CD47-SIRPα Blocker and Azacitidine Dosing for Safer AML Therapy
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Solution Overview
Problem
Existing CD47-SIRPα blocking agents for treating hematological cancers face significant safety issues, such as anemia, thrombocytopenia, and dose-limiting toxicity, limiting their efficacy in clinical use.
Innovation Solution
A combination therapy using a CD47-SIRPα blocking agent, specifically a compound of formula (I), with azacitidine, administered orally, at doses up to 400 mg BID, to modulate cytokines and chemokines effectively, ensuring high hematological safety without grade 3 or 4 adverse events.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD47-SIRPα blocking agents are used to treat hematological cancers, then therapeutic efficacy is improved, but safety deteriorates due to anemia, thrombocytopenia, and dose-limiting toxicity
Solution Approach 1:
The patent combines a CD47-SIRPα blocking agent with azacitidine to create a synergistic therapy. This combination allows the CD47-SIRPα blocker to achieve its full anti-cancer efficacy while azacitidine provides hematological support and reduces the dose-limiting toxicities, thereby improving the overall safety profile without compromising therapeutic effectiveness.
Solution Approach 2:
The patent modifies the dosing parameters by administering the CD47-SIRPα blocking agent at reduced doses (e.g., 100-400 mg orally twice daily) in combination with azacitidine. This parameter change allows the therapy to be better tolerated by patients, reducing the frequency and severity of adverse events such as anemia and thrombocytopenia while maintaining anticancer activity.
2Productivity
If maximum tolerated dose of CD47-SIRPα blocking agents is administered, then therapeutic effect is maximized, but dose-limiting toxicity increases particularly anemia and thrombocytopenia
Solution Approach 1:
By merging the CD47-SIRPα blocking agent with azacitidine, the therapy achieves enhanced therapeutic effect without requiring administration at the maximum tolerated dose alone. The combination provides synergistic anticancer activity while distributing the toxic burden, thereby reducing dose-limiting toxicities like anemia and thrombocytopenia compared to single-agent therapy at high doses.
Solution Approach 2:
Azacitidine acts as an intermediary agent that modulates the toxic effects of the CD47-SIRPα blocking agent. It provides hematological support and reduces the severity of adverse events, allowing the CD47-SIRPα blocker to be administered at doses that would otherwise be intolerable, thus maximizing therapeutic effect while minimizing harmful factors.
Data Source
AI summary
The present disclosure relates to a CD47-SIRPα blocking agent of formula (I) stereoisomers thereof, and pharmaceutically acceptable salts, solvates, amides and esters of the compound of formula (I) and stereoisomer thereof and Azacitidine for use in combination with Azacitidine in a method of treating or delaying progression of a disease or a disorder mediated by CD47-SIRPα pathway in a human subject suffering from said disease, such as hematological cancer.