Summary of Arrowhead Pharmaceuticals Conference Call Company Overview - **Company**: Arrowhead Pharmaceuticals (NasdaqGS:ARWR) - **Event**: Conference at TD Cowen's 2025 Treatment Advances in Obesity Summit - **Date**: November 24, 2025 Key Points Recent Progress and Upcoming Expectations - Arrowhead recently received the first approval for Redemplo in FCS (Familial Chylomicronemia Syndrome) and plans to provide updates on its launch progress in the upcoming quarterly call [2][28] - The company is set to release data from its INHBE and ALK-7 programs in early January 2026, following the holiday season [2][5] - Initiation of the dimer phase one study for ApoC3 PCSK9 is expected early next year [3] Obesity Treatment Focus - Arrowhead identifies a significant unmet need in obesity treatment, particularly in achieving greater fat mass loss while sparing lean tissue [5] - There is potential for therapeutics that induce moderate weight loss (7-10%) with better tolerability profiles compared to GLP-1s [5][6] - The company is exploring gene targets in adipocytes and hepatocytes to silence genes related to fat storage and metabolism [6] INHBE Program Insights - INHBE encodes Activin E, a protein involved in fat storage regulation, primarily expressed in the liver [8] - Dysregulation of Activin E signaling can lead to increased fat storage, particularly in individuals with excessive caloric intake or type 2 diabetes [9] - Preclinical studies in diet-induced obesity mouse models showed a 20% reduction in weight gain with INHBE siRNA treatment compared to controls [10] - Combination studies with GLP-1s demonstrated additive weight loss effects while preserving lean mass [11] Clinical Trial Updates - The ongoing phase one study includes single and multiple ascending dose cohorts in healthy obese volunteers and type 2 diabetic patients [13][14] - The study is nearly fully enrolled, with a focus on safety and biomarker knockdown, particularly measuring Activin E levels [15] - Initial data release is expected in early 2026, with a critical mass of data needed to make decisions on moving forward with candidates [27] ALK-7 Program Comparison - ALK-7 targets a receptor on adipocytes, utilizing a novel delivery platform, while INHBE targets the liver signaling pathway [20][21] - Preclinical data for ALK-7 showed a 40% reduction in fat mass in treated animals, suggesting it may be a more potent approach than INHBE [21][22] - Both programs are designed to address obesity but through different mechanisms, with ongoing studies to determine their relative efficacy [23] Redemplo Launch Expectations - Initial launch expectations for Redemplo are positive, with significant interest from investigators and potential patients [28] - The company is cautious about pricing strategies and will provide updates in the upcoming earnings call [28] Future Outlook - Arrowhead anticipates a robust data release in early 2026, which will inform decisions on the progression of its obesity programs and potential partnerships [27] - The company is also monitoring the competitive landscape, particularly in relation to other siRNA approaches targeting similar pathways [18] Additional Considerations - The company is focused on differentiating its products based on efficacy, tolerability, and the quality of weight loss achieved [16] - Ongoing studies will help clarify the impact of treatments on liver fat content and overall metabolic health [30][31]

Financial Data and Key Metrics Changes - For the year ended December 31, 2024, the company recorded revenues of $43.3 million, an increase from $31.6 million in 2023, representing a growth of $11.7 million largely due to collaboration arrangements for siRNA platform development [20][21] - The company's net operating loss for 2024 was approximately $63.3 million, a slight decrease from $64.4 million in 2023, attributed to increased revenue offset by rising R&D costs [26] - The net loss for 2024 was approximately $45.3 million compared to $54.2 million in 2023, with cash, cash equivalents, and short-term investments totaling $147.3 million at the end of December 2024 [27] Business Line Data and Key Metrics Changes - The Phase 2 study of zerlasiran showed positive results with Lp(a) reductions exceeding 90%, supporting a competitive profile for further development in Phase 3 [5][6] - Divesiran's Phase 1 study results indicated it completely eliminated the need for phlebotomy in well-controlled patients, with a favorable safety profile [8][14] - The company plans to prioritize investment in programs targeting rare conditions, with divesiran for polycythemia vera (PV) remaining a top priority [10][29] Market Data and Key Metrics Changes - The company has received Orphan Drug Designation for divesiran from the European Commission, and it also holds FDA Fast Track and Orphan Drug Designations for PV [8] - The market opportunity for treating high Lp(a) is significant, with few cardiovascular assets targeting this unmet medical condition [12] Company Strategy and Development Direction - The company will only initiate the Phase 3 outcomes study for zerlasiran once a partner is secured, extending its cash runway into 2027 [28][53] - The focus will be on advancing innovative siRNA therapies for rare conditions, with a commitment to delivering life-changing treatments [29][56] - The company is evaluating multiple undisclosed programs from its GOLD platform for potential development or partnership [17] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the potential of zerlasiran and divesiran, highlighting the positive feedback received from global regulatory agencies regarding the Phase 3 program design for zerlasiran [6][12] - The company is actively engaged in partnership discussions for zerlasiran, with a focus on securing the right partner for development and commercialization [61] Other Important Information - Silence has transitioned to a U.S. domestic issuer effective January 1, 2025, requiring compliance with U.S. GAAP and SEC reporting [19] - The company plans to start a Phase 1 study of SLN548, targeting complement factor B, in the second half of the year [50] Q&A Session Summary Question: Can you provide some color on partnership discussions for zerlasiran? - Management did not comment specifically on ongoing partnership discussions but noted increased funding for Lp(a) studies from companies like Novartis [59][61] Question: How ready is the company for the Phase 3 trial of zerlasiran? - The company is wrapping up Phase 3 readiness activities and is on track to complete them by mid-year, allowing for some adjustments with a partner [67] Question: What is the goal for divesiran regarding differentiation? - The goal is to be the first siRNA to market for PV, with a focus on infrequent dosing and symptomatic improvement as key differentiators [75][78] Question: What are the biggest hurdles for partnering zerlasiran? - Hurdles vary by party, but discussions often revolve around business strategy and the recognition of the large market opportunity [79][80] Question: What is the status of the candidates developed for Hansoh? - The company is interested in the programs developed under the partnership and will evaluate the opportunity to develop them independently or through partnerships [84]