Fulcrum Therapeutics Inc (FULC) 2022 Q1 法說會逐字稿

Good morning, and welcome to Fulcrum Therapeutics First Quarter 2020 Conference Call. (Operator Instructions)

I would now like to turn the call over to Naomi Aoki, Senior Vice President of Corporate Communications and Investor Relations at Fulcrum Please, proceed.

Thank you. Good morning, and welcome to 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 time lines 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; Judy Dunn, our President of R&D; and Esther Rajavelu, our CFO; Christopher Morabito, Chief Medical Officer; and Paul Bruno, our Executive 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, key updates and review of upcoming milestones. Judy will review our FTX-6058 program. Esther 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. At Fulcrum, our mission is to treat the root cause of rare genetic diseases, and we are advancing 2 important clinical stage assets that support that mission. The first is our Phase III FSHD program that is positioned to be a first-to-market therapy for an untreated patient population. The second is our program for sickle cell disease and other hemoglobinopathies, a once-daily HbF inducer, with the potential to be the first oral therapy that can broadly improve outcomes for these diseases. We have made significant progress across these programs in the first quarter.

I'll start with an update on FTX-6058, our oral HbF inducer for sickle cell disease and other hemoglobinopathies. 6058 shows great promise in addressing critical unmet needs in these patient populations. The current treatment landscape consists of therapies that only target select symptoms of sickle cell disease. HbF is the only mechanism that has been shown to broadly improve clinical outcomes, including anemia, VOC events, pain, fatigue and acute chest syndrome.

As the only agent in development with the potential to induce HbF, we believe that 6058 is uniquely positioned in the current and emerging landscape. In January, we announced that we had dosed our first patient in our Phase Ib trial at a starting dose of 6 milligrams. We plan to share initial data from the ongoing 6-milligram dosing cohort, including measures of HbF induction at the European Hematology Association Congress, taking place from June 9 through 12. We also plan to open the next dosing cohort in the Phase Ib trial this quarter, and we'll have more details to share on that cohort along with the data at EHA.

Notably, this update will be the first look at HbF protein induction in people living with sickle cell disease receiving 6058. Based on data from other HbF mechanisms, and the process of erythropoiesis, we would anticipate seeing signs of protein induction after 1 month of treatment with potentially maximal protein induction at 3 to 5 months. As a reminder, our Phase Ib trial is an early proof-of-concept study that is designed to provide evidence over a range of doses that 6058 increases HbF. For this initial data, we would consider evidence of HbF induction as a proof of concept for this program.

Typically, people with sickle cell disease have HbF levels of 5% to 10%. However, a subset of people with sickle cell trait have additional mutations that result in elevated levels of HbF, a condition known as hereditary persistence of fetal hemoglobin. These individuals have little to no symptoms of sickle cell disease. These clinical and genetic data clearly demonstrate that increases in HbF improve outcomes. Based on this well-understood data, KOLs consistently state that an absolute 5% to 10% increase in HbF baseline level -- beyond baseline levels would be transformative for patients, and would be used as standard of care.

Our robust preclinical data and our Phase I data in healthy volunteers give us reason to believe that we can achieve these absolute 5% to 10% increases that will be life-changing for people with sickle cell disease. We also believe that 6058 could be a transformative therapy for other hemoglobinopathies, including beta thalassemia, and we are committed to developing 6058 in these patient populations as well.

This morning, we updated the anticipated timing of the initiation of the trial in non-sickle cell hemoglobinopathies to the second half of the year. This shift in timing allows us to focus on expeditiously advancing our development plans in sickle cell disease while remaining well positioned to successfully execute a trial in other hemoglobinopathies.

Moving on to losmapimod, our Phase III candidate for FSHD, which is the second most common form of muscular dystrophy. We remain on track to begin dosing patients in our Phase III REACH trial this quarter. As the first ever Phase III trial in FSHD reaches a landmark study that brings us 1 step closer to delivering a potentially life-changing therapy to people with this severe and debilitating disease.

Losmapimod is positioned to be the first-to-market therapy for FSHD. And based on the data to date, we believe it has the potential to slow or stop disease progression and in some cases, even improve function. REACH will evaluate losmapimod 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 ReDUX4 Phase IIb trial, 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 time frame. Based on these insights and the data from ReDUX4 demonstrating clinical benefit, we align with regulators on key aspects of the design of REACH.

In March, we presented data supporting RWS as a quantitative and relevant measure of function at the Muscular Dystrophy Association Clinical and Scientific Conference. That same month, we hosted an event with leading KOLs to discuss the unmet need in FSHD, key measures of disease progression and the design of the REACH trial with a focus on RWS. Together with the FSHD society, we also hosted a webinar on REACH for the patient community.

Additionally, in April, at the American Academy of Neurology Annual Meeting, we presented clinical data supporting the potential of losmapimod as well as the design of REACH. We are proud of the progress that we have made with losmapimod. REACH marks an important milestone for Fulcrum and for the FSHD community.

There are currently no approved drugs for FSHD, and nothing else in the clinic. People with FSHD lose strength, function, independence and mobility as the disease advances. There is an urgent need for a drug that can slow or stop disease progression. The data we reported last year from ReDUX4 demonstrate losmapimod's potential to do exactly that, showing delayed progression and improvement in measures of function. Losmapimod is also supported by an extensive safety and tolerability database.

In addition to our progress with initiating REACH, we've also made significant gains in preparing for the potential of commercial launch. Beyond building internal infrastructure needed for success, we have progressed the commercial formulation of losmapimod. Additionally, we continue to engage with patients, care partners and care providers to ensure losmapimod has the maximal potential to meet the community's expectations.

6058 and losmapimod as well as our ongoing collaborations are a testament to the power of FulcrumSeek, our product engine and the innovation backbone of our company. FulcrumSeek has allowed us to rapidly identify novel, high-quality targets that modulate the root cause of rare genetic diseases, and it continues to power our pipeline.

We remain on track to nominate our next development candidate by the end of this year, and submit what will be Fulcrum's fourth IND by the end of the first quarter of 2023. As we advance 2 potentially life-changing therapies through clinical development, while expanding our pipeline, we are well positioned to establish Fulcrum as a leading rare disease company supported with a strong financial foundation and a cash runway into 2024.

With that, I'll turn it over to Judy.

Thank you, Bryan. As we look ahead to our data disclosure at EHA, I'd like to review our 6058 program for sickle cell disease and other hemoglobinopathies. Sickle cell disease is a genetic disorder of the red blood cells caused by a mutation in the HBB gene. It is the most common type of inherited hemoglobinopathy, and affects an estimated 100,000 people in the United States and millions more worldwide.

People with sickle cell disease experience anemia, vaso-occlusive crisis, or VOCs, and other serious morbidities such as stroke and acute chest syndrome. In addition to having a devastating impact on people's quality of life, these complications significantly increase the risk of dying from sickle cell disease.

HbF induction is the only mechanism that has been shown to broadly improve outcomes for key symptoms of sickle cell disease. To build on Bryan's remarks about the transformative potential of HbF induction, consistent with the persistence of fetal hemoglobin data, numerous published analyses demonstrated that higher HbF levels lead to better clinical outcomes. A systematic review of the literature shows that increases in HbF of 3% to 7% are associated with fewer VOC events, strokes, hospital admissions and transfusions, fewer incidences of acute chest syndrome and decreased risk of mortality.

These data support the view that we consistently hear from KOLs. The increases of 5% to 10% fetal hemoglobin over baseline would be transformative for people with sickle cell disease. As the only oral HbF inducer in the clinic, we believe that 6058 has a tremendous opportunity to address the unmet medical need for better treatment options for people with sickle cell disease. We discovered 6058 using our FulcrumSeek 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.

6058 was also generally well tolerated. We are now dosing people with sickle cell disease long enough to observe increases in HbF protein. As a reminder, this Phase Ib study is designed to have up to 3 dosing cohorts to allow us to explore a range of doses, and identify the optimal dose to take into a registration-enabling trial. We are currently dosing patients with the first dosing cohort at a 6 mg once daily dose. The data we are presenting at EHA in June will be initial data from a small number of subjects enrolled in this cohort, and will include measures of HbF protein. For these initial data, we are looking to see evidence of HbF protein induction, which would provide proof of concept for this program.

We expect to open our next dosing cohort in the Phase Ib trial this quarter, and we'll share additional details on that cohort along with the data update at EHA. We are pleased with the progress we've made in advancing both 6058 and losmapimod, both potentially life-changing therapies for populations with significant unmet medical needs.

And with that, I'll turn it over to Esther.

Thanks, Judy. Today, I will share with you an update on our financials. We are operating from a position of financial strength, ending the first quarter with $195.1 million in cash, cash equivalents and marketable securities. Based on our current plans and projections, we expect this will support our operations into 2024. During the first quarter of 2022, we recognized collaboration revenue of $2.6 million compared to $4.8 million during the first quarter of 2021. This decline is primarily tied to reduced research services we provided to our collaboration partners this quarter.

First quarter 2022 research and development expenses were $17.8 million compared to $16.3 million for the first quarter of 2021. And G&A expenses were $10.8 million this quarter compared to $5.5 million for the first quarter of 2021. These increases were primarily due to the advancement of our clinical programs as well as increases in employee-related expenses to support our growth. Our net loss for the first quarter of 2022 was $28.9 (sic) [$25.9] million compared to a net loss of $17 million for the first quarter of 2021.

With that, I'll turn it back to Bryan.

Thanks, Esther. As you've heard today, the first quarter of 2022 has been a productive one for Fulcrum, and we have even more to look forward to as we continue to advancing our promising programs in FSHD, sickle cell disease and other hemoglobinopathies as well as to leverage FulcrumSeek to build out our pipeline. We look forward to sharing additional key updates later this quarter.

Operator, you may now open the line for questions.

(Operator Instructions) Your first question comes from the line of Judah Frommer from Credit Suisse.

Just a couple for us. Is there any way you can give us some kind of enrollment update for the first cohort of the 6058 Phase Ib, and an idea of potentially how many patients we can get data on at EHA that have been dosed out to 12 weeks?

And then on the second cohort, can you remind us of key considerations you'll have in terms of deciding whether you'll dose higher or lower in that cohort, and what the read-throughs might be from that?

Sure. Thanks for the questions, Judah. So why don't I turn it over to Chris, and we can speak to both of those. One, that's the first question on enrollment. And the second question, just on the additional dosing cohorts, and how we're thinking about that as we move forward here with the Ib?

Judah, thanks for the good questions. So as you know, we are currently in the Phase Ib trial dosing the first cohort at 6 milligrams. And just Judy reminded, the 6-milligram dose was selected based on the data that we developed in the Phase I trial in healthy volunteers that showed after just 2 weeks of dosing, we saw a 2.5-fold increase in HB gamma mRNA, which our hands empirically translates into what has the potential to be robust increases in patients if patients are dosed long enough. So the Phase Ib data that we're excited to share data on at EHA coming up in just a few weeks will be an update on initial patients from that cohort that have been treated in accordance with the protocol.

And as you remember, the protocol allows for the primary analysis of 1 month, which gives us flexibility in determining using data dosing decisions. I'll answer your next question in a second. And then out to 3 months, which should give us a sense about what the ultimate potential of this drug is. And before I answer the second question, the purpose of this study is early proof of concept, is to give us a sense that we are translating HB gamma mRNA into protein, which ultimately has tremendous potential therapeutic benefit as Judy and Bryan both went through.

It's also to provide us information about dose, and it should give us information about a range of doses and their effects on HbF and people with sickle cell disease. So when we think about the next dose cohort, and what that dose is, number one, we want to make a data-driven decision. So we will be looking at not only the healthy volunteer data, but incoming data from the Ib study to inform our modeling and simulation. We will be looking at events, if any. We'll be looking at how well patients are all feeling about the drug, and make a decision based on what the dose can be. And to remind you, we have the ability to go up or down with the next cohort. And the dose range for the next cohort, I stated, is between 2 and 20 milligrams.

And your next question comes from the line of Dae Gon Ha from Stifel.

Maybe I'll just piggyback off of the 6058 question as well. So when we think about the data upcoming, I guess, in your prepared remarks, you talked about the 5% to 10% absolute improvement from baseline being transformative but you also talked about two- to three-fold induction seen preclinically. So can you maybe help us sort of set expectations going into EHA? Is it 5% to 10%? Or is it two- to three-fold induction, recognizing baseline levels could be somewhat variable? And then just to follow up on that, kind of curious on your third dose cohort. I know you have the optionality for that. You've been talking about cohorts 1 and 2 for now. So what would it take for you to consider I guess opting into cohort #3?

Yes. Thanks for the question, Dae Gon. Maybe I will take the first one, and then as it relates to dosing, I'll turn it back over to Chris Morabito. So I think first and foremost, as we've said and as you heard Judy say here earlier today, based on the strong data that exists from people with hereditary persistence of fetal hemoglobin and the consistent feedback that we get from KOLs that we think that 5% to 10% absolute increases in HbF would lead to a transformative therapy, and one that would be utilized as standard of care. So that is our goal for the program.

