Q2 2021 Fulcrum Therapeutics Inc Earnings Call

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Operator: Good morning and welcome to the Fulcum Therapeutics Conference Call. Currently, all participants are on a listen-only note.

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 Miss Christy Warren, Director of Investor Relations and Corporate Communications Portfolks.

Christy Warren: Ma'am, peace was. Thank you, operator. Good morning and welcome to the full-form Therapeutics Conference trial. 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 timeline, and financial projections. All 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.

Good morning, and welcome to Fulcrum Therapeutics Conference call. Currently all participants you may 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 Kristi Warwick.

Better up Investor Relations and corporate communications sportswear for them.

Ma'am. Please proceed.

Thank you operator, good morning, and welcome to Fulcrum Therapeutics Conference call.

And.

Yeah.

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

The private Securities Litigation Reform Act.

These may include statements that are is your expectations and standard clinical development.

And financial projections.

These forward looking statements represent our views as of today.

And they should not be relied upon as representing our views for the future.

Christy Warren: These refer to our most recent filings with the Securities and Exchange Commission for discussion of certain risks and uncertainties associated with our business. We see on today's call are Ryan Stewart, President and Chief Executive Officer, Chris Mosom, Chief Scientific Officer, and Chris Moravito, Chief Medical Officer. Let me quickly run through this morning's agenda. Given today's news, we're going to focus our call on the 6058 phase one healthy adult volunteer results. Brian will visit on a call with a corporate overview, and he will give updates from the quarter.

Let me update these statements and the future, but we are not taking on and applications.

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

With me on today's call and Bryan Stuart President and Chief Executive Officer, Chris Martin, Chief Scientific Officer, and Chris Moore.

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Let me quickly run through this morning's agenda.

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So for example.

He is 1 of the adult volunteer herself.

Brian will be handling all of the corporate overview and key updates from the quarter Theres lots and will provide a review of the SPX and E.

Christy Warren: Chris Moslin will provide a review of the FTCS 5058 preclinical data, Chris Moravito will review the clinical results and next steps for the program, and Brian will open the call for Q&A. With that, it's my pleasure to turn the call over to Brian.

Preclinical data.

Crystal Rubino will review the clinical results and next steps for the program and Brian will open the call for Q&A.

And that it's my pleasure to turn the call over to Bryan Bryan.

Brian: Brian, Thank you, Christy. Good morning, everyone, and thank you for joining us. This past quarter was particularly notable for the significant progress in both of our clinical space programs. In June, we announced positive results from the Phase 2B Redux 4 trial, where we were able to show that Los Mappamod slowed disease progression and improved function in patients with FSAHD, a severe and progressive form of muscular dystrophy that currently has no approved treatments available.

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

This past quarter was particularly notable for the significant progress and both of our clinical stage programs in June we announced positive results from the phase <unk> readout for trial, where we were able to show that lowest map and modest slow disease progression and.

And improved function in patients with F. S. H D a severe and progressive form of muscular dystrophy and currently has no approved treatments available.

Brian: These results strongly support our belief that Lousmapamont has the potential to be a safe and effective therapy for FSHD patients. With these promising data from Redux 4 in hand, we plan to meet with the FDA in the second half of 2021 to discuss potential next steps. Moving to FTS 6058, today we are very pleased to report compelling results from our ongoing phase one trial in healthy adults. As many of you know, the current treatment landscape for sickle cell disease includes therapies that target only select patients. The introduction of an oral therapy that can successfully target the root cause of sickle cell disease would represent a major advantage.

These results strongly support our belief that leaves map them on has the potential to be a safe and effective therapy for F. S. H D patients.

With these promising data from Readouts for in hand, we plan to meet with the FDA and the second half of 2021 to discuss potential next steps.

Moving to F. Yet 60.58 today, we are very pleased Shreveport compelling results from our ongoing phase 1 trial in healthy adult volunteers as many of you know the current treatment landscape for sickle cell disease includes therapies that target only select symptoms.

The introduction of an oral therapy that can successfully target the root cause of sickle cell disease would represent a major advancement.

We are especially excited about the results from this trial both in terms of Tolerability as well as the impacts we see and.

Brian: We are especially excited about the results from this trial, both in terms of tolerability, as well as the impact we see in the induction of fetal hemoglobin MRI and increase in F reticulism. In this trial, we saw an impressive 4.5 fold induction of fetal hemoglobin MRI.

And the injunction of fetal hemoglobin mrna and increase in F particular sites.

In this trial, we saw an impressive 4.5 fold induction of fetal hemoglobin mrna.

Brian: We also saw a 4.2fold increase in Ferticuliculic, which indicates fetal hemoglobin production, and we achieved maximal targeting gaites. Building on our extensive preclinical research, these results provide proof of biology and, We are also pleased to share that FTCS-6058 has been generally well-tolerated to date, and the pharmacokinetics support once daily oral administration. Encouragingly, these results provide the first evidence that

We also saw for 2 fold increase and at particular sites, which indicates fetal hemoglobin production.

And we achieved maximal target engagement.

Building on our extensive preclinical research these results provide proof of biology and mechanism.

We are also pleased to share that MTS 60, 58 has been generally well tolerated to date and the pharmacokinetics support once daily oral administration and.

Encouragingly these results.

Provide the first evidence that MTX 60, 58 may be able to achieve or exceed the 2 to threefold hbf induction we observed pre clinically this.

Brian: 6058 may be able to achieve or exceed the two to threefold HBF induction threshold we observed preclinically. This two to threefold HBF induction threshold would not only be superior to hydroxyurea, the current standard of care, but is also predicted to provide meaningful clinical benefits to single cell patients. With these results in hand, we remain on track to initiate a Phase 1B trial in sickle cell patients by the end of the year and plan to initiate a clinical trial in non-sickle cell hemoglobinopathy in 2022.

And there's 2 to 3 fold hbf induction threshold would not only be superior to hydroxyurea. The current standard of care, but it's also predicted to provide meaningful clinical benefit for sickle cell patients.

With these results in hand, we remain on track to initiate a phase 1 b trial and sickle cell patients by the end of the year and plan to initiate a clinical trial and non sickle cell Haemoglobinopathy and 2022.

Brian: I'll note that both of our development programs came from our fulcrum seek discovery platform, which is a powerful and differentiated approach to drug target identification and the innovation backbone of our. This has allowed us to rapidly identify novel, high-quality targets and modulate the root cause of genetically defined rare diseases. By enabling drug discovery at unprecedented scale in disease-relevant settings, Fulcrum C creates an unparalleled opportunity to efficiently grow our pipeline. We expect the work we are doing at the fulcrum seat will enable us to submit two new I&Ds by the first quarter of 2020.

I'll note that both of our development programs came from our fulcrum seek discovery platform, which is a powerful and differentiated approach to drug target identification and the innovation backbone of our company.

And this has allowed us to rapidly identify novel high quality targets and modulate the root cause of genetically defined rare diseases.

By enabling drug discovery at unprecedented scale and disease relevant settings for.

From C creates an unparallel opportunity to efficiently grow our pipeline. We expect to work we are doing the fulcrum is equal enable us to submit 2 new eye and DS by the first quarter of 2023.

Chris Calabrese: In addition, Fulcrum-Seek has also enabled our ongoing collaborations with both acceleron and myocardia, which continue to proceed well. As you can see, we continue to make important progress across our clinical development programs, research collaborations, and discovery platform. And with a cash runway that takes us into the first quarter of 2023, we expect to have meaningful updates from multiple key initiatives in the near. With that, I'll turn the call over to Chris Moxon to speak more about our preclinical work with FX-658. Thanks, Brian.

In addition, fulcrum fee has also enabled our ongoing collaborations with both accelerant and myocardial which continued to proceed well.

As you can see we continue to make important progress across our clinical development programs research collaborations and discovery platform and with a cash runway that takes us into the first quarter of 2023, we expect to have meaningful updates from multiple key initiatives in the near term with that.

And I'll turn the call over to Chris marks and speak more about our preclinical work with that PX and 58.

Thanks, Brian.

