Bryan Stuart - President, Chief Executive Officer Chris Morabito - Chief Medical Officer Peter Thomson - Vice President of Finance & Accounting Judy Dunn - President of R&D Paul Bruno - Senior Director of Corporate Development Naomi Aoki - Senior Vice President of Corporate Communications, Investor Relations

Good morning, and welcome to the Fulcrum Therapeutics, Third Quarter 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 Naomi Aoki, Senior Vice President of Corporate Communications and Investor Relations of Fulcrum. Ma'am, please proceed.

Thank you, Henry. Good morning and welcome to the Fulcrum Therapeutics conference call. 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 a discussion of certain risks and uncertainties associated with our business. With me on today's call are Bryan Stuart, President and Chief Executive Officer; Chris Morabito, Chief Medical Officer and Peter Thomson, Vice President of Finance & Accounting. Judy Dunn our President of R&D and Paul Bruno, our Senior Director of Corporate Development will also be available for Q&A. Let me run quickly through this morning's agenda. Bryan will begin the call with a corporate overview and key updates. Chris Morabito will review our programs in sickle cell disease and FSHD. Peter will cover our financials and then Bryan will open the call for Q&A. With that, it's my pleasure to turn the call over to Bryan.

Thank you, Naomi. Good morning everyone and thank you for joining us today. 2021 has been a remarkable year for Fulcrum and we continue to make great strides in the third quarter across our pipeline, our product engine, our business, bringing us closer to our mission of delivering life-changing medicine to people with rare genetic diseases. This past quarter was particularly notable for the compelling clinical data we reported on FTX-6058, our oral HbF inducer for sickle cell and other hemoglobinopathies. In August we reported results from our ongoing Phase1 trial in healthy adult volunteers. As many of you know, the current treatment landscape in sickle cell disease consist of therapies that only target select symptoms. Human genetics clearly demonstrate that by inducing fetal hemoglobin of HpF, that HpF treats the root cause of sickle cell disease and by inducing HpF we believe FTX-6058 has the potential to address the broad range of symptoms of sickle cell disease, providing a functional cure with an oral therapy. As you'll hear from Chris Morabito later on, we are excited about the results from this trial, both in terms of the tolerability profile and the robust induction of HbG mRNA, which has been highly correlated in our preclinical studies with HbF induction. Looking ahead, we remain on track to provide an update from our ongoing Phase 1 trial by year end, including data from our 20 mg and 30 mg dose cohorts in healthy volunteers. At that time we also plan to share new data further elucidating the relationship between EED inhibition via FTX-6058 and HBG mRNA expression. Meanwhile, we are moving quickly to initiate our Phase 1b trial in people living with sickle cell disease and are on track to begin enrolling patients by the end of the year. We also plan…

Thanks Bryan. I’ll first start with FTX-6058 our oral HbF inducer. As Bryan mentioned, we're extremely encouraged by the results we’ve reported in August, which suggests that FTX-6058 could be a transformative therapy for people with sickle cell disease. Sickle cell disease affects an estimated 100,000 people in the U.S. and millions more worldwide. In people with sickle cell disease a mutation in hemoglobin causes red blood cells to take on a characteristic sickle shape. These red blood cells often die prematurely, which causes anemia. The sickle cells may also damage blood vessels and restrict blood flow, causing vaso-occlusive crisis or VOC’s, which appeared episodes of extreme pain and can manifest a stroke, acute chest syndrome, and other forms of organ injury. Together these complications significantly impact lifespan, underscoring the tremendous need for treatments that address the root cause of disease. As an oral HbF inducer, FDX6058 has the potential to redefine the treatment paradigm. The link between HbF induction and improved outcomes in sickle cell disease is very well established, with both genetic and clinical data showing an increased HbF reduces or eliminates anemia, VOCs and other symptoms of the disease. People who carry the sickle cell mutation, and also have persistence of fetal hemoglobin, present with much milder disease and have far better clinical outcomes. Typically people with sickle cell disease have about 5% to 10% HbF and we know from those with persistence of fetal hemoglobin that any increase in each HbF beyond this has a positive impact on clinical outcomes. We believe an oral drug that induces HbF by two to three folds from baseline would be life changing for people with sickle cell disease, with potential to decrease both anemia and VOC driven symptomology. Pre-clinically FTX-6058 has been shown to induce HbF by two to…

