Q3 2021 Fulcrum Therapeutics Inc Earnings Call

[music].

Good morning, and welcome to the Falcon Therapeutics third quarter 2021 conference call. Currently all participants are in a 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 MS. Naomi Aoki Senior Vice President of corporate Communications.

Operator: Good morning and welcome to the Falkyrum Therapeutics third quarter 2021 conference call. Currently, all participants are in a 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 Ms. Naomi Ayoki, Senior Vice President of Corporate Communications and Investor Relations at Falkrum. Ms. Ayoki, please proceed.

And Investor Relations at Fulcrum Ma'am. Please proceed.

Thank you Henry and good morning, and welcome to this Awesome Therapeutics conference call. Please be reminded that remarks made during this call may contain forward looking statements within the meaning of the private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans clinical staff.

Naomi Ayoki: Thank you, Henry. Good morning, and welcome to the Folsom Therapeutics conference call. Please be reminded that remarks made during this call may contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. These may include statements about our future expectations and plans, clinical development timelines, and financial projections. While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so.

And time lines and financial projections.

These forward looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so please refer to our minutes recent filings with the Securities and Exchange Commission.

Naomi Ayoki: Please refer to our most recent filings with the Securities and Exchange Commission for a discussion of certain risks and uncertainties associated with our business. With me on today's call are Brian Stewart, President and Chief Executive Officer, Chris Moravito, Chief Medical Officer, and Peter Thompson, Vice President of Finance and Accounting. Judy Dunn, our president of R&D, and Paul Bruno, our Senior Director of Corporate Development, will also be available for Q&A. Now, let me run quickly through this morning's agenda.

Session of certain risks and uncertainties associated with our business with me on today's call are Bryan Stuart President and Chief Executive Officer, Chris Moore, Vidal, Chief Medical Officer, and Peter Thompson, Vice President of Finance and accounting.

Judy done our president of R&D and pork right now our senior director of corporate development will also be available for Q&A.

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

A review of our programs in sickle cell disease, and Fsh D P.

Naomi Ayoki: Brian will begin the call with a corporate overview and key updates. Chris Moravito will review our programs for sickle cell disease and FSHD. Peter will cover our financials, and then Brian will open the call for Q&A. With that, it's my pleasure to turn the call over to Brian.

We will cover our financials and then Brian will open the call for Q&A.

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

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

21 has been a remarkable year for both of them and we continue to make great strides in the third quarter across our pipeline our product engine, our business, bringing us closer to our mission of delivering life changing medicines to people with rare genetic diseases.

This past quarter was particularly notable for the compelling clinical data we reported on MTX 60, 58, our oral hbf inducer for sickle cell disease and other Haemoglobinopathy in August we reported results from our ongoing phase one trial in healthy adult volunteers as many of you know the current treatment landscape in <unk>.

Brian Stewart: Thank you, Naomi. Good morning, everyone, and thank you for joining us today.

Brian Stewart: 2021 has been a remarkable year for Fulcrum, and we continue to make great strides in the third quarter across our pipeline, our product engine, and our business, bringing us closer to our mission of delivering life-changing medicines to people with rare genetic diseases. This past quarter was particularly notable for the compelling clinical data we reported on FTX 6058, our oral HBF inducer for sickle cell disease and other hemoglobinopathies. In August, we reported results from our ongoing phase one trial in healthy adult volunteers. As many of you know, the current treatment landscape for sickle cell disease consists of therapies that only target select symptoms.

<unk> cell disease, consistent therapies that only target select symptoms human genetics clearly demonstrate.

Led by inducing fetal hemoglobin or hbf.

That <unk> treats the root cause of sickle cell disease and by inducing Hbf. We believe SCS 60, 58 has the potential to address the broad range of symptoms of sickle cell disease, providing a functional cure with an oral therapy as.

As Youll hear from Chris Moore Beta later on we are excited about the results from this trial both in terms of the Tolerability profile and the robust induction of <unk> mrna, which has been highly correlated in our preclinical studies with hbf induction.

Looking ahead, we remain on track to provide an update from our ongoing phase one trial by year end, including data from our 20 and 30 milligram dose course cohorts in healthy volunteers.

At that time, we also plan to share new data further elucidating the relationship between <unk> inhibition.

Brian Stewart: Human genetics clearly demonstrate that by inducing fetal hemoglobin, or HBF, HBF treats the root cause of sickle cell disease, and by inducing HBF, we believe FTX 60-58 has the potential to address the broad range of symptoms of sickle cell disease, providing a functional cure with an oral therapy. As you'll hear from Chris Morvedo later on, we are excited about the results from this trial, both in terms of the tolerability profile and the robust induction of HBG MR, which has been highly correlated in our preclinical studies with HBF and Duffin.

$6 58, and <unk> mrna expression.

Meanwhile, we are moving quickly to initiate our phase one b trial in people living with sickle cell disease and are on track to begin enrolling patients by the end of the year.

We also plan to submit an IND for SPX 60, 58 by year end in additional haemoglobinopathy, including beta thalassemia.

Now, let's turn to Loews mathematics are candidate for Fsh D.

Fsh D is the second most prevalent form of muscular dystrophy.

There are currently no approved drugs and nothing else in the clinic for this devastating disease.

People with Fsh D are typically diagnosed in their late teens or early twenty's.

As fat progressively infiltrates their muscles people with Fsh D lose strength.

Function and independence there is.

An urgent need for a drug that can slow or stop disease progression.

The data we reported earlier this year from our phase III Readouts for trial highlights loads map and lots of potential to do just that.

Brian Stewart: Looking ahead, we remain on track to provide an update from our ongoing phase one trial by year end, including data from our 20 and 30 milligram dose course cohorts and healthy volunteers. At that time, we also plan to share new data further elucidating the relationship between EED inhibition via FTX 6058 and HBGMRNA expression.

Demonstrating delayed progression and even improvement across a number of measures of muscle health.

Function and patient reported outcomes.

We remain on track to meet with regulators before the end of this year and look forward to providing an update on those discussions in the first quarter of 2022.

Turning to fulcrum fee, our product engine and innovation backbone of the company.

F T X 60, 58, and most mathematic as well as our ongoing collaborations with accelerated myocardial are a testament to the power of fulcrum fee, which has allowed us to rapidly identify novel high quality targets. The modulate the root cause of genetically defined rare diseases.

Brian Stewart: Meanwhile, we are moving quickly to initiate our Phase 1B trial for people living with sickle cell disease and are on track to begin enrolling patients by the end of the year. We also plan to submit an INV for FPX-6058 by year end in additional hemoglobinopies, including beta thalithemia. Now, let's turn to Loth Mathamod, our candidate for FSAG.

Notably in addition to our I N D. In hemoglobin off at these we expect to submit an additional IMD by the first quarter of 2023.

We have also made tremendous advancements with fulcrum seek to enable our drug discovery efforts and what we believe is an unprecedented scale in disease relevant settings positioning us to dramatically increase the pace of discovery.

