parsaclisib (INCB50465) / Incyte, Innovent Biologics - LARVOL DELTA

Feasibility assessment of indirect treatment comparison between off-label rituximab and novel treatments in patients with warm autoimmune hemolytic anemia (ASH 2025) - "Among the clinical trials included, five studied rituximab, in combination with prednisone, prednisolone, ibrutinib, or bortezomib. Three trials studied fostamatinib, while other studied treatments included pegcetacoplan, sovleplenib, parsaclisib, and rilzabrutinib...Future work should consider de novo sources of real-world evidence for rituximab that more closely align with registrational trial characteristics and endpoint definitions. However, aligning timing of endpoint measurements between registration trials and real-world data to match definitions remains challenging."

Clinical • Anemia • Autoimmune Hemolytic Anemia • Hematological Disorders • Immunology

Trial in progress: A study of roginolisib in combination with ruxolitinib in patients with myelofibrosis who are unresponsive to JAK inhibitors (HEMA-MED) (ASH 2025) - P1, P1/2 | "In contrast to the first generation PI3K inhibitors, suchas parsaclisib and umbralisib, roginolisib is a novel, oral, non-ATP competitive, allosteric small moleculeinhibitor of PI3Kδ. The study is currentlyactively enrolling at 8 sites in Italy and Spain.Conclusions. Given the safety profile of roginolisib in patients of the FiH dose study, the combination ofruxolitinib and roginolisib is expected to provide a safe combination treatment in patients with MF whoare no longer responding to JAK inhibition."

Clinical • Combination therapy • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Myelofibrosis • Solid Tumor • Thrombocytosis • PIK3CD

Management of Autoimmune Hemolytic Anemia (ASH 2025) - "For relapsed/refractory patients rituximab has become the preferred second line-therapy, comparing favorably with the traditional splenectomy, which has been progressively abandoned or moved to further lines along with classic immunosuppressors. Several novel treatments are in development for wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab)."

IO biomarker • Anemia • Autoimmune Hemolytic Anemia • Bone Marrow Transplantation • Hematological Disorders • Immunology • Infectious Disease • HP • SYK

Management of autoimmune hemolytic anemia. (PubMed, Hematology Am Soc Hematol Educ Program) - "Rituximab is now the preferred second-line option for relapsed/refractory patients, comparing favorably with the traditional splenectomy. The latter is increasingly reserved for later lines together with classic immunosuppressants. Several novel treatments are in development for refractory wAIHA, encompassing drugs targeting B-cells (parsaclisib, ibrutinib, rilzabrutinib, zanubrutinib, obexelimab, ianalumab, povetacicept), plasma cells (bortezomib, daratumumab), spleen tyrosine kinase (fostamatinib, sovleplenib), and the neonatal Fc receptor (nipocalimab)."

Journal • Review • Anemia • Autoimmune Hemolytic Anemia • Bone Marrow Transplantation • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • Infectious Disease • Oncology • Paroxysmal Nocturnal Hemoglobinuria • Transplantation • SYK

PI3Kδ Inhibitor Parsaclisib Combined With Chidamide for the Treatment of Relapsed/Refractory Peripheral T-cell Lymphoma (clinicaltrials.gov) - P1 | N=12 | Terminated | Sponsor: Henan Cancer Hospital | Phase classification: P1/2 ➔ P1 | Trial completion date: Feb 2025 ➔ Aug 2025

Phase classification • Trial completion date • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK

Characterizing the Clinical, Humanistic, and Economic Burden of Warm Autoimmune Hemolytic Anemia: A Systematic Literature Review and Evidence Gap Assessment (ASH 2024) - "While there are no FDA-approved treatments specifically for wAIHA, treatments evaluated within the set of clinical trials included fostamatinib, rituximab, ibrutinib + rituximab, sovleplenib, parsaclisib, and pulse cyclophosphamide. While wAIHA is a relatively poorly studied disease, available data suggests low Hb levels and associated risks across both clinical trials and real-world study publications, reflecting a high unmet need in this patient population. Patient-reported outcomes, including health-related quality of life measures, should be evaluated with clinical outcomes in future trials and observational studies to facilitate understanding of outcomes that are important to patients."

Clinical • HEOR • Review • Anemia • Autoimmune Hemolytic Anemia • Fatigue • Hematological Disorders • Immunology

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 (ASH 2023) - P1/2 | "Preliminary data demonstrated that selective PI3Kδ Inhibitor parsaclisib with HDACi chidamide was tolerable and produced promising responses in r/r PTCL, including patients previously exposed to chidamide. This trial is currently ongoing."

Clinical • Cytomegalovirus Infection • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukopenia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • Pneumonia • Respiratory Diseases • T Cell Non-Hodgkin Lymphoma • PIK3CD

Bullous Pemphigoid Develops Independently of DAP12. (PubMed, Biomolecules) - "In addition, pharmacological inhibition of PI3Kδ, a downstream kinase of the DAP12/TREM pathway, did not affect disease progression in anti-Col17 IgG-induced BP. Collectively, these findings indicate that while DAP12 signaling modulates local immune cell composition, the DAP12/TREM1/2-axis does not influence overall disease activity in experimental BP."

Journal • Bullous Pemphigoid • Dermatology • Dermatopathology • Immunology • PIK3CD

Safety and Efficacy of Parsaclisib in Combination with Rituximab in Patients with Previously Untreated Indolent B-Cell Lymphoma: Primary Analysis from a Phase 2 Study (REPLY) (ASH 2023) - P2 | "The combination of parsaclisib with rituximab showed a deep and durable response, with a favorable safety profile and generally good tolerability in patients with previously untreated indolent B-Cell Lymphoma."

Clinical • Combination therapy • IO biomarker • P2 data • Anemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Extranodal Marginal Zone Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Immunology • Indolent Lymphoma • Infectious Disease • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • MYC

A Phase 1/1b Study of Parsaclisib Plus Standard Immunochemotherapy for Newly Diagnosed High-Risk Diffuse Large B-Cell Lymphoma (ASH 2024) - "Our group previously reported that addition of the mTOR inhibitor everolimus to R-CHOP resulted in excellent efficacy in the Alliance N1085 trial (Witzig TE et al, Blood Cancer J, 2017, 7(6) : e576), with 23 of 24 patients achieving event-free survival at 24 months (EFS24), supporting further investigation of PI3K/mTOR targeting in DLBCL...Conclusions : Addition of the PI3K inhibitor parsaclisib to R-CHOP or Pola-R-CHP immunochemotherapy is considered safe in patients with newly diagnosed DLBCL. Combination of parsaclisib and standard immunochemotherapy resulted in high ORR and CR rate and encouraging preliminary PFS and OS outcomes patients with high-risk DLBCL. These data support further investigation of PI3K/mTOR targeting in newly diagnosed DLBCL in future trials."

IO biomarker • P1 data • Anemia • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Constipation • Diffuse Large B Cell Lymphoma • Fatigue • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • High-grade B-cell lymphoma • Leukopenia • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Thrombocytopenia • BCL2 • BCL6 • MYC

Targeting the Hypoxic Microenvironment in Cutaneous Chronic Graft-Versus-Host Disease through PI3Kδ Inhibition (ASH 2024) - "We tested the PI3Kδ inhibitor (PI3Kδi, Parsaclisib) in the Scl-cGVHD model, the major MHC-mismatched model (C57BL/6→BALB/c) and the Xeno-GVHD model...Remarkably, PI3Kδ inhibition reversed skin hypoxia, prevented the development of pathogenic TLS, and ameliorated cGVHD histopathology, suggesting PI3Kd inhibition emerges as a promising therapeutic approach, alleviating disease symptoms and addressing fundamental mechanisms of disease progression. These insights pave the way for innovative treatments targeting the hypoxic milieu in cutaneous cGVHD."

Alopecia • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Fibrosis • Graft versus Host Disease • Immunology • CD4 • CD8 • HIF1A • IL13 • PIK3CD

Autoimmune complications of lymphoproliferative diseases (ICML 2025) - "Moreover, several drugs may be responsible for immune-mediated cytopenias, including several antibiotics (ceftriaxone, piperacillin, rifampin, nafcillin, erythromycin, ticarcillin, trimethoprim, sulfamethoxazole), and various other drugs (procainamide, quinine, phenacetin, diclofenac, cimetidine, hydrochlorothiazide, chlorpropamide) [8]...Ibrutinib, through the inhibition of autoantibodies producing B-cells and restoration of T-cell homeostasis seems safe, while some case reports of autoimmune diseases have been reported for idelalisib (autoimmune hepatitis, colitis) and venetoclax (AIHA) [5, 6]...They included nivolumab, followed by pembrolizumab, ipilimumab, and atezolizumab...In particular, in CLL several therapies have been reported effective in refractory cytopenias: alemtuzumab single agent, the combinations ibrutinib-rituximab, bendamustine-rituximab, and rituximab–cyclophosphamide-dexamethasone [34-37]. Notably, some of the new/experimental treatments for primary..."

