Webcast: https://edge.media-server.com/mmc/p/wwuf7739
Presentation: https://ir.dayonebio.com/static-files/0caee55f-c481-48c7-9571-067e51543954
Call Participants:
- Joey Perrone, Senior Vice President of Finance and Investor Relations
- Jeremy Bender, Chief Executive Officer
- Samuel Blackman, Co-Founder and Head of R&D
- Charles York, Chief Operating & Financial Officer
Call Operator
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 will 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.
Joey Perrone, Senior Vice President of Finance and Investor Relations
Thank you. Good evening, and thank you for joining us. Earlier today, we issued a press release for an update on the new clinical data from our registrational Phase 2 Firefly 1 clinical trial evaluating tovorafenib and relapsed or progressive pediatric low-grade glioma. Slides to accompany this conference call are posted on the investors and media section of our website at www.day1bio.com. An audio webcast with the corresponding presentation slides is also available on the website.
Before we get started, I'd like 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 2. Actual events or results could differ materially from those expressed or implied by any forward-looking statements, including as a result of various risks, uncertainties, and other factors including set forth in our most recent filings with the SEC and any other future filings that we make with the SEC. You are caution placed in the undue reliance on these forward-looking statements, and Day 1 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've provided, Jeremy will begin on Slide 4. I will now turn the call over to Jeremy, CEO of DAWN. Thank you, Joey.
Jeremy Bender, Chief Executive Officer
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 1 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, was shown 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 1, 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 1 from other 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, tovorafenib, expanding our portfolio, resourcing the organization as we prepare for potential registration and a U.S. commercial launch. Our lead product candidate is tovorafenib, an oral brain-penetrant type 2 RAFF 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 2.1 trial evaluating Tovorafenib as once-weekly monotherapy in patients aged 6 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.
Samuel Blackman, Co-Founder and Head of R&D
Thanks, Jeremy, and thanks to all of you for joining us this evening. As can be seen on slide 5, pediatric low-grade glioma or PLGG is the most common form of 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 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 complicated 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 BRAF 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 FireflyOne program.
Jeremy Bender, Chief Executive Officer
You can see on slide six the development of Tovorafenib 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 FireflyOne 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 Tovorafenib in relapse to a progressive PLGG.
This is an important accomplishment for the day one team and was a result of a productive pre-NDA meeting with the FDA in April of 2023, during which we reviewed the evidence of clinical benefit for Tovorafeniband PLGG that we've observed to date and aligned with the agency on a rolling NDA submission on the basis of results from the FireflyOne trial.
We appreciate the FDA's continued partnership with day one. Looking forward, we expect the 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 FireflyOne.
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 FireflyOne trial. This plan sets us on a trajectory towards delivering on our initial goals, providing therapeutic options to children and families living with the severe impact of cancer. I am humbled and gratified by where we are today.
On slide seven, you'll see the study scheme for FireflyOne. Arm one of FireflyOne represents a registrational arm of the trial, which we initiated following early data for Tovorafeniband relapsed PLGG from the PNOC014 study, an investigator-sponsored trial in Dana Farber.
The FireflyOne 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 FireflyOne in contrast with other trials. Some patients enrolled in FireflyOne had already been treated with multiple MAP kinase inhibitors.
The primary endpoint of the trial is overall response rate, or ORR, by RANO HGG, as is 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 RAPNO LGG, which is currently unadjudicated, RANO-based PFS, duration of response, time to response, clinical benefit rate, and safety.
We will also be sharing the exploratory analysis of ORR by RANO HGG, as assessed by Blinded Independent Central. Sam will now walk you through the results of the trial.
Samuel Blackman, Co-Founder and Head of R&D
Thanks, Jeremy. On slide 8, I'd like to begin by reviewing the baseline demographics and characteristics of the patients on FireflyOne. We enrolled 77 patients on ARM1 of FireflyOne.
The data cutoff for this presentation is December 22, 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 in our trial sites and the distribution seen within this disease.
Nearly all patients had a Karnofsky 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 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 B600 E 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 noted 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 out of clinical trial or radiation therapy.
Moving to slide nine, of the 77 patients enrolled on arm one of Firefly1, 69 had lesions that were RANO-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 forty two patients had responses classified as a partial response, or PR, by RANO, 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, as we went and 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 RANO, and for RANO, 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 RANO, the majority had a reduction in the size of their tumor.
As you can see, several of the RANO-evaluable patients had BRAF B600E 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 with a MAP kinase inhibitor. The clinical benefit rate, defined as a confirmed CR/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 RANO-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. Seventeen patients have responses classified as a partial response, or PR, by RAPNO-LGG, meaning that the sum of 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. Eighteen 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. Twenty-five patients, or 36%, had a best response to the date of stable disease. The clinical benefit rate, defined as a confirmed CR, PR, 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 Tovorafenib, visible on both 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% 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. Similar to the waterfall plot for the primary endpoint, BRAF B600 E-mutant patients are indicated by a dot at the end of the bar. And similar to the RANO-HGG responses, the majority of B600 E-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 prior treatment with a MAP kinase inhibitor.
On slide 11, we have a waterfall for RANO-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 RANO-LGG valuable patients. As you can see, 49% of patients have achieved an overall response as assessed by Blinded Independent Central Review. 20-patients responses classified as a partial response, or PR, by RANO-LGG, of which eight are pending confirmation, with all eight unconfirmed PRs remaining on treatment as of May 23, 2023.
Similar to RAPNO-HGG, this indicates a decrease by greater than 50% from baseline. 17 patients had a minor response, or MR, or a decrease of 25% from baseline, but less than 50%, of which two are 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 RANO-LGG, defined as a CR, PR, MR, or stable disease, is 83%.
Similar to what I mentioned for RAPNO-LGG, given the fact that T2 signal abnormalities in MRI are complex, and are not always expected to fully resolve in the setting of a relapsed PLGG, we find these data to be encouraging and taken together with the RANO-HGG data, and the RAPNO-LGG data, we believe that these data, in their totality, provide a comprehensive picture of anti-tumor activity with monotherapy tovorafenib, using three different response assessment criteria. And once again, B600 e-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 RANO-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 RANO-HGG-valuable lesions. This swim lane plot displays the duration of treatment on the x-axis. Bars for patients 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 RANO 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 PNOC014 study of Tovorafenib.
We've indicated whether or not patients had a prior MEC or BRAF inhibitor along the y-axis, as well as whether or not the patient had a BRAF B600E mutation. As of the data cutoff, the median IRC accessed duration of response with confirmed responses based on RANO-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 cutoff 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 RANO-HGG and RANO-LGG. The pattern of the two plots is similar because treatment discontinuation decisions were made based on investigator readings by RANO-HGG. Again, 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 first partial response or complete response, respectively, by RANO criteria. The median time to response for the confirmed responses is shown on both plots. And by both RANO-HGG and RANO-LGG, the median time to response was rapid, 2.8 months by RANO-HGG, and 4.2 months by RANO-LGG. As noted before, as of the December 22, 2022 data cutoff, the median IRC assessed duration of response based on RANO-HGG criteria not reached.
The median IRC assessed duration of response based on RANO-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 RANO-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 discontinuity. 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 RANO-LGG swim lane plot is also notable. This patient received less than two months of Tovorafenib treatment before discontinuity. 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 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 RANO-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 SNO seventh biennial pediatric neuro-oncology research conference, which is held on June 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 RANO-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 reflected December 22nd, 2022 data cutoff date, all eight of these patients continue on treatment as of May 23rd, 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 RANO-LGG criteria. Note that disease progression by RANO-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 RANO-LGG 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 23rd, 2023.
While we're unable to know the exact cause of the 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 Tovorafenib monotherapy safety data for a total of 136 patients enrolled on both Arm 1 and Arm 2 of Firefly 1. While Arm 2 is 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 clearly aligns with the data seen at the interim analysis. The left slide of the table shows the clinically apparent treatment emergent adverse events occurring in at least 25 percent 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 CTC AE grade 1 or grade 2. The most common treatment related adverse events being hair color change, fatigue, maculopapular rash, and acneiform rash. The most common grade 3 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 have 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 higher safety of valuable population was 29 percent 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 percent of patients discontinued treatment due to an adverse event with only four patients or 3 percent 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 eight-year-old boy with an optic pathway glioma bearing a KIAA-1549 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 baseline on the T1 post-catalinium sequences, as well as enhancement on the T2 flare sequences.
This child was initially treated with standard of care of increasing 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, trametinib, for about nine months, after which he had disease progression while on trametinib before being enrolled on Firefly 1.
He was treated with monotherapy tovorafenib and the trajectory of his tumor responses 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 RENO LGG.
Of note, there has been a sustained improvement in visual acuity noted with this reduction in tumor size. Adverse events were grade 2 drug eruption and elevated CPK and grade 1 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, class, 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 rate gliomas. I'd like to turn it back to Jeremy.
