Fulcrum Therapeutics, Inc. (NASDAQ:FULC) Q4 2021 Earnings Conference Call March 3, 2022 8:00 AM ET
Company Participants
Christi Waarich – Director of Investor Relations
Bryan Stuart – President and Chief Executive Officer
Judy Dunn – President of R&D
Esther Rajavelu – Chief Financial Officer
Chris Morabito – Chief Medical Officer
Conference Call Participants
Dae Gon Ha – Stifel
Joseph Schwartz – SVB Securities
Matthew Harrison – Morgan Stanley
Judah Frommer – Credit Suisse
Ted Tenthoff – Piper Sandler
Disclaimer*: This transcript is designed to be used alongside the freely available audio recording on this page. Timestamps within the transcript are designed to help you navigate the audio should the corresponding text be unclear. The machine-assisted output provided is partly edited and is designed as a guide.
Operator
00:02 Good morning and welcome to Fulcrum Therapeutics’ Fourth Quarter and Full-Year 2021 Conference Call. Currently all participants are in listen-only mode. There will be a question-and-answer session at the end of this call.
00:15 I would now like to turn the call over to Christi Waarich, Director of Investor Relations at Fulcrum. Please proceed.
Christi Waarich
00:25 Thank you, operator. 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 financial projections.
00:47 While these forward-looking statements represent our views as of today, they should not be relied upon as representing our views in the future. We may update these statements in the future, but we are not taking on an obligation to do so. 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.
01:08 With me on today’s call are Bryan Stuart, President and Chief Executive Officer; Judy Dunn our President of R&D; and Esther Rajavelu, our CFO. Chris Morabito, our Chief Medical Officer; and Paul Bruno, our Executive Director of Corporate Development will also be available for Q&A.
01:28 Let me run quickly through this morning’s agenda. Bryan will begin the call with a corporate overview and key updates. Judy will review our FSHD program and today’s update on the Phase 3 trial, and Esther will cover our financials, while Bryan will open the call for Q&A.
01:44 With that, it’s my pleasure to turn the call over to Bryan.
Bryan Stuart
01:49 Thank you, Christi. Good morning everyone and thank you for joining us today. At Fulcrum, our mission is to treat the root cause of rare genetic diseases. 2021 was a year of important clinical and corporate progress towards that mission and we are building our net momentum in 2022 with meaningful updates across our pipeline.
02:08 I’ll start with losmapimod, our candidate for FSHD, which is the second most common form of muscular dystrophy. We believe losmapimod is positioned to be the first to market therapy for this severe and debilitating disease. Today, we announced our plan to begin enrolling people with FSHD in REACH. Our registration enabling Phase 3 clinical trial in the second quarter of 2022.
02:33 REACH will evaluate losmapimod, compared to placebo in adults with FSHD over a 48-week treatment period, with Reachable Workspace or RWS as the primary endpoint. The trial design reflects key learnings from the ReDUX4 Phase 2b study, most notably that we can show a measurable clinical benefit in 48-weeks and that RWS is a quantitative measure of function that is sensitive to disease progression in that timeframe.
03:04 Based on these insights, and the data from ReDUX4 demonstrating clinical benefit, we aligned with regulators, including the FDA on RWS as the primary endpoint. The upcoming start of our Phase 3 trial marks a significant milestone for both Fulcrum and the FSHD community. There are currently no approved drugs and nothing else even in the clinic.
03:29 People with FSHD with strength, function, independence, and mobility as that infiltrates their muscles and there is an urgent need for a drug that can slow or stop disease progression. The data that we reported last year from ReDUX4 demonstrate losmapimod’s potential to do exactly that, showing delayed progression and improvement in measuring the function including RWS. We are thrilled to be one-step closer to brining this important therapy to patients.
04:04 Our second clinical program, FTX-6058, an oral HbF inducer for sickle cell disease and other hemoglobinopathies shows great promise in addressing important unmet needs in these patient populations. The current treatment landscape in sickle cell disease consists of therapies that only target select symptoms.
04:25 HbF is the only mechanism that has been shown to broadly improve outcomes for key symptoms of sickle cell disease such as VOC events, pain, fatigue, and acute chest syndrome. A robust body of genetic data shows that increases in HbF in every patient is meaningful. Emerging clinical data from gene editing further supports the benefit of HbF induction, but in the case of gene editing, it comes with a tremendous treatment burden making it most likely to be used as a salvage therapy.
