Arrowhead's Q4 2025: Contradictions Emerge on Pancreatitis Claims, Inhibin E/ALK7 Progress, and ARO-DIMER Inclusion Criteria

Date of Call: November 25, 2025

Financials Results

• Revenue: $829.0M, driven entirely by license and collaboration agreements (≈$697M from Sarepta, $130M from Sanofi Greater China license, $2.6M from GSK milestone)
• EPS: Net loss $2M, or $0.01 loss per share, compared with a net loss of ~$599M, or $5.00 loss per share, in FY2024

Business Commentary:

* FDA Approval and Commercial Launch: - Arrowhead Pharmaceuticals received FDA approval for REDEMPLO, indicated as an adjunct to diet to reduce triglycerides in adults with Familial Chylomicronemia Syndrome (FCS) or FCS. - This approval marks Arrowhead's transition into a commercial-stage company, with drug available in channel just a week after approval. - The approval was driven by positive Phase III clinical data and the company's strategic focus on commercialization.

• Pipeline and Partnership Progress:
• Arrowhead dosed the first subject in the YOSEMITE Phase III clinical trial of zodasiran for homozygous Familial Hypercholesterolemia (HoFH).
• A licensing agreement was established with Novartis for ARO-SNCA, Arrowhead's preclinical stage siRNA therapy against alpha-synuclein for Parkinson's disease.

• These developments are part of Arrowhead's business model, focusing on strategic partnerships and license agreements to drive growth.

• Financial Performance:

• Arrowhead reported net loss of $2 million for fiscal year 2025, compared to a net loss of $599 million in fiscal year 2024.
• Revenue for fiscal year 2025 totaled $829 million, primarily from license and collaboration agreements with companies like Sarepta, Sanofi, and GSK.

• The improvement in financial performance was due to increased revenue from partnerships and a decrease in research and development expenses.

• Obesity Program Updates:

• Arrowhead expects to share initial data from the ARO-INHBE and ARO-ALK7 obesity programs in January 2026.
• Both programs have shown promising preclinical results, targeting the activin pathway involved in signaling to store fat.
• The company anticipates sharing more fulsome data by the end of the first half of 2026, indicating progress in these early-stage obesity programs.

Sentiment Analysis:

Overall Tone: Positive

• Management emphasized the FDA approval and commercial launch of REDEMPLO, calling it the company’s "first FDA‑approved medicine" and noting drug is "in channel a mere week after approval." CFO highlighted a near breakeven FY2025 (net loss $2M) and cash/investments of $919M with runway into FY2028, while multiple programs (DIMER, MAPT, obesity candidates, SHASTA readouts) were positioned as near‑term value drivers.

Q&A:

• Question from Luca Issi (RBC Capital Markets): What's the plan to show a benefit in acute pancreatitis for plozasiran — are SHASTA‑3/4 powered to show pancreatitis benefit or is SHASTA‑5 necessary?
  Response: SHASTA‑3/4 are powered for triglyceride reduction (primary endpoint) and can be pooled for pancreatitis assessment, but SHASTA‑5 is the dedicated, event‑driven trial specifically designed to demonstrate pancreatitis risk reduction.

• Question from Prakhar Agrawal (Cantor Fitzgerald): For the obesity programs, what data (SAD/MAD, combo, follow‑up) will be disclosed early next year and will ALK7 show any early weight‑loss data?
  Response: Inhibin E will report early SAD/MAD biomarker, MRI and safety data plus combo cohort follow‑up in early January; ALK7 disclosure will be limited to monotherapy safety and target‑engagement (knockdown) data with fuller datasets later in 1H‑2026.

• Question from Maurice Raycroft (Jefferies): Given the baseline profile, what are your estimates on accrual of acute pancreatitis events and how does adopting modified Atlanta criteria affect this?
  Response: They adopted the modified Atlanta criteria (per FDA/EMA guidance), which makes event accrual harder to predict; enrollment includes a meaningful proportion with prior pancreatitis, so there's a reasonable chance of sufficient events but precise forecasts are uncertain.

• Question from Dina Ramadane (BofA Securities): How does ARO‑MAPT differ from J&J's anti‑tau antibody and what's the visibility on launching a CVOT for DIMER and Sarepta milestone timing in 2026?
  Response: ARO‑MAPT delivers a BBB‑penetrant siRNA to silence intracellular tau (vs antibodies that mainly clear extracellular tau), aiming for deeper neuron intracellular reduction.

• Question from Edward Tenthoff (Piper Sandler): Will you have a first look from ARO‑DIMER‑PA next year and what other key datasets should we expect beyond early obesity data?
  Response: Key 2026 readouts: early obesity data in early January and larger datasets by late Q2; DIMER (PCSK9/APOC3) Phase I/II data expected by summer 2026, ARO‑MAPT first CSF biomarker data in summer, and SHASTA‑3/4 readouts in Q3‑2026 to support an sNDA by year‑end.

• Question from Edward Tenthoff (Piper Sandler): Any update on ARO‑RAGE?
  Response: ARO‑RAGE shows deep RAGE knockdown and biomarker signals; a challenge study has started (data unlikely in 2026) to de‑risk clinical proof‑of‑concept and inform whether to build or partner.

• Question from Mani Foroohar (Leerink Partners): How do you view DIMER's application for a CVOT and where will this technology be best applied now that balance sheet is stronger?
  Response: DIMER can uniquely target mixed hyperlipidemia by lowering both LDL and triglycerides with a single quarterly injection, addressing a large ~20M US population and enabling both LDL‑focused approvals and a potential CVOT strategy.

• Question from Patrick Trucchio (H.C. Wainwright): Has FDA clarified what evidence is required for a pancreatitis risk‑reduction claim in SHTG, are pediatric plans in place, and what CSF tau knockdown would signal MAPT PoC?
  Response: They haven't obtained regulator clarity for a formal pancreatitis label claim and believe SHASTA‑5 is mainly payer‑focused; pediatric FCS plans exist pending a weight‑based formulation; MAPT aims for ~50%–60% CSF tau reduction as a meaningful PoC benchmark.

• Question from Andrea Tan (Goldman Sachs): Now that REDEMPLO has launched, what's your expectation for the initial FCS launch cadence and how might it compare to TRYNGOLZA given pricing differences?
  Response: They expect a strong, best‑in‑class FCS launch driven by REDEMPLO's large (~80%) sustained TG reductions, favorable safety profile (no contraindications/warnings) and once‑every‑3‑month dosing, with early encouraging payer and HCP feedback.

• Question from Michael Ulz (Morgan Stanley): Now that you've adopted modified Atlanta criteria and seen core study details, are you making further adjustments to SHASTA‑3/4?
  Response: No further protocol changes are planned beyond adopting the modified Atlanta criteria; the design was negotiated with FDA and core data didn't prompt additional modifications.

• Question from Madison Wynne El‑Saadi (B. Riley): For the neuromuscular franchise and Sarepta collaboration, should we expect DMPK knockdown/splice correction comparable to peers, optimal dose expectations, and are milestones tied to PD thresholds?
  Response: They deferred DMPK/dose specifics to Sarepta; objective is peer‑comparable knockdown, but milestones are tied to regulatory/commercial events rather than PD/activity thresholds.

• Question from Joseph Thome (TD Cowen): In SHTG, what proportion of patients are on anti‑PCSK9 therapy and what were the triglyceride/LDL inclusion cutoffs for the early DIMER study?
  Response: Few SHTG patients are on PCSK9 inhibitors (many on statins); the DIMER study enrolls mixed hyperlipidemia patients with triglycerides up to 880 mg/dL and requires non‑HDL ≥100 mg/dL or LDL >70 mg/dL.

Contradiction Point 1

Pancreatitis Risk Reduction Claims and Study Design

It involves changes in the company's approach to pancreatitis risk reduction claims, which could impact regulatory and payer requirements, and thus the market impact of their products.