Thanks Chris. Following our successful August financing, we ended the third quarter with $240.3 million in cash, cash equivalents and marketable securities. Based on our current plans and projections, we expect this will support our operations into 2024. Operation revenue for the third quarter of 2021 was $4.9 million compared to $1.8 million of collaboration revenue recognized during the third quarter of 2020. Research and development expenses for the third quarter of 2021 were $17.1 million compared to $15.6 million in the third quarter of 2020. General and administrative expenses for the third quarter of 2021 were $8.6 million as compared to $5.3 million for the third quarter of 2020, and our net loss was $20.7 million for the third quarter of 2021, compared to a net loss of $19 million for the third quarter of 2020. With that, I’ll turn it back to Bryan. Bryan.

Thanks Peter. As you heard today, it’s been a tremendous year for Fulcrum so far and we are continuing to build on that momentum. We are very excited about the prospects for our programs in FSHD and sickle cell diseases, two diseases with great unmet need where we have shown very compelling data to-date and we look forward to opportunities ahead, to develop therapies, to benefit patients with these and other rare genetic diseases. Operator, you may now open the line for questions.

Thank you. [Operator Instructions] Your first question comes from Dae Gon Ha of Stiefel. Your line is now open.

Hi! Good morning guys. Thanks for taking my question. I guess I wanted to just kind of go back to the teaser for the additional data with regards to EED inhabitation and HbG mRNA. I guess can you maybe talk a little bit what we can expect there. Is this mostly in vitro or in vivo and will this cover transcriptomic analyses or proteomic analysis or something else. And I've got a follow-up, thank you.

Yeah, thanks Dae Gon for the question. So we haven't shared more detail yet. I think one of the things that we've been doing and that we’ve spoken about is doing work to try to better hallucinate that relationship between EED inhibition via FTX-6058 and this HBG mRNA increase that we’ve observed so far clinically and obviously the protein increases that we've involved pre-clinically. So we anticipate that we'll be able to share that work along with the data update towards the end of the year and we are excited to share more details on that.

Great! Thank you for that. And then the follow up is with regards to your 30 milligram cohort data. I was wondering if you can maybe walk us through kind of the thought process after you kind of saw the 2 mg, 6 mg and 10 mg, recognizing 20 mg was coming down the pike. What was sort of the driving factors that led you to 30 mg cohort and what exactly where you – are you trying to divulge from that cohort data. Thanks so much.

Hi Dae Gon, this is Chris. Yeah, so as you imply, we were very pleased with the data that we reported back in August. Up through 10 mg we already demonstrated that we have a profile that looks like it could achieve our target, which at least a two to three fold reduction. [Audio Gap]. Operator could you put that line of mute? So we were pleased to see data that implied that we could hit our guide post, our goal post of two to three fold induction already. And based on what we saw, we made some good decisions, critical decisions about this program, including initiation of the Phase 1b study and going into beta thalassemia and other hemoglobinopathies. We haven’t seen anything so far, that makes us concerned about the profile. But we have taken the opportunity in phase one to continue to learn about the profile and this is why we expanded to 20 mg and then eventually 30 mg, so that we can see more about the slope of the HBG mRNA induction, to see more about what's happening with target engagement, and continue to gather data on pharmacokinetic and safety and tolerability. So those data are helpful for us to inform the future development and we're going to use those data to continue to build in our plan for taking these implications and expeditiously bringing this towards approval.

Perfect! Thanks for taking the questions. I look forward to it.

Thank you. Your next question comes from Ted Tenthoff of Piper Sandler. Your line is now open.

Thank you so much for taking the question, and congrats on really an existing year. Again, appreciating that we're going to get an update at ASH on 6058, I wanted to get a sense for where things stands for losmapimod and what the crimsomic steps are. Thanks guys.

