• Advanced new MsPA backbone chemistry with enhanced duration into preclinical development • Advance new routes of delivery 1. Non-GAAP – please see reconciliation to GAAP in FY 2022 press release 2. $500M from royalty monetization transaction in January 2023 15 million Establish an integrated commercial organization | --- | --- | --- | |------------------------------------------------------------|---------------------------------------------------------------------------------|----------------------------- ...

Ionis Pharmaceuticals, Inc. (NASDAQ:IONS) Q4 2022 Results Conference Call February 22, 2023 11:30 AM ET Company Participants Wade Walke - SVP, IR Brett Monia - CEO Beth Hougen - CFO Eugene Schneider - Chief Clinical Development Officer Onaiza Cadoret - Chief Global Product Strategy & Operations Officer Eric Swayze - EVP, Research Conference Call Participants Yanan Zhu - Wells Fargo Securities Gary Nachman - BMO Capital Markets Do Kim - Piper Sandler Gena Wang - Barclays Yale Jen - Laidlaw & Co. Paul Matte ...

Commercialization and Market Challenges - The company has limited experience in commercializing medicines and will need to invest significant resources to develop marketing and sales capabilities[291]. - SPINRAZA revenue has decreased due to lower pricing in the U.S. and increased competition, impacting future sales potential[294][305]. - The company relies on third parties for commercialization, which may lead to lower product revenues and profitability compared to self-commercialization[292]. - The acceptance of the company's medicines by the medical community and third-party payers is crucial for generating substantial revenues[293]. - Regulatory limitations may be imposed on approved medicines, affecting marketing and distribution activities[310]. - The company is dependent on collaboration with Biogen for the development and commercialization of SPINRAZA, which poses risks if Biogen fails to fulfill its commitments[313][314]. - Future product sales may be subject to increased restrictions and pricing pressures from government and third-party payers[300][301]. - The company faces competition from numerous pharmaceutical firms, which may hinder the commercialization of its medicines[302][304]. - The need for post-marketing studies to demonstrate cost-effectiveness may require significant management time and resources[298]. - The company must comply with comprehensive government regulations regarding the manufacture and marketing of its medicines[307]. - The collaboration with AstraZeneca for the development and commercialization of eplontersen includes co-commercialization in the U.S. and AstraZeneca's sole rights in other countries, which may limit revenue if unsuccessful[315]. - A Joint Steering Committee (JSC) with equal membership from both companies oversees eplontersen's development, and disagreements could delay commercialization[316]. - The company is commercializing TEGSEDI and WAYLIVRA in multiple international markets, facing risks associated with regulatory, pricing, and reimbursement conditions[375]. Financial Performance and Position - Total revenue for 2022 was $587.4 million, a decrease of 27.5% from $810.5 million in 2021[406]. - Total operating expenses increased to $997.6 million in 2022 from $840.6 million in 2021, resulting in a loss from operations of $410.2 million[406]. - SPINRAZA royalties contributed $242.3 million in 2022, down from $267.8 million in 2021, with total SPINRAZA product sales decreasing 6% year-over-year[408]. - Total R&D revenue for 2022 was $284.0 million, significantly lower than $468.1 million in 2021, primarily due to a $200 million payment received in 2021 from AstraZeneca[408]. - Cash, cash equivalents, and short-term investments were $1,986.9 million as of December 31, 2022, compared to $2,115.0 million at the end of 2021[406]. - The company has an accumulated deficit of approximately $1.4 billion and stockholders' equity of approximately $0.6 billion as of December 31, 2022[348]. - The company recorded a net loss of $269.7 million in 2022, compared to a net loss of $28.6 million in 2021, indicating a significant increase in losses[441]. - Basic and diluted net loss per share for 2022 was $1.90, compared to $0.20 in 2021, reflecting a substantial increase in loss per share[442]. - The company has raised approximately $2.0 billion from equity securities and $2.1 billion from long-term debt since inception[443]. Research and Development - The company is currently developing seven medicines in Phase 3, focusing on cardiovascular and neurology franchises[405]. - For the year ended December 31, 2022, the company earned $77 million in joint development revenue and incurred $147 million in R&D expenses related to the eplontersen collaboration with AstraZeneca[410]. - R&D expenses, excluding non-cash compensation, rose to $759.4 million in 2022 from $547.4 million in 2021, driven by investments in the late-stage pipeline and licensing of Metagenomi's gene editing technologies[419]. - Total drug development expenses reached $457.7 million in 2022, up from $349.0 million in 2021, reflecting the expansion of Phase 3 studies from three to six[422]. - AstraZeneca is covering 55% of the costs associated with the ongoing global Phase 3 development program for eplontersen[410]. Manufacturing and Operational Risks - The company is expanding its manufacturing capabilities with a new facility in Oceanside, California, which will incur substantial expenditures and require additional staff[319]. - There is limited experience in manufacturing oligonucleotide-based medicines on a commercial scale, and reliance on a small number of suppliers for capital equipment and raw materials poses risks[320]. - Non-compliance with FDA's cGMP regulations could delay or prevent marketing authorizations for medicines, including SPINRAZA and TEGSEDI[321]. - The company relies on third-party manufacturers for TEGSEDI and WAYLIVRA, and any disruptions could limit commercial success[322]. - Distribution agreements with Sobi and PTC for TEGSEDI and WAYLIVRA may result in less revenue than direct commercialization[323]. Compliance and Regulatory Environment - Compliance with healthcare laws is critical, as violations could result in significant penalties and reputational harm[378]. - The company faces risks related to international operations, including regulatory compliance and currency exchange fluctuations[376]. - The company is subject to changing regulations for corporate governance, increasing costs and risks of noncompliance[380]. - Regulatory approval for medicines is uncertain, and failure to obtain timely approvals could negatively impact revenue generation[327]. - Clinical studies may face delays or failures due to various factors, including the COVID-19 pandemic and regulatory scrutiny[335]. - Ongoing geopolitical tensions, particularly the war between Russia and Ukraine, may restrict clinical trial operations and increase costs[337]. Corporate Governance and Internal Controls - The company has provisions in its certificate of incorporation that may discourage third-party acquisitions, potentially limiting shareholder value[366]. - The company assessed the effectiveness of its internal control over financial reporting as of December 31, 2022, and concluded that it maintained effective internal control[473]. - Ernst & Young LLP audited the effectiveness of the company's internal control over financial reporting as of December 31, 2022, and expressed an unqualified opinion[478]. - The company has established disclosure controls and procedures to ensure timely and accurate reporting of required information[470]. Stock and Financing - The market price of the company's common stock ranged from $48.82 to $28.25 per share over the 12 months preceding December 31, 2022, indicating significant volatility[364]. - The company completed a $632.5 million offering of 0% Notes and used $247.9 million of the net proceeds to repurchase $257.0 million of its 1% Notes[369]. - Future sales of approximately 17.5 million shares of common stock upon conversion of 0% Notes and 0.125% Notes could adversely affect trading prices of the company's securities[372]. - The ongoing war between Russia and Ukraine may adversely affect the global credit markets, impacting the company's liquidity and financial condition[374]. - The company may need to raise additional funds through public or private financing, which could dilute existing stockholders' shares[345]. Cybersecurity and Data Risks - The company has invested in cybersecurity measures, but risks remain regarding data breaches that could harm its reputation and lead to financial penalties[361].

