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spk05: Good evening, ladies and gentlemen, and welcome to Day 1 Biopharmaceuticals Fly 1 Trial Conference Call. At this time, all participants are in a listen-only mode. Later, we'll conduct a question-and-answer session. Please be advised that today's conference is being recorded. I would now like to turn the conference over to your host today, Joey Perrone, Senior Vice President of Finance and Investor Relations. Please go ahead.
spk07: Thank you. Good evening, and thank you for joining us. Earlier today, we issued a press release providing an update on the new clinical data from a registrational Phase II Firefly 1 clinical trial evaluating tovarapinib in relapsed or progressive pediatric low-grade glioma. Slides to accompany this conference call are posted on the Investors in Media section of our website at www.dayonebio.com. An audio webcast with the corresponding presentation slides 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 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, including as a result of various risks, uncertainties, and other factors including the step forth in our most recent filings with the SEC. and any other future filings that we make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements, and day one disclaims any obligation to update such statements. Joining me on the call today are Dr. Jeremy Bender, Chief Executive Officer, Dr. Samuel Blackman, co-founder and head of R&D, and Charles York, Chief Operating and Financial Officer. For those of you following with the slide deck, that we have provided, Jeremy will begin on slide four. I will now turn the call over to Jeremy, CEO of Day One.
spk09: Thank you, Joey. Hello, everyone, and thank you for joining us on the call today. I'm excited to be in Chicago at ASCO 2023 with our team from Day One and with so many of our important partners, partners who've joined us on our mission to bring treatment options to children and adults suffering from the effects of cancer and other life-threatening diseases. Our data from Firefly 1, which is our pivotal study in relapsed or progressive pediatric low-grade glioma, were shared this morning in an oral session by Dr. Lindsay Kilburn of Children's National Hospital. In addition to reviewing these data, we'll provide additional updates on this call about Day 1, focusing on the regulatory and clinical impact of Firefly 1. As we provide this important update, it's critical to keep in mind that Day 1 was created to address the innovation gap between pediatric and adult patients living with cancer and other life-threatening diseases. That gap is approximately six years. That's how much longer, on average, children have to wait than adults for access to life-saving cancer treatments. At Day One, we aim to re-envision cancer drug development and redefine what's possible for all people living with cancer, regardless of age. Simply put, we're a targeted therapeutics company. We conduct clinical trials in patient populations with genetic alterations that our programs are specifically designed to address. What differentiates day one from other targeted oncology companies is our goal to move as quickly as we can into pediatric populations. We generate clinical data in the pediatric setting and then we move into registrational trials in that setting as early as possible in parallel with the work we do in adolescent and adult oncology populations. Since our launch in 2020, we've been successful in building a highly qualified and experienced team, advancing our lead program, tovirafinib, expanding our portfolio, and resourcing the organization as we prepare for potential registration and a U.S. commercial launch. Our lead product candidate is tovirafinib, an oral brain-penetrant type 2 RAF inhibitor. The lead indication under investigation is relapsed or progressive pediatric low-grade glioma, for which we have breakthrough therapy designation, orphan drug designation, and rare pediatric disease designation in the U.S. Today, we'll discuss new data from the Registrational Phase 2 Firefly 1 trial, evaluating tovirafinib as once-weekly monotherapy in patients aged six months to 25 years with recurrent or progressive PLGG. Before we review the data and provide color, I'd first like to hand the call over to my colleague, Sam Blackman, to provide perspective on pediatric low-grade glioma.
spk10: Thanks, Jeremy, and thanks to all of you for joining us this evening. As can be seen on slide five, pediatric low-grade glioma, or PLGG, is the most common form of brain tumor in children. It's markedly different from high-grade tumors as well as from adult low-grade gliomas in that PLGGs rarely transform to higher-grade tumors and they typically undergo senescence by the time a child reaches their early 20s. Until recently, PLGGs have most often been treated with surgery where possible, and then chemotherapy, and eventually radiation for children who've had disease recurrences. For patients with relapsed or progressive disease, these tumors can be chronic and relentless, and depending on their location in the brain can have a substantial impact on vision, motor function, endocrine function, and quality of life. While the prognosis for PLGG is generally high in terms of overall survival, the near-term and late effects of the disease, of surgery, of traditional chemotherapy, and of radiation are significant. Survivors often experience functional, neurological, and or endocrine complications from the tumor, from the required treatment, or both. We believe that there's a huge unmet need in this disease area with no established standard of care for the majority of children. New treatments that target the MAP kinase pathway are changing the treatment landscape, but there remains a significant need for the approximately 85% of BRAC fusion patients for whom there are no approved therapies. I'll now hand it back to Jeremy to provide an overview of the status of the Firefly-1 program.
