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.

Despite this scientific success, the trajectory of parsaclisib is a study in contrasts, marked by significant regulatory and commercial setbacks in Western markets. In 2022, Incyte withdrew its New Drug Application (NDA) from the U.S. Food and Drug Administration (FDA) and its marketing authorization application from the European Medicines Agency (EMA). These decisions were not prompted by new adverse safety or efficacy data but were attributed to the challenging regulatory landscape for the PI3K inhibitor class, which demanded large, randomized confirmatory trials that were deemed not commercially viable for these niche indications.

Further narrowing its potential applications, the LIMBER clinical program, which evaluated parsaclisib in combination with ruxolitinib for myelofibrosis, was terminated after two pivotal Phase 3 trials were deemed unlikely to meet their primary endpoints for futility. Development in autoimmune indications was also discontinued. In a starkly different trajectory, development continues in China through a partnership with Innovent Biologics, where an NDA for R/R follicular lymphoma has been accepted and granted Priority Review by the National Medical Products Administration (NMPA). Parsaclisib thus stands as a poignant case study of a scientifically sound therapeutic agent whose potential in the US and Europe was ultimately curtailed by the confluence of class-wide regulatory skepticism, evolving standards for drug approval, and strategic business decisions.

2.0 Introduction: The Rationale for a Next-Generation PI3Kδ Inhibitor

Parsaclisib, also known by its development code INCB050465, is an investigational small molecule drug developed by Incyte Corporation as a potential antineoplastic and immunomodulatory agent.[1] Its creation and subsequent clinical evaluation were framed within the context of the broader therapeutic class of phosphoinositide 3-kinase (PI3K) inhibitors, a group of targeted therapies that have shown significant promise in hematologic malignancies. The PI3K signaling pathway is a critical mediator of cellular functions, including proliferation, survival, and differentiation, and its dysregulation is a hallmark of many cancers, particularly those of B-cell origin.[3]

The development of parsaclisib was directly motivated by the need to address the unmet needs and significant limitations of first-generation PI3Kδ inhibitors. The delta isoform of PI3K is expressed predominantly in hematopoietic cells, making it an attractive and specific target for B-cell cancers.[3] Early agents, such as the approved drug idelalisib, validated this therapeutic concept by demonstrating clinical efficacy. However, their use was hampered by a distinct pattern of class-associated toxicities, most notably severe, and sometimes fatal, hepatotoxicity characterized by elevated transaminases.[2] These adverse events often required dose reductions, treatment interruptions, or permanent discontinuation, thereby limiting the full therapeutic potential of the drug class.[5]

In response to this challenge, parsaclisib was rationally designed as a "next-generation" agent. The medicinal chemistry effort focused on creating a structurally distinct molecule that could retain high potency and selectivity for PI3Kδ while mitigating the off-target effects believed to cause the observed toxicities.[5] This strategic design was the central thesis of its development program: to engineer a PI3Kδ inhibitor with an improved therapeutic index and a more manageable long-term safety profile.[2] This approach was predicated on the hypothesis that the hepatotoxicity of first-generation inhibitors was related to their shared purine-based chemical scaffold, a motif that parsaclisib deliberately avoids.[5]

The initial promise of this approach led to an extensive and ambitious clinical development program. Incyte initiated multiple studies to evaluate parsaclisib across a wide spectrum of diseases where the PI3Kδ pathway is implicated. This included numerous subtypes of B-cell non-Hodgkin lymphoma (NHL), such as follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), as well as myeloproliferative neoplasms (MPNs) and several autoimmune diseases.[2] This broad scope of investigation underscored the high expectations for parsaclisib as a potentially best-in-class therapy capable of overcoming the critical hurdles faced by its predecessors.

3.0 Molecular Profile and Physicochemical Characteristics

A precise and comprehensive characterization of parsaclisib is essential for understanding its pharmacological properties and its place within the landscape of kinase inhibitors. This section provides a definitive catalog of its identifiers, chemical structure, and key physicochemical properties.

3.1 Identification and Nomenclature

Parsaclisib is a small molecule drug that has been assigned multiple identifiers across various chemical and pharmacological databases. Its primary development code from Incyte Corporation is INCB050465.[4] The non-proprietary names assigned are Parsaclisib (United States Adopted Name and International Nonproprietary Name [INN]).[4]

The hydrochloride salt form of the molecule, often used in clinical development, is identified as Parsaclisib hydrochloride (CAS Number 1995889-48-9).[13] The free base form, which is the active moiety, is registered under CAS Number 1426698-88-5.[1] Additional key identifiers are consolidated in Table 1 below.

3.2 Chemical Structure and Properties

The formal IUPAC name for parsaclisib is (4R)-4-pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl]pyrrolidin-2-one.[4] Its molecular formula is

C20​H22​ClFN6​O2​, corresponding to a molecular weight of approximately 432.9 g/mol.[4]

A defining feature of parsaclisib's structure is its pyrazolopyrimidine hinge-binding motif. This is a significant departure from the purine scaffold found in first-generation PI3Kδ inhibitors like idelalisib and dezapelisib.[5] This structural distinction is believed to be central to its differentiated safety profile, particularly the reduced incidence of hepatotoxicity observed in preclinical and clinical studies.[5]

The molecule's physicochemical properties are consistent with those of an orally bioavailable drug. It adheres to Lipinski's Rule-of-Five, with zero violations reported, indicating favorable characteristics for absorption and membrane permeability.[1] Key computed properties include an XLogP of approximately 2.88, 2 hydrogen bond donors, and 6-7 hydrogen bond acceptors, contributing to its drug-like profile.[1]

Table 1: Key Chemical and Physicochemical Properties of Parsaclisib

Property	Value	Source(s)
Drug Name	Parsaclisib	4
Development Code	INCB050465, IBI-376	4
DrugBank ID	DB14867	4
CAS Number (Free Base)	1426698-88-5	1
CAS Number (HCl Salt)	1995889-48-9	13
UNII	OS7097575K	4
IUPAC Name	(4R)-4-pyrimidin-1-yl)ethyl]-5-chloro-2-ethoxy-6-fluorophenyl]pyrrolidin-2-one	4
Molecular Formula	C20​H22​ClFN6​O2​	4
Molecular Weight	432.9 g/mol	4
Canonical SMILES	CCOC1=C(C(=C(C=C1C@HN2C3=NC=NC(=C3C(=N2)C)N)Cl)F)[C@H]4CC(=O)NC4
InChIKey	ZQPDJCIXJHUERQ-QWRGUYRKSA-N
XLogP	2.88
Hydrogen Bond Donors	2
Hydrogen Bond Acceptors	6-7
Rotatable Bonds	5
Lipinski's Rule Violations	0
ATC Code	L01EM05

4.0 Mechanism of Action and Preclinical Pharmacology

The therapeutic rationale for parsaclisib is rooted in its precise and potent inhibition of a key enzyme in hematopoietic cell signaling. Preclinical studies have thoroughly characterized its molecular target, cellular effects, and in vivo activity, providing a strong foundation for its clinical development.

4.1 Primary Molecular Target and Selectivity

Parsaclisib's primary molecular target is the delta isoform of phosphoinositide 3-kinase (PI3Kδ), a lipid kinase encoded by the PIK3CD gene. PI3Kδ is a member of the Class I PI3K family and is predominantly expressed in hematopoietic cell lineages, such as B-cells and T-cells. It plays a central role in transducing signals from various cell surface receptors, most notably the B-cell receptor (BCR), T-cell receptor (TCR), and cytokine receptors. Upon activation, PI3Kδ phosphorylates phosphatidylinositol 4,5-bisphosphate (

PIP2​) to generate the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3​). This leads to the recruitment and activation of downstream effectors, including AKT and mTOR, culminating in the activation of the PI3K/AKT/mTOR signaling pathway. This pathway is critical for regulating cell proliferation, survival, differentiation, and migration. In many B-cell malignancies, this pathway is constitutively active or dysregulated, making PI3Kδ a highly rational therapeutic target.

A hallmark of parsaclisib is its exceptional potency and selectivity. In vitro assays demonstrate that it inhibits PI3Kδ with a half-maximal inhibitory concentration (IC50​) of approximately 1 nM. This potent activity is coupled with remarkable selectivity. Parsaclisib is over 1,000-fold more selective for the PI3Kδ isoform compared to the other Class I PI3K isozymes (α, β, and γ) and shows approximately 20,000-fold selectivity in some assays. This high degree of selectivity is a key design feature intended to minimize off-target effects associated with the inhibition of other PI3K isoforms, which are more ubiquitously expressed and involved in essential physiological processes like glucose metabolism. This targeted inhibition is designed to preserve PI3K signaling in normal, non-neoplastic cells, thereby enhancing the drug's therapeutic window.

4.2 Cellular and In Vivo Antitumor Activity

The potent and selective inhibition of PI3Kδ by parsaclisib translates into significant antitumor activity at the cellular level. In preclinical studies, parsaclisib effectively inhibited the proliferation of various B-cell malignancy cell lines, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL) cell lines, with IC50​ values in the low nanomolar range (≤10 nM). For instance, in sensitive DLBCL cell lines such as Pfeiffer and SU-DHL-6, the

IC50​ values for proliferation inhibition were between 2 and 8 nM.

The pharmacodynamic effect of parsaclisib was confirmed by its ability to block downstream signaling in the PI3K/AKT pathway. In the Ramos Burkitt's lymphoma cell line, parsaclisib inhibited anti-IgM-induced phosphorylation of AKT at the Ser473 site with an IC50​ of 1 nM, demonstrating direct target engagement and pathway modulation. This activity extended to primary B-cells from multiple species (human, dog, rat, mouse), where parsaclisib inhibited proliferation with

IC50​ values ranging from 0.2 to 1.7 nM.

This potent in vitro activity was recapitulated in in vivo animal models. In a mouse xenograft model using the Pfeiffer DLBCL cell line, oral administration of parsaclisib led to significant, dose-dependent tumor growth inhibition. This antitumor efficacy correlated directly with profound inhibition of AKT phosphorylation in the tumor tissue, providing a clear link between target engagement, pathway inhibition, and therapeutic effect.

4.3 Dual Mechanism of Action and Resistance

Parsaclisib exerts its therapeutic effect through a dual mechanism, combining direct antineoplastic activity with indirect immunomodulatory functions. The primary mechanism involves the direct inhibition of PI3Kδ-mediated proliferative and survival signaling within malignant B-cells, leading to decreased proliferation and the induction of apoptosis.

In addition to its direct effects on tumor cells, parsaclisib also modulates the tumor microenvironment. The PI3Kδ pathway is crucial for the function of regulatory T-cells (Tregs), an immunosuppressive T-cell subset that can dampen anti-tumor immune responses. By inhibiting PI3Kδ, parsaclisib can lessen the immunosuppressive activity of Tregs, thereby indirectly promoting a more permissive environment for anti-tumor immunity. This immunomodulatory activity complements its direct cytotoxic effects and contributes to its overall efficacy.

Preclinical investigations have also provided insights into potential mechanisms of resistance. Studies in DLBCL cell lines revealed that those overexpressing the MYC oncogene were insensitive to the anti-proliferative effects of parsaclisib. This suggests that MYC overexpression may serve as a bypass mechanism, allowing tumor cells to circumvent their dependence on the PI3Kδ signaling pathway. This finding has important translational implications, suggesting that MYC status could be a useful biomarker for predicting response and guiding patient selection in future clinical trials.

5.0 Pharmacokinetics, Metabolism, and Drug Interaction Profile

The clinical viability of an oral targeted therapy is heavily dependent on its pharmacokinetic (PK) and metabolic profile. Preclinical and clinical studies have characterized parsaclisib as having drug-like absorption, distribution, metabolism, and excretion (ADME) properties, though with a notable susceptibility to drug-drug interactions involving the cytochrome P450 system.

5.1 Preclinical Pharmacokinetic Profile

Preclinical PK studies conducted in multiple species (rats, dogs, and monkeys) established a favorable profile for parsaclisib, supporting its development as an oral agent.

• Absorption and Bioavailability: Following oral administration, parsaclisib was rapidly absorbed, with time to maximum plasma concentration (Tmax​) values ranging from 0.3 to 2.5 hours across species. Oral exposure was high, and bioavailability was excellent, reaching 74% in rats, 79% in monkeys, and 100% in dogs.
• Distribution: The volume of distribution at steady state (Vd,ss​) was low to moderate, recorded at 1.54 L/kg in rats, 0.32 L/kg in dogs, and 0.72 L/kg in monkeys, suggesting that the drug distributes into tissues but does not exhibit extensive sequestration.
• Metabolism and Clearance: Parsaclisib displayed low systemic clearance after intravenous administration, representing only a small fraction of hepatic blood flow in rats (26%), dogs (2%), and monkeys (5%). The primary route of metabolism was identified as oxidation mediated by the cytochrome P450 3A4 (CYP3A4) enzyme.
• Elimination: The terminal elimination half-life (t1/2​) was favorable for clinical dosing, ranging from 4.0 hours in rats to 7.3 hours in monkeys after intravenous dosing, with similar values observed after oral administration.

This preclinical profile, summarized in Table 2, indicated that parsaclisib was a well-behaved molecule with predictable pharmacokinetics and excellent oral bioavailability, making it a strong candidate for clinical development.

Table 2: Summary of Key Preclinical Pharmacokinetic Parameters of Parsaclisib

Parameter	Rat	Dog	Monkey
Systemic Clearance (IV)	Low (26% of hepatic blood flow)	Low (2% of hepatic blood flow)	Low (5% of hepatic blood flow)
Volume of Distribution (Vd,ss​)	1.54 L/kg	0.32 L/kg	0.72 L/kg
Terminal Half-Life (t1/2​) (IV)	4.0 h	N/A	7.3 h
Time to Max Concentration (Tmax​) (Oral)	0.3 h	N/A	2.5 h
Oral Bioavailability	74%	100%	79%
Data compiled from source.

