thelancet.com/journals/landia/article/PIIS2213-8587(22)00353-9/fulltext

Long-term efficacy and safety of inclisiran in patients with ...

The aim of this study was to assess the effect of long-term dosing of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol.

3.

mayoclinicproceedings.org

mayoclinicproceedings.org/article/S0025-6196(24)00313-6/fulltext

Inclisiran—Amazing for Cholesterol but Outcome Data ...

Both drugs reduced cholesterol by an impressive 50 mg/dL, and both reduced the risk of cardiovascular events by a more modest 15%. The drugs are expensive and ...

4.

sciencedirect.com

sciencedirect.com/science/article/pii/S2666602222000441

Efficacy and safety of inclisiran a newly approved FDA drug

Secondary outcomes. Meta-analysis of available data showed that inclisiran significantly affected total cholesterol (TC) [n = 283, MD = −13.67% (95%CI ...

5.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1913805

Inclisiran for the Treatment of Heterozygous Familial ...

The reduction in LDL cholesterol levels of almost 50% with twice-yearly administration of inclisiran in patients with heterozygous familial hypercholesterolemia ...

6.

jacc.org

jacc.org/doi/10.1016/j.jacc.2023.10.007

Safety and Tolerability of Inclisiran for Treatment ...

This analysis indicates that long-term inclisiran is safe and generally well tolerated in a diverse population of patients with dyslipidemia ...

7.

ahajournals.org

ahajournals.org/doi/10.1161/CIRCULATIONAHA.122.063460

Results From the ORION-5 Randomized Clinical Trial

Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels.