Q4 2021 Fulcrum Therapeutics Inc Earnings Call

Good morning, and welcome to Fulcrum Therapeutics fourth quarter and full year 2021 conference call. Currently all participants are in listen only mode. There will be a question and answer session. At the end of this call I would now like to turn the call over to Kristy Wahid director of Investor relation.

Operator: Good morning, and welcome to Fulcrum Therapeutics' fourth quarter and full year 2021 conference call. Currently, all participants are in listen-only mode.

Operator: There will be a question and answer session at the end of this call. I would now like to turn the call over to Christy Wawrich, Director of Investor Relations at Fulcrum. Please continue.

At Fulcrum. Please proceed.

Christy Wawrich: Thank you. Thank you. Thank you. Thank you, operator.

Thank you operator, good morning, and welcome <unk>.

Okay.

Christy Wawrich: Good morning and welcome to the Fulcrum Therapeutics Conference. Please be reminded that remarks made during this call may contain forward-looking statements within the meeting of the private security for the Gation Reform Act of 1995. These may include statements that feature architectures and plans, clinical development timelines, and financial production. Because these forward-looking statements represent our views as a state, they should not be relied upon as representing our views in the state.

Please be reminded that remarks made during this call may contain forward looking statements.

Many of the private Securities Litigation Reform Act.

Scott.

These may include statements for future expectations, and plans clinical development timelines and financial protection.

These forward looking statements represent our views as of today.

That'll be relied upon as representing our views in the future.

These statements in the future, but we are not taking on an obligation to do so.

Christy Wawrich: We may update these statements in the future, but we are not taking on an obligation to do so. Please refer to our most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with our bid. With me on today's call are Brian Stewart, President and Chief Executive Officer; Judith Dunn, our President of R&D; and Esther Rojavello, our CFO. Luis Morrito, our Chief Medical Officer, and Paul Bruno, our Executive Director of Corporate Development, will also be available for Q&A. Now, let me quickly run through this morning's agenda.

Please refer to our most recent filings with Securities and Exchange Commission for a discussion of certain risks and uncertainties.

With me on today's call are Bryan Stuart President and Chief Executive Officer, Steven Stein, our president of R&D and Mr. Rajiv Allen our CFO .

First of all our retail our chief Medical Officer and Paul.

I can give director corporate development will also be available for Q&A.

Let me quickly run through this morning's agenda, Brian will begin the call with a corporate overview.

Christy Wawrich: Brian will begin the call with a corporate overview and key updates. Judy will review our FSHD program and today's update on the Phase 3 trial, and Esther will cover our financials, while Brian will open the call for Q&A. With that, it's my pleasure to turn the call over to Bryce. Thank you, Christy.

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Judy will review, our ethics HD program and today you can see on the phase three trial, and Esther who will cover our financial O'brien will open the call for Q&A.

With that it's my pleasure to turn the call over to Brian .

Thank you Christy good morning, everyone and thank you for joining us today.

Brian Stewart: Good morning, everyone, and thank you for joining us today. At Fulcrum, our mission is to treat the root cause of rare genetic disease. 2021 was a year of important clinical and corporate progress towards that mission, and we are building on that momentum in 2022 with meaningful updates across our pipeline. I'll start with Los Mapumat, our candidate for FSHD, which is the second most common form of muscular dystrophy.

And fulcrum, our mission is to treat the root cause of rare genetic diseases.

21 was a year of important clinical and corporate progress towards that mission and we are building on that momentum in 2022 with meaningful updates across our pipeline.

Brian Stewart: We believe Los Mapumat is positioned to be the first to market therapy for this severe and debilitating disease. Today, we announced our plan to begin enrolling people with FSHD in REACH, our registration-enabling Phase 3 clinical trial, in the second quarter of 2022. REACH will evaluate losmaphomide compared to placebo in adults with FSHD over a 48-week treatment period with REACHable Workspace, or RWS, as the primary endpoint. The trial design reflects key learnings from the Redux 4 Phase 2B study.

I'll start with lowest mathematics are candidate for Fsh D, which is the second most common form of muscular dystrophy. We believe <unk> is positioned to be the first to market therapy for this severe and debilitating disease.

Today, we announced our plan to begin enrolling people with Fsh D and reach a registration enabling phase III clinical trial in the second quarter of 2022.

Reach will evaluate <unk> compared to placebo in adults with Fsh D. Over a 48 week treatment period with reachable workspace or our W. S. As the primary endpoint.

The trial design reflects key learnings from the readout for phase II <unk> study.

Brian Stewart: Most notably, that we can show a measurable clinical benefit in 48 weeks, and that RWS is a quantitative measure of function that is sensitive to disease progression in that timeframe. Based on these insights and the data from Redux 4 demonstrating clinical benefit, we align with regulators, including the FDA, on RWS as the primary input. The upcoming start of our phase three trial marks a significant milestone for both Fulcrum and the FSHD community. There are currently no approved drugs, and nothing else is even in the clinic. People with FSHD lose strength, function, independence, and mobility as fat infiltrates their muscles.

Notably that we can show a measurable clinical benefit in 48 weeks and then our Ws is a quantitative measure of function that is sensitive to disease progression in that timeframe.

Based on these insights and the data from Readouts for demonstrating clinical benefit we aligned with regulators, including the FDA.

On our W. S as the primary endpoint.

The upcoming start of our phase III trial marks a significant milestone for both fulcrum and the Fsh D community there.

There are currently no approved drugs and nothing else even in the clinic.

People with Fsh D lose strength function independence, and mobility as fat infiltrate their muscles and there is an urgent need for a drug that can slow or stop disease progression.

Brian Stewart: And there is an urgent need for a drug that can slow or stop disease progression. The data that we reported last year from Redux 4 demonstrate Los MapaMod's potential to do exactly that, showing delayed progression and improvement in measures of function, including RWS. We are thrilled to be one step closer to bringing this important therapy to patients. Our second clinical program, F-E-X-6058, an oral HBF inducer for sickle cell disease and other hemoglobin disorders, shows great promise in addressing important unmet needs in these patient populations. The current treatment landscape for sickle cell disease consists of therapies that only target select symptoms.

The data that we reported last year from redox four demonstrate roadmap of margin potential to do exactly that.

Showing delayed progression and improvement in measures of function, including our Ws. We are thrilled to be one step closer to bringing this important therapy to patients.

Our second clinical program F 60, 58, an oral hbf inducer for sickle cell disease, and other haemoglobinopathy shows great promise in addressing important unmet needs in these patient populations.

The current treatment landscape in sickle cell disease consists of therapies that only target select symptoms.

Brian Stewart: HBF is the only mechanism that has been shown to broadly improve outcomes for key symptoms of sickle cell disease, such as VOC events, pain, fatigue, and acute chest syndrome. A robust body of genetic data shows that increases in HBF in every patient are meaningful. Emerging clinical data from gene editing further supports the benefit of HBF induction, but in the case of gene editing, it comes with a tremendous treatment burden, making it most likely to be used as a salvage there.

<unk> is the only mechanism that has been shown to broadly improve outcomes for key symptoms of sickle cell disease, such as V. Oc events pain fatigue and acute chest syndrome.

A robust body of genetic data shows that increases in hbf in every patient is meaningful.

Emerging clinical data from gene editing further support the benefit of Hbf induction, but in the case of gene editing it comes with a tremendous treatment burden, making it most likely to be used as a salvage therapy.

Brian Stewart: We discovered FTX6058 using our FulcrumSeq product. Preclinically, across multiple in vivo and in vitro assays, 6058 generated a consistent two to three fold induction in HBG mRNA that translated into the same fold induction in HBF protein.

We discovered MTX 60, 58, using our fulcrum seat product.

Pre clinically across multiple in vivo and in vitro assays 60, 58 generated a consistent 2% to three fold induction in <unk> mrna that translated into the same fold induction in hbf protein.

Brian Stewart: Last year, we transitioned to the clinic and announced positive phase one healthy volunteer data that demonstrated robust increases in HBG mRNA at multiple doses. These data gave us confidence to advance FTS 6058 into our ongoing Phase 1B study, where we will be dosing people with sickle cell disease long enough to observe protein increases. Typically, people with sickle cell disease have starting HBF levels of 5-10%.

Last year, we transition to the clinic and announced positive phase one healthy volunteer data that demonstrated robust increases in <unk> mrna at multiple doses.

These data gave us confidence to advance MTS 60, 58 into our ongoing phase <unk> study, where we will be dosing people with sickle cell disease long enough to observe protein increases.

Typically people with sickle cell disease have starting hbf levels of 5% to 10%.

Brian Stewart: As we've spoken to KOLs, we have consistently heard that a 5 to 10% increase in HBF beyond baseline levels would be transformative for patients and would be utilized as standard of care. We are highly encouraged that our robust preclinical data and phase one healthy volunteer data both predict that we can achieve these absolute increases that will be life changing for people with sickle cell disease. In December, we began enrolling the Phase 1b trial at a starting dose of 6 mg daily. We are on track to report initial data, including HPF protein levels, in the second quarter of this year. This update will be the first look at protein data in people with sickle cell disease.

As we've spoken to Kols, we have consistently heard that a 5% to 10% increase in hbf beyond baseline levels would be transformative for patients and would be utilized a standard of care.

We're highly encouraged that our robust preclinical data and phase one healthy volunteer data both predict that we can achieve these absolute increases that will be life changing for people with sickle cell disease.

In December we began enrolling the phase one b trial.

At a starting dose of 60 milligrams daily.

We are on track to report initial data, including Hbf protein levels in the second quarter of this year.

This update will be the first look at protein data in people with sickle cell disease.

Brian Stewart: Based on data from other HBF mechanisms and the process of erythropoiesis, the earliest we would anticipate seeing protein induction would be after one month of treatment, with maximal protein induction at three to five months. For this initial data in Q2, we would consider evidence of protein induction to be a very meaningful one. We also believe that FTX6058 could be a transformative therapy for other hemoglobinopathies, such as beta thalassemia, and we are on track to initiate a phase 1b trial in the second.

Based on data from other hbf mechanisms in the process of erythropoiesis. The earliest we would anticipate seeing protein reduction would be after one month of treatment with maximal protein induction at three to five months.

For this initial data in Q2, we would consider evidence of protein adoption to be a very meaningful update.

We also believe that MTX 60, 58 could be a transformative therapy for other haemoglobinopathy such as beta thalassemia.

And we are on track to initiate a phase one b trial in the second quarter.

Brian Stewart: FDX 6058 and LOSMAPIMOD, as well as our ongoing collaborations with MERC and BMS, are testaments to the power of FulcrumSeq, our product engine and the innovation backbone of our company. Fulcrum Seek has allowed us to rapidly identify novel, high-quality targets that modulate the root cause of genetically defined rare diseases.

MTX 60, 58 analyst map, a lot as well as our ongoing collaborations with FERC Merck and BMS are a testament to the power of <unk>, our product engine and the innovation backbone of our company.

Welcome Sika has allowed us to rapidly identify novel high quality targets that modulate the root cause of genetically defined rare diseases.

Judy Dunn: Notably, we expect to nominate our next development candidate by the end of this year and submit an additional new IND by the end of the first quarter of 2022. As we advance two potentially life-changing therapies through clinical development, expand our pipeline, scale up our discovery efforts, while building downstream clinical and commercial capabilities, we are well-positioned to build a leading rare disease company supported by a strong financial foundation and a cash runway that takes us into 2024. With that said, I'd like to turn it over to Judy to share more about our plans for Los Mapamons that we announced this morning. Judy?

Notably we expect to nominate our next development candidate by the end of this year and submit an additional new IMD by the end of the first quarter of 2023.

As we advance to potentially life changing therapies through clinical development expand our pipeline scale up our discovery efforts, while building downstream clinical and commercial capabilities, we are well positioned to build a leading rare disease company supported with a strong financial foundation and a cash runway that takes us into 2010.

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With that I'd like to turn it over to Judy to share more about our plans for those map a month that we announced this morning.

Judy.

Thank you Brian .

Judy Dunn: Thank you, Brian. FSHD is a genetic disorder that leads to relentlessly progressive muscular degeneration and replacement by fat. This disease begins in the face and progresses to include upper and lower limbs and the core, leading to loss of function and ultimately the loss of independence. Lesmaphimod represents a potentially life-changing therapy for people living with FSHD. Its mechanism inhibits the aberrant expression of DOX4, the genetic root cause of FSHD, responsible for muscle degeneration, fat infiltration, and loss of function.

That's S. H D is a genetic disorder that leads to relentlessly progressive muscular degeneration and replacement base that Mr.

This disease initiation of the phase and progressive strengthen upper and lower limbs and quarter, leading to loss assumption and ultimately a loss of independence.

Lets map a lot represents a potentially life changing therapy for people living with Fsh D.

Its mechanism inhibiting the aberrant expression of docs for the genetic root cause of that is HD responsible for the muscle degeneration fat infiltration and loss assumption.

Judy Dunn: As Brian mentioned, currently, there are no approved therapies, nor are there any other compounds in clinical development. Each day that people with SSHD go without therapy is another day that they risk losing strength, function, and the ability to perform basic activities like brushing their hair, dressing themselves, or holding their child. This accumulation of disability can lead to loss of independence and mobility.

As Brian mentioned currently there are no approved therapies.

Are there any other compounds in clinical development.

Each day that people with SSH key go without therapy is another day that they risk losing strength.

Function and the ability to perform basic activities like brushing your hair dressing themselves are holding their child.

It's accumulation of disability can lead to loss of independence and mobility.

Judy Dunn: We consistently hear from patients that their number one concern and number one requirement for a new therapeutic is to safely slow or stop disease progression in order to preserve the function that they have. Our Phase 2D trial, Redux 4, demonstrated that glasmaphomide slowed disease progression and improved function in people with FSHD. These data, combined with the extensive safety and tolerability data generated in more than 3,600 people, form the basis of los mapamod's very compelling benefit-risk profile as an oral medication with the potential to address the urgent need for therapy in this patient population.

We consistently hear from patients that their number one concern and number one requirement for new therapeutics is to safely slow or stop disease progression in order to preserve the function that they have.

Our phase two <unk> trial Readouts for demonstrated that let's not so much slow disease progression and improved function in people with Fsh D.

These data combined with the extensive safety and Tolerability data generated in more than 3600 people.

The basis of less snap them, a very compelling benefit risk profile as an oral medication with the potential to address the urgent need for therapy in this patient population.

Judy Dunn: Redux IV was the most comprehensive therapeutic trial ever conducted in FSHD. We gained tremendous insight into relevant clinical endpoints, as well as an understanding of the duration of time needed to show the impact of lismapimod on disease progression. We have applied those insights to the design of our Phase 3 trial, REACH, giving us confidence that REACH is optimized to demonstrate statistically and clinically significant benefits of left maplemod in FSH states and give any urgency to bring a therapy to market.

We would explore with the most comprehensive therapeutic trial ever conducted an fsh D.

We gained tremendous insight and relevant clinical endpoints as well as an understanding of the duration of time needed to show the impact of list <unk> on disease progression.

We have applied those insights to the design of our phase III trial reach giving us confidence that reaches optimized did demonstrate statistically and clinically significant benefits of less map and fsh date.