I think as we get towards this initial data, as Chris said, obviously, first and foremost, we hope to be able to see HbF protein increases. And as a reminder, when we shared our Phase I healthy volunteer data last year, we were both -- because we were dosing healthies, and we were only dosing for 14 days, that wasn't a sufficient amount of time to be able to show that. So first and foremost, we want to see that we are increasing HbF. And secondly, it's important that we see a path towards getting to that 5% to 10% absolute increase.

So our therapeutic goal hasn't changed. I think one of the things that we've always talked about that we were very encouraged by is, as we looked preclinically across different assays, we consistently saw a 2 to threefold induction in both mRNA and protein. I think we find that very encouraging as we get towards having data in patients. However, as we transition into patients, we've also said that one of the reasons we've always shared fold increases is because the assays had different starting levels. We know from other clinical trials as well as literature that patients -- people living with sickle cell disease typically have 5% to 10% baseline levels.

So moving forward, we'll be focusing on what are the absolute increases in protein. And I think that's very much what clinicians and KOLs want to see, and how they want to see the data.

With that, let me turn it over to Chris, and we can talk about dosing.

Yes. Dae Gon, as Bryan mentioned, we're looking for data that support the path forward towards establishing what the therapeutic benefit of this drug is and ultimately, that will be defined in the Phase II trial that we initiated, which we intend to be a pivotal trial. In order for us to get to that pivotal trial as fast as possible, we're doing this Ib over multiple cohorts. And to answer your question specifically about the third cohort, we'll make a data-driven decision. If we have enough data after just 2 cohorts to inform the dose selection for the Phase II, that's it. If we need more data, we'll open up that third cohort.

If I can just maybe follow up on the preclinical data. Just looking back at CTX001, there was a translational gap, right, going from preclinical two- to three-fold induction into what they're seeing in the clinic today, which is pretty phenomenal. Maybe a question for Paul. Is there a transitional gap that we should also expect with the EED inhibition? Or is that not so much the case given the guide RNA versus EED inhibition mechanistic difference?

Yes. Thanks, Dae Gon. So I mean, based on all the preclinical data that we generated today, what I would say is for all of the HbF mechanisms that we profiled, the way that it's translated to the clinic is either the same level of induction or greater. So there's always the potential. We could potentially see greater induction as we translate to the clinic. But we'll need to see what that looks like based on the emerging clinical data. And as Bryan alluded to earlier, while we're focused on the two- to three-fold induction, and the possibility for us to translate to greater levels in the clinic, what we're hearing from the KOLs, what we're seeing from emerging gene therapy data and from our FLR data suggest that a 5% to 10% increase over baseline levels would be transformative.

Your next question comes from the line of Ted Tenthoff from Piper Sandler.

Great. Thanks for the very clear guidance and expectation on 6058. Just to switch up a little bit, I'll ask on REACH. What are your expectations for enrollment? How quickly do you think that study could enroll?

In terms of when we think about REACH, what we know is the data that we have already collected from our vast experience with the ReDUX4 trial as well as how we are hearing from patients and people who treat FSHD in terms of their enthusiasm for REACH. So we are confident that we have a great runway to a reasonable time for enrollment. And in fact, as you know, we're not doing an interim analysis in this program, primarily because we think that the enrollment fee will be such that we don't want to slow down the program. And so we think our time line will be very reasonable, and perhaps better than the time line or the rate of enrollment that we had on the initial ReDUX4 trial, primarily because of the enthusiasm that the patients and clinicians have based on the ReDUX4 data.

Your next question comes from the line of Joseph Schwartz from SVB.

I was wondering if you could frame out for us how much data we should expect for 6058 at EHA in June in terms of like the number of patients and the duration of therapy? And how will you be reporting and interpreting data for different patients traded for different durations? Have you thought about the kinds of analyses that you'll be presenting? And how confident are you that you'll be able to interpret them, clearly, just given the numbers, the different numbers and perhaps low numbers of patients at different durations.

Thanks for the question, Joe. Let me turn it over to Chris, and we can speak broadly about that, about expectations for EHA, how we're thinking about this initial data set.

Yes. As I said -- Joe, this is Chris. So as mentioned before, we are showing initial data from the 6-milligram cohort and the treatment duration is up to 3 months for this cohort, which we expect to be able to provide a meaningful suggestion of the clinical benefit of 6058 in terms of its ability to increase HbF. We haven't guided specifically as to what we'll show at EHA, and we look forward to being able to share those data at EHA. But we do intend to show what we think is a meaningful increase on HbF informed by other clinical parameters and laboratory values that all suggests the potential for therapeutic benefit in these patients.