5.2 Clinical Drug-Drug Interactions

Given that parsaclisib is primarily metabolized by CYP3A4, a dedicated clinical drug-drug interaction study was conducted in healthy volunteers to quantify the impact of potent CYP3A4 modulators on its pharmacokinetics. The results of this study revealed significant interactions that have critical implications for clinical use.

• Interaction with Strong CYP3A4 Inhibitors: When a single dose of parsaclisib was co-administered with itraconazole, a potent CYP3A4 inhibitor, the systemic exposure of parsaclisib increased substantially. The maximum plasma concentration (Cmax​) increased by 21%, while the total exposure, as measured by the area under the concentration-time curve (AUC0−∞​), increased by 107% (approximately twofold).
• Interaction with Strong CYP3A4 Inducers: Conversely, co-administration with rifampin, a potent CYP3A4 inducer, led to a dramatic reduction in parsaclisib exposure. The Cmax​ of parsaclisib was reduced by 43%, and the total exposure (AUC) was reduced by 77%.

These findings clearly demonstrate that concomitant use of strong CYP3A4 inhibitors or inducers can significantly alter the plasma concentrations of parsaclisib. The study concluded that dose adjustments would likely be necessary when parsaclisib is administered with such agents to maintain appropriate therapeutic exposure and avoid potential toxicity or loss of efficacy. This is a crucial consideration for prescribing physicians, as many commonly used medications, including certain antifungals, antibiotics, and anticonvulsants, are potent modulators of the CYP3A4 enzyme.

6.0 The Parsaclisib Clinical Development Program: An Overview

The clinical investigation of parsaclisib was extensive and ambitious, reflecting the initial high expectations for its therapeutic potential. The program was strategically designed to evaluate the drug's efficacy and safety across a wide range of hematologic malignancies and other diseases, primarily under two large program banners: CITADEL and LIMBER.

6.1 Strategic Framework and Scope

The CITADEL (Clinical Investigation of TArgeted PI3K-DELta Inhibition in Lymphomas) program was the cornerstone of parsaclisib's development in oncology. This series of trials was designed to assess parsaclisib as both a monotherapy and in combination regimens for various subtypes of non-Hodgkin lymphoma (NHL) and other B-cell malignancies. Key indications explored within this program included relapsed or refractory (R/R) follicular lymphoma (FL), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL).

The LIMBER program was focused on expanding the utility of parsaclisib beyond lymphomas into the field of myeloproliferative neoplasms (MPNs). Specifically, it investigated parsaclisib in combination with the JAK1/2 inhibitor ruxolitinib for the treatment of myelofibrosis (MF). The scientific rationale was to target a potential escape pathway (PI3K signaling) in patients with a suboptimal response to ruxolitinib monotherapy.

Beyond these two main programs, parsaclisib was also evaluated in other hematologic cancers, such as peripheral T-cell lymphoma (PTCL) and Hodgkin's lymphoma, as well as in non-malignant conditions, including autoimmune hemolytic anemia (AIHA) and Sjögren's syndrome, where B-cell dysregulation is a key pathogenic feature.

6.2 Evolution of Dosing Strategy

A notable feature of the parsaclisib clinical program was the evolution of its dosing regimen. Initial studies explored continuous once-daily (QD) dosing, with dose-escalation cohorts evaluating doses from 5 mg to 45 mg QD. While this approach demonstrated efficacy, observations of class-effect toxicities with long-term administration prompted the investigation of alternative schedules designed to improve tolerability without compromising efficacy.

This led to the development of an intermittent dosing strategy, which became the standard in later-phase trials. This regimen typically involved an induction period of a higher daily dose (e.g., 20 mg QD) for the first 8 weeks to achieve a rapid response, followed by a lower-dose maintenance phase. Two main maintenance strategies were evaluated: a low-dose daily regimen (e.g., 2.5 mg QD) or a once-weekly (QW) regimen (e.g., 20 mg QW). The goal of this "daily-to-daily" or "daily-to-weekly" switch was to maintain target inhibition and clinical benefit while reducing the cumulative drug exposure and minimizing the risk of adverse events like diarrhea, colitis, and rash. Ultimately, the daily maintenance dosing (e.g., 2.5 mg QD) was selected as the preferred regimen for further study and for the NDA submissions.

6.3 Overview of Key Clinical Trials

The breadth of the parsaclisib development program is captured in the numerous clinical trials initiated across various phases and indications. Table 3 provides a master overview of the most significant studies, summarizing their design, status, and key purpose.

Table 3: Master Overview of Key Parsaclisib Clinical Trials

Trial ID	Name / Title	Phase	Indication(s)	Status	Key Purpose & Outcome
NCT02018861	CITADEL-101	1/2	R/R B-Cell Malignancies	Completed	First-in-human dose-escalation and expansion study. Established initial safety, MTD not reached. Showed promising ORRs in FL (71%), MZL (78%), and MCL (67%).
NCT03126019	CITADEL-203	2	R/R Follicular Lymphoma	Completed	Pivotal study. Met primary endpoint with high ORR (~78%) and durable responses (median DOR ~14.7 months). Formed basis of NDA.
NCT03144674	CITADEL-204	2	R/R Marginal Zone Lymphoma	Completed	Pivotal study. Met primary endpoint with ORR of 58.3% and median DOR of 12.2 months. Formed basis of NDA.
NCT03235544	CITADEL-205	2	R/R Mantle Cell Lymphoma	Completed	Pivotal study. High ORR (70.1%) in BTKi-naïve cohort but limited benefit in BTKi-experienced cohort. Formed basis of NDA for BTKi-naïve population.
NCT02998476	CITADEL-202	2	R/R Diffuse Large B-Cell Lymphoma	Completed	Study terminated for futility. Low ORR of 25.5%, indicating limited single-agent activity in this aggressive lymphoma.
NCT04551053	LIMBER-304	3	Myelofibrosis (suboptimal response to ruxolitinib)	Terminated	Combination with ruxolitinib. Terminated for futility after interim analysis showed it was unlikely to meet primary endpoint of spleen volume reduction.
NCT04551066	LIMBER-313	3	Myelofibrosis (1st line)	Terminated	Combination with ruxolitinib. Terminated for futility, failing to show benefit over ruxolitinib alone.
NCT04298879	CIBI376A201	2	R/R Follicular Lymphoma (in China)	Completed	Pivotal study in Chinese patients. Showed very high ORR (86.9%). Formed basis of NMPA submission by Innovent.
NCT05238064	N/A	1/2	Peripheral T-Cell Lymphoma (1st line)	Not Yet Recruiting	To evaluate parsaclisib in combination with CHOP chemotherapy for previously untreated PTCL.
NCT05083208	N/A	1b/2	R/R Peripheral T-Cell Lymphoma	Terminated	Combination with chidamide. Terminated as clinical development of parsaclisib was stopped by manufacturer.
NCT04774068	N/A	1	R/R T-Cell Lymphomas	Completed	Combination with romidepsin for various T-cell lymphomas, including CTCL.