IO biomarker • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hodgkin Lymphoma • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Waldenstrom Macroglobulinemia • CTLA4 • HP • IL10 • PD-1 • TGFB1

Parsaclisib Plus the Standard Drug Therapy in Patients With Newly Diagnosed, High Risk Diffuse Large B-cell Lymphoma (clinicaltrials.gov) - P1 | N=50 | Active, not recruiting | Sponsor: Mayo Clinic | Trial completion date: May 2027 ➔ May 2028

Trial completion date • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • High-grade B-cell lymphoma • Indolent Lymphoma • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • BCL2 • BCL6 • CD20 • MYC

Beneath the surface in autoimmune hemolytic anemia: pathogenetic networks, therapeutic advancements and open questions. (PubMed, Front Immunol) - "Glucocorticoids remain the standard first-line therapy for warm AIHA; in contrast, CAD/CAS is increasingly managed with agents targeting B-cell function or complement activation, including rituximab and sutimlimab...Emerging therapeutics targeting the classical complement pathway include novel anti-C1s monoclonal antibodies such as riliprubart, which exhibits an extended half-life due to enhanced affinity for the neonatal Fc receptor. Parallel strategies aim to disrupt B-cell receptor (BCR) signaling cascades, employing Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib, spleen tyrosine kinase (SYK) inhibitors such as fostamatinib and sovleplenib, and phosphoinositide 3-kinase (PI3K) inhibitors such as parsaclisib. Collectively, these advances are reshaping the therapeutic landscape of AIHA toward a precision medicine model guided by mechanistic insights into disease biology. In this review, we delineate the evolving immunopathogenesis of AIHAs and examine..."

Journal • Review • Anemia • Autoimmune Hemolytic Anemia • Complement-mediated Rare Disorders • Hematological Disorders • Immunology • SYK

A Single-arm Phase 2 Prospective Clinical Study of Linprixel in the Treatment of Relapsed/Refractory Autoimmune Hemolytic Anemia (clinicaltrials.gov) - P=N/A | N=22 | Not yet recruiting | Sponsor: Peking Union Medical College Hospital

New trial • Anemia • Autoimmune Hemolytic Anemia • Hematological Disorders • Immunology

J-MIND: To Assess the Safety and Tolerability of Tafasitamab Alone or in Combination With Other Drugs in Japanese Participants With Non-Hodgkins Lymphoma (NHL) (clinicaltrials.gov) - P1/2 | N=72 | Active, not recruiting | Sponsor: Incyte Biosciences Japan GK | Recruiting ➔ Active, not recruiting | Trial completion date: Jul 2026 ➔ Dec 2026 | Trial primary completion date: May 2025 ➔ Dec 2026

Enrollment closed • Trial completion date • Trial primary completion date • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Marginal Zone Lymphoma: Treatment Update With a Focus on Systemic Approaches (ICML 2025) - P2, P3 | "Amongst 454 enrolled patients and with a median follow up time of over 7 years, the combination of rituximab plus chlorambucil had superior EFS (5-year EFS 68% vs. 50%) but no difference in overall survival which was excellent at 90% [17]. Other approaches added bendamustine to rituximab...Initial trials with the first-in-class covalent BTKi inhibitor, ibrutinib, were promising...The second generation covalent BTKi zanubrutinib and acalabrutinib have also been evaluated in RR MZL, with zanubrutinib receiving regulatory approval in the United States and the European Union...Unfortunately, the first-in-class PI3Kδ inhibitor, idelalisib, was associated with significant toxicities, including infection and immune-mediated complications...In MZL, there is a recent publication of parsaclisib with intriguing findings [29]...ZUMA-5 is a multicenter Phase 2 trial of axicabtegene ciloleucel (axi-cel) conducted in patients with both FL and MZL [30]...Several CD20xCD3 BsAbs,..."

IO biomarker • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Extranodal Marginal Zone Lymphoma • Follicular Lymphoma • Hairy Cell Leukemia • Hematological Malignancies • Hodgkin Lymphoma • Indolent Lymphoma • Leukemia • Lymphoma • Marginal Zone Lymphoma • Nodal Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Splenic Marginal Zone Lymphoma • CD5 • CRBN • MME • MYD88 • PIK3CD

Development and validation of a UPLC-MS/MS method for the quantification of parsaclisib and its application to pharmacokinetics and metabolic stability studies. (PubMed, BMC Chem) - "Parsaclisib was detected by gradient elution on an Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm) using acetonitrile and 0.1% formic acid as mobile phases, and pilaralisib was used as an internal standard (IS). Finally, in vitro results showed that parsaclisib had a slow intrinsic clearance (Clint) value of 2.4 µL/min/mg protein with a half-life (t1/2) value of 571.3 min. These findings theoretically supported the potential metabolism of parsaclisib in vivo."

