Quote:1. The Plausible Mechanism
The Plausible Mechanism Framework requires sponsors who identify a specific molecular abnormality with a clear mechanistic rationale.
The Mapping: In MSS-CRC, the abnormality isn't a genetic mutation, but rather a TME barrier, the Cold Tumor state.
The Logic: CytoDyn’s February 20th data at the AACR Immuno-Oncology conference proved that CCR5 inhibition (Leronlimab) upregulates PD-L1. This is the Plausible Mechanism. By turning a Cold Tumor Hot, Leronlimab provides the Mechanistic Rationale the FDA now explicitly prioritizes over raw, massive patient counts.
That is not a plausible mechanism. Inducing PD-L1 is a negative when it comes to cancer as it's protective of the tumor. Which is why a PD-L1 inhibitor us needed. Increased PD-L1 is a secondary effect of one of the main mechanisms, which is affecting an M2 to M1 macrophage switch. That switch from M2 (tumor protectant) to M1 (tumor killing) macrophages along with lowering LAG3, CTLA4, TIM3 (tumor protectants) and VEGF (tumor growth factor) are the mechanisms that help kill off the tumor.
If Cytodyn told the FDA that leronlimab works because we increased PD-L1 they'd rightfully think they were crazy.
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