04:59 We discovered FTX-6058 using our FulcrumSeek product engine. Pre-clinically, across multiple in vivo and in vitro assays, 6058 generated a consistent two to threefold induction in HBG mRNA that translated into the same fold induction in HbF protein.
05:18 Last year, we transitioned to the clinic and announced positive Phase 1 healthy volunteer data that demonstrated robust increases in HBG mRNA at multiple doses. These data gave us confidence to advance FTX-6058 into our ongoing Phase 1b study, where we will be dosing people with sickle cell disease long enough to observe protein increases.
05:43 Typically, people with sickle cell disease have starting HbF levels of 5% to 10%. As we’ve spoken into KOLs, we have consistently heard that a 5% to 10% increase in HbF beyond baseline levels would be transformative for patients and would be utilized as standard of care.
06:03 We are highly encouraged that our robust preclinical data and Phase 1 healthy volunteer data, both predict that we can achieve these absolute increases that will be life changing for people with sickle cell disease.
06:17 In December, we began enrolling the Phase 1b trial at a starting dose of 6 milligrams daily. We are on track to report initial data, including HbF protein levels in the second quarter of this year. This update will be the first look at protein data and people with sickle cell disease.
06:36 Based on data from other HbF mechanisms and the process of erythropoiesis, the earliest we would anticipate seeing protein induction would be after one-month of treatment with maximum protein induction at 3 months to 5 months. For this initial data, in Q2, we would consider evidence of protein induction to be a very meaningful update.
06:57 We also believe that FTX-6058 could be a transformative therapy for other hemoglobinopathies, such as beta thalassemia, and we are on track to initiate a Phase 1b trial in the second quarter.
07:11 FTX-6058 and losmapimod, as well as our ongoing collaborations with Merck and BMS are a testament to the power of FulcrumSeek. Our product engine and the innovation backbone of our company. FulcrumSeek has allowed us to rapidly identify novel, high quality targets to modulate the root cause of genetically defined rare diseases.
07:34 Notably, we expect to nominate our next development candidate by the end of this year and submit an additional new IND by the end of the first quarter of 2023. As we advance two potentially life changing therapies through clinical development, expand our pipeline, scale up our discovery efforts, while building downstream clinical and commercial capabilities, we are well positioned to build a leading rare disease company supported with a strong financial foundation and a cash runway that takes us into 2024.
08:06 With that, I’d like to turn it over to Judy to share more about our plans for losmapimod that we announced this morning. Judy?
Judy Dunn
08:14 Thank you, Bryan. FSHD is a genetic disorder that leads to relentlessly progressive muscular degeneration and replacement by fat. This disease initiates in the face and progresses to upper and lower limbs and core, leading to loss of function and ultimately the loss of independence.
08:33 Losmapimod represents a potentially life changing therapy for people living with FSHD. This mechanism inhibits the average expression of DUX4, the genetic root cause of FSHD responsible for the muscle degeneration, fat infiltration, and loss of function.
08:51 As Bryan mentioned, currently, there are no approved therapies nor are there any other compounds in clinical development. Each day that people with FSHD go without therapy is another day that they risk losing strength, function, and the ability to perform basic activities, like brushing their hair, dressing themselves, or holding their child. This accumulation of disability can lead to loss of independence and mobility.
09:18 We consistently hear from patients that their number one concern and number one requirement for a new therapeutic is to safely slow or stop disease progression in order to preserve the function that they have.
09:32 Our Phase 2b trial ReDUX4 demonstrated that losmapimod slowed disease progression and improved function in people with FSHD. These data combined with the extensive safety and tolerability data, generated in more than 3,600 people form the basis of losmapimod’s very compelling benefit risk profile as in oral medication with the potential to address the urgent need for therapy in this patient population.
10:01 ReDUX4 was the most comprehensive therapeutic trial ever conducted in FSHD. We gained tremendous insights on relevant clinical endpoints, as well as an understanding of the duration of time needed to show the impact of losmapimod on disease progression.
