Homozygous Familial Hypercholesterolemia
Conditions
Brief 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. 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.
Interventions
DRUGARO-ANG 3 Injection
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
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 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. * 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
Exclusion criteria
* 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) * 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Fasting LDL-C at Week 24 | Baseline, Week 24 | LDL-C, computed using Friedewald formula, Martin-Hopkins methodology and preparative ultracentrifugation (PUC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Fasting LDL-C (PUC) Over Time | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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) | From first dose of study drug up to Week 36 (initial treatment period), and up to Month 24 (extension period) | 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'. |
| Number of Participants With Anti-Drug Antibodies (ADAs) to ARO-ANG3 Over Time | 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 | 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. |
| Percentage of Participants Meeting European Union (EU) Apheresis Eligibility Criteria Per German Apheresis Working Group at Week 24 | 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 |
Countries
Australia, Canada, South Africa, United States
Participant flow
Pre-assignment details
In this open-label clinical study, participants were randomized in a 1:1 ratio into ARO-ANG3 200 mg or 300 mg dose groups.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 36.4 years STANDARD_DEVIATION 18.09 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Low Density Lipoprotein Cholesterol (LDL-C) LDL-C, Friedewald Formula | 385.7 (mg/dL STANDARD_DEVIATION 226.93 |
| Low Density Lipoprotein Cholesterol (LDL-C) LDL-C, Martin-Hopkins Methodology | 426.8 (mg/dL STANDARD_DEVIATION 219.92 |
| Low Density Lipoprotein Cholesterol (LDL-C) LDL-C, PUC | 335.0 (mg/dL STANDARD_DEVIATION 225.55 |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Race/Ethnicity, Customized White | 6 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 7 / 9 | 7 / 9 |
| serious Total, serious adverse events | 2 / 9 | 1 / 9 |
Outcome results
None listed