Thesis: Arrowhead Pharmaceuticals (NASDAQ:ARWR) faces a pivotal FDA decision on November 18 for its RNAi therapy Plozasiran, developed for a rare genetic disorder. But after a 175% rally over the past 6 months, is a potential approval already priced in? A pending lawsuit further complicates the narrative.
Company: Arrowhead Pharma (ARWR)
FDA Review Date: November 18, 2025
Drug Candidate: Plozasiran
Indication: Familial Chylomicronemia Syndrome (FCS)
Odds of FDA Approval: Strong
ARWR Stock: Up more than 175% in the last 6 months, so will an FDA approval move the needle meaningfully for ARWR?
Arrowhead Pharma: Overview
Arrowhead Pharmaceuticals is approaching a key regulatory milestone, as the FDA prepares to decide on its experimental RNA interference (RNAi) therapy Plozasiran for familial chylomicronemia syndrome (FCS).
FCS is a rare, severe, inherited genetic disorder characterized by the body’s inability to properly break down and clear fats (triglycerides) from the blood. This results in extremely elevated triglyceride levels (of typically over 880 mg/dL vs. healthy levels of below 150 mg/dL) and a dramatically increased risk of acute pancreatitis, a sudden, severe inflammation of the pancreas that can be potentially fatal.
How The Drug Works
Plozasiran addresses the root cause of the dangerously high triglyceride levels in FCS by targeting protein production at the genetic level.
Mechanism: Lipoprotein lipase (LPL) is an enzyme that breaks down fats (triglycerides) in the bloodstream. Apolipoprotein C-III (ApoC3), inhibits LPL, thereby increasing triglyceride levels in the blood. Plozasiran silences the gene responsible for producing ApoC3.
Delivery: Plozasiran is administered via subcutaneous injection every 3 months and acts on the liver cells (hepatocytes), where ApoC3 is primarily produced. Once inside the liver cells, the drug targets and degrades the messenger RNA (mRNA) that carries the instructions for building the ApoC3 protein.
Effect: The end result is a significant and sustained reduction in the levels of triglycerides in the blood, which in turn reduces the risk of serious complications like acute pancreatitis.
Plozasiran’s Clinical Data:
Arrowhead’s Phase 3 PALISADE trial met its primary and all key secondary endpoints with high statistical significance vs. placebo.
- Triglyceride Reduction: Median 80% reduction in fasting triglycerides at the 25 mg dose at month 10.
- Pancreatitis Risk: 83% reduction in the risk of developing acute pancreatitis compared to placebo.
- Safety: Well-tolerated with adverse events comparable to placebo. Serious adverse events were more common in the placebo arm.
Competitive Landscape: Plozasiran vs. Tryngolza
If approved, is Plozasiran the first therapy for the FCS indication?
It is not. The FDA approved Ionis Pharmaceuticals’ Tryngolza (with generic name olezarsen) in December 2024, for treating FCS, as a diet adjunct. Like plozasiran, olezarsen also reduces the body’s production of the ApoC3 protein.
Tryngolza has generated $57 million in year-to-date sales as of Sep 30. ($6 million in Q1, $19 million in Q2 and $32 million in Q3). For fiscal 2025, Ionis now sees Tryngolza sales of $85 million to $95 million, implying Q4 sales of $28 million to $38 million.
Plozasiran’s differentiators:
Both drugs target and reduce the production of the ApoC3 protein. Tryngolza enjoys the first-mover advantage, while Plozasiran shows superior efficacy as suggested by its clinical trial data.
It should be noted that no direct head-to-head clinical trials comparing Tryngolza and Plozasiran have been conducted. This widely-held opinion is based on data from their respective pivotal trials.
Tryngolza demonstrated a placebo-adjusted mean reduction in triglycerides of 42.5% at six months, improving to 57% at 12 months compared to Plozasiran’s 80% reduction in the 25mg dose group.
Plozasiran may also offer a more convenient dosing schedule, as it is administered via a subcutaneous injection every three months, while Tryngolza is administered every month.
A Lawsuit Thrown Into The Mix
Ionis Pharmaceuticals filed a patent infringement lawsuit in September against Arrowhead Pharma over Plozasiran. While the suit is unlikely to delay the FDA’s decision, it could complicate commercialization if Ionis prevails. Ionis is seeking unspecified monetary damages, introducing potential headline risk—particularly as Arrowhead is also evaluating Plozasiran for additional indications.