spk09: As you can see on slide six, the development of tovirafenib for PLGG has come a long way in a short period of time. We started day one with the ambitious goal of building a truly differentiated oncology company, one that focuses on the unmet need in children. And in the two years since we enrolled the first patient in our pivotal Firefly One trial, which is our first company-sponsored study, we are excited to announce that in May of this year, we initiated the rolling submission of the NDA for tovirafenib in relapsed or progressive PLGG. This is an important accomplishment for the day one team, and was the result of a productive pre-NDA meeting with the FDA in April of 2023, during which we reviewed the evidence of clinical benefit for tovirapinib and PLGG that we've observed to date and aligned with the agency on a rolling NDA submission on the basis of results from the Firefly One trial. We appreciate the FDA's continued partnership with Day One. Looking forward, we expect the rolling NDA submission will be complete in October 2023, following submission of an amended clinical study report that will include safety and efficacy data from a planned June 2023 data cutoff from Firefly 1. The completed rolling NDA submission will be for the indication of relapsed or progressive pediatric low-grade glioma and will be based on the results from the Firefly 1 trial. This plan sets us on a trajectory towards delivering on our initial goals. providing therapeutic options to children and families living with a severe impact of cancer. I am humbled and gratified by where we are today. On slide seven, you'll see the study schema for Firefly 1. Arm 1 of Firefly 1 represents a registrational arm of the trial, which we initiated following early data for toforafenib and relapsed PLGG from the PNOC014 study, an investigator-sponsored trial initiated at Dana-Farber. The Firefly 1 trial enrolled patients six months to 25 years of age with relapsed or progressive PLGG harboring a BRAF alteration. It's important to note that prior use of MAP kinase therapy was allowed in Firefly 1 in contrast with other trials. Some patients enrolled in Firefly 1 had already been treated with multiple MAP kinase inhibitors. The primary endpoint of the trial is overall response rate, or ORR, by Raynaud HGG as assessed by blinded independent central review. The primary endpoint of the study remains unchanged. Today, we will also share data from the secondary endpoints of ORR by Rapinoe-LGG, which is currently unadjudicated, Raynaud-based PFS, duration of response, time to response, clinical benefit rate, and safety. We will also be sharing the exploratory analysis of ORR by Raynaud-LGG as assessed by blind and independent central review. Sam will now walk you through the results of the trial.
spk10: Thanks, Jeremy. On slide eight, I'd like to begin by reviewing the baseline demographics and characteristics of the patients on Firefly 1. We enrolled 77 patients on Arm 1 of Firefly 1. The data cutoff for this presentation is December 22nd, 2022. The patients in this data set are between the ages of 2 and 21 years of age with a median age of 8. Patients are balanced between males and females, and the distribution of patients by race is consistent with the patient demographics at our trial sites and the distribution seen within this disease. Nearly all patients had a Karnovsky or Lansky performance status of 80 to 100 on enrollment. The distribution of tumors within the CNS is noted in the illustration in the upper right corner of the slide. with approximately half of the tumors treated being within the optic pathway, which includes both the optic nerve and optic chiasm. The remainder are within the supratentorial, infratentorial, and midline or brainstem regions of the brain. All patients have tumors with confirmed BRAF alteration, and consistent with the molecular epidemiology of PLGG, approximately 85% of patients have a tumor with a BRAF fusion, while the remainder have a tumor with a BRAF B600E mutation. This is a heavily pretreated population of patients, with almost half of patients having had three or more prior lines of systemic therapy. It's noteworthy that nearly two-thirds of patients in this data set had prior treatment with one or more prior MAP kinase pathway inhibitors, either one or more MEK inhibitors, a type 1 RAF inhibitor, or combined RAF-MEK treatment. The high rate of prior MAP kinase inhibitor use is important to note in that other studies typically exclude patients with prior MAP kinase inhibitor use. It's also important to note that patients who have progressed on or after chemotherapy and a MAP kinase inhibitor have few options outside of a clinical trial or radiation therapy. Moving to slide nine, of the 77 patients enrolled on Arm 1 of Firefly 1, 69 had lesions that were renal-evaluable by blinded independent central review. As you can see, 67% of patients have achieved an overall response as assessed by blinded independent central review for the primary endpoint of the study. Four patients had a confirmed complete response, or CR, and 42 patients had responses classified as a partial response, or PR, by Raynaud, meaning that the sum of the product of the perpendicular diameters of the lesions decreased by greater than 50% from baseline. Three of those are unconfirmed and those patients still continue on treatment as of May 23, 2023. All other patients who had complete or partial responses were confirmed by a follow-up scan. We believe that the frequency and the depth of these responses are encouraging, especially when viewed in the context of the totality of the data, including the decreases seen on T2-weighted sequences and the duration of response. In addition to the partial responses, 18 patients had stable disease by Raynaud, And for Raynaud, stable disease means the tumor change from baseline is somewhere between an increase of up to 25% and a decrease of 50%. Of the 18 patients who achieved the best response of stable disease by Raynaud, the majority had a reduction from baseline in the size of their tumor. As you can see, several of the Raynaud-evaluable patients had BRAC B600 gene mutations represented by dots at the ends of the bars. with the majority achieving a complete or partial response. Finally, we have indicated patients who received prior MAP kinase treatment by shading the bars orange. You can see that there's no correlation observed between either the likelihood of achieving a response or the depth of the observed response and prior treatment with a MAP kinase inhibitor. The clinical benefit rate defined as a confirmed CR or PR stable disease is 93%. On slide 10, we now look at the response data using the secondary endpoint of RAPNO-LGG criteria. As noted previously, these data have not yet been adjudicated, and as a result, this waterfall plot shows the RAPNO-LGG data for the 69 Raynaud evaluable patients discussed on the previous slide. As you can see, 51% of patients have achieved an overall response as assessed by blinded independent central review. 17 patients had responses classified as a partial response, or PR, by Rapinoe-LGG, meaning that the sum of the product, the perpendicular diameters of the lesions on T2 flare sequences, decreased by 50% from baseline, with four of these pending confirmation. All four unconfirmed PRs remain on treatment as of May 23, 2023. 18 patients had a minor response, or MR, meaning that the sum of the product of the perpendicular diameters of the lesion decreased by more than 25% from baseline, but less than 50%. Four of the 18 minor responses are unconfirmed, with three remaining on treatment as of May 23, 2023. 25 patients, or 36%, had a best response to date of stable disease. The clinical benefit rate, defined as a confirmed CRPR MR stable disease, is 87%. We believe the frequency and depth of responses and the consistency of tumor shrinkage within this population are also very encouraging, especially given the complexity of interpreting T2 signal abnormalities in this heavily pretreated population. While these are different criteria for measuring tumor response to treatment, these data show that the majority of patients have reduction in tumor size in response to monotherapy tovirapidib visible on both T1 post-contrast and T2 flare images. It's also important to emphasize that while the RAPNO-LGG response criteria use the term minor response to define a reduction of 25 to 50% from baseline, seeing this degree of response in a heavily pretreated relapsed or refractory population is something that the pediatric neuro-oncology community has told us is important. That's because reduction of 25 to 50% in the sum of the products of the perpendicular dimensions corresponds to an approximately 40 to 65 percent reduction in tumor volume in a disease where historically tumor stabilization over time has been the goal of therapy this degree of response is noteworthy for example for patients with tumors in functionally sensitive areas such as the optic pathway in some instances a change in tumor size on the order of millimeters can make a difference between the preservation and loss of residual vision Similar to the waterfall plot for the primary endpoint, BRAC B600E mutant patients are indicated by a dot at the end of the bar. And similar to the Raynaud HGG responses, the majority of B600E mutant patients have had clear tumor shrinkage. Finally, we've indicated patients who received prior MAP kinase treatment by shading the bars orange. And again, there is no correlation observed between either the likelihood of achieving a response or the depth of the observed response and prior treatment with a MAP kinase inhibitor. On slide 11, we have a waterfall for Raynaud-LGG, which was included as an exploratory endpoint in the study. These data have been fully adjudicated, and baseline eligibility has been confirmed. Here we see the data for 76 Raynaud-LGG-available patients. As you can see, 49% of patients have achieved an overall response as assessed by blinded independent central review. Twenty patients had responses classified as a partial response, or PR, by Raynaud-LGG, of which eight are pending confirmation, with all eight unconfirmed PRs remaining on treatment as of May 23, 2023. Similar to Rapinoe-LGG, this indicates a decrease by greater than 50% from baseline. Seventeen patients had a minor response, or MR, or a decrease of 25% from baseline but less than 50%. of which two are pending confirmation with both of these patients remaining on treatment as of May 23, 2023. All the patients who had confirmed partial or minor responses were confirmed by a follow-up scan. Twenty-six patients, or 34%, had a best response to date of stable disease. The clinical benefit rate using renal LGG, defined as a CR, PR, MR, or stable disease, is 83%. Similar to what I mentioned for Rapinoe-LGG, given the fact that T2 signal abnormalities seen on MRI are complex and are not always expected to fully resolve in the setting of a relapse PLGG, we find these data to be encouraging and taken together with the Raynaud HGG data and the Rapinoe-LGG data, we believe that these data in their totality provide a comprehensive picture of anti-tumor activity with monotherapy tovirapinib using three different response assessment criteria. And once again, B600E mutant patients are indicated by a dot at the end of the bar with nearly all having tumor shrinkage. And again, there appears to be no correlation observed between either the likelihood of achieving a response or the depth of the observed response by Raynaud-LGG and prior treatment with a MAP kinase inhibitor. On slide 12, we see duration of therapy and duration of responses for all 69 patients with Raynaud-HGG-evaluable lesions. This swim lane plot displays the duration of treatment on the x-axis. Bars for patients who remain on treatment as of the data cutoff are colored blue, while those who have discontinued treatment are colored orange. The yellow and magenta dots indicate the time of the first partial response or complete response respectively by Raynaud criteria. As you can see, the majority of patients who had responses had them by the first response assessment time point, and the median time to response for the confirmed responses is 2.8 months. This is consistent with the rapid responses that we observed in the Phase 1 PNOC-014 study of tovirafenib. We've indicated whether or not patients had a prior MEK or BRAF inhibitor along the y-axis, as well as whether or not the patient had a BRAF B600E mutation. As of the data cut off the median IRC assessed duration of response with confirmed responses based on Reno HGG criteria was not yet reached. With the lower bound of the 95% confidence interval being nine months and the upper bound being not estimable. The median duration of treatment at the time of the data cut off in December was 10.8 months. On slide 13, we're showing a side-by-side comparison of the swim lane plots for patients using Raynaud HGG and Raynaud LGG. The pattern of the two plots is similar because treatment discontinuation decisions were made based on investigator readings by Raynaud HGG. Again, bars for patients who remain on treatment as of the date of cutoff are colored blue, while those who have discontinued treatment are colored orange. The yellow and magenta dots indicate the time of first partial response or complete response, respectively, by Raynaud criteria. The median time to response for the confirmed responses is shown on both plots, and by both Raynaud HGG and Raynaud LGG, the median time to response was rapid, 2.8 months by Raynaud HGG and 4.2 months by Raynaud LGG. As noted before, as of the December 22, 2022 data cutoff, the median IRC-assessed duration of response based on Raynaud HGG criteria was not reached. The median IRC-assessed duration of response based on renal LGG criteria at the time of the data cutoff was 14.4 months, with the lower bound of the 95% confidence interval being 8.4 months and the upper bound being not estimable. I do want to highlight two interesting patients on the renal LGG swim lane plot. One is a patient who had a minor response at approximately three months and who was on treatment for nearly a year before discontinuing treatment. The patient stopped drug and had durable response for an additional six months off treatment before having radiographic evidence of progression. A second patient towards the bottom of the Raynaud LGG Swimlane plot is also notable. This patient received less than two months of toviraphinib treatment before discontinuing. The patient without any additional treatment had a reduction in T2 flare signal that ultimately met the criteria for a minor response by Rano-LGG eight months later off therapy. The patient remains off therapy without evidence of disease progression. I also want to mention that we have generated a swim lane plot showing duration of treatment and duration of response data by Rapno-LGG. Given the interest of the academic pediatric neuro-oncology community in the use of Rapno-LGG data in a prospective clinical trial, We'll be showing these data at the upcoming Snow 7th Biennial Pediatric Neuro-Oncology Research Conference, which is held on June 22nd to June 24th in Washington, DC, where they will be part of an oral presentation. On slide 14, we've isolated the eight patients with unconfirmed partial responses by Raynaud-LGG to show the slope of the individual patient responses over time. You can see that As mentioned previously, T2 flare signal abnormalities may take longer to respond for some patients. While the data plotted here is reflective of the December 22, 2022 data cutoff date, all eight of these patients continue on treatment as of May 23, 2023. We'd like to show one other intriguing analysis that highlights why, in the clinic, treatment decisions are made based on a combination of imaging data as well as clinical data within the context of the patient's treatment history. On slide 15, we show a spider plot of the 11 patients who had a best response of progressive disease by Raynaud-LGG criteria. Note that disease progression by Raynaud-LGG can be due to clinical progression even with a T2 flare signal reduction. As you can see, of the 11 patients here, nearly all had an increase in T2 flare signal at the first response assessment time point. Interestingly, seven continued treatment past that three-month scan because they didn't have progressive disease by renal HGG criteria. What you can see here is that these seven patients had either disease stabilization or disease shrinkage, including two that would have met the criteria for an unconfirmed partial response, one who would have met the criteria for a confirmed minor response, and three who would have met the criteria for stable disease. In fact, five of these patients continue on treatment as of May 23, 2023. While we're unable to know the exact cause of the increase in T2 flare signal due to the difficulties in obtaining tumor biopsies in this patient population, it's clear that T2 flare increases do not always portend tumor progression and may potentially be reflective of tissue changes within the area of the tumor that subsequently goes on to respond to treatment. We believe that these data substantiate what we've been told by many practicing pediatric neuro-oncologists, that treatment decisions for patients in the clinic are ultimately based on a comprehensive evaluation of both clinical and imaging data. Turning to slide 16, here we present Tovar-Affinib monotherapy safety data for a total of 136 patients enrolled on both Arm 1 and Arm 2 of Firefly 1. While ARM2 was open to provide expanded access to patients, we collected detailed safety data to allow for an expanded safety database in the pediatric population to support our NDA filing. We're pleased to see that the safety data is largely aligned with the data seen at the interim analysis. The left side of the table shows the clinically apparent treatment emergent adverse events occurring in at least 25% of patients. Note that it does not include laboratory-only TEAEs. On the right side, we have the treatment-related adverse event data, with relatedness being determined by the treating investigator. The vast majority of adverse events observed were CTCAE Grade 1 or Grade 2, with the most common treatment-related adverse events being hair color change, fatigue, maculopapular rash, and acneoporin rash. The most common grade three or greater adverse event was maculopapular rash. And as we've disclosed previously, we have a detailed toxicity management guideline in our protocol for rash. And it found that higher grade rashes tend to respond quickly to either dose reduction or brief dose interruption. The rate of dose reduction or dose interruption required across the entire safety of valuable population was 29%, with most patients requiring either a single dose reduction or a brief dose interruption, with the median time of dose interruption being two weeks. Of note, only 4% of patients discontinued treatment due to an adverse event, with only four patients, or 3%, discontinuing for an adverse event that was treatment-related. The most common laboratory abnormalities were CPK elevation, anemia, hypophosphatemia, and AST elevation. The vast majority of these were laboratory-only AEs that did not require intervention or dose modification. On slide 17, we show the case of an 8-year-old boy with an optic pathway glioma bearing a KIAA1549 BRAF fusion. This child had very poor vision bilaterally coming into treatment, including loss of vision in the right eye and visual field loss in the left. He also had a variety of symptoms related to the tumor, including fatigue, intermittent nausea and vomiting, headaches, loss of appetite, and difficulty regulating body temperature. You can see that the very large tumor at the level of the midbrain shows contrast enhancement at baseline on the T1 postgadolinium sequences, as well as enhancement on the T2 FLIR sequences. This child was initially treated with standard of care of encrusting carboplatin chemotherapy He had an 18-month progression-free interval and then had disease progression that led to treatment with the MEK inhibitor, binimetinib. He had disease progression after about 18 months of binimetinib and was treated with a second MEK inhibitor, trimetinib, for about nine months, after which he had disease progression while on trimetinib before being enrolled on Firefly 1. He was treated with monotherapy topiraptive and the trajectory of his tumor response is seen in the graph at the bottom right of the slide by all three response assessment criteria. As you can see from both the graph and the images, by three months, there was a rapid reduction in the contrast enhancing portion of the tumor, as well as a reduction in the T2 flare visible tumor, which continued to progress, meeting criteria for a partial response by renal LGG. Of note, there has been a sustained improvement in visual acuity noted with this reduction in tumor size. Adverse events were grade two drug eruption and elevated CPK, and grade one hair color change, paronychia, and growth suppression. While this is a single case study, we've been very encouraged to see numerous instances of functional improvement, including improvement in vision, motor function, and quality of life. This case study as well as the stories of the other children enrolled on this study, are important reminders that each bar on a waterfall plot or lane on a swim lane plot represents somebody's child, somebody's brother or sister, grandchild, classmate, or friend. The number of prior lines of therapy that we refer to represent many weeks or months or years spent as a patient in the clinic or hospital and not at school or outside playing. We hope that the data that we presented here today will ultimately come to represent a new and potentially important therapeutic option for children with relapse pediatric low-ranking illness. I'd like to turn it back to Jeremy.
spk09: Thank you, Sam. In summary, we are thrilled by the results we've observed to date for relapse PLGG patients treated with investigational tovarapidinib. In the Firefly One trial, we're seeing clinically meaningful efficacy results as assessed by a three distinct response assessment criteria. We're seeing responses in patients with either BRAF fusions or BRAF B600E mutations, as well as responses among both of those types of patients who have received prior MAP kinase targeted therapy. We're seeing rapid time to response regardless of the response assessment criteria used, and we're seeing an encouraging safety and tolerability profile. Additionally, we continue to execute on our goals as a company, including key executive leadership appointments for commercial and medical. We've made substantial regulatory progress, which has resulted in initiation of a rolling submission of the NDA for tovaraphanib in relapsed or progressive PLGG in May of 2023. We expect to continue follow-up on the study with completion of the rolling submission anticipated in October of this year. Lastly, we are laser focused on continued investment and focus on Firefly 2, our phase three trial and frontline PLGG. We're actively adding sites and enrolling patients with a majority of those sites in the trial in Europe through our partnership with the logic consortium. Day one, with the help of our many partners, has charted a new course for therapeutic development for patients with childhood cancers. In closing on slide 19, Our executive team at day one would also like to extend our sincere gratitude to all of the members of the pediatric oncology community, to our partners, to our employees, and to our shareholders for all of your support. We also want to acknowledge the children who participated in this trial and their families for putting their trust in us. We're driven by our mission to help children with cancer from day one and every day after. And the encouraging data presented today reaffirms our conviction that our lead program here, tovirafenib, has the potential to be a first-in-class treatment for patients living with this disease. And now I'll hand the call back to the operator for Q&A.
spk05: Thank you. To ask a question, you'll need to press star 1-1 on your telephone. To withdraw your question, please press star 1-1 again. Please wait for your name to be announced. We ask that you please limit yourself to one question with one follow-up. Please stand by while we compile the Q&A roster. One moment for our first question. This question comes from the line of Joseph Catanzaro with Piper Sandler. Your line is now open.
spk11: Hey, guys. Thanks for taking the questions, and thanks for the update here. I guess I'll stick with two questions. Maybe first, wondering how much detail you could provide around your discussions with the FDA, I guess specifically as it relates to the different response criteria and where FDA might might place emphasis in how it might consider the minor responses with renal LGG criteria. And then my follow-up, I guess, is as I look at the patient case study and the kinetics there of tumor reduction between HGG and LGG criteria and then the difference in median time to response, I'm wondering if there should be any expectations to some extent that with longer follow-up you could see LGG response rates incrementally improve and I guess along these lines, is it well established that I guess the cystic component maybe can only fully clear once sufficient tumor regression has occurred? Thanks.
spk09: Joe, thanks for the questions. Appreciate that. I'll start with your question regarding our dialogue with the FDA and then ask Sam to comment on your question regarding the case study. Our dialogue with the agency has been quite productive as we noted We held a Type B meeting on April 19th during which we discussed a plan to submit, and it was really that meeting that led to the rolling review of the NDA that we've now initiated and will complete in October. Again, I want to emphasize that's on Firefly One data and that October completion will be – driven by inclusion of an amendment to the clinical portion of the NDA, an amendment to the CSR specifically. So full alignment on that process with the agency. Regarding your question about the nature of the agency's focus in terms of the data sets themselves and distinct sets of response criteria, what we can tell you is that The agency reiterated that their decision-making will be on the basis of the totality of the data, as we've been saying for some time. That will include, of course, data from our RANO-HGG assessment. That's the primary endpoint of the trial. But it will also include data from the RANO-LGG assessments on the trial, as well as, of course, safety and tolerability assessments. So no big surprises there. It will continue to be a process, we expect, where the agency will review everything we put in front of them. And what we'll put in front of them is all of those components. With that, let me ask Sam to comment on your question regarding kinetics of response in these different assessments.
spk10: Thanks, Joe. And thanks for noting the difference in the kinetics when you look at the T1 post-guide sequences and the T2 FLAIR sequences. This is part of the reason that we included the individual patient responses on slide 14 for the patients with unconfirmed PRs because we think that this is a really clear demonstration of the change over time in the T2 signal. And this gets to the second part of your question. What do we expect over time here in terms of potential evolution of the Raynaud LGG response rate? I think that, you know, again, what you're seeing from slide 14 is we think that it's altogether possible that that Raynaud LGG response continues to evolve as we see T2 signal resolution over time. With regard to your comment on the cystic component and changes therein, Raynaud LGG does not measure separately the cystic component. It actually looks at the whole tumor. But I want to also note that Raynaud LGG, because of its reliance on T2 flare imaging, is really picking up and integrating all of the changes within the tumor area, including the cyst, as well as tissue changes. T2 flare is not specific for tumor imaging. It enhances in response to gliosis, scarring, inflammation, edema, calcification, intratumoral hemorrhage. So all of that stuff, some of which is drug responsive, some of which just takes a long time to resolve as you treat a patient, may change more slowly over time.
spk11: Okay, great. Super helpful. Thanks for taking my questions.
spk05: Thank you. Thanks, Joe. One moment for our next question. And our next question comes from the line of Anupam Rama with JP Morgan. Your line is now open.
spk02: Hi, guys. This is Priyanka on for Anupam. First of all, congratulations on the data. Our questions are, what's the rationale for the June 2023 request? And can you confirm that was a specific FDA request? And also, just to confirm for that June 2023 request, data endpoint time. Has the primary analysis endpoint changed at all or has it stayed the same? Thank you.
spk09: Thanks, Priyanka, for the question. And what we can tell you is that the request for additional follow-up in the June data cutoff did come from the FDA and I think represents interest in seeing additional follow-up on the patients in this study. to assess both duration of response and overall response rate. There's no change to the trial with respect to what those analyses represent. We'll be looking at all of the endpoints in the trial in putting together all of the data sets that will be part of the amended CSR.
spk02: Understood. Thank you so much for taking our question.
spk09: Of course. Thank you.
spk05: Thank you. One moment for our next question. And our next question comes from the line of Mark Fromm with TD Calwin. Your line is now open.
spk08: Hey, thanks very much for my questions, and congrats on the progress here. Maybe on the case series that you're showing with the initial growth by MRI and then leading to people who might have been even classified as PRs, Reminds of the broader field in neuro-oncology and what's been seen with kind of pseudo-progressions and what that's meant. And then also maybe for Sam, just given that dynamic as well as some of the, you know, what you've been showing with the stable or unconfirmed PRs, you know, what's the treatment algorithm that you kind of see evolving in terms of how this agent will be used?
spk09: Mark, thanks for the question. I'm going to, of course, hand it to Sam here.
spk10: So with regard to what people are seeing when they look at renal LGG response rate in this population or they look in isolation in the T2 sequences, I'll tell you there's almost no published literature here, Mark. This is actually the very first trial that's ever looked prospectively at an active agent in this population defined by a molecular profiling with all three of these response assessment criteria. If you actually go back and look at the historical studies, they never show this data. So what we're seeing here is really new data, and I think it's really quite intriguing and sheds real insights into some of the challenges associated with response assessment in pediatric low-grade glioma or in low-grade glioma in general. And this was highlighted today both by Dr. Mueller, who was to discuss, as well as in the adult low-grade glioma trial, they also highlighted challenges with response assessment by MRI in this patient population. To your second question, for patients with stable disease or patients with unconfirmed partial responses or minor responses by renal LGG or on the T2 sequences, the treatment algorithm is very simple. This has been the treatment algorithm for this disease for a very long time. If you're giving an agent and you see disease stabilization or you see disease shrinkage, you keep treating the patient. The other thing that's important to recognize is that, and again, Dr. Mueller made this point very clearly in her discussion, we treat patients. We don't treat scans. And we know that there can be changes in contrast enhancement or there can be changes in T2 flare that don't necessarily represent disease progression. This is not high-grade glioma where an increase in contrast enhancement is always the beginning of a one-way increase in low-grade glioma. these things can change, and as you can see over time, will continue to decrease. So the treatment algorithm is very clear. You treat the patient. If you're seeing stabilization or reduction of signal on MRI and the patient is stable or improving, keep treating.
spk09: One add I'll include as well is that for the reasons that Sam just noted, we're really encouraged that in our trial, we continue as of the data cutoff in December to have 74% of patients on study and on drug. That's important because it's an indication that the clinicians who are really the investigators of this trial continue to believe their patients are driving some benefit.
spk08: Okay, that's helpful. And then just know based on your conversations with the fda just what's your expectation for i understand the actual approval decision will be totality of the data but what endpoints would you expect to be on or not on the fda the the label if you're ultimately granted one you know mark the the process um by which uh the fda uh uh sort of determines what's what's a part of the label really comes
spk09: you know, pretty late in the evaluation of a new drug application, and I think it's premature to project or anticipate what the FDA may be thinking with respect to the label itself.
spk08: Okay. That's fair. It may be asked in a slightly different way. From a commercial perspective, what do you view as the kind of must-haves and what's the nice-to-haves on the label?
spk09: Oh, I... from a commercial perspective would really point to the clinical data that we've generated to date, and in particular to the nature of this disease and, as Sam noted earlier in this discussion, the importance of stabilizing tumors and keeping those tumors stable, of course, shrinking them if at all possible over time as, you know, the most important objective. And by that measure, it's really what we're seeing so far with respect to clinical benefit rate that I care most about with respect to commercial opportunity and durability of that tumor control.
spk08: Okay. Thank you.
spk09: Thanks, Mark. I think we're ready for next question.
spk05: Our next question comes from the line of Andrea Tan with Goldman Sachs. Your line is now open.
spk01: Hi, everyone. Thanks for taking the questions. Sam, maybe some questions for you. Just when you look at the Slim Lane plot by Raynaud LGT criteria, it does look like many of the patients either responded or demonstrated disease progression pretty early on by their first assessment. Is there anything you can discern from the baseline characteristics that might indicate which patients are more likely to respond versus progress, or even why some might have a response but then progress later on? Thanks so much.
spk10: Yeah, no, it's a great question. So we have collected tissue from all of these patients, which we will be using for molecular profiling to support our companion diagnostic application. Of course, as part of that, we'll dig in to see whether or not there are any other genomic factors that we can tease out to see if that defines or correlates with any of the radiographic responses here. In terms of sub-analyses to understand whether or not there are any patterns with regard to other patient characteristics, including tumor location or size or volume of the tumor at the baseline, we simply haven't done that yet. I do want to highlight just one thing that's important off of your comments on the swim lane plot, which is that treatment decisions were made based on investigator assessment of response or progression by Raynaud HGG. And I think what's really important here and shows you once again, as I highlighted in the previous answer, some of the challenges with imaging is that patients who have reduction in the contrast enhancing volume by Raynaud HGG, who may even have some small increase in T2 flare signal, if you continue treating them, they will have tumor shrinkage over time. And it's evidenced by the fact that patients who had early increases in T2 flare that would qualify as progressive disease by renal LGG, if you keep treating them, stay on treatment, and that's because they're driving benefit, including tumor shrinkage post-evidence of progression. And that was highlighted on that spider plot that I showed previously.
spk02: Thanks so much. Thank you.
spk05: Thank you, Andrea. One moment for our next question. And our next question comes from the line of Robert Driscoll with Wedbush Securities. Your line is now open.
spk12: Thanks. Good evening, guys. I appreciate the update today, and thanks for taking the questions. First, can you place the duration of response data into context in terms of patient experience with prior therapy? Obviously, we have another one patient in yet, and I appreciate the majority of patients there still haven't studied it. And then just a quick follow-up, you know, we're getting to the point currently, you know, where patients can take a drug holiday. I wish one day we could talk about how that decision might be made and what factors go into that decision. Thanks.
spk09: Yeah. Sam, go ahead. Thanks, Robin, for the question.
