# US 2025/0375445 A1 · Methods of treating a ras protein-related disease or disorder > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2025/0375445 A1 - Document ID: US20250375445A1 - Status: Published application - Kind: A1 - Application number: 19/230,256 - Filed: 2025-06-06 - Published: 2025-12-11 - Earliest claimed: 2024-06-07 - Assignees: Revolution Medicines, Inc. - Applicants: Revolution Medicines, Inc. - Inventors: Jingjing JIANG; Benjamin MALDONATO; Mallika SINGH; Zhengping WANG; Zhican WANG; Michael FLAGELLA; W. Clay GUSTAFSON - Web page: https://patentgrep.com/patent/US20250375445A1 ## CPC - A61K 31/4965: Non-condensed pyrazines - A61K 31/504: forming part of bridged ring systems - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/00: Antineoplastic agents - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Disclosed are RAS(ON) multi-selective inhibitor compositions and methods of treating RAS protein-related diseases or disorders using an intermittent dosing regimen. RAS(ON) multi-selective inhibitors having tight binding to cyclophilin A (CypA) result in high exposure levels, prolonged tissue retention, and/or slow clearance rates, thereby increasing the risk of inhibition of wild-type RAS in normal tissues. Accordingly, provided herein are methods for the safe and effective dosing of low KD1 RAS(ON) multi-selective inhibitors using an intermittent dosing regimen. Also provided are methods of selecting or identifying such RAS(ON) multi-selective inhibitors suitable for intermittent administration. ## Claims ### Claim 1 A method of treating a RAS protein-related disease in a subject in need thereof, the method comprising administering to the subject a RAS(ON) multi-selective inhibitor on an intermittent dosing regimen. ### Claim 2 (depends on 1) The method of claim 1, wherein the subject has a mutation of RAS. ### Claim 3 (depends on 1, 2) The method of claim 1 or claim 2, wherein the RAS protein-related disease is cancer. ### Claim 4 (depends on 1, 2, 3) The method of any one of claims 1 to 3, wherein the RAS(ON) multi-selective inhibitor has a blood or plasma half-life of 12 hours or longer. ### Claim 5 (depends on 1, 2, 3, 4) The method of any one of claims 1 to 4, wherein the RAS(ON) multi-selective inhibitor has a KD1 of 0.1 nM to 500 nM. ### Claim 6 (depends on 1, 2, 3, 4, 5) The method of any one of claims 1 to 5, wherein the RAS(ON) multi-selective inhibitor has a clearance rate of 0.4 L/h/kg or slower. ### Claim 7 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein the intermittent dosing regimen comprises one dosing day followed by at least one day without dosing. ### Claim 8 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein the intermittent dosing regimen comprises at least two consecutive dosing days followed by at least one day without dosing. ### Claim 9 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein the intermittent dosing regimen comprises at least three consecutive dosing days followed by at least one day without dosing. ### Claim 10 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein the intermittent dosing regimen comprises at least four consecutive dosing days followed by at least one day without dosing. ### Claim 11 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein the intermittent dosing regimen comprises at least five consecutive dosing days followed by at least one day without dosing. ### Claim 12 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein the intermittent dosing regimen comprises at least six consecutive dosing days followed by at least one day without dosing. ### Claim 13 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein each dosing regimen comprises five dosing days and two days without dosing. ### Claim 14 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein each dosing regimen comprises four dosing days and three days without dosing. ### Claim 15 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein each dosing regimen comprises three dosing days and four days without dosing. ### Claim 16 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein each dosing regimen comprises two dosing days and five days without dosing. ### Claim 17 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein each dosing regimen comprises one dosing day and six days without dosing. ### Claim 18 (depends on 1, 2, 3, 4, 5, 6) The method of any one of claims 1 to 6, wherein the RAS(ON) multi-selective inhibitor is administered Q2D. ### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18) The method of any one of claims 1 to 18, wherein the intermittent dosing regimen is repeated. ### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19) The method of any one of claims 1 to 19, wherein the dosing regimen comprises administering the RAS(ON) multi-selective inhibitor and an additional therapeutic agent. ### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) The method of any one of claims 1 to 20, wherein the RAS(ON) multi-selective inhibitor is or ERAS-0015. ### Claim 22 (depends on 20, 21) The method of claim 20 or 21, wherein the additional therapeutic agent is a RAS(OFF) inhibitor. ### Claim 23 (depends on 20, 21, 22) The method of any one of claims 20 to 22, wherein the additional therapeutic agent is a pan-KRAS inhibitor. ### Claim 24 (depends on 23) The method of claim 23, wherein the pan-KRAS inhibitor is ERAS-4001. ### Claim 25 A method of treating a RAS protein-related disease or disorder comprising administering to a subject in need thereof a RAS(ON) multi-selective inhibitor and an additional RAS inhibitor, wherein the RAS(ON) multi-selective inhibitor is administered on an intermittent dosing regimen. ### Claim 26 (depends on 25) The method of claim 25, wherein the additional RAS inhibitor is administered on a daily dosing regimen or on an intermittent dosing regimen. ### Claim 27 (depends on 25, 26) The method of claim 25 or 26, wherein the additional RAS inhibitor is a RAS(OFF) inhibitor. ### Claim 28 (depends on 25, 26, 27) The method of any one of claims 25 to 27, wherein the additional RAS inhibitor is a pan-KRAS inhibitor. ### Claim 29 (depends on 28) The method of claim 28, wherein the pan-KRAS inhibitor is ERAS-4001. ### Claim 30 (depends on 25, 26, 27, 28, 29) The method of any one of claims 25 to 29, wherein the subject has a RAS mutation. ### Claim 31 (depends on 25, 26, 27, 28, 29, 30) The method of any one of claims 25 to 30, wherein the RAS(ON) multi-selective inhibitor has a blood or plasma half-life of 12 hours or longer. ### Claim 32 (depends on 25, 26, 27, 28, 29, 30, 31) The method of any one of claims 25 to 31, wherein the RAS(ON) multi-selective inhibitor has a KD1 of 0.1 nM to 500 nM. ### Claim 33 (depends on 25, 26, 27, 28, 29, 30, 31, 32) The method of any one of claims 25 to 32, wherein the RAS(ON) multi-selective inhibitor has a clearance rate of 0.4 L/h/kg or slower. ### Claim 34 (depends on 25, 26, 27, 28, 29, 30, 31, 32) The method of any one of claims 25 to 32, wherein the intermittent dosing regimen comprises one dosing day followed by at least one day without dosing. ### Claim 35 (depends on 25, 26, 27, 28, 29, 30, 31, 32, 33, 34) The method of any one of claims 25 to 34, wherein the RAS(ON) multi-selective inhibitor is administered Q2D. ### Claim 36 (depends on 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35) The method of any one of claims 25 to 35, wherein the RAS(ON) multi-selective inhibitor or ERAS-0015.