Summary of Ionis Pharmaceuticals Conference Call Company Overview - **Company**: Ionis Pharmaceuticals - **Industry**: Biotechnology, specifically focusing on genetic medicines targeting RNA for therapeutics - **Recent Achievements**: Launched two FDA-approved medicines independently in the U.S. in 2025: Tryngolza for Familial Chylomicronemia Syndrome (FCS) and Donidalorsen for hereditary angioedema [2][3] Core Points and Arguments - **Successful Product Launches**: - Tryngolza, the first FDA-approved medicine for FCS, launched successfully in 2025 [2] - Donidalorsen launched as a prophylactic treatment for hereditary angioedema [2] - **Pipeline Progress**: - Announced positive phase three data for severe hypertriglyceridemia and a neurology drug for Alexander disease [3][4] - Anticipating five phase three readouts and two to three FDA approvals in the upcoming year [4] - **Market Opportunity**: - Severe hypertriglyceridemia affects millions in the U.S., with a focus on patients at high risk for acute pancreatitis [7][9] - Plans to target both severely at-risk patients and those with mildly elevated triglycerides [10][11] - **Combination Therapy Potential**: - Exploring combination therapies for managing triglycerides and other cardiovascular risk factors [12][13] - Collaboration with AstraZeneca to combine treatments for TTR cardiomyopathy [14][17] Additional Important Insights - **Self-Administration Preference**: - Patients prefer self-administered treatments, which could enhance market penetration, especially in community settings [20][21] - **Regulatory and Market Dynamics**: - Anticipated inclusion in treatment guidelines for severe hypertriglyceridemia, with a significant patient population of over 3 million in the U.S. [40] - **Spinraza Update**: - Ionis is developing a next-generation Spinraza with once-per-year dosing, expected to re-emerge as a leading treatment for spinal muscular atrophy (SMA) [32][33] - Economic terms for the next-gen product are more favorable, with royalties in the mid-20% range compared to mid-teens for the current compound [34] Conclusion - Ionis Pharmaceuticals is positioned for significant growth with its innovative therapies targeting severe hypertriglyceridemia and SMA. The company is leveraging its unique RNA-targeting platform to address unmet medical needs and expand its market presence through strategic partnerships and a focus on patient convenience.

Core Insights - CRISPR Therapeutics (CRSP) shares have increased by 41.4% over the past three months, driven by positive data from the CTX310 study and strong sales of Casgevy in Q2 2025 [1][9]. In Vivo Pipeline Programs - CRISPR Therapeutics is advancing its in-vivo candidates, CTX310 and CTX320, in separate phase I clinical studies targeting ANGPTL3 and lipoprotein(a) respectively [2]. - Updated data from the CTX310 study showed significant reductions in low-density lipoprotein (LDL) and triglyceride (TG) levels, with peak reductions of up to 86% in LDL and 82% in TG [2][9]. - Data for CTX320 is anticipated in the first half of 2026, raising hopes for its potential in treating heart disease [3]. Casgevy Sales Performance - Casgevy, a one-shot gene therapy developed in partnership with Vertex Pharmaceuticals, was approved for sickle cell disease and transfusion-dependent beta-thalassemia [4]. - After a slow start in 2024 with only $10 million in revenue, Casgevy's sales surged to $30.4 million in Q2 2025, marking a 114.1% sequential increase [5][6]. - Over 75 treatment centers have been activated for Casgevy, with expectations for significant growth in new patient starts throughout 2025 [6]. Other Pipeline Candidates and Collaborations - CRISPR Therapeutics is developing next-generation CAR-T therapy candidates, CTX112 and CTX131, in separate phase I/II studies, with data expected later in 2025 [7]. - The company plans to expand its in-vivo pipeline with two additional programs, CTX340 and CTX450, by the end of the year [8]. - A recent collaboration with Sirius Therapeutics aims to diversify CRSP's pipeline into RNA therapeutics, focusing on the development of SRSD107 for thromboembolic disorders [10][11]. Competitive Landscape - CRISPR Therapeutics faces competition from other companies in the gene-editing space, including Beam Therapeutics and Intellia Therapeutics, which are advancing their own therapies [12]. - Casgevy also competes with chronic therapies like Bristol Myers' Reblozyl and Novartis' Adakveo [13]. Stock Performance and Valuation - CRSP shares have risen 34.8% year-to-date, outperforming the industry and the S&P 500 [14]. - The stock is trading at a price-to-book (P/B) ratio of 2.68, lower than the industry average of 2.95, indicating a potential valuation opportunity [15]. Estimate Movements - Estimates for CRISPR's 2025 loss per share have widened from $5.58 to $6.26, while estimates for 2026 have narrowed from $4.30 to $3.98 [18]. Financial Position - CRISPR Therapeutics has a strong cash balance of approximately $1.7 billion as of June-end, which supports ongoing operations and potential late-stage studies [20].

