The U.S. Food and Drug Administration (FDA) has accepted Arrowhead Pharmaceuticals' New Drug Application (NDA) for plozasiran, marking a significant milestone for the company's RNA interference (RNAi) therapeutic platform. The investigational drug, designed to treat familial chylomicronemia syndrome (FCS), has been assigned a Prescription Drug User Fee Act (PDUFA) action date of November 18, 2025, with the FDA indicating no current plans for an advisory committee meeting.
This acceptance represents Arrowhead's first NDA filing and positions the company for potential commercial launch of its lead candidate by late 2025, pending regulatory approval.
Strategic Funding Secures Future Growth
Arrowhead has significantly strengthened its financial position through strategic partnerships and financing agreements. Most notably, the company closed a global license and collaboration agreement with Sarepta Therapeutics that provides $825 million upfront, consisting of $500 million in cash and $325 million as an equity investment priced at a 35% premium.
The Sarepta deal includes additional potential payments of $250 million to be paid in equal installments over five years, plus $300 million in near-term milestone payments that Arrowhead expects to achieve within the next 12 months. The total potential value of this collaboration exceeds $11 billion, including milestone payments and royalties on commercial sales.
"This was clearly a big deal and a critical step for Arrowhead to bring balance back to our business model, which in part relies on partnering noncore assets to provide capital for us to develop and commercialize our own wholly owned assets," said Christopher Anzalone, Arrowhead's CEO, during a recent earnings call.
This strategic infusion of capital extends Arrowhead's cash runway into 2028, potentially through multiple commercial launches by the company and its partners.
Plozasiran: Addressing Unmet Needs in Lipid Disorders
Plozasiran targets APOC3, a key regulator of triglyceride metabolism. In the Phase 3 PALISADE study, the drug demonstrated impressive efficacy in FCS patients, achieving median triglyceride reductions of approximately 80% from baseline in the 25mg dose group. The study also showed a statistically significant 83% reduction in the risk of developing acute pancreatitis compared to placebo.
FCS is a severe and rare genetic disease characterized by extremely high triglyceride levels, often in the thousands of mg/dL (normal levels are below 150 mg/dL). These elevations can lead to potentially fatal acute pancreatitis, chronic abdominal pain, diabetes, and cognitive issues.
"The data continued to be promising across studies, across the spectrum of triglyceride disorders, and after short- and long-term follow-up," noted Anzalone. "In addition, plozasiran has been overall generally well tolerated to date."
Beyond FCS, Arrowhead is advancing plozasiran in multiple Phase 3 studies for severe hypertriglyceridemia (SHTG) and mixed hyperlipidemia. The company expects to complete enrollment for the SHASTA-3, SHASTA-4, and MUIR-3 studies this year, enabling study completion in 2026 and a subsequent supplemental NDA filing.
"We believe plozasiran has the potential to be a $2 billion to $3 billion per year drug in the SHTG market alone," Anzalone stated.
Expanding into Obesity and CNS Applications
Arrowhead has identified three primary value drivers for near-term growth: plozasiran, obesity programs, and central nervous system (CNS) applications.
The company has initiated a Phase 1/2a clinical trial of ARO-INHBE, its first investigational RNAi therapeutic for obesity. ARO-INHBE is designed to reduce expression of inhibin B, a ligand for adipose ALK7. Additionally, Arrowhead received regulatory clearance to initiate a clinical study of its second obesity candidate, ARO-ALK7, which targets the ALK7 receptor itself.
"Both programs are supported by published human genetic studies, and the preclinical data have demonstrated dramatic results with the potential to fill gaps in the current standard of care," Anzalone explained. "The possibility of long-acting agents that spare muscle mass and enable visceral fat loss without dependence on caloric restriction is exciting indeed."
In preclinical models, both obesity candidates demonstrated substantial reductions in fat mass while preserving lean mass, a potentially significant advantage over current obesity treatments.
Arrowhead is also developing a new version of its Targeted RNAi Molecule (TRiM) platform capable of delivering siRNA across the blood-brain barrier using subcutaneous injection. Initial efforts with this platform address Huntington's disease, Alzheimer's disease, and Parkinson's disease through the candidates ARO-HTT, ARO-MAPT, and ARO-SNCA, respectively.
"Near-term clinical proof of concept would truly be disruptive, and we think would open the door to treating many millions of patients without adequate options," said Anzalone.
Competitive Positioning and Commercial Preparation
As Arrowhead prepares for the potential launch of plozasiran, the company has built experienced market access and marketing organizations and established a fully operational medical affairs function.
Andy Davis, Arrowhead's commercial lead, highlighted several potential differentiating attributes of plozasiran compared to competitors: "First, the reduction in triglycerides is both deep and durable. Second, people living with FCS for the first time have real hope of achieving triglyceride levels below guideline-directed risk thresholds associated with acute pancreatitis. Third, the triglyceride reductions from baseline were consistent in patients with genetically confirmed and clinically diagnosed FCS."
Davis also emphasized that plozasiran is "the first and only investigational medicine to achieve a statistically significant reduction in the risk of developing acute pancreatitis in patients with genetically confirmed and clinically diagnosed FCS," and noted its convenient quarterly dosing schedule.
The company's medical science liaisons are already conducting scientific exchange, while market access colleagues are engaging with payers to communicate clinical and economic evidence. Arrowhead plans to execute its final field force hiring plans in the coming months.
Financial Outlook
Arrowhead reported a net loss of $173.1 million for the quarter ended December 31, 2024, compared to a net loss of $132.9 million for the same period in 2023. Revenue for the quarter was $2.5 million, down from $3.6 million in the prior-year period.
Including the $825 million in upfront payments from the Sarepta agreement, Arrowhead's pro forma cash and investments would be approximately $1.4 billion as of December 31, 2024. The company expects its cash and investments balance to be approximately $1 billion at the end of calendar 2025.
"We are now funded into 2028 and potentially through multiple commercial launches by Arrowhead and our partners," said Anzalone. "We believe we are now well positioned for growth in 2025 and beyond."
Looking Ahead
Arrowhead has outlined a robust catalyst calendar for 2025, including the potential commercial launch of plozasiran in FCS in the U.S. and potentially the EU, initiation of a Phase 3 study of zodasiran in homozygous familial hypercholesterolemia (HoFH), and potential data readouts from multiple clinical programs.
The company's strategic focus on cardiometabolic diseases, obesity, and CNS applications, coupled with its strengthened financial position, positions Arrowhead to potentially deliver on multiple value-creating milestones in the coming years.
As Arrowhead transitions from a clinical-stage to a potentially commercial-stage company, the acceptance of its first NDA represents a pivotal moment in the company's evolution and in the broader advancement of RNAi therapeutics for treating serious diseases.
