EMITT-1: Proof-of-mechanism immunopeptidome (ImPD) effects at target PK exposure, in a phase 1 study of GRWD5769 (a first-in-class inhibitor of Endoplasmic Reticulum Aminopeptidase 1 [ERAP1]) in patients with solid malignancies.
Authors: Lillie Thomas , Kichenadasse Ganessan , Liu Jia (Jenny) , Hernandez Guerrero Tatiana , Calvo Emiliano , Jakobsson Haakan , Moreno Victor , Gan Hui Kong , Joyce Peter , Hyland Natalie , Giovannetti Mara , Palmer Tanya , McAlpine Cheryl , Green Daniel , Symeonides Stefan N. 
Published: August 2024

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Background: GRWD5769 is a first-in-class, orally bioavailable ERAP1 inhibitor that significantly modulates the peptide repertoire displayed on MHC-1 on tumor cells, driving novel T cell response and causing tumor cell killing in preclinical studies. This unique approach has potential to overcome central mechanisms of immune resistance by driving de-novo recognition of previously hidden tumor neoantigens and addressing T cell exhaustion. Here we report initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) endpoints from Part A (monotherapy dose escalation) in the ongoing multicentre, modular phase I dose escalation study (ACTRN12623000108617). Methods: Patients with advanced refractory solid tumors are enrolled using a BOIN escalation design. GRWD5769 is administered BID on days 1-14 during 21-day cycles. The first cycle is the dose-limiting toxicity (DLT) observation period. The PK / PD relationship of GRWD5769 is being evaluated using mass spectrometry analysis of the ImPD. Tumor responses are evaluated by RECIST v1.1 / iRECIST. Results: As of 03 January 2024, a total of 12 patients had been treated with GRWD5769 in 3 dose cohorts (25 mg, 50 mg, 100 mg BID). On average patients have remained on treatment for 4 cycles (range 1-10) No Serious Adverse Reactions, DLTs, immune related AEs or deaths were reported. Two Gr 3 serious adverse events have occurred in 2 treated subjects (aspiration pneumonia and Urinary Tract Infection, neither attributable to GRWD5769). Gr 1+2 AEs were infrequent and manageable. PK analyses for the first 3 cohorts show dose proportional plasma levels, with Tmax at ~3 h and a ~8 h Thalf. The minimum biologically active dose (MBAD) is defined as an average steady state plasma concentration above the IC50 for ERAP1, which was achieved at the 100 mg BID dose level. PD data shows dose-dependent target engagement, with marked shifts in the ImPD. This is consistent with the expected mechanistic effects of ERAP1 inhibition seen in preclinical models and is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients, potentially allowing T cells to recognise new targets on tumors. Dose escalation with GRWD5769 monotherapy continues to determine the recommended phase 2 dose (RP2D). GWRD5769 in combination with Immune Checkpoint Inhibition will be investigated in Part B now that the MBAD has been reached. Conclusions: GRWD5769 has been well tolerated at doses up to 100 mg BID. PK / PD data support dose-dependent target engagement of ERAP1. Proof of mechanism has been achieved for this first-in-class therapy, and this is the first demonstration that the human ImPD can be manipulated pharmacologically in cancer patients. Further PD analyses will explore shifts in the T cell repertoire and modulation of immune cell phenotypes. Clinical trial information: ACTRN12623000108617.