Brian Stewart: FSS is the second most prevalent form of muscular dystrophy. There are currently no approved drugs and nothing else in the clinic for this devastating disease. People with FSHD are typically diagnosed in their late teens or early 20s. As fat progressively infiltrates their muscles, people with FSAHD lose strength, function, and independence. There is an urgent need for a drug that can slow or stop disease progression. The data we reported earlier this year from our Phase 2B Redux 4 trial highlights Lowe's potential to do just that, demonstrating delayed progression and even improvement across the number of measures of muscle health, function, and patient reported outcomes. We remain on track to meet with regulators before the end of this year and look forward to providing an update on those discussions in the first quarter of 2022.

As we shared this morning, Chris <unk>, our Chief Scientific officer will be leaving fulcrum to pursue new opportunities.

We are grateful for his contributions and wish him the best in the next chapter of his career.

During the transition to discovery organization will continue to report into Judy done our president of R&D.

With her leadership and strong organization already in place, we're well positioned to execute against our discovery calls.

Finally, we continue to build out our leadership team this quarter with the appointment of Mel Hayes as our Chief Commercial Officer Monte Center Ranjan as our senior Vice President of technical operations, and Naomi Aoki as our senior Vice President of corporate Communications and Investor Relations.

These newly created roles help us build out our downstream capabilities and further strengthen our team as we move closer towards becoming a commercial organization.

<unk> is in a tremendous position as we look to build a leading rare disease company.

We are advancing two potentially life changing therapies in clinical development.

Progressing additional early stage programs.

Scaling up our discovery efforts and building downstream capabilities all on a strong financial foundation with a cash runway that now takes us into 2024.

With that I'd like to turn the call over to Chris more beat up.

Brian Stewart: Turning to Folkrum Seek, our product engine and innovation backbone of the FtX 6058 and Los Mappamod, as well as our ongoing collaborations with acceleron and myocardia, are testaments to the power of Holcrumseek, which has allowed us to rapidly identify novel, high-quality targets that modulate the root cause of genetically defined rare diseases. Notably, in addition to our IND in hemoglobinopathies, we expect to submit an additional IND by the first quarter of 2020.

Yeah.

Thanks, Brian.

I'll first start with MTX 60, 58, our oral hbf inducer as Brian mentioned, we're extremely encouraged by the results. We reported in August which suggest that MTX 60, 58 could be a transformative therapy for people with sickle cell disease.

Sickle cell disease affects an estimated 100000 people in the U S and millions more worldwide.

And people with sickle cell disease and mutation in hemoglobin causes red blood cells to take on a characteristics of sickle shape.

These red blood cells, often die prematurely, which causes anemia with <unk>.

Well she sells may also damage blood vessels and restrict blood.

Causing basal occlusive crises or voc's, which appears episodes of extreme pain and can manifest as stroke acute chest syndrome and other forms of organ injury.

Together these complications significantly impact lifespan underscoring the tremendous need for treatments that address the root cause of disease.

Brian Stewart: We have also made tremendous advancements with Fulcrum to enable our drug discovery efforts at what we believe is an unprecedented scale in disease-relevant settings, positioning us to dramatically increase the pace of discovery. As we shared this morning, Chris Moxham, our chief scientific officer, will be leaving Folkham to pursue a new opportunity.

As an oral hbf inducer ft, 6058 has the potential to redefine the treatment paradigm. The link between the hbf induction and improved outcomes in sickle cell disease is very well established with both genetic and clinical data is showing the increased hbf reduces or eliminates anemia.

Poc's and other symptoms of the disease.

People, who carry the sickle cell mutation and also have persistence of fetal hemoglobin present with much milder disease. They have far better clinical outcomes typically typically people with sickle cell disease have about 5% to 10% Hbf and we know from those with persistence of fetal hemoglobin that any increase in hbf beyond this has a pause.

Brian Stewart: We are grateful for his contributions and wish him the best in the next chapter of his career. During this transition, the Discovery Organization will continue to report to Judy Dunn, our president of R&D. With her leadership and strong organization already in place, we're well positioned to execute against our discovery goals. Finally, we continue to build out our leadership team this quarter with the appointments of Mel Hayes as our chief commercial officer, Moni Sundarangen as our Senior Vice President of Technical Operations, and Naomi Aoki as our Senior Vice President of Corporate Communications and Investor Relations. These newly created roles help us build out our downstream capabilities and further strengthen our team as we move closer towards becoming a commercial organization.

The impact on clinical outcomes.

We believe an oral drug that induces hbf by two to three fold from baseline would be life changing for people with sickle cell disease with potential to decrease both anemia, and boc driven symptomatology.

Pre clinically MTX 60, 58 has been shown to induce hbf by two to threefold and a wide variety of wild type and disease models and the interim clinical trial results. We reported in August so those preclinical data is starting to translate clinically.

Data demonstrated proof of biology, and mechanism as evidenced by a dose proportional induction and <unk> mrna up to a mean for fourth.

Five fold increase in the 10 milligram dose cohort are preclinical studies consistently demonstrate the increases in <unk> mrna and HBO protein are highly correlated.

On these results we are aggressively moving ahead with this program.

We have added a cohort of people with sickle cell disease to the ongoing phase one trial.

The addition of this cohort helps us make our PK PD model more robust more quickly and we will further inform additional doses in the phase <unk> study.

Dosing for this cohort will be 14 days at six milligrams once daily.

Brian Stewart: Ulcrum is in a tremendous position as we look to build a leading rare disease company. We are advancing two potentially life-changing therapies in clinical development, progressing additional early stage programs, scaling up our discovery efforts, and building downstream capabilities, all on a strong financial foundation with a cash runway that now takes us into 2024. With that, I'd like to turn the call over to Chris Moravita.

In terms of next steps for the program, we anticipate sharing results of the 20 to 30 and 30 milligram cohorts of the ongoing phase one trial before the end of the year as well as data to shed light on the intermediary steps linking EEG inhibition ft 6058, two induction of HPT mrna expression.

As a reminder, the aim of the phase one is to evaluate safety tolerability and pharmacokinetics of MTX $6 58.

The trial has also been collecting pharmacodynamic data to assess target engagement and each D. G mrna levels.

Additionally, we are on track to begin enrolling people with sickle cell disease in the phase <unk> clinical trial before the end of this year.

This multiple dose phase <unk> open label trial will start with the six milligram dose and include a treatment period of up to three months with about 10 patients per cohort the.

Chris Moravito: Thanks, Brian. I'll first start with FDX 6058, our oral HBF inducer. As Brian mentioned, we're extremely encouraged by the results we reported in August, which suggest that FDX 6058 could be a transformative therapy for people with sickle cell disease. Sickle cell disease affects an estimated 100,000 people in the US and millions more worldwide. In people with sickle cell disease, a mutation in hemoglobin causes red blood cells to take on a characteristic sickle shape. These red blood cells often die prematurely, which causes anemia.

The study is designed to confirm and build on our current results, but the name of demonstrating early proof of concept in sickle cell disease. We.

