Company: HMDCF
Filing Date: 2025-03-19
Form Type: 20-F
Source: 0001410578-25-000377
Chunk: 436

Company: HUTCHMED (China) Ltd
Filing Date: 2025-03-19
Form: 20-F
Item: Item 4
Chunk 436
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 up to 50% of cancers. RAS and RAF mutations predict worse clinical prognosis in a wide variety of tumor types, mediate resistance to targeted therapies, and decrease the response to the approved standards of care, namely, targeted therapy and immunotherapy. ERK inhibition has the potential to overcome or avoid the intrinsic or acquired resistance from the inhibition of RAS, RAF and MEK upstream mechanisms. HMPL-295 inhibited ribosomal S6 kinase (“RSK”) phosphorylation which is a downstream signaling molecule regulated by ERK1/2 and stimulated by phorbol 12-myristate 13-acetate (“PMA”).
HMPL-295 Pre-clinical Evidence
Pre-clinical data was presented at AACR 2024 highlighting strong activity against multiple MAPK pathway activated tumor models. HMPL-295 inhibited ERK1 kinase with IC50 of 4 ± 0.04 nM and ERK2 kinase with IC50 of 4 ± 1 nM. Selectivity against a panel of 394 kinases show ≥20 folds selectivity over 384 kinases at 1 µm and <35% inhibition of 86 safety-related proteins at 1 µm. It effectively blocked ERK signaling and attenuated the growth of MAPK pathway dysregulated cancer cell lines. Combination significantly improved anti-tumor activity of targeted agents (e.g., adagrasib, encorafenib and cetuximab) and chemotherapy (e.g., gemcitabine, nab-paclitaxel, fluorouracil and irinotecan) in multiple tumor models with KRAS or BRAF mutation.
HMPL-295 Clinical Development

Treatment       Patient Focus       Sites       Phase       Status/Plan          NCT #      
HMPL-295    ​   Solid tumors    ​   China   ​   I       ​   Data presented   ​   NCT04908046
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Phase 1 dose-escalation study of HMPL-295 in advanced solid tumors (NCT04908046)
In July 2021, we initiated China Phase I open-label study of HMPL-295 in patients with advanced malignant solid tumors who have failed standard therapy. Following the initial dose escalation stage, another 10 to 15 patients would be enrolled at the RP2D to further evaluate its safety and the preliminary efficacy of HMPL-295. An exploratory study on the pharmacokinetic biomarkers of HMPL-295 was also planned.
Data was presented at ASC