10:18 We have applied those insights to the design of our Phase 3 trial REACH, giving us confidence that REACH is optimized to demonstrate statistically and clinically significant benefits of losmapimod in FSHD.
10:32 Given the urgency to bring the therapy to market, we have been preparing for this trial and engaging with patients, experts, and regulators to inform our final design. We are pleased to report that we are on track to begin REACH shortly in the second quarter of this year.
10:49 Before further describing REACH, I want to briefly highlight our learnings from ReDUX4 that informed our thinking about this Phase 3 design. ReDUX4 was a randomized placebo controlled study that evaluated 80 people with FSHD over 48 weeks. In this trial, participants received either [15 milligrams]] of losmapimod twice daily or placebo.
11:11 We were very encouraged by results from ReDUX4 in which a meaningful separation between treatment effects was observed in people receiving losmapimod versus those receiving placebo. Importantly, we saw clinically meaningful impacts on function, muscle structure, and patient reported outcomes.
11:32 Data from the trial also allowed us to identify endpoints that are sensitive to disease progression and drug effects in that timeframe. Starting with Reachable Workspace, a measure of accessible relative service area, we saw clinically relative improvements from baseline in the dominant arms of those treated with losmapimod, while those on placebo lost relative surface area over the course of the trial.
11:56 Relative service area, including reaching above the shoulders and behind the back as measured by Reachable Workspace is highly correlated to the ability to perform activities of daily living and maintain independence.
12:10 Using MRI, we also observed the slowing of muscle fat infiltration or MFI, an important marker of disease pathology. Muscles that already had some side infiltration at baseline are the muscles most likely to demonstrate disease progression over 48-weeks.
12:26 In these muscles, losmapimod showed a meaningful slowing of MFI, compared placebo. Losmapimod also preserved the health of muscles, which appeared normal at baseline, essentially stopping muscle fat infiltration, while patients on placebo worsens.
12:43 Finally, in this trial, self-reported outcomes such as the Patient’s Global Impression of Change or PGIC were used to assess the recognized value of the treatment. At the end of the 48-week treatment period, people who receive losmapimod reported feeling better than those who received placebo.
13:02 Based on the ReDUX4 data, we engaged with regulators, including the FDA to gain feedback on the proposed design of the REACH study. Based on those interactions, we have selected Reachable Workspace as the primary endpoint for REACH. We have now finalized our trial design, and are working to operationalize REACH.
13:22 REACH will be a randomized double-blind placebo controlled multinational trial to evaluate the efficacy and safety of losmapimod for the treatment of FSHD. The trial is expected to roll approximately 230 adults. Participants will be randomized one-to-one to receive losmapimod administered orally as a 15 milligram tablet twice a day or placebo over a 48-week treatment period.
13:47 The primary endpoint of this study is the absolute change from baseline in Reachable Workspace. As I outlined earlier, Reachable Workspace is a quantitative measure of upper extremity range of motion and function that specifically evaluate shoulder and proximal arm mobility with 3D motion sensor technology.
14:06 Preserving this upper extremity function is critical for maintaining the ability for self-care and other activities of daily living that directly influenced quality of life and independence.
14:17 In addition to safety and tolerability, secondary endpoints include MFI, PGIC, and quality of life in neurological disorders for the Neuro QoL of the upper extremities. REACH will also include healthcare utilization questionnaires that will help inform our thinking about payer strategies as we prepare for a potential commercial launch.
14:37 We are confident that we have selected reliable measures of disease progression in FSHD and that we will be able to clearly observe meaningful advantages for losmapimod compared to placebo after 48-weeks of treatment.
14:51 As we advance REACH, we remain steadfast in our commitment to [indiscernible] deliver a transformative drug for people with FSHD. As we announced this morning, we will be featuring two key opinion leaders in a virtual event posted by Fulcrum on Thursday, March 24 from 10:00 A.M. until noon Eastern Time.
15:11 We will be joined by Dr. Nicholas Johnson of the department of neurology at Virginia Commonwealth University; and Dr. Jay Han of the University of California, Irvine one of the originators for Reachable Workspace as an endpoint. We look forward to sharing more about the unmet need in FSHD and REACH, and how losmapimod is well-positioned to be the first drug for people with FSHD.
15:34 With that, I’ll turn it over to Esther Rajavelu.