Hi Ted! This is Chris again. So actually you know you've heard us say continuously, we are very excited about the profile of losmapimod and the data coming out of our ReDUX4 in which we show impacts on muscle structure, impacts on function and patient reported benefits and we believe that this has potentially to really importantly and profoundly impact patients with FSHD and we are working expeditiously to bring this drug forward towards approval. Our base case continues to be that we’ll have a Phase 3, where we will work really hard to prepare for that. We’ve looked deeply at the ReDUX4 data and National History data and are developing a plant to start a Phase 3 that will ultimately answer the questions. We continue to be on track to meet with the regulators by the end of this year, and as soon as the severity of what that input is, we’ll share that with you. We share the same goal as the community which is to have a drug that will profoundly and transformatively act this course of disease and are working with the regulators to do that goal.

And maybe Ted just to jump in on your perspective regarding the data update. So we are participating today. We are making a contract to be able to provide an update, both of higher dose cohorts as well as the hallucination of the mechanism by end of year. Based on the timing of abstract as well as the timing of our trial, we are going to present that data outside of the [inaudible]. That is everything remains [inaudible] as we get closer to that we’ll get to know.

That’s helpful and thanks for that clarification. And just with losmapimod, does it make sense to evaluate partnerships, even potentially overseas as we keep U.S. sites? Thanks.

Yeah, I think Ted as Chris mentioned, based on the data that we generated, we're very excited to be interacting with the FDA and moving the program forward. So as we’ve talked about a lot in the past, when we went into the Phase 2b trial, we were really enthusiastic to be able to observe these patient benefits in what was a relatively small trial of only 80 subject and in a relatively short trial of only 48 weeks. So I think that gives us a lot of confidence and enthusiasm to move forward. I think as we then transition and look at this as a commercial opportunity, we're very much focused on the patient population and the unmet need. So we know that these are patients that have this genetically defined rare disease there for the most part identified and they are – it is a worldwide disease. So there is a patient population that I think is very much waiting for a therapy and we're very fortunate that we are now building up our commercial leadership to put us in a position to be able to take advantage of that opportunity. So our focused is to continue to bring it forward and try to get it to patients as quickly as we can.

Awesome guys! Thanks for the update.

Thanks Ted.

Your next question comes from Matthew Harrison of Morgan Stanley. Sir, your line is now open.

Good morning everyone. This is Kostas for Matthew. Thanks for taking our questions and Chris, good luck with the next steps. Two questions from us on sickle cell disease. The first one is, can you talk a little bit about the relationship between the PK and the target engagement that you have seen so far with the available data, and whether the target engagement is Cmax or AUC driven. And secondly we are wondering whether you are planning to share base line mRNA levels at us. Thank you.

Hey Kostas, this is Chris. Yeah, thanks for the questions. So referring back to what we showed in August, you recall that we had achieved maximal target engagement at all three doses tests for 2 mg, 6 mg and 10 mg. It took a little longer for 2 mg to get there. By seven days 6 mg and 10 mg were about the same at roughly the maximum level and surely by 14 days all three dose levels were at maximal level. And if you recall maximal inhibition defined by changes in histone trimethylation, it retained about 20% to 30% of PRC2 activity, which we think is an intrinsic competitive advantage of this particular mechanism. So there is something here regarding the concentration and the concentration relationship to target engagement. Our preclinical data suggest that their relationship is based on exposure rather than Cmax. The data that we showed back in August also implied that there is pretty long, a residence time. It takes about a week or so for the levels of histone trimethylation to return to normal, even though the half-life of the drug is only about 9 hours. So again, it’s an exposure driven relationship that has a durable effect.

And then Kostas, we can address the second question regarding mRNA levels. Yeah, so that’s not something that would be important in people that are healthy. It’s more important in people that have sickle and so this is not something that we intend to share. The most important information that we’ll share about mRNA changes is the fold increase from baseline. When we start talking about the patient population, the [inaudible] in which there will be significant levels of HbG and ultimately of HbF where it will be relevant and where we'll have longer treatment durations, this is when we’ll begin to report on the essential parameters.