Judy Dunn: We have been preparing for this trial and engaging with patients, experts, and regulators to inform our final design. We are pleased to report that we are on track to begin recruiting shortly in the second quarter of this year. Before further describing REACH, I want to briefly highlight our learnings from Redux 4 that informed our thinking about this Phase 3 design. Redux 4 was a randomized placebo-controlled study that evaluated 80 people with FSHD over 48 weeks.

Given the urgency to bring this therapy to market, we have been preparing for this trial and engaging with patients experts and regulators to inform our final design we.

We are pleased to report that we are on track to begin read shortly in the second quarter of this year.

Before further describing reach I want to briefly highlight our learnings from Readouts for an informed our thinking about this phase III design.

We that's for was a randomized placebo controlled study that evaluated 80 people with Fsh D over 48 weeks.

Judy Dunn: In this trial, participants received either 15 milligrams of lismapimod twice daily or placebo. We were very encouraged by results from Redux 4, in which a meaningful separation between treatment effects was observed in people receiving loss macromod versus those receiving placebo. Importantly, we saw clinically meaningful impacts on function, muscle structure, and patient-reported outcomes. Data from the trial also allowed us to identify endpoints that are sensitive to disease progression and drug effect during that timeframe. Starting with reachable workspace, a measure of accessible relative surface area.

In this trial participants received either 15 milligrams <unk> twice daily or placebo.

We were very encouraged by results from Readouts for which a meaningful separation between treatment effect was observed in people receiving whatsapp amount versus those receiving placebo.

Importantly, we saw clinically meaningful impact on function muscle structure and patient reported outcomes.

Data from the trial also allowed us to identify endpoints that are sensitive to disease progression.

Andrew the fact in that timeframe.

Starting with reachable workspace, a measure assessable relative surface area.

Judy Dunn: We saw clinically meaningful improvements from baseline in the dominant arms of those treated with West Napa Mod, while those on placebo lost relative surface area over the course of the trial. Relative surface area, including reaching above the shoulders and behind the back, as measured by reachable workspace, is highly correlated to the ability to perform activities of daily living and maintain independence. Using MRI, we also observed a slowing of muscle fat infiltration, or MFI, an important marker of disease pathology.

We saw clinically relative improvements from baseline and the dominant arms of those treated with lessons from that.

Well those on placebo lost relative surface area over the course of the trial.

Relative surface area, including reaching above the shoulders and behind the back as measured by reachable workspace is highly correlated to the ability to perform activities of daily living and maintain independence.

Using MRI, we also observed a slowing of muscle fat infiltration or MSI, an important marker of disease pathology.

Judy Dunn: Muscles that already had some fat infiltration at baseline are the muscles most likely to demonstrate disease progression over 48 weeks. In these muscles, Losmacomod showed a meaningful slowing of MFI compared to placebo. Los Matlamat also preserved the health of muscles that appeared normal at baseline, essentially stopping muscle fat infiltration, while patients on placebo worsened.

Muscles, they've already had some fat infiltration at baseline or the muscles, most likely to demonstrate disease progression over 48 weeks.

And these muscles, let's not Beaumont showed a meaningful slowing of MSI compared to placebo.

<unk> also preserved the health of muscles, which appeared normal at baseline essentially stopping muscle fat infiltration.

Patients on placebo worsens.

Judy Dunn: Finally, in this trial, self-reported outcomes, such as the patient's global impression of change, or PGIC, were used to assess the recognized value of the treatment. At the end of the 48-week treatment period, people who received los maplemod reported feeling better than those who received placebo. Based on the Redux core data, we engaged with regulators, including the FDA, to gain feedback on the proposed design of the REACH study. Based on those interactions, we have selected Reachable Workspace as the primary endpoint for REACH.

Finally in this trial self reported outcomes such as the patient global impression of change for T. J, we use to assess the recognized value of the treatment.

At the end of the 48 week treatment period people, who receive loves Snapple on reported feeling better than those who received placebo.

Based on the core data, we engage with regulators, including the FDA to gain feedback on the proposed design of the reach study.

Based on those interactions we have selected reachable workspace as the primary endpoint for reach we have now finalized our trial design and are working to operationalize reach.

Judy Dunn: We have now finalized our trial design and are working to operationalize REACH. REACH will be a randomized, double-blind, placebo-controlled, multinational trial to evaluate the efficacy and safety of lismapimod for the treatment of FSHJ. The trial is expected to involve approximately 230 adults.

Each will be a randomized double blind placebo controlled multinational trial to evaluate the efficacy and safety of less map them out for the treatment of Fsh date.

The trial is expected to enroll approximately 230 adults.

Judy Dunn: Participants will be randomized one-to-one to receive either less maplomod, administered orally as a 15 milligram tablet twice a day, or placebo over a 48-week treatment period. The primary endpoint of the study is the absolute change from baseline in reachable workspace. As I outlined earlier, reachable workspace is a quantitative measure of upper extremity range of motion and function that specifically evaluates shoulder and proximal arm mobility with 3D motion sensor technology.

Participants will be randomized one to one to receive either less map a lot administered quarterly as a 15 milligram tablet twice a day or placebo over a 48 week treatment period.

The primary endpoint of the study is the absolute change from baseline in reachable workspace.

As I outlined earlier reachable workspace is a quantitative measure of upper extremity range of motion and function that specifically evaluate shoulder and proximal arm mobility with <unk> motion sensor technology.

Judy Dunn: Preserving this upper extremity function is critical for maintaining the ability for self-care and other activities of daily living that directly influence quality of life and independence. In addition to safety and tolerability, secondary endpoints include MSI, PIEGIC, and quality of life and neurological disorders for the neuroqual of the upper extremity. Reach will also include healthcare utilization questionnaires that will help inform our thinking about payer strategies as we prepare for a potential commercial launch.

Preserving the upper extremity function is critical for maintaining the ability for self care and other activities of daily living that directly influence quality of life and independence.

In addition to safety and Tolerability secondary endpoints include MSI P J and quality of life in neurological disorders for the neural quality of the upper extremity.

Which will also include health care utilization questionnaires that will help inform our thinking about payer strategy as we prepare for a potential commercial launch.

Judy Dunn: We are confident that we have selected reliable measures of disease progression in FSHK and that we will be able to clearly observe meaningful advantages for los mapumad compared to placebo after 48 weeks of treatment. As we advance REACH, we remain steadfast in our commitment to expeditiously deliver a transformative drug for people with FSHD. As we announced this morning, we will be featuring two key opinion leaders in a virtual event hosted by Fulcrum on Thursday, March 24th from 10 a.m. until noon Eastern time.

We are confident that we have selected reliable measures of disease progression and fsh D and that we will be able to clearly observed meaningful advantages formulas that ahmad compared to placebo after 48 weeks of treatment.

As we advance reach we remain steadfast in our commitment to keep expediency deliver a transformative drugs for people with Fsh date.

Judy Dunn: We will be joined by Dr. Nicholas Johnson of the Department of Neurology at Virginia Commonwealth University and Dr. Jae Han of the University of California, Irvine, one of the originators of Reachable Workspace as an influence. We look forward to sharing more about the unmet need in FSHD and REACH and how lufthanafimod is well positioned to be the first drug for people with FSHD. With that, I'll turn it over to you. Thank you, Judy.

As we announced this morning, we will be featuring two key opinion leaders to virtual events hosted by program on Thursday March 24 from 10, a M until noon eastern time.

We will be joined by Dr. Nicholas Johnson of Department of Neurology at Virginia Commonwealth University and Dr. Jay Hans I mean, you sort of referred to teeth, California, Irvine point of view originators reachable workspace as an endpoint.

We look forward to sharing more about the unmet need and fsh D and reach and how <unk> is well positioned to be the first drug for people with Fsh D.

With that I'll turn it over to Esther.

Judy Dunn: I'm thrilled to be here today as part of the Fulcrum team and to share with you an update on our financials. We are operating from a position of financial strength, ending the fourth quarter with $218.2 million in cash, cash equivalents, and marketable securities.