spk10: Absolutely. So the analysis of duration of response for patients related to their prior line of the response on their prior line of therapy is an important analysis that we'll be doing in preparation for future presentations and publications. But I can tell you, having gone through the clinical narratives for all of these patients and having seen for each patient their response and the duration of their response within the context of their prior treatment history, it's clear that as you get farther and farther out, particularly in the heavily pretreated patients, you'll have patients whose prior line of therapy, they may have seen a response or disease stabilization for a couple of months or six months or a year. So for me, as this median duration of response number continues to increase, well, it's not yet reached by Raynaud HGG, but certainly 14.4 months by Raynaud LGG is really encouraging, given the heavily pretreated nature of this population. With regard to your question on drug holiday, as you correctly note, the way that the trial was designed was treat to progression with the option for drug holiday for patients who had approximately two years or 26 years cycles of treatment. And we're now just coming up on that. Recall that the first patients on the study really were at the end of April or beginning of May, two years ago. So we don't have any data yet today. But what I can tell you from talking to pediatric neuro-oncologists, certainly in ad boards and discussions that we've had, is that this decision is oftentimes complex and multifactorial. There are multiple people involved in making decisions and multiple factors about the patient and the disease to be taken into consideration. Briefly, on the human side of this, there's the perspective of the physician, but also the perspective of the parent who is viewing their child's prior treatment history and also the perspective of the patient, particularly if that patient is older. If that patient has had multiple relapses or relapsed on prior mast kinase therapy and has had a prolonged response to therapy on a new agent, the parents may be very, very interested in keeping that patient on drug for as long as possible because they've already experienced multiple relapses, particularly if that child is tolerating the therapy well. Certainly adolescents, teenagers, if they're having side effects, they have agency in this treatment decision and are going to be part of that decision as well. So I think that there's a lot to come in the future in terms of our learning about this. But I think at the end of the day, it's going to be a decision made by physician, parent, in some cases, patient. And it's also going to be taken in the context of the number of prior lines of therapy, prior history of relapses and the consequences owing to either the location or the size of the tumor in terms of what is the risk of relapse. If you're talking about a couple of millimeters growth, ablating any residual vision, and you've stabilized or shrunk that tumor and the patients have multiple relapse, I think patients and parents may want to stay on that drug for longer. If you've got a tumor in a non-eloquent area of the brain where a little bit of growth May not be an issue that parents may want to take that drug holiday, but I think it's going to be on a case-by-case basis.
spk12: Got it. Very helpful. Thanks, Chris.
spk05: Thank you. And our next question comes from the line of Sumit Roy with Jones Trading Institutional Services. Your line is open.
spk13: Hi, everyone. Congratulations again on the data. A quick question on the dose reduction interruption process. part to the – could you tell us, like, at what time point do you see the main bolus of patients who have to undergo any dose modification and interruption? Is it a cumulative effect of the drug, or do you see it early on?
spk09: Thanks so much for the question, Sam. Can you answer this one?
spk10: Yeah, it's an important question. It does tend to be early on, although I want to be clear that we have not yet finished a complete analysis of side effects over time. Obviously, the trial's ongoing, but the pattern that's emerging appears to be that the side effects like rash that lead to dose interruption or dose reduction tend to occur early. We know that particularly for rash, which is one of the most common side effects that's clinically apparent, that brief dose interruption leads to rapid resolution of the rash and allows for resumption of treatment. We also know that for patients who have AEs that require a dose reduction is typically a one-level dose reduction. And in some cases, patients, once they continue dosing at that reduced dose level, can be dose re-escalated up to the recommended phase two dose later. It does not appear to be cumulative over time, but again, early days for this study. Sorry.
spk13: Thank you. And one last question. The slide 15 was interesting where patients who are showing progressive disease and then turn into stable responders. In the real world, do you see use of Raynaud AGG to be made or LGG and how physicians are going to make that decision whether to continue the patient's past three months on progressive disease showing or if you can give us any color?
spk10: I absolutely can give you color. I can give you color both as a former practicing pediatric neuro-oncologist, but also as somebody who's worked very closely with people in this field. I want to be very clear about this. In clinical radiology reports for patients being treated, you never have radiologists refer to Raynaud HGG or Raynaud LGG criteria. Those are for clinical trials. In clinical practice, patients are scanned. Their tumor measurements at the current scan are compared to previous scan, looking at all sequences. Patients are discussed, typically in multidisciplinary tumor board settings. The patient's clinical status and treatment history is taken into consideration, and treatment decisions are made if a patient has tumor stabilization or tumor shrinkage, and if they're doing well. In instances where you may see an increase in T2 signal or even an increase in contrast enhancement, unless it's something that is accompanied by symptomatic worsening, most often the decision at that time is to just wait and scan again if the patient is doing well and tolerating treatment well, because as you can see from slide 15, sometimes those changes don't necessarily mean that the tumor is going to continue to grow or progress. A change in signal on T2 flare or a change in contrast on T1 post-cad sequences does not equal clinical response. So that's why all of that data has to be taken into perspective.
spk13: Thank you again for the color, and congratulations again. Thank you.
spk05: Thank you. One moment for our next question, please. And our next question comes from the line of Ami Fadiyah with Needham & Company. Your line is now open.
spk03: Hello, good evening. Thank you for the update today. I've got two questions. Firstly, can you help us understand what may be the time to best respond on this treatment? The graph that you show on slide 14 is interesting because it suggests that the patients may be continuing to see some deepening in response. However, I'm trying to sort of put that in context overall response rate for Rathno that was reported in April, which is around 50%, and the response rate is about 51% as of the December cutoff. So I'm just trying to put it in context as to, you know, could we see continuing deepening in responses? And then I've got a second question.
spk09: Ami, thanks for the question. Just a quick comment. The prior data that we included on the trial for RAFNO assessments were in November of last year, and it was on the interim population of 22 patients that we described. So that, relative to what we're seeing now, I think is really what we're looking at. And Sam, why don't you comment on this?
