Q2 2022 Fulcrum Therapeutics Inc Earnings Call
Unknown Executive: Good morning and welcome to the Fulcrum Therapeutics second quarter 2022 conference call.
Good morning.
Welcome to the Fulcrum Therapeutics second quarter 2022 conference call.
Unknown Executive: Currently, all participants are in listen-only mode. There will be a question and answer session, at the end of this call. Please note, today's conference is being recorded.
Unknown Executive: We thank you all for attending today's presentation.
Currently all participants are in listen only mode.
There will be a question and answer session at the end of this call.
Please note today's conference is being recorded.
I would now like to turn the call over to Stephanie Ascher from Stern Investor Relations. Please proceed.
Unknown Executive: I would now like
Unknown Executive: You may now disconnect your lines and have a wonderful day.
Thank you Rocco good morning, and welcome to the Fulcrum 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 finance.
Unknown Executive: to turn the call over to Stephanie Ascher from Stern Investor Relations.
All projections.
While these forward looking statements represent our views as of today it 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 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 Bryan Stuart President and Chief Executive Officer, Judy done, our President of research and development and Aster Roger <unk>, Our Chief Financial Officer. In addition, Paul Bruno our executive director of corporate development will be available for Q&A.
Let me quickly run through this morning's agenda, Brian will begin the call with a corporate overview and key updates.
Steve will review our clinical program.
<unk> will cover our financials and then Brian will open the call for Q&A.
It's my pleasure to turn the call over to Brian .
Unknown Executive: Please proceed.
Thank you Stephanie good morning, everyone and thank you for joining us today.
Unknown Executive: Thank you, Rocco.
Ah Sacrum, our mission is to treat the root cause of rare genetic diseases and in the second quarter of 2022, we have made significant progress advancing two clinical stage assets that support that mission.
Unknown Executive: Good morning and welcome to the Fulcrum Therapeutics conference call.
Unknown Executive: 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.
Unknown Executive: While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future.
Unknown Executive: We may update these statements in the future, but we are not taking on an obligation to do so.
The first is our F. S. H D program, which is now in phase III.
<unk> to be the first to market therapy for an untreated patient population.
Unknown Executive: 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.
The second is the F. T X $60 58, a once daily H B S inducer with the potential to be the first oral therapy that can broadly improved outcomes in sickle cell disease and other haemoglobinopathy.
Unknown Executive: With me on today's call are Brian Stewart, President and Chief Executive Officer, Judy Dunn, our President of Research and Development, and Esther Rajavelu, our Chief, Financial Officer.
Unknown Executive: In addition, Paul Bruno, our Executive Director of Corporate Development,
I'll start with an update on MTX 60 58.
H B F induction is the only mechanism, which has been shown to broadly improve outcomes and reduce both the frequency and severity of sickle cell disease symptoms, such as Voc's anemia pain fatigue and acute chest syndrome.
Wide body of evidence that's demonstrated that increasing H b F by 5% to 10% above baseline.
Levels producers.
Producers benefits that could be transformative for patients.
With sickle cell disease, and oral therapy that can produce robust increases in each but yes.
It's been a therapeutic goal in sickle cell disease for some time, which is why our initial data from our phase one b trial are so exciting.
Unknown Executive: will be available for Q&A.
In June at the European Hematology Association Conference, we showed compelling proof of concept that S. T X 60, 58 rapidly induces H B F protein in sickle cell disease patients and demonstrated that it is able to achieve absolute H b S increases within the 5% to 10% range that cliff.
<unk> have targeted as the future standard of care.
These initial data underscore the potential of MTX 60, 58 to disrupt the sickle cell disease treatment paradigm.
They have also provided valuable insights to inform our path forward for the program and the phase one B trial.
Where we expect to complete enrollment in three cohorts.
Including a new higher dose cohort by year end.
We are also making rapid progress in our Fsh D program.
In the second quarter, we announced the enrollment of our first patient in the phase III reach trial.
Although F. S. H D is the second most common form of muscular dystrophy until now no potential F. S. H D treatments.
Progress to late stage clinical development.
Data from our phase two readouts for trial indicate that loves mathematics has the potential to slow or stop disease progression and in some cases, even improve function in F. S. H D patients.
The reach trial will enroll 230 patients at over 30 sites in the U S, Canada U K and the European Union.
As a landmark trial for this disease reaches already received a tremendous amount of enthusiasm and interest from both patients and clinicians and we expect to complete enrollment in 2023.
The progress we have made with our clinical programs position spoke room to move into the next phase of our growth as we prepare to potentially have two registrational candidates within the next year.
Unknown Executive: Let me quickly run through this morning's agenda.
This is a pivotal moment for our company and in order to facilitate this transition and to ensure that we are aligned as an organization to deliver near term value for our clinical program.
This morning, we laid out our strategic plan to realign our internal investments and operations to focus resources on our two lead programs <unk> map I'm on for F. S. H D and F. T X 60, 58 for sickle cell disease, while streamlining our discovery efforts.
Astra will provide additional details on our plans however, I would like to highlight the changes that we have institute.
Instituted extend our cash runway into mid 2024, enabling us to achieve key milestones in both clinical programs.
As part of these organizational changes we have made changes at the leadership levels, Mel Hayes, who joined fulcrum in 2020, one as Chief commercial officer has been promoted to the role of Chief operating officer.
In this new position Mel will help guide execution of the day to day operations of the company. In addition to his current commercial responsibilities.
Additionally, we have expanded the role of Kurt Oltmanns, our SVP and General Counsel Curt will now take on the role of Chief Legal Officer.
This is a very exciting time for our company.
The strategies, we are implementing are designed to enable us to deliver on our near term business imperatives, while we forge ahead with our mission of building, a leading biopharmaceutical company poised to bring transformative therapies to patients with genetically defined rare diseases.
And with that I'll turn it over to Judy to talk more about our clinical programs Judy.
Unknown Executive: Brian will begin
Thank you Brian .
Unknown Executive: the call with a corporate overview and key updates, Judy will review our clinical program,
I noted last quarter, we made significant advances in our two clinical stage programs.
Unknown Executive: Esther will cover our financials, and then Brian will open the call for Q&A.
Unknown Executive: With that, it's my pleasure to turn the call over to Brian.
Let me begin by reviewing our 68 program and the ongoing phase <unk> trial in sickle cell disease.
Unknown Executive: Thank you, Stephanie.
Unknown Executive: Good morning, everyone, and thank you for joining us today.
So there's a significant unmet need in sickle cell disease treatment landscape.
Unknown Executive: At Fulcrum, our mission is to treat the root cause of rare genetic diseases, and in the second, quarter of 2022, we have made significant progress in advancing two clinical stage assets that support that mission.
We're all familiar with the efficacy safety and Tolerability challenges associated with Hydroxyurea.
Unknown Executive: The first is our FSHD program, which is now in phase three, positioning to be the first-to-market therapy for an untreated patient population.
Even the newer treatment options only address the symptoms of the disease rather than targeting its broad symptomatology.
Other therapies in development, such as gene editing approaches present challenges due to the invasive.
And this and accessibility of the treatment.
A safe and tolerable oral small molecule that produces robust H b S increases would be the new standard of care for sickle cell disease patients.
Unknown Executive: The second is FTX6058, a once-daily HBF inducer with the potential to be the first oral therapy, that can broadly improve outcomes in sickle cell disease and other hemoglobinopathies. I'll start with an update on FTX6058. HBF induction is the only mechanism which has been, shown to broadly improve outcomes and reduce both the frequency and severity of sickle cell disease symptoms such as VOCs, anemia, pain, fatigue, and acute chest syndrome. A wide body of evidence has demonstrated that increasing HBF by 5 to 10% above baseline levels produces benefits that could be transformative for patients with sickle cell disease.
As a once daily oral H B S inducer.
16, 58 has tremendous potential to deliver life changing benefits for people living with sickle cell disease.
Unknown Executive: An oral therapy that can produce robust increases in HBF has been a therapeutic goal in sickle cell disease for some time, which is why our initial data from our phase 1b trial are so exciting. In June, at the European Hematology Association conference, we showed compelling proof of concept, that FTX6058 rapidly induces HBF protein in sickle cell disease patients and demonstrated that it is able to achieve absolute HBF increases within the 5 to 10% range that clinicians have targeted as the future standard of care.
Unknown Executive: These initial data underscore the potential of FTX6058 to disrupt the sickle cell disease, treatment paradigm.
60, 58 originated through our footprint discovery engine and is a potent and highly selective <unk> inhibitor with a clean off target profile.
Unknown Executive: They have also provided valuable insights to inform our path forward for the program, and the Phase 1b trial, where we expect to complete enrollment in three cohorts, including a new higher dose cohort, by year end.
We have strong preclinical evidence and now clinical evidence in sickle cell disease, such as demonstrating that 60 58 produces rapid and durable hbf induction.
The ongoing phase <unk> study is designed to be a dose ranging multiple cohort study.
Each cohort can enroll up to 10 subjects and is comprised of a 28 day initial treatment period at.
At the end of the treatment period, all subjects are offered the opportunity to participate in an eight week treatment extension.
Good evening, and a total of up to three months of exposure.
The goal of a phase one B study, let's just first and foremost.
<unk>. The 60 58 induces H B F protein in people with sickle cell disease.
The data from initial patients that we presented at Aha chose not just protein induction within 14 days of treatment initiation.
But it's a six Nick dose, we were already able to achieve absolute increases in H b S within that 5% to 10% range that provides broad clinical benefits.
In addition to H B S increases, we also observed meaningful changes in other biomarkers.
Absolute particular site count total hemoglobin and total bilirubin that were indicative of clinical improvement through decreased hemolysis unless anemia.
Consistent with our healthy volunteer data.
Initial data from the one year study indicate that 60 58 was generally well tolerated with no serious treatment emergent adverse events.
No what I'm, saying is reported on study drug and there were no discontinuation as reported due to treatment emergent adverse events.
Currently we continue to enroll patients who are receiving H you as well as those who are not into the sixth vegan shoemake dose cohorts of this phase one B study.
It's important to understand the efficacy and safety of these drugs in combination because although 60 58 is intended to be used as a monotherapy.
Patients not fully responsive to Hydroxyurea may receive 60 58 concomitantly.
Our preclinical data indicate that there may be an additive or synergistic effect between these two drugs.
Additionally, we plan to initiate a third higher dose cohort this fall.
The combined data from these cohorts will be critical as our aim is to move as efficiently as possible and select the optimal dose for the phase two three trial, which we intend to be registrational.
We expect to complete enrollment in three dose cohorts by the end of the year and anticipate initiating registrational trial in 2023.
We've learned a lot from the early days of enrolling sickle cell patients in this study and we've used these learnings to refine our clinical execution and site operations.
Specifically as we have better understood than some of the challenges around adherence we implemented observe dosing we've already seen a benefit.
So we're confident that as we complete the remainder of this study were collecting high quality data.
Accurately represents the effects of $6 58 in sickle cell disease patients.
Moving onto F. S H D and almost map of mine development program.
This is another area, where we are working to address a clear and critical unmet need.
As Brian mentioned.
She is the second most prevalent form of muscular dystrophy.
It's estimated that there are 16000 38000 S. S HD patients in the U S alone and approximately half a million patients worldwide.
But there are currently no available therapies.
The continually progressive nature of S. S H D.
A disease in which basic motor function and quality of life begin to decline and the patient second decade of life.
Besides the urgent need for disease modifying therapy as well as the value of our less map them on program, which is the most advance treatments in development for this disease.
In the phase two readouts for trial, we looked at the effect of our snap Ahmad and 80 S. S. HD patients over a 48 week treatment period.
In addition to assessing the safety and Tolerability of last night. We also wanted to understand how does that study F. S. H D. As our trial was the first of its kind for this disease.
We looked at everything from the length of time needed to show an effect on disease progression to the appropriate risk assessments for detecting changes.
After 48 weeks, let's map amount demonstrated clinically meaningful benefits such as preservation of muscle health as measured by MRI.
Muscle function as measured by reachable workspace.
And patient quality of life.
First by patient global impression of change.
Importantly, lets map them out was very well tolerated with no serious treatment related adverse events.
The extensive work that was done as part of the Readouts for trial has enabled us to design the phase III reach trial in a very efficient manner.
Unknown Executive: We are also making rapid progress in our FSHD program. In the second quarter, we announced the enrollment of our first patient in the Phase 3 REACH, trial.
Reaching a 48 week double blind placebo controlled trial.
Reachable workspace, a quantitative measure a function is its primary endpoint.
The secondary endpoints and the reach trial include muscle fat infiltration.
Wow, a qualitative measure a function and the patient global impression of change.
As we prepare for commercialization will also be probing health care utilization and other economic and outcomes research snack checks.
As the first ever phase III trial in this disease reach represents an enormous milestone for the S. S. H D community.
Unknown Executive: Although FSHD is the second most common form of muscular dystrophy, until now, no potential, FSHD treatments have progressed to late-stage clinical development. Data from our Phase 2 Redux IV trial indicate that losmathomide has the potential to slow, or stop disease progression, and in some cases, even improve function in FSHD patients.
Unknown Executive: The REACH trial will enroll 230 patients at over 30 sites in the U.S., Canada, U.K., and, the European Union. As a landmark trial for this disease, REACH has already received a tremendous amount of, enthusiasm and interest from both patients and clinicians, and we expect to complete enrollment in 2023.
Since enrolling our first patient in June we have been moving quickly to begin enrolling at sites across North America, and Europe , and we are on track to complete that process next year.
We are incredibly proud of both our clinical programs and we look forward to sharing more in the future.
With that I'll turn it over to Esther to walk through the financials.
Thank you Sydney.
Following up on Brian's comments on our organizational changes I'd like to first provide more detail on our strategy and focus going forward.
And then provide an update on our financial performance in the second quarter.
As you heard from both Brian and JT are two clinical stage programs have gained momentum and the business realignment that we announced today reflects our confidence in the Congress, we have made and expect to make in the near term with both programs.
Unknown Executive: The progress that we have made with our clinical programs positions Fulcrum to move into the, next phase of our growth, as we prepare to potentially have two registrational candidates within the next year.
Welcome is well positioned to transition from an early stage clinical company, Chile pivotal stage company with two assets potentially in registration, enabling trials within the next year.
We intend to build on our success by prioritizing execution on these clinical stage assets.
Unknown Executive: This is a pivotal moment for our company, and in order to facilitate this transition, and to ensure that we are aligned as an organization to deliver near-term value for our clinical program, this morning, we laid out our strategic plan to realign our internal investments and operations to focus resources on our two lead programs, losmathomide for FSHD and FTX6058 for sickle cell disease, while streamlining our discovery efforts.
Consequently, we have taken steps to realign our internal investments and organizational structure.
They are tied to these key value driving programs, while streamlining our research and discovery efforts.
Unknown Executive: Esther will provide additional details on our plans. However, I would like to highlight that changes that we have instituted extend our cash runway, into mid-2024, enabling us to achieve key milestones in both clinical programs.
Unknown Executive: As part of these organizational changes, we have made changes at the leadership levels. Mel Hayes, who joined Fulcrum in 2021 as Chief Commercial Officer, has been promoted to the, role of Chief Operating Officer. In this new position, Mel will help guide execution of the day-to-day operations of, the company, in addition to his current commercial responsibilities.
Unknown Executive: Additionally, we have expanded the role of Kurt Bultman, our SVP and General Counsel. Kurt will now take on the role of Chief Legal Officer.
Unknown Executive: This is a very exciting time for our company.
In our clinical programs, we are focused on rapidly generating value enhancing data from a phase one b sickle cell disease and phase three FSC ste programs.
Unknown Executive: The strategies we are implementing are designed to enable us to deliver on our near-term business, imperatives while we forge ahead with our mission of building a leading biopharmaceutical company poised to bring transformative therapies to patients with genetically defined rare diseases.
While in discovery, we are now scaled appropriately.
<unk> identified targets in January and <unk> in 2023.
As part of the realignment towards our lead clinical programs. We are delaying the planned initiation of the phase one b trial in beta thalassemia and other non sickle hemoglobin nasty.
As well as the ongoing discovery and preclinical projects that are not core to our areas of focus.
A key consideration of our strategy is the desire to remain nimble and adaptable.
So even if we plan to deliver on key value driving clinical programs. Our discovery engine is unable to be flexible and opportunistic towards ongoing and future collaborations.
