Background PD-1/PD-L1 antibody-based therapies have demonstrated success in the treatment of liver cancers. Most systemic immune-related adverse events (irAEs) associated with PD-1/PD-L1 antibodies are mild to moderate, but severe irAEs can be life threatening, due to the long half-lives of antibodies. Here, we report the discovery of an orally bioavailable PD-L1 small molecule inhibitor, ALG-094103, which preferentially partitions into the liver and may thereby mitigate extra-hepatic irAEs.

Methods The biochemical interaction of PD-1/PD-L1 and PD-L1 dimerization was assessed by AlphaLISA®. Cellular activity was measured using a co-culture assay of PD-1 expressing Jurkat NFAT luciferase T-cells with PD-L1 expressing CHO cells. Pharmacokinetic (PK) and tissue distribution studies were performed in C57BL/6 mice and PK in Wistar Han rats. In vivo PD-L1 target occupancy was assessed at 6 hours following a single dose in the humanized-PD-L1 MC38 subcutaneous mouse model.

Results ALG-094103 inhibits the PD-1/PD-L1 axis with similar potency to PD-1/PD-L1 antibodies. In addition, ALG-094103 has in vitro potency similar to a non-liver targeted PD-L1 small molecule inhibitor, INCB086550, which demonstrated clinical response in a phase I study. The oral bioavailability of ALG-094193 in rats following a single dose at 15 mg/kg dosing was 40%. ALG-094103 demonstrated significantly higher liver concentrations vs. other tested tissues (liver/lung ratio of 17) in mice at 12 hours after a single oral dose. In the in vivo PD-L1 target occupancy model, oral dosing of ALG-094103 at 50 mg/kg demonstrated higher PD-L1 target occupancy than oral dosing of INCB086550 at 150 mg/kg and IV dosing of durvalumab at 5 mg/kg.

Conclusions We have discovered a novel liver-targeted and orally bioavailable PD-L1 small molecule inhibitor, ALG-094103, with comparable in vitro potency to INCB086550. The properties of ALG-094103 will be further evaluated as a potential candidate for drug development.