Chris Calabrese: Sickle Cell disease is a genetic disorder of the red blood cells caused by a biomutation in the HPB gene. It is the most common type of inherited human globinopathy, and affects an estimated 100,000 people in the United States and millions more worldwide. In healthy individuals, red blood cells are round and slightly concave, enabling efficient circulation through small blood vessels to carry oxygen to all parts of the body.

Sickle cell disease, it's a genetic disorder of the red blood cells caused by mutation and the HPV gene.

It's the most common type of inherited Haemoglobinopathy and affects an estimated 100000 people and the United States millions more worldwide.

And healthy individuals' red blood cells around and by countries, enabling efficient circulation through small blood vessels to carry oxygen. So all parts of the body.

And in individuals with sickle cell disease.

Chris Calabrese: In an individual with sickle cell disease, the red blood cells take on a characteristic fickle shape. Sickled cells also die prematurely, also known as homolysis, which causes a constant shortage of red blood cells or anemia. Also, when sickled blood cells travel through blood vessels, they often get stuck and restrict normal blood flow. When this happens, fickle cell disease individuals can experience what is known as a vasoeclusive crisis, or VOC. Beyond anemia and VOCs, people living with sickle cell disease typically suffer from other serious morbidities such as stroke and acute chest syndrome.

Red blood cells take on the characteristic sickle shape.

Sickle cells, often die prematurely also known as hemolysis, which causes a constant shortage of red blood cells for anemia.

Also when sickle red blood cells travel through blood vessels, they often get stuck and restrict normal blood flow.

When this happens sickle cell disease individuals' can experience what is known as a basal occlusive crisis for boc.

Beyond anemia, and B O sees people living with sickle cell disease typically suffer from other serious morbidities, such as stroke and acute chest syndrome.

Together these complications significantly impact lifespan.

Current therapies are unable to address broad sickle cell disease, symptomology and thus underscores the tremendous unmet need that remains and this diverse population.

The therapeutic rationale at fulcrum is to induce fetal hemoglobin for H B S.

Chris Calabrese: Together, these complications significantly impact life. Current therapies are unable to address broad sickle cell disease symptomology and thus underscore the tremendous unmet need that remains in this diverse population. The therapeutic rationale at Fulcrum is to induce fetal hemoglobe, or HBS. Human genetics clearly shows this mechanism can treat the root cause of disease. People who carry the sickle cell mutation, as well as additional mutations that promote hereditary persistence of fetal hemoglobin, present with HBF levels that are often elevated above 20% and that are associated with asymptomatic disease.

Human genetics clearly show this mechanism can treat the root cause of disease.

People, who carry the sickle cell mutation as well as additional mutations that promote hereditary persistence of fetal hemoglobin and present with hbf levels that are often elevated above 20% and.

And that are associated with asymptomatic disease.

These observations suggest that novel therapies that can that can achieve similar levels have the potential to provide a functional cure.

What I'd also like to point out is that individuals with sickle cell disease have baseline hbf levels that are typically between 5 and 10% of total hemoglobin <unk>.

This implies an and effective hbf inducer may provide meaningful clinical benefit by increasing H b S levels 2 to 3 fold above baseline.

And it's been shown both clinically and genetically and such levels of Hbf can have a transformative impact for patients along the spectrum shown on the blue arrow, including progressively reduced mortality.

Reducing recurring pain crisis events and increased likelihood of asymptomatic presentation.

Chris Calabrese: These observations suggest that novel therapies that can achieve similar levels have the potential to provide a functional cure. What I'd also like to point out is that individuals with sickle cell disease typically have baseline HPF levels that are typically between 5 and 10% of total hemoglobin. This implies that an effective HBF inducer may provide meaningful clinical benefit by increasing HBF levels two to threefold above baseline. It has been shown both clinically and genetically that such levels of HPF can have a transformative impact for patients along the spectrum shown on the Blue Arrow, including progressively reduced mortality, reducing recurring pain crisis events, and increased likelihood of asymptomatic presentations. Using our Fulcum-Seek drug discovery platform, we identified EED EED is a non-catalytic subunit of the PRC2 complex.

Using our <unk> drug discovery platform, we identified <unk> as a biological targets capable of robust hbf induction.

E D as a non catalytic subunit of the PRC too complex.

<unk> to propagate system, and try and methylation and epigenetic mark that is associated with decreasing <unk> mrna and hbf protein expression.

We developed FTF and $6.58, a highly potent oral small molecule <unk> inhibitor capable of decreasing his don't try and methylation levels through PRC, 2 inhibition, and thereby inducing <unk> mrna and hbf protein expression and red blood cells.

<unk> hundred 60, <unk> has outstanding drug like properties and in addition to potent E. The binding and inhibition of PRC to activity.

<unk> is a highly selective and clean off target profile.

We were also issued a composition of matter patents, which provides protection from 2.2040.

We are profiled and $6.58 across numerous in vitro and in vivo preclinical models.

And both healthy and sickle cell disease models, we observe a consistent 2 to 3 fold induction of hbf proteins, and we observed strong correlations between mrna and protein expression.

As seen on the right, we are showing mrna and HBO protein changes from healthy CD 34 positive cells and the town's mouse model that highlight this consistent 2 to threefold correlation of mrna and protein.

Our connectivity of concentration dependent increases and target engagement with induction of H B G mrna and HBO protein expression is a very consistent findings that we observed throughout the preclinical dataset we've generated to date.

Chris Calabrese: PRC2 propagates histone trimethylation, an epigenetic mark that is associated with decreasing HBG, MRNA, and HVF protein expression. We developed FtF 6058, a highly potent, oral small molecule EED inhibitor capable of decreasing histone trimethylation levels through PRC2 inhibition and thereby inducing HBGMRNA and HBF protein expression in red blood flow. FTX 60508 has outstanding drug-like properties and, in addition to potent EED binding and inhibition of PRC2 activity, displays a highly selective and clean off-target profile. We were also issued a composition of Matter patent, which provides protection until 2004.

And preclinical studies the inhibition of <unk> with <unk> 58 also results in similar levels of Hbf induction as compared to those reported with gene editing spin.

Specifically and erythroid sales derived from CD 34 positive cells F. T X 60, 58 achieves a maximal threefold hbf induction and healthy and sickle cell donors.

This is similar to published data from vertex and CRISPR therapeutics, demonstrating an approximate threefold hbf induction and CD 34 positive cells from healthy donors by CTX Oh, 1 of <unk>.

<unk> 11, a gene editing approach now being studied and a phase 1.2 clinical trial.

On the left side of this slide you can see we've profiled CD 34 positive cells that were obtained from healthy and sickle cell donors or a donor who had the sickle cell trait.

And all cases, we have a robust increase in the amount of hbf and response to treatment with <unk> 58.

What we observe is the characteristic 2 to threefold increase above baseline.

Awaits the absolute hbf increases between 8 and 25%.

If these post treatment values for to translate into the clinic ft, 6058 has the potential to provide meaningful benefit and even potentially curative levels of hbf administered as a once daily oral pill.

Chris Calabrese: We have profiled 6058 across numerous in vitro and in vivo preclinical models. In both healthy and sickle cell disease models, we observe a consistent two to threefold induction of HPF protein, and we observe strong correlations between MRNA and protein expression. On the right, we are showing MRNA and HV protein changes from healthy CD34 positive cells and the Towns Mouse model that highlight this consistent two to threefold correlation of MRN and protein.

As we think about the value proposition of an oral small molecule that can induce hbf levels 2 to threefold. We believe this could be the preferred treatment option for patients providers and payers.

As I mentioned baseline hbf levels and sickle cell disease patients are typically 5% to 10%.

Based on a strong body of literature generated to date inducing hbf can address the root cause of sickle cell disease and.

In contrast, with symptomatic treatments or for stem cell transplant regimens used in conjunction with gene editing and effective oral small molecule hbf inducer, such as SDN and <unk> 58 has the potential to be disease, modifying addressing sickle cell disease pathology and symptomatology couple.

Chris Calabrese: The connectivity of concentration-dependent increases in target engagement with induction of HBGMRNA and HBF protein expression is a very consistent finding that we observe throughout the preclinical data set we've generated to date. In preclinical studies, the inhibition of EED with FTCX 6058 also results in similar levels of HPF induction as compared to those reported with gene editing. Specifically, in erythroid cells derived from CD-34 positive cells, FTX 60508 achieves a maximal threefold HPF induction in healthy and sickle cell donors.

Couple this potential for broad therapeutic benefit with the convenience of oral administration and distribution and scale to meet the medical need of a global patient population, we believe that MTN and $6.58 may truly transform the treatment landscape.

You will see and in our phase 1 healthy volunteer trial. We've included exploratory measures of <unk> mrna and that particular sites.

1 of the key reasons, we're quantifying these due to the biology of erythropoiesis and help individuals.

And the process of erythropoiesis greatly influences total mrna and total protein levels as human stem cells, and the bone marrow differentiate and eventually interest circulation as mature red blood cells.

Moreover, the proposed site of action for <unk> <unk> $6.58 is on the human stem cells that reside and the bone marrow.

As you can see these newly exposed sales will take approximately 2 weeks to differentiate and particular sites and enter the circulation from which we are sampling.

This provides a narrow window of time to measure any HPT mrna changes that may be occurring and the context of a 14 day study.

Chris Calabrese: This is similar to published data from Vertex and CRISPR therapeutics demonstrating an approximate threefold HPF induction in CD34 positive cells from healthy donors by CPX-O-1, a BCL11A gene editing approach now being studied in a phase one, two, clinical trial. On the left side of this slide, you can see we've profiled CD-34 positive cells that were obtained from healthy and sickle cell donors or a donor who has the sickle cell trait.

Thus, we developed a highly sensitive and robust droplet digital PCR assay to quantify HPT mrna.

Also as particular sites represent the first opportunity to determine if any HPV mrna increases have begun to translate to HBO protein and the context for 14 day trial, we utilized and F. Particular site measure that relies on specific immuno detection of hbf to quantified any early change and hbf protein.

Before turning the call over to Chris Moore veto I'd like to thank the team at Fulcrum Who's working so hard on this program and the volunteers who participated in this trial.

It's a fantastic example of innovative drug discovery that has the potential to make a real impact on people living with sickle cell disease, Chris. Thanks.

Thanks, Chris.

I'd like to take a moment to remind everyone that the results we will be sharing our from our ongoing phase 1 clinical trial and healthy volunteers.

Chris Calabrese: In all cases, we have a robust increase in the amount of HPF in response to treatment with FTX 5058. What we observe is the characteristic two to threefold increase above baseline that equates to absolute HPF increases between 8 and 25%. If these post-treatment values were to translate into the clinic, FTCX 6058 has the potential to provide meaningful benefit and even potentially curative levels of HPF administered as a once daily oral pill.

As a reminder, the aim of the ongoing phase 1 is to evaluate safety tolerability and pharmacokinetics of SPX $6.58 treatments and <unk>.

<unk> is also collecting pharmacodynamic data to assess target engagement HBV mrna levels and increases in our particular sites, which are particular sites that contain hbf protein.

Here you can see the design of the trial and the doses being studied and the sad and Mad cohorts. We've also included the expected target engagements and Pharmacodynamic effects thresholds derived from PK PD modeling of preclinical data.

Based on this modeling.

And we expected that the target engagement and Pharmacodynamic effects would be observed and a 610 and 20 milligram cohorts to.

To date, we have completed SCC cohorts, 1 through 6 and MA.

Chris Calabrese: As we think about the value proposition of an oral, small molecule that can increase HBF levels two to threefold, we believe this could be the preferred treatment option for patients, providers, and payers. As I mentioned, baseline HBF levels in sickle cell disease patients are typically 5 to 10%.

Cohorts 1 through 3.

<unk> 58 was generally well tolerated and all of the SAP and <unk> cohorts completed stage there were no serious adverse events and no discontinuation.

All treatment emergent adverse events deemed at least possibly related to $6.58 for mild and both the sad and Mad cohorts. There was 1 great for and the 10 milligram cohort that was determined to be unrelated to study drug.

Chris Calabrese: Based on a strong body of literature generated to date, inducing HBF can address the root cause of sickle cell disease. In contrast with symptomatic treatments or stem cell transplant regimens used in conjunction with gene editing, an effective oral small molecule HPF inducer, such as FTCC 6058, has the potential to be disease-modifying, addressing sickle cell disease pathology and symptoms. Combining this potential for broad therapeutic benefit with the convenience of oral administration and distribution at scale to meet the medical needs of a global patient population, we believe that FTX 6058 may truly transform the treatment landscape.

These tolerability and safety data are consistent with expectations and support advancing this trial.

<unk> 658, PK profile demonstrated dose proportionality across the sad and Mad cohorts.

Cohorts have been half life of approximately 6 to 7 hours, which was longer than what we had originally modeled this resulted in greater exposures at lower doses, which we believe directly influence the target engagement and pharmacokinetic pharmacodynamic effect observed at lower doses.

Next we will share the results from the 3 exploratory endpoints measured and our phase 1 trial.

Shown on this slide as a target engagement data demonstrating potent and robust inhibition of histone <unk> methylation and <unk>.

Key epigenetic mark facilitated directly PRC to.

We collected samples at baseline day noted as day -1 we then collected samples and measure target engagement at day, 7 and 14 on treatment and at the safety follow up visit day noted <unk>, which occurred 7 to 10 days after the last dose at day 14 and.

These results demonstrate that maximal target engagement was achieved by day, 7 and the 6% and 10 milligram cohorts.

Chris Calabrese: You'll see that in our Phase 1 Healthy Volunteer Trial, we've included exploratory measures of HPG, MRNA, and Def Ritculous. One of the key reasons we're quantifying these is due to the biology of erythrocoesis and healthy individuals. The process of erythropoiesis greatly influences total MRNA and total protein levels as human stem cells in the bone marrow differentiate and eventually enter circulation as mature red blood cells. Moreover, the proposed site of action for FTCX 6058 is on human stem cells that reside in the bone marrow.

And we'll target engagement was also achieved at 2 grams after 14 consecutive days of treatment.

I'll note that subject to retain about 20% of baseline <unk> on tray methylation levels at maximal target engagements consistent with the preclinical data we've generated.

Overall these clinical results demonstrate that <unk> hundred 58 is a potent inhibitor of PRC to activity.

And.

Next we will share the ACG mrna clinical data.

<unk> 658 treatment resulted in both time and dose dependent increases and <unk> mrna demonstrating proof of biology.

Here, representing these pharmacodynamic effects and data <unk> panels for 2 milligram 6 milligram and 10 milligram dose cohorts plotted as fold induction over placebo at each time point.

There is clear evidence of dose proportionality at 2 milligrams or as evidenced <unk> mrna induction at 7% and 14, though not statistically significant and both the 6 and 10 milligram cohorts, we observed statistically significant EQT mrna infection, but the 10 milligram cohort achieving a need for 5 fold induction.

Chris Calabrese: As you can see, these newly exposed cells will take approximately two weeks to differentiate into inter-reticulocytes and enter the circulation from which we are sampling. This provides a narrow window of time to measure any HBGMRNA changes that may be occurring in the context of a 14-day study. Thus, we developed a highly sensitive and robust droplet digital PCR assay to quantify HPG MRA.

After 14 days.

You can also see we're getting up the maximal eightfold induction and the 10 milligram cohort as indicated by the 95% confidence interval range.

Encouragingly all other results presented in a 6 and 10 milligram cohort demonstrates statistically significant changes from baseline.

I'll also point out that the <unk> industrial responds as highly durable and noticed that safety follow up 7 to 10 days. After the treatment period subjects maintained the HPT mrna induction observed at day 14.

Chris Calabrese: Also, as reticula sites represent the first opportunity to determine if any HPG MRI increases have begun to translate to HBF protein in the context of a 14-day trial, we utilize an F-ratuciriculocyte measure that relies on specific immunodetection of HBF to quantify any early change in HBF protein. Before turning the call over to Chris Morbito, I'd like to thank the team at Fulcrum who are working so hard on this program and the volunteers who participated in this trial. It's a fantastic example of innovative drug discovery that has the potential to make a real impact on people living with sickle cell disease. Chris?

