Q4 2023 Fulcrum Therapeutics Inc Earnings Call

February 27, 2024

Okay.

Good morning, and welcome to Fulcrum Therapeutics fourth quarter and full year 2023 financial results and business update conference call. Currently all participants are in a listen only mode. This call is being webcast live and can be accessed on the investors section of Paul Krump website at Www Dot Bocom, TX dot com and its being run.

Operator: Good morning and welcome to Fulcrum Therapeutics' fourth quarter and full year 2023 financial results and business update conference. Currently, all participants are in a listen-only mode. This call is being webcast live and can be accessed on the investor section of Fulcrum's website at www.FulcrumTX.com.

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Please be reminded that remarks made during this call may contain forward looking statements within the meaning of the private security Litigation Reform Act of 1995.

Operator: Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Security Litigation Reform Act of 1995. These may include statements about the company's future expectations, plans, Clinical Development Timelines, and Financial Projections, while these four were looking at statements that present Fulcrum's view of today. This should not be relied upon as presenting the company's views in the future.

These may include statements about the company's future expectations plans.

Clinical development timelines and financial projections.

These forward looking statements.

That's 12 quarters view of today, they should not be relied upon as presenting the companys views in the future Poker may update these statements in the future, but it's not taking on an obligation to do so please refer to book was most recent filing with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company's business.

Operator: Fulcrum may update these statements in the future, but it's not taking on an obligation. Please refer to Fulcrum's most recent filing with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the company. Leading the call today will be Alex Sapir, CEO and President of Fulcrum. Joining Alex on the call are Alan Musso, Chief Financial Officer, and Dr. Ian Frazier, Interim Chief Medical Officer, after providing updates on our key programs. There will be a brief Q&A, during which Alex, Alan, and Ian will be available to answer your questions. With that said, it is my pleasure to turn the call over to Alex. That's great!

Leading the call today will be Alex Sapir, CEO and president of a fulcrum.

Alex on the call are Alan Musso, Chief Financial Officer, and Dr. Ian Frazer interim Chief Medical officer, after providing updates on our key programs.

There will be a brief Q&A in which Alex Allen and in will be available to answer your questions with that it's my pleasure to turn the call over to Alex.

That's great. Thanks, Valerie and thanks to all of you for joining us today two.

Alex Sapir: Thanks, Valerie, and thanks to all of you for joining us today. 2023 was a year in which we both completed enrollment in our Phase 3 REACH trial for losmathomod for fascioscapulohumeral muscular dystrophy, or FSHD for short, and resolved the clinical hold for posiridir, which allowed us to resume clinical testing in patients with sickle cell disease. In the fourth quarter, we continue to drive forward our two key clinical programs and advance our preclinical pipeline. And with our cash runway that extends into 2026, I do believe that we are well positioned to execute our corporate objectives and deliver on key milestones in 2024 and beyond.

2023 was a year in which we completed enrollment in our phase III reach trial for those mathematics for passengers scapulohumeral muscular dystrophy or HD for sure and resolve the clinical hold for <unk>, which allowed us to resume clinical testing in patients with sickle cell disease.

In the fourth quarter, we continued to drive forward, our two key clinical programs and advance our preclinical pipeline and with our cash runway that extends into 2026 I do believe that we are well positioned to execute our corporate objectives and deliver on key milestones in 2024 and beyond.

So at this point, let me go a bit deeper and elaborate on the progress we've made toward our goal of delivering transformative therapies to improve the lives of patients with rare genetic diseases.

Alex Sapir: So at this point, let me go a bit deeper and elaborate on the progress we've made toward our goal of delivering transformative therapies to improve the lives of patients with rare genetic disorders. Let's start with our most advanced program, Losmaphamide, which is an oral small molecule P38 alpha beta MAC kinase inhibitor currently in phase three development for the treatment of FSHD. Now FSHD is a rare form of muscular dystrophy with an estimated US patient population of 30,000. It 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.

Let's start with our most advanced program <unk>, which is an oral small molecule <unk> 38 Alpha beta map kinase inhibitor currently in phase III development for the treatment of Fsh date now efforts HD is a rare form of muscular dystrophy with an estimated U S prevalent patient population of 30000.

Fsh D 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. As a result, many patients are unable to perform daily life activities that you and I take for granted.

Alex Sapir: As a result, many patients are unable to perform daily life activities that you and I take for granted, such as reaching for a cup of coffee, reaching for a cup in the kitchen cabinet, brushing your teeth, feeding yourself, even practicing good hygiene, and about 20% of patients ultimately become wheelchair-bound. Despite the high-end medical need, there are currently no approved treatment options for these patients. So in our quest to bring hope for these patients, in September of last year, we completed enrollment in our global phase three trial for Los Matamod with a total of 260 patients enrolled in the trial. The trial initiated in June 2022, and 15 months later, we had surpassed our enrollment expectations, which we believe is a real testament to the high unmet need for this rare disease.

Is reaching for a cup of coffee, reaching for a cup in the kitchen cabinet brushing your teeth feeding yourself, even practicing good hygiene and about 20% of patients ultimately become wheelchair bound.

Despite the high unmet need there are currently no approved treatment options for these patients.

So in our quest to bring hope for these patients in September of last year, we completed enrollment in our global Phase III trial for those map with a total of 260 patients enrolled in the trial.

The trial initiated in June 2022, and 15 months later, we had surpassed our enrollment expectations, which we believe is a real testament to the high unmet need for this rare disease.

Alex Sapir: We are on track to report top-line data in the fourth quarter of 2024, which will bring us one step closer to delivering the first ever FDA-approved therapy for FSHP. So just a quick reminder of some of the details around the phase three study, which we call REACH. REACH is a 48-week trial intended to be registration enabling both in the U.S. and in ex-U.S. geography. The primary endpoint for REACH is a change from baseline in the Relative Surface Area, or RSA, which is a quantitative assessment of reachable worksites. RSA is an objective measure of upper extremity range of motion and muscle function that specifically evaluates Excuse me, that specifically evaluates shoulder and arm mobility using 3D motion sensor technology.

We are on track to report topline data in the fourth quarter of 2024, which will bring us one step closer to delivering the first ever FDA approved therapy for FSA HD patients.

So just a quick reminder, some of the details around the phase III study, which we call reach reaches a 48 week.

Excuse me reaches a 48 week trial.

Intended to be registration, enabling both in the U S and ex U S geographies. The primary endpoint for reach is a change from baseline in the relative surface area or RSA, which is a quantitative assessment of reachable workspace RSA as an objective.

Measure of upper extremity range of motion and muscle function that specifically evaluates.

Excuse me.

That specifically evaluates shoulder and our mobility using three D motion sensor technology, and our phase II study <unk> demonstrated a 10% change in the RSA score relative to placebo at 48 weeks and based on interactions with FDA. We are currently.

Alex Sapir: In our Phase 2 study, Los Mapa Mod demonstrated a 10% change in the RSA score relative to placebo at 48 weeks. Based on interactions with FDA, we are currently assessing the extent to which a change in the RSA score is considered 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 that will help inform our thinking on our payer strategy as we begin preparing for a commercial launch here in the US. Now, turning to Posiridir, our oral HPF inducer for the potential treatment of patients with sick Historically, the standard of treatment for sickle cell disease has involved blood transfusions, pain medications, and hydroxyurea, focusing primarily on symptom relief.

Setting the extent to which a change in the RSA scored is considered meaningful to patients. Additionally, key secondary endpoints include muscle fat infiltration, our MSI, which is an important marker of disease pathology measured by whole body MRI shoulder diner monetary as well as.

Self reported quality of life measures that will help inform our thinking on our payer strategy as we begin preparing for our commercial launch here in the U S.

Now turning to <unk>, our oral hbf inducer for the potential treatment of patients with sickle cell disease or <unk> for short sickle cell is a lifelong inherited blood disorder that severely impact quality of life for approximately 100000 people in the U S.

And approximately $4 4 million people worldwide historically, the standard of treatment for sickle cell disease has involved blood transfusions pain medications and hydroxyurea focusing primarily on symptom relief.

Alex Sapir: 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 safe and accessible therapeutic options that are broadly protective of sickle cell symptomatology. As a first-in-class, oral, small-molecule HBF-inducer, we believe Poseridur has the potential to address a critical unmet need. Now, just as a quick reminder, in August of 2023, the FDA lifted the clinical hold for posterior dermis, and I think it's also really important to note that there were no changes either in the protocol-defined dose escalation scheme or the three-month treatment duration. Clinical trial sites have now been activated, and others have been selected and are going through the necessary steps for site activation in order to be ready for patient recruitment for the Phase 1b study we call Pioneer.

And while exciting scientific progress has enabled the advancement and more recently the approval of gene editing in therapeutic approaches. We believe there remains a high unmet need for safe and accessible therapeutic options that are broadly protective of sickle cell symptomatology.

As a first in class oral small molecule Hbf inducer, we believe <unk> has the potential to address a critical unmet need for patients now.

Now just as a quick reminder, in August of 2023, the FDA lifted the clinical hold for <unk>, there and I think it's also really important to note that there were no changes either in the protocol defined dose escalation scheme or the three month treatment duration.

Clinical trial sites have now been activated and others have been selected and are going through the necessary steps for site activation in order to be ready for patient recruitment for the phase <unk> study we call pioneer.

Alex Sapir: Based on the revised inclusion-exclusion criteria, we will be enrolling patients with high disease severity. Cohort 3 of the Pioneer Study will evaluate posterior at the 12 milligram once daily dose, followed by cohort 4 at the 20 milligram once daily dose. Both cohorts are expected to enroll approximately 10 patients, and we look forward to providing specific guidance on readout for the 12 milligram and 20 milligram cohorts as we have additional sites activated and a good basis to project enrollment trajectory. We're looking forward to building on the encouraging clinical data obtained prior to the clinical hold, which demonstrated that post-serivir 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 Procider as an oral HPF inducer has the potential to provide a differentiated therapeutic option for people living with sickle cell disease.

Based on the revised inclusion exclusion criteria, we will be enrolling patients with high disease disease severity.

Cohort three of the pioneer study will evaluate <unk> here at the 12 milligram once daily dose followed by cohort four at the 20 milligram once daily dose both cohorts are expected to enroll approximately 10 patients each and we look forward to providing specific guidance on readout of the 12 milligram.

And 20 milligram cohort as we have additional sites activated and a good basis to project enrollment trajectory.

We're looking forward to building on the encouraging clinical data obtained prior to the clinical hold which demonstrated that <unk> 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.

A 10 percentage point increase in hbf from baseline.

Or total hbf of approximately 25%.

We believe that <unk> as an oral hbf inducer has the potential to provide a differentiated therapeutic option for people living with sickle cell disease addressing the significant unmet need in the sickle cell community remains a key priority for us and we are excited to build on this momentum in the years.

Head.

So that's the clinical update for the financial update let me turn it over to Alan Musso, Our Chief Financial Officer, who will walk you through some of the numbers Alan over to you.

Thanks, Alex.

I'll now go over our results for the fourth quarter and full year ended December 31, 2023, beginning with the results for the quarter.

Collaboration revenue was <unk> 9 million for the fourth quarter of 2023 compared to <unk> 7 million for the same period in 2022.

Alan Musso: Addressing the significant unmet need in the sickle cell community remains a key priority for us, and we are excited to build on this momentum in the years ahead. For the financial update, I will turn it over to Alan Musso, our Chief Financial Officer, who will walk you through some of the numbers. Alan, over to you. Thanks Alex, I'll now go over our results for the fourth quarter and full year ended December 31st, 2023, beginning with the results for the quarter. Collaboration revenue was $0.9 million for the fourth quarter of 2023, compared to $0.7 million for the same period in 2022. Our research and development expenses were $19 million for the fourth quarter of 2023, compared to $18.6 million for the same period in 2022; the increase of 0.4 million was primarily due to higher personnel costs. General administrative expenses were $9.9 million for the fourth quarter of 2023, compared to $10.1 million for the same period in 2022.

Our research and development expenses were $19 million for the fourth quarter of 2023 compared to $18 6 million for the same period in 2022.

The increase of <unk> 4 million was primarily due to higher personnel costs.

General and administrative expenses were $9 9 million for the fourth quarter of 2023 compared to $10 1 million for the same period in 2022.

The decrease of <unk> 2 million was primarily due to lower professional service costs.

And for the fourth quarter of 2023 full <unk> reported a net loss of $24 8 million.

Impaired to $26 1 million for the same period in 2022.

I will now review the results for the year ended December 31 2023.

Collaboration revenue was $2 8 million for the year ended December 31, 2023, compared to $6 3 million for the same period in 2022.

The lower collaboration revenue during 2023 was attributable to the completion of activities under our collaboration agreement with Accelerant, which terminated in October 2022.

And due to a decrease in revenues under our collaboration agreement with myocardial as we completed our research services during the fourth quarter of 2023.

Our research and development expenses were $71 8 million for the year ended December 31, 2023, compared to $76 8 million in 2022.

The decrease in 2023 was primarily attributable to a $5 million milestone obligation incurred upon the initiation of the <unk> clinical trial in the second quarter of 2022 under our license agreement with Glaxosmithkline.

Alan Musso: The decrease of $0.2 million was primarily due to lower professional service costs. Additionally, for the fourth quarter of 2023, Fulcrum reported a net loss of $24.8 million, compared to $26.1 million for the same period in 2022. I'll now review the results for the year ended December 31st, 2023. Collaboration revenue was $2.8 million for the year ended December 31, 2023, compared to $6.3 million for the same period in 2022. The lower collaboration revenue during 2023 was attributable to the completion of activities under our collaboration agreement with Acceleron, which terminated in October 2022, and due to a decrease in revenues under our collaboration agreement with Myocardia as we completed our research services during the fourth quarter of 2023. Our research and development expenses were $71.8 million for the year ended December 31, 2023, compared to $76.8 million in 2022. The decrease in 2023 was primarily attributable to a $5 million milestone obligation incurred upon the initiation of the REACH clinical trial in the second quarter of 2022 under our license agreement with GlaxoSmithKline. Our general and administrative expenses were $41.7 million for each of the years ended December 31, 2023, and 2022.

General and administrative expenses were $41 7 million for each of the years ended December 31, 2023 and 2022.

The net loss was $97 3 million for the year ended December 31, 2023, compared to $109 9 million in 2022.

And now turning to the balance sheet. We ended 2023 with cash cash equivalents in marketable securities of $236 2 million compared to $202 9 million as of December 31, 2022.

This increase in our cash position is primarily due to net proceeds from our January 2023rd 2023 equity offering of $117 $3 million partially.

Offset by our net cash used in operating activities in 2023.

During the fourth quarter of 2023, our cash burn was $20 9 million.

We continue to operate from a strong financial position with a cash runway into 2026.

With that let me turn the call back over to Alex great. Thanks, So much Alan so as all of you can see we are well positioned for a very exciting 2024 and are encouraged by the progress across our two clinical programs <unk>, which has the potential for which has first in market potential for patients with <unk>.

<unk> HD and <unk>, which has best in class potential for patients living with sickle cell disease. So at this point Valerie Let's go ahead and open it up for questions.

Thank you.

Ladies and gentlemen, if you'd like to ask a question. Please press star one on your touch tone telephone again, if you'd like to ask a question. Please press star one one.

One moment for your first question.

Our first question comes from the line of Matthew Biegler.

Alan Musso: The net loss was $97.3 million for the year ended December 31, 2023, compared to $109.9 million in 2022. And now, turning to the balance sheet, we ended 2023 with cash, cash equivalent to marketable securities of $236.2 million, compared to $202.9 million as of December 31st, 2022. This increase in our cash position is primarily due to net proceeds from our January 2023 equity offering of $117.3 million, partially offset by our net cash used in operating activities in 2023. And during the fourth quarter of 2023, our cash burn was $20.9 million.

Yes.

Of Oppenheimer. Your line is open.

Hey, good morning, guys.

I just wanted to maybe tack on something you said about on the regulatory side of that coin here for a little snap on can you just walk us through your interactions with the FDA and where you are with discussions on the clinical benefit for reachable workspace and I guess, what youll need to show in reach to make them happy.

Yes.

So much Matt for the question, let me let me just say a couple of things that I will turn it over two years ago in a bit more detail. So.

The reach study is a very well powered study with the 260 patients that we had enrolled we've got a 96.

<unk> powering on that study and we believe.

That study has the potential to be registration, enabling based on our interactions to date with FDA, but I think more specifically to answer your question around reachable workspace, let me turn that one over to Ian.

Alan Musso: We continue to operate from a strong financial position with a cash runway into 2026. And with that, I will turn the call back over to Alan. Great. Thanks so much, Alan. So, as all of you can see, we are well positioned for a very exciting 2024 and are encouraged by the progress across our two clinical programs, Los Maphimod, which has the potential for being the first in market for patients with MSHD, and Procedure, which has best in class potential for patients living with sickle cell. So at this point, Valerie, let's go ahead and open it up for questions. Thank you. Ladies and gentlemen, if you'd like to ask a question, please press star 1-1 on your touchtone telephone. Again, if you'd like to ask a question, please press star 1-1. One moment for our first question. Our first question comes from the line of Matthew Biegler, of Oppenheimer, Utah. Hey, good morning, guys.

Thanks, Alex and thanks, Matt.

So obviously there are no drugs approved for <unk> and so there is no precedent in the regulatory sphere for endpoints.

But we have had a number of productive and indeed ongoing discussions with FDA involving both the review division, which is in neurology as well as the cooler division and we're executing on our plan that we've agreed upon with them.

We believe we will establish the clinical meaningfulness of the reachable workspace.

Specifically there are couple of components to that.

The first is that we are generating additional data from observational studies and Fsh D. So this is not involving any treatment with less map a month.

But observing these patients as requested by the agency to identify what is taught them. The most appropriate measure of change in upper extremity function.

And this is achieved through evaluating items on patient reported outcomes. The next step will be to apply those back to the reach data themselves in order to derive what is the clinically meaningful threshold for each will look space.

And then secondly, we are conducting a number of exit interviews.

Patients that have gone through the reach study and this will help to enhance our understanding as well as fda's understanding of what the changes are ws means for them.

Matthew Biegler: I just wanted to maybe touch on something you said about on the regulatory side of the coin here for Los Matamob. Can you just walk us through your interactions with the FDA and where you are with discussions on the clinical benefit of reachable workspace? And I guess what you'll need to show in reach to make them happy.

Our expectation is that at the very latest these data will be available at the time of NDA submission and of course, ultimately FDA will.

Ultimately make the final determination as to what is considered cleaning clinically meaningful considering the totality of evidence.

Alex Sapir: Thanks. Yeah, thanks so much, Matt, for the question. Let me just say a couple of things, and I'll turn it over to Ian to go in a bit more detail. So the REACH study is a very well-powered study. With the 260 patients that we had enrolled, we've got a 96% powering on that study, and we believe that that study has the potential to be registration-enabling based on our interaction to date with FDA. But more specifically, to answer your question around reachable workspace, let me turn that one over to Ian. Yeah, thanks, Alex. And thanks, Matt. So obviously, there are no drugs approved for FSHD. And so there's no precedent in the regulatory sphere for an endpoint.

Okay, Okay, so effectively.

We can say that there needs to be a little bit more validation work done on the <unk> assay is that a fair characterization.

Well I think that the.

In addition work on the instrument itself in terms of the test retest capabilities. The training process that goes into it the provision.

The technical pieces of it all of that has been done.

And he's really quite satisfactory I think it's the last remaining pieces around the clinical meaningfulness.

What is considered minimally clinically significant change.

Understood understood. Thanks, a lot.

Yes, Thanks Pat.

Thank you one moment please.

Our next question comes from the line of Karen Johnson of Goldman Sachs. Your line is open.

Good morning. This is Craig on for Karen I guess, one for us how familiar our physicians with reachable workspace endpoint and can you describe some of your physician education efforts that Youre planning.

Ian Frazier: However, we have had a number of productive and indeed ongoing discussions with FDA, involving both the review division, which is in neurology, as well as the co-advisory group. And we're executing on a plan that we've agreed upon with them that we believe will establish the clinical meaningfulness of the reachable work. Specifically, there are a couple of components to that. The first is that we are generating additional data from observational studies in FSHD, so this is not involving any treatment with PLUSmap, but observing these patients as requested by the agency to identify what is for them the most appropriate measure in the upper extremity. And this is achieved through evaluating items on patient reported outcomes. The next step will be to apply those back to the REACH data themselves in order to derive what is the clinically meaningful threshold for REACH-able work.

Once you have the data yet.

Yes, great Great question, Greg Thanks for asking that I'll start and then ill.

I'll turn it over to Ian if he has any others.

I would say that reachable workspace is not a standard.

Instrument that neuromuscular specialist currently use when evaluating.

There are patients with Sshd. It is somewhat of a novel instrument and so.

In terms of the answer to your question about what we're doing from an educational standpoint to really train them on on what reachable workspace is and what a change in reach Orange base actually means we're doing a number of programs throughout the year. We've got a program in two weeks at the at the MDA.

So CME program in which we're actually spending a lot of time with the physicians that have signed up for that program like walk through what is reachable workspace what is.

Ian Frazier: And secondly, we are conducting a number of exit interviews with patients that have gone through the REACH study, and this will help to enhance our understanding, as well as FDA's understanding, of what a change in RWS means for them. And our expectation is that, at the very latest, these data would all be available at the time of NDA submission. And of course, FDA will ultimately make the final determination as to what is considered clinically meaningful, considering the totality of it. Okay, okay. So, effectively... we can say that there needs to be a little bit more validation work done on the RWS assay. Is that a fair assessment?

What is a normal baseline for patients.

What does it change and reachable workspace actually mean.

The clinical meaningfulness of that change going back to the first question that Matt asked will ultimately be sort of determined once we have the reach data, but theres a number of activities.

We're doing this year and in 2025 to really educate physicians on reachable workspace, so that when the data thats come out they've got some they've got some context.

For those for those results.

Ian Frazier: Well, I think that the validation work on the instrument itself, in terms of the test, retest capabilities, the training process that goes into it, the provision of the technical pieces of it, all of that has been done and is really quite satisfactory. I think it's the last remaining piece around clinical meaningfulness and what is considered minimally clinically significant.

Anything you would add.

No the only thing I would add perhaps obviously all of the investigators.

Clinical studies, both the redux for phase II as well as reach in phase III are very well familiar with it now because of their participation in this study.

And they obviously speak to their colleagues as well. So I think there is some level of dissemination through the clinical trials themselves and then additionally, as Alex said, we have some CME programs.

Designed to to inform and educate physicians around that.

Got it thank you very much alright, thanks, Greg.

Matthew Biegler: Thanks, Matt. Thank you. One moment, please.

Thank you one moment please.

Our next question comes from the line of Joseph Joseph Schwartz of Leerink Partners. Your line is open.

Corinne Johnson: Our next question comes from the line of Corinne Johnson of Goldman Sachs. Your line is open. Good morning, this is Craig on behalf of Corinne. I guess one question for us: how familiar are physicians with the reachable workspace endpoint? And can you describe some of your physician education efforts that you're planning once you have the data? Yeah, great, great question, Craig.

Hi, Good morning, Andrea Park dialing in for Joe. Thank you for taking our question.

The first one is on the <unk> given reachable workspace isn't a standard instrument, how Ken physicians measure benefit in the real world. If they don't have access to the tools are there other metrics that could track with reachable workspace or.

Alex Sapir: And thanks. Thanks for asking that. I'll start, and then I'll certainly turn it over to Ian if he has any others.

Clinically meaningful benefit and I have a follow up answer okay. That's great, Yes, I think.

Thanks, So much for the question I think to answer that let me turn that over to Ian <unk>, Our Chief Medical Officer.

Alex Sapir: So I would say that reachable workspaces is not a standard instrument that neuromuscular specialists currently use when evaluating their patients with FSHD. It is somewhat of a novel instrument. And so, in terms of the answer to your question about what we're doing from an educational standpoint, really train them on what Reachable Workspace is and what a change in Reachable Workspace actually means. We're doing a number of programs throughout the year. We've got a program in two weeks at the MDA conference, a CME program, in which we're actually spending a lot of time with the physicians that have signed up for that program, really walking through, you know, what is Reachable Workspace? What is a normal baseline for patients? And, you know, what does a change in Reachable Workspace actually mean?

I think the.

Advantage of reachable workspace is that it provides a quantitative assessment that the treating physicians.

Typically using a more qualitative sense to understand how their patients are doing so allows us to put some numbers around those qualitative terms and since there haven't been any therapies that alter the course of the disease available to date Theres really been no no need to do that all the time.

Symptomatic too.

To this point, so it's really adding a little bit of.

Quantitative measures around the more quantitative sense in the clinic I think.

Courtney piece.

Pieces to point out here.

Number one that the reachable workspace has been shown previously prior to <unk> involvement.

Sshd patients exhibit a decline in their reachable workspace overtime.

In a small natural history study that was published several years ago, and that's consistent with clinical observations around.

Ian Frazier: The clinical meaningfulness of that change, going back to the first question that Matt asked, will ultimately be sort of determined once we have the Reach data. But there's a number of activities that we're doing this year and in 2025 to really educate physicians on Reachable Workspace so that when the data does come out, they've got some context for those results. Ian, anything you would add?

Measuring muscle strength by more traditional measures like Dynamometry for example.

We know that.

In addition, the reachable workspace correlates with instruments patient reported outcome instruments, such as the upper extremity.

Questionnaire and that work has been published and we've also shown from our phase two data.

The correlation between the reachable workspace in the shoulder.

Dynamometry and its the shoulder abductor dynamometry, because obviously reachable workspace is focused on the upper extremity.

Ian Frazier: No, the only thing I would add, perhaps, obviously, all of the investigators in our clinical studies, both the Redux IV Phase II as well as REACH and Phase III, are very well familiar with it now because of their studies, and they obviously speak to their colleagues as well. So I think there's some level of dissemination through the clinical trials themselves. And then additionally, as Alex said, we have some CME programs designed to inform and educate physicians around. Got it.

In the shoulder abductors major muscle component of that.

There are correlations that have been observed in the reachable workspace and as I say, probably most importantly, it's that documentation of the decline experienced by these patients and Thats. What the patients report is this this inevitable decline over time and that's something that they are treating physicians.

As those who report until there is consistency is diminish it from that respect as well.

Okay got it. Thank you and then my second question is on <unk> I know that baseline character looks like Hbf I can play a role and how much HPLC can achieve so would it be possible to provide patient baseline characteristics ahead.

Craig: Thank you very much. All right. Thanks, Craig.

Joseph Patrick Schwartz: Thank you. Our next question comes from the line of Joseph Schwartz of Lerink Partners. Your line: Hi, good morning. I'm Doreen Park dialing in for Joe. Thank you for taking our questions. The first one is on ModemAppleMod.

Update that we can better contextualize and appreciate the data on that I really thank you very much.

Okay.

Yes. This is Ian again, so maybe I can just add that.

We do have in our.

Corporate presentation on the web the data from the initial 16 patients that were enrolled in the study that includes.

Doreen Park: Given reachable workspace isn't a standard instrument, how can physicians measure benefits in the real world if they don't have access to the tools? You know, are there other metrics that could track reachable workspace or, you know, clinically meaningful benefits? And I have a follow-up. Okay, that's great.

A lot of their of their hbf and it includes the baseline.

It'll hemoglobin that they went in with the comment that I would make there is that there was a range of baseline Hbf and I think speaking from memory. It was about 3% at the low end and just under 20% at the high end and we know that in the sickle cell patient population in general it's around.

Alex Sapir: Yeah, I think, thanks so much for the question. I think to answer that, I'll turn that over to Ian, our Chief Medical Officer. Yeah, I think the advantage of the reachable workspace is that it provides quantitative assessments that treating physicians typically use in a more qualitative sense to understand how their patients are doing. So it allows us to put some numbers around those qualitative terms. And since there haven't been any therapies that alter the course of the disease available to date, there's really been no need to do that.

5% to 10%.

The average baseline so we've seen.

To date, a pretty widespread across baseline hbf and while we don't have three months data in all of those patients.

The initial slope of the increase in the Hbf.

Cross all of those baselines look pretty similar so it didn't appear that that those that were starting out.

Hi, I had a lower response or vice versa.

I think we're.

A critical piece of this is where do the patients end up with.

After three months.

It looks like from the six milligram data that we have which is the highest dose that's gone out to three months may not even be plateauing fully at the three months Mark and so that will obviously need to be evaluated further as we move through the process.

Ian Frazier: All the therapy is simply this point. So it's really adding a little bit of quantitative measures around the more qualitative sense in the clinic. I think the important things to point out here are, number one, that reachable workspace has been shown previously, prior to Fulcrum's involvement, that FSHD patients exhibit a decline in their reachable workspace over time. That was in a small natural history study that was published several years ago.

We will once we have the data.

Around the fetal hemoglobin, we will reveal a lowest baseline hbf as well because it is an important component.

Thank you.

One moment please.

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

Hey, good morning, Thanks for taking our questions and congrats on all the progress.

Three questions. If I may one Alex have you guys actually started some pre commercialization work with the payers specifically I think there was quite a bit of questions around physicians and their comfort as well as the regulators, but how does payers feel about the ratio of workspace and the magnitude you showed so far.

Ian Frazier: And that's consistent with clinical observations around measuring muscle strength by more traditional measures like dynamometry. For it, we know that, in addition, the Reachable Workspace correlates with patient-reported outcome instruments, such as the NeuroQOL Upper Extremity Questionnaire, and that work has been published. And we've also shown from our Phase II data a correlation between the Reachable Workspace and the shoulder-abducted dynamometry. And it's the shoulder-abducted dynamometry because, obviously, Reachable Workspace is focused on the upper extremity, and the shoulder abductor is a major muscle component of that.

Sticking with the snap of Mod.

10% change you detected in redox four I was wondering if you could go into a little bit more on the test retest variability I mentioned to an earlier question.

Any other evidence you can point to that kind of gives us some comfort around your phase III reach powering and then I've got a follow up on the <unk> story.

Okay, Great Yeah, why don't I.

Take question, one and then I'll turn question number two over two and then we'll come back to you for question number three thanks, Dae Gon I think really a really good question. So yes, we have done some some initial payer work.

In the U S as well as ex U S.

Ian Frazier: So there are correlations that have been observed in the reachable workspace. And, as I say, probably most importantly, it's that documentation of the decline experienced by these patients. And that's what the patients report, this inevitable decline over time. And that's something that their treating physicians and caregivers also report. And so there's consistency in the measure from that perspective. Okay, I got it. Thank you. And then my second question is on posterior deer.

