Newsfilter article unlocker

All right, good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Olds. We're the biotech analysts here. It's my pleasure to introduce the team from Dine Therapeutics. To my immediate left, John Cox, President and CEO, and to his left is Eric Lucera, CFO. And just a reminder, the format for today is a fireside chat, but if anyone in the audience has a question, you can raise your hand and we'll try and get it addressed during our discussion. But before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com backslash research disclosers. And if you have any questions, please reach out to your Morgan Stanley sales representative. And with that, I'll hand it over to John to make some introductory comments before we jump into Q&A. Terrific. Thanks, Mike. Well, I'd just mention a little bit about where we are at DIME right now. So it's an incredibly exciting time for us. This company, over the last couple of years, has been preparing for the moment right in front of us, which is to launch a very important medicine in DMD. And that's early next year, followed by DM1 the following year. So we've been building a, I guess I'd describe it as a pure play, neuromuscular, standalone, fully integrated biotech. Over the last year and a half, we have built out our leadership team and brought in people that I think are other people that know how to build a company like this. They've been part of this type of company in the past, the company we're building for the future. We know howto allocate capital, and we know howtolaunch products, andweknowhowtocommercialize. So we came here, really, and I came here because we want to launch two really important medicines in neuromuscular diseases where there really is nothing that is helping these patients. So it's an extraordinary time. We've got a PDUFA date in January, and we are working hard to be ready to launch our first product. Great. Thanks for that introduction. I'm going to switch gears a little bit and start with DM1 because I think there's interest there for obvious reasons. But let's start Z-Basavarsin for DM1, maybe to just set the stage for the discussion, give us a brief background on that program, and highlight some of the key findings so far from the ACHIEVE study. Well, you know, DM1 is one of those diseases where there is really nothing for patients, and it affects tens of thousands of patients. There's probably 30-plus thousand individuals that suffer from that disease. It shortens their life by about two decades, and they struggle and they suffer. So our company had introduced Z-bacivarsin clinically some time ago in a trial called ACHIEVE. And that trial, we presented data that had shown, first of all, that we were getting at the core fundamental biology of the disease, and that's incredibly important. This is what's known as a nuclear spliceopathy disease. So it's in the nucleus. And we had designed our platform, the FORCE platform, to deliver broadly and deeply to tissue. But we also had attached to that platform an antisense oligonucleotide. And that antisense and oligonukleotides gets to the nucleus, and so what we showed previously, importantly, related to that was that we saw DMPK knockdown. that's of the mutant DMPK that's at the source of this issue, knockdown of DMPk, we saw, as a result, splicing correction. And I don't think anybody else has been able to show that, where the mis-splicing is corrected. And we showed that in a dose-dependent way. And then what we finally presented at the end of that multisignal dose study was that we were seeing functional improvement across multiple measures. And that functional improvement was represented by things like five-time sit-to-stand. It also was represented via hand myotonia with VHOT. And we even had shown improvement on patient-reported outcomes, known as MD-HIGH, on six subscales that are arguably related to the CNS. And that disease has a CNS issue that's very significant. our our targeting moiety uh which targets tfr1 isn't as a antibody fragment and that fragment crosses the blood-brain barrier and it also gets broadly and deeply to muscle and i think it's got a very unique and differentiated distribution that's allowing us to see that kind of improvement across multiple measures yep they're very exciting data so far and i guess the question on a lot of people's minds is just, you know, what's the read-through from Novartis' recent harbor date? I know there weren't a lot of details there, so it's a little bit difficult to really understand what's happening, but maybe just share your thoughts on that and read through. Yeah, I mean, that, I think everybody knows, but their result indicated that they did not meet their primary point on video hand-opening time. We were surprised by that because VHA tends to be an endpoint that moves very easily, and it moves early. That's what we've seen. So we were surprised about that. But I would still come back to what I mentioned before. Biology really matters here. Getting to the core pathobiology of the disease is key. And that particular medicine from Novartis uses an siRNA. which does not get to the nucleus. So I think we have to realize we have two very, very different molecules. So when we start talking about read-through, you need to start with, even though we're both using TFR1 and going after the same disease, we have a completely different payload, and our FAB behaves very differently than the MAB that they use. So I would start there. Now, when we looked at our data, we had gotten to, in the multi-accenting dose study, to fairly high doses. In fact, we are at a much higher dose of oligonucleotide than the other sponsor is using, much higher. And the reason for that is that we found at a low dose, we would move VHOT, but we weren't necessarily moving the other more clinically meaningful measures. And so we kept dose escalating to a much