Inclisiran for Hypercholesterolemia

(ORION-19 Trial)

Recruiting at 23 trial locations

Overseen By Novartis Pharmaceuticals

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Novartis Pharmaceuticals

Must be taking: Statins

Must not be taking: PCSK9 antibodies, Mipomersen, Lomitapide

Disqualifiers: Null LDLR mutations, Secondary hypercholesterolemia, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 6

9 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a treatment called inclisiran, a cholesterol-lowering injection, for children with homozygous familial hypercholesterolemia (HoFH), a rare condition causing dangerously high cholesterol levels. Researchers aim to determine if inclisiran can safely and effectively lower cholesterol in these children. Participants will receive either inclisiran or a placebo (a non-active substance) through injections over two years. Eligible children have confirmed HoFH and high LDL cholesterol levels, despite taking other cholesterol-lowering medications. As a Phase 3 trial, this study is the final step before potential FDA approval, offering participants a chance to contribute to a treatment that could soon become widely available.

Will I have to stop taking my current medications?

No, you won't have to stop your current medications. Participants must stay on a stable dose of their lipid-lowering therapies, like statins or ezetimibe, for at least 30 days before the trial and continue without changes during the study.

Is there any evidence suggesting that inclisiran is likely to be safe for children with hypercholesterolemia?

Research has shown that inclisiran is generally safe and well tolerated. In studies involving individuals with high cholesterol, some experienced side effects, mainly at the injection site, but these were usually mild. Another study confirmed that long-term use of inclisiran is safe for many patients with abnormal cholesterol levels.

The FDA has already approved inclisiran for treating adults with high cholesterol, indicating its safety. This approval is a positive sign for its potential use in children with a genetic condition that causes very high cholesterol. While this trial is in the early stages for children, the results in adults are encouraging. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Inclisiran is unique because it offers a new way to tackle high cholesterol by using a mechanism called RNA interference. Unlike other treatments like statins, which work by inhibiting cholesterol production in the liver, inclisiran targets the PCSK9 protein, leading to increased removal of LDL cholesterol from the bloodstream. This approach not only promises long-lasting effects with just a few injections each year but also offers an alternative for those who may not tolerate statins well. Researchers are excited about inclisiran because it could significantly simplify cholesterol management and improve compliance with its infrequent dosing schedule.

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

Research shows that inclisiran, which participants in this trial may receive, effectively lowers LDL cholesterol, often known as "bad" cholesterol. Studies have demonstrated that inclisiran can reduce LDL cholesterol levels by about 50 mg/dL. This decrease also helps lower the risk of heart problems by around 15%. Inclisiran reduces a protein called PCSK9, which affects cholesterol levels. Researchers have found it to be safe, with no increased risk of serious side effects. This makes inclisiran a promising option for managing high cholesterol, especially in conditions like familial hypercholesterolemia. ^{1 3 4 6 7}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for children aged 2 to less than 12 with homozygous familial hypercholesterolemia (HoFH), a genetic condition causing very high cholesterol. Participants must have genetically confirmed HoFH but can't join if they have certain mutations in both LDLR alleles.

Inclusion Criteria

I am between 2 and 11 years old.

My HoFH diagnosis was confirmed through genetic testing.

I do not have negative mutations in both LDLR genes.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment (Year 1)

Participants receive either inclisiran or placebo subcutaneous injections at Days 1, 90, and 270

12 months

3 visits (in-person)

Open-label Treatment (Year 2)

All participants receive inclisiran subcutaneous injections at Days 360, 450, and 630

12 months

3 visits (in-person)

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 the safety and effectiveness of Inclisiran, a medication aimed at lowering cholesterol levels, compared to a placebo. It's designed for young patients with severe inherited high cholesterol.

How Is the Trial Designed?

Group I: Inclisiran Experimental Treatment 1 Intervention

Year 1 - inclisiran sodium subcutaneous injection (given at Days 1, 90, and 270) Day 360 only - placebo subcutaneous injection Year 2 - inclisiran sodium subcutaneous injection (given at Days 450 and 630)

Group II: Placebo Placebo Group 1 Intervention

Year 1 - placebo subcutaneous injection (given at Days 1, 90 and 270) Year 2 - inclisiran sodium subcutaneous injection (given at Days 360, 450, and 630)

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

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 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 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 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 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 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, 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 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, 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 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

Inclisiran reduces LDL‐C, PCSK9, cholesterol and apo‐B levels in the body without increasing the risk of serious adverse events.

2.

thelancet.com

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

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

Statin monotherapy results in only 20–40% of very high-risk patients achieving new, lower, recommended LDL cholesterol goals, meaning that those ...

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

According to our results, inclisiran exerts consistent, favourable effects on several lipid/lipoprotein parameters, including TC, LDL-C, HDL-C, non-HDL-C, apoB ...

5.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1913805

Inclisiran for the Treatment of Heterozygous Familial ...

Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who ...

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.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1615758

Inclisiran in Patients at High Cardiovascular Risk with ...

In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels.