Fulcrum Therapeutics, Inc. (FULC) Earnings Call Transcript & Summary

Ladies and gentlemen, the program is about to begin. Reminder that you can submit questions at any time via the ask questions tab on the webcast page. At this time, it is my pleasure to turn the program over to your host, Tazeen Ahmad.

Great. Thanks, Joe. Good morning, everybody, and thanks for joining us again at the BofA Virtual SMID Biotech Conference. It's my pleasure to have our next presenting company, Fulcrum Therapeutics and presenting for Fulcrum for the next 30 minutes will be CEO, Bryan Stuart. Bryan, good morning. Thank you for joining us.

Yes. Good morning, Tazeen. Thanks for having us.

All right. So we only have 30 minutes together today. So I think there's a lot going on at the company. So I think for the few people who may not be familiar with Fulcrum, maybe you could give us a quick intro and then we can go straight into Q&A.

Yes, absolutely. So Fulcrum is a clinical stage genetic rare disease company. And really, the company was formed around the idea of trying to identify targets and create programs that would modulate gene expression for genetically defined rare diseases and, therefore, create the ability to generate disease-modifying programs. And what that discovery approach has led to in a relatively short period of time, is 2 drugs that are in the clinic that have the potential to be transformational. One is a small molecule called losmapimod for FSHD. FSHD is the second most prevalent form of muscular dystrophy, but one that unfortunately lacks any approved treatments and limited drugs in development. So we are in a registrational trial for that program, transitioning off of a Phase II trial last year, which showed statistically significant and clinically meaningful patient benefit across muscle health, function, patient-reported outcomes and strength. So a program that we're extremely excited about due to the severity of that disease and the unmet need. Our other program in the clinic is FTX-6058 for sickle cell disease. And that is another program for which we discovered it internally. We used our own medicinal chemistry to create a compound and really our approach and what we tried to do is something that's really been the therapeutic goal in the sickle cell space for a number of decades. And that is to find a small molecule that can induce HbF. And the reason we originally went down that path is -- what's relatively unique in sickle cell disease is that human genetics clearly show us the best approach to be able to reduce or potentially eliminate all the symptoms of sickle cell disease, and that's by inducing HbF. We know this from a condition called hereditary persistence of fetal hemoglobin. So with this strong genetic data, we used our discovery approach. We uniquely identified a target EED, and then created a compound, FTX-6058, which is now in the clinic. We shared very early in emerging data earlier this year at EHA, but what we were very excited about is we are showing that we are already reinducing HbF, and we are increasing HbF to the range that would have broad clinical benefit. And that's our therapeutic goal, which is a 5% to 10% HbF increase. We are beginning to see patients reach that level even at our initial dose, and I think that's very encouraging. So those are our 2 clinical programs, and we're enthusiastic about both of them.

Yes. So -- and both of those have relatively near-term updates. So maybe let's talk about sickle cell first, if we could. So you touched upon some of the attributes of the drug, but can you give us a better sense of how relative to the competitive landscape that we see today in sickle. And fortunately for patients, there are a few companies that are working on different approaches to treating the disease. How your approach is different and maybe better than what currently is available?

Yes, absolutely. And you're exactly right. Sickle cell disease is a terrible and devastating disease. It affects over 100,000 people in the U.S. It affects millions of people globally and there's just a tremendous unmet need that exists. And independent of standard of care today, which is hydroxyurea, there are more companies taking different approaches into the space, which is really needed considering how severe the disease is and how many people are affected by it. So maybe starting off with standard of care. Standard of care today is hydroxyurea and hydroxyurea induces HbF, relatively modest levels. It can be helpful for patients but does come with relatively modest and at times waning efficacy and a lot of safety and tolerability challenges. But if you look at the landscape in sickle cell disease, either drugs that were recently approved or in development, they typically fit into 1 of 3 buckets. So one is drugs that increase total hemoglobin. And there are a number of approaches looking to increase total hemoglobin, typically with small molecules. By increasing total hemoglobin, these drugs have the potential to address the anemia aspect of sickle cell disease, but there are many more symptoms such as VOCs, pain, stroke risk, et cetera, which are not addressed by these therapies. The second bucket is gene editing approaches. I think there's a lot of very exciting data emerging from gene editing, but obviously, that comes with a very invasive procedure and long-term safety and tolerability unknowns, and I think a lot of limitations as it relates to potential access. But it is validating for our approach, which is the third bucket, which has, again, long been the desired approach in the field, which is to find a small molecule that essentially induces HbF as well. And this has been something that I think, as I said, companies have been looking for, for a very long time. And the reason for that is back to that human genetic data that I mentioned. By inducing HbF, you affect not only the anemia, but if you can increase it, and this is why our therapeutic goal is this 5% to 10% increase, you will have an impact on all of the symptoms of the disease. So it's really that combination of the only approach that has the broad benefit across symptoms and also having a small molecule. And from our perspective, access is really as important as innovation. Considering the size of the patient population, the unmet need, we want to develop a therapy that can really be used broadly. And I think that's why we are so excited about this approach.