higher dose, and that dose escalation is largely possible because we use a FAB. And with the FAB, we do not get the dose-limiting toxicities of anemia that MABs tend to see. So we could get to a higher dose, and we are well above where we think we need to be to move VHOT and even to move measures potentially into the CNS. Makes sense. Maybe just talk about your view towards the different endpoints, like a VHAT versus a five-time sit-to-stand. And I know you've had a lot of discussions with the FDA as well on this, So maybe, you know, share that for you as well. Yeah, so listen, we see VHOT, and we're using VHAT, as an intermediate clinical endpoint. So our clinical development plan has been different than others. We, and I think we have a very robust and fulsome clinical development plan as it's laying out. We're first doing a salary approval, and we have registration expansion cohort in Achieve with 71 patients. And we are using VHOT as an early indicator, in other words, an intermediate clinical endpoint, at six months. And our data previously has shown at six month, you move VHAT meaningfully. And at later time points, and at six-months, and a later time point, it is indicative and predictive of improvement on other endpoints. v-hot in our conversations with the fda and with clinicians it's not such a clinically meaningful endpoint it's just about being able to open your hand quicker or slower there are other more clinically meaningful measures and so in our phase three which is now enrolling we're using what we think to be a very clinically meaningful endpoint of five times sit to stand we would not use v-hop as a primary endpoint for phase three. We've always said that. It's just not clinically meaningful enough. Something like five times sit to stand followed by other measures is meaningful, and we can talk more about that. I guess just given the data we've seen now from Novartis with VHOT, do you think that changes how the FDA views VHAT as like an intermediate sort of endpoint? Are they less favorable there now, you think? Well, I would not, listen, the FDA doesn't talk to us about other sponsors, but if, you know, in my own view, if anything, this makes the case that it's an appropriate, it's appropriate as an intermediate clinical endpoint, not as a phase three endpoint. And so I think we feel good and confident about how we've done this, how we're organized the registration expansion cohort, how we have laid out the statistics around the endpoint, and then again we follow it up with a phase three that will be very robust with a much more clinically meaningful endpoint. Understood. You're going to share some updated data from Achieve at a couple medical meetings here. I think it's World Muscle and AANEM, you know, later this month or next month. But just, you Know, give us a sense of what to expect there and how to think about those updates. Yeah, so we recently announced that we would introduce 12-month data at AAN EM and also at World Muscles. And I tell you, Mike, the reason we organized this 12-Month Data, We went through some trouble to do that as we were anticipating that Novartis was going to be saying they hit on VHOT and present, and then they would present other functional measures. And we wanted to give people a chance to compare on functional measures that really matter. We're going to go forward and present that. And that will be 25 patients. We captured 25 patients from the ACHIEVE long-term extension study that had been on dose for at least 12 months. And we are also comparing that, we'll be comparing that to baseline, and we'll Be comparing that also to natural history where we've done a propensity matching. And we'll B looking, again, at multiple measures. You'll recall that when we had presented before, we had shown at the registration expansion cohort of 6.8 mg per kg that we had moved on QMT, VHOT, QMG, quantitative muscle testing, multiple time function tests and also on MD-HI and on the CNS subscales. But it was only six patients. And so people were, man, it's great data, but it's six patients Well, we're going to be presenting now on 25 patients Great So we look forward to seeing that and I guess, maybe just to follow the conversation, you'll still have your Achieve Registrational Cohort Data 1Q and, you know, the primary endpoint there is, you know, VHOT at six months, I guess, you know, what are your expectations, you know, for that data set? Well, that data set we have guided to Q1 of next year. So that will be the registration expansion cohort. That will be the set of data that we intend to submit to the FDA as part of an accelerated approval package. And so what we would hope to see with that and expect to see with that is that we expect to see that VHAT has responded appropriately, that it is an appropriate intermediate clinical endpoint, and then what we have to provide for accelerated approval is trends across other measures, and that data we showed from the MADD was very clear that there were trends on five-time sit-to-stand, 10-meter walk-around, et cetera, so that's what we would hope to see from that data set, and then we will rapidly put that together and submit it as an accelerated approval package. Okay. Makes sense. If we just go back to the confirmatory study, the Phase III harmonious study, and maybe talk a little bit more about the choice of the endpoint there, the five-time sit-to-stand versus, you know, some other functional endpoints which you could have chosen. Mike, this disease, I think you're fully aware, has a lot of heterogeneity to it. For some people, it's a balance issue. It's a strength issue. For others, it can be general myotonia, GI issues. For others it's CNS issues. So identifying an endpoint, and there's no endpoint that's ever got a drug approved in the field. So establishing for the first time a meaningful endpoint is something we put a tremendous amount of work into. And that is also going back to the natural history data, working with all the top KOLs, and then looking at our own data. And talking to the FDA. Five times sit to stand, I think, will become the kind of benchmark, definitive primary endpoint in this field. It looks at when you have to stand up and get up and down from the chair five times. That's telling you about strength. It's telling me about balance. It's tell you about coordination. There are mental aspects to it. It tells you about fatigue. And it's also about core truncal strength. and it relates to and it's been shown in other studies to be correlated with the likelihood of falls, which is obviously a very big deal in terms of morbidity. So that endpoint is one that we feel very good about. We've looked at our study from the ACHIEVE study. We saw that we improved on five-time sit-to-stand and what would be considered an MCID. And so we think we've got a really good end point, and we think obviously we have a very good shot at hitting that. Yep, for sure. Can you characterize your discussions with the FDA around that end point and kind of what their view was? Well, we've provided the end point and the justification and the rationale. And so I think we're aligned with the FTA on what we're putting forward. Yep, makes sense. and then just harmonia is ongoing can you talk about just the pace of enrollment there versus your you know expectations and you know are there ways to sort of accelerate that at all we're moving very quickly on harmonia so harmonia is the phase three confirmatory trial for the u.s. but it's also a trial that will enable us to go to europe and japan so it's a global trial It is essentially our global phase three. And it is enrolling. We had announced that we had initiated it. Enrollment is happening. Enrollement, I think, is going quite well. There's a lot of interest in that study. There's always been interest because I think the field has understood that uniquely to our drug, we have the potential to get to the CNS. and with the ability to get to the CNS when 50% or more of the patients have CNS issues. Doctors have been holding patients for this drug and so we're not having any issues in terms of moving on enrollment. In fact, just the opposite and we're moving aggressively. Great. Okay. I guess any risk with the top-line results about, you know, to enrollment in the study at all? Well, risk to top- line, like five times to just... Oh, I just mean ability to enroll the study. Maybe people are less, you know, they don't like VHOT for some reason, or there's questions. Oh, I think, no, not at all. In fact, I think if, with the recent news, even with the, with the other drug, people will be encouraged to come to this trial. So we see this as actively enrolling. In fact, at this point, I'll say, Mike, I think we're the only company with an active Phase III trial in DM1. That's both a registrational expansion court that's about to read out in Q1, and we'rethe only companywith an active phase III. So that puts us in a pretty good place, I think, in terms of market introduction. Yep, makes sense. All right, maybe we can shift gears now to Z. Rasta-Dierson. That's your DMD program, Exxon 51, currently under priority review, PDUFA date January, you know, so maybe just highlight some of the key learnings there, points of differentiation, et cetera. Well, you see, Rasta Dierson is for DMD, And it is for those individuals that are amenable to exon 51 skipping. That's the most prevalent category of mutations or subpopulation within DMD. What is special about our medicine is, again, the delivery. People have known for years that you can skip exon51. The challenge has been getting enough of the oligonucleotide broadly and deeply to the tissue. And as a reminder for people with this disease, it's a devastating disease. There's drugs out there, but nothing is stopping the inevitable outcome and progression. And for these boys, and it's recessive exoling mutation, so it's all boys. by the time they're six or seven, they start struggling to get up off the floor. By the time their 11, 12, 13, they're in a wheelchair. By the times they're late 20s or 30s, their heart fails or their diaphragm fails. So getting distribution to all these different tissues, including the heart, the diaphragm, and broadly the muscle, is key. And what we have done is take a look at one key measure, many measures, but six functional measures, one being rise from floor velocity. And what we found in our study, which was a registration expansion cohort study, is that we were improving on rise from floor velocity. In other words, they were getting faster. We saw improvement, in fact, on all six key functional measures in DMD. That just isn't done or seen. Now, because of that, I think we're moving really well with the FDA. Everything is about getting this product launched. The community is engaged and excited for it, and we feel a real responsibility to get this to patients as soon as we can. Can you maybe talk about the surrogate endpoint, which is dystrophin expression, what you've seen there, and how it evolves longer term, which I thought was pretty promising? Yeah, thanks for raising that. So generally in this disease, people have looked at dystrophin levels in muscle biopsies as a biomarker. And in exon 51 patients, it's likely the most difficult exon to skip. There's a little bit of natural skipping depending on the mutation. They're virtually at about 0.4 or 0.5% of normal dystrophy if you take a biopsy. almost none. What we found was that when we adjusted for muscle content at six months, we were at roughly five, five and a half percent dystrophin. We took some biopsies even longer term, four biopsied who were voluntary biopsias that were not part of the original protocol. And we found that we had roughly tripled what you would see in terms of dystorphin levels. And all of that was consistent with what we were seeing longer term. So at six months, just six months, you wouldn't have, you would not have thought rise from floor velocity would improve in six months. You wouldn't expect stride velocity 95th centile to improve to six months. It's a, it's a disease that people would have expected since it's fairly slowly progressing. You would see, take time. At six months we're seeing it, even at those dystrophin levels, which means we're getting broad, deep distribution through the tissue. but longer term then we presented the last mda 18 and 24 months across these measures and you saw continued improvement and we even saw stabilization of cardiac function and of lung function which was really important and we were seeing that across boys that were ambulatory and also non-ambulatory so it really points to you are building dystrophin over time. And the important piece is nobody's ever really understood how much dystrophin do you need to start seeing functional improvement. And people would always ask us that. And we would say, you know, we're going to be the ones that just might have the answer. And now we've seen even at fairly low dystrophy levels, four, five, six percent at six months, you're actually seeing functional improvement, not slowing the decline, but functional improvement from baseline. It's It's remarkable, and we're excited about it, obviously. And maybe you can just put some of that data you've just shared into the context of the currently available therapy in terms of the profile, like dosing maybe, touch on that as well. Well, the current therapy is Exondys, and that drug has been on the market for about 10 years. It was approved by Accelerate Approval. To date, it has not been able to show statistically. that it's having functional improvement. So, and it's dosed on a weekly basis. And so there's a lot of, I think, disappointment in that treatment and basically the current state of treatments. And so, you know, we are roughly 10x in terms of distance from production compared to what they had shown. And our dosing frequency is once a month. So it's an infusion once a months, much more convenient. it's really hard to compare those drugs, honestly. And the reason is our oligonucleotide is attached to an antibody fragment that is delivering broadly and penetrating the tissue. Can you maybe share what you've heard from some physicians on the profile? We have met with, we've worked with a lot of physicians, and we've met with so many. Those who have used the drug in the clinical trials, they see this as a foundational therapy. The notion that they would keep somebody on one of the older therapies like Exondys, they're very clear. We're switching our pitch. And so I think the receptivity among the clinicians, they're sitting up and they're positive about it and they're very excited about it. And then you've got the patient advocacy community as well and they are fully aware and they Are in tune and alert to it. So we are feeling very positive about successfully launching this drug next year. Can you talk a little bit about the Phase 3 sort of confirmatory study and the choice of the endpoint there? You talked a little about it earlier and why it makes sense, but maybe just expand on that. You know, ourselves and other sponsors of DMD clinical trials have all come to the conclusion that a rise in floor velocity is a meaningful measure. It is something, in just practical terms, as I mentioned, you know, when people start, when parents first realize their son is struggling to get up off the floor, they take them to the doctor and they get diagnosed. And then what they monitor is the time it takes for them to get off the door. And there gets to be a point in time, say over 10 seconds, where it starts to become very predictive. Okay, when they hit that sad threshold, they're going to be in a wheelchair in a fairly short period of time. So there's no question it's a very clinically meaningful measure. So that was selected as the primary. And then we have a number of secondaries. And dystrophin is not part of that. We've moved past dystorphin, done with biomarker. Now let's talk about efficacy. Rise from floor, stride velocity, 95th centile, NSAA, which is an ambulatory measure, and others, pulmonary measures, cardiac measures, all of that will be part of, and some patient report outcomes, part of the phase three. It's an 18-month endpoint and placebo control, and it's a global study. Okay, great. With the upcoming PDUFA date in January, I don't know if you can mention any kind of interaction so far with the FDA, your expectations around an adcom. Well, you know, we're having the usual interactions that you would have getting to this point. We're not going to comment on those, just to keep all of that out of respect to the process for the FDA. When we received the filing acceptance letter from the FDA, it was great. And that letter gave us prior to review, and it also said that they did not expect an outcome. So it was a positive. I like reading that letter. Great. Obviously, Purdue for Day in January, you could be launching next year, so maybe touch on some of the launch preparations so far. Well, listen, for launch, launching is, for the first time as a company, you need people that know how to do it, and they have to be on a mission, and we are. The areas of attention, regulatory execution, obviously, and that's happening. Other areas is manufacturing and supply chain execution. We brought in a team to do that, and мы работаем на это, и мы выполняем это, и мы готовим наши инвентарии, и они готовы к скалированию наших процессов. and then the other big part is is commercial and uh you know we've i mentioned before we brought in johanna friedel nader um to lead our commercial organization almost two years ago she's been building and preparing that organization to launch a rare disease drug which she and her entire team have done multiple times so um that preparation is in place we've got the market access team in place we've got patient services leadership in place uh we have uh our medical affairs team in place so market access uh preparations are kind of key at this point and all that is moving per plan it's a lot of work it's lot of fun and it's happening yeah great and can you talk a little bit about the strategy i know it's you know you haven't quite fully gone there yet but just you your early thoughts on the strategy for the launch? Well, listen, I think one of the beautiful things about doing this and being at Rare Diseases is that you can actually do it in a very capital-efficient way. And I'm going to let this guy to my left say a few words about that. Yeah, I Think when you look at the Dyn portfolio, just taking a step back with the Force platform, it is something that is amenable to multiple products. So we have seven products in the clinic with DM1, DMD, the other exons, FSHD. From that, we can scale a commercial organization that's largely seeing the same centers for all of these drugs and the manufacturing. We've got the same fab, same linker. Oligochemistry is pretty much the same, just a few tweaks went right. So there's a lot of opportunities to scale a business unlike anything I've seen in the 30 years that I've been in biotech. So from a capital and a resource standpoint, it's very capital efficient, and it's something that we think can provide patients and investors a trajectory of growth into the next decade that will be well above our peer average. Makes sense. For the launch, do you expect sort of a pent-up demand, just given the profile you've seen and the feedback you've gotten on it? Do you anticipate a lot of switching early, or just how do you think that all kind of plays out? I think the demand is absolutely there, without question. The unmet need is profound. So the demand is there. I think we're predicting this to be what you often will see in rare diseases in terms of a launch, meaning the first year is gated largely, not so much by demand in this case, but gated more by coverage. You know, it's kind of controlled. The pace is controlled largely by the payers. Now, often in rare disease, the challenge is finding the patients. DMD, the patients are known across the United States. It's about 1,600. They're known. The reimbursement pathways are there. So a lot of those kind of hurdles are not there. But you should see a launch that will be, I think, successful, but it will be a typical kind of rare disease affected by payers for a period of time, which we'll work through, and we should have a very good launch. Makes sense. I wanted to ask you about your other Exxon skippers. You have several in the pipeline. John, you mentioned Exxон 51 is probably the most difficult to skip. You've had very promising data there. So, you know, how do we think about, you know, the rest of the pipeline, timelines? How fast can you move those forward? Well, maybe I can let Eric start with how, when he first joined the company, the first thing he did was start talking about, we've got to build a franchise in DMD. So maybe you can comment a little bit. Yeah, I'd say for me personally, I'm very excited about the DMD franchise. It's something that I noticed was a disconnect in the way the market viewed the stock. It is something that when you take all of the patients that we're targeting, you start with 51, that's 13% of the boys. You get the other four exons, that'S 39% of the boys, so in terms of how we're going to get this to market, obviously, we found some money in the budget to get CMC and IND-enabling tox studies this year in advance of any discussions with the FDA. We did not want to lose any time getting these drugs to these boys. It's very important for us. Obviously, the most important thing is to get Exxon 51 approved. Once we get that approved, we will then have discussions with the USDA about finding the appropriate development pathway forward. We think the best approach is to do some kind of a basket trial where you would have four actives and one placebo. I think if you were to try and do these on an individual basis, the incidence and prevalence probably isn't big enough to run randomized trials. You just would run out of patients. So a basket trial seems like a great way for us to get this to all the boys that we can, and we will have those discussions after we get approval and knock on wood for 51 next first quarter. Mike, I really believe that we have a chance to be the leaders in DMT in the field. I think the Exxon 51 is step one and has demonstrated that we actually can see functional improvement in places where people haven't seen it before. We owe it to our shareholders and to the community to make that happen, and we're going to do our very best, and that is expand that franchise as rapidly as possible. And that will put us in a leadership position in DMD. And then right behind that, obviously, DM1 and even bigger markets. And we'll have some data on preclinical work in a couple weeks. We put that press release out about two weeks ago, so looking forward to that. And then maybe, Eric, you could just touch on that you have this efficient strategy going forward, your just current cash and how far that gets you. Yeah. Right now we have $1.3 billion of cash pro forma as of the end of the last quarter. We had a very successful raise, which you guys were instrumental in helping us get that done, so thank you very much. You know, we believe that we have a unique opportunity to capitalize a company to do one build for multiple launches, and we are going to pursue that with the most capital-efficient means possible. Great. Looks like we're just about out of time, so why don't we end it there. John and Eric, thanks so much. Really appreciate your time today. Thank you. Thank you!