Jeremy Bender, Chief Executive Officer
Thank you, Sam. We are thrilled by the results we've observed to date for relapse PLGG patients treated with investigational Tovorafenib.
In the Firefly 1 trial, we're seeing clinically meaningful efficacy results as assessed via three distinct response assessment criteria. We're seeing responses in patients with either BRAF fusions or BRAFB600E 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 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 Tovorafenib in relapse to progressive PLGG in May of 2023. We expect to 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 focused on Firefly 2, our Phase 3 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 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, Tovorafenib, 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.
Q&A Portion
Operator
Thank you. Please stand by while we compile the Q&A roster.
Joseph Catanzaro - Piper Sandler.
Hey, guys. Thanks for taking the questions and thanks for the update here. I guess I'll stick with two questions.
First, I'm wondering how much detail you could provide around your discussions with the FDA, I guess specifically as it relates to the different response and where FDA might place emphasis and how it might consider the minor responses with RANO 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 rate incrementally improve and 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.
Jeremy Bender, Chief Executive Officer
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 19, 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 1 data and that October completion will be driven by inclusion of an amendment to the clinical portion of the NDA, 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.
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, I’ll let Sam comment on your question regarding kinetics of response in these different assessments.
Samuel Blackman, Co-Founder and Head of R&D
Thanks, Joe. And thanks for noting the difference in the kinetics when you look at the T1 post-cat sequences and the T2 flare sequences. This is part of the reason that we included the individual patient responses on slide 14 for the patients with unconfirmed PR sequences. 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 RANO-LGG response rate?
I think what you're seeing from slide 14 is we think that it's altogether possible that that RANO-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, RANO-LGG does not measure the cystic component. It actually looks at the whole tumor. But I want to also note that RANO-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. It enhances in response to gliosis, scarring, inflammation, edema, calcification, intratumoral hemorrhage.
So all of that, 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.
Anupam Rama -JP Morgan.
This is Priyanka for Anupam. First of all, congratulations. 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 data endpoint time, has the primary analysis endpoint changed at all, or has it stayed the same?
Jeremy Bender, Chief Executive Officer
Thanks, Priyanka, for the question. And what we can tell you is that the request for a 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 set to be part of the amended CSR.
Mark Fromm with TD Calman.
Hi. Thanks for taking 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, can you just remind us of the broader field in neuro-oncology and what's been seen with kind of pseudo-progressions and what that's meant?
This is for Sam, just given that dynamic as well as some of what you've been showing with the stable or unconfirmed PRs, what's the treatment algorithm that you kind of see evolving in terms of how this age will be used?
Samuel Blackman, Co-Founder and Head of R&D
So, with regard to what people are seeing when they look at RANO LGG response rate in this population or they look in isolation of 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 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. Muller, who was the discussant, as well as in the adult low-grade glioma trial. They also highlighted challenges with response assessment by MRI in this patient.
To your second question, for patients with stable disease or patients with unconfirmed partial responses or minor responses, by RANO 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, and again, Dr. Muller 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.
Jeremy Bender, Chief Executive Officer
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.
Mark Fromm with TD Calman.
Okay, that's helpful. And then, just based on your conversations with the FDA, 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 label if you're ultimately granted one?
Jeremy Bender, Chief Executive Officer
The process by which the FDA sort of determines what's a part of the label really comes 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.
Mark Fromm with TD Calman.
Okay, that's fair. It may be asked a slightly different way. From a commercial perspective, what do you view as the kind of must-haves and what's the nice to have on the label?
Jeremy Bender, Chief Executive Officer
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 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.
Andrea Tan with Goldman Sachs.
Thanks for taking the question. Sam, maybe some questions for you. Just when you look at the slim-lane plot by RANO LGG 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 indicate which patients are more likely to respond versus progressed, or even why some might have a response but then progress later on? Thanks so much.
Samuel Blackman, Co-Founder and Head of R&D
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 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 baseline, we simply haven't done that yet. I do want to highlight just one thing that's important off the comments on the swim-lane plot, which is that treatment decisions were made based on investigator assessment of response or progression by RANO 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 RANO HGG, who may even have some small increase in T2, 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 RANO 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.
Robert Driscoll - Wedbush Securities
Good evening, guys. First, can you place the duration of response data into context in terms of patient experience with prior therapy?
And then just a quick follow up, we're getting to the point that is currently where patients can take the drug however, and I wish we could talk about how that decision might be made and what factors go into that decision.
