What side effects are associated with this type of intervention?

Common treatments for hypercholesterolemia, such as PCSK9 inhibitors (alirocumab and evolocumab), are generally well-tolerated. They can cause mild injection site reactions, hypersensitivity reactions like rash and urticaria, and rarely, serious allergic reactions. Neurocognitive symptoms and muscle toxicity are uncommon. ANGPTL3 inhibitors, like evinacumab, also show significant LDL-C reduction with a similar safety profile, though specific side effects are less documented. Overall, these advanced therapies are considered safe with manageable side effects.

What prior FDA approvals exist?

The FDA has approved several treatments for hypercholesterolemia, including statins, ezetimibe, and PCSK9 inhibitors like alirocumab and evolocumab. These treatments primarily work by reducing LDL-C levels through different mechanisms. Statins inhibit HMG-CoA reductase, ezetimibe blocks cholesterol absorption in the intestine, and PCSK9 inhibitors increase the number of LDL receptors on liver cells. ANGPTL3 inhibitors, such as evinacumab, represent a newer class of drugs targeting lipid metabolism, showing promise in significantly lowering LDL-C levels independently of LDL receptor activity.

What other types of research exist?

Promising novel alternatives to ARO-ANG3 for hypercholesterolemia patients in 2024 include: 1) PCSK9 inhibitors such as inclisiran, which uses RNA interference to reduce LDL cholesterol levels. 2) Bempedoic acid, an ATP citrate lyase inhibitor that lowers LDL cholesterol. 3) Evinacumab, an ANGPTL3 monoclonal antibody that has shown efficacy in reducing LDL cholesterol in patients with homozygous familial hypercholesterolemia. These alternatives offer different mechanisms of action and have shown promising results in clinical trials.

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siRNA

ARO-ANG3 Injection for Homozygous Familial Hypercholesterolemia (Gateway Trial)

Phase 2

Waitlist Available

Research Sponsored by Arrowhead Pharmaceuticals

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Women of childbearing potential must have a negative pregnancy test and cannot be breastfeeding

Weight of ≥ 40 kg and body mass index ≥ 18.5 and ≤ 40 kg/m2

Must not have

Presence of any clinically significant uncontrolled endocrine disease known to influence serum lipids or lipoproteins

Newly diagnosed (within 3 months prior to informed consent) or poorly controlled diabetes (Hemoglobin A1c > 9%)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years

Awards & highlights

No Placebo-Only Group

Summary

This trial involves giving ARO-ANG3 injections to people with severe genetic high cholesterol to see if it safely lowers their cholesterol by blocking a protein involved in its production.

Who is the study for?

This trial is for individuals with a severe form of high cholesterol called homozygous familial hypercholesterolemia (HoFH). Participants must be on stable cholesterol-lowering therapy, not have heart disease symptoms or uncontrolled diabetes, and agree to use effective contraception. They should also follow a low-fat diet and have LDL-C levels over 100 mg/dL.

What is being tested?

The study tests ARO-ANG3 injections in people with HoFH. It involves two initial doses followed by safety and effectiveness checks over 36 weeks. Those who finish can join a further 24-month extension for up to eight more doses.

What are the potential side effects?

While specific side effects are not listed here, participants will be monitored for any adverse reactions to the ARO-ANG3 injection throughout the study period.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am not pregnant or breastfeeding.

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I weigh at least 40 kg and my BMI is between 18.5 and 40.

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I have been diagnosed with HoFH either through genetic testing or based on my symptoms.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have a hormone-related condition affecting my cholesterol or fat levels.

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I was diagnosed with diabetes in the last 3 months or my diabetes is not well-controlled (HbA1c > 9%).

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I haven't used any liver-targeting RNA or antisense drugs in the past year.

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I have severe heart muscle issues or chest pain due to poor blood flow.

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I am scheduled for a heart or artery procedure.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years for reporting.

Treatment Details

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: ARO-ANG3 Dose 2Experimental Treatment1 Intervention

ARO-ANG3 Dose Level 2 SC

Group II: ARO-ANG3 Dose 1Experimental Treatment1 Intervention

ARO-ANG3 Dose Level 1 subcutaneous (SC)

0 / 8Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for hypercholesterolemia include statins, ezetimibe, PCSK9 inhibitors, and ANGPTL3 inhibitors. Statins inhibit the enzyme HMG-CoA reductase, reducing cholesterol synthesis. Ezetimibe decreases cholesterol absorption in the intestines. PCSK9 inhibitors increase LDL receptor availability on liver cells, enhancing LDL cholesterol clearance. ANGPTL3 inhibitors, like those studied in the ARO-ANG3 trial, lower LDL cholesterol by inhibiting the ANGPTL3 protein, which regulates lipid metabolism. These mechanisms are vital for hypercholesterolemia patients as they help manage cholesterol levels and reduce cardiovascular risk.

Homozygous familial hypercholesterolemia: what treatments are on the horizon?Autosomal recessive hypercholesterolaemia: normalization of plasma LDL cholesterol by ezetimibe in combination with statin treatment.