Day One Biopharmaceuticals Targeted Therapies for People of All Ages November 2023
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Cancer Drug Development For People Of All Ages NDA data set included analysis of primary (ORR by RANO-HGG) and secondary (ORR by RAPNO-LGG, PFS) efficacy endpoints, safety, and exploratory analyses (including ORR by RANO-LGG). A Mission That Creates Value Develop medicines for genomically-defined cancers Establish first-in-class position through rapid registration pathways Expand to adolescent and adult populations in parallel and pursue those opportunities with the same commitment we do for children Nasdaq: DAWN IPO: 2021 Founded: 2018 Financial Position Runway into 2026 Growing Portfolio Lead program FIREFLY-1: FDA acceptance of NDA and priority review granted with PDUFA target action of date of April 30, 2024 Frontline trial (FIREFLY-2) underway Clinical-stage MEKi asset (pimasertib), in-licensed for combination trial with tovorafenib Research collaboration and license agreement for preclinical program targeting VRK1
Our Pipeline Product Candidate Indication Preclinical Phase 1 Phase 2 Phase 3 Recent & Anticipated Milestones Tovorafenib (DAY101) Type II RAF Inhibitor Relapsed pLGG Frontline pLGG Pimasertib MEK 1/2 Inhibitor MAPK-altered solid tumors2 (Combo w/tovorafenib) VRK1 Program3 VRK1 Inhibitor Pediatric and adult cancers FDA Breakthrough Therapy Designation for relapsed pLGG FDA Orphan Drug Designation for malignant glioma EC Orphan Designation for glioma FDA Rare Pediatric Disease Designation (PRV Eligible) for pLGG FIREFLY-11 (pivotal) FIREFLY-2 (pivotal) FIRELIGHT-1* First patient dosed: March 2023 First patient dosed: May 2022 Topline data presented: September 2023 FDA acceptance of NDA: October 2023 PDUFA target action date: April 30, 2024 In-licensed: August 2023 *Includes patients ≥12 years of age. 1 FIREFLY-1 Arm 1 expected to support registration. 2 Pimasertib Phase 1 dose escalation and expansion trial previously completed. 3 Research collaboration and license agreement with Sprint Bioscience for exclusive worldwide rights to a research-stage program targeting VRK1. pLGG, pediatric low-grade glioma. Tovorafenib and Pimasertib are investigational products. Safety and efficacy have not been established by any health authority.
Tovorafenib (DAY101) Type II RAF Inhibitor
Pediatric Low-Grade Glioma (pLGG): The Most Common Type Of Brain Tumor In Children PLGGs are chronic and relentless, with patients suffering profound tumor and treatment-associated morbidity that can impact their life trajectory over the long term6 A Serious and Life-Threatening Disease Disease Symptoms7 Cerebral gliomas: Seizures, muscle weakness, behavioral changes Hypothalamic gliomas: Endocrine dysfunction and visual deficits Optic pathway gliomas: Decreased vision (acuity and/or fields), bulging or misalignment of eyes Cerebellar gliomas: Impaired balance, coordination or depth perception Brain stem gliomas: Difficulty swallowing or with speech, abnormal breathing An estimated 26,000 children/young adults are living with BRAF-altered pLGGs in the U.S. today1,2 Surgery plays a significant role in treatment, but 70% of patients require systemic therapy3,4 For the majority of patients in the relapse setting, there is no standard of care and no approved therapies ~70% of pLGGs have BRAF alterations, of these ~85% are BRAF fusions and ~15% are BRAF V600E mutations5 Majority of patients have many years of treatment until the tumors typically senesce by their mid-20s 1 CBTRUS, Qaddoumi et al 2009, Schreck et al 2019, ClearView Analysis; 2 SEER US complete prevalence counts of patients aged under 25 with Brain and Other Nervous Systems tumors as of January 1, 2017. Estimated prevalence are Day One calculations based on publicly available data. 3 Ostrum QT et al., Neuro Oncol. 2015; 16(Suppl 10):x1-x36; 4 De Blank P. et al., Curr Opin Pediatr. 2019 Feb; 31(1):21-27. 5 Jones DTW et al., Cancer Res. 2008; 68:8673–77. 6 Traunwieser T et al., Neurooncol Adv. 2020; 2:vdaa094. 7 Sievert AJ, Fisher MJ. Pediatric low-grade gliomas. J Child Neurol. 2009;24(11):1397-1408. doi:10.1177/0883073809342005.
Conventional Treatments Can Be Disruptive To Childhood and Can Have Significant Long-Term Consequences Significant recovery times Risks of complications Resection may be limited by location of tumor Potential for functional deficits based on location of tumor and extent of resection Risk of secondary malignancy Risk of malignant transformation Risk of vascular proliferation and stroke Neurocognitive impact, depending on location of tumor and radiation field Surgery Chemotherapy Radiation Requirement for indwelling catheter and weekly infusions Risk of neutropenia, hypersensitivity reactions, nausea and vomiting and peripheral neuropathy High unmet need for an effective therapy for the majority of pLGG relapsed or progressive patients that is minimally disruptive to their lives. Source: 1. Heitzer AM, Raghubar K, Ris MD, et al. Neuropsychological functioning following surgery for pediatric low-grade glioma: a prospective longitudinal study. J Neurosurg Pediatr. 2019;1-9. doi:10.3171/2019.9.PEDS19357. 2. Bryant R. Managing side effects of childhood cancer treatment. J Pediatr Nurs. 2003;18(2):113-125. doi:10.1053/jpdn.2003.11. 3. Zahnreich S, Schmidberger H. Childhood cancer: occurrence, treatment and risk of second primary malignancies. Cancers (Basel). 2021;13(11):2607. doi:10.3390/cancers/13112607. 4. National Cancer Institute. Fertility issues in girls and women with cancer. http://www.cancer.gov. Accessed June 13, 2022. 5. Alessi I., Caroleo A.M., de Palma L., Mastronuzzi A., Pro S., Colafati G.S., Boni A., Della Vecchia N., Velardi M., Evangelisti M., et al. Short and Long-Term Toxicity in Pediatric Cancer Treatment: Central Nervous System Damage. Cancers. 2022;14:1540. doi: 10.3390/cancers14061540.
Tovorafenib (DAY101) Inhibits Both BRAF Fusions And BRAF V600 Mutations Tovorafenib (DAY101) is an investigational, oral, selective, CNS-penetrant, type II RAF inhibitor that was designed to inhibit both monomeric and dimeric RAF kinase Activity in tumors driven by both RAF fusions and BRAF V600E mutations Tablet and pediatric-friendly liquid suspension Once weekly dosing Currently approved type I BRAFi are indicated for use in patients with tumors bearing BRAF V600E mutations Type I BRAF inhibitors cause paradoxical MAPK activation in the setting of wild-type RAF, increasing the risk of tumor growth in BRAF fusion-driven RAS-independent activation of the MAPK pathway MAPK pathway RAS RAF MEK ERK Proliferation and survival RAF mutation RAF fusion Proliferation and survival Proliferation and survival Tovorafenib Source: 1. Sun Y et al., Neuro Oncol. 2017; 19: 774–85; 2. Sievart AJ et al., PNAS. 2013; 110:5957-62; 3. Karajannis MA et al., Neuro Oncol 2014;16(10):1408-16.
The Current pLGG Treatment Paradigm Reflects The Unrelenting Nature Of This Chronic Brain Tumor Because many pLGGs undergo senescence when patients reach their 20s, the goal of therapy is to maximize tumor control while minimizing treatment-associated toxicities from surgery, chemotherapy, and radiation. As a result, a large number of pLGG patients will undergo multiple lines of systemic therapy over the course of their disease. Surgical Intervention Suspected pLGG GTR No Recurrence Eventual Recurrence ~80% ~20% ~35% Presentation 1L ~35% 2L Response, no recurrence 3L Chemo (~90%) Chemo (~50%) Chemo (~35%) Other (<5%) Other (<5%) Other (<20%) Targeted Tx (5-10%) Targeted Tx (40-50%) Targeted Tx (40-50%) Response, no recurrence ~50% Biopsy Only ~40% ~20% Molecular Testing Biopsy1 (>95%) No Biopsy (~5%) ≤ Partial Resection ~65% ~50% ~50% Additional lines of therapy Source: Physician Interviews, Bandopadhayay et al. Pediatric Blood Cancer. 2014; Sievert and Fischer. J Child Neurol. 2009; ClearView Analysis. GTR: Gross Total Resection 1Molecular testing of biopsied samples occurs in all patients. Kandels et. al. Retrospective analysis of comprehensive SIOP registry; Hargrave et. al. Phase I/II;Fangusaro et. al. Phase II
Pivotal Phase 2 Trial Of Monotherapy Tovorafenib (DAY101) In Relapsed Or Progressive pLGG (FIREFLY-1) – Fully Enrolled & Data Submitted to FDA Primary endpoint: ORR based on RANO-HGG1, assessed by blinded independent central review Secondary endpoints: ORR by RAPNO-LGG2 assessed by blinded independent central review; PFS, DoR; TTR, CBR; safety Exploratory analyses: ORR and CBR by RANO-LGG3 assessed by blinded independent central review Three arm, open-label, global registrational phase 2 trial Pivotal Arm 1 (recurrent/progressive pLGG, n=77): harboring a KIAA1549-BRAF fusion or BRAF V600E mutation Arm 2 (expanded access recurrent/progressive LGG, n=60): harboring an activating RAF alteration Arm 3 (extracranial solid tumors): harboring an activating RAF fusion Endpoints (Pivotal Arm 1) Trial Design Day –28 to 0 Study Drug Administration 420mg/m2 QW (not to exceed 600mg), QW in 28-day cycles After Cycle 27: patients may either continue treatment or enter drug holiday period at any time (at discretion of investigator) Screening C27D1 Enrollment/ Baseline (C1D1) End of Trial Clinical and radiological evaluations at baseline, and every 3rd cycle for pLGG and every 2nd cycle for solid tumors Eligibility evaluation Treatment period: minimum of 2 years or until progression or toxicity/intolerability Key Inclusion Criteria 6 months – 25 years of age RAF-altered tumor ≥1 prior line of systemic therapy with radiographic progression Prior use of MAPK pathway targeted therapy was permitted June 5, 2023 data cutoff. 1 Wen PY, et al. J Clin Oncol. 2010;28(11):1963-1972. 2 Fangusaro J, et al. Lancet Oncol. 2020;21(6):e305–316. 3 van den Bent MJ, et al. Lancet Oncol. 2011;12(6):583-593. Abbreviations: CBR, clinical benefit rate; IRC, independent review committee; C, cycle; D, day; LGG, low-grade glioma; ORR, objective response rate; PFS, progression-free survival; DoR, duration of response; QW, once weekly; TTR, time to response; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology; MAPK, mitogen-activated protein kinase. For more information, please refer to NCT04775485
Topline Data from Pivotal Phase 2 FIREFLY-1 Trial June 5, 2023 data cutoff
FIREFLY-1 Baseline Patient Characteristics Characteristic Arm 1 (n=77) Median age, years (range) 8 (2-21) Sex, n (%) Male Female 40 (52) 37 (48) Race, n (%) Black or African American Asian White Multiple Other Not reported 2 (3) 5 (6) 41 (53) 3 (4) 6 (8) 20 (26) Number of lines of prior systemic therapy Median (range) 1, n (%) 2, n (%) ≥3, n (%) 3 (1-9) 17 (22) 21 (27) 39 (51) Prior MAPK pathway targeted therapy, n (%) 46 (60) BRAF alteration (n=77) Location (n=77) Optic pathway 51% BRAF V600E 17% BRAF fusion# 83% Cerebellum 6% Deep midline structures 12% Brain stem 8% Cerebral hemisphere 8% Other 16%* June 5, 2023 data cutoff. *Includes tumors that were extending into multiple regions of the brain, leptomeningeal disease, and/or spinal disease. #Includes 6 patients with BRAF duplication and 2 with BRAF rearrangement per FISH (Fluorescence in situ hybridization) or ISH (in situ hybridization). MAPK, mitogen-activated protein kinase.
Topline Data From Ongoing, Fully Enrolled And NDA Submitted Pivotal Phase 2 FIREFLY-1 Trial – June 5, 2023 Data Cutoff June 5, 2023 data cutoff. RANO-HGG ORR (CR + PR). RAPNO-LGG & RANO-LGG ORR (CR + PR + MR), SPPD, Sum of Perpendicular Diameters. CBR, Clinical Benefit Rate (CR + PR + MR + SD). * Indicates the response criteria–evaluable patients within the n=77 Arm 1 population. RANO-HGG (n=69)* RAPNO-LGG (n=76)* RANO-LGG (N=76)* ORR, n (%) 46 (67%) 39 (51%) 40 (53%) CBR, n (%) 64 (93%) 62 (82%) 63 (83%) Best Overall Response, n (%) Complete Response (CR) 12 (17%) - - Partial Response (PR; >=50% reduction in SPPD) 34 (49%) 28 (37%) 20 (26%) Minor Response (MR; >=25 to <50% reduction in SPPD) NA 11 (14%) 20 (26%) Stable Disease (SD; +25% to -25% change in SPPD) 18 (26%) 23 (30%) 23 (30%) Duration of Response (DOR) (months) Median DOR (95% CI) 16.6 (11.6, not estimable) 13.8 (11.3, not estimable) 14.4 (11.0, not estimable) Median duration of tovorafenib treatment of 15.8 months, with 66% of patients remaining on treatment
Tovorafenib (DAY101) Safety Data (n=137) June 5, 2023 data cutoff. Safety data, based on the 137 patients treated in both Arm 1 and Arm 2 of FIREFLY-1, indicated monotherapy tovorafenib to be generally well-tolerated The vast majority of adverse events were Grade 1 or Grade 2, with most common treatment-related side effects, excluding laboratory abnormalities, being change in hair color (76%), fatigue (44%), maculopapular rash (41%), dry skin (33%) and dermatitis acneiform (30%) The most commonly reported treatment-related lab abnormalities were CPK elevation, LDH elevation, anemia, hypophosphatemia and AST elevation. Nearly all of the lab abnormalities had no clinical manifestations and did not require clinical intervention or change in study treatment
Data from Pivotal Phase 2 FIREFLY-1 Trial December 22, 2022 data cutoff
Tumor Response To Tovorafenib (DAY101) For All Patients With RANO-HGG Evaluable Lesions (n=69) – December 22, 2022 Data Cutoff Response (IRC) RANO-HGG1 Evaluable n=69 ORR (cCR + cPR + uPR), n (%) 46 (67%)* Clinical benefit rate, n (%) cCR, cPR/uPR, or SD cCR, cPR/uPR, or SD for 12 mo+ 64 (93%) 49 (71%) Best overall response, n (%) CR PR (includes 3 uPR) SD PD Not evaluable 4 (6%) 42 (61%) 18 (26%) 4 (6%) 1 (1%) All 3 patients with uPR remain on treatment as of May 23, 2023 Dec 22, 2022 data cutoff. Percents may not add to 100% due to rounding. Two of 69 patients are not shown in the waterfall plot; one patient passed away due to progressive disease (not related to tovorafenib) before the first imaging assessment and one did not receive T1 Gd+ follow-up imaging. *P<0.001 from two-sided exact binomial test to test null hypothesis of ORR=21% based on Bouffet et al.2 1 Wen PY, et al. J Clin Oncol. 2010;28(11):1963-1972. 2 Bouffet E, et al. J Clin Oncol. 2012;30(12):1358-1363. CBR, clinical benefit rate; cCR, confirmed completed response; cPR, confirmed partial response; CR, complete response; HGG, high-grade glioma; IRC, independent radiology review committee; MAPKi, mitogen-activated protein kinase inhibitor; MR, minor response; ORR, overall response rate; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; SD, stable disease; uPR, unconfirmed partial response. There are 17 patients with stable disease of less than 12 months duration and at the time of the data cutoff, 11 remain on treatment.
Tumor Response To Tovorafenib (DAY101) For All Patients With RAPNO-LGG Evaluable Lesions (n=69*) – December 22, 2022 Data Cutoff Response (IRC) RAPNO-LGG1 Evaluable n=69 ORR (cCR + cPR/uPR + cMR/uMR), n (%) 35 (51%) Clinical benefit rate, n (%) cCR, cPR/uPR, cMR/uMR, or SD cCR, cPR/uPR, cMR/uMR, or SD for 12mo+ 60 (87%) 36 (52%) Best overall response, n (%) CR PR (includes 4 uPR) MR (includes 4 uMR) SD PD# Not evaluable 0 (0%) 17 (25%) 18 (26%) 25 (36%) 8 (12%) 1 (1%) All 4 patients with uPR and 3 patients with uMR remain on treatment as of May 23, 2023 Dec 22, 2022 data cutoff. Percents may not add to 100% due to rounding. Two of 69 patients not shown in waterfall plot; one patient passed away due to progressive disease (not related to tovorafenib) before the first imaging assessment and one patient had visual progressive disease but no evaluable T2 measurements at the time of progression. *Pending adjudication. 1 Fangusaro J, et al. Lancet Oncol. 2020;21(6):e305-316. #PD for RAPNO-LGG was not used to determine treatment discontinuation; patients could continue treatment if there was no PD based on RANO-HGG per investigator’s assessment. CBR, clinical benefit rate; cCR, confirmed completed response; cMR, confirmed minor response; cPR, confirmed partial response; CR, complete response; HGG, high-grade glioma; IRC, independent radiology review committee; LGG, low-grade glioma; MAPKi, mitogen-activated protein kinase inhibitor; MR, minor response; ORR, overall response rate; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology; SD, stable disease; uMR, unconfirmed minor response; uPR, unconfirmed partial response. There are 28 patients with stable disease of less than 12 months duration and at the time of the data cutoff, 11 remain on treatment.
Tumor Response To Tovorafenib (DAY101) For All Patients With RANO-LGG Evaluable Lesions (n=76) – December 22, 2022 Data Cutoff Response (IRC) RANO-LGG1 Evaluable n=76 ORR (cCR + cPR/uPR + cMR/uMR), n (%) 37 (49%) Clinical benefit rate, n (%) cCR, cPR/uPR, cMR/uMR, or SD cCR, cPR/uPR, cMR/uMR, or SD for 12mo+ 63 (83%) 39 (51%) Best overall response, n (%) CR PR (includes 8 uPR) MR (includes 2 uMR) SD PD# Not evaluable§ 0 (0%) 20 (26%) 17 (22%) 26 (34%) 11 (14%) 2 (3%) All 8 patients with uPR and 2 patients with uMR remain on treatment as of May 23, 2023 Dec 22, 2022 data cutoff. Percents may not add to 100% due to rounding. #PD for RANO-LGG was not used to determine treatment discontinuation; patients could continue treatment if there was no PD based on RANO-HGG per investigator’s assessment. §Two of 76 patients are not shown in the waterfall plot; one patient passed away due to progressive disease (not related to tovorafenib) before the first imaging assessment, and one patient with missing T1 Gd+ imaging at baseline was deemed NE at all timepoints but had a best SPPD decrease of 65% on T2 imaging. 1 van den Bent MJ, et al. Lancet Oncol. 2011;12(6):583-593. BL, baseline; CBR, clinical benefit rate; cCR, confirmed completed response; cMR, confirmed minor response; cPR, confirmed partial response; CR, complete response; HGG, high-grade glioma; IRC, independent radiology review committee; LGG, low-grade glioma; MAPKi, mitogen-activated protein kinase inhibitor; MR, minor response; ORR, overall response rate; PD, progressive disease; PR, partial response; RANO, Response Assessment in Neuro-Oncology; SD, stable disease; SPPD, sum of the products of perpendicular diameters; uMR, unconfirmed minor response; uPR, unconfirmed partial response. There are 27 patients with stable disease of less than 12 months duration and at the time of the data cutoff, 19 remain on treatment.
Duration Of Tovorafenib (DAY101) Therapy For All Patients With RANO-HGG & RANO-LGG Evaluable Lesions – December 22, 2022 Data Cutoff RANO-HGG (n=69) RANO-LGG (n=76) As of the data cutoff, the median IRC-assessed DOR based on RANO-LGG criteria was 14.4 months (95% CI: 8.4, not estimable)* As of the data cutoff, the median IRC-assessed DOR based on RANO-HGG criteria was not yet reached (95% CI: 9.0, not estimable)* * * * Analysis for median time to response and median duration of response only included confirmed responses. BOR is shown; circles indicate start of response. PD for the purpose of treatment was based on RANO-HGG, not RANO-LGG. BOR, best overall response; HGG, high-grade glioma; LGG, low-grade glioma; PD, progressive disease; RANO, Response Assessment in Neuro-Oncology; DOR, duration of response; CI, confidence interval. Dec 22, 2022 data cutoff.
