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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a protein called ANGPTL3 affects cholesterol and sugar levels in the body. Researchers will compare individuals with specific genetic changes in ANGPTL3 to those without to assess the impact on metabolism. Volunteers are needed who either have these genetic changes or are healthy and willing to participate. Ideal participants have no history of liver or kidney disease and are not on medications that might interfere with the trial. As an unphased study, this trial offers a unique opportunity to contribute to groundbreaking research on metabolism and genetic factors.

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.

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

Research shows that treatments targeting ANGPTL3, such as evinacumab, are generally well tolerated. Earlier studies found that evinacumab reduced bad cholesterol by about 50% in patients, including children. Importantly, these studies reported that evinacumab was well tolerated without major safety concerns. This suggests that treatments targeting ANGPTL3 are likely safe for humans based on current evidence. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about ANGPTL3 because it targets a new pathway for managing cholesterol levels. Unlike traditional treatments like statins, which primarily work by blocking cholesterol production in the liver, ANGPTL3 focuses on a genetic approach by influencing the ANGPTL3 protein. This method offers a potential advantage for individuals with specific genetic profiles, possibly leading to more personalized and effective cholesterol management. The possibility of targeting cholesterol through genetic pathways could open new doors for those who don't respond well to existing treatments.

What evidence suggests that ANGPTL3 could be effective for low cholesterol?

Research has shown that evinacumab, a treatment targeting the protein ANGPTL3, effectively lowers bad cholesterol. Studies have found that evinacumab can reduce LDL cholesterol by about 50% in individuals with homozygous familial hypercholesterolemia (HoFH), a genetic condition causing very high cholesterol. The treatment is generally safe, with most patients not experiencing serious side effects. In this trial, researchers will compare participants with known ANGPTL3 variants to healthy volunteers without these variants to study ANGPTL3's impact on fat metabolism. These findings suggest that ANGPTL3 plays a crucial role in controlling cholesterol levels. ^{1 2 3 6 7}

Who Is on the Research Team?

Marina Cuchel, MD, PhD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

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 carry a genetic variant in the ANGPTL3 gene.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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, 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 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]

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]

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 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]

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]

Citations

1. investor.regeneron.com investor.regeneron.com/news-releases/news-release-details/evkeezar-evinacumab-dgnb-angptl3-antibody-approved-us-children

Evkeeza® (evinacumab-dgnb) ANGPTL3 Antibody ... FDA approval extends the indication of Evkeeza to treat younger patients with homozygous hypercholesterolemia (HoFH).

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40438928/

Real-World Effectiveness and Safety of Evinacumab in ... Evinacumab was generally well tolerated by patients with HoFH and lowered LDL-C by ≈50%, consistent with results from clinical trials.

3. evkeeza.com evkeeza.com/s/study-results-safety

Study Results and Safety | EVKEEZA® (evinacumab-dgnb) Patients on EVKEEZA had an average 49% reduction in their bad cholesterol at 6 months compared to placebo. †The clinical trial enrolled 20 patients; 14 were ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8057526/

ANGPTL3 Inhibition With Evinacumab Results in Faster ... ANGPTL3 (angiopoietin-like 3) inhibition with evinacumab is very effective in reducing LDL (low-density lipoprotein) cholesterol in patients with homozygous ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa2004215

Evinacumab for Homozygous Familial Hypercholesterolemia Evinacumab, a monoclonal antibody against ANGPTL3, has shown potential benefit in patients with homozygous familial hypercholesterolemia.

6. ahajournals.org ahajournals.org/doi/10.1161/ATVBAHA.123.320609

Evinacumab and Cardiovascular Outcome in Patients With ... At 6 months, the mean low-density lipoprotein cholesterol reduction with evinacumab was 3.7 mmol/L or 56% (from 6.5 mmol/L at baseline to ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT04233918

Study Details | NCT04233918 | Evaluate the Efficacy and ... The primary objective for Part B of the study is to demonstrate a reduction of low-density lipoprotein cholesterol (LDL-C) by evinacumab in pediatric (5 to 11 ...