7.0 Clinical Efficacy and Safety in Relapsed/Refractory (R/R) B-Cell Malignancies

The CITADEL clinical trial program generated a substantial body of evidence on the efficacy and safety of parsaclisib in patients with various R/R B-cell malignancies. The results demonstrated a clear pattern of high activity in indolent lymphomas, with more modest results in aggressive subtypes, and highlighted the impact of prior therapies on treatment outcomes.

7.1 Follicular Lymphoma (FL)

Follicular lymphoma was a primary focus of the parsaclisib development program, with two key Phase 2 studies providing pivotal data.

The CITADEL-203 study (NCT03126019) was a global, open-label, Phase 2 trial that enrolled patients with R/R FL (Grades 1-3a) who had received at least two prior systemic therapies. The study evaluated two dosing regimens: a weekly dosing group (WG) and a daily dosing group (DG), with the latter (20 mg QD for 8 weeks, then 2.5 mg QD) becoming the preferred regimen. In the DG (n=103), parsaclisib monotherapy demonstrated a high objective response rate (ORR) of 77.7%, with a complete response rate (CRR) of 19.4%. The responses were both rapid, with a median time to response of 8 weeks, and durable. The median duration of response (DOR) was 14.7 months, and the median progression-free survival (PFS) was 15.8 months. These robust results formed a cornerstone of the New Drug Application (NDA) submitted to the FDA.

A separate pivotal Phase 2 study (NCT04298879) was conducted in China to support local registration. This trial enrolled 61 patients with R/R FL who had received two or more prior lines of therapy. The results were even more striking, with an investigator-assessed ORR of 86.9% and a CRR of 31.1%. With a median follow-up of 9.5 months, both the median DOR and PFS had not been reached, indicating highly durable disease control. These compelling data led to the acceptance and granting of Priority Review for the NDA by China's National Medical Products Administration (NMPA).

7.2 Marginal Zone Lymphoma (MZL)

The CITADEL-204 study (NCT03144674) was a Phase 2 trial evaluating parsaclisib in patients with R/R MZL who had received at least one prior systemic therapy, including an anti-CD20 antibody. The study primarily focused on a cohort of patients who were naïve to BTK inhibitors. In the daily dosing group (DG, n=72), parsaclisib achieved its primary endpoint, demonstrating an ORR of 58.3% (95% CI: 46.1-69.8), which exceeded the protocol-defined threshold for success. The complete response rate was 4.2%. The responses were durable, with a median DOR of 12.2 months and a median PFS of 16.5 months. The median overall survival was not reached at the time of analysis. These positive results also supported the NDA submission.

7.3 Mantle Cell Lymphoma (MCL)

The CITADEL-205 study (NCT03235544) provided critical insights into the activity of parsaclisib in R/R MCL, particularly concerning the impact of prior treatment with BTK inhibitors. The trial enrolled two main cohorts: patients who were BTKi-naïve and those who were BTKi-experienced.

In the BTKi-naïve cohort (n=108), parsaclisib demonstrated significant clinical activity. The ORR in the daily dosing group was 70.1%, with a CRR of 15.6%. The responses were rapid and durable, with a median DOR of 12.1 months and a median PFS of 13.6 months.

In stark contrast, the BTKi-experienced cohort showed limited clinical benefit. The ORR in this heavily pre-treated population was only 25-29%, with a short median PFS of approximately 3.7 months. Due to this limited efficacy, enrollment in this cohort was closed early. This discrepancy underscores a significant clinical finding: prior exposure to a potent BCR pathway inhibitor like a BTKi may induce resistance mechanisms that confer cross-resistance to PI3Kδ inhibition, or it may select for a disease biology that is no longer dependent on this pathway. This has profound implications for treatment sequencing, suggesting parsaclisib's utility in MCL is largely confined to the BTKi-naïve setting.

7.4 Diffuse Large B-Cell Lymphoma (DLBCL)

The efficacy of parsaclisib in the most common and aggressive form of NHL was evaluated in the CITADEL-202 study (NCT02998476). This Phase 2 trial enrolled patients with R/R DLBCL and ultimately proved to be a negative study. The trial was terminated early after a planned interim analysis crossed a futility boundary. The ORR for parsaclisib monotherapy was only 25.5%, with a median DOR of 6.2 months. This limited activity suggests that while the PI3Kδ pathway is relevant in some DLBCL cases, it is not a universally critical driver of proliferation and survival in this heterogeneous and aggressive disease. The high selectivity of parsaclisib, while beneficial for safety, may have limited its efficacy in a disease where multiple oncogenic pathways are often active.

7.5 Other Lymphomas and Combination Studies

Parsaclisib was also explored in other lymphoma subtypes and in combination regimens. Early-phase studies showed some activity in relapsed or refractory T-cell lymphomas, including primary cutaneous T-cell non-Hodgkin lymphoma, often in combination with agents like romidepsin or chidamide. The

CITADEL-112 study (NCT03424122), a Phase 1 dose-finding trial, evaluated parsaclisib in combination with standard-of-care agents (rituximab, bendamustine/rituximab, or ibrutinib) in various R/R B-cell lymphomas. The combinations showed promising efficacy, with ORRs of 81.3% with rituximab, 55.6% with bendamustine/rituximab, and 50.0% with ibrutinib, all with an expected and manageable safety profile.

Table 4: Summary of Efficacy Outcomes Across Key CITADEL Monotherapy Trials

Indication (Trial ID)	Patient Population	ORR (%)	CRR (%)	Median DOR (months)	Median PFS (months)	Source(s)
Follicular Lymphoma (NCT03126019)	R/R, ≥2 prior therapies	77.7	19.4	14.7	15.8
Marginal Zone Lymphoma (NCT03144674)	R/R, BTKi-naïve	58.3	4.2	12.2	16.5
Mantle Cell Lymphoma (NCT03235544)	R/R, BTKi-naïve	70.1	15.6	12.1	13.6
Mantle Cell Lymphoma (NCT03235544)	R/R, BTKi-experienced	25.0	N/A	3.7	3.7
Diffuse Large B-Cell Lymphoma (NCT02998476)	R/R, BTKi-naïve	25.5	N/A	6.2	N/A
ORR: Objective Response Rate; CRR: Complete Response Rate; DOR: Duration of Response; PFS: Progression-Free Survival. Data shown for the daily dosing group where applicable.

7.6 Safety and Tolerability Profile in B-Cell Malignancies

A primary goal of the parsaclisib program was to deliver a PI3Kδ inhibitor with an improved safety profile. Across the CITADEL program, parsaclisib demonstrated a consistent and manageable safety profile, largely achieving this objective. The adverse events observed were consistent with the known class effects of PI3K inhibitors but were generally less severe than those reported for first-generation agents.

The most common treatment-emergent adverse events (TEAEs) reported across studies were diarrhea/colitis, nausea, cough, fatigue, rash, and pyrexia. Diarrhea was the most frequent TEAE, occurring in 30-50% of patients, but Grade ≥3 events were less common, typically in the range of 10-14%. Hematologic toxicities were also observed, with neutropenia being the most common Grade ≥3 event in some studies.

