PASADENA, Calif. — Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced that it has completed enrollment in the global Phase 3 YOSEMITE clinical trial of zodasiran, the company’s investigational RNA interference (RNAi) therapeutic being developed as a potential treatment for homozygous familial hypercholesterolemia (HoFH), a rare genetic condition that leads to severely elevated low density lipoprotein-cholesterol (LDL-C) and early onset cardiovascular disease. Arrowhead anticipates that YOSEMITE will be completed in mid-2027 and, pending successful clinical results, intends to seek regulatory approval in multiple geographies thereafter.
“Completing enrollment in the global YOSEMITE Phase 3 study represents an important milestone in the development of zodasiran for people living with HoFH, a rare disease with limited effective treatment options which carries a very high risk of developing atherosclerotic cardiovascular disease. By harnessing RNA interference to reduce ANGPTL3 expression, zodasiran is designed to lower atherogenic lipoproteins through a mechanism distinct from conventional LDL-C–lowering therapies,” said James Hamilton, M.D., Chief Medical Officer and head of R&D at Arrowhead. “The YOSEMITE Phase 3 study was initially designed to enroll 60 participants; however, strong global HoFH patient and physician interest led to an increased total of 70 patients enrolled. We believe this speaks to the remaining global unmet need in this population of patients with exceptionally high cardiovascular risk.”
About Homozygous Familial Hypercholesterolemia
Homozygous Familial Hypercholesterolemia is an ultra-rare treatment‐resistant genetic condition characterized by elevated LDL-C and early-onset cardiovascular disease. Most cases of HoFH are due to mutations in the gene that encodes the LDL receptor (LDLR). Thus, HoFH represents a unique disease where LDL-C lowering therapies not requiring functional LDL receptors may have benefit.
If left untreated, individuals with HoFH can have median LDL-C levels above 400 mg/dL (over 10 mmol/L), leading to early clinical manifestations of coronary artery disease1. Patients with HoFH may also have cholesterol deposits under the skin (xanthomas), around the eyes (xanthelasmas), or around the cornea (corneal arcus), but physical signs are not always present, particularly in children. HoFH remains challenging to treat and currently only patients with the more severe HoFH phenotypes get diagnosed and treated early. The estimated prevalence of HoFH globally is between 1:360,000 and 1:250,0001.
About YOSEMITE Phase 3 Study
YOSEMITE (NCT07037771) is a global Phase 3 multicenter, randomized, double blind, placebo-controlled study to evaluate the efficacy and safety of zodasiran in adolescent and adult patients with genetically or clinically diagnosed homozygous familial hypercholesterolemia (HoFH) on maximally tolerated lipid lowering therapy. 70 subjects over the age of 12 were randomized (2:1) to receive 4 doses (once every 3 months) of 200 mg zodasiran or placebo. The primary endpoint is the percent change from baseline to month 12 in fasting LDL-C. After month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension.
About Zodasiran
Zodasiran, previously called ARO-ANG3, is a first-in-class investigational RNA interference (RNAi) therapeutic designed to reduce production of angiopoietin-like protein (ANGPTL3), which is a hepatocyte expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of action, including inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL)2,3. ANGPTL3 is an emerging therapeutic target with relevance to hypercholesterolemia, hypertriglyceridemia, and mixed hyperlipidemia. Genetic studies suggest that individuals with ANGPTL3 loss-of-function variants have enhanced lipoprotein lipase and endothelial lipase activity, resulting in lower levels of atherogenic lipoproteins and a reduced risk of ASCVD4-6. Zodasiran has received Orphan Drug Designation for the treatment of HoFH from the US Food and Drug Administration.
In prior clinical studies, investigational zodasiran was associated with dose-dependent reductions in triglycerides, triglyceride rich lipoprotein remnants, and total atherogenic lipoproteins, including LDL-C, in patients with homozygous (HoFH) and heterozygous (HeFH) familial hypercholesterolemia and mixed hyperlipidemia. Zodasiran also showed a favorable safety profile. In the Phase 2 GATEWAY study in patients with HoFH, there were no drug discontinuations, drug-related serious adverse events, or deaths. The most frequent adverse events were COVID-19, nasopharyngitis, upper respiratory tract infection, and dizziness.
About Arrowhead Pharmaceuticals
Arrowhead Pharmaceuticals (NASDAQ: ARWR) is a commercial-stage pharmaceutical company developing medicines that treat intractable diseases by silencing the genes that cause them, harnessing the natural RNA interference (RNAi) mechanism. The company has built a broad portfolio of clinical and commercial RNAi therapeutics through its industry-leading targeted RNAi molecule (TRiM™) platform, which can precisely silence genes in a wide range of cell types, including liver, lung, muscle, adipose, and central nervous system tissue. At Arrowhead, we rapidly advance potential best- and first-in-class RNAi treatments for diseases with significant unmet medical need, because every day matters to the patients we serve.
For more information, please visit arrowheadpharma.com, or follow us on X (formerly Twitter) at @ArrowheadPharma, LinkedIn, Facebook, and Instagram. To be added to the Company’s email list and receive news directly, please visit ir.arrowheadpharma.com/email-alerts.
References
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Cuchel, et al. Eur Heart J. 2023;44(25):2277-91 | |
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Adam, et al. J Lipid Res. 2020;61(9): 1271-86. | |
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Rosenson. J Lipid Res. 2021:62:100060. | |
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Dewey, et al. N Engl J Med. 2017;377 (3):211-21. | |
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Minicocci, et al. J Lipid Res. 2013;54(12): 3481-90 | |
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Musunuru, et al. N Engl J Med. 2010; 363(23):2220-7 | |
Contacts
Arrowhead Pharmaceuticals, Inc.
Vince Anzalone, CFA
626-304-3400
[email protected]
Investors:
LifeSci Advisors, LLC
Brian Ritchie
212-915-2578
[email protected]
Media:
LifeSci Communications, LLC
Kendy Guarinoni, Ph.D.
724-910-9389
[email protected]