Journal • PK/PD data • Hematological Malignancies • Oncology • PIK3CD

HYPOXIA-DRIVEN T CELL-MACROPHAGE-STROMAL CROSSTALK SUSTAINS FIBROSIS IN CUTANEOUS CHRONIC GVHD VIA THE HIF1α/PI3KΔ/IL-13 AXIS (EHA 2025) - "In aggregate, our data indicated that the HIF1α/PI3Kd/IL-13 axis drives persistent fibrosis and immune dysregulation in cutaneous cGVHD under hypoxic conditions, nominating it as a novel target for intervention.To block the PI3K signaling pathway, we first tested Duvelisib, a dual inhibitor of PI3Kg and PI3Kd isoforms, and the PI3Kδ inhibitor Parsaclisib in the multiple murine cGVHD model...Besides, our results HIF1α inhibition effectively protected mice from cGVHD skin pathology, while Dapagliflozin increased HIF1α expression and thus exacerbated the condition... We used a comprehensive systems biology approach, combining spatial transcriptomics, single-cell RNA sequencing, and ultra-multiplex immunofluorescence, to investigate the mechanisms underlying cutaneous cGVHD in both human samples and murine models. Our data reveal a hypoxia-enriched gene signature in cGVHD skin and highlight aberrant macrophage-epidermal crosstalk orchestrated by elevated IL-13 under hypoxic..."

Stroma • Alopecia • Chronic Graft versus Host Disease • Dermatopathology • Fibrosis • Graft versus Host Disease • Immunology • Inflammation • HIF1A • IL13 • IL13RA2 • PIK3CD

A long-lasting PI3Kδ inhibitor zandelisib forms a water-shielded hydrogen bond with p110δ and demonstrates sustained inhibitory effects. (PubMed, Am J Cancer Res) - "The binding kinetics of zandelisib, parsaclisib, idelalisib, and duvelisib to PI3Kδ were evaluated using surface plasmon resonance (SPR) analysis with the BiacoreTM system, and their binding in living cells was confirmed using the NanoBRETTM TE Intracellular Kinase Assay system. The crystal structure of PI3Kδ in complex with zandelisib was determined at 2.5 Å resolution, revealing the benzimidazole group in zandelisib formed a hydrogen bond to the side chain of Lys779 in p110δ, the catalytic subunit of PI3Kδ. These studies demonstrated a longer duration of action of zandelisib compared to the other compounds, which was attributable to the hydrogen bond between zandelisib and Lys779 in p110δ."

Journal • B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • PIK3CD

PI3Kδ Inhibitor Parsaclisib in Japanese Patients With Relapsed or Refractory Follicular Lymphoma. (PubMed, Cancer Sci) - P2 | "In conclusion, parsaclisib monotherapy demonstrated durable responses with a manageable safety profile in Japanese patients with R/R FL. Trial Registration: ClinicalTrials.gov, NCT04434937."

Journal • Bone Marrow Transplantation • Dental Disorders • Follicular Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Stomatitis • Transplantation • PIK3CD

PI3Kδ Inhibitor Parsaclisib Combined with Chidamide for the Treatment of Relapsed/Refractory Peripheral T-cell Lymphoma (clinicaltrials.gov) - P1/2 | N=12 | Terminated | Sponsor: Henan Cancer Hospital | N=28 ➔ 12 | Trial completion date: Jan 2027 ➔ Feb 2025 | Recruiting ➔ Terminated; The clinical development of parsaclisib was stopped by it's manufacturer.

Enrollment change • Trial completion date • Trial termination • Hematological Malignancies • Hepatosplenic T-cell Lymphoma • Lymphoma • Natural Killer/T-cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • ALK

CITADEL-205: A Study of INCB050465 in Relapsed or Refractory Mantle Cell Lymphoma Previously Treated With or Without a Bruton's Tyrosine Kinase (BTK) Inhibitor (clinicaltrials.gov) - P2 | N=162 | Completed | Sponsor: Incyte Corporation | Trial primary completion date: Mar 2021 ➔ Apr 2024

Trial primary completion date • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology

Romidepsin and Parsaclisib for the Treatment of Relapsed or Refractory T-Cell Lymphomas (clinicaltrials.gov) - P1 | N=5 | Completed | Sponsor: Walter Hanel | Active, not recruiting ➔ Completed

Trial completion • Cutaneous T-cell Lymphoma • Dermatology • Hematological Malignancies • Lymphoma • Mycosis Fungoides • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • TNFRSF8

To Evaluate the Efficacy and Safety of Parsaclisib and Ruxolitinib in Participants With Myelofibrosis (LIMBER-313) (clinicaltrials.gov) - P3 | N=252 | Terminated | Sponsor: Incyte Corporation | Active, not recruiting ➔ Terminated; The study was terminated due to futility.

Trial termination • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Thrombocytosis