Inclisiran for High Cholesterol

(ORION-13 Trial)

No longer recruiting at 22 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: Active liver disease, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a medication called inclisiran to determine its safety and effectiveness in lowering bad cholesterol (LDL-C) in teens with homozygous familial hypercholesterolemia (HoFH). HoFH is a genetic disorder that causes very high cholesterol levels, even with treatment. Participants will receive either the actual medication or a placebo (a harmless substance with no effect) to compare results. Teens who might be suitable candidates have genetically confirmed HoFH and high cholesterol despite taking other cholesterol-lowering medicines. As a Phase 3 trial, this study represents 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?

The trial does not specify if you need to stop your current medications, but you must be on a stable dose of statins or other lipid-lowering therapy for at least 30 days before joining. If you are taking certain medications like mipomersen or lomitapide, you need to stop them 5 months before screening.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that inclisiran is generally safe and well-tolerated. Studies have found that it lowers bad cholesterol (LDL-C) without causing serious side effects. Long-term evidence confirms that people from various backgrounds do not experience new safety issues with inclisiran, suggesting it is safe for reducing cholesterol levels. Prospective trial participants may find this information reassuring regarding the safety of inclisiran. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Inclisiran is unique because it offers a novel approach to lowering high cholesterol by targeting PCSK9, a protein involved in cholesterol regulation. Unlike traditional statins, which reduce cholesterol production in the liver, inclisiran works by using small interfering RNA (siRNA) to block the production of PCSK9, leading to increased removal of LDL cholesterol from the bloodstream. Additionally, inclisiran is administered as a subcutaneous injection just a few times a year, providing a convenient alternative to daily oral medications. Researchers are excited about its potential to maintain consistent cholesterol reduction with less frequent dosing.

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

Research has shown that inclisiran, which participants in this trial may receive, effectively lowers LDL cholesterol, often referred to as "bad" cholesterol. In several studies, inclisiran reduced LDL cholesterol levels by about 50%, with this reduction lasting for an extended period, providing ongoing benefits. However, in individuals with the genetic condition homozygous familial hypercholesterolemia (HoFH), inclisiran did not significantly lower LDL cholesterol levels, despite reducing levels of the protein PCSK9, which helps control cholesterol. This indicates that while inclisiran generally works well, its effects may vary for those with certain genetic conditions like HoFH. ^{1 6 7 8 9}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adolescents with a genetic condition called homozygous familial hypercholesterolemia (HoFH) and high LDL cholesterol levels, despite being on the highest dose of statins they can tolerate. They should not have used certain other cholesterol drugs recently and must have decent kidney function.

Inclusion Criteria

I have been genetically diagnosed with Homozygous Familial Hypercholesterolemia.

Your cholesterol level is too high when you haven't eaten for a while.

I have been on the highest dose of statin I can tolerate for at least 30 days.

Exclusion Criteria

My tests show a negative mutation in both LDLR genes.

I have not taken mipomersen or lomitapide in the last 5 months.

Recent and/or planned use of other investigational medicinal products or devices

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
• Placebo

Trial Overview The study tests Inclisiran, a new medication aimed at lowering LDL cholesterol, against a placebo in young people with severe inherited high cholesterol. It's designed to see if it's safe and effective in reducing their cholesterol levels.

How Is the Trial Designed?

Group I: Part 2 - Inclisiran (Total) Experimental Treatment 1 Intervention

Inclisiran sodium 300 mg sc injection (given at Days 450 and 630). In addition, participants assigned to placebo in Part 1 received inclisiran sodium 300 mg sc injection on Day 360, while participants assigned to inclisiran in Part 1 received placebo sc injection on Day 360.

Group II: Part 1 - Inclisiran Experimental Treatment 1 Intervention

Inclisiran sodium 300 mg subcutaneous (sc) injection (given at Days 1, 90 and 270)

Group III: Part 1 - Placebo Placebo Group 1 Intervention

Placebo sc injection (given at Day 1, 90 and 270)

Inclisiran is already approved in European Union, United States, China for the following indications:

Approved in European Union as Leqvio for:

• Primary hypercholesterolemia (heterozygous familial and non-familial)
• Mixed dyslipidemia

Approved in United States as Leqvio for:

• Heterozygous familial hypercholesterolemia (HeFH)
• Clinical atherosclerotic cardiovascular disease (ASCVD)
• Primary hypercholesterolemia

Approved in China as Leqvio for:

• Primary hypercholesterolemia (heterozygous familial and non-familial)
• Mixed dyslipidemia

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

Acitretin is a non-immunosuppressive oral medication that has been used for treating psoriasis, indicating it may have a safer profile compared to immunosuppressive treatments.

