On September 11, 2023 Day One Biopharmaceuticals (Nasdaq: DAWN) ("Day One" or the "Company"), a clinical-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, reported the recently completed submission of the rolling New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for tovorafenib as a monotherapy in relapsed or progressive pediatric low-grade glioma (pLGG) (Press release, Day One, SEP 11, 2023, View Source [SID1234635063]). The Company anticipates the FDA will file the rolling NDA by mid-November 2023.
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
pLGG is the most common brain tumor diagnosed in children, with patients suffering profound tumor and treatment-associated morbidities that can impact their life trajectory over the long term. For the majority of patients in the relapsed setting, there is no standard of care and no approved therapies.
"We believe that tovorafenib, if approved, could change the treatment landscape for children living with this chronic and relentless disease," said Jeremy Bender, Ph.D., chief executive officer of Day One. "The NDA submission of tovorafenib is a significant milestone for Day One and an important step towards bringing a potential new targeted therapy to children with brain cancer."
The Company initiated the rolling submission of the NDA in May 2023 based on data from the FIREFLY-1 trial with a data cutoff as of December 22, 2022. An updated Clinical Study Report (CSR) was submitted to the FDA with an additional six months of safety and efficacy data through June 5, 2023.
FIREFLY-1 is an open-label, pivotal Phase 2 trial, which treated a total of 137 patients across two study arms. Arm 1 evaluated tovorafenib in 77 patients as a once-weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG. The primary endpoint of the trial is ORR by Response Assessment for Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria. Secondary endpoints include ORR by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO-LGG), progression-free survival (PFS), duration of response (DOR), time to response, clinical benefit rate and safety. The NDA submission also includes an exploratory analysis of ORR by Response Assessment for Neuro-Oncology Low-Grade Glioma (RANO-LGG). All data have been assessed by a blinded Independent Review Committee (IRC).
Updated FIREFLY-1 Data Demonstrate Consistent and Durable Response
New data from the FIREFLY-1 trial, with a data cutoff of June 5, 2023, are described below. Detailed data will be presented at an upcoming medical conference.
RANO-HGG (n=69 evaluable) data, the primary endpoint of the trial:
•
67% ORR (complete response (CR) + partial response (PR))
•
93% clinical benefit rate (CBR) (CR + PR + stable disease (SD))
•
17% (n=12) CR
•
49% (n=34) PR
•
26% (n=18) SD
•
At the time of data cutoff, the median duration of response (DOR) based on RANO-HGG criteria was 16.6 months (95% CI: 11.6, not estimable)
Among a total of 77 treated patients:
•
The median duration of tovorafenib treatment was 15.8 months, with 66% (n=51) of patients on treatment at the time of 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 side effects reported related to tovorafenib 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.
The NDA submission also included the evaluation of responses by RAPNO-LGG and RANO-LGG. Those results include:
RAPNO-LGG (n=76 evaluable) data, a key secondary endpoint of the trial:
•
51% ORR (CR + PR + minor response (MR))
•
82% CBR (CR+ PR + MR + SD)
•
37% (n=28) PR
•
14% (n=11) MR
•
30% (n=23) SD
•
At the time of data cutoff, the median DOR based on RAPNO-LGG criteria was 13.8 months (95% CI: 11.3, not estimable)
RANO-LGG (n=76 evaluable) data, an exploratory analysis of the trial:
•
53% ORR (CR + PR + MR)
•
83% CBR (CR + PR + MR + SD)
•
26% (n=20) PR
•
26% (n=20) MR
•
30% (n=23) SD
•
At the time of data cutoff, the median DOR based on RANO-LGG criteria was 14.4 months (95% CI: 11.0, not estimable)
Tovorafenib was granted Rare Pediatric Disease Designation for relapsed or progressive pLGG and, as such, may qualify for receipt of a priority review voucher, if tovorafenib is approved by the FDA in this indication. Based on Day One’s current operating plan, management believes it has sufficient capital resources to fund anticipated operations into 2026.
About Pediatric Low-Grade Glioma
Pediatric low-grade glioma (pLGG) is the most common brain tumor diagnosed in children, accounting for 30% – 50% of all central nervous systems tumors. BRAF wild-type fusions are the most common cancer-causing genomic alterations in pLGG. These genomic alterations are also found in severe adult and pediatric solid tumors.
Pediatric low-grade glioma can impact a child’s health in many ways depending on tumor size and location, including vision loss and motor dysfunction. There are no approved therapies for the vast majority of patients with pLGG, and current treatment approaches are associated with potential acute and life-long adverse effects. While most children with pLGG survive their cancer, children who do not achieve remission following surgery may face years of increasingly aggressive therapies. Due to the indolent nature of pLGG, patients generally receive multiple years of systemic therapy.
About FIREFLY-1
FIREFLY-1 is evaluating tovorafenib as once-weekly monotherapy in patients aged 6 months to 25 years with relapsed or progressive pLGG harboring a known activating BRAF alteration. The trial is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium (PNOC). The primary endpoint is overall response rate (ORR), defined as the proportion of patients with confirmed response based upon RANO-HGG criteria. Secondary and exploratory endpoints include the overall response rate based on RAPNO-LGG criteria, RANO-LGG criteria and volumetric analyses, progression-free survival, safety, functional outcomes, and quality of life measures. RANO-HGG, RANO-LGG and RAPNO-LGG are assessed by blinded independent central review. Additional information about FIREFLY-1 may be found at ClinicalTrials.gov, using Identifier NCT04775485.
About the Pacific Pediatric Neuro-Oncology Consortium
The Pacific Pediatric Neuro-Oncology Consortium (PNOC) is an international consortium with study sites within the United States, Canada, Europe and Australia dedicated to bringing new therapies to children and young adults with brain tumors.
About Tovorafenib
Tovorafenib is an investigational, oral, brain-penetrant, highly-selective type II RAF kinase inhibitor designed to target a key enzyme in the MAPK signaling pathway, which is being investigated in primary brain tumors or brain metastases of solid tumors. Tovorafenib has been studied in over 325 patients to date. Currently tovorafenib is under evaluation in a pivotal Phase 2 clinical trial (FIREFLY-1) among pediatric, adolescent and young adult patients with relapsed or progressive pLGG, which is an area of considerable unmet need with no approved therapies for the vast majority of patients. Tovorafenib is also being evaluated alone or as a combination therapy for adolescent and adult patient populations with recurrent or progressive solid tumors with MAPK pathway aberrations (FIRELIGHT-1).
Tovorafenib has been granted Breakthrough Therapy and Rare Pediatric Disease designations by the U.S. Food and Drug Administration (FDA) for the treatment of patients with pLGG harboring an activating RAF alteration. Tovorafenib has also received Orphan Drug designation from the FDA for the treatment of malignant glioma, and from the European Commission (EC) for the treatment of glioma.