Importantly, severe hepatotoxicity (elevated ALT/AST) was rare. In the pivotal CITADEL-101 study, transaminase elevations were almost exclusively Grade 1, a stark contrast to the experience with earlier PI3Kδ inhibitors. This favorable liver safety profile supports the hypothesis that parsaclisib's unique chemical structure successfully mitigated this key off-target toxicity. Most TEAEs were manageable with supportive care and dose modifications (interruption or reduction), although treatment discontinuation due to adverse events occurred in approximately 24-29% of patients in the pivotal lymphoma trials.

Table 5: Summary of Common (≥15%) and Grade ≥3 TEAEs Across Select CITADEL Trials

Adverse Event	Follicular Lymphoma (NCT03126019) All Grades (%)	Follicular Lymphoma (NCT03126019) Grade ≥3 (%)	Mantle Cell Lymphoma (NCT03235544) All Grades (%)	Mantle Cell Lymphoma (NCT03235544) Grade ≥3 (%)	Marginal Zone Lymphoma (NCT03144674) All Grades (%)	Marginal Zone Lymphoma (NCT03144674) Grade ≥3 (%)
Diarrhea	38.1	11.9	34.3	13.9	47.0	12.0
Nausea	24.6	N/A	13.0	N/A	N/A	N/A
Cough	22.2	N/A	N/A	N/A	23.0	N/A
Neutropenia	N/A	10.3	N/A	8.3	N/A	9.0
Colitis	N/A	5.6	N/A	4.6	N/A	7.0
Pyrexia	N/A	N/A	17.6	N/A	N/A	N/A
Rash	N/A	N/A	N/A	N/A	18.0	N/A
Data compiled from sources. N/A indicates not reported as meeting the threshold in the available source.

8.0 Clinical Investigation in Myeloproliferative Neoplasms (MPNs) and Other Indications

In an effort to broaden the therapeutic utility of parsaclisib beyond B-cell malignancies, Incyte launched the ambitious LIMBER clinical program to investigate its role in myelofibrosis (MF), and also explored its potential in autoimmune diseases. However, these endeavors ultimately met with significant setbacks, effectively narrowing the drug's future development path.

8.1 The LIMBER Program in Myelofibrosis

The rationale for using parsaclisib in MF was based on preclinical evidence suggesting that signaling through the PI3K/AKT pathway could be a mechanism of primary or acquired resistance to JAK inhibitors like ruxolitinib, the standard of care for MF. By combining parsaclisib with ruxolitinib, the LIMBER program aimed to achieve deeper and more durable responses by simultaneously blocking two key signaling pathways.

The LIMBER-304 study (NCT04551053) was a pivotal Phase 3, randomized, double-blind trial evaluating the addition of parsaclisib versus placebo in patients with MF who had a suboptimal response to stable-dose ruxolitinib monotherapy. The primary endpoint was the proportion of patients achieving a significant reduction in spleen volume at week 24. In March 2023, Incyte announced the discontinuation of this trial. The decision was based on the recommendation of an independent data monitoring committee following a pre-planned interim analysis, which concluded that the study was unlikely to meet its primary endpoint. This termination for futility was a major blow to the program.

A second pivotal trial, LIMBER-313 (NCT04551066), was designed to evaluate the parsaclisib-ruxolitinib combination as a first-line therapy for patients with MF who were naïve to JAK inhibitors. This trial was also terminated, further confirming the lack of synergistic or additive benefit of this combination in the MF setting. The failure of both pivotal Phase 3 trials marked the end of parsaclisib's development in MPNs and represented a significant strategic failure to expand its clinical utility.

8.2 Development in Autoimmune Diseases

Given the central role of PI3Kδ in immune cell function, parsaclisib was also investigated as a potential therapy for autoimmune diseases driven by B-cell hyperactivity. Clinical trials were initiated in conditions such as autoimmune hemolytic anemia (AIHA) and Sjögren's syndrome.

However, development in these indications was also halted. In a May 2023 update, Incyte announced that the development of parsaclisib in warm autoimmune hemolytic anemia (wAIHA) had been discontinued. The company explicitly cited the "challenging regulatory landscape associated with the PI3K class" as the reason for this decision. This statement is particularly revealing, as it suggests that the decision was not based on a lack of efficacy or a specific safety concern within the AIHA trial itself, but rather on a broader risk assessment of the entire drug class. The heightened scrutiny from regulatory agencies, particularly the FDA, regarding the long-term safety of PI3K inhibitors in less life-threatening conditions like autoimmune diseases, likely made the path to approval appear too arduous and uncertain to justify continued investment.

9.0 Global Regulatory Trajectory and Current Development Status

The regulatory journey of parsaclisib is a compelling narrative of divergent paths, where promising clinical data met with insurmountable strategic and regulatory hurdles in the United States and Europe, while finding a more receptive environment in China. This dichotomy highlights the powerful influence of the broader class context and regional regulatory philosophies on a drug's ultimate fate.

9.1 United States (FDA)

Following the positive results from the CITADEL program, Incyte submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for parsaclisib. In November 2021, the FDA accepted the NDA for the treatment of three types of R/R NHL: follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma. The agency granted Priority Review for the MZL and MCL indications, a designation that shortens the review timeline and is reserved for drugs that may offer significant improvements in treatment. The Prescription Drug User Fee Act (PDUFA) target action dates were set for April 30, 2022, for MZL and MCL, and August 30, 2022, for the standard review of the FL indication.

However, in a surprising turn of events, Incyte announced in January 2022 that it was withdrawing the NDA for all three indications. The company was explicit that this was a "business decision" and was "not related to any changes in either the efficacy or safety of parsaclisib". The decision followed discussions with the FDA regarding the requirements for confirmatory studies to support an accelerated approval. Incyte determined that these studies could not be completed within a time frame that would justify the continued investment. This outcome reflects a broader trend of increased FDA scrutiny on the PI3K inhibitor class, where the agency has moved towards requiring randomized, controlled data even for accelerated approval in R/R settings, a high bar for niche indications with small patient populations. Parsaclisib, despite its improved safety profile, became a casualty of the regulatory legacy of its predecessors.

9.2 European Union (EMA)

A similar story unfolded in the European Union. Parsaclisib was granted orphan designation by the European Commission for the treatment of MZL in July 2019, recognizing its potential in a rare disease. Incyte subsequently submitted a marketing authorization application to the European Medicines Agency (EMA).

In June 2022, Incyte withdrew this application. The EMA's public statement on the withdrawal provided more specific scientific and regulatory concerns than those articulated by the FDA. At the time of withdrawal, the EMA's provisional opinion was that the drug could not have been authorized. The agency cited several concerns, including the single-arm design of the main study without a comparator, missing pharmacokinetic data, and insufficient justification for the proposed dosing regimen. The EMA also noted that for a conditional marketing authorization, the company had not adequately demonstrated an advantage over existing treatments. The company stated it was unable to satisfactorily address these concerns, particularly regarding study design and the feasibility of conducting further studies.