Esther Rajavelu
15:36 Thank you, Judy. I’m thrilled to be here today as part of the Fulcrum team and to share with you an update on our financials. We are operating from a position of financial strength ending the fourth quarter with 218.2 million in cash, cash equivalents, and marketable securities. Based on our current plans and projections, we expect this will fund our operation into 2024.
16:06 During the fourth quarter of 2021, we recognized collaboration revenue of 5.1 million, compared to 4.2 million in the fourth quarter of 2020. The increase was primarily due to revenues associated with the milestone payment under our collaboration with Bristol.
16:26 For the full-year 2021, collaboration revenue was 19.2 million, compared to 8.8 million in 2020. This increase with due to the execution of the collaboration and license agreement with Bristol in July 2020, as well as an increase in revenue recognized under our collaboration with Merck.
16:49 R&D expenses for the fourth quarter of 2021 were 18.9 million, compared to 16.1 million for the fourth quarter of 2020. R&D expenses for the full-year 2021 was 69.7 million, compared to 59 million for the full-year 2020. This increase was primarily due to the advancement of our clinical programs.
17:15 G&A expenses in the fourth quarter of 2021 were 9.7 million, compared to 5.9 million for the fourth quarter of 2020. And for the full-year 2021 were 30.5 million, compared to 21.4 million for the full-year of 2020. This increase was primarily due to increased employee related expenses and preparation for potential commercial launches of losmapimod for FSHD and 6058 for sickle cell disease.
17:49 Finally, our net loss for the fourth quarter of 2021 was 23.5 million, compared to a net loss of 17.7 million for the fourth quarter of 2020. Our net loss for the full-year 2021 was 80.8 million, compared to a net loss of 70.8 million for the full-year 2020.
18:14 With that, I’ll turn it back to Bryan.
Bryan Stuart
18:17 Thanks, Esther. As you’ve heard today, 2021 was a year of tremendous progress for Fulcrum and we have even more to look forward to as we continue to advance our promising programs in FSHD, sickle cell disease, and other hemoglobinopathies, and continue to build out our pipeline. We look forward to keeping you up to date on our progress throughout the year.
18:38 Operator, you may now open the line for questions.
Question-and-Answer Session
Operator
18:42 Thank you. [Operator Instructions] First question is from Dae Gon Ha with Stifel.
Dae Gon Ha
19:03 Great. Good morning guys. Congrats on all the progress. I guess two on 6058 and one on FSHD. One, just going back to 6058, I recall you guys we’re doing a chronic tox study, preclinical chronic tox for the 6058 program. So, anything you can comment with regards to its progress, any signs or observations you’ve made, things like [CPK] [ph] for example? And then second question is, last month, you mentioned Cohort 1 is still enrolling for the 6058 program. So, can you comment on the rate of patient enrollment to the study given three sites are currently active and recruiting? And what’s the cadence of readout investors can expect for the remainder of 2022, including the second quarter update? And then I’ll just follow-up with the REACH study question next.
Bryan Stuart
19:55 Yes. Absolutely. Thanks Dae Gon. Why don’t I turn it over to Chris, we can give an update on the talks, which we had provided earlier this year, and then also talk about the guidance that we’ve provided for the 2Q update from the Phase 1b study.
Chris Morabito
20:14 Great. Hi, Dae Gon. Thanks for the question. So, as we reported, we have completed three-month talks and the three months talks gave us the continued encouragement to continue pursuing clinical development as planned. We made no changes to our development plans based on the results from the two months talks. We have entered chronic talks. We don’t have any updates on that and we don’t have any new findings to share at this point.
20:42 Regarding your comments about CPK or creatine phosphokinase, as we recall, we did see two unrelated events in Phase 1, but both of those cases have been after, well after the last phase dosing, in fact, 7 days to 10 days after the last date of dosing and we’re deemed to be unrelated by the primary investigator who was [indiscernible] study treatment.
21:05 So nothing new on that front. In regard to the Phase 1b trial, it is enrolling as you well stated. We have initiated enrollment sites and are actively recruiting additional sites as you also noted. The current dose is 6 milligrams and patients are anticipated to participate in this trial for up to three months. We have planned for up to 10 patients in each cohorts. We are still in cohort 1 and we are certainly on track to provide an update in Q2 that will be meaningful for HbF and for other endpoints that are relevant to this trial.
Dae Gon Ha
21:42 Okay, great. Thanks for the update. So, just pivoting to the REACH study, maybe a question for Judy or Chris. Can you talk about the powering assumptions baked into the Reachable Workspace that’s going to be the primary endpoint? And notably following the discussions with the regulators, have you made any changes or updates to how you’re going to be quantifying Reachable Workspace, I believe it was using the connect device previously, but any updates on that front? Thank you and congrats on all the progress.
Bryan Stuart
22:12 Yes. Thanks Dae Gon. Why don’t I turn it over to Judy and we could speak to at a high level our strategy as it relates to powering, and we can also talk a little bit more about Reachable Workspace and what we were able to observe in ReDUX4 as well.
Judy Dunn
22:29 Thanks, Dae Gon. Really appreciate the opportunity to talk to a little bit about Reachable Workspace and how we are thinking about it for the REACH trial. As you know, in ReDUX4, we were able show not only statistical significance, statistically significant values, but P-value of less than 0.05 on REACH, and on the RWS. And the RWS itself is a very important endpoint for us because it is quantitative, right.
22:56 When we talk about FSHD, we’re talking about the loss of function due to muscle degeneration, and this function really does impact activities of daily living. So, in the ReDUX4 trial, we were able to really understand the sensitivity of the Reachable Workspace scale and also understand the statistical implications, which you’ve asked about.
23:18 When we met with regulators, we had a number of conversations that were very collaborative and understood that what we were trying to achieve in looking at losmapimod’s ability to flow to these progression and maintain function.
23:33 What the regulators recognized was that Reachable Workspace is a functional endpoint and they were really supportive of our ability to use that as a primary endpoint in REACH study. When we talked about powering, we are powering for a difference between placebo and losmapimod at week 48 on REACH and the power of the study is over 90% to detect a difference, which we believe is clinically meaningful.
Operator
24:04 And our next question comes from Joseph Schwartz with SVB Securities.
Joseph Schwartz
24:19 Thanks very much. And let me also add my congrats on the progress you’re making. So, I was – just also, I have a question on FSHD first, and then 6058. In terms of the REACH study, given it’s much larger than ReDUX4, but it seems to not require biopsies, I was wondering if you could talk about the push and the pull in terms of the cadence of enrollment that you expect, and when do you think you could achieve full enrollment and report data from REACH? And then also a timing question on 6058, the Phase 1b data in the second quarter, when should we expect you to report this data? I’m curious because it seems like the effect is not only dose dependent, but time dependent. I’m wondering if it’s logically expected in the later part of the second quarter? So that way you can see the experience in patients treated for a longer period of time?
Bryan Stuart
25:27 Sure. Yes, thanks for the questions, Joe. And maybe I’ll take the first question on FSHD and then turn it over to Chris Morabito for the second question. So, regarding REACH, I think we really wanted to build on our experience from the ReDUX4 trial that we previously conducted.
25:46 I think one of the things that’s very interesting about this particular disease, FSHD is unfortunately there are no approved therapies, it is such a progressive and devastating disease that when we enrolled in the Phase 2b trial ReDUX4, there was tremendous interest and enthusiasm from the patient community about a potential treatment.
26:10 And as a result, we were able to enroll that trial relatively quickly, faster than expectations. We ended up enrolling more patients than we anticipated and that was due to this unmet need, and the size of the patient population. So, as we then transition here into the REACH trial, while we haven’t provided guidance yet on exact timing, I think we continue to believe in here that the patient community is extremely enthusiastic about the opportunity to get involved in a registration trial for potentially the first treatment for FSHD.
26:49 Why don’t I turn it over to Chris, and we can talk more about the guidance for the sickle update.
Chris Morabito
26:54 Yes, hi, Joe. Thanks. So, we are on track to provide this guidance in Q2. And the goal of that guidance is to provide a meaningful update specifically on HbF, the change from baseline and HbF, which we believe tightly correlates with clinical outcomes and patients. As you know, this is a 3-month trial. The participants can as to participate for up to three months of treatments.