Yes. So people talk about what level of fetal hemoglobin induction is needed. So can you give us just based on what your conversations with physicians over the last 2 years or so have been and maybe benchmark it to what other drugs in development have shown, I think people would appreciate having a better sense of what's a reasonable range to expect to show efficacy. Is it just higher is better or no?

Yes, it's a great question. And as we -- and again, we have the ability uniquely, all of us in the space to look at a tremendous amount of data and literature that exists because HbF is so well understood and the benefits are so well understood. So I think it's very clear from hereditary persistence of fetal hemoglobin and from this data that any increase in HbF is beneficial. But our therapeutic goal and back to your question about what the clinicians say what the KOLs say, our goal is to not have something that will only be beneficial but has the potential to be transformational and standard of care. And for that, that's the feedback of this 5% to 10% range, and this is consistent with the literature and with the genetics data that you will have this broad impact at those levels. So we look at the largest study done with hydroxyurea showed increases in HbF of about 3.5%. This 5% to 10% range, the literature shows that there will be this broad benefit. So that is our goal. But back to your question, we also know the potential to get above those levels would also be very well received. But at this point, really, our focus is to have something that has the potential to be standard of care. Those are the levels that we feel we need to reach and as we shared our initial data at EHA, while it was early in a small number of patients, the part that was very encouraging is we're starting to see these increases get into this 5% to 10% range at our initial dose.

Okay. Now let's talk about your target for a second, EED. How did you come to feel that, that was something we're spending time on? And are there any other companies that might also be pursuing that as a target?

Yes. So how we initially find all of our targets and how we found EED is we do our screening in a very unbiased way. So we weren't going in with a particular hypothesis, but what we do is we utilize relevant disease cell lines from patients, we do a screen, and we then look to see and because our small molecule probe library is highly annotated on the other side of our screens, we then look to see what was the target that was inducing HbF due to -- we then discovered that it was, in fact, EED. And we then -- I think one of the things that was very encouraging for us is that the amount of validating preclinical data, I think, was very strong. So we looked at the wild type mouse model. We looked at the Townes mouse model. We looked at a number of CD34 positive lines. We looked at essentially donor lines from sickle cell patients, sickle trait, and we just saw this very consistent induction of HbF, and that really gave us the enthusiasm encouragement to continue the program and now bring it into the clinic. There are -- to the best of our knowledge, there are no other companies looking at this particular target for sickle cell disease. But I think one of the things that we've been very encouraged by with our medicinal chemistry efforts, is that we've developed a highly selective compound and that we've put a lot of work and expertise into that. And obviously, that's what we've been able to transition into the clinic.

Yes. so let's talk about the clinical program. So now you're looking at a number of doses. Let's talk about the 12 mg dose for a second. How do you feel about the dose, I think that is the dose that you feel most confident in right now. But what's your view of looking at higher doses and having lower doses available as well for patients.

