Summary of Arrowhead Pharmaceuticals FY Conference Call Company Overview - **Company**: Arrowhead Pharmaceuticals (NasdaqGS:ARWR) - **Event**: FY Conference Call on September 10, 2025 - **Key Speakers**: Chris Anzalone (CEO), James Hamilton (CMO and Head of R&D) Core Points and Arguments Transition to Commercialization - Arrowhead Pharmaceuticals is transitioning into a commercial company with a PDUFA date for Plozasiran on November 18, 2025, indicating a significant milestone in their development pipeline [2][4] Plozasiran Overview - Plozasiran is designed to reduce ApoC3 expression, lowering triglycerides in patients with Familial Chylomicronemia Syndrome (FCS) [4] - Phase 3 study results showed an approximately 80% reduction in triglycerides from baseline and a significant decrease in the risk of acute pancreatitis [4][12] Market Opportunity in FCS - FCS is classified as an ultra-orphan disease with an estimated 1,000 genetically defined patients in the U.S. [6] - Arrowhead also targets clinically defined FCS patients, potentially expanding the market beyond the genetically defined group [7] Severe Hypertriglyceridemia (SHTG) Market - The SHTG market is significantly larger, targeting patients with triglyceride levels above 500 mg/dL [9] - Arrowhead is conducting several Phase 3 studies (Shasta-3, Shasta-4, Shasta-5, NEER-3) to evaluate Plozasiran's efficacy in this population [10][19] Competitive Landscape - Arrowhead acknowledges competition in the market but believes that having multiple companies addressing the same medical need is beneficial for patient education and treatment options [16][17] - Plozasiran is expected to show greater efficacy in triglyceride reduction compared to competitors' products [25] Zodasiran Development - Zodasiran is focused on the Homozygous Familial Hypercholesterolemia (HoFH) population, with a Phase 3 study (Yosemite) underway [28] - The drug has shown promising results in earlier studies, with expectations of similar LDL-C reductions as existing therapies [29] Obesity Programs - Arrowhead is developing two obesity treatments targeting the INHBE and ALK7 pathways, with data expected by the end of the year [32][33] - The company aims to demonstrate high-quality weight loss and muscle sparing in clinical trials [35] Bispecific PCSK9/ApoC3 Dimer - A new bispecific dimer targeting both PCSK9 and ApoC3 is set to enter clinical trials, aiming to lower both LDL cholesterol and triglycerides [41][42] CNS Platform - Arrowhead has a promising CNS platform with three near-term clinical programs targeting tau, Huntington's disease, and alpha-synuclein [44][45] - The company has partnered with Novartis for the alpha-synuclein program, while retaining control over the MAPT program [49] Financial Position and Future Outlook - Arrowhead's current cash position and partnerships are expected to sustain operations into 2028, allowing continued development of their pipeline [60] - Upcoming catalysts include the PDUFA update for Plozasiran, obesity data, and Phase 3 readouts for severe hypertriglyceridemia [63][64] Additional Important Points - The partnership with Sarepta Therapeutics has been financially beneficial, with nearly $1 billion received in the past year [55] - Arrowhead emphasizes the importance of maintaining a productive R&D organization while transitioning to commercialization [61] This summary encapsulates the key points discussed during the conference call, highlighting Arrowhead Pharmaceuticals' strategic direction, product pipeline, market opportunities, and financial outlook.

