On April 23, 2024 Day One Biopharmaceuticals, Inc. (Nasdaq: DAWN) ("Day One" or the "Company"), a commercial-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, reported that the U.S. Food and Drug Administration (FDA) has approved OJEMDA (tovorafenib), a type II RAF inhibitor, for the treatment of patients 6 months of age and older with relapsed or refractory pLGG harboring a BRAF fusion or rearrangement, or BRAF V600 mutation (Press release, Day One, APR 23, 2024, View Source [SID1234642278]). This indication is approved under accelerated approval based on response rate and duration of response. With the approval, Day One received a rare pediatric disease priority review voucher from the FDA.

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"OJEMDA ushers in a new day for children living with relapsed or refractory pLGG, and we are pleased that we can deliver a new medicine for these patients in desperate need of new treatment options. Moreover, OJEMDA is the first and only FDA-approved medicine for children with BRAF fusions or rearrangements, which are the most common molecular alteration in pLGG," said Jeremy Bender, Ph.D., chief executive officer of Day One. "We are very proud that our first approved medicine addresses this serious and life-threatening disease of childhood and adolescence. We are grateful to the pLGG community, including patients and their families, study investigators, non-profit organizations, and advocacy groups, for their collaboration and support as we strive to close the innovation gap for children with cancer awaiting new treatments."

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. BRAF is the most commonly altered gene in pLGG, with up to 75 percent of children having a BRAF alteration. Until now, there had been no medicines approved for patients with pLGG driven by BRAF fusions.

"pLGG is a chronic and relentless cancer that can devastate children and their families, often stealing their vision, balance and speech," said Dr. Sabine Mueller, pediatric neuro-oncologist, University of California San Francisco Benioff Children’s Hospitals. "The goal of pLGG treatment is to stabilize or shrink the tumor without further disrupting the child’s and family’s life. Historically, there has been no standard of care for children with pLGG who have relapsed. We are excited to welcome a new targeted treatment option with once-weekly oral dosing designed specifically for these kids and their families."

OJEMDA is the only systemic therapy for pLGG that offers once-weekly dosing, with or without food, as a tablet or oral suspension.

Approval Based on Multiple Criteria

The accelerated approval of OJEMDA is based on data from the Company’s pivotal open-label Phase 2 FIREFLY-1 trial, which enrolled a total of 137 relapsed or refractory BRAF-altered pLGG patients across two study arms. Arm 1, which accrued 77 patients, was used for the efficacy analyses. Arm 2 provided additional safety data from an incremental 60 patients and was initiated to enable access to tovorafenib once Arm 1 had fully accrued. Details of this trial were presented in November 2023 at the Society for Neuro-Oncology meeting through two oral plenary presentations and in parallel through a publication in Nature Medicine.

The approval of OJEMDA was based, in part, on the major efficacy outcome measure of overall response rate (ORR), defined as the proportion of patients with complete response (CR), partial response (PR), or minor response (MR) by independent review based on Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO LGG).

"This is a tremendous moment not only for Day One, but also for the broader pediatric brain tumor community. Thanks to the close collaboration between RAPNO and Response Assessment for Neuro-Oncology (RANO) working groups and the patients and families impacted by a pLGG diagnosis, the way we think about measuring response and the goals of therapy for this unique patient population truly evolved," said Dr. Samuel Blackman, co-founder and head of research and development at Day One. "As a pediatric neuro-oncologist, the approval of OJEMDA is a dream realized."

In Arm 1, data from the 76 RAPNO LGG evaluable patients include:

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A best ORR of 51% (95% CI: 40 – 63), which included 28% PRs and 11% MRs.

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The ORR for OJEMDA was 52% among the 64 patients with BRAF fusions or rearrangements and 50% for the 12 patients with a BRAF V600 mutation.

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The ORR was 49% among the 45 patients who had received a prior MAPK-targeted therapy, and 55% among the 31 patients who had not received a prior MAPK-targeted therapy.

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As of the June 5, 2023 data cutoff, the median duration of response by RAPNO LGG was 13.8 months (95% CI: 11.3, not estimable). In addition, 66% of patients remained on study and continue on treatment as of this date.

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The median time to response, following initiation of treatment, with OJEMDA was 5.3 months (range 1.6, 11.2).

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Based on RANO LGG criteria, the ORR was 53% [95% CI: (41, 64)].

The safety of OJEMDA was evaluated in 137 patients with relapsed or refractory pLGG, with the majority of adverse events being Grade 1 or Grade 2. The most common side effects were rash, hair color changes, tiredness, viral infection, vomiting, headache, fever, dry skin, constipation, nausea, acne and upper respiratory tract infection.

"This is an exciting moment for children and families living with pLGG who previously had few treatment options if their disease progressed," said Courtney Davies, president and chief executive officer of the Pediatric Brain Tumor Foundation. "The approval of OJEMDA is a testament to the power of community and industry collaboration to address a critical unmet need for children whose day-to-day living and long-term health outcomes are significantly impacted by pLGG. The potential benefit that a new treatment option provides children living with this disease and their families is crucial. There is so much to celebrate here."

The Company continues its commitment to the pLGG community with the Phase 3 FIREFLY-2/LOGGIC randomized clinical trial evaluating tovorafenib as a potential front-line therapy compared to chemotherapy in patients aged 6 months to 25 years with pLGG, which it believes will satisfy certain post-marketing requirements to the FDA. This study is currently enrolling patients in the United States, Canada, Europe, Australia, and Asia.