Great. Well, thanks everybody for joining us here on first day of Piper Sandler’s Annual Healthcare Conference. I’m Joe Kinder. I’m one of the biotech analysts. It’s my pleasure to welcome the full team from Day One Biopharma. Joining us is our CEO, Jeremy Bender, the Chief Commercial Officer, Lauren Merendino, Head of R&D, Sam Blackman, and CFO/COO, Charles York. So thanks for the full team. Obviously, a lot to talk through, especially in light of the launch of Ojemda. But maybe first, Jeremy, I could give you a minute or two, and you could sort of just introduce the company, give a quick sort of overview of what you guys have been up to and what you have to look forward to.
Certainly. Joe, thank you for both the introduction and the opportunity to talk, and thanks to all of you for participating in the session here. So Day One is an oncology company. We focus on the development and commercialization of therapeutics for both children and adults who are living with cancer. And it's really our focus to pursue those populations with equal intensity for all of our programs. The two programs that we have in development include Ojemda, now approved for relapsed refractory pediatric low-grade glioma. Low-grade glioma is the most frequent brain tumor in children. And that is a program that's also in development in the frontline pLGG setting. And then the second program we have is DAY301, which is an antibody-drug conjugate that will go into patients in December, early Q1, of this year. That's a program that targets PTK7.
With that, I'll hand it to you, Joe, to talk about questions.
Yeah, sure. So maybe we could start with the Ojemda launch, which has obviously gotten off to a good start. Maybe just a quick high-level question in terms of, you know, at this point in launch, what has sort of resonated most with physicians and families around Ojemda and its profile and what it brings to the table relative to the other options that have historically been there.
Yeah. So, Ojemda is the first approved, new medicine for relapsed, pLGG, for patients that have RAF alterations, of two kinds. One, BRAF fusions, which is the bulk of these patients, and two, V600E patients. And it's, you know, not only the first approved agent but has an efficacy and a safety profile that is very appealing, as well as an administration profile that's once weekly and oral without a food effect that really allows altogether, for you know, children who are living with a brain tumor, to fundamentally live lives as children. And it's really that package that I think is most important when we talk to physicians and even to families and patients, as well. So attractive profile and significant unmet need.
Though there are treatment options available off-label for these patients, those are, you know, items that have been used either chemotherapy or, in some cases, targeted agents, for some time, but with a lot less data and a lot less study than what we have for Ojemda.
I think a lot of things that everybody's trying to wrap their arms around is this market.
Yeah.
Pediatric low-grade glioma. It's, I think it's, there's a lot more nuance to it than maybe what people are used to in advanced oncology settings, and specifically the sort of flow of patients coming in and new patient starts.
Yeah.
So what have you learned in this first couple quarters in terms of the dynamics of that patient flow and new patient starts and how they sort of work through that process of being seen and getting put on drug?
Yeah. We estimate that there are, in the U.S., 2,000-3,000 relapsed pLGG patients on treatment at any given point in time, and the questions that we've been really debating both internally and, of course, discussing with investors is, with those 2,000-3,000 patients, how often do they come on therapy and go off therapy? This is unlike many cancers, one where there is a large prevalent pool of watch-and-wait patients because most of these patients do survive into adulthood, and the question is how they cycle through that. Our early experience has led us to believe that a significant portion of that 2,000-3,000 patients, you know, are coming up for treatment decisions relatively regularly.
We don't have a numerical estimate yet, but it's very clear that there's significant demand for a new treatment in this category based on the very consistent new patient starts that we've seen since launch. That pattern of new patient adds has been, you know, really persistent and consistent throughout the period from essentially the time that we commercially launched the product, which was May, all the way through the third quarter, which is the latest reporting quarter we've had. And it's our expectation that those new patient adds will continue. Over time, as more physicians adopt and try and become comfortable with the use of Ojemda, we do anticipate that, you know, that new patient start number will continue to grow over time.
But so far, it's been really consistent with what we'd expected, and I think confirmatory in our minds that that estimate of 2,000-3,000 patients on treatment is quite, you know, quite accurate.
So maybe if I could probe a little bit more on sort of where the confidence stems from in terms of the cadence of new patient starts that you've seen continues forward. I mean, I could say anecdotally, as I've spoken with physicians, remember before the drug was even launched, I would ask, you know, when do you expect the first patient to be put on? And it's sort of like, oh, well, whenever a patient comes in and we scan them and they need something, we'll consider it. Is that as, and if you extrapolate that to everybody, then I guess the cadence you've seen should sustain. But where do you get your confidence in that sort of dynamic?
It's from precisely that discussion, which is similar to what we see when we talk with physicians. You know, the frequency of monitoring of patients, the frequency that they come into offices and are scanned does influence whether or not that patient could go on therapy or require therapy. We see Ojemda prescribed in pLGG at times when, you know, a patient fails a prior therapy and progresses, or in a circumstance, when they're not on therapy but in watch-and-wait, they come in, they get a scan, their tumor's growing again, their physician thinks they need another therapy, that's another category, and then finally, in circumstances where patients may be on an existing therapy that's intolerable.
and the number of physicians and patients that we've talked to who have that exact experience is really encouraging and I think leading to that persistence.
I know it's probably maybe a little bit early, but I guess, do you have any sense of your penetration into that? So, you know, the population of prevalent patients who have required a new systemic therapy, you know, since April, you know, what % of those you're capturing, and what can you do to try and capture more of those patients who present and need a new systemic therapy?
So I'll ask Lauren to talk about what, you know, what we're doing to increase that rate of penetration, which, of course, is all of the effort that's going into our commercial work. We don't know the denominator with certainty yet around what fraction of patients would be eligible for a new therapy in a week or a month or a quarter. Yes, we have this estimate of 2,000-3,000 , but we don't yet know what fraction of those we're getting. We think it's an appreciable number, and we're working on ways to kind of estimate that. But I think there is still some uncertainty there.
I think the confidence that you're asking about in terms of the magnitude of that opportunity comes more from the consistent patient flow and the observation that all of the, you know, epidemiology work and all the estimates that we've run, claims analyses align around that 2,000-3,000 patient estimate. But Lauren, maybe comment on our commercial efforts as well.
Yeah, absolutely. And also tying back to your other question on confidence, you know, when we do market research with this physician population, 100% of them are telling us they're aware of Ojemda, and 90% are saying that they have an intent to use Ojemda. So now my team's job is to make sure that they pull that through and actually use the product. And so our focus really is breadth and depth. And so we've established a good pool of prescribers to date, but there's still much more potential to get new prescribers to try Ojemda, and then to get them to build their confidence in the product, to use it in multiple patients, and to use it earlier. So what we see is for those physicians trying Ojemda for the first time, they may use it in a later-line patient to get that experience.
But as they build confidence, we want to move that up to the second line, to the first relapse, right? And so we still see a tremendous amount of potential here in this market, and we continue to bring on new prescribers and continue to drive new patient starts.
So, I maybe want to switch gears a little bit and now speak to sort of duration of treatment. You know, I've done a reasonable amount of work, and one thing I've been surprised by is the duration of treatment expectations for physicians being shorter than I expected, and I wonder if it's just conservative conservatism around this prescriber base with the new drug? so I'm wondering where you think it will shake out in the real world relative to what we saw in FIREFLY-1 , which was on the order of about two years.
Yeah.
Of treatment?
So, you know, I'm not sure exactly what you're hearing when you talk with physicians. I do think when you say, and certainly I did this when I was at SNO in Houston a couple weeks ago in terms of meeting with physicians and really understanding how they think about treatment duration. You do hear a range of approaches. I think I most consistently do hear intent to treat of around two years. That's not just for Ojemda but for targeted therapies generally for pLGG. That does seem to be the intent. I think the best guide we have in terms of what we may see in the real world is the FIREFLY-1 trial, which had just under two years in terms of median duration of treatment.
It is too early to say whether we'll match that in the commercial setting. We're, you know, five months into launch fundamentally in terms of data that's available, and so far, what we're seeing is really significant persistence in you know on therapy, but we'll have to see in the coming quarters whether or not we trend towards that two years or something else.
Are there any reasons to think why the real-world experience wouldn't mirror the clinical experience? And then in terms of patients who have started but come off, I know the numbers are still very, very small. What you're seeing there, is it simply lack of clinical benefit or there's sort of tolerability challenges that maybe some are facing?
It's an important question. And, and what I would say is that our persistence rate or the discontinuation rate has been so low from the second quarter to the third quarter, and we had less than 10% discontinuation rate in that period that it's too early to provide you with any detail about why those discontinuation rates occur. In principle, they can occur for three reasons, two of which you just mentioned. One is lack of clinical benefit. And it is important to remember that while we have 80%, you know, clinical benefit rate, meaning stable disease or better, that means 20% of patients don't see stable disease, and so they're progressing. And, and you would not expect that those patients would stay on therapy past that point of progression. The second reason, as you mentioned, is tolerability. We don't anticipate a lot of discontinuations due to tolerability.
It's certainly possible. That's based largely on the clinical trial experience. And then the final reason for discontinuation would be an elective drug holiday, which could be sort of related to tolerability but might actually be because the physician feels the tumor has reached a stage where it's not posing an immediate functional consequence if it begins to progress again. And so they become comfortable recommending a holiday.
Have you ever disclosed? I know in FIREFLY-1, I feel like I've asked about this every so often, you know, the optional holiday that patients had. So for the patients who reached 24 months were still deriving clinical benefit, still tolerating well, who chose to take that.
Yes.
Optional holiday?
Yeah. In fact, we just had a presentation, a poster at SNO on that very topic. Sam, do you want to?
Yeah. The majority of patients who got to 24 months, you know, had physicians or the patients elected to take a drug holiday. The data that we presented at SNO actually had follow-up on these patients, in terms of, time to next treatment or evidence of tumor progression. And, you know, the data is maturing, but I think, you know, what we're seeing and, we're hearing from investigators is really reassuring is that, you know, two years of treatment is associated with a considerable duration of off-treatment tumor stabilization or persistence of response even off drug.
Yeah. That, I mean, that's pretty notable because I feel like I've heard over and over from physicians with other RAF/MEK inhibitors this idea of tumor rebound and, that being a major concern.
So maybe you could elaborate a little bit more on that idea and, and maybe how impactful that data point.
Yeah. You know, this phenomenon of tumor rebound, which really I think applies to V600 patients more than fusion patients, is this phenomenon of rapid regrowth as soon as you stop administering the drug. It's something that we recognized when we were developing Type I RAF inhibitors for melanoma. An adult oncologist would recognize the fact that as soon as you would take the patients off drug, the tumors would just explode. Now, that doesn't fortunately happen with the same degree of drama in pediatric low-grade glioma patients, but there's been a consensus paper published recently that defines rebound growth as acceleration of growth greater than 25%, within three months after discontinuation of treatment.
When we look at, and this was data from the SNO presentation, when we look at the patients who've been on drug holiday, we only saw one patient who actually met the definition for rebound growth out of 50-some patients who came off of drug either for drug holiday or came off of drug for non-drug holiday reasons. And that patient who was actually a V600 patient was able to be retreated and completely recaptured their response with resumption of treatment with tovorafenib. So at the end of the day, I think what we're seeing is very low rates of rebound growth off drug and some emerging evidence that confirms what we had speculated all along, that you can recapture responses for patients who progress.
We think that opens up the door to episodic treatment where it could be some period of treatment, again, could be two years or, you know, as the community determines how to use this drug, observing patients off drug, allowing them a drug holiday. Then if they do have resumption of growth, then there's an opportunity to retreat them.
So Lauren, you mentioned this idea of maybe use shifting earlier line, so from a later line to maybe a bona fide second line. As that has potentially happens, does that materially impact the trajectory of the launch of physicians working with a bigger pool of second-line patients than they are for, say, third or fourth-line patients?
Yeah. So, you know, our strategy is to move into second line over time. There's really two factors there. One is, yes, there is a larger percentage of patients who will be in the second line. Some of them may not need subsequent lines because, as you know, at a certain point, this tumor senesces, it stops growing. So if you have a teenage patient who's on their second line, they may not need a third line and for other reasons, other patients may not need subsequent lines. So moving to second line is a larger pool of patients. And if patients do need subsequent lines of therapy, oftentimes, as I think we mentioned earlier, after they take a drug holiday, if they progress, they may need another, you know, treatment. And oftentimes it's the same treatment.
And so if you're used in the second line, then the percentage of patients that do make it to third line, some of them will receive Ojemda again. And so there's two benefits really of moving earlier in the treatment paradigm.
Great.
Plus, we believe our data justifies it, right? Like, we have a great product. It's been studied more extensively than the other off-label options, and so we think that is a strong case for us to be the standard of care in second line.
Maybe, sort of a high-level question on the competitive landscape. I wonder if you have any views on the outlook of how the competitive landscape in pediatric low-grade glioma maybe evolves over the next couple of years, or is it sort of a relatively,
You know, we're the only approved therapy for the patient population in pLGG that has RAF alterations, and we don't see that changing in the near term or in the next few years. There just aren't other agents that are in development in company-sponsored studies that are looking towards that registration path. Yeah. I might even build on that just a little bit more. The Type II RAF inhibitor programs, you know, there was certainly, you know, Kinnate, Novartis had their Type II RAF inhibitor. Roche had one.
Yeah.
You know, BeiGene and SpringWorks had them in development. At the end of the day, many of these have either fallen by the wayside or really decelerated in their progress through the clinic, and none of them are moving forward in pediatric low-grade glioma. To the extent that we have any visibility to it, certainly nothing listed, and I've yet to see a company-sponsored registrational trial listed on clinicaltrials.gov. So that I think is sort of prima facie evidence for lack of anything moving forward in the next few years.
Yeah. I want to quickly touch on FIREFLY-2 and just maybe ask anything you could say there in terms of enrollment pace, what you're seeing, and, and maybe I know your partner Ipsen has, kind of guided to when they expect, an initial readout.
Yeah.
FIREFLY-2, but wondering if there's anything you guys can say there.