The changes we have implemented are expected to result in savings of $40 million to $50 million, which includes a 25% planned reduction in our workforce.
This realignment of internal investments and organizational structure to realize near term value from both our clinical programs also extends our cash runway into mid 2024.
As you can see these changes allow us to operate from a continued position of financial strength.
We ended the second quarter with 169 million in cash cash equivalence and marketable securities.
Now I will briefly review the financials for this quarter.
During the second quarter of 2022, we recognized collaboration revenue of one 9 million compared to 4.4 million recognized during the second quarter of 2021.
Second quarter 'twenty, two R&D expenses were $25 million compared to $17 4 million for the second quarter of 'twenty one.
G&A expenses for the second quarter of 2022 were $11 1 million compared to $6 7 million for the second quarter of 2021.
And our net loss for the second quarter of 'twenty, two was $34 1 million compared to a net loss of $19 6 million for the second quarter of 'twenty one.
Unknown Executive: And with that, I'll turn it over to Judy to talk more about our clinical programs.
With that I'll turn it back to Brian .
Unknown Executive: Judy?
Thanks, Esther before we close today I want to thank our incredible team at fulcrum, including those employees, who have been impacted by our recent organizational changes cause contributions we value greatly.
I'd also like to thank our patient communities clinical trial partners and shareholders for their continued support.
Unknown Executive: Thank you, Brian.
Unknown Executive: As Brian noted, last quarter we made significant advances in our two clinical stage programs.
Operator, you May now open the line for questions.
Unknown Executive: I'd like to begin by reviewing our 68 program and the ongoing Phase 1b trial in sickle cell, disease.
Thank you we will now begin the question and answer session.
Can I ask a question here My first Star then one on your Touchtone phone.
He was on a speaker phone or we ask you. Please pickup your handset before pressing the keys.
It's already a question please first starting through.
Unknown Executive: Our significant unmet needs in sickle cell disease treatment landscape.
Today's first question comes from Judah Frommer, whereas <unk> Suisse. Please go ahead.
Hi, Thanks for taking my question and for all the updates a couple from US first can we just start with the high dose cohort for the phase one b and in sickle cell can you can you remind us why you weren't low dose first and you know are now adding the high dose and then also for.
Unknown Executive: We're all familiar with the efficacy, safety and tolerability challenges associated with hydroxyurea.
Unknown Executive: Even the newer treatment options only address the symptoms of the disease rather than targeting its broad symptomatology.
Unknown Executive: Other therapies and developments such as gene editing approaches present challenges due to the invasiveness and inaccessibility of the treatment.
The phase one b can you give us any more color on how compliance has improved and what you're seeing as you enroll patients in what I think are some incremental sites versus the initial data cut.
Yeah sure sure Judy.
Happy to and look let me turn it over to Judy and we can speak both to our our approach to dosing and then some of the changes that we implemented in the clinical trial, yeah. Good morning Judah.
Unknown Executive: A safe and tolerable oral small molecule that produces robust HPF increases would be the new standard of care for sickle cell disease patients.
So as you know our one B trial was designed as a dose ranging study.
Unknown Executive: As a once-daily oral HPF inducer, 6058 has tremendous potential to deliver life-changing benefits for people living with sickle cell disease.
And so we started somewhere in the middle of that range at six milligrams, because we wanted to choose a dose that if we were going to see H B S. A we felt confident that we would and that's exactly what happened in six milligrams, we already achieved that 5% to 10% increase that we're looking for.
Unknown Executive: 6058 originated through our Fulcrum Seq discovery engine and is a potent and highly selective EED inhibitor with a clean off-target profile. We have strong preclinical evidence and now clinical evidence in sickle cell disease subjects demonstrating that 6058 produces rapid and durable HPF induction.
Unknown Executive: The ongoing Phase 1b study is designed to be a dose-ranging multiple cohort study. Each cohort can enroll up to 10 subjects and is comprised of a 28-day initial treatment period. At the end of the treatment period, all subjects are offered the opportunity to participate in an eight-week treatment extension, resulting in a total of up to three months of exposure.
Unknown Executive: The goal of the Phase 1b study was to first and foremost establish that 6058 induces HPF proteins in people with sickle cell disease.
So now in the dose ranging what we really need to do is to explore that range in the trial. It's it's two makes to 20 Megs and that's really based on our experience from healthy normal volunteers.
Unknown Executive: The data from initial patients that we presented at EHA showed not just protein induction within 14 days of treatment initiation, but at the sixth MIG dose, we were already able to achieve, absolute increases in HPF within that 5 to 10% range that provides broad clinical benefits.
Unknown Executive: In addition to HPF increases, we also observed meaningful changes in other biomarkers, absolute, reticulocyte count, total hemoglobin, and total bilirubin that were indicative of clinical improvement through decreased hemolysis and less anemia.
Unknown Executive: Consistent with our healthy volunteer data, initial data from the 1b study indicate that 6058 was generally well-tolerated with no serious treatment emergent adverse events. No SAEs were reported on study drug, and there were no discontinuations reported due to treatment emergent adverse events.
We're also going to get some experience with H U.
Unknown Executive: Currently, we continue to enroll patients who are receiving HU, as well as those who are not, into the sixth MIG and two MIG dose cohorts of this Phase 1b study. It's important to understand the, efficacy and safety of these drugs in combination, because although 6058 is intended to be used as a monotherapy, patients not fully responsive to hydroxyurea may receive 6058 concomitantly. Our preclinical data indicate that there may be an additive or synergistic effect between, these two drugs.
Unknown Executive: Additionally, we plan to initiate a third higher dose cohort this fall. The combined data from these cohorts will be critical, as our aim is to move as efficiently, as possible and select an optimal dose for the Phase 2-3 trial, which we intend to be registrational.
And so we're on track to deliver those three cohorts and select a dose that enables us to go into registration trial next year.
Unknown Executive: We expect to complete enrollment in three dose cohorts by the end of the year and anticipate, initiating a registrational trial in 2023. We've learned a lot from the early days of enrolling sickle cell patients in this study, and we've used these learnings to refine our clinical execution and site operations. Specifically, as we have better understood some of the challenges around adherence, we, implemented observed dosing, and we've already seen a benefit.
Unknown Executive: So we're confident that as we complete the remainder of this study, we're collecting, high-quality data that accurately represents the effects of 6058 in sickle cell disease patients.
In terms of the execution.
It's a great question and you know we're in really good shape in terms of how this trial is being executed currently we've made some significant changes until into how we operationalize. It. So we do have more sites and what that allows us is to access a broader base of sickle cell disease patients and also we've implemented are observed.
Unknown Executive: Moving on to FSHD and our Los Macoma Development Program, this is another area where we are, working to address a clear and critical unmet need. As Brian mentioned, FSHD is the second most prevalent form of muscular dystrophy.
Unknown Executive: It's estimated that there are 16,000 to 38,000 FSHD patients in the U.S. alone, and approximately, half a million patients worldwide, but there are currently no available therapies. The continually progressive nature of FSHD, a disease in which basic motor functions and, quality of life begin to decline in a patient's second decade of life, emphasize the urgent need for a disease-modifying therapy, as well as the value of our Los Macoma Program, which is the most advanced treatment in development for this disease.
Unknown Executive: In the Phase II Redux IV trial, we looked at the effect of Los Macoma in 80 FSHD patients, over a 48-week treatment period.
Unknown Executive: In addition to assessing the safety and tolerability of Los Macoma, we also wanted to understand, how to best study FSHD, as our trial was the first of its kind for this disease. We looked at everything from the length of time needed to show an effect on disease progression, to the appropriateness assessments for detecting changes.
Unknown Executive: The extensive work that was done as part of the Redux IV trial has enabled us to design, the Phase III REACH trial in a very efficient manner. REACH is a 48-week double-blind placebo-controlled trial.
Unknown Executive: After 48 weeks, Los Macoma demonstrated clinically meaningful benefits, such as preservation, of muscle health, as measured by MRI, muscle function, as measured by Reachable Workspace, and patient quality of life, assessed by patient global impression of change. Importantly, Los Macoma was very well tolerated, with no serious treatment-related adverse events.
Unknown Executive: Reachable Workspace, a quantitative measure of function, is its primary endpoint.
Unknown Executive: The secondary endpoints in the REACH trial include muscle fat infiltration, the NeuroQOL, a qualitative measure of function, and the patient global impression of change.
Unknown Executive: As we prepare for commercialization, we'll also be probing healthcare utilization, and other economic and outcomes research networks.
Unknown Executive: Metrics.
Unknown Executive: As the first ever phase three trial in this disease, REACH represents an enormous, milestone for the FSHG community.
Unknown Executive: Since enrolling our first patient in June, we have been moving quickly to begin enrolling at sites across North America and Europe, and we're on track to complete that process next year.
Unknown Executive: We are incredibly proud of both our clinical programs, and we look forward to sharing more in the future.
Unknown Executive: With that, I'll turn it over to Esther
Dosing, so we have patients showing up on video via computer or cellphone every morning, and this site witnesses the dosing and that's proven extremely effective we have a really great rate of compliance in terms of patients showing up very regularly and I think this puts us in a good position to.
Ensure that we're going to deliver a robust data set of high quality data.
When we finish enrollment.
Hey, that's great a quick follow up to that and then one for us or have you identified the high dose or are you still deciding on exactly whether it'll be unaddressed for us are on on the $40 million to $50 million in savings do you do you have a cadence I think you said it would be kind of over the next it sounds like 18 two.
20 months or so.
Yeah.
Yeah, I'll I'll start you know with meaning that high dose are we continue to enroll patients as I said in the notes to make it six snake and you know we're using quantitative pharmacology modeling shoot to name that high dose. So when we have that data what will start at the high dose, but we haven't shared that information yet and we're still examining that data.
Yeah, and she did that answer your question on the 40 to 50 million savings that extends our runway into mid 2024. So that's the time frame for that.
Okay. Thank you.
Thank you and our next question today comes from Matthew Harrison of Morgan Stanley . Please go ahead.
Unknown Executive: to walk through the financials.
Hi, Thanks for taking our crashes are this is a window more on behalf of Matthew. So we have one question 60, 58, and one question about the cash so for the city program.
Unknown Executive: Esther?
How have the changes you have made sure that clinical program impacted the enrollment rate.
I also have no patience for S. J D.
And when will you acetate for additional data updates do you still think and accelerated approval still possible.
For the cash are you still saying Ah you could extend that cash runway further with our current strategic change.
Are you considering potential partnership for the F. S. H D program.
If the phase III.
Starting as extends beyond 2024.
Unknown Executive: Thank you, Judy.
Thanks.
Yeah. So great question and let me just make sure we're addressing all of those maybe we'll start with 60 58 and the question being about enrolment based on some of the changes and progress that we've made as well as the potential for accelerated approval and I'll turn it over to Judy <unk> sure.
Unknown Executive: Following up on Brian's comments
Unknown Executive: about our organizational changes, I'd like to first provide more detail on our strategy and focus going forward, and then provide an update on our financial performance in the second quarter.
Unknown Executive: As you heard from both Brian and Judy, our two clinical stage programs have gained momentum, and the business realignment that we announced today reflects our confidence in the progress we have made and expect to make in the near term with both programs.
Unknown Executive: Fulcrum is well positioned to transition from an early stage clinical company to a pivotal, stage company with two assets potentially in registration enabling trials within the next year.
First of all I'll speak to the enrollment question and as I you know as I said in my earlier comments, we've made significant changes to how we operationalize. This trial. So you always start out with a fewer number of sites. We've increased our number of sites. We've increased that patient base that we can draw from and then on top of enrollment as I said that other really important.
Unknown Executive: We intend to build on our success by prioritizing execution on these clinical stage assets. Consequently, we have taken steps to realign our internal investments and organizational structure to prioritize these key value-driving programs while streamlining our research and discovery efforts.
Unknown Executive: In our clinical programs, we are focused on rapidly generating value-enhancing data from our phase 1b sickle cell disease and phase 3 FSHD programs.
Some operational I think this program is that that observe those states.
So we are enrolling at a rate that gives us confidence that we'll be able to complete enrollment by the end of this year.
So the second part of your question was around accelerated approval and that's really a question for you know what we're going to do in a registrational trial. So we're on track to complete enrollment in the one b this year.
It definitely will look at the data will select the dose we'll have a conversation with the with the regulators, but we really think that H P. Apps, it's such a it's an important biomarker. It's an important driver of efficacy and so we will have that conversation in terms of could.
E H B S. A a surrogate for an accelerated approval followed by a clinical outcome, but those conversations haven't occurred yet and we'll start that study. Our plan is to start that study in 2023.
Right and I think the second part of your question, we can turn it over to Aster and talk about F.
S S H D timing and how we think about runway yeah sure. So on.
The kind of runway guidance intimate 'twenty 'twenty four and that includes completing enrollment in the phase one b trial startup and registration, enabling phase two three and 2023 for the sickle program and also includes completing enrollment in our phase III reach program.
So we are funded into mid 2024 with that as an operating plan. In addition to N I M D in 2023.
With regards to your question on flexibility flexibility to extend it beyond mid 'twenty for you now that we are.
A company that is moving from a clinical stage III pivotal stage and we have built in enough flexibility in there to be nimble and and flexible that tens of miles and then maybe just one other point and just to reemphasize. This we've spoken about this a lot as it relates to F. S. H D.
I think one of the things we were very encouraged by how quickly we enroll the phase two b trial.
And that's just due to the severity of the disease. Unfortunately, the tremendous unmet need that exists. Obviously, we were very enthusiastic about the data that we generated in the phase B phase two b and as we transition now into a registrational trial as we mentioned, there's a lot of enthusiasm.
From patients and clinicians and caregivers for the opportunity to participate in the trial and we're excited to get that up and running and look to enroll as quickly as feasible.
Okay.
Well. Thanks, just some very quick follow up do you have an estimate of a timeline of data report for the phase one b trial being a C D.
So when do we exactly additional data for all three doses cough cold yeah.
What we've guided to is completing enrollment by year end and all three cohorts.
And we've also indicated that our next data update will be a comprehensive update for the full data set from all three cohorts in the phase one b.
Okay cool thanks, a lot.
And our next question today comes from Doug Kemp with Piper Sandler. Please go ahead.
Great. Thank you very much and thanks for the update obviously lots of questions all of them.
658, so I had a question more on <unk>.
We are continuing discovery efforts I'm really pleased to see you guys continue to invest in fulcrum seek.
Convincing this whole differentiated type words can you tell us about where sort of the lead efforts are there and maybe give us somewhat of a sense of what might be.
It's sort of a lead program that could emerge.
Thanks.
Yeah, absolutely Chad I'll turn it over to Judy and I think we from our perspective, obviously, we remain extremely enthusiastic about fulcrum seek and our discovery approach in both of these programs came.
Came from fulcrum seat and and I think one of the.
Particularly powerful elements of the engine is as we discover targets. It gives us the ability to either in license chemical matter or create our own and move very quickly into the clinic. So it's this still remains a very important focus and investment in the company and in terms of the.
Exact areas of focus I'll, let Judy go from there yeah.
Yeah, Good morning, and thanks for thanks for the question you know as Brian said poker and seek really offers us a lot of Optionality and we are identifying targets in our main therapeutic areas of interest and those are keen muscle and cardiac I'd also gives us the opportunity to do collaborations are we have a number of late stage disk.
<unk> programs and projects right now in the pipeline and we have guided to an IND in 2023, and we're on track for that.
Unknown Executive: While in discovery, we are now scaled appropriately to efficiently identify targets and generate, NIND in 2023.
Unknown Executive: As part of the realignment toward our lead clinical programs, we are delaying the planned initiation of the phase 1b trial in beta thalassemia and other non-sickle hemoglobin offices, as well as some ongoing discovery and preclinical projects that are not core to our areas of focus.
Unknown Executive: A key consideration of our strategy is the desire to remain nimble and adaptable.
And because we have a couple of things that we're considering I what I can say is it will be in one of those key areas for us he muscle or cardio, but beyond that we're not going to provide any other information until we're further along.
Understood and would this be something that could go would be to take toward more yourself or do you also see as additional partnering opportunities emerging from full crews at six.
Yeah, I would say, both guy and I think as we reference our next INV and as Judy spoke to 2023, that's something that we intend to move forward ourselves.