I don't remember the specifics of the study that we did but I think it was around 10 payers that we had spoken to and shared with them the target product profile and shared with some of the results of the <unk> study and they obviously were well aware that there was no available treatment options for these for these patients.

The objective of the work that we did was really to try to understand their thoughts around pricing and what we heard loud and clear from those from those payers is that they would expect that when this drug gets approved and comes to market that it would.

Ian Frazier: I know that baseline characteristics like HPF can play a role in how much HPF you can achieve. So would it be possible to provide patient baseline characteristics ahead of your next update so we can better contextualize and appreciate the data when they're released? Thank you very much. Yeah, yeah. This is Ian again.

Command rare disease type pricing such as in the.

Hundreds of thousands of dollars I think probably a really good comp to look at would be the.

The pricing that Biogen has with Sky Claris, So it's Scott.

<unk> targets <unk> ataxia.

Again, neuromuscular disease, not a lot of mortality, but but.

Hi, morbidity, so very very similar to what we see with Fsh D. The biggest difference between FAA, an fsh D. As is the prevalent population FSA to use about four times the size. So the payer work that we've done, albeit somewhat limited to date has really been around has really been around price.

Ian Frazier: So maybe I can just add that we do have, in our corporate presentation on the web, data from the initial 16 patients that were enrolled in the study that includes a plot of their HBF, and it includes the baseline fetal hemoglobin that they went in with. The comment that I would make there is that there was a range of baseline HBFs, and I think, speaking from memory, it was about 3% at the low end and just under 20% at the high end. And we know that in the sickle cell patient population, in general, it's around 5 to 10%, the average baseline. So we've seen, to date, pretty widespread increases in HBF across all of those baselines, and while we don't have three months of data in all of those patients, certainly, the initial slope of the increase in HBF across all of those baselines looks pretty similar. So it didn't appear that those that were starting out higher had a lower response or vice versa.

<unk> and the feedback that we've heard from payers that they would expect this as the first entrant in a rare disease to be priced in the <unk>.

<unk> of thousands of dollars similar to other rare disease therapies, I will say dig out and the other thing that we're also doing.

This hasnt been confirmed with payers I think our instinct is that payers will require a confirmed genetic test of FX HD before approving the product and as of right now because there are no treatment options for patients with <unk> HD.

Very little genetic testing is done in of the genetic testing is done it's clunky in that it takes a lot of time to get these genetic test bag, they're expensive, sometimes the insurance company will pay for it sometimes they won't so that's an area that we're going to spend a lot of time on in 2024 and 2025 to really streamline.

Ian Frazier: I think the critical piece of this is, where do the patients end up? After three months, it looks like from the six milligram data that we have, which is the highest dose that's gone out to three months, may not even be plateauing fully at the three months mark. And so that'll obviously need to be evaluated further as we move through the process. But we will, once we have the data around fetal hemoglobin, reveal those baseline HPI. Thank you. One moment, please.

And that that process of genetic testing because right now it is it is not as efficient as we feel like it needs to be at the time that we launch given our.

Instinctive assumption that payers will require confirm genetic testing before agreeing to.

Dagon Ha: Our next question comes from the line of Dagon Ha of Stiefel, Yolanda. Thank you. Thank you.

Approve the drug.

So on the second question and maybe I'll turn that one over to you yes sure.

Briefly just to recap redox four reachable workspace data as you indicated showed that 10 percentage.

Dagon Ha: Thanks for taking our questions and congrats on all the progress. Three questions, if I may. One, Alex, have you guys actually started some pre-commercialization work with payers specifically? I think there was quite a bit of questions around physicians and their comfort as well as the regulators, but how do payers feel about the reachable workspace and the magnitude you showed so far? Second, sticking with Losmapimod, the 10% change you detected in Redux 4, I was wondering if you could go into a little bit more on the test retest variability you mentioned in an earlier question.

Percentage points.

Treatment effect difference.

That was derived from repeated measures model that was used to assess that endpoint and that is the same model that will be used for the reach study and just to recap that includes evaluations at baseline week four week 12, 24, 36% and 48. So it's not just a single comparison.

Week 48 to the baseline value. So it incorporates all of those measures over time.

The treatment effect of difference on an RSA unit score was about.

0.05 with a baseline.

Reachable workspace score in those patients of five four to five <unk> III. That's five quadrants. So the theoretical Max that would be one two times.

Just to contextualize that so those are those with the data points that we are used to power the phase III reached study.

Alex Sapir: Any other evidence you can point to that kind of gives us some comfort around your phase three reach powering? And then I'm going to follow up on that with the Sierra Deer story. Okay, great. Yeah, why don't I take question one, and then I'll turn question number two over to Ann, and then we'll come back to you for question number three. Thanks, Degan. I think this is a really, really good question.

230 patients originally projected a $260 originally.

Finally enrolled in that study.

With respect to the test retest. So we do have that I don't have that number in front of you and we can circle back to you with that.

And that's in the published literature, and certainly can confirm that aspect outside of the <unk> four study the variability in the change from baseline and reachable workspace that standard deviation went into the power calculations for the reach study and so we are incorporating not.

Alex Sapir: So yeah, we have done some initial payer work, both in the U.S. as well as outside the U.S., and I don't remember the specifics of the study that we did, but I think it was around 10 payers that we spoke to and shared with them the target product profile and shared with them the results of the Redux 4 study, and they obviously were well aware that there were no available treatment options for these patients. And the objective of the work that we did was really to try to understand their thoughts around pricing, and what we heard loud and clear from those payers is that they would expect, when this drug gets approved and comes to market, that it would command prices for rare diseases, such as, you know, in the hundreds of thousands of dollars. I think a really good comparison to look at would be the pricing that Biogen has with Skyclaris. So it's Skyclaris targets Friedrich's ataxia, again, a neuromuscular disease, not a lot of mortality, but high morbidity, so very, very similar to what we see with FSHD. The biggest difference between FA and FSHD is the prevalent population.

Just the treatment effect size, but also the variability from that in <unk>.

Okay I appreciate the color there switching gears to <unk> Alex.

Site activation it seems like Youre, making some progress on.

Certain sites that have already been activate it but youre also going out to activate more.

Just wondering for those that you were working on now what are some pushes and pulls youre hearing from them before they can get onboard.

And sort of separate to that is what pieces of data are you looking to collect a further expand the tam of <unk> longer term. Thanks. So much guys, yes, great question dig on and thanks for asking those yes I think.

Or actually let me back up a little bit so at the at the Ash meeting, we had an opportunity to probably interact on a one to one on one basis with maybe 30 of the top thought leaders in the.

In sickle cell and I think while there were a minority of physicians that said that they werent interested in participating in the study primarily because of the fact that it is a small study and it's a new site and it's going to take nine months to get that site up and running and they may only be able to give us sort of wanted to do patient they said for the <unk>.

Alex Sapir: FSHD is about four times the size. So the payer work that we've done, albeit somewhat limited to date, has really been around pricing and the feedback that we've heard from payers that they would expect this as the first entry in a rare disease to be priced in, you know, hundreds of thousands of dollars, similar to other rare disease therapies. I will say, Dagon, the other thing that we're also doing, and while this hasn't been confirmed with payers, I think our instinct is that payers will require a confirmed genetic test for FSHD before approving the product. And as of right now, because there are no treatment options for patients with FSHD, very little genetic testing is done. And of the genetic testing that is done, it's clunky in that it takes a lot of time to get these genetic tests back, and they're expensive.

Time, being we're going to sit on the sidelines and come back to US. Once you are ready to enroll in a larger sort of phase two three study so that so the sites that we're talking to right now are all sites that have <unk>.

Express an interest and a lot of those are many of those physicians that we spoke to at Ash I would say the majority of those physicians that we spoke to were very interested in the potential that <unk> could bring to their patients. So all the sites that we're talking with right now we sort of screened out all those that are no longer interested in so we're essentially.

We have identified a series of sites that are very interested in participating in essentially we're just going through.

Going through the.

Getting the IRB to approve it getting the contracts.

Alex Sapir: Sometimes the insurance company will pay for it, and sometimes they won't. So that's an area that we're going to spend a lot of time on in 2024 and 2025 to really streamline that process of genetic testing because right now it is not as efficient as we feel like it needs to be at the time that we launch, given our... instinctive assumption that payers will require confirmed genetic testing before agreeing to approve the drug. So on the second question, Ian, maybe I'll turn that one over to you. Yeah, sure.

Getting the contracts through and the second question.

Second part of that question Dae gon.

Yes with regards to the trial the pioneer trial I mean, your long term goal is to eventually expand the Tam right given the high severity of disease right now so what kind of data are you looking to collect and pioneer before you can look to expand that yeah. Great question I think some of that has to do with conversations that we've had with the agency.

To date and Ian has been intimately involved in those conversations maybe I'll turn that one over to Ian Yes, yes, absolutely.

Ian Frazier: So briefly, just to recap, the Redux for reachable workspace data, as you indicated, showed that 10 percentage point Treatment Effect Difference that was derived from a repeated measures model that was used to assess that endpoint, and that is the same model that will be used for the REACH study. And just to recap, that includes evaluations at baseline, week 4, week 12, 24, 36, and 48, so it's not just a single comparison of week 48 out to the baseline value. So it incorporates all of those measures over time, and the treatment effect difference on an RSA unit score was about 0.05, with a baseline REACHable Workspace score in those patients of 0.54 to 0.53, and that's five quadrants, so the theoretical max there would be 1.25, just to contextualize it. So those were the data points that were used to power the phase three REACH study. 230 patients originally projected were originally, and 260 originally, finally enrolled in. With respect to the test-retest, we do have that. I don't have that number in front of you, but we can circle back to you with that.

It is clear that the that the agency thinks of us in terms of risk and benefit.

And they articulated that certainly in terms of there.

Dealings with the gene therapy approaches in particular, which we know are associated with with pretty significant risks, including malignancy.

With a black box warning going to to the Bluebird product.

However, they feel that they understand the upside in the benefits of those therapies much.

Much better than they do with with something like <unk>, which is still in early development. So I think the initial approach here is in the context of the pioneer study. This three months study is really to to articulate fully at doses that we think are likely to be therapeutic which are the 12 and potentially the 20 milligram once daily dose.