Yeah, so we'll be providing an update with more detailed guidance on when the trial enrollment will be complete and when data will be available in the frontline setting in 2025. The trial itself has picked up enrollment pretty significantly throughout 2024, in particular in Europe. There was a new process for protocol approvals across Europe broadly that did delay some of the start of enrollment in some sites, and with that kind of behind us in 2024, it's picked up substantially, but the fundamental guidance that we'll provide around that timeline will be in 2025.
Maybe, maybe going back to commercial experience, on the sort of data point I picked up that I don't know how much I believe is, is first line, off-line, off-label first line usage. I'm not sure if you guys have any sense of that. I know you can't promote to it. But if you are seeing that, why and what does that speak to how physicians are viewing Ojemda?
First off, it's important to note that, you know, we don't have a sufficiently granular level of detail to really differentiate true first line use from, you know, relapsed use in most cases, so we only get sort of electronically added data to our records from our patient hub when that's available. We do know anecdotally that there has been some frontline use here in the U.S., but we don't think it's been appreciable. We do see off-label use, you know, both in other brain tumors and in some adults, but the bulk of our commercial use we think is at this stage relapsed pLGG.
You know, it's our view that additional experience with Ojemda in the relapse setting, data in that frontline setting, and of course an approval in that frontline setting will eventually drive a really substantial uptick in use in that frontline setting.
So I know I mentioned Ipsen. I want to maybe go back to them and maybe you could speak to the decision to partner with them, around Ojemda, ex-U.S. geographies, sort of the EMA's view of the FIREFLY-1 data set maybe prior to outlicensing. And then I do want to cover DAY301.
Okay.
Yeah.
Charles, why don't you talk about the Ipsen deal and then we'll come.
Yeah. Look, the Ipsen deal was really fundamentally for us about positive relationship to a partner that we thought could do the best to really take care of an asset, provide access to patients, and be a true partner for us over the long term. We structured the deal financially with them as well that is aligned very much with that we participate in the longer-term upside, and you know, it was a very competitive process the whole time, but they were the clear partner for us that we thought made the most sense based on expertise both in the regulatory and commercial side. When we think about, you know, the handover to them for all the ex-U.S. geographies, including the regulatory process, there was a pediatric investigational program that we put in place originally.
They're really working though on getting some of the feedback from European geographies. They've guided, I believe, that 2025 they do a filing. That's primarily the information that we know the best as of now.
Okay. Great. I'm sorry, Jeremy. Did you?
I just got, you know, we do anticipate approval on the basis of FIREFLY-1 and a filing timeline consistent as Charles just mentioned. So yeah.
Yeah. Great. So maybe in these last couple of minutes we could cover DAY301. Maybe first, how did that asset surface? What made it interesting to you guys? What makes PTK7 a particularly interesting asset? And then have a couple of follow-ups.
That's a lot to cover in two minutes. Let me try. Clinical validation to the target through the Pfizer program, albeit with a suboptimal, we think, payload, leading to a potential best in and first in class program, which is an exatecan-containing ADC that we anticipate will dose first patients this month, or early in Q1. And because it's an ADC and because there's that clinical validation, we'd anticipate potential monotherapy activity in a broad array of adult and pediatric tumors. And that's why we like that program. That's why we're convinced that it's really worth investing substantially in an aggressive development plan. It came in through our network of kind of investors and contacts. Sam, why don't you add a little bit to that?
Yeah. No, I mean, we've been, we've spent a lot of time over the past four years looking across a variety of therapeutic modalities for targets where the underlying either driver biology or cell surface markers, intersect for both adult and pediatric patients. And there's been a list of targets there that we've been keeping an eye on. PTK7 was on that list. It's something that we've had our eye on. When we were, made aware of this program over a year ago, it immediately, was of interest to us. There was a contemporaneous publication on over-expression of PTK7 in neuroblastoma, which is a very common pediatric solid tumor. So it caught my eye.
As we dug into the asset and learned about the prior experience with PTK7 ADCs that Pfizer had, we saw a product that was truly differentiated, really represented a next-generation product and something that we could, you know, to some extent work our magic on, you know, really experienced development team moving it forward, you know, at a rapid pace in both adult and pediatric indications.
Lilly disclosed the PTK7, I think, at the Triple Meeting, and I was comparing their structure versus DAY301.
Very, very similar.
It looks very similar.
Very similar, which, by the way, that degree of external validation doesn't happen very often. We now find ourselves, you know, probably three quarters or more in advance on the precipice of dosing our first patient with a, you know, high-quality asset that we happened upon. And, you know, I think, you know, seeing Eli Lilly come forward with a, you know, very, very, very similar construct, very similar linker, very similar payload, makes me feel, you know, really quite confident not only in how we source and identify new programs, but the type of diligence that we do.
Perfect. Well, with that, I think that's a great place to stop. Thanks to the full Day One Team. Thanks, everybody, for joining us. Take care and enjoy the rest of your day. Thank you.
Thank you.