Yes, absolutely. So when we started down the path and one of the things that I had mentioned, we had seen this very robust induction preclinically. when we transitioned last year into a healthy volunteer study, we were dosing healthy volunteers for 14 days. It wasn't long enough to be able to see protein induction because of the relatively slow red blood cell turnover that exists with healthy volunteers. But what we did see was robust mRNA. And while the target engagement was relatively consistent across doses, we saw a dose proportional response in mRNA. So it was with that we transitioned into the Phase Ib trial. Our initial dose was at 6 milligrams. And the reason we chose 6 is we believe that, that was a dose based on all of the data that we had generated where we would be able to see HbF induction and that's exactly what we did observe. Within this 3-month period, you see HbF begin to increase, and again, encouragingly, get towards these levels that are our therapeutic goal. We also, as you mentioned, we have 2 other doses. We're looking at 2-milligram dose. We're looking at a 12-milligram dose. One of the things that we want to understand is essentially maybe twofold. So first and foremost, we want to understand whether or not 6058 is additive to hydroxyurea. Does it induce HbF beyond those levels induced by HU, I should say. We were not able to share that at our EHA data because the initial patients that enrolled in our trial were only on monotherapy, they were not -- or monotherapy was 6058, they were not on background HU. So that's something we are now enrolling patients who are on HU, so we'll be able to show that. In terms of the doses, what we really want to understand with the 2, the 6 and the 12 and again, this is starting off with us being very encouraged by what we're initially seeing at the 6, is because target engagement is relatively similar across the doses in the healthy volunteer, we want to understand do we get to different protein levels at different doses? Do we see greater HbF, what do the kinetics look like of core safety and tolerability. So we have the ability to go up to 20 milligrams. We feel like at these 3 doses initially, we're going to get a lot of great data to really understand HbF induction as well as any trade-offs that exist. And again, both monotherapy and on top of background HU.

Right. Yes. So I mentioned the 12 because, again, you said you were encouraged by what you saw at the 6 mix, right? So as long as you don't see safety, is it wrong to think that why not go higher? Why not use the 12 if efficacy could be higher without any additional safety concerns. And would you also be wanting to dose to your maximum tolerated dose? Or is that not really something that you feel is necessary?

Yes. I think to your -- maybe to your initial question, you're absolutely right. We want to understand -- we were encouraged by 6. We want to understand essentially 2 things. One is getting more subject at 6. One of the things that we spoke about, we spoke about at the time of the EHA data is that we had 5 subjects in our initial data, 2 of them were non-adherent. And this is based on the criteria that we set for adherence. One of those subjects transition to observe dosing. So that's information that we'll be able to share the impact of that with our next data update. But we really want to understand the 6-milligram dose, we want to essentially understand all of the doses, but to your point, yes, we want to understand at 12 milligrams, are we observing additional HbF increases and of course, the safety and tolerability as well. To your point about maximum tolerated doses, I'll probably go back to the fact that, again, we're starting off from the place -- the therapeutic goal is to consistently see this 5% to 10% increase. And then I think we're going to let the data decide whether or not additional dose cohorts will be helpful. One of the things that we have our goal for the program is to generate sufficient data from this Phase Ib trial to then transition into a registrational trial as our next trial.

Sure. Now you mentioned that you are also adding patients that are on background HU. When all is said and done, what do you think the split will be in the amount of patients you have who were on background versus not?

Yes. I think our goal for this program or for this trial, I should say, is we want to understand, is 6058 additive to patients who are on background HU? And then what is that consistency. So we're not guiding towards a particular number of patients. I think if you broadly look at the other sickle cell programs in their Phase I, they typically had between 6 and 12 total patients. So Phase I trials tend to be smaller before companies go globally to enroll registrational trials. But our focus is less so on a number and more so on quality of data and consistency. So we want to understand that variability. If the variability is greater, that likely, it will be helpful for us to enroll more patients. To the extent that we're seeing consistency, I think we would feel comfortable with fewer patients, but we really want to make a data-driven decision.

Sure. Now that brings me to my next question, which is when should we expect to see the next data readout from the program?

And so what we announced at our most recent earnings call is that we're going to continue enrollment into 2023 and we'll be providing an update earlier in the year in terms of laying out data expectations.

Okay. So once the data comes out, this is a rare disease, undermet need too. Is it reasonable to think that you would have an accelerated path to approval if the data warrants?

One of the things that we need to engage with regulators on and get clarity is the potential to use HbF as a surrogate for accelerated approval. I think we've always said as we look at HbF, it's been uniquely well studied. There's human genetics data. There's now emerging gene editing data. There's real world evidence where we understand the link between increases in HbF and impact on symptoms. Those are the reasons that I think we and others on the gene editing side have chosen HbF as the therapeutic approach. Ultimately, we need to go have those interactions with regulators. And obviously, when we get clarity, we'll share that. I think one of the things that we're equally excited about is we think about this program, and we think about transitioning into a registrational trial, we know that increasing HbF will have all of these impacts on the different symptoms. And I think that puts us in a position to not only hopefully be able to show increases in HbF, but to also know how we should design and power a trial to show the benefits on symptoms, which will follow with HbF increases.

Okay. And do you think that it's reasonable to assume that if you were to get an accelerated path, that you would still need to do any kind of confirmatory study or would that be something that FDA would discuss with you?

Yes, I think that's something that we need to gain more clarity on with our interactions with the regulators. Again, going back to just having this unique understanding about increases in HbF and the relationship to the symptoms of the disease, that puts us in a very strong position as we think about what a registrational program can look like and how we can demonstrate clear patient benefit.

Yes. I mean the FDA is going through this process of kind of revamping what they want an accelerated approval pathways. And a lot of that seems to be focused on companies getting still the ability to get drugs to patients where there's undermet need, but also trying to follow up with, I guess, making sure that they do follow up with the data that they promised. And so I was just curious as to whether you had any discussions, but it seems like it's probably too early to be asking that.

Yes. I think this is something that we'll gain clarity on. But I think one of the things that we are thinking of and we're trying to balance is it's not just the ability to be able to move forward into a registrational trial and bring the drug to patients, but it's also to generate the data set that we believe will be very compelling. And we think we have the ability to do that by approaching HbF as we are. But that's the balance. And again, we want this to be a therapy that can really be broadly utilized and that's the approach we're trying to take.

Sure. Now focusing on HbF, we understand the importance of that. But I think also for people listening, the other thing that probably the agency would be looking for would be VOC. So I guess, how would you think about overlaying VOC with HbF if you had to look at both of those together?

Yes. We did and one of the things that we've shared -- others have shared similar analysis is we did a systematic literature review which really focused on what is extremely unique about HbF, and that is how well studied it is, as I've mentioned multiple times from all this genetic data. So one of the things that we know is that, again, by increasing HbF, you will have an impact on VOCs. And you're exactly right. There are so many different symptoms associated with sickle cell disease. HbF gives us the ability to look to address all of them, but VOCs are extremely important. And they are important to patients. And as you ask patients about all of these different issues, pain crises, hospitalization, VOCs. VOC is always very high up. So that's certainly one of the things that we're very mindful of as we think about these HBF levels and this literature review that I referenced, when you get into this range, and that's this 5% to 10% range, do have a meaningful impact on VOCs. So that's certainly something that we're mindful of. We understand that from the patient perspective, that is one of the most debilitating symptoms and one that we're looking to address with the therapy.

Okay. And then maybe big picture wise, do you think that your therapy would be relevant for all sickle cell patients? Or do you think that maybe at least initially, there would be a subset that would be most amenable.

Yes. As we approach this and as we generated our preclinical data, I think one of the things that we mentioned that we were very excited about preclinically is that as we looked at hydroxyurea, which is a standard of care, we looked at a number of different cell lines. We saw about a 30% response rate. So about 30% of those donors responded preclinically to HU. With 6058, we have yet to identify preclinically a nonresponder. So I think that gave us a lot of enthusiasm that not only were we seeing robust induction of HbF, but we were seeing it in a pan cellular way preclinically, and we were seeing it across all of the donors. So we need to understand how that translates into the clinic. We need to generate that data. That's what we're trying to do in the Phase Ib, what the 6058 look like as monotherapy. What does it look like on top of hydroxyurea. And certainly, the hope is if we can induce HbF, that we can have very broad impact across patients, if we can induce HbF to levels that are incremental to hydroxyurea then that will not only have benefit -- should potentially have a benefit to everybody living with sickle cell disease. So we're excited. We need to generate the data to really understand that.

