Fulcrum Therapeutics, Inc.

Good morning, and welcome to Fulcrum Therapeutics' first quarter 2024 financial results and business update conference call. Currently, all participants are in a listen-only mode. This call is being webcast live and can be accessed on the investor section of Fulcrum's website at www.fulcrumtx.com, and is being recorded. Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about the company's future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent Fulcrum's views as of today, this should not be relied upon as representing the company's views in the future. Fulcrum may update these statements in the future, but is not taking on an obligation to do so. Please refer to Fulcrum's most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business. Leading the call today will be Alex Sapir, CEO and President of Fulcrum. Joining Alex on the call are Alan Musil, Chief Financial Officer, Dr. Ian Frazier, Senior Vice President of Early Development, and Paul Bruno, Senior Vice President of Business and Corporate Development. After providing updates on our key programs, there will be a brief Q&A in which Alex, Alan, Ian, and Paul will be available to answer your questions. With that, it's my pleasure to turn the call over to Alex.

That's great. Thanks, Shannon. And thanks to all of you for joining us on the call this morning. Beyond another solid quarter of progress across our two clinical stage assets, Los Mapamad and Posterior Dare, we are super excited to announce our collaboration and license agreement with Sanofi for the development and commercialization of Los Mapamad. So what I'd like to start off by doing this morning is just provide an overview of the structure and strategic importance of this collaboration with Sanofi. In brief, Sanofi will obtain exclusive commercialization rights for Los Mapamad outside of the U.S., and that will allow Fulcrum to focus our efforts on planning for a strong U.S. commercial launch in 2026. This collaboration allows both parties to do what we each do best. It combines Fulcrum's expertise in FSHD with Sanofi's exceptional regulatory development and commercial capabilities across approximately 100 countries outside the U.S. Importantly, having a partner like Sanofi will allow us to reach patients in XUS markets quicker than we could do on our own and mitigates the commercial execution risk that is typically inherent for any biotech company undertaking the commercial launch of its first product on its own. We believe we have selected the best possible partner for Los Mappamod, and we look forward to delivering on our shared commitment to addressing the unmet need of patients with FSHD. We're also very pleased with the deal terms, which allows us to retain substantial ex-U.S. value in both the near term and over the product lifecycle. In short, we will receive $80 million upfront, which enables us to fund the launch of Los Matamad in the U.S. with non-dilutive capital. We're also eligible to receive up to an additional $975 million in specific regulatory and sales milestones, along with the tiered royalties starting in the low teens of annual net sales of Los Mapamad outside of the US. The companies will also share equally in the global development costs for Los Mapamad going forward. Now, before providing an update on our two clinical assets, Posterior Dear, and Los Mapamad, I would also like to take the opportunity to welcome our newly appointed Chief Medical Officer, Dr. Patrick Horn, an accomplished industry veteran who has successfully guided multiple therapies in the rare disease space through late clinical development, regulatory approval, and commercial launch. This is an ideal time for Pat's appointment, and with the complimentary expertise of Dr. Ian Frazier, we are well positioned as we advance toward near-term inflection points. Pat does send his apologies as he's unable to attend today's meeting on account of a family emergency. So let's go a bit deeper and start with our most advanced program, Losmaphobod, which as most of you know, is an oral small molecule, selective P38 alpha-beta-matkinase inhibitor that inhibits ducts for expression and thus prevents downstream muscle death death in patients with FSHD. As a quick reminder, FSHD is a rare form of muscular dystrophy with an estimated U.S. prevalent patient population of 30,000. FSHD is characterized by a slow but relentless loss of muscle function year after year, resulting in significant impairment of upper extremity muscle function and mobility. And while there is a degree of heterogeneity in the onset and disease progression of FSHD, many patients are unable to perform daily life activities that you and I take for granted and thus are unable to live independently. Ultimately, 20% of FSHD patients become wheelchair-bound. There are currently no approved treatment options for these patients, which underscores the significant unmet need for this debilitating disease. Our Phase II study, the REDUX-IV trial, was recently published last month in Lancet Neurology and demonstrated improvements in functional outcomes as measured by reachable workspace, structural outcomes as measured by muscle fat infiltration, and patient-reported outcomes for patients treated with losmapamide, all as compared to placebo. Building on the encouraging clinical benefit and favorable tolerability observed in our Phase II trial, We completed enrollment in our global phase three trial for Los mapamad in September of last year with a total of 260 patients. And as of the end of April of this year, 146 of the 260 patients had completed the 48 week treatment period. And 144 of these patients elected to continue into the open label extension of the study in a fully blinded fashion. This very high percentage of patients opting to move into the open-label phase is similar to what was observed in our Phase II clinical trial and indicative of the high unmet clinical need for patients with FSHD. We are on track to report top line in the fourth quarter of this year, which will bring us one step closer to delivering the first-ever FDA-approved therapy for patients with FSHD. Now, as a quick reminder, our phase three trial, the REACH trial, it is a well-powered 48-week trial intended to be registration enabling both in the U.S. and in ex-U.S. geographies. The primary endpoint for REACH is the change for baseline in the relative surface area, or RSA, which is a quantitative assessment of reachable workspace. RSA is a measure of upper extremity range of motion and muscle function that specifically evaluates shoulder and arm mobility using 3D motion sensor technology and has been shown to correlate with abilities to perform certain activities of daily living. In our phase two study, Los Mapamon demonstrated a 10% net change in the RSA score relative to placebo at 48 weeks. Based on our collaborative interactions with FDA, and in particular with the Clinical Outcomes Assessment Group, or COA, at FDA, we are currently assessing the extent to which a specific change in the RSA score is meaningful to patients. Additionally, key secondary endpoints include muscle fat infiltration, or MFI, which is an important marker of disease pathology measured by whole body MRI, shoulder dynamometry, as well as self-reported quality-of-life measures and healthcare utilization questionnaires that will help inform our thinking on our payer strategy as we begin for our commercial launch here in the U.S. Taken together, we continue to take important steps forward to position Fulcrum for commercial readiness. Now, turning to Pasir Adir, are oral HBF inducer for the potential treatment of patients with sickle cell disease, or FCD for short. The elevation of fetal hemoglobin, or HBF, is a validated therapeutic rationale for FCD, a lifelong inherited blood disorder that severely impairs quality of life for approximately 100,000 people in the US and approximately 4.4 million people worldwide. This makes sickle cell disease one of the most prevalent nonmalignant hematologic diseases. Now, historically, the standard of treatment for SCD has involved blood transfusions, pain medications, and hydroxyurea. But all of these treatments only focus on symptom relief. And while exciting scientific progress has enabled the advancement, and more recently, the approval of gene editing therapeutic approaches, we believe there remains a high unmet need for a safe and accessible therapeutic option that are broadly protective of SCD symptomatology. As a first-in-class oral small molecule HBF inducer, we believe PercirDir has the potential to address this unmet need. So in August of 2023, the FDA lifted the clinical hold on the Phase 1B study we call the Pioneer Study. It's important to note there were no changes in the protocol-defined dose escalation scheme or the three-month treatment duration. We continue to work expeditiously to reinitiate the Pioneer study, and we have activated several new sites and are building key relationships with leading physicians in the SCD community. Cohort 3 of the Phase 1b trial will evaluate posterior at the 12-milligram once-daily dose with a dosing duration of three months. followed by cohort four at the 20-milligram once-daily dose, also for three months. Both cohorts are expected to enroll approximately 10 patients. We look forward to building on the encouraging clinical data obtained prior to the clinical hold, which demonstrated that cociradir increased total HPF of a magnitude that could translate into a meaningful improvement in disease severity. More specifically, after only 42 days of treatment, we observed up to a 10 percentage point increase in HBF from baseline or total HBF of approximately 25%. We believe that Posterior Dare as an oral HBF inducer has the potential to provide a differentiated therapeutic option for patients living with sickle cell disease. Addressing the significant unmet need in sickle cell, in the sickle cell community remains a key priority for us, and we are excited to build on this momentum in the years ahead. And so with that update on the business, let me now turn it over to our Chief Financial Officer, Alan Musso, to run through our financials. Alan, over to you.

