Arrowhead Pharmaceuticals Eyes SHTG Filing as RNAi Pipeline Expands

Key Points

• Arrowhead plans to file for SHTG approval by year-end. The company expects a potential second-quarter 2027 launch of REDEMPLO (plozasiran) for severe hypertriglyceridemia, supported by approximately 80% triglyceride reductions and substantial reductions in acute pancreatitis risk.
• REDEMPLO’s initial launch for familial chylomicronemia syndrome is progressing, with Arrowhead expanding its sales force and estimating a potential $3 billion–$4 billion U.S. peak annual market for plozasiran.
• Arrowhead is broadening its RNAi pipeline beyond liver diseases, advancing programs in cholesterol, obesity and CNS disorders. Key upcoming milestones include zodasiran data in homozygous familial hypercholesterolemia, additional obesity data and early clinical results for the Alzheimer’s candidate ARO-MAPT.

Arrowhead Pharmaceuticals NASDAQ: ARWR is expanding its commercial and clinical footprint around RNA interference therapies, with its recently launched triglyceride-lowering treatment REDEMPLO and several pipeline programs targeting cardiometabolic disease, obesity and central nervous system disorders.

Speaking at H.C. Wainwright's 28th Annual Global Investment Conference, Chief Executive Officer Chris Anzalone said the company has evolved from its initial focus on liver-targeted RNAi therapies into a broader platform company. Arrowhead now has approximately 21 or 22 drug candidates in clinical studies, he said, with clinical candidates representing five different cell types.

“The first tissue that we could address is the liver, hepatocytes,” Anzalone said. “But we decided early on that in order to extract proper value from this technology and to treat as many patients as we could, we needed to get outside the liver.”

REDEMPLO Launch and Severe Hypertriglyceridemia Filing

REDEMPLO, also known as plozasiran, is an APOC3 inhibitor designed to lower triglycerides. The drug is approved for familial chylomicronemia syndrome, or FCS, an ultra-orphan condition. Anzalone said the launch has progressed well, although contracting with payers required several quarters.

The company is now able to serve patients with both genetic FCS and what it describes as clinically defined FCS. Anzalone estimated there could be 15,000 to 20,000 clinically defined FCS patients. Arrowhead has expanded its commercial organization from an initial sales force of roughly 20 representatives and expects another phase of sales-force growth in January and February as it prepares for a potential severe hypertriglyceridemia, or SHTG, launch in the second quarter of 2027.

Arrowhead plans to submit a supplemental new drug application for plozasiran in SHTG by year-end. The company acquired a priority review voucher, which Anzalone said could reduce review timing by four months.

Chief Medical Officer and Head of R&D James Hamilton said results from the Phase 3 SHASTA-3 and SHASTA-4 trials showed about an 80% reduction from baseline in triglycerides among patients with severe hypertriglyceridemia, defined in the studies as triglycerides above 500. The triglyceride reduction was associated with statistically significant reductions in acute pancreatitis, with risk reductions ranging from 78% to more than 80%, depending on the population, he said.

In a subset of patients with triglycerides above 880 and a history of pancreatitis, Hamilton said the pooled SHASTA-3 and SHASTA-4 data showed a 100% risk reduction, with no events among patients receiving active treatment.

Hamilton also described the safety profile as “pretty clean,” citing no evidence of thrombocytopenia or hypersensitivity reactions and no clinically meaningful or statistically significant increase in liver fat versus placebo. The company’s MUIR study is complete and its database is locked. Hamilton said the study, which enrolled about 1,000 hypertriglyceridemia patients, will contribute to a safety database of at least 1,500 patients treated for one year and will be included in the supplemental application.

Anzalone said the company sees SHTG as an education-driven market that may develop gradually rather than produce an immediate rapid launch. He said Arrowhead estimates plozasiran could become a $3 billion to $4 billion annual U.S. drug at peak.

Additional Cardiometabolic Programs

Arrowhead’s zodasiran program in homozygous familial hypercholesterolemia, or HoFH, has completed enrollment in its Yosemite study, with data expected around the middle of next year, according to Hamilton. He pointed to Phase 3 data presented by Visirna, which holds Chinese rights to zodasiran and is partially funded and owned by Arrowhead. Those data showed a greater than 40% reduction in LDL cholesterol, including a reported 44% reduction in an HoFH population.

Anzalone said he expects zodasiran to be Arrowhead’s next launch after a potential SHTG launch, describing it as a relatively straightforward addition for a sales force already calling on endocrinologists, cardiologists and lipidologists. He characterized HoFH as a small, ultra-orphan indication.

The company also recently reported first-in-human data for ARO-DIMER-PA, a therapy using two linked siRNAs as a single molecule to target PCSK9 and APOC3. Hamilton said top-line single-dose data showed APOC3 reductions greater than 80%, PCSK9 reductions greater than 70%, a 54% reduction in LDL cholesterol, triglyceride reductions above 70%, and an approximately 50% reduction in ApoB.

Arrowhead plans to complete the ongoing study and review data after a second dose before selecting two or three dose levels for a potential Phase 2b study in mixed hyperlipidemia. Hamilton said the company’s goal would be to pursue approval based on LDL reduction in a biomarker-driven Phase 3 program, potentially alongside a cardiovascular outcomes trial.

Obesity and CNS Pipeline Updates

In obesity, Arrowhead is studying activin E and ALK7, targets in the same pathway. The company expects to provide additional data toward the end of the year, with an update focused primarily on ALK7. Hamilton said planned data include weight-loss measures across subpopulations, including patients with Type 2 diabetes, as well as MRI-based measurements of body composition, visceral fat, total fat and lean mass.

Arrowhead is also advancing ARO-MAPT, a subcutaneously administered siRNA designed to silence the MAPT gene and reduce tau, a protein implicated in Alzheimer’s disease and other tauopathies. Hamilton said the company expects to present healthy-volunteer data within the next month, focused mainly on safety and cerebrospinal fluid total tau knockdown. Enrollment of Alzheimer’s patients is ongoing, with those data expected next year.

Anzalone said Arrowhead expects several additional wholly owned CNS targets to enter the clinic over the next 18 months. He emphasized that the company’s broader pipeline remains central to its strategy even as investors focus on its first commercial product.

About Arrowhead Pharmaceuticals (NASDAQ:ARWR)

Arrowhead Pharmaceuticals, Inc NASDAQ: ARWR is a biopharmaceutical company focused on developing medicines that silence disease-causing genes. The company uses RNA interference (RNAi), a biological process that reduces the production of specific proteins, to target conditions that may be difficult to treat with conventional drugs.

Arrowhead's proprietary TRiM platform is designed to deliver RNAi-based therapies to different tissues, including the liver, lungs and other organs. Its investigational pipeline has included candidates for cardiovascular and metabolic diseases, liver disorders, pulmonary conditions and inflammatory diseases.

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