Ionis Pharmaceuticals Eyes TRYNGOLZA Growth as Pipeline Faces Cardio Setbacks

Key Points

• TRYNGOLZA is Ionis’ key commercial growth driver: Its expanded severe hypertriglyceridemia label increases the U.S. addressable market from roughly 3,000 FCS patients to more than 3 million, with Ionis targeting over $3 billion in peak annual U.S. sales.
• Ionis is advancing next-generation candidate ION775, which could offer once- or twice-yearly dosing, while early launch momentum continues for TRYNGOLZA and the company’s wholly owned neurology drug ZANVASTRO.
• Cardiovascular pipeline setbacks weigh on the outlook: Eplontersen failed to meet the composite endpoint in a transthyretin cardiomyopathy trial, and partner Novartis reported disappointing pelacarsen results; Ionis is evaluating whether eplontersen may still support a monotherapy indication.

Ionis Pharmaceuticals NASDAQ: IONS CEO Brett Monia outlined recent regulatory wins, commercial-launch progress and several pipeline updates at the Morgan Stanley Global Healthcare Conference, while acknowledging setbacks in late-stage cardiovascular studies.

Monia said the company has secured two FDA approvals this year and expects a third decision in October with partner GSK for a chronic hepatitis B treatment. The company’s recently approved products include TRYNGOLZA for severe hypertriglyceridemia and ZANVASTRO for Alexander disease.

TRYNGOLZA Launch Targets Large sHTG Market

Monia described TRYNGOLZA as the first meaningful treatment option for severe hypertriglyceridemia, or sHTG, and said the product’s June label expansion broadened its addressable population beyond familial chylomicronemia syndrome, or FCS.

The FCS indication addresses an estimated 3,000 U.S. patients, while the broader sHTG population exceeds 3 million people in the U.S., according to Monia. Ionis adjusted TRYNGOLZA’s price following the expansion from a rare-disease level to one more suitable for a highly prevalent condition.

Ionis continues to target more than $3 billion in U.S. peak annual product sales for TRYNGOLZA. Monia said July and August were “very good months” for the launch, citing physician enthusiasm, incoming prescriptions and payer coverage obtained through medical-exception and prior-authorization processes.

Initial prescribing has focused on patients at the greatest risk of acute pancreatitis, including people with triglyceride levels above 880 milligrams per deciliter or a history of acute pancreatitis. Monia said the company is also seeing prescriptions for patients with triglycerides in the 500-to-800 range who do not have such a history.

• TRYNGOLZA offers monthly 50-milligram and 80-milligram dosing through an autoinjector.
• Monia said physicians are using both doses, with some starting patients at 50 milligrams and others using 80 milligrams initially.
• The company is emphasizing disease awareness, physician education, patient outreach, payer coverage and patient-support services to build the market.

Monia cautioned investors against relying on third-party prescription data from Symphony and IQVIA to gauge the launch. Ionis blocks its data and now uses multiple specialty pharmacies, making comparisons with the prior FCS launch unreliable, he said. The company plans to provide additional details with its third-quarter earnings report.

On safety, Monia said TRYNGOLZA has a clean profile without required monitoring. He characterized liver-fat increases as small, on-target effects that declined toward baseline with continued treatment. The company studied approximately 250 patients using MRI, he said.

Next-Generation sHTG Program Advances

Ionis is also advancing ION775, an siRNA-based follow-on candidate designed to potentially support once- or twice-yearly dosing for sHTG. Monia said phase I data showed durable reductions in APOC3 and triglycerides, with favorable safety and tolerability in healthy volunteers and people with mildly elevated triglycerides.

The company has entered phase II development and is enrolling patients rapidly in an open-label study. Ionis intends to use the data to select a dose and dosing interval, with the potential to begin phase III development next year. Monia said the eventual commercial positioning of ION775 relative to TRYNGOLZA remains to be determined, though he expects the products could be complementary.

Cardiovascular Setbacks and Angelman Readout

Monia said Ionis was disappointed that the CARDIO-TTRansform study of eplontersen in transthyretin cardiomyopathy did not meet its composite primary endpoint, despite approximately 80% reductions in transthyretin and what he described as good safety and tolerability.

He attributed the outcome to the lack of incremental benefit from combining a TTR silencer with a stabilizer such as tafamidis. More than half of patients were taking tafamidis at baseline, he said. However, patients not on stabilizers at baseline showed nearly a 30% relative risk reduction, a result Monia described as comparable with that of another approved silencer. Ionis and AstraZeneca are evaluating whether to pursue a monotherapy indication and expect greater clarity by year-end.

Monia also cited disappointment in the phase III pelacarsen trial in Lp(a) cardiomyopathy, saying partner Novartis will present the complete data set.

In Angelman syndrome, Ionis completed enrollment in its phase III trial and expects data in the second half of the year. Monia acknowledged disappointing results from a competing program using the same broad mechanism, but argued that the competitor may have been dose-limited by safety issues. Ionis is studying an 80-milligram quarterly dose and plans to publish longer-term data from its phase II HALOS study.

Neurology and HAE Commercial Efforts

Monia said ZANVASTRO is Ionis’ first wholly owned neurology launch and the first FDA-approved disease-modifying treatment for Alexander disease. The ultra-rare condition is estimated to affect roughly 300 to 400 people in the U.S. Ionis is focused on transitioning clinical-trial and expanded-access patients to commercial therapy, while increasing disease awareness and patient identification.

Separately, Monia said DAWNZERA, Ionis’ hereditary angioedema prophylaxis treatment, is showing steady growth one year after launch. He highlighted its once-monthly or every-two-months self-administration option and storage characteristics as differentiators in a competitive market.

About Ionis Pharmaceuticals (NASDAQ:IONS)

Ionis Pharmaceuticals, Inc is a biotechnology company that discovers and develops medicines using antisense technology, which is designed to target RNA and influence the production of disease-related proteins. The company focuses on neurological, cardiovascular, metabolic and other serious diseases for which there remains a significant unmet medical need.

Ionis has developed several approved therapies, including SPINRAZA (nusinersen) for spinal muscular atrophy, QALSODY (tofersen) for a form of amyotrophic lateral sclerosis, TEGSEDI (inotersen) for hereditary transthyretin-mediated amyloidosis and WAYLIVRA (volanesorsen) for familial chylomicronemia syndrome in certain markets.

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