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

Hello, ladies and gentlemen, and welcome to the Day One Biopharmaceuticals OJEMDA Approval Conference Call. [Operator Instructions] 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.

Hello, everyone, and thank you for joining us today to discuss the U.S. FDA approval of OJEMDA. Slides to accompany this conference call are posted on the Investors and Media section of our website at www.dayonebio.com. An audio webcast with the corresponding slide is also available on the website. Before we get started, I'd like to remind everyone that some of the statements that we make on this call and the information presented in the slide deck include forward-looking statements as outlined on Slide 2. Actual events and results could differ materially from those expressed or implied by any forward-looking statements. As a result, the various risks and uncertainties and other factors, including those set forth in our most recent filings with the SEC and in any other future filings that we may make with the. These forward-looking statements are based on our current estimates and various assumptions that reflect management's intentions, beliefs and expectations about future events, strategies, competition, products and product candidates, operating plans and performance. You are cautioned not to place any undue reliance on these forward-looking statements as Day One Biopharmaceuticals disclaims any obligation to update such statements. Today, I am joined by Dr. Jeremy Bender, Chief Executive Officer, Dr. Samuel Blackman, Co-Founder and Head of R&D; Lauren Merendino, Chief Commercial Officer; 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 us on today's call. We've reached a remarkable point in Day One's evolution, one that we approach the humility and with an awareness of our responsibility to our mission to the pediatric oncology community and most importantly, to children living with relapsed or refractory pediatric low-grade glioma or PLGG. Day One was created to address the innovation gap between pediatric and adult patients living with cancer and other life-threatening diseases. That gap is 6.5 years the average time between the start of an adult Phase I trial and the start of a pediatric clinical trial. This gap, of course, leads to long delays in the approval of new medicines for pediatric cancers relative to adult cancers if those new medicines are even studied in children at all. Today is a new Day One. For those of us here at our company, but more importantly, for patients with relapsed or refractory PLGG and their families and for the broader pediatric oncology community. I am thrilled to announce the approval by the U.S. Food and Drug Administration of OJEMDA, the brand name for tovorafenib for the treatment of relapsed or refractory PLGG in patients 6 months of age and older harboring a BRAF fusion rearrangement or BRAF V600 mutation. OJEMDA is the first and only FDA-approved therapy for this broad group of patients. I am profoundly grateful to everyone who has helped us get to this point, including the PLGG patients and caregivers who participated in OJEMDA's early and pivotal clinical trials, the clinical trial investigators and supporting staff who enrolled patients on our trials and the advocacy community members who have provided critical insights along the way. I'd also like to thank the FDA and the review team that partnered constructively with us throughout OJEMDA's NDA filing and review process. Here at Day One, we are all working towards a future in which our industry makes children an equal priority in the development of new cancer medicines. And we are thankful to our co-founders for having the courage and vision to bring this company to life. And to all of our Day One colleagues past and present, who have tirelessly dedicated their immense talent, expertise and passion to the goal of providing better outcomes for children and patients of all ages living with cancer. I thank you, all of you. We've achieved this approval with remarkable efficiency. A little over 4 years after initiating a program and just 3 years after the start of our first company-sponsored trial, we now have an approval here in the U.S. and with it, the opportunity to provide a broad group of patients with access to OJEMDA. This is an enormous accomplishment. OJEMDA's label or package insert which we'll describe in a moment, marks the first time the FDA has included either minor response or RAPNO criteria in a label as a measure of efficacy for a brain tumor. The OJEMDA story is about so much more than a new medicine for PLGG. It is about pairing a deep understanding of this disease and the needs of the patients and families who live with it with expert clinical development and trial execution. I'll now turn the call over to Day One's Co-Founder and Head of R&D, Sam Blackman, to discuss OJEMDA, the first FDA-approved therapy for BRAF altered relapsed or refractory PLGG.

Thank you, Jeremy. Today marks the realization of a dream that I've had for the past 20 years, a dream that started when I was a pediatric neuro-oncology fellow who had to share a devastating diagnosis of a brain tumor with children and their families. For too many years, despite a dramatically improved understanding of pediatric brain tumor biology, pediatric oncologists and neuro-oncologists have had a limited set of tools for treating recurrent brain tumors. More often than not, we had no choice but to rely on decades old chemotherapy drugs or radiation therapy with its lifelong risk of side effects. The disproportionately slow pace of innovation in drug development for pediatric oncology has been frustrating for everyone whose life has been touched by a child with cancer. With this is our motivation. In 2018, we envisioned the company designed to develop new medicines for childhood cancers at the same pace and with the same sense of urgency that we develop them for adults. Our mission at Day One is embedded in our name. We strive to create new therapies for pediatric oncologists to be able to present to their patients and their families at future Day One talks. And with OJEMDA, that future starts today. We are here because of patients like Lily seen here on Slide 7, who is diagnosed with a brain tumor when she was just 5 months old. Lily spent a significant portion of the first 11 years of her life in the hospital with her mom. She underwent surgery, followed by years of chemotherapy, and she vividly remember throwing up every time she had to have port access. Due to the tumor pressing on her optic nerve, Lily spent her first decade of life legally blind. At 1 point, she had to learn how to walk again. PLGG impacted her whole family. As the youngest of 4 children, she and her mom would spend up to 2 months at a time at different hospitals for treatment while her dad would stay home with her older brothers. PLGG had an enormous impact on Lily's childhood and so much more. Unfortunately, this is true for so many patients in their families living with this disease. With OJEMDA pediatric oncologists treating Lily and other children with this disease who have relapsed or refractory to treatment, finally have a new medicine to offer to their patients. I am so very proud that our relatively young company has been able to accomplish just what we set out to do when we formed Day One to truly put children at the forefront of oncology drug development. Before discussing the OJEMDA FDA-approved label on Slide 8, I'd like to briefly review the disease for which OJEMDA is now approved. Pediatric low-grade glioma, or PLGG, is the most common brain tumor in children. Unlike adult low-grade gliomas, PLGGs rarely transform into high-grade gliomas. In addition, they typically undergo senescence by the time a child reaches their early 20s when for reasons that are not fully understood, the tumor stops growing. Unfortunately, there can be a significant amount of time between diagnosis, which can occur as early as 6 months of age and young adulthood meaning a significant period of time for PLGG to [indiscernible] inside the developing brain of a child, whether it's the tumor pressing on an optic nerve creating blindness, damage to the hypothalamus or pituitary gland, causing profound endocrine disorders or pressure on motor structures in the brain causing hemiparesis, or loss of balance, PLGG is a thief, robbing children of the best parts of their childhood. PLGG and treatment-related morbidities change the trajectory of these children's lives. Approximately 30% of PLGGs can be totally resected, however, about 70% of patients with a PLGG will require systemic therapy. For over 15 years, we've known that the majority of PLGGs are driven by alterations in the BRAF gene, up to 75% of PLGG patients have a tumor with a BRAF alteration. Of these, approximately 80% are BRAF fusions or rearrangements, while the remaining 20% have a V600 mutation. Despite this, chemotherapy, most commonly either vincristine and carboplatin in combination or single agent vinblastine, remains the standard of care in the frontline setting for the majority of patients. However, due to the high rate of disease recurrence, patients will commonly undergo multiple lines of systemic therapy over the course of their disease. For patients in the relapsed or refractory setting, there is no standard of care. And for the majority, there have been no approved therapies until today. On Slide 9, the goals of therapy in PLGG are fundamentally different from how we think about treating adult solid tumors or high-grade brain tumors. As a result, developing a new therapy for PLGG patients involves truly understanding the needs of children with this disease and what defines successful outcomes for them and their families. We know that PLGGs will eventually undergo a program senescence. So the primary goal of therapy is to stop the growth of the tumor in order to prevent it from causing or worsening the neurologic endocrine visual and motor complications that can result from a tumor growing in the brain and then to continue to control or, if possible, reduce the size of the tumor for as long as possible until senescence occurs. Equally important is to do so in a way that reduces the burden of treatment, which can include multiple surgeries, chemotherapy and sometimes even radiation. Treatment modalities, which can be profoundly debilitating in the long run, especially in children with developing brains. It is with these facts and goals in mind that we saw both the need for new treatments for these patients and the path for a brain-penetrant type II RAF inhibitor to potentially become an important new medicine for children with BRAF altered PLGGs. With this background, I'd like to now discuss the FDA-approved label in a bit more detail. Looking at Slide 10, and as Jeremy mentioned, OJEMDA is approved