Day One Biopharmaceuticals, Inc.

Hello ladies and gentlemen and welcome to day one biopharmaceuticals second quarter of 2024 financial and operating results conference call. At this time all participants are in a listen only mode. Later we will conduct a question and answer session. Please be advised that this conference call is being recorded. I would now like to turn the call over to Joey Perrone, Senior Vice President of Finance and Investor Relations. Thank you. You may begin.

Thank you. Hello, everyone, and good morning. Welcome to Day One's second quarter 2024 Financial and Operating Results Conference Call. Earlier this morning, we issued a press release which outlines the topics we plan to discuss today. You can access the press release and the slides to accompany this conference call on the Investors and Media section of our website at www.dayonebio.com. An audio webcast with the corresponding slides is also available on our website. Before we get started, I'd like to remind everyone that some of the statements that we make on this call and information presented in the slide deck include forward-looking statements as outlined on slide two. Actual events and results could differ materially from those expressed or implied by any forward-looking statement. We encourage you to review the various risks, uncertainties, and other factors including our most recent filings with the SEC and any other future filings that we may make with the SEC. These forward-looking statements are based on our current estimates and various assumptions and reflect management's intentions, beliefs, and expectations about future events, strategies, competition, products, and product candidates, operating plans, and performance. There are cautions not to place any undue reliance on these forward-looking statements and except as required by law, day one disclaims any obligation to update such statements. Today I'm joined by Dr. Jeremy Bender, Chief Executive Officer, Laura Marandino, Chief Commercial Officer, Dr. Samuel Blackman, Co-Founder and Head of R&D, and Charles York, Chief Operating and Financial Officer. I will now turn the call over to Jeremy.

Thank you, Joey, and thanks to all of you for joining this call. This is the first time we're reporting earnings with a new medicine on the market. We had an outstanding second quarter on multiple fronts, and we are excited to tell you about our progress building day one. 2024 has been an extraordinary year for us. I'm so proud of the day one team, each of whom have been tightly focused on our mission and on executing on our priorities, specifically launching Ojemda, and advancing and expanding our pipeline of targeted therapeutics for people of all ages. Day one was created to address the innovation gap between pediatric and adult patients living with cancer and other life-threatening diseases. In April 2024, the U.S. Food and Drug Administration approved Ojemda, the brand name for toborafenib, for the treatment of relapsed or refractory pediatric low-grade glioma, or PLGG, in patients six months of age and older harboring a BRAF fusion, rearrangement, or BRAF V600 mutation. With this achievement, Day One became a commercial company. Our team, including clinical, regulatory, manufacturing, medical, and commercial, was well prepared to launch our first new medicine. As you will see from our Q2 earnings, we are beginning to see those efforts yield results. The interest in Ojemda, we have observed post-approval demonstrates the significant need that exists for new medicines for PLGG patients. PLGG is the most common brain tumor in children. Until Ojemda's approval, no approved therapies were available for the majority of patients in the relapsed or refractory setting, and there has been no clear standard of care for these patients. Our early launch progress suggests that physicians and families are excited to have Ojemda as a treatment option for this chronic and relentless disease. I'm excited to announce very strong early results from our launch. Our net revenue for Q2 was $8.2 million. As Lauren will discuss in more detail, significant new patient starts and the rapid transition of expanded access patients to Ojemda drove these results and set us on a path to future growth. Day one's long-term success will require continued value creation through execution of the commercial opportunity for Ojemda in relapsed refractory PLGG and through progress advancing our broader pipeline. Our global frontline PLGG trial, Firefly 2, continues to enroll and is now open at 100 sites. The opportunity to demonstrate clinical benefit for tovarapinib in frontline PLGG is a critical next step for the program. and for our goal to bring new medicines to patients. We also expanded our pipeline in the second quarter with an exciting new program. In June, we in-licensed Day 301, a potential first-in-class clinical stage antibody drug conjugate targeting PTK7. Our experienced clinical and regulatory team will develop Day 301 in adult and pediatric solid tumor patients. The Day 301 IND has been cleared by the FDA and we are on track to dose the first patient in our phase one trial of day 301 in adults by the end of this year or early next year. Finally, we have significantly strengthened our financial position throughout 2024. In May, we brought in approximately $100 million in net cash through the sale of a prior review voucher. Last week, we established an ex-U.S. partnership pro agenda with Ipsen that includes approximately $111 million in upfront payments And this morning, we announced an oversubscribed private placement financing, providing day one with an additional $175 million. We have ample capital to fund our growth and our program investments, and we look forward to continued future progress and updates throughout 2024 and beyond. I'll now turn the call over to Lauren.