9.3 China (NMPA) and Rest of World

In contrast to the setbacks in the West, the development of parsaclisib has progressed positively in China. In December 2018, Incyte entered into a strategic collaboration with Innovent Biologics, granting Innovent the rights to develop and commercialize parsaclisib in Mainland China, Hong Kong, Macau, and Taiwan.

Innovent conducted a successful local Phase 2 pivotal study (NCT04298879) in Chinese patients with R/R FL, which demonstrated a very high ORR of 86.9%. Based on these strong results, Innovent submitted an NDA to China's National Medical Products Administration (NMPA). In January 2023, the NMPA accepted the NDA and granted it Priority Review designation. Innovent is also pursuing further development, with an ongoing Phase Ib/III study (NCT05867030) evaluating parsaclisib in combination with rituximab and lenalidomide for R/R FL. This divergent regulatory path suggests that the risk-benefit assessment and data requirements may differ across global agencies, providing a potential, albeit geographically limited, future for parsaclisib.

9.4 Current Status (2024-2025)

As of early 2025, the development of parsaclisib by its originator, Incyte, appears to be largely deprioritized in Western markets. The drug is conspicuously absent from the company's 2025 pipeline and portfolio presentations, which focus on other assets. Recent activities have primarily consisted of the publication of final data from completed or terminated trials, such as the final results from the Phase 2 add-on study in myelofibrosis, which were published in February 2024. The future of parsaclisib seems to rest almost entirely on the regulatory and commercial efforts of Innovent Biologics in China.

10.0 Synthesis and Future Outlook

The development history of parsaclisib presents a compelling dichotomy of scientific success and strategic failure. As a molecule, it largely achieved its primary design objective: it is a potent, highly selective, next-generation PI3Kδ inhibitor with a manageable safety profile that successfully mitigated the severe hepatotoxicity that plagued its predecessors. The clinical data generated by the extensive CITADEL program unequivocally demonstrated that parsaclisib possesses significant and durable antitumor activity in multiple subtypes of relapsed or refractory B-cell non-Hodgkin lymphoma, particularly follicular lymphoma, marginal zone lymphoma, and BTKi-naïve mantle cell lymphoma.

Despite this robust clinical profile, parsaclisib's path to market in the United States and Europe was ultimately blocked by a confluence of powerful external factors. The primary driver of its stalled trajectory was the heightened regulatory scrutiny applied to the entire PI3K inhibitor class. Following safety concerns and issues with confirmatory trial conduct for earlier drugs in the class, regulatory agencies, particularly the FDA, raised the evidentiary bar for approval. The demand for large, randomized, controlled trials to support even an accelerated approval in niche, heavily pre-treated patient populations created a significant logistical and financial challenge. Incyte's ultimate withdrawal of its applications was a strategic business decision that the cost and time required to meet these new, more stringent regulatory demands were not commercially viable. Parsaclisib thus became a victim of the "class effect," where the negative legacy of its predecessors overshadowed its own differentiated and improved profile.

This challenge was compounded by the clinical trial failures in indications outside of B-cell lymphomas. The termination of two pivotal Phase 3 trials in myelofibrosis for futility represented a major scientific setback. This failure to expand into a larger market and diversify its clinical utility left parsaclisib cornered, with promising data only in the commercially challenging and competitive R/R indolent lymphoma space. The subsequent discontinuation of its development in autoimmune diseases, explicitly due to the "challenging regulatory landscape," further cemented its limited future.

The future outlook for parsaclisib in Western markets appears bleak. Its absence from Incyte's forward-looking strategic portfolio indicates that it is no longer a priority asset for the company. Its primary hope for reaching patients now lies in China, where its partner, Innovent Biologics, is actively pursuing regulatory approval based on strong local clinical data. The story of parsaclisib serves as a powerful and cautionary case study in modern drug development. It demonstrates that scientific innovation and positive clinical trial data, while necessary, are not always sufficient to guarantee success. The interplay of regulatory precedent, commercial viability, and strategic portfolio management can ultimately determine the fate of even a promising therapeutic agent.