Unknown Executive: So even as we plan to deliver on key value-driving clinical programs, our discovery engine is enabled to be flexible and opportunistic towards ongoing and future collaborations.
Unknown Executive: The changes we have implemented are expected to result in savings of $40-50 million, which includes a 25% planned reduction in our workforce. This realignment of internal investments and organizational structure to realize near-term value from both our clinical programs also extends our cash runway into mid-2024.
As we've shown in the past with the collaboration that we've done.
Unknown Executive: As you can see, these changes allow us to operate from a continued position of financial strength as we end the second quarter with $169 million in cash, cash equivalents, and marketable securities. Now, I will briefly review the financials for this quarter. During the second quarter of 2022, we recognized collaboration revenue of $1.9 million compared, to $4.4 million recognized during the second quarter of 2021.
Unknown Executive: Second quarter 22 R&D expenses were $25 million compared to $17.4 million for the second quarter, of 2021.
There is broad applicability to the product engine, we feel like it's certainly been validated both with our collaborations but more importantly, with our clinical programs and the data we've been able to generate.
We intend to continue to follow the same strategy that we've done move programs forward ourselves in our areas of focus and look for collaboration outside of those areas and we hope to continue to do both.
Unknown Executive: T&A expenses for the second quarter of 2022 were $11.1 million compared to $6.7 million, for the second quarter of 2021.
Great. Thank you.
Unknown Executive: And our net loss for the second quarter of 2022 was $34.1 million compared to a net loss, of $19.6 million for the second quarter of 2021.
And our next question today comes from there going into <unk> with Stifel. Please go ahead.
Unknown Executive: With that, I'll turn it back to Brian.
Great. Good morning, Thanks for taking our questions and congrats on all the progress I wanted to revert back to the 60 58 program and I'll just cut it short with two questions on the <unk>.
On 60, 58 data that we saw at Ehealth appreciating the need to establish the minimally efficacious dose or a minimally safe dose.
We also saw that there was about 25% to 30% lower exposure in our city of patients versus a healthy volunteers.
So I guess just thinking about the cohort three enrollment planned for the fall what it makes sense to start sort of earlier on at say like a 10 milligram a collect all the data from six two and perhaps a little bit of a tad and then think about perhaps opening a fourth dose that could really help on the triangulation of that fine.
All registration trials level dose. That's question one and then on the second question just wanted to clarify the ongoing trial I guess cohort one it sounds like Youre enrolling now both H you experience at H, you're naive I wanted to clarify that and once that's clarified if you can comment on sort of the preclinical.
<unk> set you saw what the sort of translational gap might be once you move into the clinic, you mentioned additive or potentially synergistic, but any other con founders that we should be thinking about as you are as you dose the patients. Thanks, so much.
Unknown Executive: Thanks, Esther.
Unknown Executive: Before we close today, I want to thank our incredible team at Fulcrum, including those, employees who have been impacted by our recent organizational changes, whose contributions we value greatly.
Unknown Executive: I would also like to thank our patient communities, clinical trial partners, and shareholders, for their continued support.
Yeah. Thanks for the questions. They got all I'll turn them both over to Judy one in terms of how we're thinking about the different doses in the cohorts and maybe what what data we want to get out of that and then two as we are gaining this additional H you experience what as you said are there any gaps.
What is the value of that data as we put together our plan moving forward.
But then again you know and as you know we designed this experiment to help us select that that dose for registration and we designed it with three cohorts in mind because based on our experience in healthy normal volunteers, that's likely sufficient.
Unknown Executive: Operator, you may now open the line for questions.
Unknown Executive: Thank you.
Unknown Executive: We will now begin the question and answer session.
That said, we have the flexibility if we need to do a fourth cohort to do that we.
We would like to enroll these three cohorts and your question about exposure is a really important one are we continue to collect data at six milligrams and two milligrams will understand that exposure and then we can take that difference in exposure into consideration as we select our next dose and that's what the quantitative oncology modeling.
It's really not based on dose based on exposure and so we can.
We can select the dose I hopefully based on three but you. Your question is a good one and we have that flexibility. If we think we need for it.
I think the second part of your question is are we seeing a hydroxyurea patients and not and yes, we are enrolling patients both on and off Hydroxyurea and that's simply because people are maybe on Hydroxyurea. It's standard of care and we won't understand that interaction and then from a preclinical perspective I'll hand, it over to Paul to give us some information on what we saw second half.
Okay.
And Dan as you probably recall the CD 34 assay for us has been.
Highly predictable at least of Hbf clinical response and in our hands combinations of 60, 58, hydroxyurea have been additive or synergistic and so are our assumption based on this assay is that we would see similar additivity or synergy in the clinics.
Unknown Executive: To ask a question, you may press star then one on your touch-tone phone.
Yeah.
Thank you, ladies and gentlemen, today's much much worse than what you might be with Oppenheimer. Please go ahead.
Unknown Executive: If you are using a speakerphone, we ask that you please pick up your handset before pressing, the keys.
Unknown Executive: To withdraw your question, please press star then two.
Oh, Great Hey, guys. Thanks for the update great news to hear that you're planning to explore the higher 60 58 cohort can.
Can you tell us whether that decision was based on any new safety data that's emerged at yacht and is the goal still 5%, 10% hbf or or might you even be able to push that higher and then I have a follow up.
Unknown Executive: Today's first question comes from Judah Fromer with Credit Suisse.
Yeah, maybe let me start Matt and thanks for the questions maybe I'll start with the second question, then I'll turn it over to Judy for the first question.
Unknown Executive: Please go ahead.
Unknown Executive: Hi.
Unknown Executive: Thanks for taking the question and for all the updates.
In terms of our goal and as we've talked about we have the benefit here of their being so much data about H B F and the benefits of H B O S.
Unknown Executive: A couple from us.
That's from systematic literature reviews hereditary persistence of fetal hemoglobin real world evidence and now gene editing data, but.
And I think that very consistently shows and we continue to hear from the kols that because hbf broadly impacts all of the symptoms of the disease. The data shows when you can get to those levels all 5% to 10% can really have a transformational benefit and the feedback is that at those levels that.
60, 58 would be standard of care for sickle cell disease, So that remains our therapeutic goal.
Certainly as we explore different doses different combinations obviously.
We'll want to understand whether we can achieve that goal maybe even some cases go beyond that goal.
But that at that 5% to 10% level. The feedback is because of all of the benefits that this drug would be standard of care. So that's where our focus is.
Let me turn it back over to to Judy now.
Unknown Executive: First, can we just start with the high-dose cohort for the Phase 1b in sickle cell?
Sure in terms of that one b trial. It was always our plan to dose higher so we haven't seen anything.
Unknown Executive: Can you remind us why you went low-dose first and are now adding the high-dose?
That's clinical tolerability or anything in our ongoing toxicology program that has changed our plan in any way.
I think in terms of that 5% to 10% range. You know Brian has already spoken fairly articulately about why we have such confidence in that but I think what we need to remember is if you think back to our six milligram data on that each be up level was still increasing.
We don't know how we would need to go or if we would need to go higher and that's exactly why we're doing this study.
Right, Okay that makes sense and then I just I wanted to just have a follow up about the delay or the decision to delay the beta thal indication is there a higher bar.
For what's needed in terms of hbf induction in that indication and then I mean should we be reading into that.
I think that maybe that's why you're choosing to delay it or is there something else you know in terms of competitive landscape right now it just doesn't make sense to you.
Yeah. Thanks, Ryan So I mean, nothing has changed at least with regards to our conviction around beta Thal I think the thing to highlight here is that the dose ranging that we're doing in the single study, we can actually leverage those insights for beta thal and so we just see this as a as a more efficient way to to go into the beta field trial, rather than doing it.
Strange in that study as well.
Got it thank you.
And our next question today comes from Joseph Schwartz.
Please go ahead.
Hi, everyone. Thanks, very much I was wondering if you can talk a little bit more about your clinical affairs organization are the people that are the boots on the ground.
Any liaisons any other initiatives you have in order to ensure that you can generate inadequate quantum of data for the community with sickle cell for $6 58, and do you have any goals you can share in terms of numbers of patients.
At certain time points and maybe even for certain durations are for 60 58, as a mono and combo and your ongoing effort in the phase one b that you can share for example, you know what will we learn by the end of the year.
