Financial Data and Key Metrics Changes - The company has enhanced its financial position, providing additional cash runway to advance lead programs into clinical development [4] - An exclusive option agreement with Incyte includes an upfront fee of $35 million and a purchase of $25 million in non-voting common stock, totaling $60 million [20][22] - The deal could deliver up to $910 million in cash payments and future milestones to the company [22] Business Line Data and Key Metrics Changes - The primary focus will be on advancing two development candidates: a JAK2 V617F selective inhibitor for myeloproliferative neoplasms and a KAT6A selective degrader for ER-positive breast cancer, both expected to enter the clinic in 2026 [4][5] - The JAK2 V617F selective inhibitor targets over 200,000 MPN patients in the US alone, with a significant market opportunity [11] Market Data and Key Metrics Changes - The target patient population for the JAK2 program includes over 95% of PV patients and 50%-60% of MF and ET patients that are V617F positive [11] - The KAT6A selective degrader program aims to address the unmet need in ER-positive breast cancer, where resistance to current therapies is common [13][14] Company Strategy and Development Direction - The company is focused on optimizing capital allocation and aligning its business strategy with programs that offer the highest probability of success [4] - The strategy includes enhancing R&D focus and advancing next-generation ADCs called degrader antibody conjugates [5][20] Management's Comments on Operating Environment and Future Outlook - Management expressed confidence in the potential of their lead programs to transform treatment options for cancer patients [4] - The company is energized to enter 2026 with a strong team and financial means to support execution into 2027 [24] Other Important Information - The company plans to file an IND for the JAK2 program in the first quarter of 2026 and expects to initiate phase one trials in the first half of 2026 [11][43] - The KAT6A program is on track for an IND filing in mid-2026, with a phase one start expected in the second half of 2026 [19][43] Q&A Session Summary Question: Can you talk about the clinical development of both the mutant CALR and the KAT6A programs? - The company plans to focus on V617F-positive MPNs, with myelofibrosis as a potential initial study indication [27] - For the KAT6A program, the focus will be on ER-positive breast cancer, with plans to rapidly advance to fulvestrant combinations [30] Question: How do you differentiate the degrader approach versus previous programs? - The company learned from the SMARCA2 program to build in potency, selectivity, and important PK properties into the KAT6A program [42] Question: How does the current mutation testing for V617F perform clinically? - V617F testing has become a standard diagnostic for MPNs, especially in PV patients [39] Question: How did the deal with Incyte come about? - The deal was seen as the best option to bring in capital and leverage Incyte's expertise in the MPN space [56]

Core Insights - Prelude Therapeutics has entered into an exclusive option agreement with Incyte Corporation to advance its JAK2V617F mutant selective inhibitor program, which includes an upfront payment of $35 million and a $25 million equity investment, with potential additional payments of $100 million if the option is exercised [1][2] - The company is prioritizing the development of its KAT6A selective degrader program for ER+ breast cancer, aiming to enter clinical development in 2026 [3][6] - Prelude has decided to pause the clinical development of its SMARCA2 degrader program due to resource allocation considerations [4][6] Financial Overview - Prelude expects its cash runway to extend into 2027 based on preliminary estimates, potentially extending into the third quarter of 2028 if Incyte exercises its option on the JAK2 program [5] - As of October 31, 2025, the company had approximately $52 million in cash, cash equivalents, and marketable securities, with an additional $60 million expected from the Incyte agreement [5] Strategic Developments - The company is focusing on the JAK2V617F and KAT6A programs, believing they present significant opportunities for addressing unmet patient needs and creating value for investors [6] - Prelude's KAT6A program is positioned to potentially offer improved efficacy and safety compared to existing non-selective KAT6A/B inhibitors [8] - The JAK2V617F program targets a mutation present in approximately 95% of patients with polycythemia vera, 60% of patients with essential thrombocythemia, and 55% of patients with myelofibrosis, aiming to transform treatment outcomes for these patients [9] Leadership Changes - The company announced the departure of President and Chief Medical Officer Jane Huang, with Victor Sandor stepping in to provide strategic oversight for clinical development [7][8]