Good morning, everyone. Thanks so much for joining us. I'm Andrea Newkirk, one of the biotech analysts here at Goldman Sachs, and I'm really pleased to be joined by Jeremy Bender, CEO and COO and CFO of Day One. Thank you, you guys both, for joining us.
Andrea, thanks for having us. It's great to be here.
Great. You know, as we sit here today, OJEMDA has been on the market now for over a year. What have been the biggest learnings that you've taken from this first year of launch?
It's been a great first year since the approval in late April last year and the launch shortly thereafter. A few dynamics that have been really important for us. The first is we got a very fast start with the launch due to the expanded access program that we had in place at the time of approval. That created a base layer for us of patients on treatment that really helped to sort of establish a good commercial base to start with. Beyond that, we've had really consistent new patient starts. The new patients coming in have, for the most part, been patients in later lines of therapy, and that's probably the most important learning from the first year, is that while we're seeing some use in the second and the third line, for the most part, physicians are still getting comfortable with a new agent.
For this particular patient population, that's quite important. Much of the sort of pace of the launch is very much what we expected, which is get physicians to have experience with it, get them to try the product, get them to use it. That is going to be the key to getting adoption and then driving towards establishing OJEMDA as a standard in the second line. That second line and third line sort of effort is really pretty critical and I think is going to be the focus for us going forward throughout 2025. Overall, though, what I would say is we're ahead of where we expected to be, given those dynamics, and we continue to see steady and incremental gains.
One of the things I find to be super interesting about OJEMDA is this patient population, pLGG, the relapse setting. Maybe just taking a step back, because I think this is key for people as they think about the cadence of launch and where it can go from here, is understanding the nature of the disease, how patients are treated, how they're identified, how often they, maybe how often they progress. If you can talk through some of those dynamics.
Yeah, certainly, certainly. The relapsed pLGG patient population here in the U.S., we estimate at 26,000, and that's BRAF-altered pLGG patients who've had a prior systemic therapy and may be eligible for another therapy. That's a fairly large prevalent pool. We think at any given point in time, there are about 2,000-3,000 patients on treatment, and that's a dynamic pool. There are patients who are watch-and-wait patients from that prevalent pool who enter into that treated population when they progress, when they need a different therapy, and that patient will, those patients will cycle in and out. The question is, how often does that occur and at what points?
Typically, what will happen is a patient will be on treatment and achieve stability for some period of time, long enough that a physician may decide to take that patient off treatment and turn them into a watch-and-wait patient. Those patients are actively monitored for many years. The typical monitoring is every three months for patients that are really actively monitored. Those patients will come in for clinical evaluations and for MRIs to scan the tumor and see what the status is. That frequency is a little bit less frequent, of course, than you may be used to in other cancer settings. Once there is a signal from that MRI, it is also important to note that that is not necessarily going to trigger treatment.
It really is a holistic decision about the clinical status of the patient, in addition to that MRI information that will be critical to determining whether that patient actually gets a new therapy or not. That frequency is a little bit slower than what you see in terms of new patient acquisition or the potential for new patient acquisition than you see in acute tumors in the relapse setting, for example, when there are solid tumors or liquid tumors in adults. As a result, the timing of the acquisition opportunity for new patients for OJEMDA is just a little less frequent than what you see in other settings. That is one of the reasons why this launch we anticipate will be more like a rare disease launch, where you see stacking behavior over time, but not a very rapid adoption rate.
Importantly, not a very rapid time to peak penetration. We think it will take real time and many quarters to get there.
Got it. More a slow, steady, linear launch versus something that has an effect.
Yes, very much what we're anticipating and have been anticipating. Some of that also comes from the fact that for these particular patients, there are some options that physicians feel they have that are all off-label or clinical trials from the past, but really getting them enough experience and comfort with OJEMDA is going to be required before it really becomes a clear standard of care.
Maybe speak a little bit more to that point. What can Day One do to encourage that prescribing behavior, to help them move away from the off-label use that they've been using for years to now an approved therapy such as OJEMDA?
You know, it's really all the things that we've been doing since our launch. It's really a focus on, of course, all of the activity of the field, our direct sales force, but it's also medical efforts and making sure that we're on call for any questions that physicians or their office staff have. It's further publication on OJEMDA from the pivotal trial that's FIREFLY-1. We had two posters at ASCO last week that are really important for continued educational efforts, and those covered both changes in growth velocity on OJEMDA treatment in FIREFLY-1, as well as looking at AEs, in particular skin toxicities associated with OJEMDA use. Those were very well attended and important publications for us, both at the conference itself and, of course, through medical efforts with our customer base.
On those two posters specifically, just how meaningful is that for physicians to be able to look at this breadth of data that you've generated here? How important is that as they think about using OJEMDA and understanding the longer-term profile?
I think it's very important. This is a group of physicians that is cautious with respect to new treatments for this particular patient population. That's because it's a group that is accustomed to certain treatment patterns over time. Some of those physicians prefer chemo. Some of them will use off-label MEK inhibitors. Some of them will use other off-label targeted agents. They've been using those or trained on those products for long periods of time. Introducing a new product into the mix is both a great opportunity, but it's also one that introduces risk in their own minds among a patient population that has significant unmet need, but need that is not about near-term survival. That really differentiates this patient population from those that you see, other pediatric patients that have brain tumors.
It's a kind of delicate mix, but so far what we're seeing is real receptivity to the data. There's always going to be, and this is true not just for this product, but for virtually all products in the cancer space, a desire for longer-term data, and we'll continue to generate that data. We've extended FIREFLY-1 to continue doing so, and we think the more data we generate over time, the better. I also would emphasize that the FIREFLY-2 Trial, which is looking at OJEMDA in the frontline setting, will also be an important addition to the data set for the same group of physicians as they think about how to use OJEMDA best.
I guess maybe on the observance of growth retardation, which is one of the posters you just mentioned, how concerning is that for patients? I mean, this is a pediatric population. Maybe talk through some of the findings there.
The first thing I would emphasize is that these patients, pLGG patients, already, although there are not great studies, have a tendency to have shorter stature than average kids that do not have brain tumors. That is driven by some combination of the tumor itself and treatments that are used for that tumor independent of OJEMDA. It is an effect that is frequently observed for these children, but not tracked particularly well. Physicians are fairly accustomed to it. They are not particularly alarmed by it. I do think it was really important to establish as early as we could the reversibility of the effect, as well as the lack of any increase in bone age and the lack of any fusing of growth plates.
The reason is that there was an experience in a prior clinical trial setting with Wnt inhibitors for which there was very serious long-term growth retardation effects because of the closure of growth plates. None of that is true for OJEMDA. When we talk to physicians and they understand both the hypothesized mechanism, which is CRAF-driven for essentially the arrest of chondrocyte maturation and then the release of that arrest on cessation of treatment, that is very reassuring along with all the other data points that I mentioned. It does not seem to be a big barrier. I do think that the data we have recently published is meaningful because it shows not just all those elements I just described, but also after cessation of treatment, it shows really significant rebound growth for a large fraction of patients.
Great. You have talked now on a couple of these earnings calls about your focus on driving depth of prescribing.
Yeah.
Maybe provide an update here on those efforts and where do things stand?
What we're doing is very much focusing on the accounts where we see significant patient flow and really looking to establish that clear standard of care. It's exciting when we get a new physician that hasn't had any experience with OJEMDA to prescribe it. That's valuable for us as far as sort of the trial and the use. In terms of adoption and the numbers of patients that are out there, it's really getting repeat use that's going to be most important. I wouldn't say operationally it changes much for us as far as what we're doing day in, day out. The reality is that this is a relentless effort for us on the commercial side, and it will continue to be as we drive towards that standard of care. The significant opportunity that exists really is in that depth.
We have quantified that a bit in our corporate materials. What you really see is that there is a significant opportunity to continue driving adoption, and it is really through getting physicians who have already had some experience with OJEMDA to use it in a greater proportion of their patients. Going forward, we anticipate that is really fundamentally about moving up in terms of line of therapy and that a lot of the patients that we have been getting to date have been later lines, so third, fourth, fifth line patients. We are starting to see that shift, but I think it is really getting a depth of experience that will create that shift and give us that depth.
I guess maybe what is the key driver to getting a physician to go from their first patient treated to being that repeat prescriber? Is it a mind shift for them in terms of using OJEMDA, understanding its benefit? Is it truly just waiting to see additional patients come into the practice who are progressing?
Yeah. I think it's all of those things. It really depends on the physician, but I would emphasize at the outset that the sort of hesitancy that you see among some physicians, and it's not extraordinary. It depends on the physician, varies enormously depending on what that physician's points of view are. The big categories are really having productive experiences both from an efficacy and a safety standpoint. One, on the efficacy side, there's no question that when you talk with experienced physicians with OJEMDA, they really see this as a major move forward from an efficacy point of view, much greater depth of response than they can achieve with other options. That's really critical. It's a little nuanced when you look at the data because there aren't many data sets out there, but that's an important message. Having that experience firsthand is critical.
I think just as importantly, especially for physicians who haven't had an experience yet, having a successful experience with it for their patients from a safety standpoint is important as well. Getting through some of the early skin toxicities, which can be, they're relatively frequent for this and other MEK inhibitors for that matter, but going through that, they tend to get mild over time. They're worse in the first few doses than they often can be later. Managing through that, through some of the preventative measures, those kinds of actions are pretty important, I think, to their adoption. I think it's time as well. It's really seeing that effect over time and really understanding what the impact on the tumor is over time.
What brings, I guess, the patient profile earlier into the line, the second line?
Oh, I really think it's physician competence given all those experiences. Very straightforward. And continued data sets that we'll have. Yeah.
Okay. You've referenced now kind of the steady patient growth that you've seen over time. I think in the past couple of quarters, you've characterized as double-digit growth quarter-over-quarter, somewhat of a slowdown potentially in Q1. Maybe just talk to us about the Q1 dynamics there. And the rebound that you saw in April, is that now a new level from which we should expect linear growth from here?
Yeah. We did have a slower Q1, and that was largely driven by the holidays, actually, in December. The reasons are more intuitive when you look back. This was not necessarily driven by payer resets for those who are on commercial insurance. It was driven more by just the dynamics of when patients are evaluated and how they become eligible for prescription. In December, the holidays, there are just many fewer opportunities for office visits by virtue of holidays and offices being closed. Beyond that, there's also real reluctance among families and patients to go in for scans in that holiday period, largely because it's such an anxiety-provoking point for them that they'd rather defer that. That's what we believe happened over December as our first year of launch. We really didn't anticipate that dynamic.
In January, that means a lot of the deferred appointments occurred. Basically what that does is defer by a few weeks the potential for a new patient start. That is essentially what we observed. Going forward, we are seeing continued strong new patient starts and patient acquisitions. We are anticipating double-digit growth going forward, and that is in revenues and in.
Got it. Maybe talk to us a little bit about the dynamic of the extended duration of treatment that these patients are experiencing on OJEMDA. How should we think about the durability, both based off of your clinical trial experience, but what you're seeing works right now?
The clinical trial experience is still the only true median for duration of treatment that we have. In FIREFLY-1, what we saw was 24 months, or just under 24 months of median duration of treatment. What we're seeing for on-label patient duration of treatment in the commercial setting is consistent with what we would expect based on that clinical trial. It's too early to know what that median will be. What we're seeing, though, again, for pLGG patients, it is consistent with it. We're observing a little bit more dropout early due to safety considerations. We've had enough time to see a little bit more of that than we've observed in the trial. Overall, our duration of treatment is looking like it will be fairly lengthy. It's too early to say a number at this stage.
We're just not that far into launch yet, but it's consistent with fairly long durations of treatment, certainly by oncology standards. It's probably also important to note that one of the surprising aspects of our experience to date as far as the launch has been the extent of off-label use we're getting. Approximately 10% of our paid scripts are for off-label use. Those uses, by the way, are typically solid tumors in the adult setting. They can be high-grade tumors, high-grade brain tumors, that is, melanomas, lung cancer, pancreatic cancer, cancers where there's a RAF alteration. Typically, that's a RAF fusion, not always. Among those patients, you're seeing much more rapid progression and therefore shorter durations of treatment on the order of somewhere between three and five months is typical. That's not the case for the pLGG or the on-label patient population.
Just a quick follow-up there. The instances of AEs that are driving the higher dropouts in the commercial setting than what you saw in the clinical trials, can you talk about that?
Yeah. You know, we don't have perfect information about the dropouts, and we also don't know with certainty that the dropouts are permanent. There may be some dose omission and patients coming back onto treatment. It's a little early to say with anything definitive. I would say we're getting a little bit more early dropout than we saw in the clinical trial. That we expect is probably typically due to those skin effects. The work that we did to publish on the experience with that as an AE at ASCO, I think will be important. We have been throughout the launch period, of course, educating on this topic.
It really is a matter of continuing that educational effort and making sure that especially physicians who do not have experience with OJEMDA understand what the preventative measures are and are working with families to make sure that that information is available and so they understand the dose omission and dose skipping guidelines as well.
The preventative measures are pretty standard, right?
They're really not standard per se. They vary a lot by center. Many centers have been using, in particular, various MEK inhibitors over time and have developed their own kind of protocols for addressing skin because this is a very common AE among all MEK inhibitors effectively. In our case, the most frequently used and effective preventative measure is to use bleach pads. That's really what we recommend for patients who are going to be going on treatment.
Got it. And then quickly on the off-label use that you're seeing, the 10%, how do you expect that to trend over time? Is that a proportion that continues to grow or actually?
It hasn't really grown. It's been pretty consistent since the launch. We don't expect it to grow. Obviously, we're not promoting against it. We haven't seen a big significant sort of change over time in that proportion of sales. It's been relatively stable. We would expect it to actually shrink as a proportion of the total as we grow the pLGG market.
Yeah. Makes sense. Just a follow-up there on the duration. A little under two years that you've seen in the clinical trial. What is your research or your conversations with physicians suggesting to you as to their desire, their intent for keeping their patients on OJEMDA? What are your best guesses as to potential rebound growth or rebound tumor growth that can happen if patients were to come off?
A lot of important topics in there. The first is when we speak with physicians about their intent, the most frequent comment we get is that there's an intent to treat at 24 months. That is pretty standard, actually, for targeted agents in this patient population. It is not a surprise that that is the intent. I want to just remind everyone that even though that's the intent, that does not mean that everybody gets 24 months. You're going to have, even in our study, what you saw is a median of just under 24 months, but that meant that 1/2 of patients had less than 24 months, 1/2 had 24 months or more. That is clearly the intent. I do not see that changing significantly until we publish data that would indicate that there's another reason or another rationale for a different approach.
It's a default, and it's not based on existing data. Now, with respect to potential for rebound growth, we published data last year, actually, from a two-year follow-up on FIREFLY-1 that showed among patients who had taken a drug holiday, there were very few. I think there was one patient that had progressed after taking a drug holiday at 24 months. We are optimistic that we aren't going to see the rebound growth that is typically described for MEK inhibitors, but it's a little too early to say whether it's certain or not. It'll require additional follow-up. The median duration of follow-up after that drug holiday was about three months, which is around the period that you see what the field is calling rebound growth.
I think one of the important questions that physicians continue to have about OJEMDA, especially relative to the MEK inhibitors, is whether we're going to see, maybe driven by the biology, maybe driven by the deeper responses that are observed with OJEMDA, a decrease in any either rebound growth, which is the growth that happens immediately after a cessation of MEK inhibitors often, or whether we're going to see decreased progression over time in periods of time outside of that three-month window. What we've seen is encouraging, but it's going to require additional follow-up.
If a patient were to progress following a successful stint on OJEMDA, what are their options? Could they come back on OJEMDA for a second round of treatment, or do they need to potentially use a different agent?
We believe that there's going to be an opportunity for a significant fraction of those patients who have benefited from OJEMDA to come back on treatment if they progress off treatment. That's a belief today. We don't have data to describe that specifically, although there is a patient from that same drug holiday publication that I described that progressed after cessation of treatment, after the drug holiday, and then was retreated with OJEMDA and was observing stable disease at the time of that publication. I think there's reason to be optimistic. Part of that is mechanistic as well, because these tumors are genetically stable. They don't typically develop mutations that lead to acquired resistance. There's a likely scenario where you're going to see a fair amount of retreatment.
For that reason, we're anticipating over the long run that we may very well see some on-again-off-again treatment pattern for OJEMDA, which again differentiates it very strongly from what you see in other oncology settings where a given agent is typically, and there's some minor exceptions, really only used, especially in the relapse setting, during a defined window until a patient progresses.
Got it. Maybe talk to us a little bit about what's happening with the European filing here and then also with your frontline study.
Sure. The European filing is now in the EMA's hands. No guidance yet specifically as to the timeline for potential approval, but really good news that the EMA has actually filed that NDA. We're excited. We're also anticipating additional filings outside of just that central EMA filing that includes Japan and other countries in Europe. Ipsen, our partner, has been really moving quite rapidly to make this a new medicine in geographies outside of the U.S. as well, which is very exciting. With respect to FIREFLY-2, that study is enrolling nicely. We've been expanding the number of sites and countries at which we're making that trial available. We're on track for our completion of enrollment in the first half of next year. The data from that trial per protocol will be available 12 months after that last patient is in.
I'll remind you that the primary endpoint for that trial is a response rate by, in this case, RAPNO criteria, which is the same set of criteria that were really critical for approval in the relapsed setting.
Got it. When you think about the European launch, what can you draw from the U.S. launch? Are there parallels there, learnings that you can take from the experience here that will improve the experience over in Europe?
I think so. Anytime you have a group of physicians who are treating a similar group of patients and they're very similar in Europe, of course, there's no real differences. You learn things about what your experience is in one geography that are leverageable elsewhere. We're working with Ipsen to provide those insights. I think fundamentally it's really going to be about data, comfort with the product, and experience in the same way that it is here, albeit a greater data set available at the time of launch than we have had. That'll be, I think, important for their efforts.
Is the treatment paradigm or available therapies over in Europe similar to the U.S.? Are we still going to have that same maybe comfort with off-label use over there?
No. It's different. The reason is that just off-label treatment for targeted therapies in particular is much more challenging in Europe. It's much harder to get reimbursement for and even, in many countries, prescribe something that isn't approved. Our expectation is that the MEK inhibitors and bevacizumab and some of the other options that are used here and that we are competing with as habit for physicians will not be available as often for European physicians in particular. I think it will be a different commercial process, maybe a little bit more straightforward. That being said, I don't actually think it's the therapies per se as much as it is the comfort level and the habits that physicians have established that really creates this fairly steady and relatively cautious orientation. I think that's also likely to be the case in Europe.
How much exposure have the European physicians had to OJEMDA?
Oh, pretty significant. The FIREFLY-1 trial was run at a number of European sites. One of the important partners for us in the FIREFLY-2 trial is a consortium called LOGGIC. There are a number of the biggest academic centers for pLGG in Europe that are participating in that trial and have been really key partners in designing and implementing it. There is a fair amount of experience there. That being said, it is not going to be the same as a commercial experience. There will be a lot of new physicians to OJEMDA as well.
Of course. Maybe just going back to the frontline opportunity, we talked about numbers and you kind of laid out the addressable population or the number of patients that are on treatment in a given year. How does that expand in the frontline?
In the frontline in the U.S., it's 1,100 patients a year that we estimate that are BRAF-altered and require systemic therapy. So very straightforward, a much more straightforward incident model in the frontline setting.
Okay. Helpful. 301, and Charles, I'll bring you into the conversation as you think about in the last four minutes. As you think about Day One's strategy with BD, maybe talk to us about what interested you in the 301 asset and how you're thinking about potential in licensing opportunities from here.
Yeah, of course. 301 for us was an important asset, of course. We're really pleased to have a high-quality commercial asset with OJEMDA, with bevacizumab, both here in the U.S., progressing with the frontline trial as well. It's a really important part of the pipeline. For continued growth, we really wanted to make sure that our team had another high-quality asset for clinical development. In this case, the DAY301 was really a model of how we look at BD. Generally, in an area, we think we're competitive. The asset itself had clinical validation from a previous program, a Pfizer AbbVie program, Cofatuzumab on the target itself. We liked that. We thought there were some liabilities associated with their asset that were related to therapeutic index and a previous generation linker payload.
When we saw this new ADC with a more modern linker payload, we thought the hypothesis there was intriguing, allows us to work in a number of adult and pediatric oncology indications. Really, really quite interesting to us. It is in the clinic now, as we know. We dosed the first patient and announced that early in this year, continuing on the dose escalation. That model and that sort of asset is similar to what we look at quite frequently. As you know, we're very active in BD, have a lot of deal flow going through, but also trying to maintain a high bar. When we're evaluating, we're looking at things very similar to this. Targeted oncology is a real focus for us. We make sure that from our standpoint, there's an opportunity for a first or best-in-class asset.
The adult and pediatric indications also need to marry to make sure that the development of the strategy for the company also works as well.
Jeremy, maybe on that point, the founding of this company was based on the idea of being able to have access into these pediatric populations that otherwise might be underserved. Do you see that shifting at all? I mean, I guess with 301, you're initially starting an adult population. Do you ultimately see any asset that you bring in to be something that can fit within the pediatric population, or are you open to it being broader?
It's an important question and one we, of course, debate. There are very few programs that have no opportunity for development in the pediatric setting. That's important. It's a fairly rare opportunity that we could pursue. For now, we're really focused on those programs that have opportunities in both adult and pediatrics. I would really focus, though, on differentiating the adult versus the pediatric development plans here. The adult work, for example, in 301 that's ongoing is going to be critical, and we'll move to pediatric work as quickly as we can. We actually need to establish a dose before we can do that from a regulatory standpoint. We'll pursue those adult and pediatric paths with equal intensity, at least with the operational elements of what we pursue.
Now, from a value standpoint, just given the patient populations and the potential registration paths and the complexities, I do think that as we go forward, you will see more emphasis on the adult side and the pediatric side. We will never lose sight of the sort of original founding of the company and the real intent and mission to make more new therapies, new medicines available for children who are living with cancer. That is all critical. I want to add one element of news from this morning that is important. We have just hired a new head of R&D, Mike Vasconcelles, who will join us next Monday. It will be his first day. Really excited about what Mike brings to the table. He was previously at ImmunoGen where he was head of R&D before the AbbVie acquisition and prior to that at Takeda, oncologist by training.
I think will be a really critical voice, of course, for us as we're looking at those programs going forward.
Great. With that, thank you both for joining us. Thanks, everyone.
Thanks, Andrea.