Okay. Great. And then as far as the REACH trial execution goes, can you give us a sense of -- to what extent do you think actual enrollment of patients may be a rate-limiting factor for the pace of REACH versus setting up sites given you've got some specialized procedures being performed in order to evaluate patients? Can you give us a sense of what do you think -- where do you think the heaviest lifting will be for executing REACH in terms of like site activation versus patient enrollment?

Yes. Thanks for the question, Joe. So in terms of REACH, I think one of the things that Judy alluded to is that we were very encouraged based on what we saw last time in our ReDUX4 Phase IIb trial. And just a reminder, that was 80 subjects. It was one of the largest trials ever done in FSHD. And I think in the rare disease space, there's always a question of how quickly can enrollment take place. And as Judy mentioned, there is such unmet need in FSHD. It's the second most prevalent form of muscular dystrophy. Not only is there nothing else approved, but there's not anything else even in the clinic. And as a result of that, and I think the enthusiasm for the program, the ReDUX4 trial was able to enroll very quickly with 80 subjects.

So as we transition now to the Phase III, and we think about that both finding additional subjects for the trial as well as, like you said, site activation, we're really able to leverage the success from ReDUX4 for both. So we're able to go back and utilize some of the same sites from ReDUX4 plus an additional sites. And unfortunately, for people living with FSHD, the dynamics haven't changed since we ran ReDUX4. There are no other therapeutic alternatives. There are no other programs in the clinic. So we think as a result of both of those, we'll have a very clear path towards enrollment. And as that progresses, we intend to provide an update on both when enrollment should complete, and when data should be available.

Your next question comes from the line of Matthew Biegler from Oppenheimer.

Two quick ones for me. We obviously talked a lot about HbF and precedents for protein expression just in the development of sickle cell drugs. But something that I don't think doesn't get talked about as much, but probably should, our benchmarks for F-positive cells. Are there any precedents that you can point to for the degree of pan-cellularity that you'd like to achieve for 6058 that could have meaningful downstream impacts on things like VOC?

And second, just a quick one in terms of, can you tell us the actual data cutoff that will be included in the EHA presentation?

Yes. So why don't I turn it over to Paul, and we can talk about pan-cellularity, including what we observed preclinically, which I think we find very encouraging? And then I can turn it back over to Chris for EHA.

Thanks, Bryan. Yes, in terms of F cells, the measurement itself is somewhat subjective. It's a little hard to compare across different studies. One thing I will note is that the greater the pan-cellularity, the greater their translation to potential clinical benefit. As Bryan alluded to preclinically, we see very high levels of F cells near 100% pan-cellularity in our preclinical assays. Our hope is to see how that translates in the clinic as well. And we are collecting endpoints to inform on that.

Yes. Matt, your second question about data cutoff. As Bryan mentioned, we're going to provide initial data on the 6-milligram cohort. We haven't guided specifically as to what we're going to show but we intend to show data that should provide proof of concept -- early proof of concept for 6058 in people with sickle cell disease.

(Operator Instructions)

Your next question comes from the line of Matthew Harrison from Morgan Stanley.

This is (inaudible) for Matthew. So our question is, given that you already expect your study -- start the pivotal study for 6058 in early 2023. So we're wondering what gives you the confidence given that you are still seeking for the best dose? Like the same cohort, you haven't decided to dose, and you even plan for cohort 3 with maybe potential data-driven analysis. So how have you come up with the early 2023 timeline?

Yes. Absolutely. And you're right. Our goal, and I think as we've stated all along that if we're able to see robust HbF increases, our goal is to transition into a registrational trial as early as possible in 2023. We do believe that, that is consistent with what we're hearing from the KOLs that this would be a drug because of the benefits of a that would be broadly utilized and has the potential to be standard of care. Let me turn it over to Chris. We can talk about how we're thinking about the Phase Ib trial looking at the different doses really in order to support that and to support transitioning into a registrational trial with as few doses as is feasible.

Great. So we're doing everything possible now to prepare for the start of the study in 2023. And we're assuming just based on the strength of the preclinical and early clinical data for healthy volunteers that we should be able to demonstrate early proof of concept. And then the work becomes choosing a dose. So we'll spend the time between now and the first patient in a Phase II trial, collecting data to determine that dose. We're making drugs. We're starting to talk to sites. We're getting involved with patients and patient care partners to be ready to start this trial as soon as possible. So the infrastructure is built, and that all we need to do ultimately is that dose selection.

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

Thank you so much. Thanks, everybody, for joining us today, and we appreciate the continued support of Fulcrum. Have a great day.

Goodbye.

This concludes today's call. You may now disconnect.