What are the plans for plozasiran to demonstrate acute pancreatitis benefits? Is confidence in SHASTA-3/4’s ability to show acute pancreatitis benefits, or is SHASTA-5 necessary due to underpowered trials? - Luca Issi (RBC Capital Markets)

2025Q4: SHASTA-3 and 4 were powered on the basis of triglyceride reduction as the primary endpoint, not specifically for pancreatitis. The design allows pooling for evaluating pancreatitis comparisons. SHASTA-5 is specifically designed to demonstrate a benefit versus placebo in acute pancreatitis. - Bruce Given(Chief Medical Scientist)

Given your SHTG focus with SHASTA-3/4 trials, how do you assess the impact of Ionis’ September core study results, particularly triglyceride reduction and acute pancreatitis signals? - Farzin Haque (Jefferies)

2025Q3: We're focused on our own studies. We have good data in Phase II and Phase III for FCS. Expect best-in-class triglyceride reducer here. Look forward to seeing SHTG data, but we'll focus on our own. - Dr. Christopher Anzalone (President and CEO)

Contradiction Point 2

Inhibin E and ALK7 Study Progress

It involves the progress and data expectations from Inhibin E and ALK7 studies, which are critical for the development and potential launch of new treatments.

Can you provide details on the inhibin E update expected early next year, including the amount of MAD-related data and follow-up for monotherapy and combo cohorts? For ALK7, what cohorts will be disclosed and will there be any weight loss data available early in the year? - Prakhar Agrawal (Cantor Fitzgerald & Co.)

2025Q4: Inhibin E is more mature with data in SAD and MAD healthy volunteer cohorts, including biomarker and MRI data. Combo cohorts are almost fully enrolled, with follow-up data planned to be included in the first data release. ALK7 is limited to monotherapy, focusing on safety and knockdown data. - James Hamilton(Chief Medical Officer and Head of R&D)

What obesity-related updates does the company anticipate later this year? - Edward Tenthoff (Piper Sandler)

2025Q3: We don't go into studies with preconceived ideas. We'll see the data and move forward based on that. - Dr. Christopher Anzalone (President and CEO)

Contradiction Point 3

Pancreatitis Event Rate Expectations

It involves differing expectations about pancreatitis event rates in patients with severe hypertriglyceridemia (SHTG), which is crucial for understanding the potential impact of Arrowhead's therapies on clinical outcomes.

What are the expected baseline rates of acute pancreatitis and potential effect magnitude for plozasiran in SHTG? - Jasmine Fels (UBS)

2025Q4: The baseline pancreatitis rate is expected to be similar to FCS levels, around 2,000 mg/dL. The expectation is substantial triglyceride reductions, supporting the primary endpoint of reducing pancreatitis risk. - Christopher Anzalone(CEO)

How does Arrowhead's pancreatitis data compare to Tringolza's? What is the label differentiation? - Jason Gerberry (Bank of America)

2025Q2: The baseline pancreatitis rate is expected to be similar to FCS levels, around 2,000 mg/dL. The expectation is substantial triglyceride reductions, supporting the primary endpoint of reducing pancreatitis risk. - Christopher Anzalone(CEO)

Contradiction Point 4

ARO-DIMER Patient Population and Inclusion Criteria

It involves differences in the description of the patient population and inclusion criteria for the ARO-DIMER study, which affects the potential market size and patient eligibility.

What percentage of dimer study patients are on anti-PCSK9 therapy? What are the triglyceride and LDL inclusion criteria? - Joseph Thome (TD Cowen)

2025Q4: Few patients are on PCSK9 inhibitors. The inclusion criteria allow for triglycerides up to 880 and non-HDL or LDL greater than 70 or 100. - James Hamilton

Compare Arrowhead's pancreatitis data to Tringolza's? How does Arrowhead's label differentiate from Tringolza's? - Jason Gerberry (Bank of America)

2025Q2: ARO-DIMER targets both PCSK9 and APOC3, treating the mixed hyperlipidemia population with 20 million patients in the U.S. It can address LDL and triglycerides, unlike current treatments. It could provide a significant marketing opportunity. - Bruce Given