Arrowhead Pharmaceuticals Presents New Phase 2 Data of Zodasiran in Patients with Mixed Hyperlipidemia
Arrowhead Pharmaceuticals has reported positive results from its Phase 2b ARCHES-2 study on zodasiran (ARO-ANG3) for treating mixed hyperlipidemia. The treatment showed significant reductions in triglycerides, LDL-C, and other atherogenic lipoproteins at 24 weeks. Zodasiran also demonstrated a favorable safety profile with balanced adverse events between treatment and placebo groups. These findings were presented at the European Atherosclerosis Society 92nd Congress and published in the New England Journal of Medicine.
The study included various doses (50, 100, and 200 mg) and highlighted dose-dependent efficacy with the highest dose achieving up to a 63% reduction in triglycerides and 74% reduction in ANGPTL3 levels compared to placebo. Additionally, liver fat reductions were observed in patients with higher baseline liver fat fractions.
- Significant reductions in triglycerides: -51% (50 mg), -57% (100 mg), -63% (200 mg).
- Dose-dependent reduction in ANGPTL3 levels: -54% (50 mg), -70% (100 mg), -74% (200 mg).
- Reduction in remnant cholesterol: -73% (50 mg), -76% (100 mg), -82% (200 mg).
- Improvements in other atherogenic lipoproteins: LDL-C -20%, ApoB -22%, Non-HDL-C -36% (200 mg dose).
- Liver fat reductions: -28% in patients with >8% baseline liver fat for the 200 mg dose.
- Favorable safety profile with balanced TEAEs between treatment and placebo groups.
- No clinically meaningful changes in laboratory safety evaluations or mean platelet counts.
- Modest changes in HbA1c, indicating good tolerability.
- No clinically significant changes noted in safety evaluations might indicate a need for longer-term studies to fully ascertain safety.
- The study may require additional Phase 3 trials to confirm findings, suggesting a longer time to potential market approval.
Insights
Arrowhead Pharmaceuticals’ recent Phase 2b study results for Zodasiran offer promising insights into the potential treatment for mixed hyperlipidemia. Zodasiran demonstrated significant reductions in triglycerides and atherogenic lipoproteins, which could considerably impact cardiovascular risk factors. The robust data, with a
However, while the Phase 2b results are encouraging, Phase 3 trials will be crucial to confirm these benefits and assess the long-term safety and efficacy of Zodasiran. The genetic basis for ANGPTL3 inhibition aligns well with the observed biochemical outcomes, suggesting a strong scientific rationale. Nevertheless, the ultimate clinical benefit will depend on demonstrating a tangible reduction in cardiovascular events in a broader and more diverse patient population.
Retail investors should monitor the progress of Phase 3 trials and any regulatory updates closely. The current results are promising, but final approval and widespread clinical use are contingent on further validation.
The positive Phase 2b results for Zodasiran position Arrowhead Pharmaceuticals favorably in the biopharmaceutical market, particularly in the niche of RNAi-based therapies. This breakthrough could potentially expand Arrowhead's market share and open new revenue streams if Zodasiran proves effective in Phase 3 trials and gains regulatory approval. Investors should consider the competitive landscape, which includes other lipid-lowering therapies and RNAi drugs from competitors like Alnylam Pharmaceuticals. Arrowhead's strategic focus on targeting ANGPTL3 differentiates it, but market adoption will depend significantly on the pricing strategy, insurance coverage and head-to-head comparisons with existing therapies.
The simultaneous publication in the New England Journal of Medicine adds scientific credibility and visibility, possibly enhancing investor confidence. However, the market will watch closely for Phase 3 trial outcomes and any strategic partnerships or collaborations Arrowhead might pursue to bolster its market presence and commercialization efforts.
Investors should also keep an eye on upcoming industry conferences and presentations, which could provide additional insights into the drug’s development and strategic positioning.
Arrowhead Pharmaceuticals’ stock might experience positive momentum in the short term due to the optimistic Phase 2b results for Zodasiran. The drug’s potential to address a significant unmet need in hyperlipidemia could attract investor interest and likely support higher valuation multiples. However, the financial outlook will largely depend on the success of Phase 3 trials and subsequent FDA approval. Additionally, the market will scrutinize Arrowhead's ability to effectively scale production and commercialization, balancing R&D expenses with revenue generation.
Investors should consider the
- Zodasiran significantly reduced triglycerides and atherogenic triglyceride rich lipoproteins across all dose levels at Week 24
- Data presented at European Atherosclerosis Society 92nd Congress and simultaneously published in the New England Journal of Medicine
“Results from clinical studies of zodasiran, including those for the ARCHES-2 study in patients with mixed hyperlipidemia presented today at EAS and published in the New England Journal of Medicine, continue to support ANGPTL3 as an exciting target for an RNAi-based gene silencing strategy,” said Bruce Given, M.D., interim chief medical scientist at Arrowhead. “Genetic studies show that ANGPTL3 loss-of-function variants lead to enhanced lipoprotein lipase and endothelial lipase activity, resulting in lower concentrations of most plasma lipoproteins, including triglyceride rich lipoproteins, LDL-C, VLDL/remnant cholesterol, and HDL-C. Individuals with these variants also have demonstrated a markedly reduced risk of ASCVD and have no known adverse clinical phenotypes1-3.”