We anticipate providing initial data from the phase <unk> trial in the second quarter of 2022.

Following proof of concept in the phase one b, we anticipate moving into a potentially pivotal phase two three clinical trial in 2023.

As we look at the existing and emerging treatment landscape for sickle cell disease, we see a tremendous opportunity for <unk> 658.

Only hbf induction has been demonstrated to broadly ameliorates symptoms of the disease.

Approved therapy showed modest benefit and only target certain symptoms other.

Other oral or IV programs in clinical development in either to increase total hemoglobin or to reduce poc's.

Clinical studies have shown that increasing total hemoglobin F alone has limited impact on symptoms.

Italy drugs that may reduce the rate of poc's have minimal to no impact on anemia.

Chris Moravito: The sickle-shaped cells may also damage blood vessels and restrict blood flow, causing basal occlusive crises or VOCs, which appear as episodes of extreme pain and can manifest as stroke, acute chest syndrome, and other forms of organ injury. Together, these complications significantly impact lifespan, underscoring the tremendous needs for treatments that address the root cause of the disease. As an oral HBF inducer, FDX 6058 has the potential to redefine the treatment paradigm. The link between HBF induction and improved outcomes in sickle cell disease is very well established, with both genetic and clinical data showing that increased HBF reduces or eliminates anemia. EOCs, and other symptoms of the disease.

Gene editing approaches which share the same therapeutic rationale was MTX 60, 58 have shown promising results across the broad spectrum of symptoms that come with an extremely challenging treatment burden for patients and families.

We believe that an oral once daily medicine that can reduce or eliminate anemia, POC stroke and other symptoms essentially providing a functional cure.

To find a new treatment standard for sickle cell disease.

We also believe VX 658 could be transformative therapy for other haemoglobinopathy such as beta thalassemia.

Correct.

The results to date support initiating a trial in this patient population and as Brian mentioned, we intend to submit an IND by the end of this year.

Now, let's turn to lose map of mob, a potentially life changing therapy for Fsh D. S.

As many of you know most macro <unk> targets, the aberrant expression of Dex for the genetic root cause of Fsh D.

This aberrant expression causes muscle fat infiltration, which leads to the degeneration and muscular dystrophy and relentless progressive loss of function.

Chris Moravito: People who carry the sickle cell mutation and also have persistence of fetal hemoglobin present with much milder disease and have far better clinical outcomes. Typically, people with sickle cell disease have about 5% to 10% HBF, and we know from those with persistence of fetal hemoglobin that any increase in HBF beyond this has a positive impact on clinical outcomes. We believe an oral drug that induces HBF by two to threefold from baseline would be life-changing for people with sickle cell disease, with potential to decrease both anemia and VOC-driven symptomatology. Preclinically, FTC-X-658 has been shown to induce HBF by two to three-fold in a wide variety of wild type and disease models.

We consistently hear from patients that their number one concern.

Number one objective in a new therapeutic is to slow or stop disease progression and in order to preserve the function they have.

<unk> four is the most comprehensive therapeutic trial and fsh each day 48 weeks comparing lift them up about 50 milligrams twice daily to placebo.

And read ups for we saw clinically meaningful impacts them up the structure function and patient reported outcomes.

On MRI, we showed a slowing of muscle fat infiltration of patients treated with <unk> compared to placebo, which speaks to preservation of muscle structure.

Patients treated with both Napa Mountain also demonstrated improvement in solar strengths are key muscle groups impacted by the disease.

Importantly, we stopped preservation of function measured by reachable workspace and trends towards improvement in timed up and go which is an assessment of lower extremity function.

With reachable workspace, both Napa <unk> treatment resulted in improvements from baseline and reachable surface area in key areas that impact activity of daily living and <unk>.

Chris Moravito: And the interim clinical trial results we reported in August show those preclinical data starting to translate clinically. The data demonstrated proof of biology and mechanism, as evidenced by dose-proportional induction in HBGMRNA, up to a mean 4.5-fold increase in the 10 milligram dose cohort. Based on these results, we are aggressively moving ahead with this program.

Maintenance of independence, including reaching above the shoulders and behind the back.

And finally.

Study participants on drug reported feeling better compared to participants on placebo at the end of the 48 week treatment period.

<unk> also has a well established safety and Tolerability profile approximately 3600 patients have been exposed to lift up a modern across multiple indications and the safety profile remains favorable, especially for severe and progressive disease for which there are no therapies.

In terms of next steps as Brian mentioned, we plan to talk with regulators before the end of the year and we will be providing an update on those interactions in the first quarter of 2022.

We're currently planning for a phase III trial, which is our base case scenario, we gained significant insights from lead us for about meaningful and measurable clinical endpoints that showed sensitivity to disease progression and drug effect and we are applying those insights to inform the design of a trial with the aim of expeditiously delivering the first disease model.

Chris Moravito: We have added a cohort of people with sickle cell disease to the ongoing phase one trial. The addition of this cohort helps us make our PK PD model more robust, more quickly, and will further inform additional doses in the phase 1B study. Dosing for this cohort will be 14 days at 6 milligrams once daily.

<unk> trucks for people with FX HD.

On behalf of Fulcrum I wanted to express our deep appreciation to the sickle cell disease, and FX HD communities for their insights and guidance and their support as we work towards our shared goal of developing much needed therapies for these difficult to teach us with that I'll turn it over to Peter.

Chris Moravito: In terms of next steps for the program, we anticipate sharing results of the 20 to 30 and 30 milligram cohorts of the ongoing phase one trial before the end of the year, as well as data that shed light on the intermediary steps linking EED inhibition via FTX 6058 to induction of HBGMRNA expression. As a reminder, the aim of phase one is to evaluate the safety, tolerability, and pharmacokinetics of FTX The trial has also been collecting pharmacodynamic data to assess target engagement and HBGMRNA levels.

Thanks, Chris.

Following our successful August financing, we ended the third quarter with $243 million in cash cash equivalents and marketable securities based on our current plans and projections. We expect this will support our operations into 2024.

Duration revenue for the third quarter of 2021 was $4 9 million.

Compared to $1 8 million of.

Collaboration revenue recognized during the third quarter of 2020.

Research and development expenses for the third quarter of 2021 were $17 1 million.

Compared to $15 6 million.

In the third quarter of 2020.

General and administrative expenses for the third quarter of 2021, or $8 6 million as compared to $5 3 million for the third quarter of 2020.

And our net loss was $20 7 million for the third quarter of 2021 compared to a net loss of $19 million for.

For the third quarter of 2020.

With that I'll turn it back to Bryan Bryan Thanks, Peter as you've heard today, it's been a tremendous year for fulcrum, so far and we are continuing to build on that momentum.

We're very excited about the prospects for our programs and Fsh D and sickle cell disease to diseases with great unmet need where we have shown very compelling data to date and we look forward to opportunities ahead.