Samuel Blackman, Co-Founder and Head of R&D
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 narrative 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 further out, particularly in the heavily
pre-treated 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 response number continues to increase, or it's not yet reached by RENO HGG, but certainly 14.4 months by RENO LGG is really encouraging given the heavily pre-treated 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 cycles of treatment. And we're 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 multi-factorial. There are multiple people involved in making the 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 therapy and has had a prolonged response to therapy on a new agent, the parents may be very, very interested in keeping that patient 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. 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 relapses, I think patients and parents may want to stay on that drug for longer. If you've got a tumor in a non-elegant area of the brain where a little bit of growth might not be an issue, then parents may want to take that drug holiday. But I think it's going to be on a case-by-case
Sumit Roy with Jones Trading Institutional Services
Hi, everyone. Congratulations again on the detail. A quick question on dose reduction and interruption part. Could you tell us 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?
Samuel Blackman, Co-Founder and Head of R&D
Yes. 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 trials. 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, it's typically able dose reduction, and in some cases, patients, once they continue dosing at a 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.
Sumit Roy with Jones Trading Institutional Services
The slide 15 was interesting where patients were showing progressive disease and then turned into stabler responders. In the real world, do you see a use of RANO AB main or LGG and how physicians are going to make that decision, whether to continue the patient's past third three months on progressive disease showing or if you can give us any color?
Samuel Blackman, Co-Founder and Head of R&D
I absolutely can give you color. I can give you color both as a form of 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 radiology referred to RANO HGG or RANO 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 as 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, the 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, some of 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-cat sequences does not equal clinical response. So that's why all of that data has to be taken into perspective.
Ami Fadia - Needham & Company
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 patient may be continuing to see some deepening in response. However, I'm trying to sort of put that in context.
Overall response rate 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 could we see continuing deepening in responses.
Jeremy Bender, Chief Executive Officer
Ami, thanks for the question. A quick comment. The prior data that we included on the trial for RAPNO assessments were in November of last year, and it was on the interim population, 22 patients that we described. So that, relative to what we're seeing now, I think is really whatwe're looking at.
Samuel Blackman, Co-Founder and Head of R&D
On the swim lane plots, the numbers that we have for time to response, 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 RANO LGG or RAPNO.
Because as you correctly noted, and again, as we've demonstrated on slide 14, the patient's best response on care 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 certainly an intriguing analysis, time to best response, but really what we're able to highlight right now is the time to response, that is the initiation of what is a complete response or partial response or a minor response.
Ami Fadia - Needham & Company
How should we interpret the FDA for an additional follow up as to whether the data for the December cutoff are acceptable for approval? 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?
Jeremy Bender, Chief Executive Officer
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 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.
Noein Kubria with Capital One Securities
Hi. Good afternoon and congrats on the results. Dr. Kilburn showed the case study with the BRAF fusion patient with the optic pathway glioma. So how 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?
Samuel Blackman, Co-Founder and Head of R&D
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 give 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 and the middle of them 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 in the pituitary gland. And as a result, these optic pathway glioma patients oftentimes have devastating endocrinopathies as a result of 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.
Noein Kubria with Capital One Securities
And then in terms of the rolling NDA submission in October, 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?
Jeremy Bender, Chief Executive Officer
The only additional data that will be included in that is really an amended CSR with the follow-up from the patient as of June.
Andreas Maldonado with HC Wainwright.
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, 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 tissue changes.
And curious on how, you know, as we look at RANO HGG or LGG, how uniform is the suppression of water across those pulse sequences? And how should we be thinking about that?
Samuel Blackman, Co-Founder and Head of R&D
I will attempt to answer this question as best as I can. And I will just qualify this by saying that I am a neuroradiologist, and I am not great at physics. But what I can tell you from my understanding of MRI sequences, 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 via, you know, proximity to a cerebral ventricle or some other source of CSF.
You know, I think that that is built into this, and it is part of the reason why the T2 flare is part of the MRI protocol that is 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 is hard for me to be authoritative here. I am not a neuroradiologist.
But there has been published data, certainly, on challenges, you know, in reproducibility of measuring on T2 flare sequences. And that has been published.
Andreas Maldonado with HC Wainwright.
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 trametinib over another MEK inhibitor, in the context that trametinib has a kind of unique and novel MOA compared to other MEK inhibitors?
Samuel Blackman, Co-Founder and Head of R&D
Trametinib was the most commonly used MEK inhibitor for patients on our study who had prior MEK inhibitors. We have not done an analysis to compare the prior trametinib -treated patients versus those who were treated with, say, selumetinib. 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 dataset.
Operator
This concludes today's call. Thank you for your participation. You may now disconnect.
Everyone, have a wonderful day. Thank you.
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