Thank you J D.

Thrilled to be here today as part of the <unk> and to share with you an update on our financials.

We are operating from a position of financial strength, ending the fourth quarter with $218 2 million in cash cash equivalents and marketable securities.

Esther Rojavello: Based on our current plans and projections, we expect this will fund our operation into 2024. In the fourth quarter of 2021, we recognized collaboration revenue of $5.1 million compared to $4.2 million in the fourth quarter of 2020. The increase was primarily due to revenues associated with a milestone payment under our collaboration with Chris. For the full year 2021, collaboration revenue was $19.2 million, compared to $8.8 million in 2020. This increase is due to the execution of the Collaboration and License Agreement with Bristol in July 2020, as well as an increase in revenue recognized under our collaboration with Merck.

Based on our current plans and projections, we expect this will fund our operations into 2024.

Esther Rojavello: R&D expenses for the fourth quarter of 2021 were $18.9 million compared to $16.1 million for the fourth quarter of 2020. R&D expenses for the full year 2021 were $69.7 million compared to $59 million for the full year 2020. This increase is primarily due to the advancement of our clinical program. G&A expenses in the fourth quarter of 2021 were $9.7 million compared to $5.9 million for the fourth quarter of 2020, and for the full year 2021, they were $30.5 million compared to $21.4 million for the full year of 2020.

During the fourth quarter of 2021, we recognized collaboration revenue of $5 1 million compared to $4 2 million in the fourth quarter of 2020.

The increase was primarily due to revenues associated with the milestone payment under our collaboration with Bristol.

For the full year 2021 collaboration that new was $19 2 million compared to $8 8 million in 2020.

This increase was due to the execution of the collaboration and license agreement with Bristol in July 2020.

As well as an increase in revenue recognized under our collaboration with Merck.

R&D expenses for the fourth quarter of 2021 was $18 9 million compared to $16 1 million for the fourth quarter of 2020.

R&D expenses for the full year 2021 was $69 7 million compared to $59 million for the full year 2020.

This increase was primarily due to the advancement of our clinical programs.

G&A expenses in the fourth quarter of 2021 were $9 7 million compared to $5 9 million for the fourth quarter of 2020.

And for the full year 2021, $35 million compared to $21 4 million for the full year of 2020.

Esther Rojavello: This increase was primarily due to increased employee-related expenses and preparation for potential commercial launches of lismathamide for FSHD and 6058 for sickle cell disease. Finally, our net loss for the fourth quarter of 2021 was $23.5 million compared to a net loss of $17.7 million for the fourth quarter of 2020. Our net loss for the full year 2021 was $80.8 million, compared to a net loss of $70.8 million for the full year 2020.

This increase was primarily due to increased employee related expenses.

And preparation for potential commercial launches.

Mathematics, Fsh D and $60 58 for sickle cell disease.

Finally on <unk>.

Net loss for the fourth quarter of 2021 was $23 5 million compared to a net loss of $17 7 million for the fourth quarter of 2020.

Our net loss for the full year 2021, with 88 million compared to a net loss of $70 8 million for the full year 2020.

Brian Stewart: With that, I'll turn it back to Brian. Thanks, Esther. As you've heard today, 2021 was a year of tremendous progress for Fulcrum, and we have even more to look forward to as we continue to advance our promising programs in FSHD, sickle cell disease, and other hemoglobinopathies and continue to build out our pipeline. We look forward to keeping you up to date on our progress throughout the year. Operator, you may now open the line for questions. Thank you. And to ask a question, simply press star 1 on your telephone. To withdraw the question, press the pound or hash key.

With that I'll turn it back to Brian .

Operator: Again, that is Star 1 if you have a question. Please stand by while we compile the Q&A roster. The first question is from Dae Gun Ha with Stifo.

Thanks, Esther as you've heard today 2021 was a year of tremendous progress for fulcrum.

And we have even more to look forward to as we continue to advance our promising programs and Fsh D sickle cell disease, and other haemoglobinopathy and continue to build out our pipeline. We look forward to keeping you up to date on our progress throughout the year.

Operator, you May now open the line for questions.

Thank you and to ask a question simply press star one on your telephone to withdraw that question press the pound or hash key again that is star. One if you have a question. Please standby, while we compile the Q&A roster.

First question is from Dae Gon ha with Stifel.

Dae Gun Ha: Great. Good morning, guys. Congratulations on all the progress. I guess two on 6058 and one on FSHD.

Great. Good morning, guys. Congrats on all the progress I guess, two on 60 58, and one on Fsh D.

Unknown Executive: One, just going back to 6058, I recall you guys were doing a chronic tox study, preclinical chronic tox for the 6058 program. So anything you can comment with regard to its progress, any signs or observations you've made, things like CPK, for example. And then the second question is, last month you mentioned cohort one is still enrolling for the 6058 program. So can you comment on the rate of patient enrollment in this study, given three sites are currently active and recruiting?

One just going back to 60 58, I recall you guys were doing a chronic tox study preclinical chronic talks for the 60 58 programs. So anything you can comment with regards to its progress any signs or observations you've made.

Things like see PK for example, and then second question is last month, you mentioned CT one is still enrolling for the $6 50, a program. So can you comment on the rate of patient enrollment to the study given three sites are currently active and recruiting and what's the cadence of readout investors can expect for the remainder of 2022.

Unknown Executive: And what's the cadence of readouts investors can expect for the remainder of 2022, including the second quarter update? And then I'll just follow up with the REACH study question next. Yeah, absolutely. Thanks, Dagon. Why don't I turn it over to Chris?

Including the second quarter update and then I'll just follow up with the reach study question next.

Unknown Executive: We can give an update on the talks, which we provided earlier this year, and then also talk about the guidance that we've provided for the 2Q update from the Phase 1B study. Great. Hi Dagon.

Yeah, absolutely thanks Dae gon.

Why don't I turn it over to Chris we can give an update on the Tox, which we had provided earlier this year and then also talk about the guidance that we've provided for the two Q update from the phase <unk> study.

Unknown Executive: Thanks for the question. So, yeah, as we reported, we have completed three-month talks, and the three-month talks gave us continued encouragement to continue pursuing clinical development as planned. We made no changes to our development plans based on the results of the three-month talks.

Alright. Thanks.

Thanks for the question. So as we reported we have completed three month Tox and the three month Tox gave us the continued.

<unk> to continue pursuing clinical development as planned we made no changes to our development plans based on the results for the three.

Unknown Executive: We have entered into chronic talks. We don't have any updates on that, and we don't have any new findings to share at this point. Regarding your comments about CPK or creatine phosphokinase, as you recall, we did see two unrelated events in phase one, but both of those cases happened well after the last day of dosing. In fact, seven to 10 days after the last day of dosing and were deemed to be unrelated by the primary investigator who was blinded to study treatment.

Three month Tox, we have entered chronic tox, we don't have any updates on that.

And we don't have any new findings to share at this point.

Regarding your comment about CDK are increasing but the plan is as you recall, we did see two unrelated events in phase one, but both of those cases happened after well after the last day of dosing and facts. So seven to 10 days after.

The last day of dosing and were deemed to be unrelated by the primary investigator who was blinded study treatment so nothing new on that front.

Unknown Executive: So nothing new on that front. In regard to the Phase 1b trial, it is enrolling, as you have well stated. We have initiated enrollment at three sites and are actively recruiting additional sites, as you also noted. The current dose is six milligrams, and patients are anticipated to participate in this trial for up to three months. We have plans for up to 10 patients in each cohort. We are still in cohort one, and we are certainly on track to provide an update in Q2 that will be meaningful for HPF and for other endpoints that are relevant to this trial. Okay, great.