Which we believe will translate to hbf protein expression as well.

This type of durability is also consistent with what we've demonstrated pre clinically and the town's mouse model.

Before we move on I want to contextualize. This mean for 5 fold <unk> induction by reminding you that we observed 2 to 3 fold induction of mrna across multiple models preclinical data, suggesting that these results are meeting and potentially exceeding the induction thresholds predicted to provide meaningful clinical benefit for <unk>.

So patients I'll.

I'll also note that pre clinically <unk> mrna induction was also strongly correlated with each be up protein induction.

Yeah.

Last we will present, the particular site clinical results.

Where we again see evidence of a dose proportional PD effects to remind you and a particular site as a particular site that contains hbf protein while.

Chris Moravito: Thanks, Chris. I'd like to take a moment to remind everyone that the results we will be sharing are from our ongoing phase one clinical trial on healthy volunteers. As a reminder, the aim of phase one is to evaluate safety, tolerability, and pharmacokinetics of STX 6058 treatment. The trial is also collecting pharmacodynamic data to assess target engagement, HBGMRNA levels, and increases in our particulate sites, which are reticular sites that contain HBF protein.

While we did not observe a particular site increases and the 2 milligram cohort. After 14 days on treatment, we observed statistically significant increases at safety follow up after the 14 day treatment periods and both the 6 and 10 milligram cohorts <unk>.

<unk> 658 treatment and the 10 milligram cohort demonstrated a mean for 2 fold increase in our particular sites, which indicates that persistent hcg mrna induction is translating to hbf protein and strongly correlates with the HPT mrna induction observed to date.

Chris Moravito: Here, you can see the design of the trial and the doses being studied in the SAD and MAD cohorts. We've also included the expected target engagement and pharmacodynamic effects thresholds derived from PKPD modeling of pre-clinical data. Based on this modeling, we expected that the target engagement in pharmacodynamic effects would be observed in a 6, 10, and 20 milligram MAD cohort. To date, we have completed SAT cohorts 1 through 6 and MAD cohorts 1 through 3. FDX 6058 was generally well tolerated in all the SAD and MAD cohorts completed to date. There were no serious adverse events and no discontinuation.

As we laid out earlier the kinetics observed across these target engagement and PD endpoints are consistent with the recent polices and healthy individuals.

We observed maximal target engagement by 7 days <unk> mrna induction by day, 2014, and a particular sites demonstrating ETF protein expression by 21% to 24 days.

These results demonstrate a robust relationship between target engagement mrna induction and protein expression and the healthy volunteer setting.

Okay.

In summary, the results presented today and meet the induction thresholds predicted to provide meaningful clinical benefit for sickle cell disease patients.

Extensive genetic and clinical literature indicate that a 2 to 3 fold induction and hbf protein as the potential to translate the broad clinical benefits we.

We have also demonstrated pre clinically that <unk> mrna induction and hbf protein expressing our highly correlated these clinical results demonstrate proof of biology and mechanism. Additionally, we predict the mean for 5 fold induction and <unk> demonstrated to date is predicted to translate the hbf protein based on the strong <unk>.

Chris Moravito: All treatment-emergent adverse events deemed at least possibly related to 6058 or mild in both the SAD and MAD cohorts. There was one grade four event in the 10 milligram cohort that was determined to be unrelated to study drugs. These tolerability and safety data are consistent with expectations and support advancing this trial. FTX 6058 TK profiles demonstrated dose proportionality across the SAD and MAD cohorts. The mean half-life is approximately six to seven hours, which is longer than what we had originally modeled.

Relation between mrna and protein expression based observed pre clinically as well as the strong correlation observed between <unk> mrna and at particular sites clinically.

And <unk> induction and results continue to translate in the clinic, we believe ft X 60, 58 could provide clinical benefits for sickle cell patients.

In terms of next steps for the program, we anticipate sharing additional results from the ongoing phase 1 trial and a medical conference at the end of the year pending abstract acceptance.

Chris Moravito: This resulted in greater exposures at lower doses, which we believe directly influenced the target engagement and pharmacodynamic effect observed at lower doses. Next, we will share the results from the three exploratory endpoints measured in our phase one trial. On this slide, we present the target engagement data demonstrating potent and robust inhibition of histone trimethylation, the key epigenetic mark facilitated directly by PRC2.

Based on what we reported today, we also intend to on <unk> sickle cell patients on a clinical trial and the fourth quarter of this year the.

For multiple dose phase <unk> trial to start with with the 6 milligram dose and include a treatment period of up to 3 months. It will be designed to confirm and build on our current results with and aim to demonstrate early proof of concept and individuals with sickle cell disease.

We are planning that the subsequent study will be a phase 2.3 clinical trial that will start in 2023 and.

In addition, the clinical results to date support the initiation of a clinical trial and non sickle cell disease, haemoglobinopathy, including beta thalassemia, and we intend to submit an IND by the end of this year.

Chris Moravito: We collected samples at baseline, denoted as F. We then collected samples and measured target engagement at days 7 and 14 on treatment and at the safety follow-up visit, denoted SFU, which occurred 7 to 10 days after the last dose at day 14. These results demonstrate that maximal target engagement was achieved by day seven in the 6 and 10 milligram cohort. Maximal target engagement was also achieved at 2,000 grams after 14 consecutive days of treatment.

With that I'll turn it back for you Brian.

Thanks, Chris and clinical results presented today exceeded our expectations and expand on our understanding of the preclinical data that we've generated.

These results provide proof of biology, and mechanism and the increases and F. Particular sites also provide the first indication that robust increases in <unk> mrna are translating to hbf protein.

The opportunity to bring a new oral once daily therapy for people living with sickle cell disease is a very exciting prospects and we believe SPN $6.58 has the potential to be a significant advancement in treatment and the years ahead.

Chris Moravito: I'll note that subjects retained about 20% of baseline histone trimethylation level at maximal target engagement, consistent with the preclinical data we've generated. Overall, these clinical results demonstrate that FDX 6058 is a potent inhibitor of PRC2 activity.

These results further bolster our plans to enroll sickle cell patients and a clinical trial by the end of the year.

We are very excited about the prospects for our programs and FX HD and sickle cell disease to diseases with great unmet need where we have shown compelling data to date and.

And we look forward to identifying additional programs with great potential from our product engine as we seek to expand our development pipeline.

Chris Moravito: Next, we will share the HBGMRNA clinical data. F.EX 6058 treatment resulted in both time and dose-dependent increases in HBGMRNA, demonstrating proof of biology. Here we're presenting these pharmacodynamic effects in data S3 panels, with the 2 milligram, 6 milligram, and 10 milligram dose MAD cohorts plotted as fold induction over placebo at each time point. There is clear evidence of dose proportionality. At two milligrams, there is evidence of HBGMRNA induction at days 7 and 14, so it is not statistically significant.

We look forward to keeping you updated on our progress and the months ahead on.

Operator, you May now open the line for questions.

Yes.

Thank you Sir and as a reminder, if you wish to ask a question simply press Star then the number 1 on your telephone keypad.

Once again, if you wish to ask a question.

And simply press Star then the number 1 and your telephone keypad.

The first question is from the line of debt burnt off from Piper Sandler. Your line is now open.

Great. Thank you very much remarkable results.

Sure.

And from a model and do you anticipate to see from 20 minutes.

And.

Chris.

About the differences per truly healthy and sickle cell patients.

And then I appreciate it and that we're able to Hercules debt, but are on.

Is there any room for.

True.

Her from her work either better or worse and peso. Thank you for Mercury and congrats for the great data.

Yes, Thanks, Ted and I turn it over to Chris Moore, Vito and you could speak a little more too.

Chris Moravito: In both the 6 and 10 milligram cohorts, we observe statistically significant HBG MRNA induction, but the 10 milligram cohort achieves a mean four and a half fold induction after 14 days. You can also see we're getting up to a maximal eightfold induction in the 10 milligram cohort as indicated by the 95% competence interval range. Encouragingly, all of the results presented in the 6-10 milligram cohort demonstrated statistically significant changes from baseline. I'll also point out that the HBGMRNA induction response is highly durable.

The phase <unk> study and what we would anticipate seeing there.

So Ted Thanks for the question. The first question was about 20 milligrams and I assume you mean, the ongoing clinical trial is that correct.

Yes.

Thank you. So first I think that we just go by the PD Biomarkers I think we will not.

<unk> the target engagement that we've achieved and you've already achieved maximal target engagement.

All 3 doses and so I don't think it will exceed that and there might be some differences and the kinetics to get the Max we will target and engagement but.

And the limit will be exceeded.

<unk>.

<unk>.

Induction of could be increased and again, we will likely see a difference and the kinetics to get to a maximal amounts. We expect there will be and increase but we can't I can't predict what that number will be at this point and then similarly with that protects.

Chris Moravito: You notice that at safety follow-up, 7 to 10 days after the treatment period, subjects maintain the HBG MRNA induction observed at day 14, which we believe will translate to HBF protein expression as well. This type of durability is also consistent with what we've demonstrated preclinically in the Towns Mouse model.

And we would expect debt, we would see an increase over what we currently have today, especially in terms of kinetics. So the time course of when that will happen.

Chris Moravito: Before we move on, I want to contextualize this mean four and a half fold HBMRNA induction by reminding you that we observed a two to threefold induction of MRNA across multiple models preclinically, suggesting that these results are meeting and potentially exceeding the induction thresholds predicted to provide meaningful clinical benefit for sickle cell. I'll also note that preclinically, HBGMRNA induction was also strongly correlated with HBF protein induction Last, we will present the F-particular site clinical results, where we again see evidence of a dose-proportional PD effect. To remind you, an F-raticular site is a reticulous site that contains HBF protein.

We are regardless thrilled about what we're seeing so far and the 6% to 10 milligram seeing over 2 to 3 fold induction, which is what we predicted to us as of what we mean.

And for results and we look forward to continuing that.

And continue with that goalpost and minus we move forward into the phase <unk> study.

Your second question was about what we might expect to see and sickle cell patients versus healthy volunteers.

We know from our preclinical data that we would expect to see at least the same.

And of increases just based on what we have seen.

And our preclinical models, which demonstrate equally robust increases and healthy comps.

Compared to sickle cell patients.

Having said that and patient human patients, where the bone marrow and spent more permissive and where RBC half life is shorter because of the pathology of the disease.

It's quite likely that we will see.

More significant changes more fold induction or potentially faster induction compared to what we're seeing and healthy of course. This is the point of the <unk> study that will be starting later on this year and we'll certainly be excited to share those results as they come forward.

Chris Moravito: While we did not observe F particulate increases in the 2 milligram cohort after 14 days on treatment, we observed statistically significant increases at safety follow-up after the 14-day treatment periods in both the 6th and 10 milligram cohorts. FTX 6058 treatment in the 10 milligram cohort demonstrated a mean 4.2 fold increase in the particular sites, which indicates that persistent HBG MRNA induction is translating to HBF protein and strongly correlates with the HBG MRNA induction observed to date.

Great. Thank you guys congrats.

Yes.

Your next question is from the line of <unk>.

And from Stifel. Your line is now open.

Sure and taking our questions and congrats from me as well.

Just to kind of follow up on the net.

<unk> plan or the patient trial phase 1 be Mad study.

Just wondering given the chronic dosing and thats likely from this oral administered drug what are your thoughts on I guess the treatment magnitude.

But you can expect I know you mentioned 2 to 3 fold. So should we expect for 2 to 4.5 that we saw on healthy volunteers or can you provide a little bit more I guess bookends around that and then second part to that question is.

I guess, given the chronic dosing what kind of safety signal or should we be expecting going forward given that this is basically temporary and with the epigenetics. Thank you.

Thanks, Dae gon I turn it over to Chris <unk> again, and you can break that question up into 2 answers 1 is just contextualized thing.

Chris Moravito: As we laid out earlier, the kinetics observed across these target engagement and PD endpoints are consistent with the resopoietis and healthy individuals. We observed maximal target engagement by seven days, HBG MRNA induction by day 14, and effort ticulocytes demonstrating HBF protein expression by 21 to 24 days. These results demonstrate a robust relationship between target engagement, MRNA induction, and protein expression and the healthy volunteer setting. In summary, the results presented today meet the induction threshold predicted to provide meaningful clinical benefits to sickle cell disease patients.

Increases that we're observing.

Relative to the starting fetal hemoglobin levels that most sickle cell patients have and then we can comment on what we've observed from a safety and Tolerability perspective.

Great So dig on thanks.

The phase <unk> will be our first chance to see the effects of this drug and patients who are really excited about doing that and indicated on slide it will be on open label study and so we'll be able to get a feedback relative.

Eligible and <unk>.

And as we progressed for the study.

And the goalposts for the study will be 2 to 3 fold induction, but ultimately aspire and intimated setting up.

To answer for what we wanted to do is get to a percent.

Chris Moravito: Extensive genetic and clinical literature indicate that a two to three-fold induction of HBF protein has the potential to translate into broad clinical benefit. We have also demonstrated preclinically that HBGMRNA induction and HBF protein expression are highly correlated. These clinical results demonstrate proof of biology and mechanisms. Additionally, we predict the mean 4.5-fold induction in HBG MRNA demonstrated to date is predicted to translate the HBF protein based on the strong correlation between MRNA and protein expression observed preclinically, as well as the strong correlation observed between HBGMRNA and F particulate sites clinically.

Target percent and patient and somewhere between 10% and 30% up which is where we know based on genetics and other clinical data, we could see potentially profound effects on patient pay.

Patients with sickle cell disease art, with roughly 5% to 10% EPS level and increasing by a magnitude of 2 to 3 would get us from blood.

And then to 30% range, which is where we would expect to see.

Importantly, clinical changes.

Essentially you start to see even in the phase 1 b, but certainly which we would expect to observe and the future.

To restart.

In terms of the safety and Tolerability and so far we're actually really quite pleased with what we're seeing this has a very well tolerated by all based on day 1.

Non.

The date is 2 weeks of dosing as you point out and this is not chronic dosing, but based on these results and based on the levels that we're achieving from a pharmacokinetic perspective, we're optimistic that moving into patients over a longer period of time.

Chris Moravito: If these HBGM RNA induction results continue to translate in the clinic, we believe FDX 6058 could provide clinical benefits to sickle cell patients. In terms of next steps for the program, we anticipate sharing additional results from the ongoing face-month trial at a medical conference at the end of the year, pending abstract. Based on what we reported today, we also intend to involve sickle cell patients in a clinical trial in the fourth quarter of this year.

So give us these kinds of results as we're seeing now and healthy.

Oh and 1 more question.

Good question.

And then.

Volume.

For the.

And $4.5.

Hi.

Okay.

Perfect.

And good morning.

Dig on I'm, sorry, we're having a tough time hearing you.

Operator.

Yes, ma'am I'm, sorry, yes, or you might have been speaking on your speakerphone. Please pick up per handset until we can hear you clearly.

And can you guys hear me now.

We can thanks, great great. Yes. So just a quick follow up was this might be a really dumb question, but you.

And you just mentioned the percent target being 10% to 30% and the patient study, but any chance we can do something similar a similar exercise and these healthy volunteers now that you've seen a 4 fold increase or induction do we have.

And then get the percentage value on the hbf or is that completely out of the question. Thank you.

So.

Yes dig on why don't I turn it over to Chris marks and we can speak more to what we've seen pre clinically and CD 30 for us both from Sickleds owners as well as healthy donors.

Sure. So again, what we've observed pre clinically is this 2 to 3 fold induction above baseline.

Chris Moravito: The multiple dose phase 1B trial would start with a 6 milligram dose and include a treatment period of up to three months. It will be designed to confirm and build on our current results with the aim of demonstrating early proof of concept in individuals with sickle cell disease. We are planning that the subsequent study will be a phase two, three clinical trial that will start in 2023. In addition, the clinical results to date support the initiation of a clinical trial in non-sickle cell disease hemoglobinopathy, including beta thalassemia, and we intend to submit an I&D by the end of this year. With that, I'll turn it back to you, Brian.