Unknown Executive: And then also for the Phase 1b, can you give us any more color on how compliance has improved, and what you're seeing as you enroll patients in what I think are some incremental sites versus the initial data cut?
Hum and and that's really the crux of my main questions. Thank you.
Sure, Yeah, and Joe maybe we can we'll split those up and Judy can broadly speak to just some of the clinical initiatives and the things that we've been undertaking which is also.
A meaningful part of part of the broader announcement today is that we are ensuring that we are really investing sufficiently in this program because of our enthusiasm about its potential in the data that we've already generated.
Then after can guide just a little bit more to what we've shared in terms of enrollment and data disclosure.
Sure.
I'll start out with our outreach into the sickle cell community. We have a what we think is a really robust onsite presence here in our clinical organization and what we haven't been able to do is is very quickly integrate ourselves into working with the community based organizations in the sickle cell community so really import.
Group within this community and one that our patient advocacy group has been working closely with so in terms of that that's really kind of where we are from a clinical perspective.
Sure on the <unk> study.
We're going to realize we said up to 10 patients per cohort.
Couple of those in each cohort will be on HQ.
And that's really just to help us to understand that potential synergy and we will have this enrolled them all.
All three cohorts enrolled by the end of the year.
Great. Thanks will we get an update on the first patients exposed to 60 58, perhaps at ash or a press release at any point.
Yeah, I think Joe is at this point, what we've guided to and I think one of the reasons that we chose to share. The initial data at <unk> high as we had made a commitment to do so and we were very enthusiastic about the fact that we were seeing hbf increases we were seeing them very quickly we are already.
Robust increases.
And that obviously gives us a lot of conviction for the program moving forward, what we want to do now is to get all three dose cohorts enrolled and then be able to share a complete dataset rather than on a piecemeal basis, we feel like we've certainly established proof of concept and now moving forward, we want to share the complete data set which is really.
To inform what dose we take into a registrational trial.
Understood. Thank you.
Thanks, Joe.
And ladies and gentlemen, as a reminder, if you'd like to ask a question. When it was first stars in the warm weather.
Last question comes from her parents for me Joe with Guggenheim. Please go ahead.
Uh huh.
Guys. Thank you.
A quick question for me on the sickle cell program can you just talk about.
What is your estimation off peak time to H B F induction.
Are you thinking about perhaps a little bit longer.
Phase one b.
A longer call for longer duration, just to just to get a better idea of when you are reaching the peak and if the next cohort that you're stocking for that thanks.
Yeah. It's a great question and I think that was really one of the key questions that we wanted to understand going into the phase. One b was both how quickly are we seeing H b F increases knowing that there will be patient benefit that will follow and then what does that curve look like one of the things that we talked about as we look.
At other H B F. Inducing mechanisms is typically maximal occurred within three to five months, but we wanted to understand these curves.
As Judy referenced we've been encouraged that based on the early data that we shared a D. HOTT H B F was still increasing at the three month time point.
And it was already getting into this 5% to 10% range. So both of those were highly encouraging at this point I think we need to gather more data, which we will during the course of the trial to understand these curves do the curves vary based on dose, but the fact that we're already seeing robust increases we're seeing the increases occur.
Within weeks I think it's all very encouraging and more data will better inform this.
Unknown Executive: Yeah, sure, Judah.
Thank you.
Unknown Executive: Happy to.
Unknown Executive: And let me turn it over to Judy, and we can speak both to our approach to dosing and then, some of the changes that we implemented in the clinical trial.
Unknown Executive: Yeah.
Thank you. This concludes the question and answer session for today.
Unknown Executive: Good morning, Judah.
Unknown Executive: Good morning.
Unknown Executive: So, as you know, our 1b trial was designed as a dose-ranging study. And so we started somewhere in the middle of that range at 6 milligrams because we wanted, to choose a dose that if we were going to see HBF, we felt confident that we would. And that's exactly what happened in 6 milligrams.
Unknown Executive: We already achieved that 5 to 10% increase that we're looking for.
Unknown Executive: So now in the dose ranging, what we really need to do is to explore that range.
I would like to turn the call over to Brian for closing remarks.
Unknown Executive: So, as you can see in the trial, it's 2 mg to 20 mg, and that's really based on our, experience from Healthy Normal volunteers, and we're also going to get some experience with HU.
Unknown Executive: In terms of the execution, it's a great question, and, you know, we're in really good shape, in terms of how this trial is being executed currently.
Unknown Executive: And so we're on track to deliver those three cohorts and select the dose that enables us, to go into registration trial next year.
Unknown Executive: We've made some significant changes into how we operationalize it.
Unknown Executive: So we do have more sites, and what that allows us is to access a broader base of sickle cell, disease patients.
Unknown Executive: And also we've implemented observed dosing. So we have patients showing up on video via computer or cell phone every morning, and, this site witnesses the dosing, and that's proven extremely effective.
Great. Thank you thanks, everybody for joining us we very much appreciate the support of fulcrum and have a great day.
Unknown Executive: And we have a really great rate of compliance in terms of patients showing up very regularly, and I think this puts us in a good position to ensure that we're going to deliver a robust data set of high-quality data when we finish enrollment.
Unknown Executive: Okay.
Unknown Executive: That's great.
Unknown Executive: A quick follow-up to that, and then one for Esther.
Unknown Executive: Thank you, sir.
Unknown Executive: Have you identified the high dose, or are you still deciding on exactly what it'll be?
Unknown Executive: This includes today's conference call.
Unknown Executive: I'll start, Judah, with naming that high dose.
Unknown Executive: We continue to enroll patients, as I said, in the 2MIG and 6MIG, and you know we're using, quantitative pharmacology modeling to name that high dose.
Unknown Executive: So when we have that data, we'll start the high dose, but we haven't shared that information, yet, and we're still examining that data.
Thank you Sir This concludes today's conference call. We thank you all for attending today's presentation. You may now disconnect your lines and have a wonderful day.
Unknown Executive: Yes, and Judah, to answer your question on the $40 to $50 million savings, that extends, our runway into mid-2024, so that's the timeframe for that.
Unknown Executive: Okay, thank you.
Unknown Executive: Thank you, and our next question today comes from Matthew Harrison and Morgan Stanley.
Unknown Executive: Please go ahead.
Unknown Executive: Hi, thanks for taking our questions.
Unknown Executive: This is Wenjiang Ma on behalf of Matthew.
Unknown Executive: So we have one question on 6058 and one question about the cash.
Unknown Executive: So for the SCD program, how have the changes you have made to the clinical program impacted, the enrollment rate of the new patients for SCD, and when will you estimate for additional data updates?
Unknown Executive: Do you still think an accelerated approval is still possible?
Unknown Executive: And for the cash, do you still think you could extend the cash runway further with, the current strategic change?
Unknown Executive: Are you considering potential partnership for the FSHD program if the phase three studies, extend beyond 2024?
Goodbye.
Unknown Executive: Thanks.
Unknown Executive: Yeah, so great questions, and let me just make sure we're addressing all of those.
Unknown Executive: So I think we'll start with 6058, and the question being about enrollment based on some, of the changes and progress that we've made, as well as the potential for accelerated approval, and I'll turn it over to Judy.
Unknown Executive: Sure.
Unknown Executive: First, I'll speak to the enrollment question, and as I said in my earlier comments, we've, made significant changes to how we operationalize this trial.
Unknown Executive: So you always start out with a fewer number of sites.
Unknown Executive: We've increased our number of sites.
Unknown Executive: We've increased that patient base that we can draw from, and then on top of enrollment, as I said, that other really important piece of operationalizing this program is that observed dosing.
Unknown Executive: So we are enrolling at a rate that gives us confidence that we'll be able to complete, enrollment by the end of this year.
Unknown Executive: So the second part of your question was around accelerated approval, and that's really a, question for what we're going to do in that registrational trial.
Unknown Executive: So we're on track to complete enrollment in the 1B this year.
Unknown Executive: At that point, we'll look at the data.
Unknown Executive: We'll select the dose.
Unknown Executive: We'll have a conversation with the regulators, but we really think that HBF is such a – it's, an important biomarker.
Unknown Executive: It's an important driver of efficacy, and so we will have that conversation in terms, of could it be HBF a surrogate for an accelerated approval followed by a clinical outcome, but those conversations haven't occurred yet, and we'll start that study.