Thank you, Jeremy. While it's still very early days, Ojemda launch is off to an extremely strong start. Our prelaunch planning prepared us to move quickly to generate considerable new patient demand, transition our EAP patients rapidly, and enable a favorable response from payers. These three drivers resulted in strong revenue for the first two months of launch, and I'm pleased to share some of the details of our performance. As Jeremy mentioned, In Q2, we delivered $8.2 million in net product revenue, about $6 million of which is patient demand. The remainder is specialty pharmacy inventory. This performance is a testament to the dedication of our cross-functional team and to excellent execution across the board. One example of this is getting our product packaged into the channel and shipping to patients just 11 business days post-approval. From a commercial perspective, we moved quickly to communicate our approval with live engagements with over 90% of our 200 target accounts. On these calls, we ensured that prescribers were aware of our approval, familiar with Ojemda's efficacy, safety, and dosing, and aware of how to expedite patient access to Ojemda by leveraging our specialty pharmacy network and patient support programs. With the majority of physicians aware of Ojemda prior to approval, it was easy for them to understand the benefits that Ojemda delivers for patients. It was important for our sales team to update their knowledge with the latest data, safety, and dosing from our label. These messages were well-received with many physicians expressing gratitude for a new option for children with PLGG. In addition to our work with HCPs, The efforts of our payer team, both pre- and post-launch, to educate payers on the unmet needs of PLGG patients and the science behind Ojemda were an important part of enabling early access, which I'll talk more about in a moment. First, let's talk about the most important measure of our impact, patients. We ended the quarter with 157 patients initiated on Ojemda. including both those on paid drug or on one of our commercial free drug programs. This demand was driven almost equally by patients transitioning from our early access program, or EAP, and patients newly starting on Ojemda. There were 84 patients who converted to commercial drug from our EAP, which was opened after the enrollment in Firefly 1 was completed. The efficiency of our process and the speed of payer approvals enabled us to transition most EAP patients in May, faster than initially expected. It's important to note that the large majority of EAP patients were transitioned this quarter, with only a handful of patients remaining to transition in Q3. So moving forward, new patient starts will be the primary driver of incremental demand. We had 73 new patients start Ojemda in Q2, representing strong underlying demand. Two-thirds of the physicians starting these new patients had no prior experience with Ojemda through clinical trials or early access, demonstrating the broad HCP awareness of the product and the unmet need for PLGG patients. This quarter, over 100 HCPs prescribed Ojemda, This is an excellent start, but there remains tremendous potential to expand our prescriber base. In the 200 accounts that treat 90% of the PLGG patients, there are approximately 1,500 target prescribers. By expanding our pool of prescribers, more patients will be able to experience the benefits of Ogenda in the future. Payers have been quick to respond to the needs of PLGG patients. As we expected, our payer mix is approximately 60% commercial and 40% Medicaid. Since it is still very early in launch, most commercial payers have not yet published policies for Ojemda, which you can see here in the pie chart on the left. Medicaid coverage, however, has grown quickly, with 50% of covered lives now having Ojemda covered to label. Across both payer types, we're seeing approval rates significantly higher than reported coverage, with over 80% of commercial patients and over 70% of Medicaid patients receiving approval for coverage. Overall, the response to Ojemda launch has been very positive, with physicians expressing excitement about our product profile and our patient support programs, and an openness to trying Ojemda in their relapsed refractory PLGG patients. To continue our strong launch trajectory, we have three areas of focus. First, we must increase the breadth and depth of our prescriber base. Recent market research shows that over 80% of physicians surveyed intend to use Ojemda in the future. So for those physicians who have not written yet, increasing their confidence to get their first patient started on Ojemda is critical. For those ACPs who have tried Ojemda, expanding their use to multiple patients will be an important next step. Secondly, we want to establish Ojemda as the first choice in second-line treatment of BRAF-altered PLGG patients. Not surprisingly, in the early weeks of launch, we've seen a number of late-line patients receiving Ojemda. As you can imagine, there are many existing patients who may have run through other options and are now in need of new treatments, and Ojemda is a great choice for them. Over time, however, we want to increase the use of Ojemda in patients in the second line. With our compelling efficacy and safety profile and once-weekly dosing, we believe that Ojemda can offer unique benefits to many of these patients. And finally, we're continuing to actively engage with payers to establish broad coverage for patients consistent with our label. While we are pleased with the current approval rates, we want to continue to move payers towards formalizing their coverage with a published coverage decision. This will help streamline the process for patient access in the future. We're excited about the speed of our progress this quarter, and the results confirm that there is a substantial and sustainable market in serving children with PLGG. This is just the beginning, and we've been encouraged by the positive response from HCPs patients, and payers. Our team continues to be energized by the promise of Ojemda to make a difference in the lives of more patients challenged by PLGG. We're also excited about building the future of our company and potentially expanding our impact to other patients. For more on that, I'll turn it over to Sam for a pipeline update. Sam?

Thanks, Lauren, and good morning, everyone. I'm very excited to be able to provide some updates on our pipeline and programs. I'll start with our newest program, Day 301. As we announced last month, we in-licensed a potentially first-in-class antibody drug conjugate program from Mabcare Therapeutics, which we've named Day 301. This model fuel targets PTK7, or protein tyrosine kinase 7. which has been shown by multiple groups to be consistently and highly expressed on the cell surface of multiple adult and pediatric cancers. PTK7 is a pseudotyrosine kinase, meaning it lacks catalytic activity, but because of its high degree of cell surface expression and internalization upon antibody binding, it makes for an important ADC target. There are multiple reasons why we're excited to add Day 301 to our pipeline. First, and importantly, PTK7 has been clinically validated as an ADC target with first-generation or statin-based ADC programs showing anti-tumor activity in a variety of tumor types, including platinum-resistant ovarian cancer, triple negative breast cancer, and non-small cell lung cancer. We believe that a better engineered next-generation ADC program has the potential to take full advantage of PTK7 as a target. Second, PTK7 has been shown to be highly expressed in various pediatric cancers that have seen little to no new drug development activity in the past 30 years, including neuroblastoma, rhabdomyosarcoma, and osteosarcoma. In keeping with the mission of Day 1, we intend to develop Day 301 with equal intensity in adult and pediatric patients. And finally, we're excited about the properties that have been carefully engineered into this particular ADC. Day 301 is built around a proprietary monoclonal antibody coupled to a novel hydrophilic linker and exotecan payload. Preclinical studies have demonstrated the potential of this linker payload to overcome resistance to other topoisomerase inhibitors. Other features of Day 301 that made this program exciting include a comprehensive preclinical evaluation showing tumor regressions at tolerable doses in multiple patient-derived xenograft models, favorable stability for the ABC construct, and a large exposure-based therapeutic index based on data from SinoTox studies. With an IND cleared by the FDA, we're working hard towards operationalizing the phase one study and plan to have the first patient dosed by the end of the year or shortly thereafter. Our initial clinical development plan outlined here leverages the tolerability seen in the GLP tox studies. We believe that the FDA-approved starting dose puts us within one to three dose escalation steps of a dose level expected to be therapeutically relevant. Following conversations with some of the premier Phase I clinical trial sites and investigators in the United States, we'll be focusing enrollment in dose escalation on tumor types known to have high PTK7 expression. In the Phase IIa dose expansion and optimization, we will likely select patients based on PTK7 expression and focus on indications where patients continue to have limited therapeutic options, including platinum-resistant ovarian cancers, squamous non-small cell lung cancer, esophageal squamous cell carcinoma, endometrial cancers, and others. The exact choice of indications for expansion cohorts will be determined based on data from the Phase I portion of the study, as well as an expanded analysis of PTK7 expression in tumor samples. In keeping with the day one approach to clinical development, in parallel with the monotherapy dose expansion in adults, we will initiate a Phase 1b pediatric monotherapy dose confirmation study in tumor types with high PTK7 expression, leveraging the adult Phase 1 dose escalation data to allow us to start a pediatric study at a dose level that has been shown to have the potential for anti-tumor activity. We are very excited for the Day 301 program and look forward to providing additional updates in the quarters to come as the Phase 1 study progresses. Now turning to PLGG. Evaluation of data emerging from the Firefly 1 trial continues as patients move into long-term follow-up. We performed a data cut on May 10th of this year in order to gain an updated understanding of safety, duration of response, and durability of response and to support our post-marketing commitments around long-term safety. While we continue to clean and analyze the data to prepare for future presentations and publications, I can share with you that we're seeing, as expected, a long duration of treatment. For the 77 patients enrolled in Arm 1, which was the dataset used to assess the efficacy of Ojemda in our NDA, the median duration of treatment is now 23.7 months. with some patients being on treatment up to 32 months. Additional analyses will be presented at future medical conferences. We also had the opportunity to present data on the recovery in the rate of growth velocity at both ASCO and the International Society for Pediatric Neuro-Oncology meetings. Over the course of the past nine months, we've discussed the decrease in growth velocity observed in some patients treated with Ojemda with experts within the pediatric neuro-oncology community and their feedback has been both reassuring and valuable. There's a broad awareness that children with brain tumors and children receiving anti-cancer therapy can have alterations in the rate of growth. And they've indicated that an understanding of the potential mechanism of growth velocity decrease and demonstration of recovery of growth velocity after holding the drug or after completion of treatment would be helpful for them in discussions with patients and families. The two presentations included a proposed reversible mechanism of action for the observed decrease in growth velocity, as well as data showing, for the 15 patients where we had post-treatment height measurements, a 100% rate of recovery of growth velocity. Moreover, these presentations included data showing that 87% of patients had evidence of catch-up growth and that no patient had deficiencies in bone integrity or fusion of growth plates. The feedback from physicians was that these data were extremely helpful and reassuring. We will continue to monitor growth and development of patients on Firefly1, and we have included routine bone age monitoring on and off treatment as part of the Firefly2 trial. The Firefly2 trial continues to make excellent progress in its accrual. We are now open at 100 sites worldwide and plan to add a few more sites. We held a successful investigator meeting last month in parallel with the ISP&O meeting in Philadelphia that was extremely well attended, and it was clear that enthusiasm for enrollment to the study is high. In addition, we recently gained alignment with the FDA on some updates to Firefly 2 that are being incorporated into a protocol amendment. First, we'll be harmonizing the starting dose of toborafenib in Firefly 2 to the FDA-approved starting dose for Ojemda of 380 milligrams per meter squared. Second, consistent with the accelerated approval of Ojemda, which is based on overall response rate based on RACNO low-grade glioma criteria, we will be changing the response assessment criteria in Firefly 2 from RANO-LGG, which are the adult low-grade glioma criteria, to RACNO-LGG, which is the appropriate criteria for pediatric low-grade glioma. And finally, we'll be adding monthly carboplatin to the list of acceptable standard of care regimens in the control arm in response to investigator feedback. This option may reduce the travel burden for patients and families enrolled on this trial. Finally, I'd like to mention both our work on our MEK inhibitor, Pimasertib, as well as our work on developing a small molecule VRK1-specific inhibitor in collaboration with Sprint Biosciences. First, with regard to Pimasertib, We've been evaluating the combination of tocorafenib and Pimasertib in adolescent and adult patients with MAP kinase-driven solid tumors as part of a phase 1B dose-ranging combination study that we call FireLight1. Preclinical data from our group, as well as other companies and academic groups, have shown the potential for therapeutic synergy when a type 2 RAP inhibitor is combined with a MEK inhibitor. This is a concept known as vertical MAP kinase pathway inhibition. This is a different type of combination compared to a type 1 RAS inhibitor with a MEK inhibitor, where the MEK inhibitor in that combination adds activity and offsets some of the specific type 1 RAS toxicities. Our trial was open to patients with a variety of RAS and RAS alterations. After evaluating a variety of dose combinations and schedules, we've concluded that the therapeutic synergy predicted by preclinical models was not evident at dose combinations that we believed would be tolerated over a sufficient period of time to lead to true clinical benefit for patients. While we did see responses in patients with multiply relapsed solid tumors with MAP kinase alterations, the frequency and duration of responses was not sufficient to give us confidence that the benefit-risk profile of this combination would have a sufficiently high probability of success in subsequent clinical trials. In addition, it was more challenging to identify relapsed N-RAS mutant patients than was predicted by the published molecular epidemiology data. We view this as a more limited opportunity than was necessary to support further investment. As a result, we've made the decision to close the PIMSERTA program and focus our development resources on day 301. We look forward to sharing results from the study and our experience at a future medical meeting or in a future presentation or publication. We will also have updated data on tovaracanib as monotherapy in adolescent and adult RAC-altered solid tumors at a medical meeting later this year. And finally, with regard to VRK1, we continue to make progress in our effort to identify a drug development candidate. To remind everyone, VRKs are a family of kinases that are critical for cell cycle entry nuclear envelope formation and regulation of various transcription factors. BRK1 and BRK2 are paralogs. Recent data from multiple groups has revealed that BRK2 is epigenetically silenced in two-thirds of high-grade gliomas, as well as a significant proportion of low-grade gliomas and in a large percent of aggressive neuroblastomas, one of the more common solid tumors of childhood. A synthetic lethal interaction between BRK1 and BRK2 results in the sensitization of BRK2-silenced tumors, the inhibition of BRK1 kinase activity, supporting BRK1 as a novel drug discovery target. We anticipate providing updates on our research program for BRK1 in 2025. To wrap up, the past 12 months in their totality have been both remarkable and transformative for day one from a research and development perspective. We've added two new programs in VRK1 and Day 301, have seen tovirapidin advance to approval, and have reached an important decision point for our efforts to combine tovirapidin and Femiservin. We continue to recognize the potential value of tovirapidin in PLGG as data from the Firefly 1 program has matured further and have made considerable progress in accruing our Firefly 2 trial. Our pipeline has evolved and will continue to grow and evolve to develop value for patients. I am personally very proud and even a little verklempt about the addition of Day 301 to the pipeline, and I look forward to seeing this molecule enter clinical development. Beyond this, our research and development and business development teams will continue our work of identifying, in-licensing, and developing additional novel therapeutics in order to build a long-term, sustainable company. And now, Charles will share our second quarter financial results.

Detailed second quarter financial results can be found in the press release we issued earlier this morning. For this call, I'd like to touch on a few key highlights where a strong quarter of execution throughout the company has built a solid foundation for the remainder of 2024. The relapse PLGG opportunity for Ojemda represents a substantial market Strong commercial execution paired with clear patient demand generated $8.2 million in net revenue for the first eight weeks of Ojemda's launch. Included in net revenue is inventory in the channel, which totaled $2.1 million at the end of the second quarter. As is expected and customary in the early months of launch, we shipped Ojemda to our specialty pharmacies in order to meet the needs of our growing customer base. As we move into the back half of 2024, we expect limited revenue from channel inventory stocking as we target two to four weeks of inventory on hand to ensure we are able to meet demand. Cost of sales for the current quarter include intangible amortization and sales-based royalties. Cost of sales did not include any product cost as inventory produced prior to FDA approval was fully expensed at the time of production. We expect cost of sales to be in the range of 9% to 12% of revenue for the second half of the year. Our operating expenses were $122.3 million for the current quarter, compared to $49.3 million for the prior year quarter. Of note, the second quarter of 2024 includes a one-time charge of $55 million in R&D expense associated with the in-license of day 301. In addition to the OJEMDA launch, we're maintaining a disciplined fiscal approach. We've discontinued the Firelight One program and reallocated our resources to day 301. We sold the priority review voucher for $108 million in May 2024, and we licensed ex-US rights of OJEMDA to Ipsen for approximately $111 million upfront. This agreement includes cash, an equity investment and a premium, and up to $350 million in additional sales milestone payments. We will also receive a tier of royalty percentages in net sales between the mid-teens and high 20s. And finally, we continue to form and allocate capital in a manner that focuses on generating durable growth for day one. It's also important to note that we continuously review BD opportunities that align with our mission and fit in our pipeline of targeted oncology focused on adult and pediatric patients. Our future growth requires pipeline expansion, clinical development, and commercial execution. These attributes are optimized with a strong balance sheet, and we ended June of 2024 with $361.9 million in cash, cash equivalents, and short-term investments. The June 30, 2024 cash balance does not include proceeds from the recent XUS licensing agreement or our announcement this morning of an over-scribed private placement of approximately $175 million. In closing, and before we turn to Q&A, we would like to thank the investigators, patients, and caregivers who participated in our clinical trials, as well as our team for advanced planning, continued effort, and patient focus that allows for a great start to the OJEMDA launch and the work in the clinical portfolio. We recognize that we have much to do and work ahead of us together, and we will continue to execute on our goals to bring agenda to the patient community and build durable growth over time.

Thank you.

We are ready for the question and answer session. For the Q&A session, we ask that all participants limit their questions to one with an opportunity to have one follow-up question. If you would like to ask a question, please press star one on your telephone keypad. The confirmation tone will indicate your line is in the question queue. You may press star two if you would like to remove your question from the queue. Our first question is from Anupram Rama with JP Morgan. Please proceed.

Hey, guys. Thanks for taking the question and congrats on the early metrics here. I think you guys just briefly commented on this, but wanted to get a little bit more color on what you're seeing in the early innings of the launch for OGEM from a gross net perspective and how you expect this to evolve over time. Thanks so much.

Anupam, thanks much for joining in the question. I'm going to ask Charles to comment on gross nets.

Good morning, Anupam. So from our perspective, we won't provide guidance over the long term, but I think it's important here in the early days of launch to recognize some level of understanding this. As you heard from Lauren in earlier notes during the call, we're seeing a payer mix, at least at this point, that is consistent with what we believed to be prior to launch, about a 60-40 commercial to Medicaid. Our standard discounts here put us in a situation where we believe over time we'll be in that 15% to 18% range of gross nets. We think that absent any change in that mix, that's where the long-term space was planted, around 15 to 18%.

Great. Thanks so much for taking our question. Thanks, Anupam.

Our next question is from Joe Cantazzaro with Piper Sandler. Please proceed.

Hey, guys. Thanks for taking my questions. Congrats on all the execution here. I guess my first question is maybe on the new patient starts and what you're seeing there. I know you said that they are tending to maybe be later line patients. Is there anything else sort of a common shared feature that you're seeing in these new patient starts? And then I guess maybe going back to the new patient starts being later line patients, Any potential impact there on your expected duration of treatment? Anything that far or fly one tells you about what you might expect in those later line patients? Thanks. And I have maybe a follow-up.

Okay. Thanks, Joe. I appreciate you joining the call this morning. Let me ask Lauren to comment on both of those elements, and then I'll add.

Yeah. Thank you, Joe. So from a new patient starts perspective, we're actually seeing a pretty broad population. So when we look at the location of tumor, fusion or mutation, we're seeing a broad mix. From a line perspective, we see about half of those new patients are in the second to third line, and about half are in later lines. And so that's something we'll want to change over time because the second line patients are a larger population. And we do believe that Ojemda is best used in the second line. So that will be the focus for the commercial team in order to move that up in consideration.

Okay, thanks. That's helpful. And I maybe had one follow-up, I guess, as I try to think about maybe early days of patient turnover. Wondering if you could tell us what the average duration of treatment was on Ojemda for patients who are on the EAP and transition before they transition? So how long were they on the EAP for and on drug before they transitioned to commercial product?

Yeah, important question. Lauren, go ahead. Yeah, thank you. So on average, patients were on Ojemda approximately six months prior to transitioning to commercial. That's an average for all of those who transition. There were about 15%. that were on drug for over a year.

Thanks, Lauren. And Joe, one other comment regarding what we're seeing in the early days of the launch that I think is important to emphasize is in particular with respect to the new patient start. So these patients who have not been on tovirafenib through the EAP but are new to agenda post-approval. The pace of new patient starts has been consistent since launch, and we're expecting that that consistency will continue, not specifically guiding to what we'll see in the rest of the year, but I think it's important to note that that incremental growth is going to be driven by the process that we've discussed in the past by which those patients who our relapsed PLGG patients may come on to a new therapy, either because they have a progression event, either on a treatment or off a treatment, or because they're intolerable to a current treatment. That pattern means that we are going to see that steady incremental growth, and that's consistent with what we've observed so far post-approval.

Okay, great. That's all really helpful. Appreciate you taking my questions. Thanks again.

Thank you, Joe.

Our next question is from Andrea Tan with Goldman Sachs. Please proceed.

Good morning. Thanks for taking my question, and congratulations on the quarter. Jeremy, maybe a follow-up to some comments that you just made there. Just curious if you could speak a little bit more as to how you're seeing physicians utilize Ojemda. Are you seeing patients being switched off of active therapy because of intolerance, whether it's chemotherapy or another MEK inhibitor? Or is it more so that these are patients who are progressing and eligible for treatment? And then I have a follow-up. Thank you.

Thanks, Andrea, for the question. Let me ask Lauren to comment on that, what we're seeing in the field at this stage.

Yeah, thanks, Andrea. So there are limits to our data at this point. So what we're able to see is if a patient was on a prior treatment, What we aren't able to see is why they change treatment. So did their disease progress? Did they have an intolerable AE? Or was it a more of a preference switch? We don't have the ability to see that information. So at this point, there's, you know, there's just limits to what we know about switching and the reasons for that switch.

Okay. And then, Lauren, maybe one more question here. If you could speak to the dynamics that you have been seeing with prescribers to date, and maybe specifically for those who have yet to prescribe, if you could provide some color on the reason for that and what you believe is needed to get them to write their first script.

Yeah. So, we're talking about a broad population here. So, as I mentioned, we are targeting 1,500 physicians. Each conversation is different, but if I were to draw a trend, I would say that many of the physicians who haven't utilized Ojemda yet, who have expressed a desire to use it, are simply expressing they're waiting for the right patient, right? And so, to Jeremy's point, they need a patient to either, in watch and wait, progress, or on a product, progress, or have intolerable AE. in order for them to consider a new treatment. And that doesn't always happen every day, right? And so they're waiting for the opportunity. And then, of course, it's our sales team's job to help paint the picture of appropriate patients and help physicians see the broad application we see for Ojemda over time.

Thanks so much.

Thanks, Andrea.

Our next question is from Mark Fram with TD Cowen. Please proceed.

Thanks for taking my questions and congrats on all the progress so far on the launch. Maybe on that 23-month median duration of therapy so far, can you speak to the maturity of that and how much that may change as follow-up continues? And then this is kind of a follow-on to one of Joe's questions. Just can you speak to the what you're seeing for duration kind of impact of the line of therapy there, how that changes duration and maybe looking forward to the first line trial, how much longer could it get by moving to those patients or in first lines are really just going to be driven by the decision to start a drug holiday, maybe at 24 months or a bit after that?

Mark, thanks for the question. Let me start with with your second question and just let you know that with respect to the commercial effort, It's too early to say anything definitive about what we may observe in terms of duration of treatment for commercial use. Similarly, in the frontline setting, I think in the absence of real data from the real-world trial, Firefly 2 here, it's going to be difficult to state what the potential change in possible duration of treatment may be in the frontline relative to the relapse setting. With respect to the Firefly 1 result and the new cutoff from May that has resulted in the updated duration of treatment, let me ask Sam to comment on maturity.

Yeah, you know, we'll probably look at the data once last time as part of our long-term follow-up, but You know, I think at the end of the day, you know, as more patients come off trial or reach treatment or go into drug holiday, I don't expect that number to shift significantly more. One other point that I think is important to make is that the duration of treatment data from Firefly 1, the 23.7 months that I mentioned, represents data from a population where the median line of therapy prior to the initiation of treatment was three. So this is a median fourth-line patient population. So when I think about the impact of line of therapy on duration of treatment, I think the data from Firefly 1 makes it clear that duration of treatment does not seem to be significantly impacted by what line of therapy that you're in.

Okay, thanks. Very helpful. Thanks, Mark.

Our next question is from Amy Sada with Neiman Company. Please proceed.

Hi, good morning. Thanks for taking my question and congrats on the strong initial launch. Firstly, just following up on the comment regarding duration of treatment, could you clarify what drives the decision for a patient to take a drug holiday? Is it just duration of treatment or is it some other aspect? And with regards to the mix of patients You mentioned that going forward, or at least over time, you expect the mix of second-line patients to increase. But I guess what I'd like to understand is, given the high pool of prevalent populations and some of the reasons that you mentioned, such as lack of tolerability of other treatments, Is it not possible that there would still be a meaningful percentage of patients that are in later lines of treatment? Thank you.

Ami, thanks for the questions. Let me start with that second question first. I do think, and we've discussed in the past this property of the prevalent pool of PLGG patients, that there will be an appreciable number of patients who are later line, so to speak, you know, third, fourth, fifth line and beyond, just given the, you know, relative sort of survival dynamics of this population, fortunately. That being said, I think what we're expecting based on just prior experience in commercializing oncology therapies and even in clinical trials we observe this is that as physicians have additional experience with a new medicine, they tend to use it in earlier lines of therapy. And that's the reason that we're expecting that over time, we will see agenda use in patients in the second line setting at a higher rate than perhaps we're observing earlier in our launch. So I think that's the overall dynamic that I would anticipate with respect to the element. And now I've forgotten the second element of your question. Apologies.

The decision for drug holiday.

Yeah. On that front, I think it's a little bit early, but I'll ask Sam to comment on, from a clinical standpoint, you know, what he would expect based on knowledge of the space.

Yeah, it's a great question. And, you know, I want to just sort of preface my remarks by saying that, you know, it's hard to speak for all families and all pediatric neuro-oncologists because this really is, you know, such a different disease going from patient to patient owing to the location of the tumor, the risks to the patient of progression of that tumor, And also the age of the patient. Recall that low-grade gliomas tend to spontaneously synapse when patients get to their third decade of life. That is their early to mid-20s. And so the decision to take a drug quality integrates all of that in addition to the prior velocity of growth of the tumor. as well as how the patient is tolerating the drug. So you can imagine many, many different permutations for different patients. A patient in their late teens who may be a second or third relapse patient who may be close to the point of having their tumor undergo senescence, where the growth of the tumor may not necessarily have significant impact on vision or on motor function, there may be a greater willingness to take a drug holiday because it's possible that the tumor may have undergone senescence or may be close to undergoing senescence. On the other hand, a much younger patient who may have had many relapses and has an optic pathway tumor where the risk of growth of that tumor may mean complete loss of vision, there may be a greater hesitation to take a drug holiday if the patient, for example, is tolerating the drug well. So it's hard to come up with a single heuristic for how long to treat a patient because it really takes into account so many different variables.

That's very helpful. Thank you.

Our next question is from Sumit Roy with Jones Research. Please proceed.

Good morning, everyone, and congrats again on the second quarter. A question about... The safety profile, has it improved 420 milligram versus 380 milligram or still staying in line with the Firefly 1 when you look at Firefly 2 trial or the commercial product?

Shaman, thanks for the question. Let me ask Sam to comment on the safety question as it relates to dose.

Yeah, it's a great question. You know, we've not conducted a formal analysis of 420 versus 380. Recall that 380 was the approved commercial dose. And obviously for commercial patients, we don't collect day-to-day or garden variety adverse events. But there's certainly been nothing that we've detected thus far in our pharmacovigilance database to indicate any change in pattern of adverse events.

Okay. And you are seeing any

for the dose reduction on top of 380 for any reason, or if patients are fairly staying on that dose.

I know it's still early in the launch process.

I can't comment on whether or not we have visibility into that data.

Yeah, I don't think we're anecdotally hearing or seeing anything that's inconsistent with what we've observed in the clinical trial.

Thank you, and congratulations again. Thanks, Helen. Yeah.

With no further questions in the CLU, we will conclude today's conference. You may disconnect your lines at this time, and thank you for your participation.

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