Company: DAWN
Filing Date: 2025-02-25
Form Type: 10-K
Source: 0000950170-25-026654
Chunk: 74

Company: Day One Biopharmaceuticals, Inc.
Filing Date: 2025-02-25
Form: 10-K
Item: Item 1
Chunk 74
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ristine/carboplatin. Outcomes for a subgroup of patients with pLGG not associated with neurofibromatosis, which included those with BRAF alterations, were inferior, showing a 5-year event-free survival of 39%. Of note, the overall response rate to chemotherapy in newly diagnosed patients with pLGG was 30%-35%. In addition to chemotherapy’s efficacy limitations, treatment-related morbidity was significant, with more than 95% of patients having experienced at least one Grade 3 or Grade 4 adverse event. A number of therapies targeting pathway have been assessed in tumor types harboring molecular alteration on the MAPK pathway, including BRAF and MEK, as further discussed below. While some of these agents have been approved for the treatment of tumors harboring BRAF V600 mutation including in children with pLGG, there is no consensual standard-of-care therapy for patients whose tumors progress following the failure of these chemotherapy regiment or targeted therapies.

Because many pLGGs undergo senescence when patient ages 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 patients with pLGG will undergo multiple lines of systemic therapy over the course of their disease.

Based on incidence results published in academic journals, we estimate that approximately 1,100 patients under the age of 25 are newly diagnosed with BRAF-altered pLGG every year. We partnered with an epidemiology firm to perform SEER and CBTRUS registry analysis that estimates the prevalence, as of January 1, 2017, in the United States for BRAF-altered patients with pLGG under the age of 25 to be 26,000. The estimated addressable pool of recurrent, progressive, or refractory patients with pLGG for tovorafenib is approximately between 2,000 to 3,000 per year at steady state.

Over the last decade, it has been found that between 50% and 60% of pLGGs are driven by abnormal signaling due to alterations in RAF, approximately 85% to 90% of which are a gene fusion known as KIAA1549-BRAF. This gene alteration results in the expression of a wild-type BRAF catalytic domain without its normal regulatory domain, thereby rendering constitutively active BRAF activity. In addition, between 5% and 17% of children with pL