California-based Ionis Pharmaceuticals IONS is focused on the discovery and development of RNA-targeted therapies using its proprietary platform for itself and its partners. It uses this technology to generate a broad pipeline of medicines, targeting neurological, cardiovascular and specialty rare diseases.

Despite marketing no wholly-owned drug in its portfolio, IONS enjoys a diverse stream of revenues, including commercial products and royalties and numerous sources of collaborative and R&D revenues.

The company earns commercial revenues primarily in the form of royalty payments on net sales of Spinraza, approved in the United States to treat spinal muscular atrophy (SMA) worldwide. Ionis licensed this drug to Biogen BIIB, which is responsible for commercializing it. IONS receives royalties from Biogen on Spinraza’s sales. Ionis and Biogen also market Qalsody (tofersen), which was approved by the FDA in April 2023 for amyotrophic lateral sclerosis (ALS) with superoxide dismutase 1 (SOD1) mutations.

Apart from Biogen, it also has collaboration deals with leading drugmakers/biotech companies, like AstraZeneca AZN, GSK plc GSK, Novartis and Roche, to develop and market its medicines.

Last December, the FDA approved Wainua (eplontersen) for treating patients with hereditary transthyretin-mediated amyloid polyneuropathy, commonly called hATTR-PN or ATTRv-PN. The drug has been developed in partnership with AstraZeneca. While Ionis and AstraZeneca will jointly market Wainua for ATTRv-PN in the United States, AZN has exclusive rights to commercialize Wainua outside U.S. markets. The drug was commercially launched in the United States in first-quarter 2024. Regulatory filings seeking approval for eplontersen in ATTRv-PN are under review in the EU and some other countries.

AstraZeneca and Ionis are also developing eplontersen as a treatment for cardiomyopathy caused by hATTR amyloidosis (ATTR-CM) in the phase III CARDIO-TTRansform study, which is on track for a data readout in first-half 2025.

Novartis and GSK are its partners for pelacarsen and bepirovirsen, respectively. While the GSK-partnered drug is being developed in two late-stage studies for chronic hepatitis B (CHB), the Novartis-partnered drug is being developed in a late-stage study for patients with cardiovascular disease due to elevated Lp(a) levels. Data readout from the Novartis- and GSK-partnered drug studies are expected in 2025 and 2026, respectively.

Revenues generated from the above collaboration partners in the form of license fees, upfront payments and milestone payments help Ionis fund the development of its internal pipeline. Some of its wholly-owned candidates include olezarsen [for familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG)], ulefnersen (for ALS), donidalorsen [for hereditary angioedema (HAE)] and zilganersen (for Alexander’s disease), which are already being evaluated in late-stage studies.

AstraZeneca and Ionis are also developing eplontersen as a treatment for cardiomyopathy caused by hATTR amyloidosis (ATTR-CM) in the phase III CARDIO-TTRansform study, which is on track for a data readout in first-half 2025.

In June, the FDA accepted the company’s regulatory filing seeking approval for olezarsen to treat FCS. This filing is based on results from the phase III BALANCE study, which showed that treatment with olezarsen led to significant triglyceride-lowering and substantial reductions in acute pancreatitis attacks in FCS patients. If approved, olezarsen will be Ionis’ first medicine that will be launched independently. A final decision from the FDA is expected before Dec 19, 2024. Management completed enrolment in all three late-stage studies evaluating olezarsen in SHTG indication, which is a much larger patient population. Data from these studies are expected in second-half 2025. The company has a first-mover advantage in FCS and SHTG indications.

In May, Ionis reported top-line results from two phase III studies — OASIS-HAE and OASISplus — which evaluated donidalorsen in HAE patients. Data from these studies showed that treatment with the drug achieved a significant and sustained reduction in the rate of HAE attacks for monthly and every two-month dosing. Based on these results, Ionis is making preparations to file an NDA for donidalorsen with the FDA in 2024. Additionally, Ionis’ partner, Otsuka, is preparing to submit for marketing approval in Europe before 2024-end.

Management is also progressing well with the development of its other wholly-owned pipeline drugs. In the first half of 2024, Ionis reported that a mid-stage study on MASH/NASH candidate ION224 and a phase I/IIa study on Angelman syndrome drug ION582 achieved their respective primary endpoints. A phase III study on ION582 is expected to begin in the first half of 2025.

Ionis is advancing and expanding its wholly-owned pipeline to drive future revenue growth. While the company does have a broad pipeline of partnered programs with leading drugmakers/biotech companies, its recent decision to increase investments in its internal pipeline gets a thumbs up from us, given the recent positive data readouts. The expansion of its internal pipeline will help Ionis further diversify its revenue stream and narrow down its dependence on collaboration partners.

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