Company: WHWK
Filing Date: 2025-01-21
Form Type: PREM14A
Source: 0001193125-25-009599
Chunk: 188

Company: Whitehawk Therapeutics, Inc.
Filing Date: 2025-01-21
Form: PREM14A
Chunk 188
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 (sperm protein, enterokinase and agrin) domains, a transmembrane domain and a cytoplasmic tail. MUC16 is unique in its large number of SEA domains, as other mucins such as MUC1, MUC12, MUC13 and MUC17 only possess a single SEA module. SEA domains and their functions are not fully understood but MUC16 is speculated to have two proteolytic sites in the SEA domains, at the 55 thand 56 thSEA domains. It is believed that MUC16 cleavage occurs at these sites, whereby CA125 is released or “shed” into the bloodstream. The serum levels of CA125 serve as a biomarker for cancer screening and disease monitoring; CA125 is one of the best-known blood biomarkers for ovarian cancer and elevated levels are strongly associated with poor prognosis. - 125 -

MUC16 is a clinically validated tumor target, including by DMUC4064A, a first generation MMAE-based ADC
targeting the tandem repeat region of MUC16, that demonstrated efficacy in PROC in an open-label Phase 1 trial. DMUC4064A, which has a protease-cleavable linker with a DAR of 2, demonstrated 42% ORR at the recommended Phase 2 dose.

Despite this promising response rate, DMUC4064A development was discontinued in 2021 due to a limited therapeutic index, toxicities consistent with MMAE class
effects and binding to circulating CA125 that may have hindered effectiveness, also known as an “antigen sink.” Patients treated with DMUC4064A experienced toxicities consistent with other MMAE-based therapies, with 40% of patients
reporting ocular toxicities, including Grade 3 ocular events in 9%. Although MUC16 is expressed in certain ocular cell types, we believe the frequency and severity of ocular toxicities were primarily driven by the MMAE payload rather than on-target effects from MUC16 binding. Overall, 25% experience Grade 3 or higher treatment-related adverse events. Common adverse events included fatigue, nausea, abdominal pain, constipation, blurred vision,
diarrhea, anemia and peripheral neuropathy. Additionally, lower doses did not produce objective responses, likely due to a portion of the ADC binding to circulating CA125. Consequently, higher doses were necessary to first saturate most of the
circulating CA125 before achieving therapeutic efficacy and tumor cell killing.

Sources:
Liu J,