ANGPTL3 Variant Effects for Low Cholesterol

Overseen By Marina Cuchel, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Pennsylvania

Disqualifiers: Liver disease, Kidney disease, Hypertension, Diabetes, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 13 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

To evaluate the role of ANGPTL3, on lipid metabolism. To explore the role of this protein on glucose metabolism.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but if any medication you are taking could affect your safety or the study's results, you may need to stop. This decision will be made by the study investigator.

What data supports the effectiveness of the drug ANGPTL3, Evinacumab, Evkeeza for low cholesterol?

Evinacumab, which inhibits ANGPTL3, has been shown to effectively lower LDL cholesterol levels in patients with familial hypercholesterolemia, a condition characterized by high cholesterol. It is approved for use in patients with homozygous familial hypercholesterolemia and has demonstrated a good safety profile with significant cholesterol-lowering effects. ^{1 2 3 4 5}

How does the drug evinacumab differ from other treatments for low cholesterol?

Evinacumab is unique because it targets ANGPTL3, a protein that affects lipid metabolism, and is used to lower cholesterol and triglycerides in patients with familial hypercholesterolemia. Unlike other treatments, it is a monoclonal antibody that specifically inhibits ANGPTL3, offering a novel approach for those with resistant forms of high cholesterol. ^{3 5 6 7 8}

Research Team

Marina Cuchel, MD, PhD

Principal Investigator

University of Pennsylvania

Eligibility Criteria

This trial is for adults who either carry genetic variants in the ANGPTL3 gene or are unaffected controls matched by age, race, and gender. Participants must be willing to follow study procedures and provide informed consent. It excludes those with a history of significant health issues like drug abuse, cancer, liver or kidney disease, uncontrolled hypertension or diabetes, recent major surgery, anemia, or those on certain medications.

Inclusion Criteria

Able to provide informed consent

I match the age, race, and gender of the study's control group.

I am 18 years old or older.

Exclusion Criteria

Any medical or psychological conditions that, in the opinion of the investigator, would compromise the subject's safety or successful participation in the study, or confound the study data

My blood pressure is not higher than 160/100 mmHg.

I am not pregnant or nursing.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo oral fat tolerance test, lipoprotein kinetics, and glucose tolerance test to evaluate the role of ANGPTL3 on lipid and glucose metabolism

13 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ANGPTL3

Trial Overview The trial aims to understand how the protein ANGPTL3 affects lipid (fat) metabolism and glucose (sugar) metabolism in humans. Participants will undergo tests including a kinetics test to measure fat processing speed after eating fats; an oral fat tolerance test; and an oral glucose tolerance test to see how well their body handles sugar.

Participant Groups

Group I: Variant Experimental Treatment 1 Intervention

Volunteers with known ANGPTL3 variants

Group II: Non-variant Experimental Treatment 1 Intervention

Healthy volunteers with no ANGPTL3 variants

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

In a study of 320 subjects, plasma levels of ANGPTL3 and ANGPTL8 were significantly higher in patients with hyperalphalipoproteinemia (HALP) compared to healthy controls, indicating their potential role in lipid regulation, especially in high HDL-cholesterol conditions.

While ANGPTL3 levels were elevated in both HALP and severe hypertriglyceridemia (HTG) groups, ANGPTL8 levels were only increased in HALP, suggesting that ANGPTL3 and ANGPTL8 may have distinct functions in managing different types of lipid disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ANGPTL3 and ANGPTL8 in Thai subjects with hyperalphalipoproteinemia and severe hypertriglyceridemia. Kaewkrasaesin, C., Chatchomchuan, W., Muanpetch, S., et al.[2022]

Evinacumab, an ANGPTL3 inhibitor, is a promising treatment for homozygous familial hypercholesterolemia (HoFH), a condition that causes extremely high LDL cholesterol levels and increases the risk of early heart disease.