Yes.

What sort of fetal hemoglobin induction, we can see in those patients and I think really demonstrating that and based on our initial experience with the 12 milligram dose, which only went up to six weeks or so we feel that their patients will be able to reach that high 20%, maybe even low 30% range.

With the disease becomes transformative and so its really filling out the efficacy side at least in the first instance on hbf before being able to go back to the agency.

Ian Frazier: That's in the published literature, and certainly can confirm that aspect outside of the Redux 4 study. The variability in the change from baseline in reachable workspace, that standard deviation, went into the power calculation for the REACH study. And so we're incorporating not just the treatment effect size but also the variability. Inreda.

Eight.

Relax some of the inclusion exclusion criteria in the first instance, and be to extend the dosing beyond three months, which is the context of the current trial.

Excellent. Thank you very much guys. Thanks Dae gon.

Thank you. This concludes the question and answer portion of the call I will now turn the call back over to force Com CEO, Alex <unk> for closing remarks.

Yes, thanks, so much Valerie and I guess just to wrap up as you can see from our progress that we've made and our plans for 2024, we remain deeply committed to treat the root causes of genetically defined rare diseases and bringing these transformative therapies to patients.

Dagon Ha: Okay. I appreciate the color there. Switching gears to posterior deer, Alex, on the site activation, it seems like you're making some progress on certain sites that have already been activated, but you're also going out to activate more. Just wondering, for those that you're working on now, what are some pushes and pulls you're hearing from them before they can get on board? And sort of separate from that is, what pieces of data are you looking to collect to further expand the TAM of posterior deer over the longer term?

Before we conclude today's call as I always 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.

Again to everyone. Joining this morning, and please stay safe and healthy thanks, so much.

Alex Sapir: Thanks so much, guys. Yeah. Great questions, Dagon. And thanks for asking those. Yes. I think of the... Or actually, let me back up a little bit.

Ladies and gentlemen, this does conclude today's conference. Thank you all for participating you may now disconnect have a great day.

[music].

Sure.

Alex Sapir: So at the ASH meeting, we had an opportunity to probably interact on a one-to-one-on-one basis with maybe 30 of the top thought leaders in sickle cell. And I think while there were a minority of physicians that said that they weren't interested in participating in the study, primarily because of the fact that it is a small study and it's a new site, and it's going to take nine months to get that site up and running, and they may only be able to give us sort of one to two patients, they said, for the time being, we're going to sit on the sidelines and come back to us once you are ready to enroll in a larger sort of phase two, three study.

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Alex Sapir: So the sites that we're talking to right now are all sites that have expressed an interest. And a lot of those are, many of those physicians that we spoke to at ASH, I would say the majority of those physicians that we spoke to were very interested in the potential that Passiridere could bring to their patients. So all the sites that we're talking with right now, we sort of screened out all those that are no longer interested.

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Alex Sapir: And so we've essentially identified a series of sites that are very interested in participating. And essentially, we're just going through the process of getting the IRBs to approve it, getting the contracts through. And the second question? The second part of that question, Dagon?

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Yes.

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Alex Sapir: Yeah, with regard to the trial, the Pioneer trial, I mean, your long-term goal is to eventually expand the TAM, right, given the high severity of disease right now. So what kind of data are you looking to collect in Pioneer before you can look to expand that? Yeah, great question.

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Ian Frazier: And I think some of that has to do with conversations that we've had with the agency to date, and Ian has been intimately involved in those conversations. Maybe I'll turn that one over to you. Yeah, yeah, absolutely, Alex. And it's clear that the agency thinks of this in terms of risk and benefit. And they articulated that certainly in terms of their dealings with the gene therapy approaches in particular, which we know are associated with pretty significant risk, including malignancy, with a black box warning going to the Bluebird product. However, they feel that they understand the upside and the benefits of those therapies much better than they do with something like Posertia, which is still in early development. So I think the initial approach here, in the context of the pioneer study, this three-month study is really to fully articulate fully at doses that we think are likely to be therapeutic, which are the 12 and potentially the 20 milligram ones daily dose, what sort of fetal hemoglobin inductions we can see in those patients.

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Ian Frazier: And I think really demonstrating that and based on our initial experience at the 12 milligram dose, which only went out for six weeks or so, we feel that patients will be able to reach that high 20%, maybe even the low 30% range where the disease becomes transformative. And so it's really filling out the efficacy side, at least in the first instance with HBF before being able to go back to the agency and A, relax some of the inclusion exclusion criteria in the first instance, and B, to extend the dosing beyond the three months, which is the context of the current study. Excellent Thank you very much, guys. Yeah, thanks Dagan.

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Alex Sapir: Thank you. This concludes the question and answer portion of the call. I will now turn the call back over to Fulcrum's CEO, Alex, for closing remarks.

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Alex Sapir: Yeah, thanks so much, Valerie. And I guess just to wrap up, as you can see from the progress that we've made and our plans for 2024, we remain deeply committed to treating the root causes of genetically defined rare diseases and bringing these transformative therapies to patients. Before we conclude today's call, as I always 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 again to everyone who joined us this morning, and please stay safe and healthy. Thanks so much.

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Operator: Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. Have a great day. ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? Thanks for watching!

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Operator: See you next week! Currently, all participants are in a listen-only mode. This call is being webcast live and can be accessed in the investor section of Fulcrum's website at www. FulcrumTX.com, Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Security Litigation Reform Act of 1995. These may include statements about the company's future expectations, plans, Clinical Development Timelines, and Financial Projections, while these four were looking at statements, present Fulcrum's view of today. This should not be relied upon as expressing the company's views for the future.

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Alex Sapir: 2023 was a year in which we both completed enrollment in our Phase 3 REACH trial for los mathemades, for fascio-scapulohumeral muscular dystrophy, or FSHD for short, and resolved the clinical hold for posiridere, which allowed us to resume clinical testing in patients with sickle cell disease. In the fourth quarter, we continue to drive forward our two key clinical programs and advance our preclinical pipeline. And with our cash runway that extends into 2026, I do believe that we are well positioned to execute our corporate objectives and deliver on key milestones in 2024 and beyond.

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Alex Sapir: So at this point, let me go a bit deeper and elaborate on the progress we've made toward our goal of delivering transformative therapies to improve the lives of patients with rare genetic disorders. Let's start with our most advanced program, Losmaphamide, which is an oral small molecule P38 alpha beta MAP kinase inhibitor currently in phase three development for the treatment of FSHD. Now FSHD is a rare form of muscular dystrophy with an estimated US patient population of 30,000. It 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.

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Good morning, and welcome to Fulcrum Therapeutics fourth quarter, and full year 2023 financial results and business update conference call.

Currently all participants are in a listen only mode. This call is being webcast and can be accessed on the investors section of <unk> website at Www Dot Fulcrum, TX dot com and is being recorded.

Alex Sapir: In our Phase 2 study, Losmath-Ahmad demonstrated a 10% change in the RSA score relative to placebo at 48 weeks. Based on interactions with FDA, we are currently assessing the extent to which a change in the RSA score is considered 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 that will help inform our thinking on our payer strategy as we begin preparing for a commercial launch here in the U.S. Now, turning to Posiridir, our oral HBF inducer for the potential treatment of patients Historically, the standard of treatment for sickle cell disease has involved blood transfusions, pain medications, and hydroxyurea, focusing primarily on symptom relief.

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 1095.

These may include statements about the companys future expectations plans clinics.

Clinical development timelines and financial projections.

These forward looking statements.

Paul Krump view of today this should not be relied upon.

The company's views in the future focal may update these statements in the future, but it's not taking on an obligation to do so please refer to <unk>. Most recent filing with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with the Companys business.

Leading the call today will be Alex Sapir CEO.

President Paul Krump, joining Alex on the call are Alan Musso, Chief Financial Officer, and Dr. Ian Frazer interim Chief Medical officer, after providing updates on our key programs.

There will be a brief Q&A in which Alex Allen and Ian will be available to answer your questions with that is my pleasure to turn the call over to Alex.

That's great. Thanks, Valerie and thanks to all of you for joining us today.

2023 was a year in which we both completed enrollment in our phase III reach trial for those map of Mod for passenger Scapulohumeral muscular dystrophy, our fsh D for sure and resolve the clinical hold for <unk>, which allowed us to resume clinical testing in patients with sickle cell disease.

Alex Sapir: 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 need for safe and accessible therapeutic options that are broadly protective of sickle cell symptomatology. As a first-in-class, oral, small-molecule HBF-inducer, we believe Poseridur has the potential to address a critical unmet need. Now, just as a quick reminder, in August of 2023, the FDA lifted the clinical hold for posterior dare, and I think it's also really important to note that there were no changes either in the protocol-defined dose escalation scheme or the three-month treatment duration. Clinical trial sites have now been activated, and others have been selected and are going through the necessary steps for site activation in order to be ready for patient recruitment for the Phase 1b Based on the revised inclusion-exclusion criteria, we will be enrolling patients with high disease severity.

So at this point, let me go a bit deeper and elaborate on the progress we've made toward our goal of delivering transformative therapies to improve the lives of patients with rare genetic diseases.

Let's start with our most advanced program <unk>, which is an oral small molecule P 38 Alpha beta map kinase inhibitor currently in phase III development for the treatment of Fsh date now FX HD is a rare form of muscular dystrophy with an estimated U S prevalent patient population of 30000.

Alex Sapir: Cohort 3 of the Pioneer Study will evaluate posterior at the 12 milligram once daily dose, followed by cohort 4 at the 20 milligram once daily dose. Both cohorts are expected to enroll approximately 10 patients. And we look forward to providing specific guidance on readout of the 12 milligram and 20 milligram cohorts as we have additional sites activated and a good basis to project enrollment trajectories. We're looking forward to building on the encouraging clinical data obtained prior to the clinical hold, which demonstrated that post-serivir 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 Procider as an oral HPF inducer has the potential to provide a differentiated therapeutic option for people living with sickle cell disease.

Despite the high unmet need there are currently no approved treatment options for these patients.

So in our quest to bring hope for these patients in September of last year, we completed enrollment in our global phase III trial for <unk> with a total of 260 patients enrolled in the trial.

The trial initiated in June 2022, and 15 months later, we had surpassed our enrollment expectations, which we believe is a real testament to the high unmet need for this rare disease.