And in absolute terms, we have certainly seen absolute levels of hbf as I pointed out with the upper end of 25% absolute increases of 25% above baseline. So we've definitely been able to achieve levels that are that are associated with a curative effect.

And the context of the healthy volunteer study again this is only a.

And frankly on a 21 day study for 14 days of dosing within the safety follow up period and as we highlighted we need to then overlay the normal process of erythropoiesis, which had US then pointed towards detecting hbf protein and the context of a particular sites for <unk>.

Question on whether we can quantify absolute levels of hbf and the context of a 21 day study is really not possible and that would require a study of longer duration.

And which will be the focus of <unk>.

On measurement that using HPLC to quantify hbf and.

In absolute terms as it typically done and a longer duration and phase <unk> study.

Awesome well. Thank you very much for those responses I'll hop back on the Q.

Brian: Thanks, Chris. The clinical results presented today exceeded our expectations and expanded on our understanding of the preclinical data that we've generated. These results provide proof of biology and mechanism, and the increases in F reticula sites also provide the first indication that robust increases in HBG, MRNA, are translating to HBF proteins.

And for your next question is from the line of Joseph Schwartz from SBB Leerink. Your line is now open.

So much and congratulations from me as well I.

I was wondering.

If you have any more thoughts on why and why you saw great and saw greater efficacy and healthy volunteers and the 2 to 3 fold increases in and learn mrna you expected based on your preclinical work do you think that's purely due to greater exposure due to longer half life and expected or are there any other factor.

And your view that might have contributed.

Brian: The opportunity to bring a new oral once daily therapy to people living with sickle cell disease is a very exciting prospect, and we believe FTX 60-58 has the potential to be a significant advancement in treatment in the years ahead. These results further bolster our plans to enroll sickle cell patients in a clinical trial by the end of the year. We are very excited about the prospects for our programs in FSA HD and sickle cell disease, two diseases with great unmet need where we have shown compelling data to date.

Sure that's a very good question and.

We don't have any clear indicators as to why today I think.

A notable difference perhaps between the preclinical data again, where we showed very robust 2 to 3 fold increases and hbf and for example, and the town's mouse model system, which again is humanized and the context of the globin genes, but still is operating under the control of the mouse for the murine transcription factors now we're in a fully human <unk> system and the healthy volunteer.

And that May in fact, the accounting for some of the differences, we're seeing and the the level of fold induction that have exceeded the levels that we saw on the preclinical study.

We're certainly very pleased with these results again, we remain focused on a 2 to 3 fold induction to provide meaningful clinical benefit and certainly look to see whether this translates now into the sickle cell setting and as Chris Marr veto implied and.

Brian: And we look forward to identifying additional programs with great potential from our product engine as we seek to expand our development. We look forward to keeping you updated on our progress in the months ahead. Operator, you may now open the line. Thank you, sir. And as a reminder, if you wish to ask a question, simply press star, then the number one on your telephone. Your first question is from the line of Ted Pentoff from Piper Sandler. Your line is now open.

Commented that we believe that the sickle cell setting likely will be even more permissive given the fact that we know that erythropoiesis is elevated baseline hbf levels are elevated.

And that the red blood cells have any shorter half life and sickle cell setting. So I think that whole context gives us a greater opportunity to see even greater induction.

Okay, that's very interesting.

And then I recall that <unk> 58 has been developed to have.

Hi, and cellular linearity I was wondering if you could talk about whether you have been able to evaluate that net attribute and.

Operator: Thank you very much, remarkable results. Is there any, from the modeling, what would you anticipate to see from 20-mig, and just thinking about the differences between health and Peace. Again, appreciating that we haven't seen the protein yet, but is there any reason to think that this might work either better or worse in patients? Thank you so much, and congratulations. This is a great day.

Healthy volunteers and what the implications are for when you get into patients.

Yes, yes, and John I'll turn it over to Chris and we can remind you of what we did observe pre clinically and then what we expect share yes. So again pre clinically what we did observe is a very robust pan cellular induction were now 90% of the sales were demonstrated too.

And be expressing very high levels of hbf protein and the context of the healthy volunteer study for not able to assess that and it's really would be in the context of the sickle cell study, where we'd have a much greater chance to.

Brian: Yes, thanks, Ted. I will turn it over to Chris Morvito, and we can speak a little more about the Phase 1B study and what we would anticipate seeing there. So Ted, thanks for the question.

Comment and collect data that would speak to the pan cellular induction, but certainly.

And again based upon the preclinical data either and healthy volunteer cells that were derived from a healthy donor or CD 34 cells obtained from a sickle cell donor we see a very.

And 2 to 3 fold induction and a very consistent 10 cellular and Dr. <unk> induction and either setting.

Chris Moravito: The first question was about 20 milligrams. I assume you mean the ongoing clinical trial. Is that correct?

Okay, Great and then if I could just ask a bigger picture question.

Chris Moravito: Yeah. Thank you. First, I think that we, just go by the PD biomarkers, I think we will not exceed the target engagement that we've achieved. We've already achieved maximal target engagement at all three doses. I don't think we'll exceed that.

What do you think.

And the implications of this work on the broader fulcrum Sikh platform are there other particular programs and your development pipeline, where there might be more direct read through.

And then others based on any similarities and the biology and or your approach to modulate gene expression and a congruent way.

Yes, Thanks, Joe.

Broadly obviously, we're very enthusiastic about.

Chris Moravito: And there might be some differences in the kinetics to get to maximum target engagement, but the limit will be exceeded. HBG MRN induction could be increased. And again, we will likely see a difference in the kinetics to get to a maximum amount. We expect there will be an increase, but we can't, I can't predict what that number will be at this point. And then similarly with effort ticks, we would expect that we would see an increase over what we currently have today, especially in terms of kinetic energy. So the time course of when that will happen.

About this data and the FSA speed data in terms of being validating for fulcrum seats and our approach. So both of these programs as we've talked about came out of the fulcrum seek engine 1 of them $60.58, we used our own medicinal chemistry and created.

This compound that we're very excited about and the in and the other and FSA T. We identified a target that had chemical matter that we were able to in license. So we feel like this is great validation, we're very excited with $60.58 to be taking that into other select haemoglobinopathy as we referenced and feel like that really broadens.

And the opportunity and and Additionally, I would say hematology as we think about fulcrum seek remains an area of focus and the type of commitment and expertise we're building and the area. We feel like we're really lend itself to other programs as well.

Great.

Chris Moravito: We are, regardless, thrilled about what we're seeing so far in the 6 to 10 milligram range, seeing over two to threefold induction, which is what we predicted as a very meaningful result. And we look forward to continuing that, continuing with that goal post in mind as we move forward into the phase 1B study. Your second question was about what we might expect to see in Cypil Cell patients versus healthy volunteers.

Well congrats and thank you.

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

Great. Good morning, I guess, a couple of things I wanted to touch on and so I know others have asked about higher doses and dose range and it just wasn't clear to me. So maybe if you could just expand is your expectation to look at a wider dose range or do you feel happy.

With 10 makes and Thats, what youre going to take into the next study and then.

Chris Moravito: We know from our preclinical data that we would expect to see at least the same amount of increases just based on what we have seen in our preclinical models, which demonstrate equally robust increases in healthy individuals compared to a sickle cell patient. Having said that in patients, human patients, where the bone marrow is a bit more permissive and where the RBC half-life is shorter because of the pathology of the disease, it's quite likely that we will see more significant changes, more fold induction, or potentially faster induction compared to what we're seeing in Healthies.

And secondly.

I guess I wanted to ask a question about sort of cumulative change or aggregate change. So would you expect in sickle cell patients being dosed over a longer period of time.

For these improvements to.

Get larger than what you've seen and sort of the short period of time and healthy volunteers.

Okay, Thanks, Matthew and turn it over to Chris if we could talk about how.

We're thinking about dosing and the <unk> as well as the second question on cumulative change great.

So as I said, the first dose for the upcoming Phase <unk> study will be 6 milligrams, and we intend to dose up to 3 months and.

Open label way at.

6 milligrams, we havent yet determined the second dose for the study.

It could be 10 milligrams based on these data that we read each day and maybe 20 milligrams based on the data that will come in from the healthy Volunteer study that's still running.