for relapsed or refractory pediatric low-grade glioma in patients 6 months of age and older harboring a BRAF fusion rearrangement or BRAF V600 mutation. This indication enables treatment of patients with tumors that are progressing either radiographically or symptomatically both of which are the clinical situations that would drive a pediatric oncologist or neuro-oncologists to prescribe a systemic therapy. Importantly, given the many lines of therapies that PLGG patients typically undergo, OJEMDA can be used at any point in the disease journey for patients with BRAF fusions or BRAF V600 mutations who have had disease progression after their initial line of systemic therapy. The recommended dosage of OJEMDA is based on body surface area as is common with pediatric patients and is 380 milligrams per meter square orally once weekly. Notably, OJEMDA can be taken with or without food. It should be noted that the FDA recommended starting dosage is at 10% reduction from the dosage used in the Phase II FIREFLY 1 study. The label dosage is based on an analysis of exposure response and exposure safety data and has been adopted to reduce the risk of adverse events, while maintaining the effectiveness of OJEMDA. This dosage was determined by the FDA to be safe and effective for the treatment of patients 6 months of age and altered. Day One works closely with the FDA to identify the optimal dosage of OJEMDA during the NDA review and is fully supportive of FDA's assessment and recommendation. The approval of OJEMDA is based on data from our Phase II FIREFLY-1 trial, which was a global open-label trial that enrolled a total of 137 relapsed or refractory BRAF altered PLGG patients across 2 study arms. Arm 1, which accrued 77 patients was used for the efficacy analysis. Arm 2 was designed to provide safety data from an additional 60 patients. Details of this trial were presented in November of 2023 at the Society for Neuro-Oncology through 2 oral plenary presentations and in parallel to a publication in Nature Medicine, providing full details from this study. Turning to the efficacy data on Slide 11. As we have previously discussed, response assessment criteria for brain tumors is a complex topic and one that has been shifting even since the start of the FIREFLY-1 trial. As a result, this trial ended up evaluating response by 3 different and distinct sets of neuro-oncology response assessment criteria, RANO-HGG, RANO-LGG and RAPNO-LGG As a reminder, the 2010 RANO-HGG criteria were the original criteria used for the primary endpoint of the study because at the time of study design, these were the only response assessment criteria used for the approval of a drug for brain tumor patients. More recently, the 2011 RANO-LGG criteria designed for adult low-grade gliomas were used for the approval of a 2-drug combination for BRAF V600 mutant PLGG. In 2020, the response assessment for pediatric neuro-oncology or RAPNO working group published criteria specifically for PLGG, which we included in our study as a key secondary endpoint. As detailed in the Nature Medicine paper, we saw evidence of clinically meaningful tumor shrinkage by all 3 of these criteria. This is the first study to ever look at all 3 of these response criteria in any low-grade glioma population and has provided remarkable insights. In our paper, we described the overall response rates for RANO-LGG and RAPNO-LGG as being inclusive of [indiscernible] minor responses. As this criteria was intentionally included by the academic working group that design these criteria. As Jeremy indicated previously, minor responses by these criteria represent a decrease in the bi-dimensional measurements of the tumor from baseline of 25% or more, but less than 50%. This bidimensional change corresponds to an approximate volumetric reduction between 40% and 65%, which we and the authors of these criteria have asserted is clinically relevant, particularly for a disease such as PLGG where tumor stabilization has been the historic goal of treatment. As such, we are particularly pleased to state that the major efficacy outcome measure described in the USPI for OJEMDA is overall response rate by RAPNO-LGG criteria and is defined as the proportion of patients with a complete response, partial response or minor response by independent review. In Arm 1 of the FIREFLY-1 study for the 76 RAPNO-LGG evaluable patients, we saw a response rate of 51%, which included 28 PRs and 11 MRs. The 95% confidence interval around this point estimate range from 40% to 63%. The duration of response by RAPNO-LGG was 13.8 months as of the June 5, 2023 data cutoff, with the lower bound of the 95% confidence interval being 11.3 months and the upper bound being not estimable given that at the end of the data cutoff, 66% of patients remained on study. Looking at key subgroups, the response rate for OJEMDA was 52% amongst the 64 patients with BRAF fusions or rearrangements and 50% for the 12 patients with a BRAF V600 mutation. In addition, the response rate was 49% among the 45 patients who had received a MAP kinase targeted therapy and 55% among the 31 patients who had not. The median time to response following initiation of treatment with OJEMDA was 5.3 months. Additional outcome measures based on RANO-LGG criteria are also described in the USPI. We are very pleased that the FDA approved label includes these data, which we believe are extremely compelling, given that they were generated in a heavily pretreated group of patients. As noted in the label, patients received a median of 3 prior systemic regimens prior to study entry with a range of 1 to 9. This means that nearly all of these patients had received and progressed on or after chemotherapy and more than that, a significant proportion of these patients have been previously treated with a MAP kinase inhibitor. Seeing this degree of antitumor activity in this setting is as a pediatric neuro-oncologist, very exciting. We also want to take a moment to highlight the fact that this is the first time that RAPNO-LGG criteria have been used as the basis for regulatory decision-making. We want to thank the RAPNO Low-grade glioma working group for their hard work in defining response assessment criteria specific to the unique biology of pediatric brain tumors. In addition, this is the first time that minor response has been included in an FDA-approved label for a brain tumor medicine. We are grateful to the FDA for working with the pediatric brain tumor community to gain a deep understanding of PLGG and the goals of therapy for this unique patient population. Moving on to the safety summary on Slide 12, the warnings and precautions are consistent with the FIREFLY-1 trial data and are listed as hemorrhage skin toxicity, including photosensitivity, hepatotoxicity, effect on growth, embryo-fetal toxicity and use in NF1-associated tumors. We've also listed on this slide the most common adverse drug reactions occurring in at least 30% of patients, which include rash, hair color changes, fatigue, viral infection as well as several others as seen on this slide. In the FIREFLY-1 trial, most of these side effects were managed with the typical supportive care measures, the pediatric oncologists and neuro-oncologists are very familiar with. I should also note that the U.S. prescribing information does not include a boxed warning or REMS program or any country indications. I'd like to highlight 3 key points regarding the warnings and precautions. With regard to hemorrhage in our pooled safety population, we saw bleeding events occurring in 37% of patients. The majority of these were epistaxis or nose bleeds, which occurred in 26% of patients. Intratumoral hemorrhage, which is known to occur in relapsed PLGG occurred in 9% of patients. Serious events of bleeding occurred in 5% of patients, including 1 fatal case of tumor hemorrhage in a patient in the setting of disease progression. OJEMDA was permanently discontinued for hemorrhage in 2% of patients. With regard to effects on growth as described in the label, OJEMDA can cause reductions in growth velocity. In FIREFLY-1, treatment-emergent adverse events on growth occurred in 15% of patients 18 years of age or younger, including grade 3 events in 5% of patients. OJEMDA was permanently discontinued for reduction in growth velocity in 2% of patients. Data indicates that this effect is reversible. Patients followed after interruption of treatment with OJEMDA showed recovery of growth. In addition, among 19 patients who experienced reduction in growth velocity and who had hand radiographs taken to assess bone age and growth plates. There was no evidence of premature closure of the epitaxial growth fleets or advancement of bone age as is common for children undergoing other forms of cancer therapy, physicians are instructed to monitor growth routinely during treatment with OJEMDA. Finally, as noted in the USPI, OJEMDA led to increased phosphorylation of ERK in laboratory studies in cells with loss of function of the gene NF1. In addition, in studies using an NF1 genetically engineered mouse model of plexiform neurofibroma an NF1 driven solid tumor OJEMDA did not have antitumor activity and while not statistically significant, an increase in tumor volume in 2 of 12 mice were noted. Because NF1 mutations do not overlap with BRAF alterations, the presence of a BRAF alteration in a PLGG effectively rules out NF1 loss of function. As such, the presence of a BRAF fusion rearrangement or BRAF V600 mutation should be confirmed prior to initiation of treatment with OJEMDA. All in all, we are delighted with the OJEMDA label. We are all very excited to be able to deliver the first ever approved type II RAF inhibitor the first ever approved therapy for relapsed or refractory PLGG patients with BRAF fusions or rearrangements and a new approved therapy for children with relapsed or refractory PLGGs driven by BRAF V600 mutations. We're also pleased to be able to provide patients and families within oral once-weekly therapy available as both a tablet and a powder for oral suspension. Additional details about OJEMDA are available in the important safety information and prescribing information. Before I hand off the call to our Chief Commercial Officer, Lauren Merendino, I'd like to take a moment to say 1 more thing from the heart. Of the many things that I experienced as a young physician that made me choose to become a pediatric oncologist, there was 1 moment that bound me to this field forever. It was the first time that a parent put their sick child in my hands in the hope that I could help them. The trust that those parents were willing to have in me in that moment was so profoundly and deeply humbling that it took my breath away. It is with the same sense of humility and gratitude that I would like to thank on behalf of all of us at Day One, the children and their families who participated and continue to participate in our studies. Your participation made this day possible. To the parents of the patients on our trials, I'd like to say this as both a pediatric oncologist and as a parent, enrolling your child in a clinical trial, any clinical trial, is an act of profound bravery and generosity. It is an enduring gift to science and medicine and a gift to future patients. Thank you for putting your trust in us. I also want to thank our study investigators and the staff at our clinical trial sites around the world, our academic advisers and collaborators, and the many, many people who, over the years, worked on the molecule that is today known as OJEMDA and the patient advocacy groups who have been partners with us since the very beginning, and importantly, to my truly remarkable colleagues here at Day One. Creating a new medicine for childhood cancer patients is truly a dream realized for all of us.

Thank you, Sam, and hello, everyone. Our team couldn't be more excited and honored to make a difference for the PLGG community by making OJEMDA available broadly, and I'm pleased to share our launch plans with you. The PLGG patient population has some unique dynamics due to the nature of the disease. As Sam mentioned, up to 75% of PLGG tumors are BRAF altered. So let's focus just on patients with these tumors. While there are over 26,000 prevalent systemically treated patients, many of these patients are either already on treatment or not on treatment because their tumor is currently stable. We estimate that each year, 2,000 to 3,000 BRAF altered relapsed or refractory patients will be seeking therapy. Approximately 80% of these patients have tumors with BRAF fusions, and OJEMDA is the first and only FDA-approved option for these children. The other 20% of patients have tumors with BRAF V600 mutations and they now have a new option with OJEMDA. When we ask physicians what's important to them in a PLGG treatment, they tell us 3 things: a therapy that's effective in stopping or shrinking tumors, a manageable safety profile with minimal long-term risk and a treatment that is minimally disruptive to a child's life. When we speak to parents of these children, they have similar priorities. In addition to treating the disease, they are looking for therapies that enable their child to live as normal of a childhood as possible without interruptions. They want their child to have minimal impact from the disease and minimal disruption to their lives from hospital stays medical visits and drug treatments. With OJEMDA, we believe we can meet many of these needs. The FIREFLY-1 clinical trial demonstrated that OJEMDA is effective in treating patients with relapsed or refractory PLGG tumors with either BRAF fusion or mutation. With more than half of patients seeing their tumors decrease in size by 25% or more and 8 out of 10 patients seeing a clinical benefit, the efficacy of OJEMDA is compelling. Sam reviewed our full safety information, and we believe OJEMDA has a manageable safety profile as evidenced in part by the fact that 9 out of 10 patients in the pivotal study remained on treatment. OJEMDA is an oral medication taken at home once weekly with or without food and with the option to be taken as either a pill or liquid formulation. We believe this has the potential to reduce daily interruptions in the child and families' lives. For a successful launch, we're focused on physicians, payers, and patients and their families. For physicians, our goal is to establish OJEMDA as the first choice for appropriate PLGG patients. We are already seeing anticipation in the community with almost 90% of target physicians aware of OJEMDA and approximately 65% of those that are aware intend to prescribe the product. This is a great foundation off of which to build a successful launch, and our fully dedicated sales team will continue to build on this momentum. With payers, our priority is to rapidly establish broad coverage for patients, consistent with our label. At steady state, we expect our payer mix to be about 60% commercial and 40% Medicaid. In preparation for launch, we've engaged with commercial and Medicaid payers covering approximately 90% of patients to introduce Day One and provide information on PLGG to help inform their decision. Now that we're approved, our payer team is following up with these customers to announce our approval and provide additional information to expedite their coverage physicians. Most importantly, for patients and families, our goal is to provide a positive and supportive experience when they're initiating OJEMDA therapy. To do this, we've established a closed distribution model with 2 specialty pharmacy partners. Biologics and Onco360. Through these 2 specialty pharmacies and our dedicated patient support services, we believe we can provide high-quality and consistent support to all patients. Next slide. When a child is diagnosed with a brain tumor, parents seek out pediatric experts for treatment. These physicians, pediatric oncologists or pediatric neuro-oncologists are concentrated at approximately 200 accounts across the U.S. This enables us to have a very focused and efficient sales effort because approximately 90% of children with PLGG are treated at these accounts. In January, we hired a sales team of 18 account managers. It's a highly experienced group with a depth of expertise in oncology and rare diseases and many coming to the team with prior clinical experience. Additionally, most of our account managers came with existing relationships at our key institutions, which is important to accelerate access to our customers. The team has been fully trained and has been in the field engaging and learning about their customers in advance of launch. Today, following approval, they're now at our top priority accounts introducing HCP's to OJEMDA. Our most important goal is to provide patients with access to OJEMDA and ensure that their experience is a positive one. To do this, we've put a comprehensive patient support program in place, which I'll talk about in a moment. To establish a price for OJEMDA, we took a thoughtful approach considering a variety of factors, including the size of the PLGG population, the clinical value our product brings to patients and our mission to create a sustainable company that can continue to support PLGG patients while further investing in research and development in pediatric oncology and beyond. Based on this, we've set the wholesale acquisition cost, or WAC, for OJEMDA at $33,916 for a 28-day supply of either tablets or powder for oral suspension. The price is consistent across all packages to minimize price differences as a patient grows and needs higher doses. We believe that no matter the insurance costs should not be a barrier to access and that treatment decisions should be left to providers and patients. So we're excited to introduce our patient support program, EveryDay support from Day One. EveryDay support is a high-touch service that makes it easy for patients to access OJEMDA with customized solutions based on the patient's needs. For all patients, we offer support to help secure reimbursement and coverage through their insurance provider. For those with a delay or interruption in coverage, we're able to provide temporary free drug so that they can start on therapy quickly and avoid interruptions in treatment. The agenda co-pay card can reduce commercially insured patients co-pay to as little as $0 per month. And for those eligible patients who are uninsured or underinsured, our patient assistance program can help provide drug at no cost. In addition, our specialty pharmacy partners will ship OJEMDA directly to patients' homes and provide ongoing prescription and refill support throughout the patient's journey. Everyday support makes initiating and staying on OJEMDA a smooth and simple process. Some of the first patients to use our support services will be those who are enrolled in our expanded access program, or EAP. This program was started when enrollment for FIREFLY-1 trial was closed, and it provided access to OJEMDA for patients who needed a new option to treat their relapsed or refractory PLGG. Enrollment in this program is now closed and a coordinated effort between our medical affairs and market access teams is underway to transition patients from the EAP to commercial drug over the next few months. Everyday support will assist in making this a seamless process for patients. We've assembled a team of extremely passionate people who are energized around our mission to prioritize advancing care for children with cancer. Many of them have personal reasons that have brought them to this mission. And as a mother of a 5-year-old and a caregiver on a loved one's cancer journey, I count myself as one of them. We've channeled our passion into preparing for this moment, and now we can direct that passion into making a difference for children living with PLGG. We are ready. We are energized and we are grateful for the opportunity to serve the PLGG community and make a difference with OJEMDA.

Thank you, Lauren. We have been laying the groundwork for our transformation into a commercial company for years, 1 that grows sustainably and outperforms. We have all of the key elements in place to achieve this expansion successfully, and I'm confident that our team will deliver a successful launch. I speak for everyone at Day One. When I say that we are grateful for and humbled by the opportunity to bring a new medicine to the childhood cancer community. Our commitment will not stop here. This is the first step in our journey to advance potential new medicines for patients of all ages living with cancer.

[Operator Instructions] Our first questions come from the line of Anupam Rama with JPMorgan.

Congrats on the approval. The Nature publication did highlight clinical benefit rate as kind of a key endpoint and you guys highlighted in the slides as well. Just wondering how regulators view CBR in your discussion and how important it is to physicians. And then a second question, the product label, as you guys highlighted, includes RAPNO-LGG and RANO-LGG, but not RANO-HGG which was the primary endpoint of FIREFLY-1. Can you walk us through the regulatory discussions here across the endpoints? And now as you look forward, how you think about the frontline FIREFLY-2 study endpoints?

Thanks, Anupam, for the question. I'm going to ask Sam and Lauren to comment on CBR and then Sam to comment on the endpoint question. Much appreciate it.

So from a physician perspective, when we do -- when we've done research, they've shared with us that CBR is the most important endpoint for them. It really aligns with their treatment goals for this patient population. And so we do believe that, that is the most important data set, and we will be able to share that with physicians.

Yes. Thanks, Anupam, for the question. Again, I think as Lauren said, CBR is important to physicians. As we've said clearly many times before, historically, the goals of treatment for this disease has been disease stabilization. So clinical benefit rate, which represents the sum of objective responses, minor responses, partial responses, complete responses and stable disease added together, really, I think, highlights the ability of OJEMDA to impact the disease in a meaningful way. Because if you stabilize the tumor through biological senescence of the tumor and the patient can go on to live their life without any additional treatment. And you certainly -- I think that with also therapy -- and if you shrink the tumor, then obviously, we think that, that is above and beyond and clearly important to patients and families as well. So we've highlighted in the Nature Medicine publication clinical benefit rate and physicians are aware and all that data is absolutely out there. With regard to your second question around end points, it's been really quite fascinating for us to be part of the evolution of response assessment criteria over the past 5 years that we've been working on the study. As I indicated in the call, when we initially designed the trial and talked to the FDA. RANO-HGG was the only response assessment criteria used at that time for the basis of regulatory decision-making. Of course, things change as we understand more about how these response assessment criteria give us insights into the activity of drugs in pediatric low-grade gliomas, the agency when they were evaluating other applications in the past 3 or 4 years. We used RANO-LGG where of course, those criteria were designed for adult low-grade gliomas, which are biologically fundamentally different than pediatric low-grade gliomas. As we brought forward our study, we worked closely with the agency included assessments by both RANO-HGG and RANO-LGG, but also RAPNO-LGG, which were designed specifically for pediatric low-grade gliomas. And we're very pleased that the dialogue that we had with the agency in conjunction with key opinion leaders in the field allow them to understand this as a measure of activity. Similarly, it allowed them to understand and align with us on the value of minor response as an indicator of benefit to patients and I think that, that's now all clearly reflected in our label. With regard to FIREFLY-2, obviously, when we designed that trial a couple of years ago, we were talking to the agency all along the process, and we continue that dialogue with them, including an active dialogue about the primary input for FIREFLY-2 in the setting of now approval for OJEMDA using RAPNO-LGG as the basis for activity.

And I would just add, of the aspects of this approval that I'm most excited about, and it was obviously really great news for us at the company and for patients more broadly. The discussion we've had with the agency around these endpoints and the resolution to focus on RAPNO is 1 of the more just exciting aspects of the approval because I do think we've now started to move towards an end point for these trials that is a better one. And of course, we're going to be in discussions with the FDA to consider that for FIREFLY-2 as well.

Our next questions come from the line of Marc Frahm with TD Cowen.

Let me offer my congrats also to the whole team for getting this approval. Maybe can you just give us a little bit of a sense of the trajectory of enrollment into the EAP and maybe more broadly, kind of at those centers that have been very active in the trial and just kind of how many patients are sitting at those centers that are obviously deeply familiar with the product and how to use it?

Marc thanks much for the comments and the question. We've seen pretty consistent interest in access to tovorafenib once we closed both arm 1 and arm 2 of FIREFLY-1, we haven't provided a specific listing of the patients that are on the EAP in the U.S. That program actually covers the FIREFLY-1 sites, not just here in the U.S. but outside of the U.S. as well. But let me just hand to Lauren to tell you about the process that we will be employing going forward now that we're approved for access for those patients who are in the U.S. on the EAP program.

Yes. Thank you, Jeremy. So the med affairs and market access teams are working closely together in order to help reach out to all the physicians who have enrolled patients in our EAP program and offer them an opportunity to shift those patients over to commercial product. We have very easy forms for them to fill out in order to get that process started. And then our EveryDay support program will kick in. And so that will help to navigate the payer environment to establish whether that patient has payer coverage and if not, then to leverage 1 of our programs in order to bridge the gap until they're able to get coverage or to provide free drug if they do not have any coverage. So we anticipate this process to run over the next few months because it does take payers to make -- time to make decisions on new products, but we expect to have that completed over the next few months.

Okay. That's really helpful. And then maybe as Sam laid out, the treatment goals here are a little bit different than a lot of other areas of oncology and safety is really a big focus for patients and physicians. Would you expect the patients coming on to commercial product now to be entirely patients who are actively progressing and having tumor growth? Or would you expect a meaningful number of people who may have, at one point, progressed or relapsed but are currently kind of seeing tumor control with the existing options that have been available to them, but maybe are more toxic than OJEMDA to start touching as well.

Marc, I'll ask Sam to answer that one.

Yes. So I think, Marc, it's a good question. Thank you for asking it. I would look at the sort of the landscape of patients at any given moment as follows: One, and I think Lauren did a beautiful job of elucidating is there are patients who have undergone treatment, maybe they've undergone chemotherapy and their tumor is stable right now, there's no clinical evidence of progression and radiographic evidence of progression. But there's a likelihood of course, that, that tumor is going to grow. If that patient is doing well, there's no radiographic or clinical indication of growth and that tumor sitting there quietly at the moment. And I don't think that that's necessarily an indication for treatment, and I'm saying this is a pediatric neurooncologist. And I think most of my clinical colleagues would agree with that. I think for patients who have tumors that are actively growing following the span on line of therapy. And certainly, the OJEMDA could be something that's being considered. I think the question that you're asking, though, is what about somebody who's on an active therapy right now whether or not physicians would consider switching. I think at the end of the day, it's a complex discussion and 1 where I don't think you can create any broad generalizations because the decision to switch treatments is really multifactorial, and it takes into account how well the patient is tolerating whatever therapy it is that they're on whether or not that therapy is achieving the goals of treatment as per the physician and the patient and the family. So I anticipate that there will be those types of discussions out there for some patients now that there's a new approved therapy. But I don't think that we can really predict whether or not physicians would consider switching. I think we'll learn more over time as we hear more from physicians who are taking care of patients as we engage with the market. That's pretty much, I think, what I can say as of right now.

Our next questions come from the line of Joe Catanzaro with Piper Sandler.

And of course, let me add my congrats to the whole team there. Maybe my first couple of questions are actually on FIREFLY-1. First one, maybe somewhat related to this idea of transitioning EAP patients onto commercial product. Wondering if there's any opportunity to transition patients on FIREFLY-1 on to commercial drug. I know as the June 2023 data cut there were still about 100 or so patients still on drug. So wondering how many are still actively being dosed within FIREFLY-1? And then maybe somewhat relatedly on FIREFLY-1. Any updates on median duration of treatment? I know last year was 15.8 months, but within Arm 1. But I think 66% of patients were still on drug. So any updates there as we try and think about sort of the total duration of treatment patients can see in the real world. And I have maybe one quick follow-up.

Joe, thanks for the comments and the question. So we've extended FIREFLY-1 and will continue to follow the patients on that trial in part to get additional data, including, as you know, the duration of treatment over time. We do not anticipate that those patients, certainly for the life of that trial, will be converted over to commercial product at this stage. So that certainly is an option for EAP patients, but not for FIREFLY-1 patients at this point. Yes. And then just maybe to the second part of your question there, Joe. We will, of course, as the study winds up have the opportunity, I'm sure to present updated data, but we don't have -- we've not wrapped up the study and obviously don't have any additional data cuts right now that we presented, but we're always, again, looking for opportunities to compile that data as we learn more and present them in appropriate settings like a medical conference or a publication.

Okay. Great. And if I could just maybe squeeze in a follow-up, if that's okay. I know you guys have long spoken to the 26,000 prevalent pool of systemically treated patients. You more recently noted sort of the 2,000 to 3,000 annual incidents of patients seeking treatment. Maybe can you just sort of walk us through what informs that estimate of the incident rate and your level of confidence in that number?

So let me first summarize what we have said. It's 26,000 as a prevalent pool of BRAF altered PLGG patients who have been treated systemically at some point. The 2,000 to 3,000 number is not an incidence rate. That's the population that we estimate at any given point in time is on a systemic therapy here in the U.S. who has PLGG and a RAF alteration. So it's not incidents rather the pool of patients that are receiving an active therapy. And what we've used to get to that number is really all of the historical data that's available on essentially PFS from studies of agents that have been tested in PLGG patient populations paired with incidence data in a cohort-based model. The incidence of PLGG is distinct, and we estimate that it's 1,100 a year PLGG patients that have a BRAF change in the tumor, either a RAF fusion implication or duplication V600 new change.

Our next questions come from the line of Andrea Tan with Goldman Sachs.

Congratulations on the approval. Lauren or Sam, maybe as a follow-up, Marc's question. But how are you thinking about the cadence of this launch? And should we expect the bolus of patients to be treated relatively quickly? Or do you anticipate it will be more gradual as physicians gain some real-world experience with the drug? And then just curious, when you note the 65% of physicians who intend to prescribe what is needed to get the remaining 35% on board?

Andrea, thanks much for the question, and I'll ask Lauren to speak to it.

Yes. Thanks, Jeremy. So from a cadence of launch perspective, in the research that we've done leading up to launch, we've heard some physicians a great interest in our product. What we haven't heard is that the warehousing patients or that they have patients queued up for the product. In this case, because of the nature of this disease, if a patient needs treatment, they are likely on treatment, right? So they're not going to hold treatment for those patients. And so for that reason, we wouldn't expect a significant bolus at launch. With the exception of what Sam laid out, if a patient isn't tolerating the therapy they're on very well or the parent or caregiver feels that tovorafenib may be a better option that could possibly lead to a switch, but in the most case, those who are treated will continue on their treatment if it's working for them. So we do not expect a bolus. And then from an uptake perspective, there are patients who are -- who have received multiple lines of therapy to maybe have utilized the options that are already available. And therefore -- so there's a pool of those patients who are likely to receive a new treatment when is available like tovorafenib and so some of the early experience with the product may be in patients with later lines. However, we do hear from physicians who are intending to prescribe that they have an interest in using it in second line and beyond. And we do believe that there will be some physicians who -- we actually see our physicians make decisions on different information, right? Like so they all consider the same things, but they have different priorities. For those who prioritize cutting-edge scientific data. We believe that we have compelling data that will get resonate with them. For those who put patient needs first as far as not disrupting the childhood, we also believe we have a compelling story. I think the folks who are in the bucket of not yet intending to prescribe are in the last bucket, which is going to long-term -- follow-up long-term safety data and are comfortable with some of the older products that are on the market and tend to prioritize using chemotherapy. And so that doesn't mean that they aren't going to use tovorafenib, that is what our job as a commercial organization is to educate them on which patients would be appropriate. But it may just take them a little bit more time to gain comfort with a new product and they want to hear from their colleagues that they're using it and having success with it before they try the product. And so that's the remaining physicians who have not indicated that they intend to prescribe yet.

Got it. And maybe just 1 quick question. I'm not sure if I missed this, but when will drug be first available to patients? And how are you thinking about duration of use?

Yes. So thank you for the question on drug availability. So we do believe we will have drug in the channel and ready to be shipped to patients in about 2 weeks post approval. So our team is working to make drug available as quickly as possible. From a duration perspective, we do anticipate it will be similar to what we're seeing in our studies, right? And so in our last data cut, which is from June, we had a median duration of close to 14 months...

No, it's just under 16 months.

Sorry. So just under 16 months, apologies. So just under 15.9 months. So that's 66% of patients remaining on therapy. So it's something north of that, and we anticipate the same will be true in the commercial setting.

Our final questions will come from the line of Soumit Roy with Jones Research.

Congratulations again on the approval. One question on the status of any European filing or if you're thinking of partnering, what is the near-term action on the European front? And the second is, what do you -- are you going to provide any launch metrics or target launch metrics, how many centers to cover in third quarter or fiscal year 2024?

Soumit, thanks much for the questions, and I appreciate the congrats. Let me hand to Charles to answer those questions for you.

So I'll answer the second question first. From our perspective, Yes. We've been pretty clear and consistent in regards to forward-looking guidance. And we believe that the best way for us to proceed is with our actual information and don't intend on providing any forward-looking guidance in the near future, either through launch metrics or even cap from debt financial information ourselves. This is, as you know, a new therapy and an area where the market still needs to be built and the team is working hard to do that. So we'll stay focused on that as our alternative. And then on the second piece or on your first question in regards to ex U.S. I think it's important to step back and look at how we think about commercialization and growing the company in total. It's clear from words of Lauren and Sam put together today that the team is ready to go in the U.S. for launch, seems ready to win there. And we've looked at the ex U.S. side as an area of real value and something we're very interested in. We've also looked at it from the standpoint of understanding who could be good partners there to help partner with us during the regulatory process and for long-term commercialization, both in the relapse setting and what we anticipate in front line. So we will continue partnership conversations over time. Always hard to decide the exact timing of that. But given the approval now of OJEMDA, it is important for us to start making some progress on that front as well.

Understood. One last question on the -- looking a little beyond pediatric glioma. Any color you can provide on the FIRELIGHT trial? It looks like you're going to present the RP2D in that trial with the MEK inhibitor combo. Any color on how many patients' tumor types, specific tumor types getting enrolled?

Clearly not at this point, we are going to provide an update on the FIRELIGHT-1 trial in the second half of the year, as we've emphasized previously. And that will include some details of the experience to date in the Phase I portion, really the dose escalation portion of that study as well as the next step in Phase II. Phase, including any expansion cohorts that we plan to go into. But nothing beyond those details at this stage.

That does conclude today's call. We appreciate you joining. You may now disconnect.