We are on track to report top line data in the fourth quarter of 2024, which will bring us one step closer to delivering the first ever FDA approved therapy for FSC HD patients.

So just a quick reminder, some of the details around the phase III study, which we call reach reaches a 48 week.

Alex Sapir: Addressing the significant unmet need in the sickle cell community remains a key priority for us, and we are excited to build on this momentum in the years ahead. For the financial update, I will turn it over to Alan Musso, our Chief Financial Officer, who will walk you through some of the numbers. Alan, over to you. Thanks Alex, I'll now go over our results for the fourth quarter and full year ended December 31st, 2023, beginning with the results for the quarter. Collaboration revenue was $0.9 million for the fourth quarter of 2023, compared to $0.7 million for the same period in 2022. Our research and development expenses were $19 million for the fourth quarter of 2023, compared to $18.6 million for the same period in 2022; the increase of 0.4 million was primarily due to higher personnel costs. General administrative expenses were $9.9 million for the fourth quarter of 2023, compared to $10.1 million for the same period in 2022. The decrease of $0.2 million was primarily due to lower professional service costs. Additionally, for the fourth quarter of 2023, Fulcrum reported a net loss of $24.8 million, compared to $26.1 million for the same period in 2022.

Excuse me reaches a 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 a change from baseline in the relative to surface area, our RSA, which is a quantitative assessment of reachable workspace RSA as an objective.

Measure of upper extremity range of motion and muscle function that specifically evaluates.

Excuse me.

That's specifically evaluates shoulder and our mobility using three D motion sensor technology, and our phase III study <unk> demonstrated a 10% change in the RSA score relative to placebo at 48 weeks and based on interactions with FDA. We are currently at.

Self reported quality of life measures that will help inform our thinking on our payer strategy as we begin preparing for our commercial launch here in the U S.

And approximately $4 4 million people worldwide historically, the standard of treatment for sickle cell disease has involved blood transfusions pain medications that hydroxyurea, focusing primarily on symptom relief.

Alan Musso: I'll now review the results for the year ended December 31st, 2023. Collaboration revenue was $2.8 million for the year ended December 31, 2023, compared to $6.3 million for the same period in 2022. The lower collaboration revenue during 2023 was attributable to the completion of activities under our collaboration agreement with Acceleron, which terminated in October 2022, and due to a decrease in revenues under our collaboration agreement with Myocardia as we completed our research services during the fourth quarter of 2023. Our research and development expenses were $71.8 million for the year ended December 31, 2023, compared to $76.8 million in 2022. The decrease in 2023 was primarily attributable to a $5 million milestone obligation incurred upon the initiation of the REACH clinical trial in the second quarter of 2022 under our license agreement with GlaxoSmithKline. Our general and administrative expenses were $41.7 million for each of the years ended December 31, 2023, and 2022.

As a first in class oral small molecule Hbf inducer, we believe <unk> has the potential to address a critical unmet need for patients now.

Based on the revised inclusion exclusion criteria, we will be enrolling patients with high disease disease severity.

And 20 milligram cohort as we have additional sites activated and a good basis to project enrollment trajectory.

A 10 percentage point increase in hbf from baseline or total hbf of approximately 25%, we believe that <unk> as an oral hbf inducer has the potential to provide a differentiated therapeutic option for people living with sickle cell disease addressing this.

Significant unmet need in the sickle cell community remains a key priority for us and we are excited to build on this momentum in the years ahead.

Alan Musso: We continue to operate from a strong financial position with a cash runway into 2026. And with that, I will turn the call back over to Alan. Great. Thanks so much, Alan. So, as all of you can see, we are well positioned for a very exciting 2024 and are encouraged by the progress across our two clinical programs, Los Maphimod, which has the potential to be the first in market for patients with MSHD, and Posiridir, which has best in class potential for patients living with sickle cell. So at this point, Valerie, let's go ahead and open it up for questions. Thank you. Ladies and gentlemen, if you'd like to ask a question, please press star 11 on your touchtone telephone. Again, if you'd like to ask a question, please press star 11. One moment for our first question. Our first question comes from the line of Matthew Biegler, of Oppenheimer, Ireland.

So that's the clinical update for the financial update let me turn it over to Alan Musso, Our Chief Financial Officer, who will walk you through some of the numbers Alan over to you.

Thanks, Alex.

Now I'll go over our results for the fourth quarter and full year ended December 31, 2023, beginning with the results for the quarter.

Collaboration revenue was <unk> 9 million for the fourth quarter of 2023 compared to <unk> 7 million for the same period in 2022.

Our research and development expenses were $19 million for the fourth quarter of 2023 compared to $18 6 million for the same period in 2022.

The increase of <unk> 4 million was primarily due to higher personnel costs.

General and administrative expenses were $9 9 million for the fourth quarter of 2023 compared to $10 1 million for the same period in 2022.

The decrease of <unk> 2 million was primarily due to lower professional service costs.

And for the fourth quarter of 2023, <unk> reported a net loss of $24 8 million.

Third to $26 1 million for the same period in 2022.

I will now review the results for the year ended December 31 2023.

Collaboration revenue was $2 8 million for the year ended December 31, 2023, compared to $6 3 million for the same period in 2022.

Matthew Biegler: Hey, good morning, guys. Um, I just wanted to maybe touch on something you said about on the regulatory side of the coin here for Los Matamob. Can you just walk us through your interactions with the FDA and where you are with discussions on the clinical benefit of reachable workspace, and I guess what you'll need to show in reach to make them happy?

The lower collaboration revenue during 2023 was attributable to the completion of activities under our collaboration agreement with accelerating which terminated in October 2022, and.

And due to a decrease in revenues under our collaboration agreement with myocardial <unk> as we completed our research services during the fourth quarter of 2023.

Our research and development expenses were $71 8 million for the year ended December 31, 2023, compared to $76 8 million in 2022.

Our general and administrative expenses were $41 7 million for each of the years ended December 31, 2023 and 2022.

The net loss was $97 3 million for the year ended December 31, 2023, compared to $109 9 million in 2022.

And now turning to the balance sheet.

We ended 2023 with cash cash equivalents marketable securities of $236 2 million compared to $202 9 million as of December 31, 2022.

This increase in our cash position is primarily due to net proceeds from our January 2023rd 2023 equity offering of $117 3 million, partially offset by our net cash used in operating activities in 2023.

And during the fourth quarter of 2023, our cash burn was $20 9 million.

We continue to operate from a strong financial position with a cash runway into 2026.

And with that let me turn the call back over to Alex great. Thanks, So much Alan.

As all of you can see we are well positioned for a very exciting 2024 and are encouraged by the progress across our two clinical programs <unk>, which has the potential for which has first in market potential for patients with advanced <unk>, HD and <unk>, which has best in class.

<unk> potential for patients living with sickle cell disease. So at this point Valerie Let's go ahead and open it up for questions.

Thank you.

Ladies and gentlemen, if you'd like to ask a question. Please press star one on your Touchtone telephone again, if you'd like to ask a question. Please press star one one.

One moment for our first question.

Our first question comes from the line of Matthew Biegler.

Yes.

Of Oppenheimer. Your line is open.

Hey, good morning, guys.

I just wanted to maybe tack on something you said about on the regulatory side of that coin here for a little snap a month can you just walk us through your interactions with the FDA and where you are with discussions on the clinical benefit for reachable workspace and I guess, what youll need to show in reach to make them happy.

Ian Frazier: And, of course, FDA will ultimately make the final determination as to what is considered clinically meaningful, considering the totality of it. Okay, okay, so effectively, we can say that there needs to be a little bit more validation work done on the RWS assay. Is that a fair characterization?

Yes.

So much Matt for the question, let me let me just say a couple of things that I will turn it over two years ago in a bit more detail. So.

The reach study is a very well powered study with the 260 patients that we had enrolled we've got a 96.

<unk> powering on that study and we believe that.

Thanks, Alex and thanks, Matt.

So obviously there are no drugs approved for <unk>. So there is no precedent in the regulatory sphere for endpoints.

But we have had a number of productive and indeed ongoing discussions with FDA involving both the review division, which is in neurology as well as the coal division and we are executing on a plan that we've agreed upon with them.

Corinne Johnson: Our next question comes from the line of Corinne Johnson of Goldman Sachs, from the line of, Good morning, this is Craig on behalf of Corinne. I guess one question for us is, how familiar are physicians with the reachable workspace endpoint? And can you describe some of your physician education efforts that you're planning once you have the data? Yeah, great, great question, Craig.

We believe we will establish the clinical meaningfulness of the reachable workspace.

Specifically there are a couple of components to that.

The first is that we are generating additional data from observational studies and Fsh D. So this is not involving any treatment with less map of mud.

But observing these patients as requested by the agency to identify what is taught them. The most appropriate measures of change in upper extremity function.

Alex Sapir: And thanks. Thanks for asking that. I'll start, and then I'll certainly turn it over to Ian if he has any others.

Alex Sapir: So I would say that reachable workspaces is not a standard instrument that neuromuscular specialists currently use when evaluating their patients with FSHD. It is somewhat of a novel tool. And so, in terms of the answer to your question about what we're doing from an educational standpoint, really train them on what Reachable Workspace is and what a change in Reachable Workspace actually means. We're doing a number of programs throughout the year. We've got a program in two weeks at the MDA conference, a CME program, in which we're actually spending a lot of time with the physicians that have signed up for that program, really walking through what Reachable Workspace is, what is a normal baseline for patients, and what does a change in Reachable Workspace actually mean.

And then secondly, we are conducting a number of exit interviews.

Patients that have gone through the reach study and this will help to enhance our understanding as well as fda's understanding of what the changes are ws means for them.

And our expectation is that at the very latest these data will be available at the time of NDA submission and of course, ultimately FDA will.

Ultimately make the final determination as to what is considered cleaning clinically meaningful considering the totality of evidence.

Okay. Okay. So effectively we can say that there needs to be a little bit more validation work done on the <unk> assay is that a fair characterization.

I think the validation work on the instrument itself in terms of the test retest capabilities that training process that goes into it the provision.

Alex Sapir: The clinical meaningfulness of that change, going back to the first question that Matt asked, will ultimately be determined once we have the Reach data. But there's a number of activities that we're doing this year and in 2025 to really educate physicians on Reachable Workspace so that when the data does come out, they've got some context for those results. Ian, anything you would add?

