Ionis Q3 2025 Earnings Call Contradictions: Olezarsen Pricing, Peak Revenue, and Launch Strategy in sHTG

Date of Call: October 29, 2025

Financials Results

• Revenue: $157M in Q3, up 17% YOY; $740M for first 9 months, up 55% YOY; full-year guidance raised to $875M–$900M (increase of $50M vs prior guidance); TRYNGOLZA net product sales $32M in Q3 (nearly +70% QoQ); Q3 royalty revenue ~$76M, +~13% YOY.

Guidance:

• Total 2025 revenue guidance raised to $875M–$900M (up $50M vs prior guidance).
• TRYNGOLZA product sales expected $85M–$95M for full year.
• Full-year operating loss expected $275M–$300M.
• Olezarsen sNDA targeted for U.S. submission by year-end with launches planned next year; zilganersen NDA planned Q1 2026; DAWNZERA launch contribution modest in 2025, larger in 2026.
• Expect >$2.1B cash at year-end and aim for cash‑flow breakeven by 2028.

Business Commentary:

* Revenue Growth and Strong Product Launches: - Ionis Pharmaceuticals reported revenue of $157 million for Q3 2025, marking a 17% increase year-over-year and a 55% increase for the first 9 months of 2025 compared to the prior year. - The growth was driven by strong commercial execution and disciplined financial management, with TRYNGOLZA and DAWNZERA achieving significant momentum in their respective launches.

• Record TRYNGOLZA Sales:
• TRYNGOLZA reported net product sales of $32 million in the third quarter, reflecting a nearly 70% increase over the second quarter.

• The increase in sales was attributed to effective patient identification efforts, positive physician and patient experiences, and growing awareness of FCS.

• Positive Pipeline Developments:

• Ionis reported positive top-line results from two pivotal programs, olezarsen in severe hypertriglyceridemia and zilganersen in Alexander disease.

• These results underscore the strength of Ionis' science and position the company for potential multibillion-dollar revenue opportunities.

• Increased Financial Guidance:

• Ionis raised its 2025 financial guidance, reflecting strong performance across its pipeline and commercial portfolio.
• The guidance was increased to expect between $875 million and $900 million in total revenue for the year, with TRYNGOLZA product sales between $85 million and $95 million, reflecting the strong performance of their marketed medicines.

Sentiment Analysis:

Overall Tone: Positive

• Management: "we are raising our 2025 financial guidance"; CEO: "TRYNGOLZA... continues to build strong momentum"; CFO: "generated $157 million in revenue, representing a 17% increase year-over-year"; multiple team members highlighted successful launches (TRYNGOLZA, DAWNZERA), positive Phase III readouts (olezarsen, zilganersen) and strengthened cash position (> $2.1B) with a path to breakeven by 2028.

Q&A:

• Question from Jessica Fye (JPMorgan Chase & Co, Research Division): How should we think about the shape of the launch curve for olezarsen in sHTG — physician targeting, patient coverage, pent-up demand vs gradual ramp?
  Response: Expect strong uptake; expanding HCP target from ~3,000 to ~20,000 covering ~360,000 sHTG patients and initially targeting patients not at goal on standard therapies as the beachhead.

• Question from Huidong Wang (Barclays Bank PLC, Research Division): Any concerns in CORE/CORE2 regarding acute pancreatitis events balance between studies and anything else to watch; and peak revenue views for DAWNZERA, olezarsen and Alexander disease?
  Response: No concerns—AP outcome is groundbreaking and will be detailed at AHA; peak sales guidance: DAWNZERA >$500M, olezarsen >$1B, Alexander disease >$100M.

• Question from Michael Ulz (Morgan Stanley, Research Division): Any updated thoughts on pricing for olezarsen and timing for clarity?
  Response: Pricing work is ongoing with additional analyses (ER visits, hospitalizations, NNT) and more clarity expected next year; final price will be set upon approval.