And Kostas I think we would also add one of the things that we mentioned and been very enthusiastic about, is just this consistency that we have observed to-date as Chris mentioned across both mRNA, as well as protein pre-clinically. So whether we looked at the Townes mouse model, a wild type mouse, CD34 cells from sickle patients from healthy volunteers, we have seen this very consistent two to three fold induction of both mRNA and protein and obviously as we looked at our initial Phase 1 healthy volunteer data, where we looked at mRNA, we are very enthusiastic to see this induction that was even beyond that two to three fold. So I think that gives us a lot of confidence as we look to translate into sickle cell patience and the other element that does as well, is just looking at some of these other opportunities such as the gene editing where we have seen that very meaningful translation from the CD34 positive assay pre-clinically, into now what's being observed with BCL-11A gene editing in patient. So I think all of that gives us confident that as we get into patients here by the end of the year, in the translation that we have the potential to observe.

Very helpful, thank you.

Your next question comes from Joseph Schwartz from SVB Leerink. Your line is now open.

Thanks very much. Congrats on all the progress as well. I was wondering how well developed is the understanding about potential natural variability around the thresholds of HbF that are associated with varying degrees of symptoms and sickle cell, and how are we measuring symptoms in the Phase 1b study in SCD patients. Is it just VOCs or are there any other finer metrics you’ll be evaluating?

Yeah, so Joe, why don’t I turn it over to Paul Bruno and he can speak to not only what is known from both data, as well as other clinical trials about starting HbF levels, but also what is very clearly known about induction of HbF and the benefits from human genetics. And you know I think as we’ve talked about inducing HbF, it is the only way to be able to treat the root cause of the disease and we have such a wealth of data from these patient that have hereditary persistence of fetal hemoglobin that we’re really able to build on that.

[Inaudible] what Bryan said. So looking across the various clinical trials that are currently ongoing, so looking at CRISPR therapeutics and even past trials of hydroxyurea as well as observational studies in sickle cell disease, a population that we do feel very confident that this baseline level of in between 5% and 10%. As Bryan alluded to, what we do know from the genetics in sickle cell disease and residuals that also have mutations leading to hereditary persistence of fetal hemoglobin, we know that any increase in fetal hemoglobin level results in amelioration of a broad swamp of symptoms within sickle cell disease and residual. So the thing about things like anemia, VOCs, acute chest syndrome as well as hemobiotism [ph]and maybe I can have Chris Morabito speak to the Phase 1b expectations there.

Yeah great, thanks Paul. So as Paul mentioned, HbF is a surrogate and increases in HbF in the setting of sickle cell disease are suddenly associated with not only improvements in anemia, but also improvements and symptoms from anemia and improvements in things like VOC and VOC related phenomena. We will be studying this in the 1b study for up to three months, which is about the time that we expect to have maximal impact on HbF in patients and see the multiple significant changes in HbF and we will of course be looking at symptoms. We don't expect in a few months period in an open label study without a placebo group to be able to provide robust data on changes in VOCs, certainly compared to anything because we don't – we just have a baseline to compare to, but we will be looking for any signs that would impact that. Again, the surrogacy behind HbF in this setting, in particular when we have a drug that induces pancellular HbF as our oral HbF inducer does, we do expect that taking this into a longer study such as the Phase 2, we will be able to demonstrate a significant new improvements in clinical outcomes.

Okay, thank you. And then for your meetings with the FDA for Losmapimod, I was curious how much patient advocates may be able to chime in on the merits and need for the drug. Can you give us any sense for how much bandwidth might be allocated by the FDA to receive the case for approval from the company versus patient advocates?

Yeah Joe, why don’t I turn it over to Chris to address that and we can also just speak to some of the things that have been done from the community perspective in terms of engaging with the FDA, the patient focused drug development that took place in 2020 and just some of the discussions that have been having from a patient community that as you point out is obviously very enthusiastic about the potential for a therapy.