Estimated BRAF-Altered pLGG Patient Population In The U.S. 1 Selt F, van Tilburg CM, Bison B, et al. Response to trametinib treatment in progressive pediatric low-grade glioma patients. J Neurooncol. 2020;149(3):499-510. doi:10.1007/s11060-020-03640-3. 2 Ryall S, Tabori U, Hawkins C. Pediatric low-grade glioma in the era of molecular diagnostics. Acta Neuropathol Commun. 2020;8(1):30. doi:10.1186/s40478-020-00902-z. 3 SEER US complete prevalence counts of patients aged under 25 with Brain and Other Nervous Systems tumors as of January 1, 2017. 4 CBTRUS, Qaddoumi et al 2009, Schreck et al 2019, ClearView Analysis. 5 US Census. Estimated annual incidence, estimated prevalence, and estimated recurrent/progressive total addressable patient population are Day One calculations based on publicly available data. 6 Source: Internal market research conducted by EpidStrategies, A Division of ToxStrategies, Inc. on behalf of Day One. An estimated 26,000 children/young adults are living with BRAF-altered (BRAF fusions or BRAF V600E mutations) pLGGs in the U.S. today1-5 Despite significant disease burden, many pLGGs undergo senescence when patients reach their 20s driving the need to both maximize tumor control while minimizing treatment-associated toxicities As a result, a large number of pLGG patients will undergo multiple lines of systemic therapy over the course of their disease Based on progression free survival curves modeled from published literature, the estimated addressable pool of recurrent or progressive pLGG patients is ~2,000-3,0006 per year at steady state Estimated BRAF-Altered Patients in the U.S. Prevalence of Systemically-Treated Patients Under 253,4 Recurrent/Progressive Total Addressable Patient Population per Year6 Incidence of Treatment-Eligible Frontline Patients4,5 ~26,000 ~2,000-3,000 ~1,100
Key Takeaways From FIREFLY-1 Data And Next Steps Next Steps Priority review granted with PDUFA target action date April 30, 2024 Clinically meaningful data from FIREFLY-1 for pediatric patients with recurrent or progressive LGG harboring BRAF fusions or BRAF V600E mutations (“BRAF-altered”) 67% ORR by RANO-HGG (primary endpoint) 51% ORR by RAPNO-LGG (secondary endpoint) 53% ORR by RANO-LGG (exploratory endpoint) Deepening of responses observed in patients from December 2022 to June 2023 data cutoffs across all three assessment criteria Responses were observed in patients with either BRAF fusion or BRAF V600E mutations (“BRAF-altered”) Responses seen in a heavily-pretreated population where the majority (60%) of patients progressed on or after one or more prior MAPK inhibitors Safety and tolerability profile indicating monotherapy tovorafenib to be generally well-tolerated June 5, 2023 data cutoff.
FIREFLY-2/LOGGIC Pivotal Phase 3 Trial of Tovorafenib (DAY101) in Frontline pLGG
FIREFLY-2/LOGGIC Pivotal Phase 3 Trial Of Tovorafenib (DAY101) In Frontline pLGG 1:1 Randomization Tovorafenib, 420mg/m2 QW (not to exceed 600 mg) Investigator's choice of vincristine/carboplatin* or vinblastine Long-term follow-up (48 months) Stratified by Location of tumor Genomic alteration CDKN2A status Infant CHG diagnosis Non-resectable or sub-total resected LGG AND Requiring first-line systemic therapy N ≈ 400 Primary endpoint: ORR based on RANO-LGG criteria, assessed by blinded independent central review1 The ORR primary analysis is expected to occur ~12 months after the last patient randomized Key secondary endpoints: PFS and DoR by RANO criteria, ORR by RAPNO criteria Other secondary endpoints: changes in neurological and visual function, safety, and tolerability Key exploratory objectives: QoL and health utilization measures Randomized, global, registrational Phase 3 trial of monotherapy tovorafenib (DAY101) vs SoC chemotherapy Eligibility: Patients aged 6 months to <25 years with LGG harboring a RAF alteration and requiring first-line systemic therapy Tovorafenib (DAY101) available as tablets and pediatric-friendly liquid suspension Patients who progress after stopping tovorafenib (DAY101) may be re-challenged Patients who progress in the SoC arm during or post-treatment may cross-over to receive tovorafenib Endpoints Trial Design * COG or SIOPe-LGG regimen. Abbreviations: CHG, chiasmatic, hypothalamic glioma; DoR, duration of response; LGG, low-grade glioma; ORR, objective response rate; QoL, quality of life; QW, once weekly; SoC, standard of care. 1 Primary endpoint of FIREFLY-2 will be ORR by RANO-LGG (2017) following full approval by FDA on March 16, 2023 of dabrafenib with trametinib in pediatric patients with low-grade glioma with a BRAF V600E mutation who require systemic therapy based on a study with the same primary endpoint.
FIRELIGHT-1 Phase 1b/2 Trials Evaluating Tovorafenib (DAY101) as a Combination with Pimasertib
Pimasertib: Investigational Allosteric MEK1/2 Inhibitor With Demonstrated Activity In MAPK-Driven Solid Tumors Pimasertib is an investigational orally-bioavailable, selective, non-competitive MEK1/2 inhibitor in-licensed from Merck KGaA in February 2021 Extensive non-clinical and clinical development work through Phase 2, including a solid tumor trial in Japan and combinations with other MOAs Main AEs typical for all in-class allosteric MEK inhibitors (GI, CPK elevation, skin rash, visual disturbances) Nearly three-fold higher CNS penetration than other MEKi inhibitors (trametinib or selumetinib) Pimasertib showed monotherapy clinical activity, including an improvement in median PFS versus dacarbazine in NRAS mutant melanoma Combination with tovorafenib (DAY101) and other targeted therapies may unlock the full value of pimasertib in advanced solid tumors Sources: Pimasertib Investigator Brochure, v12, 2019; de Gooijer et al., Int J Cancer, 2018; Shaw et al., AACR LB-456, 2012; Lebbe et al., Cancers, 2020.