Financial Data and Key Metrics Changes - The net loss for Q3 2025 was $175.2 million, or a loss of $1.26 per share, compared to a net loss of $170.8 million, or a loss of $1.38 per share in Q3 2024 [35] - Revenue for Q3 2025 was $27.8 million, primarily from the collaboration agreement with Sarepta, with $20 million from initial consideration and $7 million from reimbursement of collaboration costs [35][36] - Total operating expenses for Q3 2025 were $193.3 million, an increase from $176.1 million in the prior year, driven by higher R&D costs and SG&A expenses [37][38] - Cash and investments totaled $900.4 million as of June 30, 2025 [38] Business Line Data and Key Metrics Changes - The company achieved full enrollment in Phase 3 studies for clozaran, targeting severe hypertriglyceridemia, with approximately 2,200 patients enrolled across 24 countries [9][24] - The Phase 3 study for zodasiran began with the first patients enrolled in July 2025, targeting homozygous familial hypocholesterolemia [10][27] - The company is on track to meet its 2025 initiative of having 20 individual drug candidates in clinical studies or at market, with nine partnered and 11 wholly owned candidates [16] Market Data and Key Metrics Changes - The collaboration with Sarepta is expected to continue, providing capital to fund internal programs, despite Sarepta's recent setbacks [6] - The company is preparing for the US launch of clozaran, with a PDUFA date set for November 18, 2025, and has engaged with payers representing over 85% of US covered lives [29][30] Company Strategy and Development Direction - The company aims to create value through novel medicines, generate capital for development, and build a growth engine [7] - The focus is on expanding the cardiometabolic franchise and addressing unmet medical needs in various patient populations [14][31] - The company is building a commercial organization to support the launch of its products, particularly clozaran and zodasiran [21][40] Management's Comments on Operating Environment and Future Outlook - Management acknowledged the challenging biotech market but emphasized their commitment to serving patients and creating shareholder value [7] - The company is optimistic about the upcoming regulatory submissions and the potential for multiple product launches between late 2025 and 2028 [12][16] - Management expressed confidence in the collaboration with Sarepta and the potential for significant future milestones [6][36] Other Important Information - The company has made significant progress in sourcing new capital, including a $130 million upfront payment from Sanofi for rights to develop clozaran in Greater China [18][36] - The company expects to achieve a $100 million milestone payment from Sarepta and anticipates a second milestone of $200 million by the end of the year [36][38] Q&A Session Summary Question: How does the company view competitors' programs in triglyceride reduction? - Management stated that they focus on their own studies and have had positive data in their Phase 2 and Phase 3 studies, expecting to demonstrate best-in-class triglyceride reduction [44][46] Question: What are the baseline demographics for the Phase III studies? - Management confirmed that their baseline demographics are similar to those published by competitors, but emphasized the importance of focusing on adjudicated cases of pancreatitis rather than abdominal pain [52][56] Question: How does clozaran address unmet clinical needs? - Management highlighted that clozaran offers deep triglyceride reduction and is the only agent in a registrational Phase 3 study that has shown a statistically significant reduction in acute pancreatitis risk [61][62] Question: What is the expected pricing strategy for clozaran? - Management indicated that they expect clozaran to be priced higher than treatments for severe hypertriglyceridemia, but specific pricing details are still under consideration [65] Question: What is the expected timeline for the auto-injector for clozaran? - Management stated that the initial presentation will be a prefilled syringe, with development underway for an auto-injector expected to be available at launch or soon thereafter [88][89]

