Eplontersen NDA submitted to FDA; tofersen under regulatory review for marketing approval in U.S. and EU

Phase 3 data planned for eplontersen and olezarsen; robust late-stage pipeline expanding with two new Phase 3 programs

Ionis provides full year 2023 financial guidance

CARLSBAD, Calif., Feb. 22, 2023 /PRNewswire/ -- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), a genetic medicines company, today reported financial results for the fourth quarter and full year ended December 31, 2022. Financial results are summarized below:

Financial Highlights

• 2022 revenue was in line with expectations, reflecting revenue from numerous diverse sources. The prior year fourth quarter and full year benefited from the $200 million earned from AstraZeneca to jointly develop and commercialize eplontersen
• 2022 operating expenses increased as planned compared to the prior year, reflecting investments in pipeline, technology and go-to-market activities for eplontersen, olezarsen and donidalorsen
• Further strengthened financial position with royalty monetization and sale and leaseback transactions worth up to $1.5 billion, including more than $700 million already received
• Initiated construction of a new manufacturing facility to support Ionis' goal to sustainably deliver genetic medicines to the market

Recent Late-Stage Pipeline Highlights

• Submitted the eplontersen NDA in the U.S. for patients with polyneuropathy caused by hereditary TTR amyloidosis
• FDA Advisory Committee meeting planned for March 22, 2023 to review Biogen's NDA for tofersen for patients with SOD1-ALS (PDUFA date of April 25, 2023); EMA accepted MAA for review
• FDA granted olezarsen Fast Track designation for the treatment of patients with FCS
• Reported positive Phase 2 data from the open label extension study of donidalorsen in patients with hereditary angioedema treated for one year, including new data showing clinically meaningful improvement in angioedema quality of life score; Phase 3 study expected to complete enrollment in 2023
• GSK advanced bepirovirsen into Phase 3 development in patients with chronic hepatitis B

Recent Additional Pipeline Highlights

• Biogen initiated a Phase 2 study of IONIS-MAPTRx (BIIB080) in patients with mild cognitive impairment or mild dementia due to Alzheimer's disease
• Roche initiated a Phase 2 study of tominersen in patients with prodromal or early manifest Huntington's disease
• Biogen initiated a Phase 1 study of ION306 (BIIB115) for the treatment of spinal muscular atrophy with the potential for long interval dosing

Recent Technology Advancement Highlights

• Partnered with Metagenomi to add gene editing capabilities to Ionis' technology platform
• Advanced programs incorporating muscle LICA technology and MsPA backbone chemistry into preclinical development

"We made substantial progress in 2022, marked by important achievements, including the December submission of the eplontersen NDA for people with ATTRv-PN. We also delivered multiple positive data readouts, enabling us to advance and expand our rich late- and mid-stage pipeline. And we took important steps to expand and diversify our technology, including our Metagenomi collaboration to add DNA editing to our platform," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "As we start 2023, we are positioned to build upon our achievements by bringing our first near-term commercial opportunities to the market. We look forward to reporting the 66-week results from the eplontersen NEURO-TTRansform study in the first half of this year. Importantly, we are prepared to co-commercialization eplontersen with our partner, AstraZeneca. We also look forward to Phase 3 data from olezarsen in FCS patients, positioning us for our first independent launch. With the talent and resources we have today, we anticipate a highly productive year that will enable us to drive increasing value for all stakeholders."

Fourth Quarter and Full Year 2022 Financial Results

Revenue

Ionis' revenue was comprised of the following:

Ionis' 2022 revenue continued to be derived from diverse sources, with just over half coming from commercial products and the balance from numerous partnered programs. SPINRAZA royalties, the largest contributor to the Company's commercial revenue, increased each quarter in 2022. Total SPINRAZA product sales increased six percent in the fourth quarter of 2022 compared to the prior quarter and also increased four percent compared to the same quarter in 2021. The increases were driven by stabilization in the U.S. and growth in Asian markets partially offset by competition in Europe. Total SPINRAZA product sales decreased six percent year-over-year due to foreign currency exchange and competition in Europe. TEGSEDI and WAYLIVRA revenue in 2022 reflected the shift to distribution fees.

R&D revenue for 2022 included $112 million from Biogen for advancing several neurology disease programs, $77 million from AstraZeneca for its share of the global Phase 3 development costs for eplontersen and $64 million from Roche for licensing and advancing IONIS-FB-LRx, among other partner payments. R&D revenue was higher in 2021 compared to 2022 primarily due to the $200 million Ionis earned in the fourth quarter of 2021 from AstraZeneca to jointly develop and commercialize eplontersen.

Operating Expenses

Ionis' operating expenses increased for the three months and year ended December 31, 2022 compared to the same periods in 2021, in line with expectations. For both periods, higher R&D expenses were driven by the increased number of Phase 3 studies the Company is conducting, which doubled from three to six studies in 2021, and the $80 million upfront payment for Ionis' collaboration with Metagenomi. SG&A expenses increased for the three months ended December 31, 2022 compared to the same period in 2021 driven by Ionis' go-to-market activities for eplontersen, olezarsen and donidalorsen. SG&A expenses were lower for 2022 compared to 2021 largely due to the substantial savings the Company achieved from integrating Akcea and restructuring the Company's commercial operations in 2021.

Gain on Sale of Property and Related Tax Impact

In October 2022, Ionis entered into a sale and leaseback transaction for several of its real estate assets. Under the agreement, Ionis received net proceeds of $200 million, with the potential to receive additional payments of up to $40 million plus funding to expand the Company's R&D campus. As a result, the Company recognized a $150 million gain on sale of property and $9 million in related income tax expense in the fourth quarter of 2022. In conjunction with the sale and leaseback transaction, the Company extinguished its mortgage debt for the related properties and recorded a new right of lease asset and liability on its balance sheet.

Balance Sheet

As of December 31, 2022, Ionis had cash, cash equivalents and short-term investments of $2.0 billion compared to $2.1 billion at December 31, 2021. Ionis' year-end cash balance does not include the $500 million the Company received from Royalty Pharma in January 2023. From December 31, 2021 to December 31, 2022, Ionis' debt obligations decreased by $50 million because the Company repaid its mortgage debt and Ionis' working capital decreased modestly driven by the Company's slightly lower cash and short-term investments balance.

2023 Financial Guidance

The Company's 2023 guidance reflects its ability to earn substantial revenue from its commercial portfolio and partnered programs. It also reflects the Company's commitment to investing in advancing its rich late-stage pipeline and preparing to commercialize its near-term commercial opportunities, eplontersen, olezarsen and donidalorsen, while maintaining a healthy balance sheet to continue investing for future growth.

Full Year 2023 Guidance
Revenue		>$575 million
Operating expenses on a non-GAAP basis		~$970 - $995 million
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