Parsaclisib (INCB050465): A Comprehensive Monograph on a Next-Generation PI3Kδ Inhibitor – From Clinical Promise to Regulatory Crossroads

1.0 Executive Summary

Parsaclisib (INCB050465) is an investigational, orally active, small molecule drug representing a next-generation inhibitor of the delta isoform of phosphoinositide-3 kinase (PI3Kδ). Developed by Incyte Corporation, its design was a strategic medicinal chemistry effort to address the significant class-limiting toxicities, particularly hepatotoxicity, that hampered the clinical utility of first-generation PI3Kδ inhibitors. Characterized by exceptional potency and high selectivity for the PI3Kδ isoform, parsaclisib demonstrated a dual mechanism of action, exerting direct antineoplastic effects on malignant B-cells and immunomodulatory activity within the tumor microenvironment.

The extensive clinical development program, primarily under the CITADEL banner, established robust efficacy in several relapsed or refractory (R/R) B-cell malignancies. In pivotal Phase 2 studies, parsaclisib monotherapy achieved high and durable objective response rates in follicular lymphoma (FL), marginal zone lymphoma (MZL), and Bruton's tyrosine kinase (BTK) inhibitor-naïve mantle cell lymphoma (MCL). This clinical activity was coupled with a manageable safety profile that largely avoided the severe transaminitis associated with its predecessors, thereby validating its core design principle.