In regards to the phase one b trial. It is enrolling as you well stated.

We have initiated enrollment at three sites and are actively recruiting additional sites. As you also noted the current doses six milligrams and patients are anticipated to participate in this trial for up to three months.

Planned for up to 10 patients in each cohort we are still in cohort one and we are certainly on track to provide an update in Q2 that will be a meaningful for hbf and for other endpoints that are relevant to this trial.

Unknown Executive: Thanks for the update. So just pivoting to the REACH study, maybe a question for Judy or Chris, can you talk about the powering assumptions baked into the reachable workspace that's going to be the primary endpoint? And notably, following the discussions with the regulators, have you made any changes or updates to how you're going to be quantifying reachable workspace? I believe it was using the Connect device previously, but any updates on that front?

Okay, great. Thanks for the update so just pivoting to the reach study.

Maybe a question for Judy or Chris can you talk about the powering assumptions baked into the reachable workspace, that's going to be the primary endpoint.

Notably following the discussions with the regulators have you made any changes or updates to how youre going to be quantifying reachable workspace I believe it was using the connect device previously, but any updates on that front. Thank you and congrats on all the progress.

Unknown Executive: Thank you and congratulations on all the progress. Yeah, thanks, Dagon. Why don't I turn it over to Judy, and we can speak at a high level about our strategy as it relates to powering, and we can also talk a little bit more about reachable workspace and what we were able to observe in Redux 4 as well. Thanks, Daegan.

Yes, Thanks, Dae gon, why don't I turn it over to Judy and we can speak to at a high level.

Our strategy as it relates to bring and we can also talk a little bit more about reachable workspace and what we were able to observe in redux for as well.

Judy Dunn: I really appreciate the opportunity to talk to you a little bit about Reachful Workspace and how we are thinking about it for the REACH trial. As you know, in Redux 4, we were able to show not only statistically significant values but values of less than 0.05 on REACH and on RWS. And the RWS itself is a very important endpoint for us because it is quantitative. When we talk about FSHD, you know we're talking about the loss of function due to muscle degeneration, and this function really does impact activities of daily living.

Thanks, Dae gon really appreciate the opportunity to talk to you little bit about reachable workspace and how we are thinking about it for the reach trial as you know and Readouts for we were able to show not only statistical significance statistically significant values with P values less than <unk> five on reach and on the <unk>.

U S and the R. W. S itself is a very important endpoint for us because it is quantitative.

When we talk about Fsh D. You know, we're talking about the loss of function due to muscle degeneration and this function really does impact.

Activities of daily living.

Judy Dunn: So in the REDUX IV trial, we were able to really understand the sensitivity of the reachable workspace scale and also understand the statistical implications, which you've asked about. When we met with regulators, we had a number of conversations that were very collaborative, and it was understood that what we were trying to achieve in looking at Les MacLemans' ability to slow disease progression and maintain function. What the regulators recognized was that Reachable Workspace is a functional endpoint, and they were really supportive of our ability to use that as a primary endpoint in the REACH study.

So in the <unk> four trial, we were able to really understand the sensitivity of the reachable workspace scale and also understand the statistical implications, which you asked about.

When we met with regulators, we had a number of conversations that were very collaborative and understood that what we were trying to achieve and looking at <unk> ability to slow disease progression and maintain function.

What we what the regulators recognized was that reachable workspace is a functional endpoint and they were really supportive of our ability to use that as a primary endpoint and the reach study.

Judy Dunn: When we talk about powering, we are powering for a difference between placebo and lasmapomod at week 48 in REACH, and the power of the study is over 90 percent to detect a difference which we believe is clinically meaningful. And our next question comes from Joseph Schwartz with SBB Security. Hi, thanks very much, and let me also have my congratulations on the progress you're making. So I was also, I have a question on FSHD first and then 6058.

When we talk about powering we are powering for a difference between placebo.

And I'll ask Matt Beaumont at week 48 on reach and power of the study is over 90%.

To detect a difference, which we believe is clinically meaningful.

Okay.

And our next question comes from Joseph Schwartz with SBB Securities.

Alright, Thanks, very much and let me also add my congrats on the progress you're making so I was just also.

A question on Fsh D first and then $6 58 in terms of the reach study.

Joseph Schwartz: In terms of the REACH study, given it's much larger than Redux IV, but it seems to not require biopsies, I was wondering if you could talk about the push and the pull in terms of the cadence of enrollment that you expect and, you know, when do you think you could achieve full enrollment and report data from REACH? And then also a timing question on 6058, the Phase 1b data in the second quarter. When should we expect you to report this data? I'm curious because it seems like the effect is not only dose-dependent but time-dependent.

Given its much larger than redux, four but it seems to not require biopsies I was wondering if you could talk about the push and the pull in terms of.

The cadence of enrollment that you expect and when do you think you could achieve full enrollment and report data from reach and then.

Also a timing question on $60 58.

Phase one.

Data in the second quarter.

When should we expect you to report this data.

I'm curious because it seems like the effect is not only dose dependent but.

I'm dependent I'm wondering if it's logical to expect it in the later part of the second quarter. So that way you can.

Brian Stewart: I'm wondering if it's logical to expect it in the later part of the second quarter so that way you can see the experience in patients treated for a longer period of time. Yeah, thanks for the questions, Joe. And maybe I'll take the first question on FSHD and then turn it over to Chris Morabito for the second question. So regarding REACH, I think we really wanted to build on our experience from the Redux 4 trial that we previously conducted. I think one of the things that's very interesting about this particular disease, FSHD, is that, unfortunately, there are no approved therapies.

See the experience in patients treated for a longer period of time.

Sure Yeah. Thanks for the questions, Joe and maybe I'll take the first question on Fsh D. And then turn it over to Chris <unk> for the second question so regarding reach.

I think we really wanted to build on our experience from the Readouts for trial that we previously conducted I think one of the things that's very interesting.

About this particular disease Fsh D is unfortunately, there are no approved therapies. It is such a progressive and devastating disease that when we.

Brian Stewart: It is such a progressive and devastating disease that when we enrolled in the Phase 2B trial, Redux 4, there was tremendous interest and enthusiasm from the patient community about a potential treatment. And as a result, we were able to enroll that trial relatively quickly, faster than expectations. We ended up enrolling more patients than we anticipated. And that was due to this unmet need and the size of the patient population.

Enrolled in the phase two B trial Redux, four there was tremendous interest and enthusiasm from the patient community about a potential treatment and as a result, we were able to enroll that trial relatively quickly.

Faster than expectations, we ended up enrolling more patients than we anticipated and that was due to this unmet need and the size of the patient population.

Brian Stewart: So as we then transition here into the REACH trial, while we haven't provided guidance yet on exact timing, I think we continue to believe and hear that the patient community is extremely enthusiastic about the opportunity to get involved in a registration trial for potentially the first treatment for FSHD. Why don't I turn it over to Chris, and we can talk more about the guidance for the sickle update. Yeah. Hi Joe.

So as we then transition here into the reach trial, while we haven't provided.

Yet on exact timing I think we continue to believe in here that the patient community is extremely enthusiastic about the opportunity.

To get involved in a registration trial for potentially the first treatment for Fsh date, why don't I turn it over to Chris and we can talk more about the guidance for the sickle update yes, Joe Thanks.

Chris Morabito: Thanks. We are on track to provide this guidance in Q2, and the goal of that guidance is to provide a meaningful update specifically on HBF, the change from baseline in HBF, which we believe tightly correlates with clinical outcomes in patients. As you know, this is a three-month trial, and the participants can opt to participate for up to three months of treatment. So the longest treatment duration that we're going to have in any individual is three months. And I think you're correct in your assumption that, and in fact, the data have shown that the effect of 6058 is time and dose dependent.

