Fulcrum Therapeutics, Inc.

Good morning, and welcome to Fulcrum Therapeutics' fourth quarter and full year 2021 conference call. Currently, all participants are in listen-only mode. There will be a question-and-answer session at the end of this call. I would now like to turn the call over to Christy Warich, Director of Investor Relations at Fulcrum. Please proceed.

Thank you, Operator. Good morning, and welcome to the Fulcrum Therapeutics conference calls. 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 our future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so. Please refer to our most recent filings with the Securities and Exchange Commission for discussion of certain risks and uncertainties associated with our business. With me on today's call are Brian Stewart, President and Chief Executive Officer, Judith Dunn, our President of R&D, and Esther Rangeveld, our CFO. Chris Moravito, our Chief Medical Officer, and Paul Brunner, our Executive Director of Corporate Development, will also be available for Q&A. Let me quickly run through this morning's agenda. Brian will begin the call with a corporate overview and key updates. Judy will review our FSHD program and today's update on the phase three trial. And Esther will cover our financials, while Brian will open the call for Q&A. With that, it's my pleasure to turn the call over to Brian.

Thank you, Christy. Good morning, everyone, and thank you for joining us today. At Fulcrum, our mission is to treat the root cause of rare genetic diseases. 2021 was a year of important clinical and corporate progress towards that mission, and we are building on that momentum in 2022 with meaningful updates across our pipeline. I'll start with Los Mapamot, our candidate for FSHD, which is the second most common form of muscular dystrophy. We believe Los Mapamot is positioned to be the first to market therapy for this severe and debilitating disease. Today, we announced our plan to begin enrolling people with FSHD in REACH, our registration-enabling Phase III clinical trial in the second quarter of 2022. REACH will evaluate losmaphimod compared to placebo in adults with FSHD over a 48-week treatment period with reachable workspace, or RWS, as the primary endpoint. The trial design reflects key learnings from the REDUX-IV Phase IIb study, most notably that we can show a measurable clinical benefit in 48 weeks and that RWS is a quantitative measure of function that is sensitive to disease progression in that timeframe. Based on these insights and the data from REDUX-IV demonstrating clinical benefit, we align with regulators, including the FDA, on RWS as the primary endpoint. The upcoming start of our Phase III trial marks a significant milestone for both Fulcrum and the FSHD community. There are currently no approved drugs and nothing else even in the clinic. People with FSHD lose strength, function, independence, and mobility as fat infiltrates their muscles, and there is an urgent need for a drug that can slow or stop disease progression. The data that we reported last year from REDUX-IV demonstrate LosMapimod's potential to do exactly that, showing delayed progression and improvement in measures of function, including RWS. We are thrilled to be one step closer to bringing this important therapy to patients. Our second clinical program, FTX6058, an oral HBF inducer for sickle cell disease and other hemoglobinopathies, shows great promise in addressing important unmet needs in these patient populations. The current treatment landscape in sickle cell disease consists of therapies that only target select symptoms. HBF is the only mechanism that has been shown to broadly improve outcomes for key symptoms of sickle cell disease, such as VOC events, pain, fatigue, and acute chest syndrome. A robust body of genetic data shows that increases in HBF in every patient is meaningful. Emerging clinical data from gene editing further support the benefit of HBF induction But in the case of gene editing, it comes with a tremendous treatment burden, making it most likely to be used as a salvage therapy. We discovered FTX6058 using our FulcrumSeq product engine. Preclinically, across multiple in vivo and in vitro assays, 6058 generated a consistent two- to three-fold induction in HBG mRNA that translated into the same fold induction in HBF protein. Last year, we transitioned to the clinic. and announced positive Phase I healthy volunteer data that demonstrated robust increases in HBG mRNA at multiple doses. These data gave us confidence to advance FTX 6058 into our ongoing Phase Ib study, where we will be dosing people with sickle cell disease long enough to observe protein increases. Typically, people with sickle cell disease have starting HBF levels of 5 to 10 percent. As we've spoken to KOLs, we have consistently heard that a 5% to 10% increase in HBF beyond baseline levels would be transformative for patients and would be utilized as standard of care. We are highly encouraged that our robust preclinical data and Phase I healthy volunteer data both predict that we can achieve these absolute increases that will be life-changing for people with sickle cell disease. In December, we began enrolling the Phase 1b trial at a starting dose of 6 milligrams daily. We are on track to report initial data, including HBF protein levels, in the second quarter of this year. This update will be the first look at protein data in people with sickle cell disease. Based on data from other HBF mechanisms and the process of erythropoiesis, the earliest we would anticipate seeing protein induction would be after one month of treatment, with maximal protein induction at three to five months. For this initial data in Q2, we would consider evidence of protein induction to be a very meaningful update. We also believe that FTX6058 could be a transformative therapy for other hemoglobinopathies, such as beta thalassemia, and we are on track to initiate a Phase Ib trial in the second quarter. FDX 6058 and Los Mapamod, as well as our ongoing collaborations with Merck and BMS, are a testament to the power of FulcrumSeq, our product engine and the innovation backbone of our company. FulcrumSeq has allowed us to rapidly identify novel, high-quality targets that modulate the root cause of genetically defined rare diseases. Notably, We expect to nominate our next development candidate by the end of this year and submit an additional new IND by the end of the first quarter of 2023. As we advance two potentially life-changing therapies through clinical development, expand our pipeline, scale up our discovery efforts while building downstream clinical and commercial capabilities, we are well positioned to build a leading rare disease company supported with a strong financial foundation and a cash runway that takes us into 2024. With that, I'd like to turn it over to Judy to share more about our plans for losmaphomods that we announced this morning. Judy?