IONIS PHARMACEUTICALS INC Q4 FY2025 earnings call

• 2025 was a defining year for Ionis, marked by successful execution of the first 2 independent launches (TRYNGOLZA and DAWNZERA) and multiple positive data readouts across the pipeline. TRYNGOLZA exceeded expectations in its first year on the market and was launched in Europe. DAWNZERA was FDA-approved and launched in Europe. - Olezarsen had pivotal results in severe hypertriglyceridemia, submitted a sNDA, and is on track to be launch ready by June. Zilganersen submitted its NDA for Alexander disease. - Holly Kordasiewicz discussed Olezarsen's Phase III results showing highly significant reductions in triglycerides and acute pancreatitis events, zilganersen's NDA submission for Alexander disease, and Obudanersen's breakthrough therapy designation for Angelman Syndrome. - Kyle Jenne talked about TRYNGOLZA's strong momentum in 2025 with continued growth in prescriptions and patient starts, DAWNZERA's encouraging launch start with early adoption and high conversion from referral to patient start, and olezarsen's launch preparations including field team expansion and engagement with payers.

In 2025, revenue increased over 30% compared to 2024. TRYNGOLZA, the first FDA-approved treatment for familial chylomicronemia syndrome (FCS), had full-year revenue of $108 million. In the fourth quarter, it generated $50 million in net product sales, a 56% quarter-over-quarter increase. DAWNZERA, the FDA-approved prophylactic treatment for hereditary angioedema (HAE), had $8 million in product sales in 2025 from its initial launch months. Royalty revenues grew 11% to $285 million in 2025, driven by contributions from SPINRAZA and WAINUA. R&D revenue increased by over 20% year-over-year, fueled by progress across multiple partner programs. For 2026, Ionis projects revenue in the range of $800 million to $825 million, a ~20% increase compared to 2025 when adjusting for the one-time Sapablursen license fee. TRYNGOLZA revenues are expected to decline throughout the year ahead of the sHTG launch but then accelerate as uptake builds. DAWNZERA is expected to meaningfully contribute to commercial revenue growth as its launch progresses.

• Ionis projects 2026 revenue to be in the range of $800 million to $825 million, representing a ~20% increase over 2025 after adjusting for the one-time $280 million Sapablursen license fee. - Guidance assumes a standard review for olezarsen's sNDA, and if priority review is achieved, the guidance is expected to improve. - The company projects a non-GAAP operating loss between $500 million and $550 million in 2026, with revenue growing faster than expenses, driving improved operating leverage. - TRYNGOLZA revenues are expected to decline ahead of the sHTG launch due to payer engagements, then accelerate as olezarsen is launched. DAWNZERA is expected to contribute to commercial revenue growth as its launch progresses.

• Regulatory risks related to the timeline of the FDA review for olezarsen's sNDA. - Uncertainties in payer negotiations and pricing strategies for TRYNGOLZA and olezarsen, which could impact revenue projections. - Risks associated with the success of partner pipeline programs, such as Bepirovirsen and pelacarsen achieving positive Phase III results and obtaining regulatory approvals.

Q: Yaron Werber inquired about Ionis' guidance, TRYNGOLZA pricing, and WAINUA.

A: Elizabeth L. Hougen and Kyle Jenne responded, discussing guidance assumptions, TRYNGOLZA payer engagements, and WAINUA's growth.

Q: Salveen Richter asked about reimbursement in FCS and sHTG pricing.

A: Kyle Jenne responded, addressing FCS patient access and sHTG payer engagement.

Q: Chi Meng Fong asked about olezarsen's peak revenue confidence and ION532.

A: Kyle Jenne and Brett Monia responded, with Kyle Jenne discussing olezarsen's peak revenue drivers and Brett Monia talking about ION532's market opportunity.

Q: Michael Ulz asked about sHTG filing FDA interactions and priority review.

A: Brett Monia and Eugene Schneider responded, with Brett Monia discussing FDA review expectations and Eugene Schneider noting regulatory interactions are on track.

Q: Luca Issi asked about prior review vs standard review and the Angelman program.

A: Brett Monia and Holly Kordasiewicz responded, with Brett Monia discussing review expectations and Holly Kordasiewicz addressing the Angelman program's European site status.

Q: Moritz Reiterer asked about TRYNGOLZA sHTG pricing and BBB platforms.

A: Kyle Jenne and Brett Monia responded, with Kyle Jenne discussing pricing finalization and Brett Monia talking about BBB platform progress.

Q: Joseph Stringer asked about GSK partnered HBV program.

A: Brett Monia and Elizabeth L. Hougen responded, with Brett Monia discussing HBV program data and Elizabeth L. Hougen talking about peak sales estimates and royalties.

Q: Andy Chen asked about Alexander disease opportunity.

A: Holly Kordasiewicz and Kyle Jenne responded, with Holly Kordasiewicz discussing community response and Kyle Jenne talking about launch plans and revenue expectations.

Q: Manoj Eradath asked about HORIZON Lp(a) Phase III, pelacarsen, and next-gen Lp(a) asset.

A: Brett Monia and Eric Swayze responded, with Brett Monia discussing HORIZON Lp(a) trial confidence and Eric Swayze talking about next-gen Lp(a) programs.