Chris Moravito: Additionally, we are on track to begin enrolling people with sickle cell disease in the phase 1d clinical trial before the end of this year. This multiple dose phase 1B open label trial will start with a 6 milligram dose and include a treatment period of up to 3 months with about 10 patients per cohort.

Develop therapies to benefit patients with these and other rare genetic diseases.

Operator, you May now open the line for questions.

Thank you as a reminder, in order to ask a question Press Star then the number one on your telephone keypad.

Your first question comes from that couldn't have Stifel. Your line is now open.

Hi, Good morning, guys. Thanks for taking my question I guess I wanted to just kind of go back to the teaser for the additional data with regards to E. D inhibition in H P. G. Mrna I guess can you maybe talk a little bit about what we can expect there is this mostly in vitro or in vivo.

Chris Moravito: The study is designed to confirm and build on our current results, but the name of the study is demonstrating early proof of concept in sickle cell disease. We anticipate providing initial data from the phase 1B trial in the second quarter of 2022. Following proof of concept in phase 1B, we anticipate moving into a potentially pivotal phase 23 clinical trial in 2020. As we look at the existing and emerging treatment landscape for sickle cell disease, we see a tremendous opportunity for FDX 6058. Only HBF induction has been demonstrated to broadly ameliorate symptoms of the disease.

And while this cover transcriptome analyses or proteomics analysis or something else and then I've got a follow up thank you.

Yeah. Thanks, Dae gon for the question so we haven't shared.

More detail yet I think one of the things that we've been doing that that we spoken about is doing work to try to better elucidate that relationship between <unk> inhibition via F. T X $60 58.

And this <unk> mrna increase that we've observed so far clinically and obviously the protein increases that we've involved pre clinically. So we anticipate that we'll be able to share that work along with the data update towards the end of the year and we're excited to share more details on that.

Great. Thank you for that and then the follow up is with regards to your 30 milligram cohort data I was wondering if you could maybe walk us through kind of a thought process. After you kind of saw that two 6% 10, recognizing 20 milligram was coming down the Pike, what was sort of a driving factor that led you to a 30 milligram cohort and what is that.

Chris Moravito: Approved treatments show modest benefits and only target certain symptoms. Other oral or IV programs in clinical development aim either to increase total hemoglobin or to reduce VOCs. Clinical studies have shown that increasing total hemoglobin Ness alone has limited impact on symptoms. Similarly, drugs that may reduce the rate of DOCs have minimal to no impact on anemia. Gene editing approaches, which share the same therapeutic rationale as FDX 6058, have shown promising results across the broad spectrum of symptoms but come with an extremely challenging treatment burden for patients and families. We believe that an oral, once daily medicine that can reduce or eliminate anemia, VOCs, stroke, and other symptoms, essentially providing a functional cure, will define a new treatment standard for sickle cell disease.

Actually where you are you trying to divulge from that cohort data. Thanks, so much.

Hi, guys. This is Chris Yeah. So as you imply we were very pleased with the data that we reported back in August by.

Up through 10 milligrams, we already demonstrated that we have a profile that looks like it could achieve our target which is at least the two to three fold induction planning contact your financial advisor for a free consultation.

Before embarking on an investment strategy. It is imperative that investors determine their per operator, but that line on mute.

So we were pleased to see data that implied that we could hit our guideposts.

We'll post of two to three fold induction already and based on what we saw we made some good decisions critical decisions about this program, including the initiation of the phase <unk> study in going into beta thalassemia other hemoglobin up fees.

We haven't seen anything so far that makes us concerned about the profile will.

But we have taken the opportunity in phase one to continue to learn about the profile and this is why we expanded the 20 and then eventually 30 milligram. So that we could see more about the slope of HPT mrna induction to see more about what's happening with target engagement and continue to gather data on pharmacokinetics and safety and Tolerability. So those data are helpful for us to <unk>.

Chris Moravito: We also believe FDX 6058 could be transformative therapy for other hemoglobinopathies, such as beta thalassemia. The clinical results to date support initiating a trial in this patient population. And as Brian mentioned, we intend to submit an I&D by the end of this year. Now, let's turn to Lismapamad, a potentially life-changing therapy for FSSD. As many of you know, Lysmapimod targets the apparent expression of Dux 4, the genetic root cause of FSHD. This apparent expression causes muscle fat infiltration, which leads to degeneration and muscular dystrophy and relentless progressive loss of function.

Form the future development and we're going to use those data to continue to build our plan for taking this invitations and expeditiously, bringing us towards approval.

Perfect. Thanks for taking the question I look forward to it.

Hey, guys. Thank you. Your next question comes from.

First handler.

Mean from Ted <unk> of.

Piper Sandler your line is now open.

Thank you so much for taking requests and congrats on really credit here.

Again, appreciating that we're going to get an update that as unsecured.

I wanted to get a sense for where things stand with Carlos map about of what's the capsule sorry, thanks guys.

I would tell you this again.

So as you know you've heard us say continuously we're very excited about the profile the data coming out of <unk>.

<unk>, Florida, which we show.

Impacts on.

Muscle structure impacts on function and patient reported benefit and we believe that this has potential to really importantly, and profoundly impact patients with fsh fees and we're working expeditiously to bring this drug forward towards approval. Our base case continues to be that we'll have a phase III trial, we're working really hard to compare.

Chris Moravito: We consistently hear from patients that their number one concern and number one objective in a new therapeutic is to slow or stop disease progression in order to preserve the function they have. Redux 4 is the most comprehensive therapeutic trial in FSSD to date, 48 weeks, comparing Mopamod 50 milligrams twice daily to placebo. In Redux 4, we saw clinically meaningful impacts on muscle structure, function, and patient-reported. On MRI, we showed a slowing of muscle fat infiltration in patients treated with napomod compared to placebo, which speaks to preservation of muscle structure. Patients treated with Lhomad also demonstrated improvement in shoulder strength, a key muscle group impacted by the disease.

For that we've looked deeply at the Readouts for data and natural history data.

And are developing a plan.

Our phase III trial that will ultimately answer.

Yes.

We continue to be on track to meet with the regulators by the end of this year and as soon as there's clarity about what that input.

We'll share that with you.

Uh huh.

We share the same goal as the community wishes to have a drug that will profoundly transformative lead pack. This disease and are working with the regulators to do that goal.

And maybe Ted just to jump in on your first question regarding the data update so we are okay.

We remain on track to be able to provide that update both.

Higher dose cohorts as well as the elucidation of the mechanism by end of year based on IV <unk>.

Chris Moravito: Importantly, we saw preservation of function measured by reachable workspace and trends towards improvement in timed up and go, which is an assessment of lower extremity function. With reachable workspace, Mapamon treatment resulted in improvements from baseline and reachable surface area and key areas that impact activities of daily living and maintenance of independence, including reaching above the shoulders and behind the back. And finally, study participants on the drugs reported feeling better compared to participants on placebo at the end of the 48-week treatment period. Lismapamad also has a well-established safety and tolerability profile.

Abstract as well as the timing of our trial.

We are going to present that data either.

And for US that is everything remains on track to be able to do that as we get closer to that.