ARC-520 Tolerability and Mechanism - ARC-520 has been very well tolerated in 84 humans with single doses, showing no serious or severe adverse events or discontinuations due to AEs[15, 16] - Chimpanzee studies showed that ARC-520 leads to deep HBsAg reduction, with HBeAg(+) chimps showing a mean peak knockdown of 99% (2 log) and HBeAg(-) chimps showing 81% (0.7 log)[17] - The DPC platform is potent and consistent, de-risking ARC-520 and future candidates built on the same DPC, with HBeAg knockdown in HBeAg(+) patients reaching 92% (1.2 log) mean max KD and 98% (1.7 log) max KD after a single 4mg/kg dose[19] ARC-520 Efficacy and Target Population - ARC-520 achieved a 99% (1.9 log) maximum knockdown of HBsAg after a single dose, the highest ever reported in a human using RNAi[20] - In NUC-naïve HBeAg(+) patients, ARC-520 administration resulted in a mean max HBsAg knockdown of 1.05 log, with a maximum knockdown of 99% (1.9 log) through Day 15[21] - In the US, 95% of estimated CHB patients are NUC-naïve, with approximately 50% estimated to be HBeAg(+), making them an important target population for ARC-520[25] - In Western Europe, 90% of estimated CHB patients are NUC-naïve, with approximately 33% estimated to be HBeAg(+)[25] Integrated DNA and ARC-521 - Integrated DNA becomes an increasingly important source of HBsAg as cccDNA is reduced, influencing the response to ARC-520[19] - Two HBeAg neg chimps treated with siRNA targeting integrated DNA showed a mean nadir of HBsAg reduction of 99.8% after switching from ARC-520, representing an additional 2 log decline[77] - The company nominated an additional candidate, ARC-521, optimized to include integrant KD, with an IND or equivalent expected by mid-year 2016[29, 30]

Summary of Arrowhead Pharmaceuticals (ARWR) 2025 Conference Call Company Overview - Arrowhead Pharmaceuticals is focused on developing RNAi-based therapeutics with a strong pipeline aimed at addressing severe diseases, particularly in the areas of hypertriglyceridemia and alpha-1 antitrypsin deficiency [2][3] Key Developments - The company has solidified its balance sheet and has capital projected to last until 2028, which is crucial for upcoming drug launches [3][4] - Planned drug launches include: - **Plazasiran** for familial chylomicronemia syndrome (FCS) expected in late 2025 - **Fazisiran** for alpha-1 antitrypsin deficiency (AAT) in 2027-2028 - **Olpassiran** with Amgen also anticipated around the same timeframe [4] Drug Pipeline Insights - **Plazasiran**: - First drug from Arrowhead's pipeline expected to receive FDA approval with a PDUFA date set for November 18, 2025 - Demonstrated significant triglyceride reduction in clinical trials, with 100% of patients showing lowered triglycerides and an average reduction of around 80% from baseline [6][7] - Safety profile appears favorable, with no anticipated advisory committee meeting [6][7] - **Shasta Five Trial**: - A dedicated trial to assess the acute pancreatitis benefit of plazasiran, targeting patients with triglycerides above 1000 mg/dL and a history of pancreatitis [24][25] - This trial is not required for regulatory approval but is seen as beneficial for payer acceptance [25] Competitive Landscape - The market for severe hypertriglyceridemia is viewed as underserved, with Arrowhead positioned to be among the first to provide effective treatments [16][17] - The company acknowledges competition but believes that having multiple players will enhance market education and acceptance [19] Safety and Efficacy Considerations - Concerns regarding HbA1c levels were addressed, with the company viewing any increases as a biological signal rather than a safety issue [22][23] - The company is focused on ensuring that the drug's efficacy translates into meaningful clinical benefits for patients [22][23] Obesity Pipeline - Arrowhead is pursuing dual targets (inhibin E and ALK7) for obesity treatment, with the rationale that both pathways could induce lipolysis and fat burning [28][30] - The company plans to evaluate which target performs better in human trials before advancing one into later-stage development [35] Alpha-1 Antitrypsin Program - The collaboration with Takeda is seen as transformative, with expectations for full enrollment in the pivotal trial by the end of the year [74][75] - The drug is anticipated to significantly impact the treatment landscape for alpha-1 antitrypsin deficiency, with a profit-sharing model in place [78] Business Development Strategy - Arrowhead aims to pursue additional business development deals to extend its runway, with a focus on maintaining a balance between new partnerships and internal drug development [79][80] - The company is open to exploring discovery components in future deals to enhance its pipeline [80] Conclusion - Arrowhead Pharmaceuticals is strategically positioned with a robust pipeline and a clear focus on addressing significant unmet medical needs in hypertriglyceridemia and alpha-1 antitrypsin deficiency, while also exploring opportunities in obesity treatment and maintaining a proactive approach to business development [2][3][4][79]