Core Insights - CRISPR Therapeutics reported a second-quarter 2025 loss of $2.40 per share, wider than the previous year's loss of $1.49, primarily due to a $96.3 million expense related to a collaboration with Sirius Therapeutics [1][6] - Adjusted loss, excluding special items, was $1.29 per share, better than the Zacks Consensus Estimate of a loss of $1.47 [2] - Total revenues for the quarter were $0.89 million, significantly below the Zacks Consensus Estimate of $6.6 million, compared to $0.5 million in the same period last year [2] Financial Performance - CRISPR Therapeutics' stock fell over 8% in after-market trading following the wider-than-expected loss, continuing the downward trend in pre-market trading [3] - The stock has increased by 51% year-to-date, outperforming the industry growth of 2% [3] - Research and development expenses decreased by 13% year-over-year to $69.9 million, while general and administrative expenses fell by 3% to $18.9 million [8] Product Development and Sales - Casgevy, a CRISPR/Cas9 gene-edited therapy developed in partnership with Vertex Pharmaceuticals, saw sales of $30.4 million in Q2, up from $14.2 million in the previous quarter [5][6] - Over 75 treatment centers have been activated globally for Casgevy, with approximately 115 patients completing their first cell collection since its launch [6][7] - The company is advancing its CAR-T and in-vivo therapy pipelines, with updates expected later this year [10][11] Pipeline Expansion - CRISPR Therapeutics is developing two next-generation CAR-T therapy candidates, CTX112 and CTX131, currently in phase I/II studies [10] - The company is also studying in-vivo candidates CTX310 and CTX320, with promising early data showing significant reductions in LDL and triglyceride levels [11] - A collaboration with Sirius Therapeutics has diversified the pipeline into RNA therapeutics, with a focus on the investigational siRNA candidate SRSD107 [12][13] Financial Position - As of June 30, 2025, CRISPR Therapeutics had cash and marketable securities totaling $1.72 billion, down from $1.86 billion at the end of March 2025 [9]

Financial Data and Key Metrics Changes - Total operating loss from continuing operations increased from $6.6 million in 2023 to $6.9 million in 2024 [22] - Research and development expenses rose to $3.7 million in 2024 from $3.4 million in 2023 [22] - General and administrative expenses decreased from $3.5 million in 2023 to $3.2 million in 2024 [22] - Net loss for 2024 was $8.5 million compared to $4.3 million in the previous year [23] - Cash and cash equivalents at year-end 2024 increased to $1 million from $700,000 at the end of 2023 [25] Business Line Data and Key Metrics Changes - The RNA delivery business showed progress with new partnerships and improved manufacturing processes [6] - The company aims to advance at least one flagship program to an investigational new drug IND filing with the FDA in 2026 [14] - The legacy assets, including the nasal spray products, are expected to see significant commercial opportunities with ongoing discussions for partnerships [20] Market Data and Key Metrics Changes - The global radiopharmaceutical market reached $8.4 billion in size in 2024 and is expected to grow to $17.1 billion by 2033 [13] - The company received marketing approval for its nasal spray in Mainland China, indicating a major commercial opportunity [17] Company Strategy and Development Direction - The company plans to spin off a majority of its RNA delivery subsidiary, Altamira Therapeutics AG, to better capitalize on growth opportunities [8] - The strategy includes licensing the RNA delivery platform technology to partners in the biotech and pharma industry [12] - The company is transitioning to a holding company model, focusing on managing and monetizing its participations and assets [25] Management's Comments on Operating Environment and Future Outlook - Management acknowledged the challenges posed by the NASDAQ delisting but expressed optimism about the planned spin-off and private equity involvement [28] - The company is focused on building its RNA delivery business and addressing the potential for RNA therapeutics [28] Other Important Information - The financial statements for 2024 were presented in U.S. dollars for the first time, reflecting a shift in reporting [20] - The company has filed several patent applications to protect its proprietary programs [14] Q&A Session Summary Question: What are the expectations for the RNA delivery business? - Management highlighted the growing momentum in the RNA delivery business and the importance of appropriate funding to continue progress [27] Question: How does the company plan to address the NASDAQ delisting? - Management discussed the painful experience of the delisting but emphasized the planned spin-off and private equity involvement as beneficial alternatives [28]