Works cited

1. parsaclisib | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 22, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10098
2. parsaclisib | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 22, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=10098
3. What is Parsaclisib used for? - Patsnap Synapse, accessed August 22, 2025, https://synapse.patsnap.com/article/what-is-parsaclisib-used-for
4. Parsaclisib | C20H22ClFN6O2 | CID 86677874 - PubChem, accessed August 22, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Parsaclisib
5. INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of ..., accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6862339/
6. Parsaclisib Is a Next-Generation Phosphoinositide 3-Kinase δ Inhibitor with Reduced Hepatotoxicity and Potent Antitumor and Immunomodulatory Activities in Models of B-Cell Malignancy - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/32345620/
7. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory mantle cell lymphoma (CITADEL-205): a phase 2 study - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10433033/
8. INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ) | ACS Medicinal Chemistry Letters, accessed August 22, 2025, https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.9b00334
9. Full article: Safety and efficacy of parsaclisib in combination with rituximab, bendamustine + rituximab, or ibrutinib in patients with previously treated B-cell lymphoma: analysis of a phase 1 dose-finding study (CITADEL‑112), accessed August 22, 2025, https://www.tandfonline.com/doi/full/10.1080/10428194.2024.2331626
10. Incyte Corporation - Parsaclisib - AdisInsight - Springer, accessed August 22, 2025, https://adisinsight.springer.com/drugs/800039479
11. Incyte Provides Update on Parsaclisib and MCLA-145, accessed August 22, 2025, https://investor.incyte.com/news-releases/news-release-details/incyte-provides-update-parsaclisib-and-mcla-145/
12. Parsaclisib (INCB050465) | PI3Kδ Inhibitor - MedchemExpress.com, accessed August 22, 2025, https://www.medchemexpress.com/Parsaclisib.html
13. Parsaclisib Hydrochloride | C20H23Cl2FN6O2 | CID 122507744 - PubChem, accessed August 22, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/122507744
14. Parsaclisib Hydrochloride Therapy Introduction - Ontosight, accessed August 22, 2025, https://ontosight.ai/glossary/term/parsaclisib-hydrochloride-therapy-introduction--67a262e5c445bf945af00084
15. General Information of Drug (ID: DMYBIFS) - Details of the Drug | DrugMAP, accessed August 22, 2025, https://drugmap.idrblab.net/data/drug/details/DMYBIFS
16. Parsaclisib: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 22, 2025, https://go.drugbank.com/drugs/DB14867
17. PI3Kδ Inhibitor Parsaclisib in Japanese Patients With Relapsed or Refractory Follicular Lymphoma - PMC - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12317384/
18. An Open-Label Study to Assess the Effect of Itraconazole and Rifampin on Parsaclisib Pharmacokinetics When Administered Orally in Healthy Participants - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/32515832/
19. Incyte Announces Acceptance of NDA for Parsaclisib for Three Types of Relapsed or Refractory Non-Hodgkin Lymphomas - FirstWord Pharma, accessed August 22, 2025, https://firstwordpharma.com/story/5432403
20. Innovent and Incyte Announce Strategic Collaboration and Licensing Agreement for Three Clinical-stage Product Candidates in China, accessed August 22, 2025, https://investor.incyte.com/news-releases/news-release-details/innovent-and-incyte-announce-strategic-collaboration-and/
21. Post Essential Thrombocythaemia Myelofibrosis (PET-MF) Terminated Phase 3 Trials for Parsaclisib (DB14867) - DrugBank, accessed August 22, 2025, https://go.drugbank.com/indications/DBCOND0056619/clinical_trials/DB14867?phase=3&status=terminated
22. Incyte Provides Update on Interim Analysis of Phase 3 LIMBER-304 Study of Parsaclisib and Ruxolitinib in Patients with Myelofibrosis, accessed August 22, 2025, https://investor.incyte.com/news-releases/news-release-details/incyte-provides-update-interim-analysis-phase-3-limber-304-study/
23. Phase 2 study of add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: final results | Blood Advances | American Society of Hematology, accessed August 22, 2025, https://ashpublications.org/bloodadvances/article/8/6/1515/514765/Phase-2-study-of-add-on-parsaclisib-for-patients
24. Adding Parsaclisib to Ruxolitinib Improves Myelofibrosis Symptoms and Spleen Volume, accessed August 22, 2025, https://www.bloodcancerstoday.com/post/parsaclisib-added-to-ruxolitinib-for-myelofibrosis-improves-symptoms-and-spleen-volume
25. Hodgkin's Lymphoma Active Not Recruiting Phase 1 Trials for Parsaclisib (DB14867), accessed August 22, 2025, https://go.drugbank.com/indications/DBCOND0030382/clinical_trials/DB14867?phase=1&status=active_not_recruiting
26. Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma Completed Phase 1 Trials for Parsaclisib (DB14867) - DrugBank, accessed August 22, 2025, https://go.drugbank.com/indications/DBCOND0091068/clinical_trials/DB14867?phase=1&status=completed
27. Parsaclisib Not Yet Recruiting Phase 1 / 2 Trials for CHOP / PI3Kδ Inhibitor / Peripheral T-Cell Lymphoma (PTCL) / Parsaclisib Treatment - DrugBank, accessed August 22, 2025, https://go.drugbank.com/drugs/DB14867/clinical_trials?conditions=DBCOND0140077%2CDBCOND0146179%2CDBCOND0079798%2CDBCOND0146178&phase=1%2C2&purpose=treatment&status=not_yet_recruiting
28. Parsaclisib Completed Phase 1 Trials for Recurrent Anaplastic Large Cell Lymphoma / refractory, primary Cutaneous T-Cell Non-Hodgkin Lymphoma / T-Cell Non-Hodgkin Lymphoma / Refractory Anaplastic Large Cell Lymphoma / Refractory Transformed Mycosis Fungoides / Recurrent Primary Cutaneous T-Cell Non-Hodgkin Lymphoma / Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma / Recurrent Transformed Mycosis Fungoides / Recurrent Mature T- Cell and NK-Cell Non-Hodgkin Lymphoma Treatment - DrugBank, accessed August 22, 2025, https://go.drugbank.com/drugs/DB14867/clinical_trials?conditions=DBCOND0045771%2CDBCOND0122751%2CDBCOND0091067%2CDBCOND0137413%2CDBCOND0078800%2CDBCOND0058165%2CDBCOND0137414%2CDBCOND0112302%2CDBCOND0041117&phase=1&purpose=treatment&status=completed
29. Ongoing phase 1/2 study of INCB050465 for relapsed/refractory (R/R) B-cell malignancies (CITADEL-101). - ASCO Publications, accessed August 22, 2025, https://ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.7530
30. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/30803990/
31. CITADEL-203: Parsaclisib in follicular lymphoma - YouTube, accessed August 22, 2025, https://www.youtube.com/watch?v=lAPhYPaVMqA
32. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory follicular lymphoma (CITADEL-203): a phase 2 study - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/37662520/
33. Paper: Phase 2 Study Evaluating the Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Follicular Lymphoma (CITADEL-203), accessed August 22, 2025, https://ash.confex.com/ash/2020/webprogram/Paper134869.html
34. Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory mantle cell lymphoma (CITADEL-205): a phase 2 study - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/37599908/
35. A phase 2 study of the PI3Kδ inhibitor parsaclisib in relapsed and refractory marginal zone lymphoma (CITADEL-204) | Blood Advances | American Society of Hematology, accessed August 22, 2025, https://ashpublications.org/bloodadvances/article/8/4/867/506667/A-phase-2-study-of-the-PI3K-inhibitor-parsaclisib
36. Study Details | A Phase 1/2, Open-Label, Dose Escalation, Safety ..., accessed August 22, 2025, https://clinicaltrials.gov/study/NCT02018861
37. FDA Considers Parsaclisib for Approval in FL, MZL, and MCL - Targeted Oncology, accessed August 22, 2025, https://www.targetedonc.com/view/fda-considers-parsaclisib-for-approval-in-fl-mzl-and-mcl
38. A phase 2 study of the PI3Kδ inhibitor parsaclisib in relapsed and refractory marginal zone lymphoma (CITADEL-204) - AIR Unimi, accessed August 22, 2025, https://air.unimi.it/retrieve/3955d22d-68b1-414a-8b0b-c88c77a16eec/bloodadvances.2023.pdf
39. A phase 2 study of the PI3Kδ inhibitor parsaclisib in relapsed and refractory marginal zone lymphoma (CITADEL-204) - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/38113459/
