Homozygous Familial HypercholesterolemiaPhase 2GatewayNCT05217667
Study of ARO-ANG3 in Participants With Homozygous Familial Hypercholesterolemia (HOFH)
A Phase 2 study testing ARO-ANG 3 Injection in people with Homozygous Familial Hypercholesterolemia, run by Arrowhead Pharmaceuticals at 7 sites in 4 countries.
Trial summary
Participants with documented homozygous familial hypercholesterolemia (HoFH) who have provided informed consent will receive 2 open-label doses of ARO-ANG3 and be evaluated for safety and efficacy parameters through 36 weeks. Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Homozygous Familial Hypercholesterolemia
- What is being tested?
- ARO-ANG 3 Injection
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 18 participants
- Where
- 7 sitesin 4 countries
- Study dates
- 22 Apr 2022to 13 Nov 2025
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Fasting LDL-C >100 mg/dL at Screening
- Weight of ≥ 40 kg and body mass index ≥ 18.5 and ≤ 40 kg/m2
- Diagnosis of HoFH based on a supportive genetic test or clinical diagnosis
- On stable maximally tolerated lipid lowering therapy
- Willing to abide by stable low-fat, low-cholesterol, heart-healthy diet for at least 4 weeks prior to Day 1
- Participants of childbearing potential (males \& females) must agree to use highly-effective contraception during the study and for at least 24 weeks from the last dose of study medication.
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- Women of childbearing potential must have a negative pregnancy test and cannot be breastfeeding
- Women of childbearing potential on hormonal contraceptives must be stable on the medications for > 2 menstrual cycles prior to Day 1
- Willing to provide written informed consent and to comply with study requirements
Who cannot join
- Current use or use within 365 days from Day 1 of any hepatocyte targeted small interfering RNA oligonucleotides (siRNA) or antisense oligonucleoside molecule
- Use of evinacumab (some exceptions apply)
- Fasting TG > 300 mg/dL at Screening
- 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%)
- Use of systemic corticosteroids (some exceptions apply)
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- Symptoms of myocardial ischemia or severe left ventricular dysfunction
- History of metastatic malignancy within 3 years of Day 1 (some exceptions apply)
- Planned cardiac procedure/surgery such as coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention (PCI), carotid surgery or stenting, or carotid revascularization
- Note: additional inclusion/exclusion criteria may apply per protocol
Trial locations and contacts
7 sites in 4 countries.
7 sites in 4 countries
United States2 sites
Research Site 5
Cincinnati, Ohio, 45227
Research Site 4
Mount Sinai, New York, 10029
Australia2 sites
Research Site 8
Camperdown, New South Wales, 2050
Research Site 3
Nedlands, Western Australia, 6009
Canada2 sites
Research Site 2
Chicoutimi, Quebec, G7H 7K9
Research Site 1
Québec, Quebec, G1V 4W2
About this study
Official title: Phase 2 Study to Evaluate the Safety and Efficacy of ARO-ANG3 in Subjects With Homozygous Familial Hypercholesterolemia (HOFH)
Participants with documented homozygous familial hypercholesterolemia (HoFH) who have provided informed consent will receive 2 open-label doses of ARO-ANG3 and be evaluated for safety and efficacy parameters through 36 weeks. Participants who complete the first 36 week treatment period may opt to continue in an additional 24-month extension period during which they will receive up to 8 doses open-label doses of ARO-ANG3.
- Conditions
- Homozygous Familial Hypercholesterolemia
- Being tested
- ARO-ANG 3 Injection
- Medical subject headings
- Homozygous Familial Hypercholesterolemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ARO-ANG 3 InjectionDrug
Participants will be randomized to receive ARO-ANG3 SC on Day 1 and Day 84 during the initial 36 Weeks of the study and on Day1 and Months 3, 6, 9, 12, 15, 18, and 21 of the extension period
| Study group | Role | What they receive |
|---|---|---|
| ARO-ANG3 Dose 1 | Experimental | ARO-ANG3 Dose Level 1 subcutaneous (SC) Receives: Drug: ARO-ANG 3 Injection |
| ARO-ANG3 Dose 2 | Experimental | ARO-ANG3 Dose Level 2 SC Receives: Drug: ARO-ANG 3 Injection |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent Change From Baseline in Fasting LDL-C at Week 24
LDL-C, computed using Friedewald formula, Martin-Hopkins methodology and preparative ultracentrifugation (PUC).