Still, the Ionis lawsuit invites a few questions: if Plozasiran were merely a copycat, how did it deliver superior efficacy versus Tryngolza? And why did Ionis wait until Arrowhead was close to an FDA decision to act? These questions merit a separate discussion—beyond the scope of this article. Arrowhead, for its part, is defending the suit, asserting that Plozasiran is based on internally developed proprietary technology and is in turn accusing Ionis of using the lawsuit to stifle competition.
What are the odds of approval for Arrowhead Pharma’s Plozasiran?
While an approval is not guaranteed until an official decision is made, the body of evidence and regulatory signals suggest a high probability of a positive outcome for Arrowhead’s Plozasiran on November 18, 2025.
The key factors supporting a favorable FDA decision include:
Compelling efficacy and safety record: Plozasiran’s phase 3 results demonstrated clinically meaningful reductions in triglyceride and pancreatitis risk with a favorable safety profile vs. placebo.
Absence of an advisory committee meeting signals positive regulatory outlook: The FDA has not convened an advisory committee meeting for evaluating Plozasiran. This could imply regulatory confidence in the sufficiency of data and no major unresolved issues.
Significant need for new therapies: While Ionis’s Tryngolza is already approved, a second effective option is still highly valuable to the FCS patient population.
Expedited designations: Breakthrough Therapy, Orphan Drug, and Fast Track status highlight both medical urgency and FDA engagement.
Arrowhead Pharma’s Long-term Catalysts
1. Plozasiran’s Expansion Beyond FCS
Plozasiran is also being assessed as a treatment for severe hypertriglyceridemia (SHTG) — defined as fasting triglycerides above 500 mg/dL
- Phase 2b SHASTA-2 Trial: About 90% of patients treated with Plozasiran achieved triglyceride levels below the 500 mg/dL pancreatitis-risk threshold after two doses, while 48% of patients achieved normal triglyceride levels of less than 150 mg/dL.
- Ongoing Phase 3 Trials: SHASTA-3 and SHASTA-4 are fully enrolled, with study completion expected in mid-2026 and data readouts expected subsequently.
- A successful outcome could significantly expand Plozasiran’s commercial potential beyond FCS.
2. Novartis Deal Derisks Arrowhead Pharma’s Balance Sheet
Recently, Arrowhead Pharma completed a global licensing agreement with Novartis for the development of ARO-SNCA, a preclinical RNA interference (RNAi) therapy targeting synucleinopathies such as Parkinson’s disease. The deal provides Arrowhead with an immediate $200 million cash infusion, plus up to $2 billion in potential milestone payments and tiered royalties from commercial sales of up to low-double digits.
Following completion of Arrowhead’s preclinical studies, Novartis will assume full responsibility for clinical development, manufacturing, and worldwide commercialization. The Novartis deal is a major validation of Arrowhead Pharma’s RNAi platform, while also significantly derisking its balance sheet ahead of commercialization.
Financials: Arrowhead Pharma said in a September presentation that it has a strong balance sheet with funding into 2028 to push candidates to commercialization – a reiteration of what it said during its earnings call in August.
Will FDA Approval Move The Needle For ARWR Stock?
A potential FDA approval for Plozasiran would represent a significant milestone for Arrowhead Pharma, marking its transition from a development-stage biotech to a commercial one.
However, with ARWR shares already up more than 175% over the past six months—largely in anticipation of this event and the Novartis collaboration—much of the potential upside may already be reflected in the current valuation. The stock currently trades at 7.5x forward sales, representing a nearly 80% premium to the sector median of 4.2x. It has also pulled back about 9% from its 52-week high reached on October 31, likely reflecting profit-taking.
That raises the question of whether ARWR may offer limited near-term upside even if Plozasiran is approved, while any regulatory delay or negative outcome could trigger meaningful downside pressure. Adding to near-term uncertainty, is Ionis’ lawsuit, which somewhat muddys ARWR’s near-term bullish narrative.
The FCS market opportunity remains relatively modest, estimated at around $1.2 billion by 2033, though a successful launch could pave the way for Plozasiran’s expansion into the broader SHTG indication, with key data expected next year. Arrowhead Pharma also has a promising pipeline in obesity and cardiometabolic disorders, which may provide additional long-term optionality.
These developments will be critical in determining the sustainability of Arrowhead Pharma’s revenue potential beyond the initial FCS indication, subject to Plozasiran’s approval and subsequent commercialization. Given ARWR’s sharp appreciation and what appears to be a nearly fully-priced valuation—along with profit-taking risk and the pending lawsuit—it may be more prudent to wait for a pullback before considering a position. Analysts currently assign ARWR a “Buy” rating with a $47.50 price target, implying about 20% upside from its last closing price of $39.61.
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