27:20 So, the longest treatment duration that we’re going to have in any individual is up to 3-months. And I think you’re correct in your assumption that – and in fact, the data have shown that the effects of 6058 is time and dose dependent.
27:33 We are seeing at 2-weeks in healthy volunteers, but look to be very substantial increases in HBG or HBG mRNA, which we believe will translate into HbF Protein. And the range of increase goes from 2.5-fold from baseline to up to 6-fold from baseline, and that’s just in two weeks. And as you recall, the data actually hadn’t plateaued by two-weeks. So, it’s possible that the maximum increase having yet been seen in a clinical trial.
28:02 So, we’re going to dose out to three months. We want to have a number of patients add three months for us to be able to substantially inform the absolute increase on HbF and when we have those data in Q2, we’ll be able to share them more publicly.
Joseph Schwartz
28:19 Great. Thanks for the color.
Operator
28:24 Your next question comes from Matthew Harrison with Morgan Stanley.
Matthew Harrison
28:31 Great. Good morning. Thanks for the taking the question. I guess two for me. So, first on 6058, Bryan, could you just maybe contextualize the comment you made at the beginning of the call? And I just want to make sure, how you’re trying to set expectations around the data we can expect? I believe you said something to the effect, given the amount of time required to get to peak protein production that you would view any amount of protein as a positive signal. Can you just, sort of help people think about the message you were trying to convey with that? And then I guess second, just on reach, can you just talk about how much that trial is going to cost and how you think about allocation of capital to that program versus some of the rest of the programs? Thanks very much.
Bryan Stuart
29:23 Yes, sure Matthew. So, I think in terms of 6058, as we’ve indicated, our therapeutic goal is to see a two to three-fold increase in HbF. I think one of the things that’s very encouraging is that those are the levels of both mRNA and protein that we observed preclinically, and as we transitioned into the clinic, that was consistent with what we saw in the Phase 1 healthy volunteer trial.
29:53 So, as we also mentioned, we come at this from a position of tremendous strength. There’s a tremendous amount of human genetic data that clearly demonstrates the benefit of increasing HbF. And I think that’s extremely well understood by the community, that’s extremely well understood by clinicians. And as we talk to clinicians and ask the question about what would it take for this to be a transformational therapy, and standard of care, we consistently hear back that these 5% to 10% absolute increases.
30:28 So, as we look towards this Phase 1b update that we’ll have in the second quarter, what we were not able to do in the Phase 1 healthy volunteer study is we were not dosing long enough to be able to see protein increases. But we certainly believe as we look at other HbF mechanisms that the 3-month time period will be sufficient in the Phase 1b study. So, as we go into the data update, our hope is to begin to see robust increases in HbF and to further give us conviction that we have the potential to achieve these levels within two to three-fold increases and levels that will be transformational for patients.
31:14 So, as Chris mentioned, there are certainly some elements of dose dependency and time dependency, but our hope is certainly that three months will be sufficient to see robust increases in HbF.
31:28 And why don’t I turn it over to Esther and we can talk a little bit more about capital allocation and the REACH study.
Esther Rajavelu
31:35 Yeah. Thanks, Matt. So, we plan to initiate the Phase 3 REACH trial in the second quarter of 2022, and the trial, as Judy mentioned, will enroll about 230 patients. And as we had demonstrated in our Phase 2b ReDUX trial, we enrolled that very efficiently and in a timely manner. And that’s because we have a strong network of relationships with the FSHD Patient Communities and know the treatment providers for this disease.
32:04 Now, for the Phase 3 REACH trial, we’re well-positioned with the insights we’ve gained from the ReDUX4 trial to continue to be cost effective and the guidance for our cash runway incorporates the cost of this trial. And another important point to keep in mind is that losmapimod could potentially be the first to market therapy for this untreated patient population. And as we look at the unmet need in this indication, we believe the investment in this program will have a meaningful impact on the patient community.
Matthew Harrison
32:39 Thanks very much.
Operator
32:43 Thank you. Your next question comes from Judah Frommer with Credit Suisse.
Judah Frommer
32:50 Hi, good morning. Thanks for taking the question. First on 6058 and just kind of the enrollment timelines and in general, there are obviously several modalities recruiting in terms of SCD clinical trials and the timing doesn’t always align, but is there anything you can, kind of help us with in terms of feedback from patients or investigators as to enrollment for your trial versus potentially others that may have somewhat overlapping timelines, whether their different modalities or not?