Unknown Executive: Our plan is to start that study in 2023.
Unknown Executive: Great.
Unknown Executive: I think the second part of your question, we can turn it over to Esther and talk about FSHD timing and how we think about runway.
Unknown Executive: Yeah, sure.
Unknown Executive: So the current runway guidance is into mid-2024, and that includes completing enrollment in the Phase 1B trial, the start of a registration enabling Phase 2-3 in 2023 for the SIGL program, and also includes completing enrollment in our Phase 3 REACH program.
Unknown Executive: So we are funded into mid-2024 with that as an operating plan, in addition to an IND in 2023.
Unknown Executive: With regards to your question on flexibility to extend it beyond mid-2024, we are a company that is moving from a clinical stage to a pivotal stage, and we have built in enough flexibility in there to be nimble and flexible as our plans evolve.
Unknown Executive: And maybe just one other point, and just to reemphasize this, we've spoken about this a lot as it relates to FSHD, and one of the things we were very encouraged by was how quickly we enrolled the Phase 2B trial.
Unknown Executive: And that's just due to the severity of the disease, unfortunately, the tremendous unmet need that exists.
Unknown Executive: Obviously, we were very enthusiastic about the data that we generated in the Phase 2B, and as we transition now into our registrational trial, as we mentioned, there's a lot of enthusiasm from patients and clinicians and caregivers for the opportunity to participate in the trial, and we're excited to get that up and running and look to enroll as quickly as is feasible.
Unknown Executive: Well, thanks.
Unknown Executive: Just a very quick follow-up.
Unknown Executive: Do you have an estimate of the timeline of data report for the Phase 1B trial in SCD?
Unknown Executive: So when are you expecting additional data for all the three doses called?
Unknown Executive: Yeah, so what we've guided to is completing enrollment by year-end in all three cohorts, and we've also indicated that our next data update will be a comprehensive update with a full data set from all three cohorts in the Phase 1B.
Unknown Executive: Okay, cool.
Unknown Executive: Thanks a lot.
Unknown Executive: And our next question today comes from Ted Tenthoff with Piper Sandler.
Unknown Executive: Please go ahead.
Unknown Executive: Great.
Unknown Executive: Thank you very much, and thanks for the update.
Unknown Executive: Obviously, lots of questions on 6058.
Unknown Executive: So I had a question more on the continued discovery efforts.
Unknown Executive: I'm really pleased to see you guys continue to invest in Fulcrum Seek, and advancing additional differentiated pipelines.
Unknown Executive: Can you tell us about where sort of the lead efforts are there, and maybe give us somewhat of a sense of what might be sort of a lead program that could emerge as the next I&D?
Unknown Executive: Thanks.
Unknown Executive: Yeah, absolutely, Ted.
Unknown Executive: I'll turn it over to Judy.
Unknown Executive: And I think we, from our perspective, obviously we remain extremely enthusiastic about Fulcrum Seek, and our discovery approach, and both of these programs came from Fulcrum Seek.
Unknown Executive: And I think one of the particularly powerful elements of the engine is as we discover targets, it gives us the ability to either enlicense chemical matter or create our own and move very quickly into the clinic.
Unknown Executive: So this still remains a very important focus and investment in the company.
Unknown Executive: And in terms of exact areas of focus, I'll let Judy go from there.
Unknown Executive: Yeah.
Unknown Executive: Good morning, Ted, and thanks for the question.
Unknown Executive: You know, as Brian said, Fulcrum Seek really offers us a lot of optionality.
Unknown Executive: We are identifying targets in our main therapeutic areas of interest, and those are skiing, muscle, and cardio.
Unknown Executive: It also gives us the opportunity to do collaborations.
Unknown Executive: We have a number of late-stage discovery programs and projects right now in the pipeline, and we have got it to an I&D in 2023, and we're on track for that.
Unknown Executive: And because we have a couple of things that we're considering, what I can say is it will be in one of those key areas for us, ski, muscle, or cardio.
Unknown Executive: But beyond that, we're not going to provide any other information until we're a bit further along.
Unknown Executive: Understood.
Unknown Executive: And would this be something that the goal would be to take forward more yourself, or do you also see as additional partnering opportunities emerging from Fulcrum State Sinks?
Unknown Executive: Yeah, I would say both, Ted.
Unknown Executive: I think as we reference our next IND, and as Judy spoke to 2023, that's something that we intend to move forward ourselves.
Unknown Executive: But as we've shown in the past with the collaborations that we've done, there is broad applicability to the product engine.
Unknown Executive: We feel like it's certainly been validated both with our collaborations, but more importantly, with our clinical programs and the data we've been able to generate.
Unknown Executive: So we intend to continue to follow the same strategy that we've done, move programs forward ourselves in our areas of focus, and look for collaborations outside of those areas. And we hope to continue to do both.
Unknown Executive: Great.
Unknown Executive: Thank you.
Unknown Executive: And our next question today comes from Dagon Ha with Stiefel.
Unknown Executive: Please go ahead.
Unknown Executive: Great.
Unknown Executive: Good morning.
Unknown Executive: Thanks for taking our questions, and congrats on all the progress.
Unknown Executive: I wanted to revert back to the 6058 program, and I'll just cut it short with two questions.
Unknown Executive: On the 6058 data that we saw at EHA, appreciating the need to establish the minimally efficacious dose or minimally safe dose, we also saw that there was about 25 to 30 percent lower exposure in STD patients versus healthy volunteers.
Unknown Executive: So I guess just thinking about the Cohort 3 enrollment plan for the fall, would it make sense to start sort of earlier on at, say, like a 10 milligram, collect all the data from 6.2 and perhaps a little bit of the 10, and then think about perhaps opening a fourth dose that could really help on the triangulation of that final registration trial level dose?
Unknown Executive: That's question one.
Unknown Executive: And then on the second question, just wanted to clarify, the ongoing trial, I guess Cohort 1, it sounds like you're enrolling now both HU Experience and HU Naive.
Unknown Executive: I wanted to clarify that.
Unknown Executive: And once that's clarified, if you can comment on sort of the preclinical assessments that you saw, what the sort of translational gap might be once you move into the clinic?
Unknown Executive: You mentioned additive or potentially synergistic, but any other confounders that we should be thinking about as you dose the patients?
Unknown Executive: Thanks so much.
Unknown Executive: Yeah, thanks for the question, Dagon.
Unknown Executive: I'll turn them both over to Judy.
Unknown Executive: So one, in terms of how we're thinking about the different doses and the cohorts, and maybe what data we want to get out of that, and then two, as we are gaining this additional HU experience, what, as you said, are there any gaps?
Unknown Executive: What is the value of that data as we put together our plan moving forward?
Unknown Executive: Hi, Dagon.
Unknown Executive: You know, as you know, we designed this experiment to help us select that dose for registration, and we designed it with three cohorts in mind because based on our experience in helping normal volunteers, that's likely sufficient.
Unknown Executive: That said, we have the flexibility if we need to do a fourth cohort to do that.
Unknown Executive: We would like to enroll these three cohorts.
Unknown Executive: And, you know, your question about exposure is a really important one.
Unknown Executive: We continue to collect data at 6 milligrams and 2 milligrams.
Unknown Executive: And then we can take that difference in exposure into consideration as we select our next dose. And that's what the quantitative pharmacology modeling does.
Unknown Executive: It's really not based on dose.
Unknown Executive: It's based on exposure.
Unknown Executive: And so we can select a dose, hopefully based on three.
Unknown Executive: But, you know, your question is a good one, and we have that flexibility if we think we need four.
Unknown Executive: I think the second part of your question is, are we seeing hydroxyurea patients and not?
Unknown Executive: And, yes, we are enrolling patients both on and off hydroxyurea.
Unknown Executive: And that's simply because people may be on hydroxyurea.
Unknown Executive: It's standard of care, and we want to understand that interaction.
Unknown Executive: And then from a preclinical perspective, I'll hand it over to Paul to give us some information on what we saw mechanistically.
Unknown Executive: Yeah, and Dayana, as you probably recall, you know, the CD34 assay for us has been, you know, highly predictable at least of HPF clinical response.
Unknown Executive: And in our hands, combinations of 60-58 and hydroxyurea have been additive or synergistic.
