A Phase 3 Study of Zodasiran in Adolescent and Adult Subjects With Homozygous Familial Hypercholesterolemia (YOSEMITE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Arrowhead Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

7 Apr 2026 → ongoing

Decision date (initial)

2026-01-26

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Arrowhead Pharmaceuticals, Inc.

External identifiers

EU CT number

2025-521792-31-01

WHO UTN

U1111-1320-7617

ClinicalTrials.gov

NCT07037771

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To demonstrate reduction of low-density lipoprotein cholesterol (LDL-C) with zodasiran compared with placebo in subjects with HoFH

Secondary objectives 4

1. 1. To evaluate the effect of zodasiran compared with placebo on other lipid parameters (eg, ApoB, non-HDL-C, TGs, ANGPTL3, total cholesterol, HDL-C, and Lp[a]) in subjects with HoFH
2. 2. To evaluate the proportion of subjects with LDL-C <100 mg/dL (2.6 mmol/L) in subjects with HoFH
3. 3. To evaluate the effect of zodasiran compared with placebo on LDL-C apheresis eligibility criteria in subjects with HoFH
4. 4. To evaluate the safety and tolerability of zodasiran in subjects with HoFH

Conditions and MedDRA coding

Homozygous Familial Hypercholesterolemia (HoFH)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 1. Age ≥12 years, non pregnant, non lactating, do not plan to become pregnant during the study
2. 2. Body weight ≥35 kg at Screening as patients could theoretically be <35 kg as the study continues.
3. 3. HoFH based on a supportive genetic test or a clinical diagnosis (total cholesterol >500 mg/dL[13 mmol/L] OR treated LDL-C concentration of ≥300 mg/dL [≥8 mmol/L] either accompanied by TGs <300 mg/dL [3.4 mmol/L] AND both parents with documented total cholesterol >250 mg/dL [6.5 mmol/L] OR cutaneous or tendinous xanthoma before 10 years of age)
4. 4. LDL-C ≥70 mg/dL (1.8 mmol/L). For adolescents 12 to <18 years of age LDL-C ≥116 mg/dL (3 mmol/L)
5. 5. Hemoglobin A1c (HbA1c) ≤9.5%
6. 6. Total bilirubin <2xULN, unless in previously confirmed cases of Gilbert's syndrome
7. 7. Alanine aminotransferase or aspartate aminotransferase <3×ULN
8. 8. On standard of care, maximally tolerated lipid-lowering therapy

Exclusion criteria 7

1. 1. Use of a hepatocyte-targeted siRNA within 365 days before Day 1 (except inclisiran, which is permitted; administration of inclisiran and study drug must be separated by at least 4 weeks)
2. 2. Use of an antisense oligonucleotide molecule within 3 months before Day 1 (exception: use of inclisiran is permitted; administration of inclisiran and study drug must be separated by at least 4 weeks)
3. 3. Use of evinacumab within 3 months before Day 1. Evinacumab use is prohibited during the study. In regions where evinacumab is available, the physician must justify and document in source documents and eCRF(s) why a patient is not receiving evinacumab therapy as part of standard of care (eg, safety, tolerability, reimbursement/cost, patient choice, etc.)
4. 4. Non-response to evinacumab, defined as LDL-C reduction <15% from baseline after 2 doses
5. 5. Use of any other investigational agent or device within 30 days or 5 half-lives (whichever is longer) before Day 1
6. 6. Use of systemic corticosteroids (unless used as replacement therapy for pituitary/adrenal disease with a stable regimen)
7. 7. Estimated glomerular filtration rate <30 mL/min

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percent Change from Baseline to Month 12 in Fasting Low Density Lipoprotein Cholesterol (LDL-C) (Randomized period)

Secondary endpoints 14

1. 1. Percent Change from Baseline to Month 12 in Fasting Apolipoprotein B (ApoB) (Randomized Period)
2. 2. Percent Change from Baseline to Month 12 in Fasting Non-High Density Lipoprotein Cholesterol (non-HDL-C) (Randomized Period)
3. 3. Change from Baseline to Month 12 in Fasting LDL-C (Randomized Period)
4. 4. Area Under the Plasma Concentration Versus the Time Curve (AUC) from Baseline to Month 12 for Fasting LDL-C (Randomized Period)
5. 5. Percent Change from Baseline to Month 12 in Fasting Triglycerides (TGs) (Randomized Period)
6. 6. Percent Change from Baseline to Month 12 in Fasting Angiopoietin-like Protein 3 (ANGPTL3) (Randomized Period)
7. 7. Percent Change from Baseline to Month 12 in Fasting Total Cholesterol (Randomized Period)
8. 8. Percent Change from Baseline to Month 12 in Fasting High-Density Lipoprotein Cholesterol (HDL-C) (Randomized Period)
9. 9. Proportion of Participants who Meet European Union (EU) LDL-C Apheresis Eligibility Criteria (per German Apheresis Working Group) at Month 12 (Randomized Period)
10. 10. Proportion of Participants who Meet United States (US) Apheresis Eligibility Criteria (per National Lipid Association) at Month 12 (Randomized Period)
11. 11. Proportion of Participants with Fasting LDL-C <100 mg/dL (2.6 mmol/L) at Month 12 (Randomized Period)
12. 12. Change from Baseline in Fasting LDL-C Over Time (Randomized Period)
13. 13. Percent Change from Baseline in fasting LDL-C Over Time (Randomized Period)
14. 14. Percent Change from Baseline to Month 12 in Fasting Lipoprotein(a) [Lp(a)] (Randomized Period)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Arrowhead Pharmaceuticals Inc.

Sponsor organisation

Arrowhead Pharmaceuticals Inc.

Address

177 East Colorado Boulevard Suite 700

City

Pasadena

Postcode

91105-1976

Country

United States

Scientific contact point

Organisation

Arrowhead Pharmaceuticals Inc.

Contact name

Medical Monitor

Public contact point

Organisation

Arrowhead Pharmaceuticals Inc.

Contact name

Medical Monitor

Third parties 6

Locations

10 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 88 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications