Fulcrum Therapeutics Inc (FULC) 2020 Q4 法說會逐字稿

Good morning, and welcome to Fulcrum Therapeutics Fourth Quarter Year-End 2020 Conference Call. (Operator Instructions)

I would now like to turn the call over to Christi Waarich, Director of Investor Relations and Corporate Communications at Fulcrum. Please proceed.

Thank you, operator. Good morning, and welcome to the Fulcrum Therapeutics conference call to discuss our fourth quarter and full year 2020 financial results and recent corporate highlights.

Earlier today, we issued a press release. For those of you who don't have a copy, you can access it in the Investor Relations section of our website at fulcrumtx.com.

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're 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 Robert Gould, President and CEO; Bryan Stuart, Incoming President and CEO; Chris Moxham, Chief Scientific Officer; and Peter Thomson, Vice President of Finance and Accounting.

Let me quickly run through this morning's agenda. Robert will begin the call with a corporate overview. Bryan will give an update on the LOSVID trial with losmapimod for COVID-19 and review our upcoming data from the ReDUX4 trial with losmapimod for FSHD. Chris will then provide a more detailed review of our program in sickle cell disease and our product engine. And Peter will cover our financials.

With that, it's my pleasure to turn the call over to Robert. Robert?

Thank you, Christi. Good morning, everyone, and thank you for joining us today. 2021 is poised to be another important year for Fulcrum as we expect to have meaningful updates from multiple key initiatives. The full losmapimod data from ReDUX4 late in the second quarter of this year will provide new insights that will inform the clinical path forward in FSHD. Following data availability, we'll meet with the FDA to discuss the path to registration.

With FTX-6058, we'll have data from the Phase I trial in healthy adult volunteers midyear, and we anticipate initiating a trial in people with sickle cell disease by the end of the year.

We're also continuing our efforts to advance additional treatments for genetically defined rare diseases with FulcrumSeek, both internally and through our partnerships with the goal of bringing forward 2 INDs over the next 24 months.

This morning, we also announced my retirement and that Bryan Stuart, who has been our Chief Operating Officer since 2018, will be promoted to President and CEO at the end of this month. I look forward to staying engaged with Fulcrum as I continue on the Board. Bryan will join Fulcrum's Board. And Mark Levin, our Board Chair, will assume the role of Executive Chair upon my retirement.

As many of you know, Bryan has been a key contributor to Fulcrum. His leadership within the organization and breadth of experience will be a key driver of our success going forward. In addition to his many accomplishments over the past 2 years, Bryan has significant experience within the rare disease space where he has played a critical role in helping to advance multiple successful programs through the clinic to commercialization. Bryan's leadership will be invaluable as we advance our current clinical programs and continue to advance our pipeline with our product engine.

To everyone at Fulcrum, I'm proud of the strong foundation we've built together and I'm privileged to have worked alongside you. I look forward to serving as an adviser and working with Bryan and the other Board members as we drive continued success.

With that, I'll turn it over to Bryan. Bryan?

Thank you, Robert. I'm looking forward to working together in our new roles. It's a privilege to build on the foundation that you helped create, and I'm honored to be taking over as CEO during such an exciting time for the company.

Like all of my teammates, I was drawn to Fulcrum by the opportunity to develop transformative therapies for people living with genetically defined rare diseases. This is evidenced in our lead programs in both FSHD and select hemoglobinopathies where we're targeting the root cause of severe diseases as well as our enhanced proprietary product engine, which now allows us to rapidly identify novel targets that ameliorate disease phenotypes utilizing insights derived directly from patients. The strength of this platform is evidenced in both our internal preclinical pipeline as well as our collaborations with Acceleron and MyoKardia, and it positions us very well to take advantage of drug discovery at a scale far beyond our previous capabilities. As we make this transition, Fulcrum is very well positioned to build on our great momentum and develop impactful therapies in the years ahead.

Before providing more color on our FSHD and sickle cell trials, I'd first like to provide an update on our program with losmapimod for COVID-19 as announced in our press release earlier this morning. After a strategic review, we have decided to discontinue the LOSVID trial. This decision is a reflection of the significant changes in the COVID-19 treatment paradigm, including the introduction of new therapeutic options and emerging vaccines.

After careful consideration, we have decided to redeploy our resources to Fulcrum's other clinical programs and discovery efforts with a continued focus on rare diseases.

I'd like to note that losmapimod was generally well-tolerated and there were no safety concerns with losmapimod. I would also like to thank the patients and investigators who participated as well as the Fulcrum team who worked so hard on this trial.

Now let's turn our focus to the rare disease programs, beginning with the development of losmapimod in facioscapulohumeral muscular dystrophy or FSHD. As a reminder, FSHD is a rare, progressive and disabling disease characterized by muscular degeneration that occurs as skeletal muscle is replaced by fat. We estimate there are approximately 16,000 to 38,000 patients in the U.S. and similar incidents worldwide, leading to an estimated global patient population of 300,000 to 780,000. There are currently no approved therapeutics for FSHD, and Fulcrum is developing the only known industry-sponsored clinical trial evaluating a potential treatment.

Unlike other diseases that are characterized by the lack of a gene, FSHD is characterized by the unwanted expression of the gene, DUX4, which experts have identified as the root cause of the disease. Through our own research at Fulcrum, we discovered losmapimod, a selective p38 MAP kinase inhibitor, reduced the expression of DUX4 in preclinical studies. Research to date also reinforces that even modest reductions in DUX4-driven gene expression have the potential to translate to meaningful benefit for patients.

Our development programs in FSHD builds on the established safety of losmapimod demonstrated in approximately 3,600 subjects in studies conducted by GSK and by Fulcrum.

We've made tremendous progress with our integrated FSHD clinical development strategy evaluating molecular biomarkers as well as structural and functional measures. This strategy includes natural history studies to better understand disease progression, preparatory studies to establish a biomarker and clinical endpoints as well as studies that have demonstrated muscle penetration and target engagement for losmapimod.

This work helped enable Fulcrum's current ongoing studies of losmapimod in patients with FSHD, which include a single-site Phase II open-label study as well as ReDUX4, which utilizes the biomarker of DUX4-driven gene expression and also includes functional measures like musculoskeletal MRI and patient-reported outcomes.

The ReDUX4 trial is an international Phase IIB, double-blind, placebo-controlled trial of losmapimod in approximately 80 patients with genetically confirmed FSHD. We are on track to report results from this trial in the second quarter of the year.

The encouraging biomarker data reported from ReDUX4's interim analysis indicates that muscles with the highest DUX4-driven gene expression in pretreatment biopsies showed large reductions following treatment with losmapimod compared to placebo. As you may recall, we and others have demonstrated that DUX4's expression occurs on a spectrum and we believe that all people with FSHD will have muscles that exhibit high DUX4-driven gene expression during the course of disease progression.

We look forward to the ReDUX4 data readout, which will include the molecular biomarker data as well as structural, functional and patient-reported outcome measures, which were not part of the interim analysis. We'll be encouraged if we continue to observe evidence of trends similar to the interim analysis and high expressing muscle biopsies from losmapimod-treated patients. Additionally, we'll be encouraged if secondary endpoints like MRI and exploratory endpoints like clinical outcome assessments and patient-reported outcomes showed trends indicating patient benefit.

I'd like to acknowledge the remarkable tenacity of the patients, investigators and the Fulcrum team who continued the trial in such a challenging environment. We believe losmapimod has the potential to establish a new treatment paradigm for people with FSHD and reflects our continued commitment to research that targets the root cause of genetically defined rare diseases with high unmet medical needs.

I'd like to turn the call over to Chris.

Thanks, Bryan. Our unique research focus at Fulcrum positions us to pursue targeted indications where we believe we can develop safe and effective therapies to rebalance gene expression. By working to understand and then target the root cause of disease, we have the best chance to optimize the potential efficacy of treatments, and more broadly, transform the way these diseases are being treated. This research approach has enabled us to rapidly progress clinical programs intended to treat serious diseases beyond FSHD, including sickle cell disease and beta-thalassemia.

Sickle cell disease is the most common type of inherited hemoglobinopathy and affects an estimated 100,000 people in the United States and millions more worldwide. It is a genetic disorder caused by a mutation in the adult form of hemoglobin. The result of the mutation is less efficient oxygen transport and the formation of sickle red cells. People living with sickle cell disease typically suffer from serious complications, which can lead to anemia, pain and vaso-occlusive crisis or VOCs as well as shortened lifespan.

Increasing fetal hemoglobin can have a transformative impact for patients, including reduced recurring pain crisis events, reduced mortality and increased likelihood of asymptomatic presentation.

We believe significant unmet need remains with existing sickle cell disease treatments. Most therapies focus on the symptoms, either on reducing pain episodes or ameliorating anemia. More elaborate attempts aimed at functional cures, namely, hematopoietic stem cell transplants and cell therapies utilize harsh conditioning regimens, which have inherent safety risks that may limit when and how they will be utilized.

We remain excited about the opportunity within FTX-6058, a projected oral once-daily therapy intended to treat the root cause of the disease, and therefore, address both anemia and VOCs.

People living with sickle cell disease and beta-thalassemia represent a diverse global population in great need of an effective therapy that can be accessed and administered with ease. We believe that an oral small molecule that can meaningfully increase levels of fetal hemoglobin will not only provide the therapeutic benefit and convenience of oral administration, but also the distribution at scale that this global population needs. And thus, we believe FTX-6058 has the potential to be an impactful therapy.

At our recent KOL event in December 2020, we were very excited to share that FTX-6058 selectively up-regulates fetal hemoglobin in a pan-cellular manner in both human cellular models and mouse models of sickle cell disease. The treatment of human CD34-positive cells from healthy and sickle cell disease donors with FTX-6058 resulted in fetal hemoglobin levels of up to approximately 30% of total hemoglobin with no observed effects on cell health. We believe this is a superior preclinical profile relative to the standard of care, hydroxyurea, as well as other mechanisms that have been reported to induce fetal hemoglobin. These data, along with the perspective provided by our respective KOLs, have created considerable enthusiasm and interest in our program.

We're actively enrolling our Phase I single-ascending and multiple-ascending dose or SAD and MAD trial with FTX-6058 in healthy volunteers to evaluate safety, tolerability, pharmacokinetics and target engagement. Based on our PK/PD modeling, we anticipate that the pharmacological doses will be in the 6-milligram to 20-milligram range, which is where we anticipate maximum levels of target engagement.

Reports suggest that red blood cell half-life in healthy volunteers is as high as 120 days, which limits the opportunity to observe effects on fetal hemoglobin in a 14-day MAD study. However, we will be measuring fetal hemoglobin mRNA levels and the number of reticulocytes containing fetal hemoglobin in the MAD cohorts to monitor potential early signs of efficacy.

We expect to report the SAD and MAD cohorts mid-2021, which is when we'll also outline our future clinical plans. And we anticipate initiating a trial in sickle cell patients by the end of the year.

Going forward, we intend to continue our dialogue with the FDA and other health authorities as the program progresses. As the data warrant, we plan to seek orphan drug, fast-track and breakthrough therapy designations. The opportunity to bring a new oral therapy to patients is a very exciting prospect for us with the potential to be a significant advance in treatment in the years ahead.

We also continue to advance our clinical strategy for investigation of FTX-6058 in people living with beta-thalassemia.

Moving to our research efforts. We are excited about the productivity of the product engine. We have several discovery programs that span our core focus areas of muscular, hematologic and CNS disorders. Our unique approach is designed to identify starting points that are more technically enabled from a drug discovery perspective as evidenced by the rapid progression from target ID to IND for our FSHD and sickle cell programs. For the targets currently being assessed, we continue to explore both internal medicinal chemistry campaigns as well as opportunities to in-license advanced chemical matter. Our goal is to bring forward 2 INDs over the next 24 months.

Our proprietary target discovery platform, FulcrumSeek, has advanced significantly on many fronts. Today, this proprietary platform allows us to rapidly identify novel targets that revert disease phenotypes informed directly from patients. Whether through the use of patient-derived cells or via the application of single cell genomics to patient biopsies that revealed the dysregulated cell states of a given disease, the resulting high fidelity assays offer a remarkable level of clinical relevance and translatability. From this sophisticated product engine, we use machine learning algorithms to analyze the large amounts of functional, morphological and transcriptional data that are generated with great precision and at great scale. The result is highly derisked targets that are extensively enabled for further characterization.

We believe FulcrumSeek is an important evolution in our product engine to identify targets informed by clinical biology and thus more predictive of desired therapeutic outcomes.

Moreover, FulcrumSeek has supported the development of the clinical programs discussed today and has enabled our ongoing collaborations with Acceleron and MyoKardia. I'm pleased to report that both collaborations are proceeding well. In fact, we successfully achieved our first milestone with Acceleron at the end of 2020.

In summary, we believe we are well positioned to deliver a constant stream of therapeutic innovation from our labs and with our partners.

With that, I will now turn the call over to Peter.

Thanks, Chris. We entered 2020 with $112.9 million in cash, cash equivalents and marketable securities, not including the $46.4 million in net proceeds from our January 2021 financing. Based on our current plans and projections, we expect this will support our operations into the fourth quarter of 2022.

Collaboration revenue for the fourth quarter of 2020 was $4.2 million compared to no collaboration revenue recognized during the fourth quarter of 2019.

Collaboration revenue for the full year 2020 was $8.8 million compared to no collaboration revenue recognized during the full year 2019.

Research and development expenses for the fourth quarter of 2020 were $16.1 million compared to $12.1 million in the fourth quarter of 2019.

R&D expenses for the full year 2020 were $59 million compared to $71.1 million for the full year 2019.

General and administrative expenses for the fourth quarter of 2020 were $5.9 million as compared to $4.4 million for the fourth quarter of 2019.

G&A expenses for the full year 2020 were $21.4 million compared to $13.1 million for the full year 2019.

Our net loss was $17.7 million for the fourth quarter of 2020 compared to a net loss of $16.1 million for the fourth quarter of 2019.

Net loss for the full year 2020 was $70.8 million compared to $82.7 million for the full year 2019.

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

Thanks, Peter. We have a lot of work ahead as we continue to execute on our plans. We'll report the full losmapimod data from ReDUX4 later in the second quarter.

We'll have data from the Phase I trial with FTX-6058 in healthy volunteers midyear and anticipate initiating a trial in people with sickle cell disease by the end of the year.

And we're planning on bringing forward 2 INDs from the product engine over the course of the next 24 months.

In closing, we have made important progress over the course of 2020, and we expect 2021 to be a year of many significant advancements and clinical updates across our pipeline. At our core, we'll always maintain our commitment to putting the patients first and to innovation that can help us identify advancing, promising therapies that target the root cause of genetically defined diseases.

I'm excited to serve as Fulcrum's new CEO and look forward to keeping you updated on our progress.

Operator, you may now open the line for questions.

(Operator Instructions) Our first question comes from the line of Ted Tenthoff from Piper Sander.

So Robert, I just want to start by saying thank you for all of your hard work friendship. It's such a pleasure and I wish you nothing but good things. And Bryan, sincere congratulations, very well deserved and I'm excited to work with you guys all going forward.

Thanks, Ed.

Yes. I want to get a sense from just basically wrapping up on the COVID study. Is there anything that you kind of learned about that, that has read through to FSHD? Obviously, very, very different conditions, but just want to see if there is any takeaways from discontinuing LOSVID.

I think first and foremost, we would point out, Ted, that there were no safety concerns, and that's obviously very important as we look at the LOSVID trial and we also think about the ongoing trials in FSHD. At this point, what we can communicate is when the data becomes available, we'll certainly plan on sharing that. And to the extent that there are any learnings that would be helpful as it relates to losmapimod for the treatment of COVID-19, those are things that we'll certainly plan on sharing.

Great. And looking forward to the other study readouts this year, too.

Our next question comes from the line of Joseph Schwartz from SVB Leerink.

So my first question on FTX-6058 is what would you like to see in the healthy volunteers on different PD biomarkers in order to give you the sense that you're on track to seeing meaningful changes once you get into sickle cell patients, if you could just give us your thoughts on that?

And also, what -- how -- given that you have seen in preclinically an increase in HbF up to approximately 30%, what's the threshold, the minimum threshold level, of HbF induction do you think that is clinically meaningful and likely to translate into improvements in things like VOCs?

Sure. And I'll turn it over to Chris to answer that.

Yes. Thank you for the question. In the context of the Phase I healthy volunteer study, obviously, we're very much focused on safety, tolerability, pharmacokinetics and target engagement. And as I mentioned, we will be making measures of HBG1 mRNA as well as of reticulocytes. Of course, we know in healthy volunteers during a 14-day study and just given the slow rate of turnover of the red blood cell population that the likelihood of seeing changes in HP1 (sic) [HBG1] mRNA is low, but not 0.

So our primary focus, again, is really on safety and tolerability and a focus on target engagement. And that really helps set the stage for how do we move forward now in select doses to take into the sickle cell patient population for continuing our clinical development.

As we think about the pharmacodynamic biomarkers and the data that we've generated preclinically, we've seen an amazing level of consistency across the different assays, either in vitro or in vivo, and you mentioned that the data that we shared where we see up to 30%. And so as we've talked to KOLs and clinicians about what's a meaningful increase in HbF, many of them point to increases in the upper single-digit range as being really providing clinical benefit. So the data that we've generated to date preclinically certainly demonstrates that we can produce those types of increases in absolute HbF in the models that we've used.

I think the other key point is that we know that other companies have been talking with the FDA and have disclosed they've been focused more around a threshold of 3% absolute increase in HbF. And again, based upon the preclinical data that we've generated with FTX-6058, we see increases well above that.

And so again, we're very excited about the preclinical data. And of course, if that translates into the clinical realm, we believe that we can -- FTX-6058 has the potential to provide great benefit for patients living with sickle cell disease.

That's very helpful. And then maybe one on losmapimod and FSHD. I know that you have a prespecified sensitivity analysis to focus on patients with the highest level of DUX4 gene expression. But have you considered just given the wide -- very wide range of DUX4 gene expression in patient's muscle samples to -- before you look at the data, would it be possible to -- or have you considered whether it makes sense to change from just the reduction in average DUX4 gene expression across all of these samples to maybe something more like an integral analysis that could account for the wide range by looking at like the weighted average of gene expression? It just seems like mathematically, it might do more justice to what the drug is able to push.

Yes. Great question, Joe. I think one of the things, and as we reiterated and as you alluded to, that we were very enthusiastic about is obviously the interim analysis data, which did show this large reduction in DUX4-driven gene expression in the biopsies that had the highest pretreatment levels of DUX4. I think one of the things that we had mentioned at the time is that also were similar to trends that we were seeing in the open-label study that we're running out of a single site.

So as we look towards the total data set, we're going to do another prespecified sensitivity analysis. One of the key learnings that obviously we're observing here is that there is this spectrum of DUX4-driven gene expression. So we'll focus on these biopsies that have the highest pretreatment DUX4 levels.

At the same time, I think we're also obviously very encouraged, we'll certainly look at the totality of the biomarker data. But obviously, this gives us an opportunity as well to look at the structural functional patient-reported outcomes and all of those other measures as well.

And what we spoke to last time as well is, certainly, we believe that all patients have high and lower expressing muscles. So therefore, we don't think the benefit of losmapimod would necessarily be limited to those patients that have these highest pretreatment biopsies, that all patients have the potential to benefit from losmapimod.

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

Let me add my congrats to Robert for your retirement. Thanks for your leadership. And Bryan, look forward to working with you as well and congrats on the promotion.

Two questions for me, one on losmapimod and one on 6058. On the losmapimod side, just wondering if you have -- I guess before we get that readout in second quarter, do you guys have any certain prespecified analyses you will conduct on your secondaries looking at the heterogeneity of the patient population, just wondering what kind of hierarchy or order that we should be mindful of before we get that full totality of the data in the second quarter.

And then on 6058, just looking into the literature, it does seem like the trimethylation and the epigenetics can be sort of more broad-based on the effects beyond HbF induction. So Chris, maybe a question for you is, can you speak to the characterization of the gene expression profile when you do administer this in both the in vitro model as well as the in vivo model to just talk about sort of the off-target effects, if you will.

Yes. Thank you, Dae Gon. And maybe why don't I start on FSHD and then I can turn it over to Chris on 6058. Yes, in terms of -- as we spoke to, one of the things we're obviously enthusiastic about in this data set is being able to show the totality of the data, including, as you alluded to, a number of secondary and exploratory endpoints that we're measuring, such as whole body MRI, a Timed Up and Go, reachable workspace.

And I think one of the things that I would highlight is, one, obviously, there's a significant amount of unmet needs that exist as we talk about no approved therapies, and unfortunately, nothing else in the clinic. In addition to the efficacy measures, we're still going to be very focused on safety and tolerability as this is a chronic disease.

But without pointing to any particular secondary exploratory measures, one of the things that I would point out is as we've spoken about in the past, we have done a number of preparatory studies where we've really established these endpoints as endpoints that are not only relevant towards this trial, but most importantly, are relevant towards the patients. So these are for people living with FSHD. We believe we're measuring a lot of the measures that are going to be very important to them, such as the ability to lift their arms, the ability to get out of bed and consistent with what we're hearing from them.

So certainly, as we look towards the secondary and exploratory, while we didn't power the study to achieve statistical significance and then if we are able to identify trends of benefit, we would view that I think highly encouraging.

Sure. And with respect to FTX-6058 and its profile, if you will, first of all, the nonclinical safety package indicated that we had an acceptable window that warranted moving into the clinic. We've also done extensive profiling of the molecule, both within the histone (inaudible) family and across diverse target families as well. And again, FTX-6058 demonstrated a very clean profile in that regard.

The other thing that I'll point to is that we've done broader gene expression analysis in multiple different cell types, looking at differentiated neurons, cardiomyocytes, myotubes. And really, we see very selective effects on gene expression in the CD34 cells (inaudible) up-regulation of fetal hemoglobin.

So again, to reiterate, FTX-6058 has a very acceptable therapeutic index. We've now taken into the clinic, we'll get a couple more data in [convenience] with respect to safety and tolerability. And we also continue to characterize the mechanism of action. And then we'll try to connect this up, if you will, between (inaudible) fetal hemoglobin gene expression.

(Operator Instructions) Our next question comes from the line of Matthew Harrison from Morgan Stanley.

This is Kostas on for Matthew. I would like to add my congratulations to Robert for his retirement, and Bryan, on your new role. Two questions from us on FSHD. One is on the prespecified sensitivity analysis. I was wondering whether this type of analysis is powered to detect a statistically significant improvement versus placebo? You mentioned that many patients, if not all, have both high and low DUX4 levels in the muscles, but I was wondering whether you have made sure somehow that this analysis will be powered sufficiently?

Yes. So we did not power the prespecified sensitivity analysis for statistical significance. But one of the things that we view as being very relevant is, again, and as we mentioned at the time of the interim analysis, that this was -- this observation was based on learnings from our single-site, open-label study. And we did do this prespecified sensitivity analysis prior to looking at our interim analysis data, and we plan on recapitulating that for the full data set. And again, if we do observe these trends that we saw in the interim analysis, we think that, that has a potential to be very beneficial for patients as it is affecting the root cause of the disease.

And one quick follow-up. Have you engaged with the FDA to discuss what they would potentially want to see in the Phase IIb data? Or you are planning to do that after you see the data?

Yes. We certainly have had a constructive dialogue with the FDA to date. We'd also point out we were very pleased that there was a patient-focused drug development day that took place last year where the FDA was able to hear directly from patients, caregivers and just really understand the disease burden from those living with FSHD.

So we think on the other side of this Phase IIb data, that will certainly represent a good time for us to continue our engagement with the FDA and determine our regulatory path forward.

There are no further questions at this time, I'll be handing the call over back to Bryan Stuart. Please continue.

Thank you, and thank you for -- all for joining us today. We appreciate your support of Fulcrum. Have a great day.

Ladies and gentlemen, that does conclude our conference for today. Thank you all for joining. You may all disconnect. Goodbye.