Thanks, Alex. I'll now go over our financial results for the first quarter ended March 31st, 2024. As of March 31, 2024, cash, cash equivalents, and marketable securities were $213.3 million, as compared to $236.2 million as of December 31, 2023. The decrease in our cash position of $22.9 million is due to net cash used in operating activities. As of March 31, 2024, on a pro forma basis, considering the $80 million milestone, due under the collaboration and license agreement with Sanofi, our cash, cash equivalents, and marketable securities were $293.3 million. We had no collaboration revenue in the first quarter of 2024 compared to $0.3 million for the first quarter of 2023. The decrease was attributable to the completion of our research services during the fourth quarter of 2023 under our Myocardia collaboration agreement. Research and development expenses were $19.8 million for the first quarter of 2024 as compared to $16.7 million in the first quarter of 2023. The increase of $3.1 million was primarily due to increased costs related to the advancement of the REACH clinical trial. General and administrative expenses were $10.1 million for the first quarter of 2024 as compared to $11.5 million for the first quarter of 2023. The decrease of $1.4 million was primarily due to decreased employee compensation costs. And our net loss was $26.9 million for the first quarter of 2024, as compared to $24.8 million for the first quarter of 2023. Finally, based on our current operating plans, we now expect that our cash, cash equivalents and marketable securities, together with the $80 million upfront payment to be received from Sanofi, will be sufficient to fund its operating requirements into 2027. With that, let me turn it back over to you, Alan.