Robert Rosenson, M.D., Icahn School of Medicine at Mount Sinai, and Principal Investigator for the ARCHES-2 study added, “The potent reductions in serum lipids and lipoproteins and favorable safety profile seen in the ARCHES-2 clinical study of zodasiran suggest its potential to treat residual ASCVD risk in patients with elevated triglyceride rich lipoproteins. The genetic data around ANGPTL3 as a target are very compelling and support further Phase 3 studies to determine whether the large reductions in triglyceride rich lipoproteins observed after zodasiran treatment can replicate the genetic data and reduce ASCVD risk.”
Select ARCHES-2 Results
Zodasiran treatment was associated with dose-dependent placebo adjusted reductions in triglycerides, remnant cholesterol, LDL-C, ApoB, and Non-HDL-C across all dose levels in patients with mixed hyperlipidemia.
At week 24, representing trough effect, zodasiran treatment at 50, 100, and 200 mg on day 1 and week 12 was associated with placebo adjusted reductions in triglycerides of -
Changes in other atherogenic lipoprotein parameters were also observed across all three dose levels. At week 24, the following placebo adjusted changes were observed for the 200 mg dose: LDL-C -
In a subset of patients with baseline liver fat fraction greater than
Safety and Tolerability
Zodasiran demonstrated a favorable safety profile in patients with mixed hyperlipidemia in the ARCHES-2 study. Treatment-emergent adverse events (TEAEs) were generally balanced between treatment and placebo groups and generally reflected the comorbidities and underlying conditions of the study population. There were no clinically meaningful changes in laboratory safety evaluations, no changes in mean platelet counts, and modest changes in HbA1c.
Details about the EAS presentation is listed below.
European Atherosclerosis Society (EAS) 92nd Congress – May 26-29, 2024
Title: ZODASIRAN SILENCES HEPATIC ANGPTL3 LEADING TO DEEP AND DURABLE REDUCTIONS IN ATHEROGENIC LIPIDS AND LIPOPROTEINS IN MIXED DYSLIPIDEMIA PATIENTS: FINAL RESULTS FROM ARCHES-2, DOUBLE-BLIND PERIOD
Date/Time: May 29, 2024, 11:30 a.m. CEST
Presenter: Robert Rosenson, M.D.
Session: Late Breaker Session 2: New Therapeutic Agents
Presentation materials may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website after the presentation concludes.
About ARCHES-2
ARCHES-2 (NCT04832971) is a double-blind, placebo-controlled dose-ranging Phase 2b clinical study of zodasiran in 204 participants with mixed hyperlipidemia. Participants with fasting triglycerides between 150-499 mg/dL and either LDL-cholesterol greater than 70 mg/dL or non-HDL-cholesterol greater 100 mg/dL were randomly assigned in a 3:1 ratio to receive subcutaneous injections of 50, 100, or 200 mg zodasiran or placebo on day 1 and week 12 and followed through week 36. The primary objective of the study was to evaluate the safety and efficacy of plozasiran in adults with mixed hyperlipidemia.
About Mixed Hyperlipidemia
Mixed hyperlipidemia, also called mixed dyslipidemia, is a highly prevalent disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride levels. Despite the efficacy of LDL-C-lowering therapies in reducing atherosclerotic cardiovascular disease (ASCVD) risk in mixed hyperlipidemia, there remains substantial residual risk attributed to elevated non-HDL driven by remnant cholesterol in triglyceride-rich lipoproteins4-7h. Genome-wide association and Mendelian randomization studies also support a causal role for triglyceride rich lipoproteins in ASCVD8-11.
About Zodasiran
Zodasiran, previously called ARO-ANG33, 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)12,13. Genetic studies suggest that individuals with ANGPTL3 loss-of-function variants have enhanced lipoprotein lipase and endothelial lipase activity, resulting in lower levels atherogenic lipoproteins and a reduced risk of ASCVD1-3.
In clinical studies, investigational zodasiran demonstrated a favorable safety profile and was associated with dose-dependent reductions in triglycerides, triglyceride rich lipoprotein remnants, and total atherogenic lipoproteins, including LDL-C, in patients with homozygous and heterozygous familial cholesterolemia (HoFH) and mixed hyperlipidemia.
About Arrowhead Pharmaceuticals
Arrowhead Pharmaceuticals develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing.
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Source: Arrowhead Pharmaceuticals, Inc.
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Arrowhead Pharmaceuticals, Inc.
Vince Anzalone, CFA
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Source: Arrowhead Pharmaceuticals, Inc.
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