Approved in the USA in 2021, evinacumab has demonstrated a strong ability to lower LDL cholesterol with a good safety profile, making it a valuable option for patients who do not respond well to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia. Khoury, E., Croteau, L., Lauzière, A., et al.[2022]

Evinacumab, a monoclonal antibody that inhibits ANGPTL3, has been shown to effectively reduce LDL cholesterol and triglyceride levels in patients with homozygous familial hypercholesterolemia (FH), making it a promising treatment option.

Clinical trials indicate that evinacumab is both effective and safe for patients with homozygous and heterozygous FH, as well as those with resistant hypercholesterolemia and hypertriglyceridemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evinacumab, an ANGPTL3 Inhibitor, in the Treatment of Dyslipidemia. Sosnowska, B., Adach, W., Surma, S., et al.[2023]

Evinacumab is a monoclonal antibody that effectively lowers low-density lipoprotein cholesterol (LDL-C) by about 50%, making it a promising treatment for patients with familial hypercholesterolemia (FH), particularly those with homozygous FH (HoFH).

The drug has shown good short-term tolerability with mild and transient side effects, but long-term safety data is still needed, and its high cost and intravenous administration may limit its widespread use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evinacumab for treatment of familial hypercholesterolemia. Warden, BA., Duell, PB.[2021]

Evinacumab is a monoclonal antibody that inhibits ANGPTL3 and has been approved for treating homozygous familial hypercholesterolaemia (HoFH) in patients aged 12 and older, based on the successful phase III ELIPSE HoFH trial.

It is intended to be used alongside other LDL-C lowering therapies, highlighting its role as an adjunct treatment for patients with severe cholesterol issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evinacumab: First Approval. Markham, A.[2021]

Evinacumab, an ANGPTL3 inhibitor, was well-tolerated in two Phase 1 studies involving 139 hypertriglyceridemic subjects, with no serious adverse events reported, indicating a favorable safety profile.

The treatment led to significant dose-dependent reductions in triglycerides, with a maximum reduction of 76.9% observed at day 3 for intravenous doses, suggesting that evinacumab could effectively lower lipid levels and potentially reduce cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia. Ahmad, Z., Banerjee, P., Hamon, S., et al.[2021]

ANGPTL3, 4, and 8 play crucial roles in regulating lipid metabolism, and their deficiency can lead to low lipid levels, while increased levels are linked to higher cardiovascular risk.

Evinacumab, an ANGPTL3 inhibitor, has shown promising results in clinical trials by significantly lowering cholesterol and triglyceride levels in patients with severe lipid disorders, suggesting its potential as a treatment for hypertriglyceridemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiopoietin-like proteins inhibitors: New horizons in the treatment of atherogenic dyslipidemia and familial hypercholesterolemia. Surma, S., Romańczyk, M., Filipiak, KJ.[2023]

Evinacumab, a monoclonal antibody targeting ANGPTL3, significantly reduced LDL cholesterol levels by 47% in patients with homozygous familial hypercholesterolemia (HoFH), while the placebo group experienced a 2% increase.

The treatment was well-tolerated, with common side effects including nasopharyngitis and dizziness, indicating a favorable safety profile for patients with HoFH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evinacumab for the treatment of homozygous familial hypercholesterolemia. Gao, Y., Zhang, B., Yang, J.[2022]

References

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

ANGPTL3 and ANGPTL8 in Thai subjects with hyperalphalipoproteinemia and severe hypertriglyceridemia. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Evinacumab, an ANGPTL3 Inhibitor, in the Treatment of Dyslipidemia. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Evinacumab for treatment of familial hypercholesterolemia. [2021]

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

Evinacumab: First Approval. [2021]

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

Inhibition of Angiopoietin-Like Protein 3 With a Monoclonal Antibody Reduces Triglycerides in Hypertriglyceridemia. [2021]

7. Poland pubmed.ncbi.nlm.nih.gov

Angiopoietin-like proteins inhibitors: New horizons in the treatment of atherogenic dyslipidemia and familial hypercholesterolemia. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Evinacumab for the treatment of homozygous familial hypercholesterolemia. [2022]