Technical pieces of it all of that has been done and he is really quite satisfactory I think it's the last remaining pieces around the clinical meaningfulness in what is considered minimally clinically significant change.

Understood understood. Thanks, a lot.

Thanks Pat.

Thank you one moment please.

Our next question comes from the line of Karen Johnson of Goldman Sachs. Your line is open.

Ian Frazier: No, the only thing I would add, perhaps, obviously, all of the investigators in our clinical studies, both the Redux IV Phase II as well as REACH and Phase III, are very well familiar with it now because of their work, and they obviously speak to their colleagues as well. So I think there's some level of dissemination through the clinical trials themselves. And then additionally, as Alex said, we have some CME programs designed to inform and educate physicians around. Got it.

Good morning. This is Craig on for Karen I guess, one for us how familiar our physicians with reachable workspace endpoint.

And can you describe some of your physician education efforts that Youre planning.

Once you have the data.

Yes, great Great question, Craig and thanks, Thanks for asking that I'll start and then I'll certainly turn it over to Ian if he has any others.

Ian Frazier: Thank you very much. All right. Thanks, Greg.

I would say that reachable workspace is not a standard.

Instrument that neuromuscular specialist currently use when evaluating.

There are patients with Sshd. It is somewhat of a novel instrument and so.

Ian Frazier: Yeah, I think thanks so much for the question. I think to answer that, I think I will turn that over to Ian, our Chief Medical Officer. Yeah, I think the advantage of the reachable workspace is that it provides a quantitative assessment that treating physicians typically use in a more qualitative sense to understand how their patients are doing. So it allows us to put some numbers around those qualitative terms. And since there haven't been any therapies that alter the course of the disease available to date, there's really been no need to do that.

The CME program in which we're actually spending a lot of time with the physicians that have signed up for that program click walk through what is reachable workspace what is a.

What is a normal baseline for patients and what does it change and reachable workspace actually mean.

The clinical meaningful momentum that change going back to the first question that Matt asked will ultimately be sort of determined once we had the reach data, but theres a number of activities that we're doing this year and in 2025 to really educate physicians on reachable workspace, so that when the data thats come out they've got some they've got some cash.

Ian Frazier: All the therapy is at this point. So it's really adding a little bit of quantitative measures around the more qualitative sense in the clinic. I think the important pieces to point out here are, number one, that reachable workspace has been shown previously, prior to Fulcrum's involvement, that FSHD patients exhibit a decline in their reachable workspace over time. That was in a small natural history study that was published several years ago.

<unk>.

For those for those results.

Anything you would add.

No the only thing I would add perhaps obviously all of the investigators.

Clinical studies, both the redux for phase II as well as reaching the phase III are very well familiar with it now because of their participation in the study.

Ian Frazier: And that's consistent with clinical observations around measuring muscle strength by more traditional measures like dynamometry. We know that, in addition, the Reachable Workspace correlates with patient-reported outcome instruments, such as the NeuroQOL Upper Extremity Questionnaire, and that work has been published. And we've also shown from our Phase II data a correlation between the Reachable Workspace and the shoulder-abducted dynamometry. And it's the shoulder-abducted dynamometry because, obviously, Reachable Workspace is focused on the upper extremity, and the shoulder abductor is a major muscle component of that.

Designed to to inform and educate physicians around that.

Got it thank you very much alright, thanks, Greg.

Thank you one moment please.

Our next question comes from the line of Joseph Joseph Schwartz of Leerink Partners. Your line is open.

Hi, Good morning, Andrey and park dialing in for Joe. Thank you for taking our question.

The first one is on <unk>, given reachable workspace isn't a standard instrument now how Ken physicians measure benefit in the real world. If they don't have access to the tools are there other metrics that could track with Mr. <unk> workspace or.

Clinically meaningful benefit and I have a follow up answer okay. That's great, Yes, I think.

Ian Frazier: So there are correlations that have been observed in the reachable workspace, and as I say, probably most importantly, it's that documentation of the decline experienced by these patients. And that's what the patients report, is this inevitable decline over time, and that's something that their treating physicians and caregivers also report. And so there's consistency in the measure from that perspective. Okay, I got it. Thank you. And then my second question is on posterior deer.

Thanks, So much for the question I think to answer that let me turn that over to Ian <unk>, Our Chief Medical Officer.

I think the.

Advantage of reachable workspace is that it provides a quantitative assessment that the treating physicians.

Typically used in a more qualitative sense to understand how their patients are doing so allows us to put some numbers around those qualitative terms and since there haven't been any therapies that alter the course of the disease available to date Theres really been no no need to do that all the <unk>.

Symptomatic.

To this point, it's really adding a little bit of.

Quantitative measures around the more qualitative sense in the clinic I think.

Courtney piece.

Pieces to point out here are number one that that reachable workspace has been shown previously prior to <unk> involvement.

That FSA HD patients exhibit a decline in their reachable workspace over time.

In the small natural history study that was published several years ago, and thats consistent with clinical observations around <unk>.

Measuring muscle strength by more traditional measures like Dynamometry for example.

We know that.

In addition, the reachable workspace correlates with instruments patient reported outcome instruments, such as the neuro coil upper extremity quest.

Questionnaire and that work has been published and we have also shown from our phase two data.

The correlation between the reachable workspace and the shoulder abductor dynamometry and its the shoulder abductor dynamometry, because obviously reachable workspace is focused on the upper extremity and the shoulder abductors major muscle component of that.

Ian Frazier: And we know that in the sickle cell patient population, in general, it's around 5 to 10%, the average baseline. So we've seen, to date, pretty widespread increases across baseline HBFs, and while we don't have three months of data in all of those patients, certainly, the initial slope of the increase in HBF across all of those baselines looks pretty similar. So it didn't appear that those that were starting out higher had a lower response or vice versa. I think the critical piece of this is, where do the patients end up? After three months, it looks like from the six milligram data that we have, which is the highest dose that's gone out to three months, may not even be plateauing fully at the three months mark.

So there are correlations that have been observed in the reachable workspace and as I say, probably most importantly, it's that documentation of the decline experienced by these patients and Thats. What the patients report is this this inevitable decline over time and that's something that they are treating physicians.

It gives us all to report until there is consistency in diminish it from that respect as well.

Update that we can better contextualize and appreciate the data on that I really thank you very much.

Yes. This is Ian again, so maybe I can just add that.

Ian Frazier: And so that'll obviously need to be evaluated further as we move through the process. But we will, once we have the data around fetal hemoglobin, we will reveal those baselines. Thank you. One moment, please. Our next question comes from the line "Day Gone High on Steeple, Yolanda." Thank you.

Do have in our.

Corporate presentation on the web with data from the initial 16 patients that were enrolled in the study that includes.

A lot of their of their hbf and it includes the baseline.

It'll hemoglobin that they went in with the comment that I would make there is that there was a range of baseline Hbf and I think speaking from memory. It was about 3% at the low end.

Dagon Ha: Thanks for taking our questions and congrats on all the progress. Three questions, if I may. One, Alex, have you guys actually started some pre-commercialization work with payers specifically? I think there was quite a bit of questions around physicians and their comfort as well as the regulators, but how do payers feel about the reachable workspace and the magnitude you showed so far? Second, sticking with Losmapimod, the 10% change you detected in Redux 4, I was wondering if you could go into a little bit more on the test-retest variability you mentioned in an earlier question.

Just under 20% that they are at the high end and we know that in the sickle cell patient population in general it's around 5% to 10%.

The average baseline so we've seen.

To date, a pretty widespread across baseline hbf and while we don't have three months data in all of those patients certainly the initial slope of the increase in the hbf.

Cross all of those baselines look pretty similar so it didn't appear that that those that were starting out.

Hi, I had a lower response or vice versa.

Where.

The critical piece of this is where do the patients end up with.

After three months.

It looks like from the six milligram data that we have which is the highest dose that's gone out to three months may not even be.

Dagon Ha: Any other evidence you can point to that kind of gives us some comfort around your Phase 3 reach powering? And then I'm going to follow up on that, plus your story. Okay. Great. Yeah.

Towing fully at the three months, Mark and so that will obviously need to be evaluated further as we move through the process.

We will once we have the data.

Around the fetal hemoglobin, we will reveal a lowest baseline hbf as well because it is an important component.

Alex Sapir: Why don't I take question one and then I'll turn question number two over to Ian and then we'll come back to you for question number three. Thanks, Dagon. I think this is a really, really good question.

Yes.

One moment please.

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

Yes.

Hey, good morning, Thanks for taking our questions and congrats on all the progress three.

Three questions. If I may one Alex have you guys actually started some pre commercialization work with the payers specifically I think there was quite a bit of questions around physicians on their comfort as well as the regulators, but how does payers feel about the rate of our workspace and the magnitude you showed so far.

Alex Sapir: So yeah, we did some initial payer work both in the US as well as outside the US, and I don't remember the specifics of the study that we did, but I think it was around 10 payers that we spoke to and shared with them the target product profile and shared with them some of the results of the Redux 4 study, and they obviously were well aware that there were no available treatment options for these patients. And the objective of the work that we did was really to try to understand their thoughts around pricing, and what we heard loud and clear from those payers is that they would expect that when this drug gets approved and comes to market, it would command rare disease type pricing, such as, you know, in the hundreds of thousands of dollars. I think probably a really good comp to look at would be the pricing that Biogen has with Skyclaris.

Sticking with the snap of Mod the 10% change you detected in Redux four I was wondering if you could go into a little bit more on the test retest variability I mentioned to an earlier question.

Any other evidence you can point to that kind of gives us some comfort around your phase III reach powering and then I've got a follow up on the <unk> story.

Okay, Great, Yes, why don't I I'll take question, one and then I'll turn question number two over to Andy and then we'll come back to you for question number three thanks, Dae Gon I think really really good question. So yes, we have done some some initial payer work both in the U S as well as ex U S and I don't remember the specifics.

Alex Sapir: So Skyclaris targets Friedrich's ataxia again, a neuromuscular disease, not a lot of mortality, but high morbidity. So, very, very similar to what we see with FSHD. The biggest difference between FA and FSHD is that the prevalent population for FSHD is about four times the size.

