Background/Purpose: There is strong pre-clinical validation for Bruton’s Tyrosine Kinase (BTK) as a therapeutic target for autoimmune diseases based on multiple animal models. Principia discovered a potent, selective inhibitor of BTK that forms a reversible covalent bond to a cysteine residue (Cys481) which results in prolonged residence time. We characterized the potency, selectivity and durability of target binding of PRN1008 in addition to testing its efficacy in an animal model of arthritis. Furthermore the safety, tolerability and PK/PD profile of PRN1008 was tested in a phase 1 clinical trial to assess its potential as a treatment for RA.

Methods: PRN1008 was tested for potency, durability and selectivity in biochemical and cell-based functional assays. The in vivo efficacy of PRN1008 was tested in a rat model of collagen-induced arthritis (CIA). The first-in-human study consisted of two randomized, double-blind, placebo-controlled parts: Part A, 5 SAD cohorts (50-1200 mg) and Part B, 4 MAD cohorts with 10 days treatment (300mg and 600mg QD, 300mg and 450mg BID). Safety was assessed clinically and by ECG, vital sign and laboratory measurements. PRN1008 pharmacodynamic coverage was assessed by BTK occupancy; Pharmacokinetic/pharmacodynamic analysis was performed to characterize the relationship between BTK occupancy and PRN1008 PK.

Results: PRN1008 is very potent against BTK (IC50 = 1.3 ± 0.5 nM) and highly selective when tested against a broad panel of kinases. Cysteine targeting by PRN1008 results in a slow off-rate demonstrated by retention of 79 ± 2% of binding to BTK in PBMC 18 hours after washout in vitro. The covalent cysteine binding was completely reversible after denaturation of the target. Human B cell proliferation and activation (CD69 expression) were inhibited by PRN1008 with IC50 of 5 ± 2.4 nM and 123 ± 38 nM, respectively. Dose dependent efficacy in rat CIA was observed at trough BTK occupancies of 16 ± 3.6% to 79 ± 4.2%. PRN1008 was safe and well-tolerated in both parts of the human study without changes in vital signs, ECG or laboratory measurements. In humans dosed with PRN1008, BTK maximal occupancy was 90 ± 6% (mean ± SD) and 93 ± 2% at four hours on day 1 and day 10, respectively. BTK maximal occupancy at trough (12 or 24 hours) on day 10 ranged from 59 ± 11 to 80 ± 6%, when plasma PRN1008 was essentially cleared, demonstrating an extended PD effect. PK/PD analyses revealed that maximum occupancy was exposure-dependent; the rate of occupancy loss tended to be faster in subjects who did not achieve > 90% occupancy at 4h. Intersubject variability in occupancy was very low, particularly in subjects whose plasma exposures resulted in >90% occupancy at 4 hrs.

Conclusion: PRN1008 is a potent, selective and reversible covalent inhibitor of BTK with extended PD effects in vivo. PRN1008 was safe and well tolerated after single and 10 day dosing in humans. Dosing to achieve > 90% occupancy after a dose results in consistent and prolonged target occupancy. BTK target coverage with a daily dose of  ≥300mg reached therapeutic levels based on translational studies in a rat model of arthritis. These data support continued development of PRN1008 as a therapeutic agent for rheumatoid arthritis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-prn1008-a-novel-reversible-covalent-btk-inhibitor-in-clinical-development-for-rheumatoid-arthritis/