So we are on track to provide this guidance in Q2 and the goal of that guidance is to provide a meaningful update specifically on the hbf, but changed from baseline in <unk>, which we believe tightly correlated with clinical outcomes in patients.

As you know this is a three month trial.

The participants can.

After participate for up to three months of treatment. So the longer treatment duration that we're going to have in any individual is up to three months and I think you're correct in your assumption that and in fact, the data have shown that the effects of $6 58 is time and dose dependent we are seeing at two weeks in healthy volunteers, but look to be very.

Chris Morabito: We are seeing at two weeks in healthy volunteers what look to be very substantial increases in HBG or HB gamma mRNA, which we believe will translate into HBF protein. And the range of increase goes from two and a half fold from baseline to up to six fold from baseline. And that's just at two weeks.

Substantial increases in each BG or HP gamma mrna, which we what we believe will translate into HBO protein in the range of increase goes from two and a half folds from baseline to up to six fold from baseline and Thats just in two weeks and as you recall the data actually haven't plateaued by two weeks so it's possible.

Chris Morabito: And as you recall, the data actually hadn't plateaued by two weeks. So it's possible that the maximum increase hasn't yet been seen in a clinical trial. So, you know, we're going to dose out to three months. We want to have a number of patients at three months for us to be able to substantially inform the absolute increase in HBF. And when we have those data in Q2, we'll be able to share them more publicly. Great, thanks for the color.

That's the maximum increase hasnt, yet been seen in our clinical trial.

We're going to dose up to three months, we want to have a number of patients at three months for us to be able to substantially inform the absolute increase on HBO and when we have those data in Q2, we'll be able to share them publicly.

Publicly.

Great. Thanks for the color.

Matthew Harrison: Your next question comes from Matthew Harrison with Morgan Stanley. Um, great. Good morning. Thanks for taking the questions. I guess two for me.

Your next question comes from Matthew Harrison with Morgan Stanley .

Matthew Harrison: So first on 6058, Brian, could you just maybe contextualize the comment you made at the beginning of the call? And I just want to make sure how you're trying to set expectations around the data. We can expect, I believe you said something to the effect, um... given the amount of time required to get to peak protein production, that you would view any amount of protein as a positive signal? Can you just sort of help people think about the message you were trying to convey with that?

Great. Good morning, Thanks for taking my questions I guess two for me. So first on <unk>, Brian could you just maybe <unk>.

Contextualize the comment you made at the beginning of the call.

And I just want to make sure. How you are trying to set expectations around the data. We can expect I believe you said something.

To be effective.

Given given the amount of time required to get to peak protein production that you would view any amount of.

Protein as a positive signal can you just sort of help people think about the message we're trying to convey with that and then I guess second just just on reach.

Brian Stewart: And then I guess, second, just on REACH. Can you just talk about how much that trial is going to cost and how you think about the allocation of capital to that program versus some of the rest of the programs. Thanks very much. Yeah, sure, Matthew.

Can you just talk about.

How much how much that trials in our costs and how you think about allocation of capital to that program versus some of the rest of the program. Thanks very much.

Brian Stewart: So I think in terms of 60-58, as we've indicated, our therapeutic goal is to see a two to three-fold increase in HBF. I think one of the things that's very encouraging is that those are the levels of both mRNA and protein that we observed pre-clinically, And as we transitioned into the clinic, that was consistent with what we saw in the phase one healthy volunteer trial. So, as we have also mentioned, we come at this from a position of tremendous strength.

Yes, sure Matthew So I think in terms of $6 58, as we've indicated our therapeutic goal is to see a two to three fold increase in Hbf I think one of the things. That's very encouraging is that those are the levels of both mrna and protein that.

We observed pre clinically and.

And as we transitioned into the clinic that was consistent with what we saw in the phase one healthy volunteer trial.

So as we also mentioned we come at this from a position of tremendous strength, there's a tremendous amount of human genetic data that clearly demonstrates the benefit of increasing hbf and I think that's extremely well understood by the community that's extremely well understood by clinicians.

Brian Stewart: There's a tremendous amount of human genetic data that clearly demonstrates the benefit of increasing HBF, and I think that's extremely well understood by the community. That's extremely well understood by clinicians. And as we talk to clinicians and ask the question about what it would take for this to be a transformational therapy and standard of care, we consistently hear back that these 5% to 10% absolute increases. So as we look towards this Phase 1b update that we'll have in the second quarter, what we were not able to do in the Phase 1 healthy volunteer study is we were not dosing long enough to be able to see protein increase.

And as we talk to clinicians and asked the question about what would it take.

For this to be a transformational therapy and standard of care, we consistently hear back that these 5% to 10% absolute increases.

As we look towards this phase one b update that we'll have in the second quarter, what we were not able to do in the phase one healthy volunteer study as we were not dosing long enough.

To be able to see protein increases, but we certainly believe as we look at other hbf mechanisms that the three month time period will be sufficient in the phase <unk> study. So as we go into the data update our hope is to begin to see robust.

Brian Stewart: But we certainly believe, as we look at other HBF mechanisms, that the three month time period will be sufficient in the Phase 1B study. So as we go into the data update, our hope is to begin to see robust increases in HBF and to further give us conviction that we have the potential to achieve these levels within two to three fold increases and levels that will be transformational for patients. So, as Chris mentioned, there are certainly some elements of dose dependency and time dependency, but our hope is certainly that three months will be sufficient to see robust increases in HBF. And why don't I turn it over to Esther, and we can talk a little bit more about capital allocation and the REACH study. Yeah, thanks, Matt.

<unk> in Hbf.

And to further give us conviction that we have the potential to achieve these levels.

Within two to three fold increases in levels that will be transformational for patients.

So as Chris mentioned, there are certainly some element of.

Dose dependency and time dependency.

But our hope is certainly that three months will be sufficient to see robust increases in hbf.

And why don't I turn it over to Esther and we can talk a little bit more about capital allocation in the reach study.

Esther Rojavello: So we plan to initiate the phase three REACH trial in the second quarter of 2022, and the trial, as Judy mentioned, will enroll about 230 patients. And as we demonstrated in our phase 2b REDOX trial, we enrolled that very efficiently and in a timely manner. And that's because we have a strong network of relationships with the FSHD patient communities and know the treatment providers to this degree. Now, for the Phase 3 REACH trial, we're well positioned with the insights we've gained from the Redux 4 trial to continue to be cost effective, and the guidance for our cash runway incorporates the cost of this trial.

Yes, Thanks, Matt.

We plan to initiate the phase III reach trial in the second quarter of 2022, and the tile as Judy mentioned.

230 patients.

And as we have demonstrated in our phase <unk> trial, we enrolled that very efficiently and in a timely manner and that's because we have a strong network of relationships with the Fsh D patient communities and know the treatment providers for the shipping now.

Now for the phase three trial were well positioned with the insights we gained from the meat export child to continue to be cost effective and the guidance for our cash run rate incorporates the cost of this trial.

Esther Rojavello: And another important point to keep in mind is that lismapimot could potentially be the first-to-market therapy for this untreated patient population. And as we look at the unmet need in this indication, we believe the investment in this program will have a meaningful impact on the patient community. Thank you very much.

And another important point to keep in mind is that this mathematics could potentially be the first to market therapy for this untreated patient population.

As we look at the unmet need in this indication we believe the investment in this program will have a meaningful impact on the patient community.

Thanks very much.

Thanks, Matt for your question. Thank you.

Esther Rojavello: Thank you. Your next question comes from Judah Frommer with criticism. Hi, good morning.

Your next question comes from Judah Frommer with credit Suisse.

Judah Frommer: Thanks for taking the question. First, on 6058 and just kind of the enrollment timelines and, in general, you know, there are obviously several...modalities, recruitment, in terms of SCD clinical trials and the timing doesn't always align, but is there anything you can kind of help us with? Of the, Yes, yeah, hi, to thank you for the question. We have had nothing but excitement from sites and feedback from patients about participating in this trial. And frankly, we have not felt any competition risk here.

