Day One Biopharmaceuticals, Inc. (DAWN) Earnings Call Transcript & Summary

Welcome, everyone, to the 40th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by Malcolm Kuna, Priyanka Grover and Caleb Smith from the team. Our next presenting company is Day One. Presenting on behalf of the company, we have CEO, Jeremy Bender. [Operator Instructions] With that, Jeremy, take it away.

Thank you, Anupam. Big thanks to you and the team at JPMorgan for the opportunity to present here. I also want to thank each of the participants in watching the presentation today and the Q&A session. My name is Jeremy Bender, I'm CEO of Day One Biopharmaceuticals, and I'm excited to tell you about the company today. If we go to the next page, I want to just emphasize that I will be making forward-looking statements today. On the next page is a summary of the company, Slide 3. Day One was created to address the innovation gap between pediatric and adult patient populations living with cancer and life-threatening disease. What that means is we focus on targeted therapeutics, in particular, clinical development of programs that aren't tested in patient populations that have genetic alterations for which our programs are specifically addressed. Our goal is to move as quickly as we can to pediatric populations, which really differentiates us from any of the targeted oncology companies that are out there. We do that work in order to move as quickly as we can to generate clinical data and to move into registration. And we do that work in parallel with the work that we do in adult oncology populations. We've been pretty successful since our launch in 2020 in building out a team, in advancing our lead program tovorafenib or Day 101 and expanding our portfolio and resourcing the organization. As I mentioned, the team is deeply experienced in oncology, in pediatric oncology specifically, in rare disease more broadly. That crosses all of the key functions that we'll need to continue expanding in the future years. Our lead program is an oral pan-RAF type II pan-RAF inhibitor. It's CNS penetrant and it's in a pivotal study in relapsed pediatric low-grade glioma. This is an indication for which there are no approved therapies and for which we have the opportunity to establish a new standard of care. The pivotal study rests on some early encouraging data that was generated through an investigator-sponsored trial at Dana-Farber that I'll tell you about in a subsequent page. It's data from that study that has led to our Breakthrough Therapy designation from the FDA in that indication. We also have rare pediatric disease designation, which in combination with the orphan designations that we've established, will make us eligible for a priority review voucher upon approval. That relapsed pediatric low-grade glioma indication is really the tip of the iceberg for the development plan for tovorafenib and for our broader portfolio. There are opportunities I'll tell you about for additional monotherapy development of tovorafenib as well as a combination development of tovorafenib and pimasertib, one of the MEK inhibitors that we in-licensed from Merck KGaA in the first quarter of last year. The company has a strong financial position. We have cash projected to take us into 2024, which will be critical as there are a number of key milestones that I'll tell you about as well between now and that time. On the next page, you'll see a diagram of my senior team. As I mentioned, this is a group that has deep experience in many settings, of both big and small companies in particular, in transforming organizations to grow and meet new challenges. That really comes to fore in the oncology setting. This is a group that has decades of experience and judgment in that oncology setting, in particular in the pediatric oncology space, where the network of relationships and the experience we have in assessing and developing clinical programs we think will be quite important, given the tightened nature of the global investigator community in the pediatric oncology setting as well as the relationships with global regulators will be critical for collaborating to define registrational pathways. The next slide is a diagram of our pipeline. And what I want to emphasize here is each of the development programs that we have ongoing or planned. For tovorafenib, that includes 3 monotherapy studies. The top line is FIREFLY-1 our pivotal study in relapsed pediatric low grade glioma. This is a study that's been ongoing since second quarter of last year. This is also a study that we'll provide an update on in the first half of this year. That update will be on a subset of the patients from the study. It will include both safety and efficacy data from those patients that have been on therapy for a minimum of 6 months. Around the time that we announce that interim data, we will also discuss and initiate a Phase III study in the front-line pediatric low-grade glioma market. This is the FIREFLY-2 study which we will also initiate in the first half. That study will be a randomized Phase III global study intended to support indication expansion into the front-line setting in this space. That constitutes the pediatric development plan. The bottom 2 lines are the work that we're doing in solid tumors in patients 12 and above, so adolescents and adults. Right now, we have an ongoing study of monotherapy tovorafenib that we initiated in the second half of last year called FIRELIGHT-1. The patients in this study are those that we think are most likely to benefit from monotherapy, tovorafenib or pan-RAF inhibition. It includes patients that have BRAF and CRAF fusions as well as CRAF amplifications. We also think there's an opportunity to expand tovorafenib development in combination with pimasertib into patient populations that have other activating lesions in the MAP kinase pathway. And to that end, we'll initiate an additional substudy as part of FIRELIGHT-1 this quarter, first quarter of 2022, exploring that combination. That will have a dose finding portion as well