40. Phase 2 study of parsaclisib (INCB050465), a highly selective, next-generation PI3Kδ inhibitor, in relapsed or refractory diffuse large B-cell lymphoma (CITADEL-202) - PubMed, accessed August 22, 2025, https://pubmed.ncbi.nlm.nih.gov/33140664/
41. Phase 2 study of parsaclisib (INCB050465), a highly selective, next-generation PI3Kδ inhibitor, in relapsed or refractory diffuse large B-cell lymphoma (CITADEL-202), accessed August 22, 2025, https://www.tandfonline.com/doi/abs/10.1080/10428194.2020.1832660
42. A Phase 2 Safety and Efficacy Study of INCB050465 in Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (CITADEL-202) | ClinicalTrials.gov, accessed August 22, 2025, https://www.clinicaltrials.gov/show/NCT02998476
43. Study Details | To Evaluate Efficacy and Safety of Parsaclisib and ..., accessed August 22, 2025, https://clinicaltrials.gov/study/NCT04551053
44. Study of Parsaclisib Plus Ruxolitinib in Myelofibrosis Discontinued - Targeted Oncology, accessed August 22, 2025, https://www.targetedonc.com/view/study-of-parsaclisib-plus-ruxolitinib-in-myelofibrosis-discontinued
45. Study Details | To Evaluate the Efficacy and Safety of Parsaclisib ..., accessed August 22, 2025, https://clinicaltrials.gov/study/NCT04551066
46. To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313) - larvol clin, accessed August 22, 2025, https://clin.larvol.com/trial-detail/NCT04551066
47. A phase II, multicenter, single-arm study of parsaclisib, a PI3Kδ inhibitor, in relapsed or refractory follicular lymphoma in China - ASCO Publications, accessed August 22, 2025, https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.7574
48. A Phase II, Multicenter, Single-Arm, Open-Label Study of Parsaclisib, a PI3Kδ Inhibitor, in Relapsed or Refractory Follicular Lymphoma in China, accessed August 22, 2025, https://ashpublications.org/blood/article/138/Supplement%201/3536/479699/A-Phase-II-Multicenter-Single-Arm-Open-Label-Study
49. Innovent Announces the National Medical Products Administration in China Has Accepted and Granted Priority Review Designation to the New Drug Application for Parsaclisib (PI3Kδ inhibitor) for the Treatment of Relapsed or Refractory Follicular Lymphoma - PR Newswire, accessed August 22, 2025, https://www.prnewswire.com/news-releases/innovent-announces-the-national-medical-products-administration-in-china-has-accepted-and-granted-priority-review-designation-to-the-new-drug-application-for-parsaclisib-pi3k-inhibitor-for-the-treatment-of-relapsed-or-refractor-301715196.html
50. Study Details | PI3Kδ Inhibitor Parsaclisib Combined With Chidamide for the Treatment of Relapsed/Refractory Peripheral T-cell Lymphoma | ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT05083208
51. Paper: Selective PI3Kδ Inhibitor Parsaclisib Combined with HDAC Inhibitor Chidamide in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma: Preliminary Results of a Phase Ib/Ⅱ Study, accessed August 22, 2025, https://ash.confex.com/ash/2023/webprogram/Paper185902.html
52. A Study of INCB050465 in Relapsed or Refractory Follicular Lymphoma - NCI, accessed August 22, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2017-01662
53. A Study of INCB050465 in Subjects With Relapsed or Refractory Marginal Zone Lymphoma (CITADEL-204) - ClinicalTrials.Veeva, accessed August 22, 2025, https://ctv.veeva.com/study/a-study-of-incb050465-in-subjects-with-relapsed-or-refractory-marginal-zone-lymphoma-citadel204
54. Parsaclisib for MCL: next steps? - YouTube, accessed August 22, 2025, https://www.youtube.com/watch?v=_0y1yab05dk
55. Study Details | Maximum Tolerated Dose, Safety, and Efficacy of ..., accessed August 22, 2025, https://clinicaltrials.gov/study/NCT03235544
56. Parsaclisib Offers New Hope for Patients With BTK Inhibitor-Naïve Relapsed/Refractory MCL, accessed August 22, 2025, https://www.targetedonc.com/view/parsaclisib-offers-new-hope-for-patients-with-btk-inhibitor-na-ve-relapsed-refractory-mcl
57. Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Mantle Cell Lymphoma Not Previously Treated with a BTK Inhibitor: Primary Analysis from a Phase 2 Study (CITADEL-205) | Blood | American Society of Hematology, accessed August 22, 2025, https://ashpublications.org/blood/article/138/Supplement%201/382/478184/Efficacy-and-Safety-of-Parsaclisib-in-Patients
58. Incyte Announces Parsaclisib Treatment Results in High Rate of Rapid and Durable Responses in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphomas - Business Wire, accessed August 22, 2025, https://www.businesswire.com/news/home/20201207005129/en/Incyte-Announces-Parsaclisib-Treatment-Results-in-High-Rate-of-Rapid-and-Durable-Responses-in-Patients-with-Relapsed-or-Refractory-B-Cell-Non-Hodgkin-Lymphomas
59. Full article: Phase 2 study of parsaclisib (INCB050465), a highly selective, next-generation PI3Kδ inhibitor, in relapsed or refractory diffuse large B-cell lymphoma (CITADEL-202), accessed August 22, 2025, https://www.tandfonline.com/doi/full/10.1080/10428194.2020.1832660
60. Efficacy and Safety of Parsaclisib in Patients with Relapsed or Refractory Marginal Zone Lymphoma: Primary Analysis from a Phase 2 Study (CITADEL-204) - American Society of Hematology, accessed August 22, 2025, https://ashpublications.org/blood/article/138/Supplement%201/44/477497/Efficacy-and-Safety-of-Parsaclisib-in-Patients
61. Parsaclisib, a potent and highly selective PI3Kδ inhibitor, in patients with relapsed or refractory B-cell malignancies - PubMed Central, accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6543513/
62. P1104: A PHASE 1 STUDY EVALUATING SAFETY AND EFFICACY OF PARSACLISIB IN COMBINATION WITH BENDAMUSTINE + OBINUTUZUMAB IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR LYMPHOMA (CITADEL-102), accessed August 22, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9431125/
63. To Evaluate Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis Who Have Suboptimal Response to Ruxolitinib (LIMBER-304) - National Cancer Institute, accessed August 22, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-09614
64. Incyte Abandons Phase III Trial for Myelofibrosis Treatment - BioSpace, accessed August 22, 2025, https://www.biospace.com/incyte-abandons-phase-iii-trial-for-myelofibrosis-treatment
65. To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313) - National Cancer Institute, accessed August 22, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2021-01110
66. Incyte Reports 2023 First Quarter Financial Results and Provides Updates on Key Clinical Programs, accessed August 22, 2025, https://investor.incyte.com/news-releases/news-release-details/incyte-reports-2023-first-quarter-financial-results-and-provides/
67. FDA Accepts NDA for Parsaclisib for Non-Hodgkin Lymphomas - Pharmacy Times, accessed August 22, 2025, https://www.pharmacytimes.com/view/fda-accepts-nda-for-parsaclisib-for-non-hodgkin-lymphomas
68. FDA Will Review New Drug to Treat Non-Hodgkin Lymphoma - Cure Today, accessed August 22, 2025, https://www.curetoday.com/view/fda-will-review-new-drug-to-treat-non-hodgkin-lymphoma
69. Incyte Withdraws FDA Submission for Parsaclisib for FL, MZL, MCL, accessed August 22, 2025, https://www.ajmc.com/view/incyte-withdraws-fda-submission-for-parsaclisib-for-fl-mzl-mcl
70. EU/3/19/2185 - orphan designation for treatment of marginal zone lymphoma | European Medicines Agency (EMA), accessed August 22, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-19-2185
71. Parsaclisib Incyte Biosciences Distribution B.V. | European Medicines Agency (EMA), accessed August 22, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/parsaclisib-incyte-biosciences-distribution-bv
72. Parsaclisib in Patients With Relapsed or Refractory Follicular Lymphoma - ClinicalTrials.gov, accessed August 22, 2025, https://clinicaltrials.gov/study/NCT05867030
73. Incyte Portfolio June 27, 2025, accessed August 22, 2025, https://cdn.incyte.com/Assets/Pipeline/portfolio.pdf
74. Incyte Highlights Commercial Growth, Clinical Progress and 2025 Milestones at the 43rd Annual J.P. Morgan Healthcare Conference, accessed August 22, 2025, https://investor.incyte.com/news-releases/news-release-details/incyte-highlights-commercial-growth-clinical-progress-and-2025/