Good morning, Thanks for taking the question first one on 6058 and I'm, just kind of the enrollment timelines and in general you know there are obviously several modalities recruiting and in terms of SCD clinical trials. The timing doesn't always align but is there anything you can kind of help us with in terms of feedback from patients or investigator.

<unk>.

As to enrollment for your trial versus potentially others that may have somewhat overlapping timelines, whether theyre different modalities or not.

Unknown Executive: I think the excitement comes from the fact that we've generated evidence now that says that we are in fact what we promised to be, which is an oral HPF inducer, and the mechanism behind HPF is well understood, and its impact on this disease has been well characterized, and it is well appreciated not just by the patient community but also by the physician community. And the fact that we can do this with an oral medicine is also quite compelling. So, we haven't felt any competitive pressure so far with enrollment, and that's been a good sign. That's great!

Sure, Yes, yes, hi, Tito Thank you for the question.

We have had nothing but excitement from.

Right.

Feedback from patients about participating in this trial and frankly, we have not felt any.

Competition risk here I think the excitement generates from the fact that we've generated now evidence that says that we are in fact, what we promised to be which is an oral hbf inducer and the mechanism behind each be up as well understood. Its impact on this disease are have been well characterized and are well appreciated not just by the patient community, but also by <unk>.

The physician community and the fact that we can do this with an oral medicine is also additionally, quite compelling. So we haven't felt any competitive pressure, so far with enrollment and thats been a good sign.

Unknown Executive: And then just switching gears to Los Mathemat, anything you can help us with in terms of conversations with the agency on kind of how relevant, you know, ducts for gene expression biopsies are kind of an assessment. Lee's Berlin firm, for Disease here. And also, there's certainly a decent amount of natural history work being done in this space. So did that come up as a potential competitor? Maybe not now, but if the trial was going to happen at a later date, whether natural history would be more helpful than it would be today.

Okay. That's great and then just switching gears to tell US a lot of anything you can help us with in terms of conversations with the agency on kind of how relevant you know dux for gene expression in biopsies are kind of in assessing disease burden for.

For disease here and then also there there is certainly a decent amount of natural history work being done in this space. So did that come up in terms of a potential comparator or maybe not now, but you know if if the trial.

What's going to happen at a later date, whether natural history. It would be more helpful than it would be today.

Yeah.

Judy Dunn: Thanks for the questions. I'll take the question around DUX4 first. When we meet with regulators, what they're most concerned about, and they have been even since the DUX4 trial and before, is how patients function and feel. And in reDUX4, we demonstrated very clearly that we have an improvement in how patients function, and patients recognize the value of the medicine. In terms of the DUX4 biomarker, there is so much biologic variability. There is so much technological variability, too.

Thanks for the questions I'll take the question around DOCSIS four <unk>.

We meet with regulators, what they're most concerned about and they have been even since the ducks for trial and before is that what is important is how patients function and field.

And then Readouts for we demonstrated very clearly that we have an improvement in how patient function and patients recognize the value of the medicine.

In terms of the ducks for biomarker.

There is so much biologic variability there is so much tech novel object variability and really putting patients through a muscle biopsy. When we know that we can hit and what's ultimately most important which is function for us and for the regulators, thus far as the biomarkers really kind of off the table.

Judy Dunn: And really, putting patients through a muscle biopsy when we know that we can hit on what's ultimately most important, which is function, for us and for the regulators, DUX4 as a biomarker is really kind of off the table because of the data that we have in hand that's more relevant to patients. So they were very supportive of moving away from that biomarker in our case and being able to just talk about how this drug helps patients to function better, and do patients recognize that value. So we won't be continuing; we won't be continuing with DUX4.

Because of the data that we have in hand, that's more relevant to patients.

So they were very supportive of moving away from that biomarker in our case and being able to just talk about how does this help patients to function better and do patients recognize that value. So we won't be continuing we won't be continuing with docs for.

Judy Dunn: Now in terms of the natural history studies, those are studies that we are involved in, that we're watching closely, and we utilize them actually in addition to DUX4 to design our REACH trial. So we have a lot of confidence that we understand the course of disease progression, both from our REDUX4 trial as well as from these natural history studies. And we're very appreciative of the investigators and patients that are being followed to help inform our trial. And those continue to be ongoing, and we've learned a lot from them.

Now in terms of the natural history study those are studies that we are we are involved in that we're watching closely and we utilized actually in addition to docs for she was design a reach trial. So we have a lot of confidence that we understand of course of disease progression both from a readouts for trial as well as from these natural history studies and we're very appreciative.

<unk> for the investigators and patients that are being followed to help inform our trial and those continue to be ongoing and we've learned a lot from them and we're looking forward to being able to show significantly.

Judy Dunn: And we're looking forward to being able to show significantly clinically relevant differences, both in function and feel, at the end of the REACH trial. All right, as a reminder, ladies and gentlemen, to ask a question, simply press star one on your telephone. We have a question from Ted Tenthoff with Piper Sandler.

Clinically relevant differences both in function and field at the end of the reach trial.

Alright, Okay reminder, ladies and gentlemen to.

Ask a question simply press star one on your telephone.

We have a question from Ted Hoff with Piper Sandler.

Ted Tenthoff: We have a question from Ted Tenthoff. Great. Thank you very much. Good morning, everyone. I'm sorry. I apologize. I turned the call in a little bit late.

Great. Thank you very much good morning, everyone.

I apologize if that's on the call a little bit late so if this has already been answered.

Have you repeat but.

When it comes to their fellow last answer really interesting and informative. Thank you for that.

Ted Tenthoff: So if this has already been answered, I don't mean to have you repeat it. But when it comes, and Judy, I found that last answer really interesting and informative. Thank you for that.

When it comes to the primary endpoint what it is.

A clinically meaningful change or reachable workspace.

Have you given any sense for sort of what the powering looks like with 230 patients approximately 115 on trunk.

Yeah.

Judy Dunn: When it comes to the primary endpoint, what is a clinically meaningful change in reachable workspace? You know, have you given any sense of sort of what the powering looks like with 230 patients, approximately 115 on the trunk? Thanks for the question.

Thanks for the question I think that is really what people want to know about and what we continue to work on to be able to relate the clinical meaningfulness of this difference in terms of outcomes.

So we have a number of data points that we've used to Q1 talk with the regulators to support reached forward state, but also to help us to understand the clinical relevance. So probably first and foremost there's just such a strong correlation between changes in reachable workspace and activities of daily living that are measured by other scales like.

Judy Dunn: I think that is really what people want to know about and what we continue to work on to be able to relate the clinical meaningfulness of this difference in terms of outcomes. So we have a number of data points that we've used to, one, talk with the regulators to support reachable workspace, but also to help us to understand the clinical relevance. So, probably first and foremost, there's just such a strong correlation between changes in reachable workspace and activities of daily living that are measured by other scales like the NeuroQL. Why we prefer reachable workspace is that it's quantitative, and it's very reliable because we are still using that Connect system, and that 3D technology really takes quantification to a different level.

And our own cloud why we prefer reachable workspace is that its quantitative and its very reliable because we are still using that connect system and that three D technology really takes quantification to it to a different level.

Judy Dunn: In addition to that, when we looked at our own data, there was also a strong correlation between how patients feel and those changes in reachable workspace. So we're beginning to quantify those differences in patients who are improving and how their reachable workspace scores are changing, and for those who don't feel better. And what we saw there is also a strong correlation. And then finally, the third correlation, I think probably the most important correlation, are those changes in disease pathology.

In addition to that when we looked at our own data there is.