IONIS | --- | --- | --- | --- | --- | |------------------|-------|-------|-------|-------| | | | | | | | November 9, 2022 | | | | | | Nasdaq: IONS | | | | | | | | | | | On Today's Earnings Call 2 Brett Monia, Ph.D. Chief Executive Officer Richard Geary, Ph.D. Executive Vice President, Development Beth Hougen Chief Financial Officer Eric Swayze, Ph.D. Executive Vice President, Research Eugene Schneider, M.D. Executive Vice President, Chief Clinical Development Officer Onaiza Cadoret Executive Vice President, ...

UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, DC 20549 Form 10-Q (Mark One) ☒QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the Quarterly Period Ended September 30, 2022 OR ☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file number 000-19125 Ionis Pharmaceuticals, Inc. (Exact name of Registrant as specified in its charter) (State or other jurisdiction of ...

Financial Data and Key Metrics Changes - The company reported revenues of $134 million for Q2 2022 and $276 million for the first half of the year, showing an increase compared to the same periods last year [16] - SPINRAZA's global sales were $431 million for Q2 and $904 million year-to-date, resulting in $60 million and $113 million in royalty revenue for the corresponding periods [17] - Cash and investments remained flat at $2 billion from Q1 to Q2 [17] - Non-GAAP operating expenses increased due to higher R&D expenses, while SG&A expenses decreased year-over-year [23][24] - The company anticipates Q3 revenues to be similar to Q2, with R&D expenses projected to increase by 25% to 30% compared to last year [25][26] Business Line Data and Key Metrics Changes - The company is advancing its late-stage pipeline, with positive results from the Phase III NEUROTTRansform study of eplontersen in patients with TTR polyneuropathy [8][30] - Enrollment in the BALANCE study of olezarsen for familial chylomicronemia syndrome has been completed, with data expected next year [11][33] - The company reported positive data from six mid-stage programs, with plans to advance two new medicines into Phase III studies next year [13] Market Data and Key Metrics Changes - SPINRAZA sales in the US stabilized year-to-date, with a decrease in discontinuations during the quarter [18] - The company expects SPINRAZA to return to growth as positive trends in the US market are observed [18] - The Lp(a) HORIZON cardiovascular outcome study of pelacarsen has enrolled over 8,000 patients, solidifying the company's first-mover advantage [12][40] Company Strategy and Development Direction - The company aims to deliver transformational medicines to the market, with a focus on expanding its Phase III pipeline to at least eight medicines across ten indications [14][46] - The partnership with AstraZeneca is crucial for the global go-to-market strategy for eplontersen and other products [9][76] - The company is also focused on advancing new chemistries and expanding its LICA platform beyond the liver [47] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the positive results from ongoing studies and the potential for eplontersen and tofersen to enter the market soon [10][48] - The company is well-positioned to maximize value for patients and shareholders through its strategic investments and pipeline advancements [14][27] - Management highlighted the importance of generating robust clinical data to support the competitive positioning of its products in the market [111][114] Other Important Information - The NDA for tofersen is under priority review with the FDA, with a PDUFA date set for January 25, 2023 [10][36] - The company is preparing for additional studies related to eplontersen as part of its life cycle management strategy [70] Q&A Session Summary Question: What do you hope to show at the upcoming presentation at the ISA meeting regarding Eplontersen? - Management expressed excitement about sharing the efficacy, safety, and tolerability data at the ISA meeting, emphasizing the importance of the primary and secondary endpoints [50][51] Question: Will you consider filing any of your other neuro or ALS programs with NFL as a surrogate endpoint? - Management indicated that while biomarkers are important, they do not plan to file based solely on biomarkers but will use them as part of a robust study design [62][64] Question: Can you provide an update on the HBV program with GSK? - Management highlighted encouraging data from GSK's Bepirovirsen and the intention to move into Phase 3 development [84][85] Question: What is the differentiation of your Angelman program from other therapies? - Management noted that their drug targets the antisense transcript and aims to be the best molecule in the space, with a focus on safety and target engagement [102][104] Question: Can you confirm if you have done an interim analysis on cardio transform before expanding to 1,000 patients? - Management clarified that the decision to expand the study was based on demographics rather than event rates, emphasizing the importance of a robust data set [131][132]

IONIS | --- | --- | --- | --- | --- | |----------------|-------|-------|-------|-------| | | | | | | | August 9, 2022 | | | | | | Nasdaq: IONS | | | | | | | | | | | On Today's Earnings Call 2 Brett Monia, Ph.D. Chief Executive Officer Beth Hougen Chief Financial Officer Richard Geary, Ph.D. Executive Vice President, Development Eric Swayze, Ph.D. Executive Vice President, Research Eugene Schneider, M.D. Executive Vice President, Chief Clinical Development Officer Onaiza Cadoret Executive Vice President, Chi ...

UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, DC 20549 Form 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 Delaware 33-0336973 2855 Gazelle Court, Carlsbad, California 92010 (Address of Principal Executive Offices) (Zip Code) 760-931-9200 For the Quarterly Period Ended June 30, 2022 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file nu ...

Ionis Pharmaceuticals, Inc. (NASDAQ:IONS) Q1 2022 Earnings Conference Call May 4, 2022 11:30 AM ET Company Participants Brett Monia - Founder, CEO & Director Elizabeth Hougen - EVP, Finance & CFO Eugene Schneider - EVP & Chief Clinical Development Officer Eric Swayze - EVP, Research Onaiza Cadoret - EVP and Chief Product Strategy & Operations Officer Conference Call Participants Yanan Zhu - Wells Fargo Securities Brendan Smith - Cowen and Company Luca Issi - RBC Capital Markets Jessica Fye - JPMorgan Chase ...

UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, DC 20549 Form 10-Q (Mark One) ☒ QUARTERLY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the Quarterly Period Ended March 31, 2022 OR ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF SECURITIES EXCHANGE ACT OF 1934 For the transition period from _____ to _____ Commission file number 000-19125 Ionis Pharmaceuticals, Inc. (Exact name of Registrant as specified in its charter) (State or other jurisdiction of i ...