FULC - NASDAQ

Good morning, and welcome to Fulcrum Therapeutics' First Quarter 2024 Financial Results and Business Update Conference Call. [Operator Instructions] This call is being webcast live and can be accessed on the Investors 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 Musso, Chief Financial Officer; Dr. Iain Fraser, 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, Iain 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 2 clinical stage assets, losmapimod and pociredir, we are super excited to announce our collaboration and license agreement with Sanofi for the development and commercialization of losmapimod. 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 losmapimod 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 ex-U.S. 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 losmapimod, 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's life cycle. In short, we will receive $80 million upfront, which enables us to fund the launch of losmapimod in the U.S. with nondilutive 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 losmapimod outside of the U.S. The companies will also share equally in the global development cost for losmapimod going forward. Now before providing an update on our two clinical assets, pociredir and losmapimod, 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 complementary expertise of Dr. Iain Fraser, we are well positioned as we advance toward near-term inflection points. Pat does send his apologies that he is 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, losmapimod, which, as most of you know, is an oral small molecule selective p38 alpha/beta MAP kinase inhibitor that inhibits DUX4 expression and thus prevent downstream muscle 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 ReDUX4 trial was recently published last month in Lancet Neurology and demonstrated improvement in functional outcomes as measured by reachable workspace, structural outcomes as measured by muscle fat infiltration and patient-reported outcomes for patients treated with losmapimod, 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 III trial for losmapimod 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 III 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 evaluate 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 II study, losmapimod 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 health care utilization questionnaires that will help inform our thinking on our payer strategy as we begin for a 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 pociredir, our oral HbF inducer for the potential treatment of patients with sickle cell disease or SCD for sure. The elevation of fetal hemoglobin or HbF is a validated therapeutic rationale for SCD, a lifelong inherited blood disorder that severely impairs quality of life for approximately 100,000 people in the U.S. 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 pociredir has the potential to address this unmet need. So in August of 2023, the FDA lifted the clinical hold on the Phase Ib study we call the PIONEER study. It's important to note there were no changes in the protocol-defined dose escalation scheme or the 3-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 Ib trial will evaluate pociredir at the 12-milligram once daily dose with a dosing duration of 3 months, followed by Cohort 4 at the 20-milligram once daily dose also for 3 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 pociredir increased total HbF 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 pociredir 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 31, 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 MyoKardia 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. 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, Alex.

That's great. Thanks so much, Alan. So before opening up for questions, Shannon, I just wanted to remind everybody of the key events for this quarter. We selected the ideal partner in Sanofi to commercialize losmapimod outside the U.S., we extended our cash runway into 2027, we enriched our leadership team, and we activated several new sites for our Phase Ib PIONEER trial of pociredir. We remain on track to report top line data for the Phase III REACH trial in the fourth quarter of 2024 and continue to prepare for the potential NDA filing and commercial launch of losmapimod in the U.S. We look forward to building on this momentum in the months and years ahead. And with that, Shannon, let's go ahead and open it up for questions.

[Operator Instructions] Our first question comes from the line of Edward Tenthoff with Piper Sandler.

Congratulations on the partnership and all the progress of the corner.

Thanks, Ed.

So a quick question. When it comes to actually manufacturing drug and things like that for the partnership, can you walk us through how that works? And then just anything else we should think about in terms of final things that need to happen ahead of the Phase III data? Obviously, final patient visits and all of that stuff. But just anything else that you guys are focused on as we drive towards the end of the fourth quarter for losmapimod?

Yes. It's great, Ed. Thanks so much. And joining us on the call is Paul Bruno, and Paul is our Head of Corporate Strategy and Business Development, really the individual at Fulcrum who really led the deal efforts with Sanofi. So maybe Paul, I'll turn that over to you to address the manufacturing question and then the more general question, Ed had.

Yes. Thanks, Ed. So right now, the plan is for us to continue supplying for both clinical and commercial globally. There is the opportunity and flexibility for Sanofi to take over manufacturing and supply in the future.

Great. And then just in terms of final work towards the Phase III readout, anything we need to be focused on?

Nothing planned, but maybe I'll turn it over to Iain.

This is Iain. No, that's all pretty much on track and unaffected by this. We are proceeding with that. We know who the last patients in the study are, where they are, and obviously, we're working with those sites to make sure there are no delays there. But that continues unaffected at this point.

Well, tough to imagine a better partner. Congratulations, guys.

Thanks so much, Ed.

Our next question comes from the line of Gregory Renza with RBC Capital Markets.

Alex and team, congrats on the progress in the deal. And maybe just a couple from us. Just first question. When we look across the competitive landscape for FSHD development, especially when it comes to trial design and endpoints. Maybe beyond DUX4 expression, we do know that Avidity plans to report data on the changes to gene expression in downstream to DUX4. Just curious, what can you tell us about losmapimod's ability to impact that expression downstream of DUX4? And maybe how can we think about that and losmapimod being positioned competitively in light of this? And then I have a follow-up.

Yes. Great question, Greg. And let me start, and then I'll turn it over to Iain for some more detail. And yes, Avidity talked a lot about the fact that AOC 1020 directly inhibits DUX4. I think the clinical impact of that still remains to be seen. They have talked a lot about being able to measure gene downstream to DUX4 because of the challenges that we've spoken about and they've spoken about, about the stochastic nature of DUX4 and how difficult it is to measure. Now we do know that losmapimod works upstream from DUX4, but we also know that losmapimod can reduce DUX4 gene expression in preclinical models. And we also know that losmapimod has been able to reduce gene expression that are downstream to DUX4 in preclinical models as well. And maybe, I guess, Iain, just to elaborate on that a little bit, maybe I'll turn it over to you to maybe talk a bit more detail about some of the genes that we have been able to reduce downstream to DUX4.

Yes, absolutely. Yes, all the work that was done to identify losmapimod as a potentially useful agent in FSHD was done in vitro in cells derived from patients with FSHD. The myoblast from those patients differentiated in vitro into myotubes in that process. DUX4 typically is upregulated. We've been able to grow across a range of cells derived from different patients with FSHD 1 and FSHD 2 that there very clearly is a significant reduction in DUX4 itself, which you can measure in vitro somewhat more readily than you can in vivo. And then along with those concentration-dependent reductions in DUX4 across those myotube cultures, you see a concomitant decrease in a number of the downstream genes that we know are impacted by DUX4 that are regulated by DUX4 and show a concentration-dependent decrease in all of those as well as decreases in markers of apoptosis in the muscles and ultimately decrease in muscle cell death. So that mechanism is fully fleshed out in cultures. And as Alex alluded to, the challenge in the clinic is demonstrating that in the biopsies from these patients. And I think one of the challenges in addition to the stochastic nature of DUX4 expression is the variability in the tissue content of the biopsy. In the clinic these are not normal muscles, so there's a bunch of fat, fibrous tissue, inflammatory tissue, extracellular matrix components and so on, that leads to the variability in documenting that. But the overall pathway in vitro in those myotube cultures is very clear, concentration-dependent reduction in DUX4, and similarly, reduction in the downstream gene impacted by DUX4.

That's great. Really appreciate that. And then just on the deal this morning. I certainly heard you mention of the benefit of Sanofi reaching multiple countries and you're building now to focus it state side and on the U.S. I just wanted to ask just to receive a little more color on maybe some of those additional inputs that you and the team had in consideration of these deal terms reflecting the full value of losmapimod. Can you just talk through some of the deal terms and what inputs that you use to feel comfortable with the value calculus here?

Yes. Thanks, Greg. And I'll start and then, Paul, if I miss anything, please jump in. I think, first and foremost, we've been very clear that it has always been our goal to try to find a partner outside of the U.S. And I think the reason for that is it would -- finding a partner outside the U.S. allows us to do a couple of things, Greg, right? It allows us to get losmapimod to patients around the world faster than we could do on our own simply because of the scale of the commercial infrastructure that Sanofi has. And then with the upfront payment and the cost sharing, we obviously can take that capital, that nondilutive capital and really apply our effort, and more importantly, our focus on ensuring that we can have the best possible launch here in the U.S., which obviously we've been obviously gearing up for. I think one of the reasons you'll see that the deal terms were quite competitive and significantly above comps for products that have yet to flip over the Phase III card is, I think, simply because of the competitive nature of this, there was a number of parties that were interested. Not surprising, FSHD is a large market in the U.S., about 30,000 patients, some estimate about 1 million patients outside of the U.S. and there are currently no treatment options. And Fulcrum has what we believe to be probably about a 3-year head start before the next closest competitor comes into play. So I think for all of those reasons, we could not be happier with the partner that we've selected. It allows us to get the drug faster to patients than we could do on our own outside of the U.S., but it also allows us as a small biotech company to focus on what still continues to this day to be the most profitable and lucrative market in the world, that being the U.S. market.

Our next question comes from the line of Corinne Jenkins with Goldman Sachs.

You mentioned in the answer to the last question that you plan to use this upfront capital in supporting the launch. I guess what are your top priority action items that you think will be necessary to set up a strong launch out of the gate? And then I'd be curious if you could talk to what you view as Sanofi potentially bringing to the table as a potential partner or as a partner now for ex-U.S. commercialization beyond just kind of the financial terms?

Sure. Sure. No, absolutely. Thanks, Corinne, for asking the question. Yes, I think one of our key priorities on the commercial side is to bring on board a very, very strong Chief Commercial Officer that has experience of launching rare diseases in the pharmacy benefit portion of the payer space. And we were having a number of conversations with a number of very, very talented Chief Commercial Officers that meet that criteria. So that's obviously going to be our first important hire. And then we'll be doing a couple of additional hires this year, particularly around market access, and we more than likely will end up recruiting somebody who is exclusively focused on ensuring that genetic testing does not become an impediment to access at launch. So I think those are some of our key priorities right now for the U.S. I think what Sanofi brings, and we talked a little bit about this during our prepared remarks, I think beyond the financials -- I mean they have a very, very strong neuromuscular franchise with their programs such as Fabrazyme and Cerezyme, Myozyme. I mean that's a $3 billion portfolio globally. So they've got a very, very strong commercial footprint. But beyond that, they obviously have very strong regulatory as well as clinical expertise in the neuromuscular space as well. So having that expertise as we're negotiating with the various regulatory agencies around the world as well as with the various pricing and reimbursement agencies in various countries around the world, I think that experience that Sanofi brings to the table will be invaluable.

Our next question comes from the line of Joe Schwartz with Leerink Partners.

Congratulations on the deal. I have a question on losmapimod and also one on pociredir. So first on losmapimod. I was just wondering if you can tell us how your work to establish the clinical meaningfulness of certain changes in RWS is going? Can you outline the process of performing that analysis and where you are in that process? When we might see some data on that front?

Yes. That's great. Thanks so much, Joe, and thanks for your kind words earlier. Yes, I think to answer the question, we're doing a lot of work on clinical meaningfulness. We've been working very closely with COA division of the FDA, but maybe just get into some of the specific point, I'd turn it over to Iain.

Yes. Thanks, Alex. Thanks, Joe. So there are three main steps as part of the work that's ongoing and that we've aligned with the agency. The first is a survey that is now being completed, and that is asking patients with FSHD what is most important to them in terms of activities of daily living. So that was a 100 patient survey unrelated to treatment with losmapimod. Again, that is completed. The two other components are ongoing at the moment. The first is a cross-sectional study, again, inpatients with FSHD, but not being treated with losmapimod and performing reachable workspace assessments on those patients and then matching up the ability of those patients to do the important activities of daily living, which were identified in the initial step. And so that's my questionnaire in those patients, so mapping reachable workspace there to the questionnaire of their ability to perform those activities. And that assessment, recruiting those patients into that is active and ongoing at the moment, and that's going to be a total of about 50 patients. And then the last component, the third component of this is as part of the REACH study, so patients who've been treated with either losmapimod or placebo undergoing structured exit interviews from the study to get insight from them on what difficulties they had with activities of daily living as part of their participation in the study. That work is ongoing and will only complete once the REACH study itself is complete and we have all the data. So we expect all of these strands of data to be pulled together and available in around the same timeframe as we expect the top line data from the REACH study and that those will be around the same time.

That's very helpful. And then can you update us on site activation in the ongoing study for pociredir? And at what point do you think you could share some data from this study either in terms of calendar timing or how you're thinking in terms of numbers of patients you're aiming for before giving us the first look? That would be very helpful.