Vertical MAPK Pathway Inhibition With Tovorafenib (DAY101) And Pimasertib May Unlock Potential Synergy For Adult Solid Tumors Type II RAFi + MEKi is synergistic in BRAF fusion melanoma PDX model ex vivo (internal data) Sensitivity of KRAS Q61 mutant cells to pimasertib is enhanced when cells are treated with the type II BRAF inhibitor BGB-283 (Yuan et al., Mol Onc 2020) Tovorafenib (DAY101) + MEK inhibitor is synergistic in KRAS G12C and Q61 mutant tumor cells (Venetsanakos et al., 2021 AACR poster presentation) B C Type II RAFi + MEKi KRAS or NRAS mutant Proliferation, survival RAF/ MEK/ERK RAL PI3K/m TOR A Type II RAFi + MEKI BRAF non-V600 mutant Targeting multiple nodes of MAPK pathway will drive deeper and more durable response Non V600 BRAF dimers are effectively inhibited by type II RAFi , but not type I BRAFi Proliferation, survival MEK ERK
Tovorafenib (DAY101) / Pimasertib Combination In Solid Tumors (FIRELIGHT-1) Pre-identified patients with advanced solid tumors and available clinical molecular profiling information. Phase 1b Tumors with MAPK pathway alterations *Additional biomarker-selected cohorts may be pursued based on developing data Phase 2* NRASmut Selected tumors BRAF fusion selected tumors BRAF Class 1 (non-E/K) and Class 2 mutant tumors DAY101 + Pimasertib until disease progression3 Safety Follow Up Phase 1b: PK, PD and Safety, MTD/RP2D Phase 2: Efficacy (ORR, DOR) Combination dose escalation, global phase 1b/2 trial2 Phase 1b, BOIN (adaptive), n = 10/cohort (approximately) Phase 2, Simon 2-stage, n = 25/cohort (approximately) Eligibility: Patients aged 12 years and older, dose escalation will be performed in advanced solid tumor patients with any MAPK alteration. Expansion cohorts will focus on indications with a potential path to accelerated approval Endpoints Trial Design1 Abbreviations: BOIN, Bayesian Optimal Interval Design; BRAF, B-Raf proto-oncogene, serine/threonine kinase; MAPK, mitogen-activated protein kinase; NRAS, neuroblastoma rat sarcoma viral oncogene. 1Umbrella master study – DAY101-102 (main protocol) DAY101 and MAPK pathway aberration, Sub-study 1 monotherapy (DAY101-102a), Sub-study 2 MEK combo (DAY101-102b).2Intend to open U.S. and ex-U.S. clinical sties. 3DAY101 + Pimasertib until disease progression, intolerable toxicity, withdrawal of consent, or death
Summary
Financial Summary: DAWN $ Millions Nine Months Ended 9/30/23 Nine Months Ended 9/30/22 R&D Expense $93.2 $59.6 G&A Expense $53.4 $44.6 Net Loss $134.4 $102.1 Projected cash runway into 2026 FIREFLY-1: Pivotal Phase 2 clinical trial of tovorafenib (DAY101) Initiated rolling NDA1 in May 2023 Topline data presented in September 2023 FDA acceptance of NDA and priority review granted in October 2023 PDUFA target action date of April 30, 2024 FIREFLY-2/LOGGIC: Pivotal Phase 3 clinical trial of tovorafenib (DAY101) in newly diagnosed pLGG First patient dosed in March 2023 Cash, cash equivalents and short-term investments as of September 30, 2023: $405.5 million (no debt) ~87.0 million shares of common stock outstanding as of November 1, 2023 All financial and share information is unaudited. 1NDA data set includes analysis of primary (ORR by RANO-HGG) and secondary (ORR by RAPNO, PFS) efficacy endpoints, safety, and exploratory analyses (including ORR by RANO-LGG).
Next Steps FIREFLY-1 Initiated rolling NDA in May 2023 New topline data presented in September 2023 FDA acceptance of NDA and priority review granted in October 2023 PDUFA target action date of April 30, 2024 FIREFLY-2 Advance tovorafenib as a frontline therapy for patients with pLGG Currently activating sites and enrolling patients Commercial Continue investment in market and launch preparation activities Business Development Research collaboration and license agreement for preclinical program targeting VRK1 Further investment in business development activities to expand our multiple asset portfolio FIRELIGHT-1 Evaluate tovorafenib in combination in adolescent and adult populations
Appendix
Duration Of Tovorafenib (DAY101) Therapy For All Patients With RANO-HGG Evaluable Lesions (n=69) 11/17 patients with stable disease <12 months remain on treatment as of data cutoff Partial response Complete response Progressive disease Discontinuation due to AE Death Ongoing treatment Discontinued treatment Follow-up after discontinuation of treatment BRAF V600E mutation Prior MEK inhibitor therapy Prior BRAF inhibitor therapy 10.8 MONTHS Median duration of treatment* 2.8 MONTHS Median time to response* * Analysis for median time to response and median duration of treatment only included confirmed responses. HGG, high-grade glioma; RANO, Response Assessment in Neuro-Oncology. Dec 22, 2022 data cutoff.