spk10: Yeah, just I think to your question. On the swim lane plots, the numbers that we have for time to response are the way that it's typically represented, which is the time to the beginning of response. You don't consider response to be when you have your confirmation. You've got to confirm responses at the beginning of the response. And so the time to best response obviously would be something that we'd have to really understand later on in the study, particularly for Raynaud, LGG, or Rapinoe. Because as you correctly noted, and again, as we've demonstrated on slide 14, the patient's best response on T2 flare may not come four months later. That is their deepest response. So we really do need to look at this over a longer timeframe. So I think that that's a, you know, certainly an intriguing analysis time to best response, but really what we, what we're able to highlight right now is the time to response that is the initiation of what is a complete response or a partial response or a minor response.
spk03: Understood. Okay. Thank you. And my next question is, you know, how should we interpret the FDA for an additional follow-up as to whether the data for the December cutoff are acceptable for approval? You know, if the response rate holds up through June, will that be adequate for approval, or do we need to see a deepening in response for approval?
spk09: Yeah, Ami, I don't want to speculate about the specifics of the FDA's assessment. I think it's quite clear that they'll go through their internal assessment and look at the totality of the data. I'd also highlight that they don't typically provide, and haven't in this case, a specific response rate level that would be sufficient for approval. So I think you should view the request for the additional follow-up on the study as we do, which is interest in really looking at the duration of response and how the overall response rate progresses with additional time on study.
spk03: Understood. Thank you.
spk05: Thank you. One moment for our next question. And our next question comes from Noein Kubria with Capital One Securities. Your line is still open.
spk04: Hi. Good afternoon, and congrats on the results. So apologies if this has already been asked or partly answered, but Dr. Kilburn showed the case study with the BRAF fusion patient with the optic pathway glioma. common are these, and are these patients more challenging to treat vis-a-vis other BRAF patients with glioma in other locations? So is there like a disparity in outcomes or responses based on location?
spk10: Thank you for your question, Sam. You want to answer that one? Yeah. So again, I'll put on my neuro-oncologist hat. Optic pathway glioma patients are challenging right from the get-go for the main reason that you cannot resect them. without rendering the patient blind, and that's almost never done. And we know that complete resection at the time of diagnosis gives the best chance for relapse-free survival. So if you just take 100 newly diagnosed pediatric low-grade gliomas, the ones with tumors that are right in the middle of the posterior fossa, in the middle of the cerebellum, that can be easily resected completely, those have great outcomes, but those are never optic pathway glioma patients if you look. They literally sit right next to the midbrain, and so they can't be resected. The other challenge with optic pathway glioma patients, obviously the impact on vision, is that right proximal to the optic chiasm is the hypothalamus and the pituitary gland. And as a result, these optic pathway glioma patients oftentimes have devastating endocrinopathies. as a result of literally the tumor pressing on and disrupting the function of the hypothalamic pituitary axis. So these patients have a host of comorbidities associated with them, including growth abnormalities, temperature regulation abnormalities, really sometimes devastating hypothalamic obesity associated with dysregulation of the HPA axis. So they are challenging patients to treat.
spk04: Got it. And then in terms of the rolling NDA submission and the October time frame, the data that needs to be provided at that time point, is there anything outside of the efficacy and safety data from the June cutoff date that's also supposed to be expected to include at that later time point, or is it just that, the follow-up?
spk09: The only additional data data that will be included in that is really an amended CSR with, you know, follow-up from the patients on study as of June.
spk04: Okay. Terrific. Thank you. Thanks.
spk05: Thank you. And our last question comes from the line of Andreas Maldonado with HC Wainwright. Your line is now open.
spk06: Great. Thank you again for taking my question and congrats on the progress. Maybe circling back on some of the differences that come about measuring these particular tumors via MRIs, curious on how much of the variance could be ascribed based on the differences in how these pulse sequences deal with the suppression of water over just differences stemming from the impact of the use of contrast or other physiological changes. And curious on how You know, as we look at Raynaud HGG or LGG, how uniform is the suppression of water across those pulse sequences, and how should we be thinking about that?
spk10: Dan, do you want to take this one? I will attempt to answer this question as best as I can. And I will just qualify this by saying that I am not a neuroradiologist, and I am not great at physics. But what I can tell you from my understanding of MRI sequences is that part of the reason that the T2 flare, which stands for fluid attenuation inversion recovery, is used is because it suppresses the signal from nearby pools of fluid, be it proximity to a cerebral ventricle or some other source of CSF. So, you know, I think that that is built into this, and it's part of the reason why the T2 flare is part of the MRI protocol that's used for these patients, along with T1 and T1 post-gad imaging. But beyond that, in terms of the impact of fluid either proximal to the tumor or within the tumor, in terms of difficulty of measuring on the T2 sequences, It's hard for me to be authoritative here. I'm not a neuroradiologist. But there has been published data certainly on challenges, you know, in inter- and intra-reader reproducibility of measuring on T2 flare sequences. And that's been published, you know, probably the most that I can comment on that.
spk06: Great. And then really quickly, among the patients that had prior MEK inhibitors, I know these are the early days, but would you expect a difference of response based upon if those patients had specifically Tremetinib over another MEK inhibitor in the context that Tremetinib has a kind of unique and novel MOA compared to other MEK inhibitors? Curious on your thoughts there. And thank you very much for taking my question.
spk10: No, of course. Tremetinib was the most commonly used MEK inhibitor for patients on our study who had prior MEK inhibitors. We've not done an analysis to compare the prior Tremetinib-treated patients versus those who were treated with, say, selumetinib or bitumetinib. I empirically can't imagine why there would be a difference, but I say that in the absence of us having run that type of analysis. So maybe what I can say is it's a really interesting thought and one that I'll put on our list for subgroup analyses that we do as we prepare for publication and continued exploration of this data set.
spk06: Great. Very helpful. Thank you.
spk10: Thanks, Andrea.
spk05: This concludes today's conference call. Thank you for your participation. You may now disconnect. Everyone, have a wonderful day.
spk12: Thank you.
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