• Question from Yaron Werber (TD Cowen, Research Division): Will AP reduction be principally in patients with prior AP or also prevent new events; and clarification on U.S. HAE prevalence assumptions?
  Response: AP reductions align with higher baseline triglycerides and prior‑AP patients (higher event rates in high‑risk groups), and Ionis continues to use a ~7,000 U.S. HAE prevalence estimate (~75% on prophylaxis).

• Question from Gary Nachman (Raymond James & Associates, Inc., Research Division): Where are the additional TRYNGOLZA patients coming from (physician counts, genetic vs clinical diagnoses) and why does Q4 guidance show a slower acceleration; could olezarsen get priority review?
  Response: TRYNGOLZA growth driven by patient identification, clinical scoring tools and streamlined payer policies (no specific genetic/clinical split provided); Q4 guidance reflects a shorter quarter (10 weeks) and unknown seasonality rather than an expected slowdown; olezarsen sNDA assumed standard 10‑month review though other regulatory paths will be pursued.

• Question from Jason Gerberry (BofA Securities, Research Division): How to maximize CARDIO‑TTRansform benefit for combination use vs tafamidis and how to contextualize NNT for payers (all‑comer vs high‑risk)?
  Response: CARDIO‑TTRansform will generate the largest combo vs monotherapy dataset and may show added benefit but results are pending; for olezarsen the totality of data (large TG reductions, 85% AP reduction, NNT, hospitalization/ER reductions) will drive payer value assessments.

• Question from Yanan Zhu (Wells Fargo Securities, LLC, Research Division): Color on early DAWNZERA prescriptions (switches vs new patients) and reason for WAINUA polyneuropathy revenue bump?
  Response: DAWNZERA early uptake includes switches from prophylactics, additions to on‑demand patients, and newly diagnosed patients; WAINUA growth reflects new patient identification (centers of excellence) and continued market expansion, not just share shifts.

• Question from Myles Minter (William Blair & Company L.L.C., Research Division): Any data on hepatic fat fraction in CORE studies and concern about shunting to liver?
  Response: Hepatic fat fraction is a secondary endpoint and will be presented at AHA; management declined to comment ahead of the detailed presentation.

• Question from Luca Issi (RBC Capital Markets, Research Division): Rationale behind the >$1B peak‑sales estimate for olezarsen given TAM and pricing assumptions, and will you file both 50mg and 80mg doses?
  Response: They will file both 50 mg and 80 mg doses; the >$1B peak figure is a conservative current estimate pending further payer/pricing clarity and additional market research.

• Question from Jay Olson (Oppenheimer & Co. Inc., Research Division): With a strong balance sheet, what are capital allocation priorities (external vs internal investments)?
  Response: Top priority is disciplined internal investment to fund pipeline advancement and marketed‑product growth while maintaining a strong cash position.

• Question from Mitchell Kapoor (H.C. Wainwright & Co, LLC, Research Division): Reasons for dropouts in sHTG trials (90% rolling into OLE) and any launch‑relevant concerns?
  Response: Dropout rate was about half of expectations; discontinuations were heterogeneous (personal reasons, moves, pregnancies) with no safety/tolerability signal of concern.

Contradiction Point 1

Pricing Strategy for Olezarsen in sHTG

It involves the pricing strategy for olezarsen in the sHTG market, which is crucial for revenue projections and market positioning.

Any updates on pricing for olezarsen and sHTG? - Michael Ulz (Morgan Stanley)

2025Q3: Pricing work is ongoing, considering ER visits and hospitalization rates. The market is greater than 3 million patients. Payers will view the market in terms of total exposure. The final pricing decision will be announced upon FDA approval. - Kyle Jenne(CMO)

Could you clarify the read-through from the ESSENCE safety study to the olezarsen and sHTG core studies? - Michael Ulz (Morgan Stanley)

2024Q4: We think pricing for TRYNGOLZA and olezarsen in the sHTG population should capture the clinical benefits and market dynamics. Payers will be interested in the prevention of ER visits and hospitalizations. So we think we can price competitively, pricing will be set upon FDA approval. - Brett Monia(CEO)

Contradiction Point 2

Peak Revenue Expectations for Olezarsen

It involves the peak revenue expectations for olezarsen, which is a critical indicator for investors regarding the potential financial impact of the drug.