Okay, great. We'll be looking forward to seeing all those updates. So in the few minutes we have left, maybe we can touch upon losmapimod, which you talked about at the beginning of our conversation for FSHD. Can you talk to the steps that have gone into where you are now, which is your Phase III program, the REACH study. How did you decide with FDA that, that was the right path in order to get the drug approved. And just remind us what would be good data when it does read out.

Yes. It's a great question. And again, a program that we're equally excited about. So we approached FSHD initially for a number of reasons, tremendous unmet need, very severe and debilitating and relentless disease, people typically get diagnosed in their second decade. And it's just a very debilitating form of muscular dystrophy that it just is going to continue to get worse. What made it a good approach for Fulcrum is that it has a known root cause, and that's the expression of DUX4 and that's what causes the fat infiltration into muscle. Preclinically, we identified -- uniquely identified that P38 met kinase inhibition reduces DUX4-driven gene expression. That was a discovery we made, but it has since been validated by a number of other papers and another of independent researchers and investigators over the last few years. We in-license losmapimod from GSK, had a very strong safety and tolerability profile as GSK had studied it broadly in inflammatory diseases. They were unaware of the relationship to DUX4-driven gene expression as they obviously had not done these screens. So it gave us a very strong basis to continue. We did a Phase II trial last year, this is called ReDUX4. And initially, our focus was on a molecular biomarker. Can we demonstrate via needle biopsy that we are reducing DUX4-driven gene expression. And then we had a number of other endpoints related to what the FDA is very focused on, which is function and feel. So we were looking at fat infiltration via whole body MRI, looking at strength via dynamometry, something called reachable workspace, which is a measure of a patient's ability to move their arms above their shoulders. And why that's particularly relevant is that reachable workspace is highly correlated with activities of daily living for people with FSHD and FSHD typically progresses from the upper body to the lower body. So we looked at all of these measures in the Phase II trial. It turned out that the molecular biomarker, the ability to measure DUX4-driven gene expression itself, that proved to be very challenging as DUX4 is stochastic. So we can measure it preclinically, but it's not clear that it can be measured clinically. I think the surprise and what was very exciting is that in only a 48-week trial with only 80 subjects, we did see the statistically significant and clinically meaningful patient benefit across these other measures. Patient-reported outcome, fat infiltration, reachable workspace, et cetera. And that put us in a very strong position to then go interact with regulators about what should be the primary endpoint for a registrational trial. The reason we approach them about reachable workspace is it is so relevant to people living with FSHD, highly correlated with activities of daily living, the ability to live independently, to brush your teeth, to come your hair, to drink a cup of coffee and that resonated with regulators, both in the U.S. and in Europe. And we have then sort of taken the elements of our Phase II trial that were effective in terms of the time period, utilizing reachable workspace, continuing to keep the trial at 48 weeks and now making it a larger in terms of an registrational trial. So we believe it's an appropriate endpoint. In terms of what we're looking for here, we're really looking for that separation. As you -- one of the elements of reachable workspace that we saw in the Phase II, patients on placebo decline and typical or at least consistent with what was published previously is that they typically decline about 5% to 10% per year, and this deficit just accumulates. What we saw with losmapimod, both in our 48-week trial and our open-label extension is stability. And what our goal is for the registrational trial is if we continue to see that separation between losmapimod and placebo, you are having this very meaningful impact on patients, their ability to live independently and that we hope will also accumulate over time. So that's the goal as we go into this trial. Obviously, also looking at safety and tolerability and looking for this continue to be a drug that is well tolerated as it has been to date.

Okay. With that, we're just about out of time. We would love to talk with you for another half an hour. I'm sure we'd have plenty to discuss, but we'll do that next time. In the meantime, I want to say thank you for joining us this morning. It's always good to see you and catch up with you. And hope you have a great rest of December and a happy, healthy and safe 2023, and we'll talk to you soon.

Thanks so much, Tazeen. We appreciate it.

Thanks, Bryan, and thanks, everyone, for joining. Have a good day.

Bye-bye.