Okay helpful. Thanks for that clarification.

With a smartphone.

Hence crew evaluate partnerships.

Potentially overseas every keep U S Reits, but.

Yeah, I think Ken as Chris mentioned based on the data that we generated we're very excited to be interacting with the FDA and moving the program forward. So as we've talked about a lot in the past.

When we went into the phase II B trial, we were really enthusiastic to be able to observe these patient benefits in what was a relatively small trial of only 80 subjects in a relatively short trial of only 48 weeks.

I think that gives us a lot of confidence and enthusiasm to move forward I think as we then transition and look at this as a commercial opportunity. We're very much focused on the patient population and the unmet need. So we know that these are patients that have this genetically defined rare disease, they're for the most part identified.

Chris Moravito: Approximately 3,600 patients have been exposed to Lismapamad across multiple indications, and the safety profile remains favorable, especially for a severe and progressive disease for which there is no therapy. In terms of next steps, as Brian mentioned, we plan to talk with regulators before the end of the year, and we will be providing an update on those interactions in the first quarter of 2022. We're currently planning for a phase three trial, which is our base case scenario.

And they are it is a worldwide disease. So there is a patient population that I think is very much waiting for a therapy and we're very fortunate that we are now building up our commercial leadership to put us in a position to be able to take advantage of that opportunity. So our focus is continue to bring.

Going forward and and try to get it to patients as quickly as we can.

Chris Moravito: We gain significant insights from Redux 4 about meaningful and measurable clinical endpoints that show sensitivity to disease progression and drug effects, and we are applying those insights to inform the design of a trial with the aim of expeditiously delivering the first disease-modifying drugs for people with FSAHD. On behalf of Folkrum, I want to express our deep appreciation to the sickle cell disease and FFD communities for their insights, their guidance, and their support as we work towards our shared goal of developing much needed therapies for these difficult diseases. With that, I'll turn it over to Peter. Thanks, Chris. Following our successful August financing, we ended the third quarter with $240.3 million in cash, cash equivalence, and marketable security.

Awesome guys. Thanks for the update.

Thanks, Ed.

Your next question comes from Matthew Harrison of Morgan Stanley. Sir Your line is now open.

Good morning, everyone.

It's cost us on for Matthew Thanks for taking our questions sent Cris good luck with the next steps to.

Two questions from us on sickle cell disease.

First one is can you talk a little bit about the relationship between the PK and the target engagement.

You have seen so far with the available data and whether the target engagement T box or AUC, driven and secondly, we are wondering whether you are planning to share baseline mrna levels.

Thank you.

And Chris This is Chris.

Yes, thanks for the question so.

Referring back to what we showed in August you'll recall that we had achieved maximal target engagement at all three doses tested with two six and 10 milligrams it took a little longer to.

Peter Thompson: Based on our current plans and projections, we expect this will support our operations into 2024. Collaboration revenue for the third quarter of 2021 was $4.9 million compared to $1.8 million of collaboration revenue recognized during the third quarter of 2020. Research and development expenses for the third quarter of 2021 were $17.1 million, compared to $15.6 million in the third quarter of 2020. General and administrative expenses for the third quarter of 2021 were $8.6 million as compared to $5.3 million for the third quarter of 2020.

To get there by seven days fixed and 10 were about the same at roughly the maximum level and certainly by 14 days all three dose levels, where we are at maximum level and if you recall a maximal <unk> inhibition defined by changes into Sunshine methylation.

<unk> about 20% to 30% of PRC to activity, which we think is an intrinsic competitive advantage of this particular mechanism.

Brian Stewart: And our net loss was $20.7 million for the third quarter of 2021, compared to a net loss of $19 million for the third quarter of 2020. With that, I'll turn it back to Brian.

Okay.

Of hcg and ultimately of Hbf.

Where it will be relevant and where will have longer treatment durations. This is when we will begin to report on these kinds of parameters and closest I think we would also add one of the things that we've mentioned and been very enthusiastic about is justice consistency that we have observed to date as Chris mentioned across both <unk>.

Operator: Thanks, Peter. As you've heard today, it's been a tremendous year for Fulcrum so far, and we are continuing to build on that moment. We are very excited about the prospects for our programs in FSHD and sickle cell disease, two diseases with great unmet need where we have shown very compelling data to date. And we look forward to opportunities ahead to develop therapies to benefit patients with these and other rare genetic diseases.

As well as protein preclinically, so when whether we looked at the town's a map mouse model the wild type malice.

34 cells from.

Sickle patients from healthy volunteers, we have seen this very consistent two to three fold induction of both mrna and protein and obviously as we looked at our initial phase one healthy volunteer data.

Operator: Operator, you may now open the line for Thank you. As a reminder, in order to ask a question, press TARD and the number one on your telephone keypad. Your first question comes from Daganha of Stifel. Your line is now open.

Where we looked at mrna we were very enthusiastic to see this induction that was even beyond that two to three fold. So I think that gives us a lot of confidence as we look to translate into sickle cell patients and the other element that does as well is just looking at some of these other opportunities such as the gene editing where we've seen this.

Daganha: Hi, good morning, guys. Thanks for taking the question. I guess I wanted to just kind of go back to the teaser for the additional data with regard to EED inhibition and HBGMRNA. Can you maybe talk a little bit about what we can expect there? Is this mostly in vitro or in vivo?

Very meaningful translation from the C. D 34 positive assay preclinical <unk> into now what's being observed.

<unk>, Jean editing and patient so I think all of that gives us confidence that as we get into patients here by the end of the year in the translation that we have the potential to observe.

Very helpful. Thank you.

Chris Moravito: And will this cover transcriptomic analyses or proteomic analysis or something else? And then I've got a follow-up question. Thank you. Yeah, thanks, Dagon, for the question.

Your next question comes from Joseph Schwartz off S V V Leerink.

Mine is now open.

Thanks, very much congrats on all the progress as well.

I was wondering how well developed as the understanding about potential natural natural variability around the thresholds of hbf that are associated with varying degrees of <unk>.

Chris Moravito: So we haven't shared more detail yet, but I think one of the things that we've been doing that we've spoken about is doing work to try to better elucidate that relationship between EED inhibition via FX 6050A and this HBGM RNA increase that we've observed so far clinically, and obviously the protein increases that we've observed preclinically. So we anticipate that we'll be able to share that work along with the data update towards the end of the year, and we're excited to share more details on that. Great, thank you for that!

Symptoms and sickle cell and how we would be measuring symptoms in the phase wouldn't be studying SCD patients is it just voc's are there any other finer metrics you'll be evaluating.

Yeah, So Joe why don't I turn it over to Paul Bruno and he can speak to not only what is known from both data as well as other clinical trials about starting hbf levels, but also what is very clearly known about induction of hbf and the benefits from human genetics and.

And I think as as we've talked about inducing hbf is the only way to be able to treat the root cause of the disease and we have such a wealth of data from these patients that have hereditary persistence of fetal hemoglobin that were really able to build on that.