All RANO-LGG Unconfirmed PR Patients Continue On Treatment With Demonstrable Deepening Of Response (n=8) Responses for Patients with Unconfirmed Partial Response by RANO-LGG Percent Change from Baseline (%) Months from Baseline SD MR PR CR All 8 patients with unconfirmed partial response by RANO-LGG remain on treatment as of May 23, 2023 Spider plot for SPPD – baseline and after treatment (RANO-LGG by IRC) – unconfirmed PR patients EOT status based on May 23, 2023 EDC data. Individual patient response data is current as of the data cutoff of December 22, 2022; treatment status data is current as of May 23, 2023.
Nearly Half Of Patients With Best Response Of PD By RANO-LGG Have Tumor Stabilization And Response With Continued Treatment (n=11) 5/11 patients with best response of PD by RANO-LGG remain on treatment as of May 23, 2023 Ongoing treatment Discontinued treatment Individual patient response data is current as of the data cutoff of December 22, 2022; treatment status data is current as of May 23, 2023.
Tovorafenib (DAY101) Safety Data (n=136) Preferred term, n (%) Treatment-emergent AEs Treatment-related AEs Any grade Grade ≥3 Any grade Grade ≥3 Any AE 136 (100) 68 (50) 133 (98) 47 (35) Hair color changes 96 (71) - 96 (71) - Fatigue 68 (50) 4 (3) 54 (40) 4 (3) Vomiting 59 (43) 3 (2) 24 (18) 3 (2) Rash maculo-papular 56 (41) 10 (7) 51 (38) 10 (7) Headache 53 (39) 1 (1) 27 (20) - Pyrexia 43 (32) 2 (1) 15 (11) 1 (1) Nausea 40 (29) - 21 (15) - Dry skin 39 (29) - 34 (25) - Dermatitis acneiform 37 (27) 1 (1) 36 (26) 1 (1) Constipation 36 (26) - 28 (21) - Decreased appetite 35 (26) 4 (3) 25 (18) 3 (2) Epistaxis 34 (25) - 22 (16) - The vast majority of treatment-emergent AEs were Grade 1 or 2 39 patients (29%) required dose modifications due to treatment-related AEs Dose interruptions were brief, with the median time of dose interruption being 2 weeks 5 patients (4%)* discontinued due to AE, with 4 patients (3%) discontinuing due to treatment-related AEs The most commonly reported lab abnormalities were CPK elevation, anemia, hypophosphatemia, and AST elevation Nearly all had no clinical manifestations and did not require clinical intervention or change in study treatment Dec 22, 2022 data cutoff. Table shows treatment-emergent AEs with frequency ≥25% of any grade. Rash erythematous treatment-emergent: any grade, 14 (10%); grade ≥3 1 (1%); treatment-related: any grade, 14 (10%), grade ≥3 1 (1%). *One patient had 2 events (shunt malfunction [not related to tovorafenib] and tumor hemorrhage [related to tovorafenib]). AEs, adverse events.
Diagnostic biopsy Months A 7-years-old female child with an optic pathway glioma, with very poor vision, entropion, folliculitis, eczema, mouth ulceration and xerosis Case Study: Activity Of Tovorafenib (DAY101) In KIAA1549-BRAF Fusion Optic Pathway Glioma PR 1L: Vincristine/carboplatin Best response SD 2L: Trametinib Best response PD 3L: Tovorafenib -24 -18 -12 -6 0 6 -30 -36 PR (-58%) and improvement in vision reported at cycle 3 AEs included grade 3 erythematous rash requiring dose interruption and dose reduction (400 mg QW to 300 mg QW in cycle 1), and grade 2 eczema and maculopapular rash Patient continues to receive weekly tovorafenib Tumor kinetics (RANO) Tovorafenib After 6 cycles Baseline Apr 14, 2022 data cutoff. Tovorafenib is an investigational agent. Safety and efficacy have not been established by any health authority.
Months An 8-years-old female child with a posterior fossa pilocytic astrocytoma, eczema, nausea and constipation Case Study: Activity Of Tovorafenib (DAY101) In KIAA1549-BRAF Fusion Posterior Fossa Pilocytic Astrocytoma Suboccipital craniotomies 2L: Carboplatin/vincristine Best response PR PR 3L: Vinblastine Best response SD -84 -48 -36 -24 -12 0 12 -72 4L: Trametinib Best response SD 5L: Tovorafenib -60 1L: Carboplatin Best response PD After 6 cycles After 3 cycles After 9 cycles Tumor kinetics Tovorafenib Baseline PR (-69%) at cycle 3 with 500 mg QW tovorafenib, with a deepening of response (80% and 91% in cycles 6 and 9, respectively) over time AEs included grade 2 decrease in neutrophil count, pustular rash, and upper respiratory infection Patient continues to receive weekly tovorafenib Apr 14, 2022 data cutoff. Tovorafenib is an investigational agent. Safety and efficacy have not been established by any health authority.
Months A 9-year-old female child with deep midline BRAF V600E-mutant astrocytoma with precocious puberty -60 Case Study: Activity Of Tovorafenib (DAY101) In BRAF V600E Mutation Deep Midline Astrocytoma PR -48 -36 -24 -12 0 12 2L: Dabrafenib Best response PR 3L: Tovorafenib 1L: Carboplatin/vincristine Best response PR Subtotal resection Tumor kinetics Tovorafenib After 6 cycles After 3 cycles Baseline PR (-74%) at cycle 3, with a deepening of response (-94%) at cycle 6 AEs included grade 3 maculopapular rash and increased CPK, requiring drug interruption and dose reduction (500 mg QW to 400 mg QW in cycle 1) Tovorafenib dose was re-escalated back to 500 mg QW in cycle 4; patient continues on treatment Apr 14, 2022 data cutoff. Tovorafenib is an investigational agent. Safety and efficacy have not been established by any health authority.