The study that we did but I think it was around 10 payers that we had spoken to and shared with them the target product profile and shared with some of the results of the Redux study and they obviously were well aware that there was no available treatment options for these for these patients.

The objective of the work that we did was really to try to understand their thoughts around pricing and what we heard loud and clear.

Alex Sapir: So the payer work that we've done, albeit somewhat limited to date has really been around, has really been around pricing and the feedback that we've heard from payers that they would expect this as the first entrant in a rare disease to be priced in the, you know, hundreds of thousands of dollars, similar to other rare disease therapies. I will say, Dagon, the other thing that we're also doing and while this hasn't been confirmed with payers, I think our, our instinct is that payers will require a confirmed genetic test of FSHD before approving the product. And as of right now, because there are no treatment options for patients with FSHD, very little genetic testing is done. And of the genetic testing that is done, it's clunky in that it takes a lot of time to get these genetic tests back. They're expensive.

From those from those payers is that they would expect that when this drug gets approved and comes to market that it would come.

Command rare disease type pricing such as.

Hundreds of thousands of dollars I think probably a really good comp to look at would be the.

The pricing that Biogen has with Sky Claris so.

Scott <unk> targets <unk> ataxia.

Again, neuromuscular disease, not a lot of mortality, but but.

Hi, morbidity, so very very similar to what we see with Fsh D. The biggest difference between FAA, an fsh D. As is the prevalent population FSA Chi is about four times the size. So the payer work that we've done, albeit somewhat limited to date has really been around has really been around price.

Alex Sapir: Sometimes the insurance company will pay for it. Sometimes they won't. So that's an area that we're going to spend a lot of time on in 2024 and 2025 to really streamline that process of genetic testing because right now it is not as efficient as we feel like it needs to be at the time that we launch, given our instinctive assumption that payers will require confirmed genetic testing before agreeing to approve the drug. So on the second question, maybe I'll turn that one over to you. Yeah, sure. So, briefly, just to recap, the Redux for reachable workspace data, as you indicated, showed that 10 percentage point Treatment Effect Difference that was derived from a repeated measures model that was used to assess that endpoint, and that is the same model that will be used for the REACH study.

<unk> and the feedback that we've heard from payers that they would expect this as the first entrant in a rare disease to be priced in that.

The one thousands of dollars similar to other rare disease therapies, I will say dig out and the other thing that we're also doing and while this hasnt been confirmed with payers I think our instinct is that payers will require a confirmed genetic test of FSA, Steve before approving the product and as of right now because.

There are no treatment options for patients with <unk> HD very little genetic testing is done in of the genetic testing that is done it's clunky in that it takes a lot of time to get these genetic tests bag, they're expensive, sometimes the insurance company will pay for it sometimes they won't so that's an area that we're going to spur.

And a lot of time on in 2024, and 2025 to really streamline that process of genetic testing because right now it is it is.

Alex Sapir: And just to recap, that includes evaluations at baseline, week 4, week 12, 24, 36, and 48. So it's not just a single comparison of week 48 out to the baseline value. So it incorporates all of those measures over time, and the treatment effect difference on an RSA unit score was about 0.05, with a baseline REACHable Workspace score in those patients of 0.54 to 0.53, and that's five quadrants. So the theoretical max there would be 1.25, just to contextualize it.

Not as efficient as we feel like it needs to be at the time that we launch given our.

Instinctive assumption that payers will require confirm genetic testing before agreeing to approve.

Approve the drug.

So on the second question and maybe I'll turn that one over to you yes sure.

Briefly just to recap redox four reachable workspace data as you indicated showed that 10 percentage.

Percentage points.

Treatment effect difference.

Week 48 to the baseline value. So it incorporates all of those.

<unk> over time.

Ian Frazier: So those were the data points that were used to power the phase three REACH study. 230 patients were originally projected to be enrolled, and 260 were finally enrolled. With respect to the test-retest, so we do have that. I don't have that number in front of you, and we can circle back to you with that. That's in the published literature, and I certainly can confirm that aspect outside of the Redux 4 study. The variability in the change from baseline in reachable workspace, that standard deviation, went into the power calculation for the REACH study. And so we're incorporating not just the treatment effect size but also the variability. Inreda.

The treatment effect of difference on an RSA unit score was about 0.05 with a baseline.

Reachable workspace score in those patients of <unk> five four to five three thats five quadrants of the theoretical Max that would be one two times.

Just to contextualize that so those those are the data points that we're used to.

To power the phase III reach study.

230 patients originally projected a 260 originally.

Finally enrolled in that study.

With respect to the test retest. So we do have that I don't have that number in front of you and we can circle back to you with that.

And that's in the published literature, and certainly confirm that aspect outside of the <unk> four study the variability in the change from baseline and reachable workspace that standard deviation went into the power calculations for the reach study and so we are incorporating not.

Dagon Ha: Okay, appreciate the color there. Switching gears to posterior deer, Alex, on the site activation, it seems like you're making some progress on certain sites that have already been activated, but you're also going out to activate more. Just wondering, for those that you're working on now, what are some pushes and pulls you're hearing from them before they can get on board? And sort of separate from that, what pieces of data are you looking to collect to further expand the TAM of posterior deer over the long term?

The treatment effect size, but also the variability from that in <unk>.

Okay I appreciate the color there switching gears to <unk> there Alex.

Site activation it seems like Youre, making some progress on certain.

Certain sites that have already been activate it but youre also going out to activate more.

Just wondering for those that you were working on now what are some pushes and pulls youre hearing from them before they can get onboard.

And sort of separate to that is what pieces of data are you looking to collect to further expand the tam of <unk> longer term. Thanks. So much guys, yes, great question dig on and thanks for asking those yes I think.

Alex Sapir: Thanks so much, guys. Yeah, great question, Dagon, and thanks for asking those. Yeah, so I think, you know, the or actually, let me back up a little bit.

Or actually let me back up a little bit so at the at the Ash meeting, we had an opportunity to probably interact on a one to one on one basis with maybe <unk> 30 of the top thought leaders in the.

Alex Sapir: So at the ASH meeting, we had an opportunity to probably interact on a one-to-one-on-one basis with maybe 30 of the top thought leaders in sickle cell, and I think while there were a minority of physicians that said that they weren't interested in participating in the study, primarily because of the fact that it is a small study and it's a new site and it's going to take, you know, nine months to get that site up and running, and they may only be able to give us sort of one to two patients, they said, you know, for the time being, we're going to sit on the sidelines and come back to us once you are ready to enroll in a larger sort of phase two, three study. So the sites that we're talking to right now are all sites that have expressed an interest, and a lot of those are, many of those physicians that we spoke to at ASH, I would say the majority of those physicians that we spoke to were very interested in the potential that Paseer Der could bring to their patients.

<unk>, we're going to sit on the sidelines and come back to US. Once you are ready to enroll in a larger set of phase two three study so that so the sites that we're talking to right now are all sites that have <unk>.

Alex Sapir: So all the sites that we're talking with right now, we sort of screened out all those that are no longer interested, and so we've essentially identified a series of sites that are very interested in participating, and essentially we're just, you know, going through the process of getting the IRBs to approve it, getting the contracts, getting the contracts through. And the second question. Second part of that question, Dagon? Yeah, with regard to the trial, the Pioneer trial, I mean, your long-term goal is to eventually expand TAM, right, given the high severity of the disease right now. So what kind of data are you looking to collect in Pioneer before you can look to expand that? Yeah, great question.

Sites that we're talking with right now we screened out all those that are no longer interested in so we're essentially have identified a series of sites that are very interested in participating in essentially we're just going through.

Going through the.

Getting the <unk> to approve it getting the contracts.

The contracts through and the second question.

Second part of that question Dana.

With regards to the trial the pioneer trial I mean, your long term goal is to eventually expand the Tam right given the high severity of disease right now so what kind of data are you looking to collect and pioneer before you can look to expand that yes. Great question I think some of that has to do with conversations that we've had.

With the agency to date and Ian has been intimately involved in those conversations maybe I'll turn that one over to Ian Yes, yes, absolutely.

It is clear that that that the agency thinks of us in terms of risk and benefit.

And they articulated that certainly in terms of there.

Dealings with the gene therapy approaches in particular, which we know are associated with with pretty significant risks, including malignancy.

With a black box warning going to to the Bluebird product.

However, they feel that they understand the upside in the benefits of those therapies much.

Much better than they do with with something like <unk>, which is still in early development. So I think the initial approach here is in the context of the pioneer study. This three months study is really to articulate fully at doses that we think are likely to be therapeutic which are the 12 and potentially the 20 milligram once daily dose.

Yes.

Ian Frazier: And I think really demonstrating that and based on our initial experience at the 12 milligram dose, which only went out for six weeks or so, we feel that there, you know, patients will be able to reach that high 20%, maybe even the low 30% range where the disease becomes transformative. And so it's really filling out the efficacy side, at least in the first instance with HBF, or being able to go back to the agency and A, relax some of the inclusion exclusion criteria in the first instance, and B, extend the dosing beyond the three months, which is the context of the current study.

With the disease becomes transformative until its really filling out the efficacy side at least in the first instance on hbf before being able to go back to the agency.

Eight.

Relax some of the inclusion exclusion criteria in the first instance, and be to extend the dosing beyond the three months, which is the context of the current trial.

Dagon Ha: Excellent. Thank you very much, guys. Yeah, thanks Dagan. Thank you. This includes the question and answer portion of the call.

Excellent. Thank you very much guys, yes, thanks Dae gon.

Thank you. This concludes the question and answer portion of the call I will now turn the call back over to force Com CEO, Alex <unk> for closing remarks.

Alex Sapir: I will now turn the call back over to Fulcrum's CEO, Alex, for closing remarks. That's great. Yeah, thanks so much, Valerie. And I guess just to wrap up, as you can see from the progress that we've made in our plans for 2024, we remain deeply committed to treating the root causes of genetically defined rare diseases and bringing these transformative therapies to patients. Before we conclude today's call, as I always 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 again to everyone who joined us this morning, and please stay safe and healthy. Thanks so much. Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. Have a great day!

Before we conclude today's call as I always 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 again to everyone. Joining this morning, and please stay safe and healthy. Thanks, so much.

Thank you ladies and gentlemen, this does conclude today's conference. Thank you all for participating you may now disconnect have a great day.

Q4 2023 Fulcrum Therapeutics Inc Earnings Call

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