Yeah, so it’s a wonderful question and certainly something that we've been thinking deeply about. And we've engaged now, we’ve built now an internal group focusing specifically on patient engagement and patient advocacy. As Bryan said, the patient advocacy network in the U.S. and outside the U.S., in Europe and U.K. for example are very strong, very active, very engaged and even outside of those organizations the patient themselves are very engaged and very willing to help us and importantly to help regulators like the FDA understand the burden of this disease. Bryan referred to a conference that was held in June of 2020, which produced a voice of the patient record, which held in conjunction with the FDA through panels of experts including patients that participated in this conference. The number one report out of that was that the patient request for new therapy that would slow or halt disease progression, something like what we think the profile, what [inaudible] can achieve. We’re absolutely engaged with these organizations to communicate the burden of disease in FSHD and to help regulators understand what kinds of functional interventions or patient reported interventions are important to this community, and we're engaged with this community as well to help us think about what kinds of assessments we need to be able to measure and ongoing clinical trials in order to provide the substantial evidence to support those approvals. The FDAs been very engaged and we're encouraged by this involvement and look forward to continued partnership with the regulators.

Thanks again.

[Operator Instructions] Your next question comes from Judah Frommer of Credit Suisse. Your line is now open.

Hi! Thanks for taking the question and congrats on all the progress. Just a couple of follow ups on the 1b design. Can you just remind us you know why you decided to dose with the 6 mg dose and not the 10 mg and how impactful could the 1b read out be to moving into phase 2 versus the data generated in healthy volunteers given that it is that one dose.

Yes, so just to give you just the context of the study design, so it will be up to three months of therapy in patients with sickle cell disease and it’s all converse with sickle cell disease. And we're looking for first and foremost safety and tolerability and then also looking for changes in key pharmacodynamic parameters, including HbF, and we think the three month treatment duration gives us the opportunity to assess this. We anticipate having after three dose cohorts. So we anticipate each cohort having up to 10 patients. We do have a DMC that will, it's an internal DMC that will be monitoring the study and giving us information at intervals that will form a continued development and progression through those cohorts. We decided to start at 6 mg, because this is the dose level that achieved a three-fold induction at HBG mRNA in healthy volunteers and I do prefer to say lots of times, our goal posts for this is two to three fold induction on top of baseline in sickle cell patients. So we hypothesized that this is the dose that will have the potential for clinical benefit. We’re also – you know we believe that we will have at least the same amount of HBG induction in patients as we see in healthy volunteers and there’s also a potential for more HBG induction, just because of the bone marrow environment, the erythropoiesis environment in sickle cell compared to healthy. So well you know we started a 6 mg in order to give us room in order to detach HBG changes and ultimately HbF changes, HbF protein changes in patients and we’ll be looking at this continually as we dose through 6 mg.

That's helpful, thanks.

Just to be informed, I’ll just quickly finish this off. Subsequent footnotes will be informed by the incoming data and also by the PK/PD model that we're building.

Okay, that makes a lot of sense. And then can you remind us, from a clinical perspective, is higher HbF better or is there a kind of a threshold effect once you get to a 2x, 3x, 4x induction level?

So any increase from baseline has been demonstrated in genetic and clinical experiments to provide benefit. And you know we know from very good population studies that even in the small change from baseline, it had a ten-fold impact overall survival, you know over very long periods of time, but certainly has that kind of impact. We also know from the genetics that levels in the 20% range impact symptoms very well and levels in the 25% to 35% range start to impact absolute symptomatology and can induce essentially a functional cure. Overseeing from the incoming data from the gene editing programs it’s had very high levels of HbF, up to about 50%. We can eliminate the disease and it doesn't appear to cause any adverse events. So you know while we're seeing levels so far in healthy volunteers that imply we can induce to that kind of range, you know obviously we'll see this in patient. We're not concerned about the potential for adverse events at this point related to that.

Great, thank you. [End of Q&A]:

Thank you. This concludes the Q&A session for today. I would like to turn the call over to our CEO, Bryan Stewart for closing remarks.

Thank you. Thank you everybody for joining us today and we appreciate your support of Fulcrum. Have a great day!