On January 09, 2023 Day One Biopharmaceuticals (Nasdaq: DAWN), a clinical-stage biopharmaceutical company dedicated to developing and commercializing targeted therapies for people of all ages with life-threatening diseases, reported positive topline results from the ongoing, open-label, pivotal Phase 2 FIREFLY-1 trial evaluating the investigational agent, tovorafenib (DAY101), as a monotherapy in recurrent or progressive pediatric low-grade glioma (pLGG) (Press release, Day One, JAN 9, 2023, View Source [SID1234626050]). Pediatric low-grade glioma is the most common brain tumor diagnosed in children and for which there is no standard of care, and for which there are no approved therapies for the majority of patients. Additional data will be submitted for presentation at an upcoming medical meeting in the second quarter of 2023.

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The primary endpoint of the FIREFLY-1 trial is overall response rate (ORR) by Response Assessment for Neuro-Oncology (RANO) criteria as assessed by blinded independent central review. Topline results as of September 28, 2022 include:

Among 69 RANO-evaluable patients:

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64% ORR and 91% clinical benefit rate (complete response + partial response/unconfirmed partial response + stable disease)

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4% (n=3) confirmed complete responses

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59% (n=41) partial responses (31 confirmed and 10 unconfirmed)

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28% (n=19) patients with stable disease

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86% (n=59) of patients had a BRAF fusion alteration, for which there are no approved systemic therapies, while the remaining 14% (n=10) had a BRAF mutation

Safety data, based on 77 treated patients, indicated monotherapy tovorafenib to be generally well-tolerated. The most common side effects reported related to tovorafenib were change in hair color (75%), increased creatine phosphokinase (64%), anemia (46%), fatigue (42%) and maculopapular rash (42%).

Among a total of 77 treated patients:

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Participants were heavily pretreated, with a median of three prior lines of systemic therapy (range: 1-9)

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The median duration of tovorafenib treatment was 8.4 months, with 77% (n=59) of patients on treatment at the time of the data cutoff

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Nearly 60% (n=46) of patients had already received at least one prior MAPK inhibitor prior to study participation

"The responses we’ve observed in the FIREFLY-1 study with weekly monotherapy tovorafenib in children with recurrent or progressive low-grade gliomas are very encouraging," said Samuel Blackman, M.D., Ph.D., co-founder and chief medical officer of Day One. "As tovorafenib progresses in the clinic, we want to thank the patients, their families, the clinical investigators, and the advocates who have chosen to participate in the FIREFLY-1 clinical trial and support the development of a potential new treatment for children in need of new therapeutic options."

FIREFLY-1 is evaluating tovorafenib as once-weekly monotherapy in patients aged 6 months to 25 years with recurrent or progressive pLGG. The trial is being conducted in collaboration with the Pacific Pediatric Neuro-Oncology Consortium (PNOC) and is designed to support the potential regulatory approval of tovorafenib.

"Based on the efficacy and safety profile of tovorafenib observed to date from the FIREFLY-1 trial population, we plan to submit a New Drug Application in the first half of this year that will include additional follow up from the full study population," said Jeremy Bender, Ph.D., chief executive officer of Day One. "We look forward to continuing our discussions with regulatory authorities with the hope of bringing this therapy to children in need of new options as soon as possible."

In addition to FIREFLY-1, Day One is expanding the development of tovorafenib as a front-line therapy for patients newly diagnosed with pLGG. The global, Phase 3, registrational FIREFLY-2/LOGGIC clinical trial is evaluating once-weekly monotherapy tovorafenib in newly-diagnosed patients with pLGG harboring a known activating RAF alteration.

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 system tumors. BRAF wild-type fusions are the most common cancer-causing genomic alterations in pediatric low-grade gliomas. These genomic alterations are also found in several 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 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 Tovorafenib

Tovorafenib is an investigational, oral, brain-penetrant, highly-selective type II pan-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 recurrent or progressive pLGG, which is an area of considerable unmet need with no approved therapies. 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.

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.