And just expanding artwork, what Brian said looking across the various clinical trials that are currently ongoing so looking at crisper therapeutic Samara, even have problems with hydroxyurea as.

Chris Moravito: And then the follow-up is, with regard to your 30-millimeter cohort data, I was wondering if you could maybe walk us through kind of the thought process after you kind of saw the 2-6-and-10 recognizing 20-migram was coming down the pike. What was sort of the driving factor that led you to a 30-millimeter cohort, and what exactly were you trying to divulge from that cohort data? Thanks so much. Hi Deghan, this is Chris.

As well as observational studies and sickle cell disease population, we do feel very confident that the baseline level is in between five and 10%.

Ryan alluded to.

What we do know from the genetics and sickle cell disease individuals, but also have mutations leading to hereditary persistent fetal hemoglobin, we know that any increase in fuel hemoglobin levels, resulting amelioration of abroad swap of symptoms within sickle cell disease individuals so thinking about things like anemia voc's.

<unk> syndrome is laws.

Cause and maybe I can have Chris more beta speak to the base when b.

Expectations there yep.

Great. Thanks, Thanks, Paul.

Chris Moravito: Yeah, so as you imply, we were very pleased with the data that we reported back in August. By up through 10 milligrams, we already demonstrated that we have a profile that looks like it could achieve our target, which is at least the two to three fold induction. As your financial advisor for a free council embarking on an investment strategy, it is imperative that investors determine their personal tolerance. Operator, can you put that line on mute?

So as Paul mentioned Hbf as a surrogate and increases in hbf in the setting of sickle cell disease are strongly associated with not only improvements anemia, but also improvements in symptoms from anemia and improvements in things like <unk> and boc related phenomenon.

We.

We will be studying this in the lumpy study for up to three months, which is about the time that we expect to have maximum impact on hbf and patients and see demonstrable significant changes in hbf and.

And we will of course be looking at symptoms, but we don't expect and a three month period and open label study without a placebo group to be able to provide robust data on changes and voc's certainly compared to anything because we just have a baseline to compare too, but we will be looking for any signs that would in fact that.

Operator: So we were pleased to see data that implied that we could hit our guidepost, our goal post of a two to threefold induction already. And based on what we saw, we made some good decisions, critical decisions about this program, including initiating the phase 1B study and going into beta thalcemia and other human gloomyopies. We haven't seen anything so far that makes us concerned about the profile.

Again.

Surrogacy behind Hbf in this setting in particular, when you have a drug that induces pan cellular hbf as our our oral hbf and just your does but we do expect that taking this into a longer study such as a phase two we will be able to demonstrate a significant improvements in clinical outcomes.

Okay. Thank you and then for your meetings with the F D. A for a <unk>.

Chris Moravito: So we took the opportunity in phase one to continue to learn about the profile, and this is why we expanded to 20 and then eventually 30 milligrams so that we could see more about the slope of HPG MRI induction, see more about what's happening with target engagement, and continue to gather data on pharmacokinetics, safety, and tolerability. So those data are helpful for us to inform future development, and we're going to use those data to continue to build, you know, our plan for taking this in the patient and expeditiously bringing this toward approval. Perfect. Thanks for taking the questions. I look forward to it.

Just curious how much.

Patient advocates may be able to chime in on the merits of need for the drug can you give us any sense for how much bandwidth might be allocated.

F D a to receive the case for.

Approval from the company versus patient advocates.

Yeah, Joe what can I turn it over to Chris to address that and we can also just speak to some of the things that have been done from the community perspective in terms of engaging with the FDA. The patient focused drug development days that took place in 2020 and just some of the discussions that have been having from a patient community that.

As you point out is obviously very enthusiastic about the potential for therapy.

Yeah. So it's a wonderful question and there's certainly something that we've been thinking deeply about uhm and reef engaged now.

Bill now an internal group focusing specifically on.

Patient engagement and patient advocacy as Brian said, the patient advocacy network in the us and outside of the U S. In Europe and in UK. For example, very strong very active very engaged in even outside of those those organizations. The patient themselves are very engaged very willing to help us.

Edward Andrew Tenthoff: Thank you. Your next question comes from... Piper's Handler. I mean, Ted Tenth of Piper's Handler. Your line is now open.

And importantly to help regulators like the FDA understand the burden of this disease, Brian referred to.

Chris Moravito: Thank you so much for taking the question, and congratulations on a really exciting year. Again, I'm appreciating that we're going to get an update at Ash on 605-8. I wanted to get a sense for where things stand in front of us, the Map of Mod, and what potential next steps are. Thanks, guys. Hi Ted, this is Chris again.

A conference that was held in June of 2020, which produced voice of the patient report was held in conjunction with the FDA or panels of experts, including patients that have participated in this conference. The number one report out of that was the patient request for a new therapy that was.

Slow or halt disease progression something like what we think the profile, let's not can't achieve were absolutely engaged with these organizations to communicate the burden of disease, and Fsh C and to help regulators understand what kinds of functional.

Chris Moravito: So, you know, I say continuously, we're very excited about the profile of the data coming out of a Redux floor in which we show impacts on muscle structure, impacts on function, and patient-reported benefits. And we believe that this has the potential to really importantly and profoundly impact patients with F&HD, and we're working expeditiously to bring this drug forward toward approval. Our base case continues to be that we'll have a phase three trial; we're working really hard to prepare for that.

<unk> or patient reported interventions are important to this community and we're in case with this community as well to help us think about what kinds of assessments, we need to be able to measure and ongoing clinical trials in order to provide the substantial evidence to support those approvals FTA has been very engaged and we were encouraged by.

This involvement and look forward to continued partnership with the regulators.

Thanks again.

At this time I would like to remind everyone in order to ask question pressed hard into number one on your telephone keypad.

Chris Moravito: We've looked deeply at the Redux 4 data and natural history data and are developing a plan to start a phase three trial that will ultimately answer questions. We continue to be on track to meet with the regulators by the end of this year. And as soon as there's clarity about what that input is, I will share that with you.

Your next question comes from Judith Frommer out credit suites your lines now okay.

Hi, Thanks for taking my question Congrats on all the progress just a couple of follow ups on the one B design can you just remind us why he decided to go with the the six milligram dose and and not the 10 and how how impactful could that one be read out b two moving into phase two versus the data generated and.

Chris Moravito: We share the same goal as the community, which is to have a drug available that will profoundly and transformatively impact this course of disease, and I'm working with the regulators to achieve that goal. And maybe, Ted, just to jump in on your first question regarding the data update. So we are, for 60K, we remain in the contract to be able to provide that update for both of the entire dose cohorts, as well as the elucidation of the mechanism by the end of the year.

Healthy volunteers given that it is that one dose.

Yeah. So C.

Just give you that the context of the study design so it will be.

Up to three months of months of therapy and in patients with sickle cell disease, and it's all commerce with sickle cell disease.

And we're looking for.

