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NCT07037771PHASE3Recruiting

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

Arrowhead Pharmaceuticals

Start Date

6/17/2025

Completion Date

8/20/2027

Summary

This multicenter, randomized, placebo-controlled study will evaluate the efficacy and safety of zodasiran subcutaneous (SC) injection in subjects 12 years of age and older with genetically or clinically diagnosed Homozygous familial hypercholesterolemia (HoFH). After completion of the double blind (DB) treatment period subjects will be eligible to continue in the optional open-label extension (OLE) period of the study. All placebo subjects who opt to continue will transition to active drug during the OLE Period.

Eligibility Criteria

Age Range: 12 years to No maximum

Inclusion Criteria: * Age ≥12 years, non pregnant, non lactating, do not plan to become pregnant during the study * Body weight ≥35 kg at Screening as patients could theoretically be \<35 kg as the study continues. * 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) * LDL-C ≥70 mg/dL (1.8 mmol/L). For adolescents 12 to \<18 years of age, screening LDL-C ≥116 mg/dL (3 mmol/L). * Hemoglobin A1c (HbA1c) ≤9.5% * Total bilirubin \<2xULN, unless in previously confirmed cases of Gilbert's syndrome * Alanine aminotransferase or aspartate aminotransferase \<3×ULN * On standard of care, maximally tolerated lipid-lowering therapy to include a maximally tolerated statin, ezetimibe, and a PCSK9 inhibitor Exclusion Criteria: * 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) * Use of an antisense oligonucleotide molecule within 3 months before Day 1 (except inclisiran, which is permitted; administration of inclisiran and study drug must be separated by at least 4 weeks) * Use of evinacumab within 3 months before Day 1. Evinacumab use is prohibited during the study. * Non-response to evinacumab, defined as LDL-C reduction \<15% from baseline after 2 doses * Use of any other investigational agent or device within 30 days or 5 half-lives (whichever is longer) before Day 1 * Use of systemic corticosteroids (unless used as replacement therapy for pituitary/adrenal disease with a stable regimen) * Estimated glomerular filtration rate \<30 mL/min NOTE: Additional Inclusion/exclusion criteria may apply per protocol

Interventions

DRUG

zodasiran Injection

DRUG

Placebo

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Conditions

Homozygous Familial Hypercholesterolemia

Locations

Research Site 7

Park Ridge, Illinois 60068

United States

Research Site 2

New York, New York 10029

United States

Research Site 1

Cincinnati, Ohio 45227

United States

Research Site 14

Pittsburgh, Pennsylvania 15213

United States

Research Site 13

Camperdown, New South Wales 2050

Australia

Research Site 9

Saint Leonards, New South Wales 2065

Australia

Research Site 21

Heidelberg, Victoria 3084

Australia

Research Site 3

Nedlands, Western Australia 6009

Australia

Research Site 40

Innsbruck, 6020

Austria

Research Site 39

Linz, 4021

Austria

Research Site 42

Vienna, 1090

Austria

Research Site 37

Vienna, 1130

Austria

Research Site 33

La Louvière, 7100

Belgium

Research Site 34

Leuven, 3000

Belgium

Research Site 24

Cerqueira César, São Paulo CEP-05403-000

Brazil

Research Site 5

Vancouver, British Columbia V6Z 2H2

Canada

Research Site 6

Chicoutimi, Quebec G7H 7K9

Canada

Research Site 4

Québec, G1V 4W2

Canada

Research Site 30

Hradec Králové, General E3 500 0

Czechia

Research Site 23

Paris, 75013

France

Research Site 17

Tbilisi, 0159

Georgia

Research Site 18

Tbilisi, 160

Georgia

Research Site 19

Tbilisi, 186

Georgia

Research Site 35

Berlin, 13353

Germany

Research Site 10

Jerusalem, 9112001

Israel

Research Site 15

Tel Litwinsky, 5265601

Israel

Research Site 26

Kanazawa, Ishikawa-ken 920-8641

Japan

Research Site 27

Suita, Osaka 564-8565

Japan

Research Site 20

Fukushima, 960-1295

Japan

Research Site 16

Okayama, 700-8558

Japan

Research Site 22

Saitama, 350-0495

Japan

Research Site 25

Tokyo, 113-8510

Japan

Research Site 12

Christchurch, 8011

New Zealand

Research Site 31

Riyadh, 12713

Saudi Arabia

Research Site 11

Parktown, Johannesburg 2193

South Africa

Research Site 8

Cape Town, 7925

South Africa

Research Site 43

Barcelona, 8907

Spain

Research Site 28

Córdoba, 14004

Spain

Research Site 29

Madrid, 28041

Spain

Research Site 32

Gothenburg, 413 46

Sweden

Research Site 36

Afyonkarahisar, 03200

Turkey (Türkiye)

Research Site 41

Bornova/Izmir, 35100

Turkey (Türkiye)

Research Site 38

Melikgazi/Kayseri, 38030

Turkey (Türkiye)