Also a strong correlation between how patients feel and those changes and reachable workspace. So we're beginning to quantify those differences in patients who are improving and how they reach full workspace scores are changing and for those who don't feel better and what we saw there is also a strong correlation and then finally the third.

I think probably the most important correlation or those changes and disease pathology, we had some correlations between the changes in muscle fat infiltration.

Judy Dunn: We had strong correlations between the changes in muscle fat infiltration and functional outcome on reachable workspace. So when we powered the study, we powered it at over 90% to be able to detect the difference between placebo and drug-informed use. And when you think about this, reachable workspace, it's just so intuitive, right?

And function functional outcome are reachable workspace. So when we powered the study was powered at over 90%.

To be able to detect a difference between placebo and drug and 48 weeks and when you think about this reachable workspace.

It's just so intuitive right. If you can reach more areas, you're going to be able to function better being able to continually work on how Q related quantitatively as part of the analysis plan for reachable workspace. So we won't be able to put those additional measurements in comparison to get.

Judy Dunn: So if you can reach more areas, you're going to be able to function better. Being able to continually work on how to relate this quantitatively is part of the analysis plan for reachable workspace. So we'll be able to put those additional measurements and comparisons together and speak with people about them as the trial data is released. Great, that's really helpful.

And speak with.

With people about them.

As the trial data is released.

Esther Rojavello: And then, if I may, just a quick clarification for Esther, the guidance that you gave for cash through year-end, I understand that that includes expenditures for Phase 3, but that doesn't assume the Phase 3 readout by the end of 2024. Is that correct, just to clarify? So, Ted, thanks for that question.

Great. That's really helpful. And then equipment, just a quick clarification request or.

The guidance that you gave for cash through year end.

I understand that that that includes expenditures for the phase III, but that doesn't assume the phase III readout.

2024 is that correct just to clarify.

So okay. Thanks for that question, we have not guided to readout by the end of 2024 just to be clear on the reach side.

Esther Rojavello: We have not yet been guided to a readout by the end of 2024. Just to be clear on the reach chart. So, for the Phase 3 REACH trial, you know, we are planning a 48-week treatment period with enrollment commencing in the second quarter of this year, and we believe we're well-positioned to enroll efficiently. But, as I said, we're not guiding beyond this at this time. With regard to your question on cash runway... We're fortunate to have a robust pipeline with three programs in the clinic this year, a potential new IND early next year, and a discovery engine that is highly productive.

So for the phase III reach trial, we are planning a 40 week treatment period with enrollment commencing in the second quarter of this year.

And we believe we're well positioned to handle efficiently, but as I said, we're not guiding beyond this at this time with regards to your question cash runway.

We're fortunate to have a robust pipeline with three programs in the clinic. This year a potential new <unk> early next year and a discovery engine that is highly productive. So we're executing on multiple fronts here with a cash position of about $218 million as a P. O N E.

Esther Rojavello: So we're executing on multiple fronts here with a cash position of about $218 million as a PRN. And we're in a strong financial position and well-funded to execute on our plans as we've laid out into 2024. Fred, Fred.

And we're in a strong financial position and well funded to execute on our plan as we laid out into 2024.

Okay. Thank you.

Thank you.

Esther Rojavello: Thank you. And our last question comes from Tiffany Tassin with the Bank of America. Please go ahead. Okay, I think that sounds like me, so I'm going to go for it.

And our last question comes from Tiffany <unk> with Bank of America. Please go ahead.

Okay, I think that sounds like me, so I'm going to go for it.

Tiffany Tassin: And you guys give me a little bit of color on when you expect to see the two to three-fold fetal hemoglobin impact. I think that it is reasonable to assume, based on what you said, that three months should show a robust effect. But so that I'm clear, do you think three months would be enough time to show that three to two to three fold increase? and then can you just remind us how many patients' worth of data will be released?

You guys give me a little bit of color on them.

You expect to see that two to three fold.

Fetal hemoglobin impact I think that it is reasonable to assume based on what you said that that three months.

So you know a robust effect, but so that I'm clear do you think three months would be enough time to show that three of them two to three fold increase.

And then can you just remind us how many patients worth of data will be released thank you.

Tiffany Tassin: Thank you. Yeah, thanks, Zazine. In terms of the timing to see a two to threefold induction, we focused on essentially two data points to kind of guide us and set expectations for us. One is just the process of erythropoiesis.

Yeah. Thanks, Susan.

In terms of the timing to ceded to see a two to three fold induction.

We focused on essentially two data points to kind of guide us and set expectations for US one is just the process of erythropoiesis.

Second is we looked at other mechanisms that had been known to induce hbf and we looked at the timing of those and.

Brian Stewart: The second is that we looked at other mechanisms that were known to induce HBF, and we looked at the timing of those. And as we looked across a number of mechanisms. Typically, we saw maximal HBF induction in a time period of about three to five months, and the earliest that HBF increases were observed was at one month. So that's really informing us going into the phase one B study. And our expectation is that three months will be a sufficient amount of time to see robust increases in HBF. We don't yet know if those will be maximal.

And as we looked across a number of mechanisms.

Typically.

We saw a maximal hbf induction in a time period of about three to five months.

And the earliest that hbf increases were observed was at one month. So that's really informing us going into the phase one b study. So our expectation is that three months will be a sufficient amount of time to see robust increases in hbf, we don't yet know if those will be <unk>.

Brian Stewart: And for that, we'll have to wait to see the data in terms of guidance for the number of patients. What we've announced is up to three cohorts and up to 10 patients per cohort. As Chris mentioned, we're currently enrolling in our first cohort, which is six milligrams. We will provide an update as we open up additional cohorts. So we haven't provided exact guidance on the number of patients.

<unk> and for that we'll have to wait to see the data in terms of the guidance.

For the number of patients what we've announced is up to three cohorts and up to 10 patients per cohort as Chris mentioned, we are currently enrolling in our first cohort, which is six milligrams. We will provide an update as we open up additional cohorts. So we haven't provided exact guidance on number of patients.

But again the hope is that it will be a sufficient number of patients and a sufficient time period to see robust hbf induction.

Okay, and then the time that it could take to get the maximum amount just directionally speaking would that be closer to six months or would you or do you think it would be closer to a year.

Brian Stewart: But again, the hope is that it will be a sufficient number of patients and a sufficient time period to see robust HBF induction. Okay. And then the time that it could take to get the maximal amount, just directionally speaking, would that be closer to six months or would you think it would be closer to a year? So, hi Sadeen. This is Chris.

So hi, <unk> this is Chris.

Yes.

We'll go back to what Brian said, we think it will take three to five months to see Maxwell increases will certainly at this Q2 update will be a patient's dosing to after three months, we will see strong directional changes and.

Chris Morabito: Yeah, going back to what Brian said, we think it will take three to five months to see maximal increases. Well, certainly at this Q2 update, where we have patients dosing for up to three months, we'll see strong directional changes. And, you know, they may not be maximal, but we do expect to see robust increases in HPF by that time. Okay, so I guess closer to six months would be the answer.

They may not be maximum but we do expect to see robust increases in each be up at a time.

So I guess closer to six months and began thing.

Chris Morabito: Thank you. Thank you. And with that, we conclude the Q&A session. I will turn the call back to Brian Stewart for his final remarks. Great. Thanks again for everybody's time today, and we appreciate the continued support of Fulcrum. Have a great day. Thank you, ladies and gentlemen, for participating in today's program. You may now disconnect and have a wonderful day. BF-WATCH TV 2021, [music]

Thank you.

Thank you and with that we conclude the Q&A session I will turn the call back to Brian <unk> for his final remarks.

Great. Thanks.

Thanks again for everybody's time today and we appreciate the continued support have a great day.

Thank you, ladies and gentlemen for participating in today's program you may now disconnect and have a wonderful day.

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