What is the expected launch trajectory for olezarsen in sHTG? What factors are driving the ramp in olezarsen adoption? - Jessica Fye (JPMorgan Chase & Co.)

2025Q3: Peak sales for DAWNZERA is greater than $500 million, olezarsen is expected to be greater than $1 billion, and for Alexander's disease, it's greater than $100 million. - Kyle Jenne(CMO)

Can you clarify the read-through from the ESSENCE safety study to the core studies for olezarsen and sHTG? - Michael Ulz (Morgan Stanley)

2024Q4: For TRYNGOLZA and olezarsen, the market opportunity is huge. There are more than 3 million patients in the United States, and we expect peak sales of this combined franchise to exceed $1 billion. - Brett Monia(CEO)

Contradiction Point 3

Launch Strategy and Market Assessment for Olezarsen in sHTG

It involves differing perspectives on the launch strategy and market assessment for olezarsen in the sHTG population, which could impact revenue expectations and market positioning.

What is the expected launch trajectory for olezarsen in sHTG? Is pent-up demand or a warehouse effect driving the ramp? - Jessica Fye (JPMorgan Chase & Co)

2025Q3: There's strong interest in using TRYNGOLZA and olezarsen in the sHTG population. The target is to reach approximately 20,000 HCPs, which cover around 360,000 patients with sHTG. - Kyle Jenne(CEO)

What is the overlap between FCS and sHTG physician prescribers, and how will you leverage this overlap? Is the 20% pancreatitis history in pivotal sHTG study patients sufficient to demonstrate AP reduction, and what AP reduction level are you targeting? - Jay Olson (Oppenheimer)

2025Q1: I think it's like, you know, it's a very complex kind of calculation to do, but you know, it's kind of like, depending on how the pricing does, the potential patient population and the current patient population, and then how many of those patients we expect to be able to attract or enroll could all play into that. So we're going to kind of see how the launch plays out, but I expect it to be over $500 million. - Brett Monia(CEO)

Contradiction Point 4

Pancreatitis Data Presentation in Core Studies

It relates to the disclosure and presentation of critical safety data, which can influence market perceptions and regulatory processes.

Are there concerns about acute pancreatitis events in the CORE and CORE2 data? What is the peak revenue potential for olezarsen? - Huidong Wang (Barclays Bank PLC)

2025Q3: The AHA presentation will focus on how rapid and durable the protection against AP is. The studies have different triglyceride medians, reflecting the AP events. More details will be available at AHA. - Brett P. Monia(CEO)

When will Phase III sHTG core data be available, and what pancreatitis data will be included in the top-line results? - Michael Eric Ulz (Morgan Stanley)

2025Q2: We will provide a statement on AP in the top-line release, alongside triglyceride data, and plans to present full data at a medical congress later in the year. - Brett P. Monia(CEO)

Contradiction Point 5

Price Erosion and Pricing Strategy for TRYNGOLZA

It involves differing expectations regarding price erosion and the pricing strategy for TRYNGOLZA, which could impact revenue projections and market positioning.

Are there any updates on the pricing for olezarsen and sHTG? - Michael Ulz (Morgan Stanley)

2025Q3: The pricing work is ongoing, considering ER visits and hospitalization rates. The market is greater than 3 million patients. Payers will view the market in terms of total exposure. The final pricing decision will be announced upon FDA approval. - Kyle Jenne(CEO)

Regarding the FCS launch, how confident are you in the 2,000+ patient estimate, and how quickly can you convert these patients to commercial therapy before significant price erosion occurs with the sHTG launch? - Debjit Chattopadhyay (Guggenheim)

2025Q1: The FCS launch pricing reflects the current patient population, with TRYNGOLZA priced appropriately. As the sHTG population expands, the pricing strategy will be revised to address the larger market. - Kyle Jenne(CEO)