Tofacitinib, an oral Janus kinase inhibitor, also shows efficacy in psoriasis treatment but comes with significant safety risks, highlighting the need for careful patient selection and monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small Molecules for Psoriasis. Leonardi, CL.[2019]

Acitretin is a non-immunosuppressive oral medication that has been used for treating psoriasis, providing efficacy without the risks associated with immunosuppressive therapies.

Tofacitinib, an oral Janus kinase inhibitor, also shows effectiveness in psoriasis treatment but comes with significant safety concerns, highlighting the need for careful patient selection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small Molecules for Psoriasis. Leonardi, CL.[2016]

In a pilot study of nine patients with severe chronic hand dermatitis (CHD), acitretin showed promising results, with 33.3% of patients achieving a physician global assessment (PGA) of clear or almost clear skin after treatment.

The study found a significant reduction in symptoms, with a 45% decrease in the modified total lesion symptom score (mTLSS), indicating that acitretin may be an effective treatment option for severe CHD, although further research is needed to confirm its safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Open-label exploratory study of acitretin for the treatment of severe chronic hand dermatitis. Tan, J., Maari, C., Nigen, S., et al.[2018]

Acitretin is a valuable treatment option for psoriasis, effective both alone and in combination with other therapies, due to its long-term efficacy and lack of direct immunosuppressive effects.

The consensus guidelines from the Spanish Academy of Dermatology provide comprehensive information on the safe use of acitretin, including its pharmacological properties, indications, contraindications, and treatment strategies for clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guidelines for the use of acitretin in psoriasis. Psoriasis Group of the Spanish Academy of Dermatology and Venereology. Carretero, G., Ribera, M., Belinchón, I., et al.[2022]

In a study of 22 patients treated with acitretin for psoriasis, gemfibrozil significantly reduced high triglyceride levels associated with retinoid treatment, indicating its efficacy in managing hyperlipidemia (p < 0.01).

Gemfibrozil did not adversely affect the effectiveness of acitretin or cause additional side effects, suggesting it is a safe option for patients experiencing retinoid-induced hyperlipidemia that does not respond to diet changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of gemfibrozil (Lopid) on hyperlipidemia in acitretin-treated patients. Results of a double-blind cross-over study. Vahlquist, C., Olsson, AG., Lindholm, A., et al.[2019]

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 ... In the inclisiran-only arm, LDL cholesterol was reduced by 47·5% (95% CI 50·7–44·3) at day 210 and sustained over 1440 days. The 4-year averaged ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1912387

Two Phase 3 Trials of Inclisiran in Patients with Elevated ... In one trial, the LDL cholesterol level was lowered by 52.6% at 180 days after two doses of 284 mg of inclisiran (equivalent to 300 mg of inclisiran sodium) ...

4. 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.

5. novartis.com novartis.com/news/media-releases/novartis-presents-new-long-term-leqvio-inclisiran-data-demonstrating-consistent-efficacy-and-safety-beyond-six-years

Novartis presents new long-term Leqvio® (inclisiran) data ... Nearly 80% (78.4% (95% CI: 76.8, 80.0)) of patients reached their pre-specified LDL-C targets**, and on average, LDL-C levels were reduced by ...

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

Safety and Tolerability of Inclisiran for Treatment ... Long-term treatment with inclisiran was well tolerated in a diverse population, without new safety signals, supporting the safety of inclisiran in patients ...

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

Inclisiran—Amazing for Cholesterol but Outcome Data ... Inclisiran is a relatively new drug for low-density lipoprotein (LDL) cholesterol lowering, with important and sustaining data reported in this issue of Mayo ...

8. 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 ...

9. leqvio.com leqvio.com/

Cholesterol-Lowering Injection | LEQVIO® (inclisiran) When taken with a statin, 2 doses a year after 2 initial doses of LEQVIO is proven to lower bad cholesterol by ~50% and keep it low.*. LEQVIO is the only bad- ...