Yes, absolutely. Thanks, Joe. I'm happy to take that one. Yes. So we will be sharing information when we have completed the 10 patients in the 12-milligram cohort and all 10 of those patients have completed the 3-month study duration. And we intend to share that with everybody in advance of Cohort 4, which is the 20-milligram cohort. Again, our expectation there is that we would share the 20-milligram cohort data once those 10 patients have completed the full 3 months of dosing. We have been pleased with the site activation efforts to date. I would say that there is a strong interest from many sickle cell centers about the promise of having a once daily oral medication that has the potential to raise levels of HbF to that seen with the cell and gene therapies. We haven't yet provided any specific guidance on when we would be able to share that information because what we want to make sure that we do, Joe, is -- I mean, first and foremost, we want to make sure that we don't give a number that we don't feel comfortable with in terms of a particular quarter. So what we've said to folks is that we want to have a critical mass of patients in that 12-milligram cohort before we come back to everyone and let them know what -- in what quarter we'll have the 12, and in a subsequent quarter, the 20-milligram. And I think just having that critical mass of patients, it allows us to know a couple of things, right? It allows us to sort of see what that enrollment trajectory looks like, but it also allows us to see which sites have been the strong enrollers. And to be able to go back to those PIs at those sites and really ask them point blank how many more patients that they have. So until we have that critical mass -- or once you have that critical mass of patients, then we can more accurately predict what that enrollment trajectory looks like that will be the point in time in which we'll come back to everybody with more specificity around which quarter we would share the 12-milligram followed by the quarter in which we would share the 20-milligram.

[Operator Instructions] Our next question comes from the line of Dae Gon Ha with Stifel.

Congrats on the deal on progress as well. I'll start with the losmapimod question. In your prepared remarks, Alex, you talked about 146 of your patients being completed as of April 24, 144 electing to go into open label. So curious, in terms of the Sanofi deal, I guess when did this deal kind of get underway? And to what extent were they kind of given the access to the data room? I know it's blinded, but just kind of curious how much access they have there? And I've got a follow-up.

Sure. Absolutely, Dae Gon. And maybe to -- and thanks for your kind words as well. Maybe to answer that question, I'll turn it over to Paul who's really been the person that's been leading the charge on the -- we've been in conversations, obviously, for some period of time with the folks at Sanofi. But Paul, do you want to maybe just talk a little bit about kind of when these conversations got quite serious?

Yes. I mean the conversations have been taking place for over the past year. Again, it's been a competitive process with a number of parties. They have had broad access to all the confidential information related to the program. I will explicitly note that they have not seen any blinded REACH data neither have we, but other than that, they have broad access to the program materials.

Okay. Great. Thanks for the details, Paul. Maybe the next question is, when you think about the Sanofi infrastructure, especially ex U.S. -- access to ex-U.S. regulators, I guess, can you just remind us where things stand in terms of the Phase III REACH design? How comfortable is the EMA as well as ex-U.S. regulators about that particular endpoint as it pertains to FSHD approvability?

Yes. Absolutely, Dae Gon. Thanks for the question. Maybe let me turn that one over to Iain.

Yes. Thanks, Dae Gon. So we have engaged with the European regulators. There were some initial engagement prior to the study, which was done on a country-by-country basis rather than central process with the EMA. But more recently, we have engaged with the EMA somewhat late in the process while the trial was underway. I think they recognized the endpoints that we've established. They also recognized that our interactions with them were after the trial that already been initiated. And so opportunities to impact that were limited. But I think there's an understanding of our primary endpoint and the way that we structured the secondary endpoints. And I think an overall agreement that, that seems to be a reasonable design from that point of view.

Our next question comes from the line of Matthew Biegler with Oppenheimer.

I extend my congrats as well. I just wanted to maybe tag along to that last question about the partnering process here. And specifically, if you can comment on how receptive the partners were to the RWS endpoint. Is this something that they've seen before? Or did it kind of require a lot of handholding with Paul and team throughout the due diligence process?

Yes. Great question, Matt. Maybe add to that, probably the best person to answer that would be Paul.

Yes. Thanks, Matt. No, we have been broadly educating folks on RWS. I don't think to a greater degree than you would for any other novel endpoint. I think it was also one of the major reasons that we were excited about Sanofi as a potential partner between their deep neuromuscular expertise but also their expertise with novel endpoints. I think this really was an ideal match for Fulcrum, particularly for this rare disease drug development program.

And I'm currently showing no further questions at this time. I'd like to hand the call back over to Alex for any closing remarks.

That's great. Thanks so much, Shannon, and thanks to all of you for joining again. Maybe just in closing, we, as always, remain deeply committed to treating the root cause of genetically defined rare diseases and bring transformative therapies to patients. And before we conclude today's call, as I always like to do, I would like to extend my sincere appreciation and gratitude to my fellow Fulcrum teammates, to the physicians we work with to advance our clinical studies, and finally and most importantly, to the patients and their families. Thanks, everybody, who joined this morning, and please stay safe and healthy. Thanks.