Chris Moravito: Of course, this is the point of the 1B study that will be starting later this year, and we'll certainly be excited to share those results as they come forward. Great, excellent. Thank you guys. Your next question is from the line of Daigonha, Franz Thiefel. Your line is now open.

We want to choose.

2 doses that will give us dose ranging information and the and the <unk> study so that we could select 1 dose for the potentially pivotal phase II study.

So the broad range of doses and the <unk> would give us a broad range of PK and PD responses with which we can build a robust model and select that dose we cannot yet comment on what the upper and dose will be but that's the approach that we'll take as we move that study forward and we will make the dose determination as we get closer to the initiation of the trial.

Chris Moravito: Sure, taking our questions and congrats from me as well. Just to kind of follow up on the next plan or the patient trial, Phase 1B, Mad Study, just wondering, given the chronic dosing that's likely from this oral administered drug, what are your thoughts on, I guess, the treatment magnitude that you can expect? I know you mentioned two to threefold, so should we expect 4 to 4.5 like we saw in the Healthy Volunteers? Or can you provide a little bit more, I guess, bookends around that?

Now in terms of the magnitude of changes.

Again, we stick to what we've been saying that our goalpost here would be and a 2 to 3 fold increase and sickle cell patients.

And in either of the doses or any other doses that we test and the phase <unk> study and of course, we'll be thrilled to see increases over that especially and hbf protein levels, but as I mentioned before and Chris and Brian and reiterated a 2 to 3 fold increase would be transformational, particularly when this is given us on all of medicine.

Chris Moravito: And then the second part to that question is, I guess given the chronic dosing, what kind of safety signals should we be expecting going forward given that this is basically tampering with the epigenetics? Thank you.

Once again, if you wish to ask a question simply press Star then the number 1 on your telephone keypad. Once again that is star 1.

And your telephone keypad. Your next question is from the line of <unk> from Bank of America. Your line is now open.

Chris Moravito: I turn it over to Chris Moravito again, and you can break that question up into two answers. One is just contextualizing the increases that we're observing relative to the starting fetal hemoglobin levels that most sickle cell patients have. And then, too, we can comment on what we've observed from a safety colorability perspective. Yeah, great.

Okay. Good morning, I think that's me hi, guys. Just wanted to ask a couple of questions for point of clarification. So.

And just from that I am clear when should we expect to report there.

For the increases and hbf protein.

Chris Moravito: So, Big on thanks. So phase one B will be our first chance to see the effects of this drug in patients, and we're really excited at doing that and indicated in slide, it will be an open label study, so we'll be able to get feedback relatively genuine as we progress to this study. The goalpost for the study will be a three-fold induction, but, you know, as ultimately as Brian intimated setting up this dancer, what we want to do is get to a percent, a target percent in patients, somewhere between 10 and 30 percent, which is where we know based on genetics and other clinical data, we could see potentially profound effects on, Patients with sickle cell disease start with roughly 5 to 10% HBF level, and increasing by magnitude of 2 to 3 would get us into that 10 to 30% range, which is where we would expect to see important clinical changes.

And then I have a couple of follow ups.

Yes, so we plan to begin enrollment.

The phase <unk> trial, and the fourth quarter of this year and we plan on providing an update in the second quarter of next year, Okay, and then how.

How long from the time you start treating patients.

And you ideally expect to start to see the impact on HBO.

Is there something that would be and media or what it would take.

For a certain level of time certain amount of time and then can you just remind us what you're expecting your dosing regimen today.

Yes so.

And as we discussed as we laid out and the site, where we talk about the process of re for polices.

And first time that you would expect to see hbf protein quantifiable hbf protein would be and patients around the months and then after 3 months, we will be much more likely to see that it just takes longer for the hbf protein to be quantifiable in the periphery.

And our free tenant and.

And patients uniformly with bond or is there variability.

So go ahead Chris.

Chris Moravito: We can essentially start to see even in Phase 1B, but certainly what we would expect to observe in the future of Phase 2, 3 studies. In terms of safety and tolerability so far, we're actually really quite pleased with what we're seeing. This has a very well-tolerated profile based on the case one result to date. It's two weeks of doping, but as you point out, this is not chronic dosing. But based on these results and based on the levels that were achieved from a pharmacokinetic perspective, we're optimistic that moving into patients over a longer period of time will give us these kinds of results, as we're seeing now in healthy Gaghan. Operator.

To that question, what we've seen pre clinically is that all the donors that we have tested to date have been very robust increased to <unk> 58, whether they are derived from a healthy donor of sickle cell donor or even that donor with sickle cell trade on.

That is in.

Contradistinction to Hydroxyurea, which has a much more varied response, and frankly, much weaker efficacy and the context for our preclinical data. So we're very encouraged by the fact that we see universally to date, a very robust and significant increase and hbf protein levels after treatment with <unk> 58.

Okay and then last question for me based on that.

Would you expect that the entire ITT population would be eligible or would you.

From criteria at least for trial enrollment.

Yes, and the entire population is eligible for this.

Absolutely.

Great. Thank you.

Last question is from the lineup from Judah Frommer from Credit Suisse. Your line is now open.

Chris Calabrese: Yes, ma'am, I'm sorry, sir, you might have been speaking on your speakerphone; please speak louder on your handset so we can hear you clearly. Hi, can you guys hear me now? We can't, thanks. Great, great. Yeah, so just a quick follow-up question: this might be a really dumb question, but you just mentioned the percent target being 10 to 30 percent in the patient study, but any chance we can do something similar or similar in these healthy volunteers now that you've seen the four-fold increase or induction? Do we even get the percentage value on the HBF or is that completely out of the question? Thank you. So yeah, Dagon. Why did I turn it over to Chris Moxman?

And a question just 1 on the potential regulatory path forward I think in the past you've referenced.

Our competitors bar of 3% improvement.

And hbf protein and I mean, the results today seem to indicate that you should be or could be well above that so any thoughts on that bar or any conversations with with the agency that that may help you.

Move forward on other a biomarker.

Or and other perspective.

Yes.

Yes, I would say in terms of the bar as you referenced there is just a very clear understanding from human genetics from these patients who have hereditary persistence of fetal hemoglobin and even these small increases and referenced as a percentage of.

Fetal hemoglobin and had very meaningful impact on patients and obviously.

Chris Calabrese: We can speak more to what we've seen preclinically, and CD34 is both from sickle donors as well as healthy donors. Sure, so again, what we've observed preclinically is this two to threefold induction above baseline. And in absolute terms, we certainly have seen absolute levels of HPF, as I pointed out, with the upper end of 25% absolute increases of 25% above baseline. So we've definitely been able to achieve levels that are associated with a curative effect in the context of the Healthy Volunteer Study. Again, this is only a frankly, a 21-day study, 14 days of dosing within the safety follow-up period.

And the greater increases and fetal hemoglobin and have even greater impact on patients up to the point, where they are essentially asymptomatic.

And what we've observed and relative to that 3%, which would be maybe.

Maybe about a little over a 1 fold increase what we're observing is significantly greater so we're very enthusiastic about that our goal right now.

As Chris Moore, and Vito mentioned is to get into a phase <unk> trial to be able to select a dose with the hope to then move into a phase III registration trial and the opportunity to potentially bring this to patients as quickly as possible.

Great. Thanks.

Okay.

There are no further questions and with that and this concludes today's conference call everyone. Thank you for attending you may now disconnect have a great day.

Chris Calabrese: And as we highlighted, we need to then overlay the normal process of erythropoietin, which points us towards detecting HBF protein in the context of efforticular sites. The question of whether we can quantify absolute levels of HPF in the context of a 21-day study is really not possible, and that would require a study of longer duration, which will be the focus of a measurement using HPLC to quantify HPF in absolute terms, as is typically done in a longer duration phase 1B study.

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Chris Calabrese: Awesome. Well, thank you very much for those responses. I'll hop back in the queue.