Unknown Executive: And so our assumption based on this assay is that we would see similar additivity or synergy in the clinic.
Unknown Executive: Thank you, and ladies and gentlemen, today's next question comes from Matt Biegler at Oppenheimer.
Unknown Executive: Please go ahead.
Unknown Executive: Great.
Unknown Executive: Hey, guys.
Unknown Executive: Thanks for the update.
Unknown Executive: Great news to hear that you're planning to explore the Higher 6050-H as cohort.
Unknown Executive: Can you tell us whether that decision was based on any new safety data that's emerged, at EHA, and is the goal still 5% to 10% HPF, or might you even be able to push that higher than I have a follow-up?
Unknown Executive: Yeah, maybe let me start, Matt, and thanks for the question.
Unknown Executive: Maybe I'll start with the second question, then I'll turn it over to Judy for the first, question.
Unknown Executive: In terms of our goal, and as we've talked about, we have the benefit here of there being, so much data about HPF and the benefits of HPF, and that's from systematic literature reviews, hereditary persistence of fetal hemoglobin, real-world evidence, and now gene editing data.
Unknown Executive: And I think that very consistently shows, and we continue to hear from the KOLs, that, because HPF broadly impacts all of the symptoms of the disease, the data shows when you can get to those levels of 5% to 10%, you can really have a transformational benefit in the feedback is that at those levels, that 60-58 would be standard of care for sickle cell disease.
Unknown Executive: So that remains our therapeutic goal.
Unknown Executive: Certainly as we explore different doses, different combinations, obviously we'll want to understand, whether we can achieve that goal, maybe even in some cases go beyond that goal.
Unknown Executive: But at that 5% to 10% level, the feedback is, because of all of the benefits, that this, drug would be standard of care.
Unknown Executive: So that's where our focus is.
Unknown Executive: And let me turn it back over to Judy now.
Unknown Executive: Sure.
Unknown Executive: In terms of that 1B trial, it was always our plan to dose higher.
Unknown Executive: So we haven't seen anything, whether that's clinical tolerability or anything in our ongoing, toxicology program, that has changed our plan in any way.
Unknown Executive: I think in terms of that 5% to 10% range, you know, Brian's already spoken earlier, particularly about why we have such confidence in that.
Unknown Executive: I think what we need to remember is if you think back to our 6 milligram data, that HPF, level was still increasing.
Unknown Executive: So we don't know how high we would need to go or if we would need to go higher, and that's, exactly why we're doing this study.
Unknown Executive: Right.
Unknown Executive: Okay.
Unknown Executive: That makes sense.
Unknown Executive: And then I just, I wanted to just have a follow-up about the delay or the decision to delay the, beta cell indication.
Unknown Executive: Is there a higher bar for what's needed in terms of HPF induction in that indication?
Unknown Executive: And, I mean, should we be breeding into that as to think of that maybe that's why you're, choosing to delay it, or is there something else, you know, in terms of competitive landscape that it's right now, it just doesn't make sense to you?
Unknown Executive: Thanks.
Unknown Executive: Yeah.
Unknown Executive: Thanks, Matt.
Unknown Executive: So, I mean, nothing's changed, at least with regards to our, you know, conviction around, beta cell.
Unknown Executive: I think the thing to highlight here is that the dose ranging that we're doing in the sickle, study, we can actually leverage those insights for beta cell, and so we just see this as a more efficient way to go into the beta cell trial rather than doing dose ranging in that study as well.
Unknown Executive: And our next question today comes from Joseph Schwartz at SVB, please go ahead.
Unknown Executive: Hi everyone, thanks very much.
Unknown Executive: I was wondering if you could talk a little bit more about
Unknown Executive: your clinical affairs organization, the people that are the boots on the ground, any liaisons, any other initiatives you have in order to ensure that you can generate an adequate quantum of data for the community with sickle cell for 6058 and do you have any goals you can share in terms of numbers of patients and at certain time points and maybe even for certain durations for 6058 as a mono and combo in your ongoing effort in the phase 1B that you can share.
Unknown Executive: For example, you know, what will we learn by the end of the year, and that's really the crux of my main question.
Unknown Executive: Thank you.
Unknown Executive: Yeah, and Joe, maybe we can, we'll split those up and Judy can broadly speak to just some, of the clinical initiatives and the things that we've been undertaking, which is also a meaningful part of the broader announcement today is that we are ensuring that we are really investing sufficiently in this program because of our enthusiasm about its potential and the data that we've already generated.
Unknown Executive: And then Esther can guide just a little bit more to what we've shared in terms of enrollment and data disclosure.
Unknown Executive: Sure.
Unknown Executive: You know, I'll start out with our outreach into the sickle cell community.
Unknown Executive: We have what, we think is a really robust on-site presence here in our clinical organization and what we have been able to do is very quickly integrate ourselves into working with the community-based organizations in the sickle cell community. It's a really important group within this community and one that our patient advocacy group has been working closely with.
Unknown Executive: So in terms of that, that's really kind of where we are from a clinical perspective.
Unknown Executive: Your question around the 1D study, you know, we're going to enroll, as we said, up to 10 patients per cohort.
Unknown Executive: A couple of those in each cohort will be on HU and that's really just to help us to understand that potential synergy and we'll have this enrolled, all three cohorts enrolled by the end of the year.
Unknown Executive: Thanks.
Unknown Executive: Will we get an update on the first patients exposed to 6058, perhaps at ASH or press release at any point?
Unknown Executive: Yeah, I think, Joe, at this point, what we've guided to and I think one of the reasons that, we chose to share the initial data at EHA is we had made a commitment to do so and we were very enthusiastic about the fact that we were seeing HBF increases. We were seeing them very quickly. We were already seeing robust increases and that obviously gives us a lot of conviction for the program.
Unknown Executive: Moving forward, what we want to do now is to get all three dose cohorts enrolled and then be able to share a complete data set rather than on a piecemeal basis.
Unknown Executive: We feel like we've certainly established proof of concept and now moving forward, we want to share the complete data set, which is really going to inform what dose we take into our registrational trial.
Unknown Executive: Understood.
Unknown Executive: Thank you.
Unknown Executive: Thanks, Joe.
Unknown Executive: And ladies and gentlemen, as a reminder, if you'd like to ask a question, please press star then 1.
Unknown Executive: Today's next question comes from your team's Suneejo with Guggenheim.
Unknown Executive: Please go ahead.
Unknown Executive: Hey, guys.
Unknown Executive: Thank you.
Unknown Executive: Thank you.
Unknown Executive: Yeah, quick question for me on the SQL Server program.
Unknown Executive: Can you just talk about what is your estimation of peak time to HPF induction?
Unknown Executive: Are you thinking about perhaps a little bit longer phase 1b, longer duration just to get a better idea of when you're reaching the peak?
Unknown Executive: And is the next cohort that you're starting a queue for that?
Unknown Executive: Thanks.
Unknown Executive: Yeah, it's a great question.
Unknown Executive: And I think that was really one of the key questions that we wanted to understand going into the phase 1b was both how quickly are we seeing HPF increases, knowing that there will be patient benefit that will follow?
Unknown Executive: And then what does that curve look like?
Unknown Executive: One of the things that we talked about as we looked at other HPF inducing mechanisms is typically maximal occurred within three to five months.
Unknown Executive: But we wanted to understand these curves.
Unknown Executive: As Judy referenced, we've been encouraged that based on the early data that we shared at EHA, HPF was still increasing at the three month time point. And it was already getting into this five to 10% range.
Unknown Executive: So both of those are highly encouraging.
Unknown Executive: At this point, I think we need to gather more data, which we will during the course of the trial to understand these curves.
Unknown Executive: Do the curves vary based on dose?
Unknown Executive: But the fact that we're already seeing robust increases, we're seeing the increases occur within weeks, I think is all very encouraging and more data will better inform this.
Unknown Executive: Thank you.
Unknown Executive: Thank you.
Unknown Executive: This includes the question and answer session for today.
Unknown Executive: I would like to turn the call over to Brian Stewart for closing remarks.
Unknown Executive: Great.
Unknown Executive: Thank you.
Unknown Executive: Thanks everybody for joining us.
Unknown Executive: We very much appreciate the support of fulcrum and have a great day.