as a dose expansion portion once we have the cohorts that of specific interest. And I'll talk a little bit more about the design of that in the subsequent page as well. On Page 6, what you'll see is a mechanism of action slide for this agent. As I mentioned, tovorafenib is a type 2 RAF inhibitor. Like type 1 RAF inhibitors, tovorafenib does inhibit the V600E and V600K alterations that are often found in melanoma, and we've seen clinical activity of this agent in that setting previously. But in addition to inhibiting those changes, because this molecule inhibits a dimeric RAF kinase signaling, we can also target a broader set of genetic alterations. And that means RAF alterations, but also other MAP kinase alterations through the use of this agent. We have also seen activity in that other setting where you require a dimeric RAF kinase to going to see a variance in tumor growth. That's notable in the case of RAF fusions in particular, where we've observed responses as monotherapy for tovorafenib in a couple of different clinical settings. The first of which I'll start telling you about in the next slide, Page 7. Page 7 summarizes an investigator-sponsored trial called PNOC 014 that was initiated at Dana-Farber Cancer Institute. This was a study -- a Phase I dose escalation study of monotherapy tovorafenib, once-weekly dose in relapsed pediatric glioma patients. This study treated a total of 9 patients. Of those 9 patients, 8 of them had RAF fusions -- BRAF fusions and 1 CRAF fusion. Among those 8 patients, what we observed from this study is 5 responses, 2 CRs and 3 PRs as well as 2 patients that had prolonged stable disease. So very encouraging signs of efficacy in this patient population. The AE profile here was a tolerable and fairly straightforward, as expected. We saw some skin rash and hair color changes that's the most frequent AEs. So overall, this early data was quite encouraging for future development in the same clinical setting. This is a setting that -- this is a data set, I should say, that we then review with the FDA, and it was this data that led to our Breakthrough Therapy designation. We also, of course, through this study, we're able to identify our Phase II dose which we're using now in our pivotal study of 420-mgs per meter square per week. The next slide shows the spider plot, the efficacy results from the PNOC 014 study. And I want to highlight a couple of important features of the results. The first is that these were active and growing tumors at the time these patients entered the study. If you look at the left-hand portion of this graph, the tumors that we -- the tumors from the patients that we brought into this study were actively growing and progressing. We went back and obtained the Antisedan scans for these patients in order to demonstrate this, which we think is an important aspect of the efficacy results we've observed. Once on therapy, what you see is quite significant reductions in tumor burden. This is a measure -- the measure here of tumor burden is RANO, which is a regulatory standard for brain tumors with the FDA. So that's the y-axis. Again, you see rapid, deep and durable responses in -- with tovorafenib monotherapy treatment. So very -- again, very encouraging activity. The next page is a summary of our AE profile in the same patient population, but call your attention to the orange columns in the middle. As you can see, very, very few grade 3 AEs, just a single CPK elevation in one patient. All of the remainder of the AEs were grade 1 and 2 and reversible and manageable. Again, the most frequent AEs that we observed with this agent in this patient population are rash as well as hair color changes, which is achromotrichia. The fact that this is a fairly tolerable profile, we think, is quite important as we consider the potential clinical benefit of keeping patients on therapy for long periods of time in this patient population. That AE profile will become more and more important. And notably, we did not observe any dose reductions in the Phase I program here under PNOC 014 which again shows a very tolerable safety profile. I also do want to contrast that with one of the other MEK inhibitors that is -- has been studied in this patient population selumetinib. That's the table on the right. As you can see, there are significantly more grade 3 and 4 AEs for selumetinib in the same group of patients. And you do see some of the skin effects and cardiovascular, ocular toxicity that can be associated with MEK in this patient population as well. So overall, a differentiated safety profile and one that looks quite tolerable. As you think about treating patients for long periods of time with a once-weekly oral regimen, this looks like a fairly attractive approach for patients. The next slide is a summary of our ongoing pivotal study, FIREFLY-1. This is a single-arm open-label Phase II study, approximately 60 patients total. The primary endpoint here is overall response rate based on that RANO criteria that I mentioned previously. In this study, we are enrolling patients that have BRAF alterations, in particular, those patients that have a BRAF wild-type fusions, the KIAA1549 fusion as well as patients that have a BRAF V600 alterations. Among those 2 patient populations, it's the patients that have the fusions that constitute the bulk of BRAF-altered pediatric low-grade glioma. 70% of pediatric low-grade glioma is BRAF-altered. And among that 70%, a 45% in here consists of the fusions that we're enrolling in the study. As I mentioned, this is a study where we'll have an interim update in the first half. And we'll be in position, assuming the data are positive when we move forward to a filing to push -- to put the NDA in place in 2023. So let me also tell you about -- in starting on the next slide, the patient population that we're targeting here. What you're looking at are incidents and prevalence estimates for those patients that have pediatric low-grade glioma that have both received a systemic therapy and have those BRAF alterations. These are the patients that should they require an additional systemic therapy, will be eligible for therapy, assuming we have an approval on the basis of FIREFLY-1. And as you can see, there is a substantial both incident pool of 1,100 and a prevalent pool of approximately 26,000 here in the U.S. The reason that you see such a large prevalent pool relative to the incident pool for an oncology indication is that the bulk of these patients, 90% plus, do survive them to adulthood. And as a result of that, the goal of therapy is very much to arrest the tumor growth, shrink it if possible, preserve function and prevent some of the safety effects or side effects that can result from subsequent therapies. So this is the overall patient population that we'll be addressing in the relapse setting with this particular study. Of course, the frontline setting is an additional opportunity. That's the low-grade glioma story for us. I also want to tell you briefly about the work that we're doing in adult patients. At the time that we in-licensed this program, there were a data from approximately 225 patients that have been treated with tovorafenib previously. The bulk of those patients were melanoma patients that had V600E alterations in their tumors. And among those patients, we did see responses that looked quite similar to what you observed with type I BRAF inhibitors. So tovorafenib is active in adult solid tumors in the V600E setting. It also, through the once-weekly regimen that was established for this program has a differentiated safety profile relative to those type I RAF inhibitors and relative to some of the MEK inhibitors that can be used in the adult solid tumor setting. In particular, we do not observe any of the ophthalmologic or cardiovascular liability associated with MEK inhibitors or any of the effects of paradoxical activation that can be as the type I RAF inhibitors, the prior generation. So on the basis of that data set and the early data that we observed for a RAF fusion patients, we've now initiated a monotherapy study. The reason -- one reason that we're as optimistic about the potential activity in this monotherapy study as we are is that if you look on the next page, 13, but we've also observed a CR from a compassionate use patient, in this case, the spindle cell carcinoma patient that's been treated with tovorafenib. This is a patient that, like the low-grade glioma, patient has a wild-type fusion. In this case, it's a different molecular fusion than what you often observed in pediatric low-grade glioma, but also a very encouraging outcome. This patient had been on therapy on trametinib, had achieved a response and then progressed on trametinib before being put on tovorafenib and achieved a rapid CR and is still on therapy today. So again, in the extracranial setting, very encouraging signs of activity for tovorafenib in RAF fusion patients. That's the patient population that extracranial group of RAF fusion patients that we'll be targeting on in our monotherapy FIRELIGHT-1 study, which is summarized on Page 14. This is a study that is now ongoing. And again, we'll enroll patients that have BRAF and CRAF fusions as well as CRAF amplifications. We're going to look at 2 patient populations specifically. One is a melanoma cohort, the other a tissue-agnostic cohort. We've separated that out just to simplify and see the most common group of melanoma patients. We observed a signal there or in the tissue-agnostic or both before we decide whether we'll progress this. The final element of the development program is the combination of work that we'll do with pimasertib. What you see on Page 15 is an overview of the pimasertib program. This is an allosteric MEK inhibitor that we brought in from MEK -- from Merck last year, as I mentioned. It is an orally bioavailable program that has undergone extensive nonclinical and clinical development work by Merck previously. Spanning over 800 patients, it has a safety and an efficacy profile that is quite similar to other MEK inhibitors that you may be familiar with and has a significant body of data that will allow us to move quickly into combination studies. We'll initiate that study in combination with tovorafenib this quarter. That study is summarized on the next page. This is a sub study that will be part of the FIRELIGHT-1 program. It will have a dose finding portion -- a dose finding Phase Ib as well as expansion cohorts in the Phase II setting. The specific patient populations that we'll target in that expansion phase will include NRAS-mutant melanoma. It will include BRAF-altered tumors that -- a Class I 9K as well as Class II BRAF alterations. And we may also look at fusion patients as well. We'll continue to monitor both the external data that can be generated for these tumors to see what specific patient populations make sense to target in these cohorts as well as additional preclinical data that we're working on internally. The next page shows a quick snapshot of our financial position. We ended the third quarter of '21 with just under $300 million in cash. Our cash position will take us, as I mentioned, into 2024. We'll have some of that cash available to continue doing work building out our portfolio through business development activities, which is a key priority for the company. And we have no debt. So in summary, on Slide 18, we've had a transformative 2021 setting up 2 company-sponsored studies, executing those studies to key time points and milestones that will occur this year. That will include the update on the clinical data from FIREFLY-1 in the first half, the initiation of our Phase III in the first half as well as the combination work that we'll initiate this quarter of tovorafenib and pimasertib. With that, I'll close and say that we look forward to a transformational 2022 and beyond. And thanks for your time. We look forward to talking with you in the Q&A session. To my left is Sam Blackman, CMO, Co-Founder of the company and to my right is Charles York, Chief Operating Officer and Chief Financial Officer of the company.

I just want to remind the listeners of the session that if you want me to ask a question on your behalf, I'm happy to do so. Just put it on the portal on we'll ask. We do have a couple of questions in the portal already, which is for FIREFLY-1 first half update, what is the bar for ORR in your opinion?

So Anupam, our perspective is that the most important aspect of the data set that we'll generate in that interim is whether or not this generates clinical benefit for patients. And the way that we think about that is by looking at the historical benchmarks in this setting. So the largest study of another monotherapy in relapsed pediatric low-grade glioma is Vinblastine, that's a 50-patient study. This was a study that we referenced in the protocol that we reviewed in the fiscal analysis plan with the FDA. And that study showed a 21% overall response rate for Vinblastine in this group. Anything north of that 21%, we think, will be positive. Of course, the further north, the better. And that's the way we think about the sort of efficacy bar. We'll also, of course, want to see over time how those responses mature. So it's important to note that the interim data we'll have coming out in that first half will just be that, and we'll look to the full data set to further expand on what the activity of the agent is.

Another question that we have in the portal is for the interim look later this year, what should we be expecting in terms of patient numbers and duration of follow-up?

Yes. So the duration of follow-up will be a minimum of 6 months on therapy for all of the patients in that interim. It will be a spread, of course, depending on the time of enrollment, but it will be a minimum of 6 months follow-up. Of the patient numbers we haven't guided to at this stage Anupam, what I can say is that it will be an appreciable portion of the overall study. We just haven't set the specific numbers.

One of my questions is how do we think about sort of time to response and duration of therapy? Maybe you can remind us of some of the prior data here. And how much duration data do you think regulators will require?

I'll ask Sam, if you can answer that question.

Yes. Thank you for the question. I think it's important to preface the answer by saying that our focus at Day One is really on delivering solutions that can both change the outcome and change the outlook for the patients that we care so much about and aim to achieve a new standard of care. Obviously, for a disease like pediatric low-grade glioma, for a number of patients to survive, durable responses are really critical, not just to patients but their families and their treating physicians. We've seen in the Phase I study durations that are measured in years, not just single-digit months. And we think that even though this is a small number from that Phase I study, it's very important as a signal. It's part of what encouraged us to in-license the molecule and felt it in our Phase II study. At the end of the day, when it comes to looking at durability of response, the FDA typically is looking for responses that are not at femoral. They've commented to us that responses of at least 6 months duration are interesting to them. At the end of the day, they're going to look at the totality of the data, both safety, efficacy in terms of the rate of response as well as the durability of response to making a decision.

Okay. And then for FIREFLY-1, should we be thinking about the data in conjunction with the medical conference? Or is this like a top line press release, webcast type of scenario?

Charles, do you want to answer that?

Yes, of course. Yes. So we anchor that decision Anupam, really in thinking about users data, both of our investigators and our regulators. And if you push that thread forward a little bit also into ensuring that it's available in front of our pivotal -- excuse me, our frontline trial for FIREFLY-2. So what we'll do is we'll determine the timeline that best meets those needs of the investigators and the regulators of the house. And as the data is complete and ready to go, we'll ensure that we're releasing it at that time.

Yes. And on FIREFLY-2, the frontline study here, it sounds like you're waiting for this initial FIREFLY-1 readout. Is that a gating factor to starting that study? Or what are the gating factors to starting that study?

Yes. Yes. Anupam, we're moving forward rapidly with that Phase III program, and it's part of the plan. It is not a gated study per se. It's a fairly large effort to get a global registrational Phase III launch and requires a fair amount of work coordinating with global regulatory authorities in order to ensure that we have best chance of really expanding the opportunity to get this to patients into that frontline setting across geographies. So that effort has been underway for some time. We're reasonably close to finalizing the details of the study. We would like to see the data from FIREFLY-1 for 2 reasons. One is to inform some of the assumptions that we'll need to make around the final design of the study. And 2, to publish the data from that interim in FIREFLY-1 to generate interest among investigators and prospective patients and families in order to launch and drive enrollment as quickly as possible for the frontline program. So it's a combination of factors. But I would not say that it's a gated decision as much as it is an aligned plan that allows us to really inform the Phase III with the Phase II results.

I know that FIRELIGHT-1 only just started here in November in sort of adult RAF-altered solid tumors. How is enrollment going in that study? Have you seen any impact from the new variant? And how do we think about potential timelines there on the data side?

Yes. We haven't guided and won't at this point to when data will be available from that FIRELIGHT-1 monotherapy component. I'll ask Sam to comment on the status of enrollment in the study itself.

Yes. We announced our first patient treated back at the very end of 2021. The study remains on track. It's open at, at least 6 sites as of today and a number of sites looking to initiate in the next month or 2. As you know, the study is enrolling patients with solid tumors or adolescents and adults with solid tumors that are relapsed and have BRAF altered fusions, CRAF-altered fusions or RAF-1 amplifications. These are relatively uncommon lesions. BRAF-wild fusion represent about 1% of the genomic alterations found in relapsed adult solid tumors. And so we're employing a number of strategies, including choosing clinical trial sites that sequence a number of patients and can readily identify these patients, but also creative ways of either bringing patients from geographies or places in the country or places around the world that don't have this trial open to sites that have the trial open or bringing the trial to sites where it's not open in a just-in-time manner. So we remain confident that we'll be able to approve independent of any of the effects of the pandemic and overcoming the relative rarity -- relative scarcity of these patients, we're able to find them at the sites that we've chosen.

And then on sort of the combination within the circuit, I think the guidance here is to start that Phase 1b/II study this quarter with Day 101. I guess, what are the gating factors to starting that?

Sam, do you want to comment on that?

We are on track to protocol. The protocol has been finalized for a couple of months now, and we're in the process of getting it through the site initiation process, and we aim to be on track for initiating site this quarter.

And maybe final question for me here. I don't see any questions in the portal, but final question for me here, which is how should we think about additional business development to kind of supplement the pipeline here with Day 101 and pimasertib?

I think I'll ask Charles to answer that one as well.

Yes. Sure. So we've really looked at business development as part of the quarter -- core to what we do here at Day One. We've invested in it very early from our standpoint. And we're active looking at multiple opportunities on a regular basis. Also, as you know, finding the next asset, looking to the next thing that we find compelling, doesn't necessarily hang on a calendar as neatly as we'd like. So the time of it does alternate shift. But as we demonstrated with the in-license of the MEK earlier last year, we're truly into the market. When we find something that we think fits in our strategy and what we want to proceed with, we'll aggressively and certainly pursue that opportunity.

Okay. Well, I don't see any more questions in the queue. And so Jeremy and team, I want to thank you guys so much for a super productive session here. And I hope you guys have a great rest of the conference.

Thanks, Anupam. Thanks again for the opportunity. I hope you have a great conference as well. Take care.