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Operator: Your next question is from the line of Joseph Swartz, from SVB Learing. Your line is now open, much and congratulations for me as well. I was wondering if you have any more thoughts on why you saw greater efficacy in healthy volunteers than the two to threefold increases in MRNA you expected based on your preclinical work. Do you think that's purely due to greater exposure due to a longer half-life than expected, or are there any other factors in your view that might have contributed? Sure, that's a very good question. We don't have any clear indicators as to why today.

And.

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Chris Calabrese: I think a notable difference, perhaps, between the preclinical data, again, where we showed very robust two to threefold increases in HPF, for example, in the town's mouse model system, which, again, is humanized in the context of the globin genes but still is operating under the control of the mouse or the murine transcription factors. Now we're in a fully humanized system in the healthy volunteer, and that may, in fact, be accounting for some of the differences we're seeing in the level of fold induction.

Chris Calabrese: that have exceeded the levels that we saw in the pre-clinical study. We are certainly very pleased with these results. Again, we remain focused on a two-to-three-fold induction to provide meaningful clinical benefit and certainly look to see whether this translates now into the sickle cell setting, and as Chris Morbito implied and commented that we believe that the sickle cell setting likely will be even more permissive, given the fact that we know that erythroproesis is elevated, baseline HBF levels are elevated, and that red blood cells have a shorter half Okay, yeah, that's very interesting.

Chris Calabrese: And then I recall that FDX60-58 has been developed to have high pancellularity. I was wondering if you have been able to evaluate that attribute in healthy volunteers and what the implications are for when you get into patients.

Chris Calabrese: Yeah, and I'll turn it over to Chris, and we can remind you of just what we did observe preclinically and then what we expect here. Yeah, so again, preclinically, what we did observe is a very robust pancellular induction where now 90% of the cells were demonstrated to be, I think, I would be expressing very high levels of HPF protein. In the context of the Healthy Volunteer Study, we're not able to assess that, and it really would be in the context of the sickle cell study where we'd have a much greater chance to comment on and collect data that would speak to pancellular induction.

Chris Calabrese: But certainly, again, based upon the preclinical data, either in healthy cells that were derived from a healthy donor or CD34 cells obtained from a sickle cell donor, we see a very consistent two-to-threefold induction and a very consistent pancellular induction in either setting. Okay, great. And then, could I just ask a bigger picture question?

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Brian: What do you think are the implications of this work on the broader Fulcrum-Seek platform? Are there particular programs in your development pipeline where there might be more direct read-through than others based on any similarities in the biology or your approach to modulate gene expression in a congruous way? Yeah, thanks, Joe. I would be broadly, obviously, we're very enthusiastic about this data and the FSS data in terms of being validation for Fulcrum Siege and our approach. So both of these programs, as we talked about, came out of the Fulcrum Seek engine.

Brian: One of them, 6058, we used our own medicinal chemistry and created this compound that we're very excited about. In the other, FSSD, we identified a target that had chemical matter that we were able to enlist. So we feel like this is great validation. We're very excited with 6058 to be taking that into other select hemoglobinopathies, as we referenced, and feel like that really broadens the opportunity. Additionally, I would say hematology, as we think about Fulcrum See, remains an area of focus and the type of commitment and expertise we're building in the area. We feel that it will really lend itself to other programs as well.

Brian: Great. Well, congratulations. Thank you. Your next question is from the line of Matthew Harrison from Morgan Stanley. Your lines are now open.

Operator: Great, good morning. I guess I have a couple things I want to touch on. So I know others have asked about higher doses and the dose range. It just wasn't clear to me, so maybe if you could just expand. Is your expectation to look at a wider dose range, or do you feel happy with 10 migs, and that's what you're going to take into the next study? And then, secondly, I guess I want to ask a question about some sort of cumulative change or aggregate change.

Operator: So, would you expect in sickle cell patients being dosed over a longer period of time for these improvements to get larger than what you've seen in sort of this short period of time and healthy volunteers? Thanks. Thank you, Matthew, and turn over to Chris.

Chris Moravito: We could talk about how we're thinking about dosing in the 1B as well as the second question, do you move change. Yeah, great. So, as said, the first dose for the upcoming phase 1B study will be 6 milligrams, and we intend to dose for up to three months in an open label way at 6 milligrams. We haven't yet determined the second dose for the study. It could be 10 milligrams based on the data that we reviewed today.

Chris Moravito: and maybe 20 milligrams based on the data that will come in from the Healthy Volunteer Study that's still running. We want to choose two doses that will give us range information in the 1B study so that we can select one dose for the potentially pivotal phase two study. So a broad range of doses in the 1B would give us a broad range of PK and PD responses with which we can build a robust model and select that dose.

Chris Moravito: You can't yet comment on what the upper end dose will be, but that's the approach that we will take as we move that study forward. And we'll make the dose determination as we get closer to the initiation of the trial. Now in terms of the magnitude of changes, Again, we stick to what we've been saying that our goal post here would be a two to threefold increase in sickle cell patients at either of the doses or any of the doses that we tested in the phase 1B study.

Chris Moravito: Of course, we'll be thrilled to see increases over that, especially in HBF protein levels. But as I mentioned before, and Chris and Brian have reiterated, a two to threefold increase would be transformational, particularly when this is given us as an oral medicine. Once again, if you wish to ask a question, simply press star, then number one on your telephone keypad.

Operator: Your next question is from the line of Dynamas from Bank of America. Your line is now open. Okay, good morning. I think that's me.

Operator: Hi guys, just wanted to ask a couple of questions for points of clarification. So just so I'm clear, when should we expect to see you report the results of increases in HBF protein? And then I have a couple of followers.

Chris Moravito: Yeah, so we plan to begin enrollment in the phase 1b trial in the fourth quarter of this year, and we plan on providing an update in the second quarter of next year. Okay, and then how long from the time you start treating patients would you ideally expect to start to see the impact on HBF? Is this something that would be immediate, or would it take, you know, a certain level of time, a certain amount of time?

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Chris Moravito: And then can you just remind us what your dosing regimen to me? Yeah, so, as we discussed, as we laid out in the slide where we talked about the process of refroquising, the first time that we would expect to see HBF protein, quantifiable HBF protein, would be in patients around a month. And then after three months, we would be much more likely to see that.

Chris Moravito: It just takes longer for the HBF protein to be quantified in the periphery. And our patients, do the patients uniformly respond, or is there variability? So, Chris.

Chris Moravito: Yeah, to that question, what we've seen preclinically is that all the donors that we have tested to date have a very robust increase to FTCC-60-58, whether they're derived from a healthy donor or a sickle cell donor or even a donor with a sickle cell trait. That is in, you know, contradistinction to hydroxyurea, which has a much more varied response and, frankly, much weak So we're very encouraged by the fact that, universally, we see a very robust and significant increase in HBF protein levels after treatment with 60-58. Okay, and then last question from me: based on that, would you expect that the entire CD population would be eligible, or would you have certain criteria at least for trial enrollment? Yeah, the entire population is eligible for this. Absolutely not.

Chris Moravito: Great, thank you. Your last question is from the line of Juno Farmer from Credit Suisse. Your line is now open, just went on the potential regulatory path forward. I think in the past you've had a competitor's bar of 3% improvement in HBF protein. I mean, the results today seem to indicate that you should be or could be well above that. So any thoughts on that bar?

Brian: with the agency that may help you move forward on either a biomarker or another perspective. Yeah, I would say in terms of the bar, as you referenced, there's just a very clear understanding from human genetics, from these patients who have hereditary persistence of fetal hemoglobin, that even these small increases, expressed as a percentage of fetal hemoglobin, can have very meaningful impacts on patients. And obviously, the greater increases in fetal hemoglobin have an even greater impact on patients up to the point where they're, essentially, symptomatic.

Brian: What we've observed, and relative to that 3%, which would be maybe about a little over a one-fold increase, what we're observing is significantly greater. So we're very enthusiastic about that. Our goal right now, as Chris Moribito mentioned, is to get into a phase 1B trial, be able to select a dose with the hope of then moving into a phase 2-3 registration trial and the opportunity to potentially bring this to patients as quickly as possible.

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Operator: Great, thanks. There are no further questions. And with that, this concludes today's conference call. Everyone, thank you for attending. You may now disconnect. Have a great time. Goodbye.

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