First and foremost safety and Tolerability and then also looking for changes in key pharmacodynamic parameters, including Hbf and we think the three months treatment duration gives us the opportunity to assess this.

We anticipate having up to three dose cohorts can we anticipate each cohort having up to 10 patients.

We do have a DMC that will it's an internal DMC that will be monitoring the study and giving us information at intervals that will reform continued development and progression through those close cohorts you.

Chris Moravito: Based on the timing of abstracts as well as the timing of our trial, we are going to present that data outside of the ad forum. That is, everything remains to be able to set. As we get closer to that, we will be able to.

We decided to started six because this is the dose level that achieved a three fold induction and <unk> and healthy volunteers and as you've heard to say lots of times.

Our goalposts for this is two to three fold induction on top of baseline sickle cell patients.

Brian Stewart: Thank you. Great, helpful, and thanks for that clarification. And just with Lasmap, does it make sense to evaluate partnerships, even potentially overseas, on the PPS rights thing?

So we hypothesized that this is a dose that will have the potential for clinical benefit. We're also.

We believe that we will have at least the same amount of HVA HPT induction and patience as we see in healthy volunteers and there is also a potential for.

More <unk> induction just because of of the the bone marrow environment.

Brian Stewart: Yeah, I think, as Chris mentioned, based on the data that we generated, we're very excited to be interacting with the FDA and moving the program forward. So, as we've talked about a lot in the past, when we went into the phase 2B trial, we were really enthusiastic to be able to observe these patient benefits in what was a relatively small trial of only 80 subjects and a relatively short trial of only 48 weeks. So I think that gives us a lot of confidence and enthusiasm to move forward.

Police this environment and sickle cell compared to help these so well we started at fixed in order to give us a room in order to detect.

<unk> changes and ultimately hbf changes hbf protean changes in patients and we'll be looking at this continually as we go through six.

That's helped us.

<unk>.

This disc quickly finished this office subsequent windows will be informed by the incoming data and also by the P. K P. D model that we're building.

Okay that makes a lot of sense and then just can you remind us but from a clinical perspective is.

You know higher hbf better or is there a kind of a threshold is that once you get to a 234 X induction level.

Brian Stewart: I think as we then transition and look at this as a commercial opportunity, we're very much focused on the patient population and the unmet needs. So we know that these are patients that have this genetically defined rare disease. They are, for the most part, identified, and it is a worldwide disease. So there's a patient population that I think is very much waiting for therapy. And we're very fortunate that we are now building up our commercial leadership to put us in a position to take advantage of that opportunity.

So any increase from baseline has been demonstrated in genetic and clinical experiments to provide benefit and we know from very good population studies that even in the small change from baseline potential impact overall survival over very long periods of time, but certainly has that kind of impact.

And we also know from from the genetics that levels in the 20% range impact symptoms, very well and levels and the 25% to 35% range start to impact.

Absolute since symptomatology and can induce essentially a functional cure.

Overseeing from the incoming data from the gene editing programs is that very high levels of hbf up to about 50%.

Brian Stewart: So our focus has continued to bring it forward and try to get it to patients as quickly as we can. Awesome, guys. Thanks for the update. Thank you. Your next question comes from Matthew Harrison of Morgan Stanley. Sir, your line is now open.

Can eliminate the disease and doesn't appear to cause any adverse events. So while we're seeing level so far and.

In healthy volunteers that imply we can induce to that kind of range. Obviously, we will see this in patients were not concerned about the potential for adverse events at this point related to that.

Great. Thank you.

Thank you. This concludes the Q&A session for today I.

Operator: Good morning, everyone. This is Costason speaking for Matthew. Thanks for taking our questions, and Chris, good luck with the next step. Here are two questions from us on sickle cell disease. The first one is, can you talk a little bit about the relationship between the PK and the target engagement that you have seen so far with the available data and whether the target engagement is CMAX or AUC driven? And secondly, we are wondering whether you are planning to share baseline MRNA levels with us. Thank you. Hi Costa, this is Chris.

I would like to turn the call over it's R. C O Brian Stewart for closing remarks.

Thank you. Thank you everybody for joining us today and we appreciate your support of welcome have a great day.

Goodbye.

[music].

Chris Moravito: Yeah, thanks for the question. So referring back to what we showed in August, you recall that we achieved maximal target engagement at all three doses, so two, six, and ten milligrams. It took a little longer for two to get there.

Chris Moravito: By seven days, six and ten were about the same at roughly the maximum level, and certainly by 14 days, all three dose levels were at the maximum level. And if you recall, a maximum inhibition defined by changes in histomethalation retained about 20 to 30 percent of PRC2 activity, which we think is an intrinsic competitive advantage of this particular mechanism. So there is something here regarding concentrations and the concentration relationship to target engagement.

Chris Moravito: Our preclinical data suggests that their relationship is based on exposure rather than CMAX. The data that we showed back in August also implied that there is a pretty long residence time, that it takes about a week or so for the levels of histone trimethylation to return to normal, even though the half-life of the drug is only about nine hours.

[noise].

Chris Moravito: So again, it's an exposure-driven relationship that has a durable effect. And then, Costa, maybe we could address the second question regarding MRA levels. Yeah, so that's not something that would be important in people that are healthy. It's more important than people that have sickle cell disease. And so this is not something that we intend to share.

Chris Moravito: The most important information that we'll share about MRNA changes is the fold increase from baseline. When we start talking about the patient population in which there will be significant levels of HPG, and ultimately of HBF, where it will be relevant, and where we'll have longer treatment durations, that is when we'll begin to report on these kinds of parameters. And Kosis, I think we would also add one of the things that we've mentioned and been very enthusiastic about is just this consistency that we have observed to date, as Chris mentioned, across both MRNA and protein preclinically. So whether we looked at the Towns Mouse model, the wild type, mice, CD-34 cells from sickle patients and healthy volunteers. We have seen this very consistent two-to-three-fold induction of both MRNA and protein.

Brian Stewart: And obviously, as we looked at our initial phase one healthy volunteer data, where we looked at MRNA, we were very enthusiastic to see this induction that was even beyond that two-to-threefold. So I think that gives us a lot of confidence as we look to translate this into sickle cell patients. And the other element that does as well is just looking at some of these other opportunities, such as gene editing, where we've seen this very meaningful translation from the CD-34 positive assay preclinically into what's being observed with BCL11A, gene editing, and patients.

Brian Stewart: So I think all of that gives us confidence that as we get into patients here by the end of the year, in the translation that we have the potential to observe. Very helpful, thank you. Your next question comes from Joseph Swartz of SVV Lyrink. Your line is now open.

Joseph Patrick Schwartz: Thanks very much. Congratulations on all the progress as well. I was wondering how well developed is the understanding about potential natural variability around the thresholds of HBF that are associated with varying degrees of symptoms in sickle cell and how we'd be measuring symptoms in the phase 1B study in STD patients. Is it just VOCs?

