Inclisiran for Hypercholesterolemia

(ORION-19 Trial)

Recruiting at 5 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

Trial Summary

What is the purpose of this trial?

This is a pivotal phase III study designed to evaluate safety, tolerability, and efficacy of inclisiran in children (aged 2 to \<12 years) with homozygous familial hypercholesterolemia (HoFH) and elevated low density lipoprotein cholesterol (LDLC).

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.

What data supports the effectiveness of the drug Inclisiran for treating hypercholesterolemia?

Research shows that Inclisiran effectively lowers LDL cholesterol (a type of bad cholesterol) by about 50% in patients with high cholesterol, even when they are already on other cholesterol-lowering medications. It also helps reduce the risk of heart-related events and is safe and well-tolerated. ^{1 2 3 4 5}

Is Inclisiran safe for humans?

Inclisiran has been tested in several clinical trials, and no severe adverse effects or safety concerns directly related to the drug have been reported. It is considered safe and well-tolerated for lowering cholesterol levels. ^{2 3 6 7 8}

How does the drug inclisiran differ from other treatments for hypercholesterolemia?

Inclisiran is unique because it is a small interfering RNA drug that lowers cholesterol by blocking the production of a protein called PCSK9, which helps reduce bad cholesterol (LDL-C). Unlike other treatments, it is administered only twice a year, making it easier for patients to stick to their treatment plan. ^{3 4 9 10 11}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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 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 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 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 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 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 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 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]

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 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 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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Estimation of the major cardiovascular events prevention with Inclisiran. [2022]

2. United States 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. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Inclisiran: a small interfering RNA strategy targeting PCSK9 to treat hypercholesterolemia. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Inclisiran for the Treatment of Hyperlipidemia and for Atherosclerotic Cardiovascular Disease Risk Reduction: A Narrative Review. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Clinical implications and outcomes of the ORION Phase III trials. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Can Clinicians Start Prescribing Inclisiran for Hypercholesterolemia Today? A Review of Clinical Studies for Internal Medicine Physicians and Endocrinologists. [2021]

7. United States pubmed.ncbi.nlm.nih.gov

Serious adverse events of Inclisiran in patients with hypercholesterolemia, a meta analysis of ORION trials. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Inclisiran: A First-in-Class siRNA Therapy for Lowering Low-Density Lipoprotein Cholesterol. [2023]

9. New Zealand 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. [2023]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Inclisiran for the Treatment of Cardiovascular Disease: A Short Review on the Emerging Data and Therapeutic Potential. [2020]

11. England 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. [2022]