Case Study: Activity Of Tovorafenib (DAY101) In KIAA1549-BRAF Fusion Optic Pathway Glioma Tumor kinetics Trametinib Tovorafenib Months -48 -36 -24 -12 0 12 -60 24 VC Binimetinib PR Initiated treatment with tovorafenib 400 mg/QW following 3 prior therapies, including binimetinib and trametinib, which were discontinued due to PD At cycle 3, PR (-88%) per RANO-HGG, and MR (-32% and -40%) per RAPNO-LGG and RANO-LGG, respectively Sustained improvements in visual acuity reported; logMAR change 0.2 → 0 PD criteria met (-94% to -91%) with RANO-HGG at cycle 15; continued treatment as investigator deemed no radiographic progression with subsequent reduction in target lesion (-97%) AEs were G2 (drug eruption, elevated CPK) and G1 (hair color change, paronychia, growth retardation) 8-year-old boy with relapsed pilomyxoid astrocytoma of the optic pathway, with visual loss in right eye, visual field loss in left eye, fatigue, intermittent nausea/vomiting, intermittent headaches, anorexia, and temperature regulation disorder T1 + C (baseline and post-cycle 3) T2 (baseline and post-cycles 3 & 12) Dec 22, 2022, data cut-off. AEs, adverse events; C, contrast; CPK, creatine phosphokinase; G, grade; HGG, high-grade glioma; LGG, low-grade glioma; logMAR, Logarithm of the Minimum Angle of Resolution; MR, minor response; PD, progressive disease; PR, partial response; QW, once weekly; RANO, Response Assessment in Neuro-Oncology; RAPNO, Response Assessment in Pediatric Neuro-Oncology; VC, vincristine-carboplatin.
Collaboration between Day One and the LOGGIC consortium, internationally recognized experts in pLGG research Coupled with the LOGGIC-CORE molecular diagnostic program Worked jointly on the study design and discussions with the U.S. and EU regulatory authorities FIREFLY-2/LOGGIC: Pivotal Phase 3 Study Of Tovorafenib (DAY101) In Newly Diagnosed pLGG ~5 Sites Approximately 100 potential sites (~65 from the LOGGIC consortium) ~20 Sites ~65 Sites ~10 Sites
Results From Independent Radiology Review Of PNOC014 RAPNO: Response assessment for pediatric neuro-oncology (exploratory) RANO-HGG: Response assessment for neuro-oncology-high grade glioma Volumetric image analysis (exploratory) Best response from baseline Date of data cutoff: 02 JAN 2020. Wright K et. al. Neuro Oncology Abstract CTNI-19. 2020
Multiple Rapid, Deep And Durable Responses Observed Following Initiation Of Tovorafenib (DAY101) Treatment Of pLGG Patients In PNOC014 Growth kinetics of Target Lesions from Screening Date of data cutoff: 02 JAN 2020. Adapted from Wright K et. al. Neuro Oncology Abstract CTNI-19. 2020. Fangusaro J et al. Lancet Oncol 2019
Drug-related Adverse Events Observed for Tovorafenib (DAY101) in PNOC014 Showed Favorable Safety and Tolerability Profile in pLGG Toxicities Grade 1-2 Grade 3 Grade 4 Anemia 6 (67%) Hypophosphatemia 4 (44%) Fatigue 5 (55%) Rash 8 (89%) Achromotrichia 7 (78%) Pruritis 6 (67%) Photosensitivity 1 (11%) Nevus 7 (78%) Alopecia 3 (34%) Epistaxis 2 (22%) Dry skin 3 (34%) Myalgias/arthralgias 3 (34%) Anorexia 2 (22%) Cheilitis 3 (34%) Hypermagnesemia 1 (11%) Bleeding gums 1 (11%) Increased AST 4 (44%) Nausea/vomiting 3 (33%) CPK elevation 1 (11%) Weight loss 2 (22%) DAY101 AE summary Most common toxicity: skin AEs reversible and all manageable Single, reversible Grade 3 event No Grade 4 AEs No dose reductions (vs. 40% of patients on selumetinib montherapy required dose reductions) Drug-related AEs for Tovorafenib (DAY101) Toxicities Grade 1-2 Grade 3 Grade 4 Increased ALT 20 (40%) 1 (2%) CPK elevation 34 (68%) 5 (10%) Diarrhea 27 (54%) 2 (4%) Decreased ejection fraction 19 (38%) 1 (2%) Gastric haemorrhage 1 (2%) Headache 14 (28%) 1 (2%) Decreased lymphocyte count 19 (38%) 1 (2%) Neutropenia 14 (28%) 3 (6%) Paronychia 19 (38%) 3 (6%) Rash (acneiform) 29 (58%) 2 (4%) Rash (maculopapular) 26 (52%) 5 (10%) Skin infection 7 (14%) 1 (2%) Tooth infection 1 (2%) Weight gain 5 (10%) 1 (2%) Vomiting 22 (44%) Nausea 21 (42%) Increased AST 25 (50%) Anemia 28 (56%) Pruritis 10 (20%) Dyspnea 30 (60%) Drug-related AEs for selumetinib Date of DAY101 data cutoff: 02 JAN 2020; Wright K et. al. Neuro Oncology Abstract CTNI-19. 2020; Fangusaro J et al. Lancet Oncol 2019