Bryan Stuart
33:23 Yes. Hi, Judah. Thank you for your question. We have had nothing, but excitement from sites and feedback from patients about participating in this trial. And frankly, we have not felt any competition risk here. I think the excitement generates from the fact that we’ve generated now evidence that says that we are, in fact what we promised to be, which is an oral HbF inducer, and the mechanism behind HbF is well understood. It’s impact on this disease have been well characterized and are well appreciated, not just by the patient community, but also by other physician community.
33:59 And the fact that we can do this with an oral medicine is also traditionally quite compelling. So, we haven’t felt any competitive pressure so far with enrollment and that’s been a good sign.
Judah Frommer
34:09 Okay. That’s great. And then just switching gears to losmapimod, anything you can help us with in terms of conversations with the agency on, kind of how relevant DUX4 gene expression biopsies are, kind of an assessing disease burden for disease here? And then also there’s certainly a decent amount of natural history work being done in the space. So, did that them up in terms of a potential [comparator] [ph], maybe not now, but if the trial was going to happen at a later date whether natural history will be more helpful than it would be today?
Judy Dunn
34:47 Thanks for the questions. I’ll take the question around DUX4 first. When we meet with regulators, what they are most concerned about, and they have been even since the DUX4 trial and before, is that what is important is how patients function and feel. And in ReDUX4 we demonstrated very clearly that we have an improvement in how patients function and patients recognize the value of the medicine. In terms of the DUX4 biomarker, there is so much biologic variability.
35:16 There’s so much technologic variability and really putting patients through a muscle biopsy when we know that we can hit on what’s ultimately most important, which is function for us and for the regulators. DUX4 as a biomarker is really kind of off the table because of the data that we have in hand that’s more relevant to patients. So they were very supportive of moving away from that biomarker in our case, and being able to just talk about how does this drug help patients to function better and do patients recognize that value. So, we won’t be continuing, we won’t be continuing with DUX4.
35:53 Now, in terms of the natural history study, those are studies that we are involved in, that we’re watching closely, and we utilized actually in addition to DUX4 to design our REACH trial. So, we have a lot of confidence that we understand the course of disease progression, both from our ReDUX4 trial, as well as from these natural history studies and we’re very appreciative for the investigators and patients that are being followed to help inform our trial.
36:20 And those continue to be ongoing and we’ve learned a lot from them and we’re looking forward to being able to show significantly, clinically relevant differences both in function and feel at the end of the REACH trial.
Operator
36:40 Alright. [Operator Instructions] We have a question from Ted Tenthoff with Piper Sandler.
Ted Tenthoff
36:55 Great. Thank you very much. Good morning, everyone. I apologize, I turned the call a little bit late. So, if this has already been answered, I don’t need to have you repeat. But when it comes and Judy I felt that last answer really interesting and informative. Thank you for that.
37:11 When it comes to the primary point, what is a clinically meaningful change in Reachable Workspace? Have you given any sense for, sort of what’s the powering looks like with 230 patients, approximately 115 on drug? Thanks.
Judy Dunn
37:30 Ted. Thanks for question. I think that is really what people want to know about and what we continue to work on to be able to relate the clinical meaningfulness of this difference in terms of outcomes. So, we have a number of data points that we’ve used to, one, talk with the regulators to support Reachable Workspace, but also to help us to understand the clinical relevance.
37:58 So, probably first and foremost, there’s just such a strong correlation between changes in Reachable Workspace and activities of daily living that are measured by other scales like the Neuro QoL. While we prefer Reachable Workspace is that it’s quantitative and it’s very reliable because we are still using that connect system and that 3D technology really takes quantification to a different level. In addition to that, when we looked at our own data, there’s also strong correlation between how patients feel and those changes in Reachable Workspace.
38:31 So, we’re beginning to quantify those differences in patients who are improving and how the Reachable Workspace scores are changing. And for those who don’t feel better. And what we saw there is also a strong correlation. And then finally, the third correlation, I think probably the most important correlation are those changes in disease pathology. We had some correlations between the changes in muscle fat filtration and functional outcome on Reachable Workspace.