Paul Bruno: Are there any other finer metrics you'll be evaluating? Yeah, so Joe, why don't I turn it over to Paul Bruno, and he can speak to not only what is known from both data as well as other clinical trials about starting HBF levels but also what is very clearly known about induction of HBF and the benefits from human genetics. And Joe, I think, as we've talked about, inducing HBF is the only way to be able to treat the root cause of the disease.

[music].

Paul Bruno: and we have such a wealth of data from these patients that have hereditary persistence of fetal hemoglobin that we're really able to build on. Just expand on what Brian said. So looking across the various clinical trials that are currently ongoing, so looking at CRISPR therapeutics and Mara and even past trials with hydroxyurea, as well as observational studies in the sickle cell disease population, we do feel very confident that this baseline level is in between 5% and 10%.

Paul Bruno: As Brian alluded to, what we do know from the genetics in sickle cell disease individuals that also have mutations leading to hereditary persistence of fetal hemoglobin, we know that any increase in fetal hemoglobin levels results in amelioration of a broad range of symptoms within sickle cell disease individuals.

Paul Bruno: So I'm thinking about things like anemia, VOCs, acute chest syndrome, as well as even bifism. And maybe I can have Chris Morbito speak to the phase 1B expectations there. Yeah, great. Thanks, thanks, Paul.

Chris Moravito: So, you know, as Paul mentioned, HPF is a surrogate, and increases in HBF in the setting of sickle cell disease are strongly associated with not only improvements in anemia but also improvements in symptoms from anemia and improvements in things like VOOC and VOC-related phenomena. We will be studying this in the 1B study for up to three months, which is about the time that we expect to have maximal impact on HBF in patients and see demonstrable significant changes in HBF.

Chris Moravito: And we will, of course, be looking at symptoms. But we don't expect, in a three-month period in an open label study without a placebo group to be able to provide robust data on changes in VOC certainly compared to anything because we don't we just have a baseline to compare to. But we will be looking for any signs that would impact that. Again, the surrogacy is behind HBF in this setting, particularly when you have a drug that induces pancellular HV as our oral HBF inducer does. We do expect that taking this into a longer study, such as phase two, we will be able to demonstrate significant improvements in clinical outcomes. Okay, thank you.

Chris Moravito: And then for your meetings with the FDA for Los Mappamad, I was curious how much patient advocates may be able to chime in on the merits and need for the drug. Can you give us any sense for how much bandwidth might be allocated by the FDA to receive the case for approval from the company versus patient advocates? Yeah, Joe, why don't I turn it over to Chris to address that?

Chris Moravito: And we can also just speak to some of the things that have been done from the community perspective in terms of engaging with the FDA, the patient-focused drug development days that took place in 2020, and just some of the discussions that we have been having with a patient community that, as you point out, is obviously very enthusiastic about the potential for a therapy. Yeah, so it's a wonderful question, and it's certainly something that we've been thinking deeply about.

Chris Moravito: And we've engaged now, we've built an internal group focusing specifically on patient engagement and patient advocacy. As Brian said, the patient advocacy network in the U.S. and outside the U.S., in Europe and in the U.K., for example, is very strong, very active, very engaged. And even outside of those organizations, the patients themselves are very engaged and very willing to help us and, importantly, to help regulators like the FDA understand the burden of this disease. Brian referred to a conference that was held in June of 2020, which produced a Voice of the Patient report. It was held in conjunction with the FDA.

[music].

Chris Moravito: There were panels of experts, including patients, that participated in this conference. The number one report out of that was that patients wanted a new therapy that would slow or halt disease progression, something like what we think the profile of MAP-Mod can achieve. We're absolutely engaged with these organizations to communicate the burden of disease in FSHD and to help regulators understand what kinds of functional interventions or patient-reported interventions are important to this community.

Chris Moravito: And we're engaged with this community as well to help us think about what kinds of assessments we need to be able to measure in ongoing clinical trials in order to provide the substantial evidence to support those approvals. FDA has been very engaged, and we're encouraged by this involvement and look forward to continuing partnership with the regulator. Thanks again.

Operator: At this time, I would like to remind everyone in order to ask a question, press TARD and the number one on your telephone keypad. Your next question comes from Judah Frommer of Credit Suisse. Your line is now open.

Judah C. Frommer: Hi, thanks for taking the question and congrats on all the progress. Just a couple follow-ups on the 1B design. Can you just remind us why you decided to dose with the 6 milligram dose and not the 10.

Chris Moravito: And how impactful? And be readout, moving into phase two versus the data generated in healthy and that it is at one. Yeah, so, just to give you just the context of the study design, so it will be, um, up to three months of therapy in patients with sickle cell disease, and it's all comers with sickle cell disease. And we're looking for first and foremost safety and tolerability and then also looking for changes in key pharmacodynamic parameters, including HPF.

Chris Moravito: And we think the three month treatment duration gives us the opportunity to assess this. You anticipate having up to three dose cohorts, and we anticipate each cohort having up to 10 patients. We do have a DMC that will, it's an internal DMC that will be monitoring the study and giving us information at intervals that will inform continued development and progression through those cohorts. We decided to start at six because this is the dose level that achieved a threefold induction at HBGMRNA in healthy volunteers.

Chris Moravito: And as you've heard us say lots of times, our goal pose for this is a two to three fold induction on top of baseline in sickle cell. So we hypothesize that this is a dose that will have the potential for clinical benefit. We also believe that we will have at least the same amount of HBG induction in patients as we see in healthy volunteers. And there's also a potential for more HBG induction just because of the bone marrow environment, the refoesis environment, and sickle cell compared to healthy people.

[music].

Chris Moravito: So, well, you know, we started at six in order to give us room in order to detect HPG changes and ultimately HBF changes, HBF changes in patients. And we'll be looking at this continually as we dose through six, that's how it works. Subsequent doses will be informed. I'll just quickly finish this off. Subsequent doses will be informed by the incoming data and also by the PKPD model that we're building. Okay, that makes a lot of sense.

Chris Moravito: And then just can you remind us, from a clinical perspective, higher HBF is better, or is there kind of a threshold effect once you get to a 23, 4X induction? Right, so any increase from baseline has been demonstrated in genetic and clinical experiments to provide benefit. And, you know, we know from very good population studies that even a small change from baseline has potential impact on overall survival, you know, over very long periods of time, but certainly has that kind of impact.

Chris Moravito: And we also know from genetics that, you know, levels in the 20% range impact symptoms very well, and levels in the 25 to 35% range start to impact them. absolute symptomatology and can induce essentially a functional cure. What we're seeing from the incoming data from the gene editing programs is that very high levels of HBF, up to about 50%, can eliminate the disease and doesn't appear to cause any adverse events. So, you know, while we're seeing levels so far in healthy volunteers that imply we can induce to that kind of range, obviously, we'll see this in patients. We're not concerned about the potential for adverse events at this point related to that.

Operator: Thank you. This concludes the Q&A session for today. I would like to turn the call over to our CEO, Brian Stewart, for closing remarks. Thank you. Thank you, everybody, for joining us today, and we appreciate your support of Fulcrum. Have a great day.

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