Measured: Baseline, Week 24
Secondary outcomes (24)
Percent Change From Baseline in Fasting LDL-C (PUC) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting LDL-C (PUC) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Calculated LDL-C (Friedewald Formula) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Calculated LDL-C (Friedewald Formula) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Calculated LDL-C (Martin-Hopkins Methodology) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Calculated LDL-C (Martin-Hopkins Methodology) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Angiopoietin-like 3 (ANGPTL3) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting ANGPTL3 Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Total Apolipoprotein B (ApoB) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Total ApoB Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting High-Density Lipoprotein-Cholesterol (HDL-C) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting HDL-C Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Non-HDL-C Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting Non-HDL-C Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Very-Low-Density Lipoprotein-Cholesterol (VLDL-C) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting VLDL-C Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Total Cholesterol (TC) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting TC Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Percent Change From Baseline in Fasting Triglycerides (TG) Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Absolute Change From Baseline in Fasting TG Over Time
Measured: Baseline, Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 (Day 1 of Extension Period), Extension Months 1, 2, 3, 6, 9, 12, 15, 18, 21
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) is any untoward medical occurrence, which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) is an AE occurring during any study phase that: results in death; is immediately life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medically important event or reaction that may require medical intervention to prevent one of the outcomes listed above. AEs are considered treatment-related if the relationship to the study drug is 'possibly related', 'probably related'. A TEAE is defined as an AE that occurs following IP administration or a pre-existing condition exacerbated following IP administration. Injection site reactions are assessed at every visit starting on Day 1 and include any Preferred Term containing 'Injection Site'.
Measured: From first dose of study drug up to Week 36 (initial treatment period), and up to Month 24 (extension period)
Number of Participants With Anti-Drug Antibodies (ADAs) to ARO-ANG3 Over Time
Measured: Baseline, Day 1, Weeks 4, 12, 16, 24 (initial treatment period), Week 36/Day 1, Months 1, 3, 6, 9, 12, 15, 18, 21 (extension period)
Percentage of Participants Meeting United States National Lipid Association Apheresis Eligibility Criteria of LDL-C ≥ 300 mg/dL at Week 24
Apheresis is the extracorporeal process of removing one or more blood constituents from whole blood and returning the remainder to the circulation.The National Lipid Association outlines eligibility criteria for apheresis, particularly for patients with familial hypercholesterolemia who have not achieved target LDL cholesterol levels despite maximally tolerated pharmacotherapy. LDL-C ≥ 300 mg/dL is a criterion.
Measured: Week 24
Percentage of Participants Meeting European Union (EU) Apheresis Eligibility Criteria Per German Apheresis Working Group at Week 24
Apheresis is the extracorporeal process of removing one or more blood constituents from whole blood and returning the remainder to the circulation. The European Union (EU) apheresis eligibility criteria (per German Apheresis Working Group) include the following categories:
- A patient with primary cardiovascular disease (CVD) prevention is considered as meeting German apheresis eligibility criteria if LDL-C >160 mg/dL
- A patient with secondary CVD prevention is considered as meeting German apheresis eligibility criteria if LDL-C >120 mg/dL
Measured: Week 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Feb 2022
- Study start22 Apr 2022
- Primary completion2 May 2023
- Study completion13 Nov 2025
Why it stopped: Business decision, unrelated to safety concerns.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Homozygous Familial HypercholesterolemiaStudies of the same condition, open and under way.
- More trials run by Arrowhead PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 18 participants (actual)
Sponsor and investigators
- Lead sponsor
- Arrowhead Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05217667
- Sponsor's protocol ID
- AROANG3-2003
- Acronym
- Gateway
- Status last verified
- May 2026
- First submitted
- 20 Jan 2022
- Last updated
- 12 Jun 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Raal FJ, Bergeron J, Gaudet D, Rosenson RS, Sullivan DR, Turner T, Hegele RA, Ballantyne CM, Knowles JW, Leeper NJ, Goldberg IJ, Zhou R, Muhsin M, Hellawell J, Hamilton J, Watts GF. Zodasiran, an RNAi therapeutic targeting ANGPTL3, for treating patients with homozygous familial hypercholesterolaemia (GATEWAY): an open-label, randomised, phase 2 trial. Lancet Diabetes Endocrinol. 2026 Feb;14(2):123-136. doi: 10.1016/S2213-8587(25)00290-6. Epub 2025 Dec 18.
PubMed 41422812Dimitriadis K, Theofilis P, Iliakis P, Pyrpyris N, Dri E, Sakalidis A, Soulaidopoulos S, Tsioufis P, Fragkoulis C, Chrysohoou C, Tsiachris D, Tsioufis K. Management of dyslipidemia in coronary artery disease: the present and the future. Coron Artery Dis. 2024 Sep 1;35(6):516-524. doi: 10.1097/MCA.0000000000001375. Epub 2024 Apr 29.
PubMed 38682459