38:57 So, when we powered the study, we’ve powered it at over 90% to be able to detect the difference between placebo and [drug at 48-weeks] [ph]. And when you think about this Reachable Workspace, it’s just so intuitive, right. If you can reach more areas, you’re going to be able to function better being able to continually work on how to relate this quantitatively as part of the analysis plan for Reachable Workspace.
39:23 So, we’ll be able to put those additional measurements in comparison to get and speak with people about them as the trial data is released.
Ted Tenthoff
39:34 Great. That’s really helpful. And then if I may, just a quick clarification for Esther. The guidance that you gave for cash through year-end. I understand that that includes expenditures for the Phase 3, but that doesn’t assume the Phase 3 readout by end of 2024, is that correct? Just to clarify.
Esther Rajavelu
39:56 So, Chad, thanks for that question. We have not guided to readout by the end of 2024, just to be clear on the REACH trial. So, for the Phase 3 REACH trial, we are planning a 48-week treatment period with enrollment commencing in the second quarter of this year. And we believe we’re well-positioned to enroll efficiently, but as I said, we’re not guiding beyond this at this time.
40:24 With regards to your question, cash runway, we’re fortunate to have a robust pipeline with three programs in the clinic this year. A potential new IND early next year and a discovery engine that is highly productive.
40:40 So, we’re executing on multiple frontier with a cash position of about 218 million as pf year-end. And we’re in a strong financial position and well-funded to execute on our plans as we laid out into 2024.
Ted Tenthoff
40:56 Great. Thank you.
Operator
41:00 Thank you. And our last question comes from [Tiffany Tazeen] [ph] with Bank of America. Please go ahead.
Unidentified Analyst
41:09 Okay. I think that sounds like me. So, I’m going to go for it. Can you guys give me a little bit of color on when you expect to see the two to three-fold fetal hemoglobin impact? I think that it is reasonable to assume based on what you said that that 3-months should show in a robust effect, but so that unclear, do you think 3-months would be enough time to show that two to three-fold increase? And then can you just remind us how many patients worth of data will be released? Thank you.
Bryan Stuart
41:50 Yes, thanks Tazeen. In terms of the timing to see a two to three-fold induction, we focus on essentially two data points to, kind of guide us and set expectations for us. One is, just the process of erythropoiesis. The second is, we looked at other mechanisms that had been known to induce HbF and we looked at the timing of those. And as we looked across a number of mechanisms, typically, we saw maximal HbF induction in a time period of about three to five months. And the earliest that HbF increases were observed with that one-month.
42:31So that’s really informing us going into the Phase 1b study. So, our expectation is that 3-months will be a sufficient amount of time to see robust increases in HbF. We don’t yet know, if those will be maximal and for that, we’ll have to wait to see the data.
42:50 In terms of the guidance for the number of patients, what we’ve announced is up to three cohorts, and up to 10 patients per cohort. As Chris mentioned, we’re currently enrolling in our first cohort, which is 6 milligrams. We will provide an update as we open up additional cohorts. So, we haven’t provided exact guidance on number of patients, but again, the hope is that, it will be a sufficient number of patients, and a sufficient time period to see robust HbF induction.
Unidentified Analyst
43:23 Okay. And then the time that it could take to get some maximal amount, just directionally speaking, would that be closer to 6-months or would you think it would be closer to a year?
Chris Morabito
43:37 So, Hi Tazeen. This is Chris. Going back to what Bryan said, we think it will take 3-months to 5-months to see maximal increases. Well certainly, at this [Q2 update] [ph] will be at patient dosing to up to 3-months. We’ll see strong directional changes. And it may not be maximal, but we do expect to see robust increases in HbF by the time.
Unidentified Analyst
44:00 Okay. So, I guess, closer to 6 months will be answer. Thank you.
Operator
44:07 Thank you. And with that, we conclude the Q&A session. I will turn the call back to Bryan Stuart for his final remarks.
Bryan Stuart
44:15 Great. Thanks again for everybody’s time today, and we appreciate the continued support for Fulcrum. Have a great day.
Operator
44:22 Thank you, ladies and gentlemen, for participating in today’s program. You may now disconnect, and have a wonderful day.
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