Prelude Therapeutics Incorporated

Good morning, everyone, and welcome everyone to the Prelude Therapeutics Investor Conference Call. Today's call is being recorded and is expected to last up to 45 minutes. At this time, I will now turn the call over to Prelude's Chief Financial Officer and Chief Legal Officer, Bryant Lim. Please go ahead.

Thank you, Operator. During today's call, we will make forward-looking statements based on current expectations, including statements concerning anticipated discovery, preclinical, and future clinical development activities for our product candidates, the potential safety, efficacy, benefits, and addressable market for our product candidates, and clinical trial results for our product candidates, together with other statements regarding our plans, prospects, and expectations. Such statements represent our judgments as of today, are not promises or guarantees, and as you know, may involve risks and uncertainties that may cause actual results to differ from the results discussed in the forward-looking statements. Please refer to our filings with the SEC, which are available through the investor relations section of our website for information concerning risk factors that may affect the company. We undertake no obligation to update forward-looking statements. except as required by law. During this call, we will also be referring to certain slides from our corporate presentation that are available on the Investors section of our corporate website under Presentations and Events. Also on this call are Chris Vadde, Prelude's founder and chief executive officer, as well as Peggy Shirley, our chief scientific officer, and Sean Bruski, our chief business officer. I will now turn the call over to Chris to kick things off.

Thank you, Brian, and good morning to everyone joining us today. Over the past quarter, we've made a series of strategic decisions designed to sharpen our R&D focus, optimize our capital allocation, and align our business strategy with programs that we believe offer the highest probability of success. These steps strengthen our ability to deliver on our mission, to discover and develop transformative medicines that can meaningfully improve patient outcomes in cancer. Importantly, as part of these efforts, we've also enhanced our financial position, providing us with additional cash runway to advance our lead programs into clinical development. Looking ahead, our primary focus will be on rapidly advancing two development candidates that we believe represent compelling opportunities for our investors with both programs expected to enter the clinic in 2026. The first is a JAK2-V617F selective inhibitor for myeloproliferative neoplasms, or NPN. is a Cas6A selective degrader for ER-positive breast cancer. Both of these programs target clinically validated pathways and have the potential to demonstrate efficacy and safety differentiation in early clinical development. In addition, we believe that these molecules significantly expand clinical options over currently available treatments for cancers we are targeting. Meanwhile, our discovery team made significant progress in advancing next-generation ADCs called degrader antibody conjugates, or DACs. Our early-stage DAC program targeting mutant calreticulin, or mCalR, which is a very promising target in MPM, shows potential to drive deeper clinical and molecular responses in our preclinical studies. We look forward to presenting additional data from this program at the American Society of Hematology at ASH meeting, annual meeting in December. I'll begin this morning with an overview of our JAK2V617F selective inhibitor program, which will also be featured as an oral presentation at the upcoming ASH. Given that the content of our oral presentation is embargoed and delashed, I will limit my remarks to our approach and the opportunity we see in targeting this mutation as a potential disease-modifying approach for a large subset of MPM patients. Peggy will then review the CAP6A selective degrader program with our lead candidate poised to enter the clinic in 2026. Our Chief Business Officer, Sean Bruski, will then provide an overview of the exclusive option agreement with Insight for the DAC program that we announced last week and future plans for our DAC program. And I'll return for closing comments before opening up the call for your questions. Let me draw your attention to the JAK stat pathway on slide seven of our corporate deck. One of the JAK enzymes, called JAK2, plays a key role in a normal hematopoiesis by mediating growth factor signaling. These growth factors include erythropoietin for red blood cell production, thrombopoietin for platelet production, and GM-CSF for white blood cell production. In MPNs, an activating mutation in JAK2 called JAK2V617F results in an unchecked activation of JAK stat signaling and hyperproliferation of myeloid and erythroid cells and platelets, which can lead to multiple forms of MPNs. including polycythemia vera or PV, essential thrombocytemia or ET, and then even a more serious condition known as myelofibrosis or MF. Currently approved JAK2 inhibitors inhibit normal and mutant JAK2 similarly. This lack of selectivity results in inhibiting normal and abnormal bone marrow function equally. and to a very narrow therapeutic window. Ruxolitinib, or JAK-FI, is the first approved JAK2 inhibitor for MDM. As the first targeted therapy to be approved for MF and the only JAK2 inhibitor approved for PV, Ruxolitinib has been absolutely transformative for many patients. It should be noted that several members of our team played significant roles in its discovery and development in our previous roles at Insight. It was tremendously gratifying to see ruxolitinib become the gold standard in the treatment of MPN, especially in the spleen and symptom benefits it delivers to MPN patients with a debilitating disease. However, despite the clinical benefits it offers, Ruxolitin treatment is associated with high rates of anemia and thrombocytopenia that require dose modifications and often limit the use in patients that are anemic and or thrombocytopenic at baseline, along with the limitation of dosing for maximal efficacy. And because Rux does not specifically target B617F mutated progenitor cells, Molecular responses occur at very low rates and take years to achieve. Ever since the discovery of JAK2-V617F mutation in 2004, what we really wanted is an inhibitor that is selective for the mutant cells and one that does not interfere with normal bone marrow function. Such a molecule could provide the same transformative treatment for MPMs that VCR-able inhibitors like Gleevec delivered for CML. We are excited about the possibility of finally achieving that goal by the breakthroughs in designing molecules that can directly target JAK2V617S. As shown on slide nine, the challenge had been that the mutation occurs in the part of the enzyme called the JH2 domain that is distinct from the catalytic kinase domain called the JH1 domain where the current JAK2 inhibitors bind. Our scientists were able to design potent inhibitors of JAK2 that bind an allosteric JH2 binding site where the V617S mutation resides. We further achieved selectivity over normal JAK2 by directly targeting what we refer to as deep pocket, which contains three phenylalanine residues that include the third phenylalanine coming from the V617F mutation. By utilizing X-ray structure-based approaches, our chemists identified a novel series of compounds that can access the deep pocket to selectively target mutant JAK2 over wild type of normal JAK2 that is present in normal cells. Digging a bit more into the specifics of our lead development candidate, the picamolar JAK2-JH2 binder with significant selectivity for mutant JAK2 over normal JAK2. In addition to the biochemical and cellular potency and selectivity, Our lead candidate has demonstrated that acquired physicochemical and pharmacokinetic properties that enable achieving high levels of mutant JAK2 inhibition. In preclinical efficacy and toxicology studies, this molecule achieved better efficacy compared to rexalitinib without impacting wild-type JAK2 and normal bone marrow functions. We look forward to providing additional preclinical data once it's presented at ASH in December, but I can inform you that we're well along with our IND enabling activities and we're planning to file an IND in the first quarter of 2026 and expect to initiate the phase one in the first half of 2026. In terms of prevalent market size and opportunity, The target patient population includes greater than 95% of TB patients, 50 to 60% of patients with MF and ET that are V617F positive. Collectively, more than 200,000 MPM patients in the U.S. alone could ultimately benefit from a JAK2-V617F selective inhibitor with disease-modifying potential. We did announce last week, and Sean will provide more detail, that we entered into an exclusive option agreement with Insight that provides them an opportunity to acquire the program during a defined time period. As we aggressively drive forward the clinical development of our lead candidate and preclinical development of potential backup candidates during that option period. We look forward to sharing more details at ASHE. I'll now turn the call over to Peggy to provide an overview of our Selective Cat6A Degrader Program. Peggy?