eganelisib (IPI-549) / Infinity Pharma - LARVOL DELTA

Defining a Targetable Leukemia Intrinsic Dependency on Noncanonical PI3Kgamma Signaling (ASH 2023) - "We conclude that inflammatory signaling-activated PIK3R5 is a biomarker for sensitivity to PI3Kγ inhibition via an unappreciated PI3Kγ-PAK1 axis. Synergy with cytarabine unmasked eganelisib sensitivity in additional leukemias, expanding the therapeutic potential of targeting PI3Kγ."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Skin Cancer • Solid Tumor • Targeted Protein Degradation • PIK3CG • SPI1

Inhibition of PI3Kγ/δ Signaling Promotes an Early Memory State in CAR T Cells and Enhances Their In Vivo Persistence and Efficacy (ASH 2024) - "We screened a library of FDA-approved drugs for those capable of enhancing TSCM in CAR T cell products and identified the PI3K gamma/delta (γ/δ) inhibitor, duvelisib (Duv), as the lead compound warranting investigation...Selective PI3Kδ inhibition with idelalisib similarly increased proportions of TSCM CAR T cells (p<0.01), while selective PI3Kγ inhibition (eganelisib) did not (p=0.48), suggesting the predominant effect of PI3Kγ/δ inhibition with Duv is mediated through PI3Kδ...Pharmacological manipulation of CAR T cells offers a safe, affordable, and rapid approach to improve CAR T cell therapy efficacy. This work provides the rationale for early phase clinical trials of Duv-treated CAR T cells for pts with R/R DLBCL."

CAR T-Cell Therapy • Preclinical • B Cell Lymphoma • B Cell Non-Hodgkin Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CCR7 • CD8 • IFNG • PIK3CD • PIK3CG • TCF7 • TNFA

A Phase 1b Open-Label Study to Evaluate the Safety and Tolerability of Eganelisib As Monotherapy and in Combination with Cytarabine in Patients with Relapsed/Refractory Acute Myeloid Leukemia (ASH 2024) - P1 | "Dose levels will be considered for escalation until the RDE is reached.Once the RDE of eganelisib as monotherapy and in combination with cytarabine is established, an OPT part will be initiated. All patient data from the DE part will be combined with the data from the corresponding doses at the OPT part to select the Recommended Phase 2 Dose that will be studied further.Primary endpoints are safety, tolerability, determining the RDE, and evaluating the preliminary clinical activity of eganelisib administered as monotherapy and in combination with cytarabine."

Clinical • Combination therapy • Monotherapy • P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Acute Promyelocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Solid Tumor • CDKN1A • PAK1 • PIK3CA • PIK3CB • PIK3CD • PIK3CG • RAC1

Immunomodulatory microbubbles targeting integrin αvβ3 in combination with immunotherapy for the theranostic of anaplastic thyroid cancer in mice. (PubMed, J Control Release) - "UTMD mediated delivery using IPI549@αIMBs combined with anti-PD1 therapy markedly inhibited subcutaneous ATC tumor growth in mice, effectively reduced the proportion of M2-like tumor associated macrophage, and increased CD8+ T cell infiltration, which alleviated the tumor immunosuppressive state. In summary, this study explored a novel therapeutic strategy for ATC, demonstrating the efficacy of the IPI549@αIMB-based UTMD approach combined with anti-PD1 therapy and validating the underlying immunomodulatory mechanisms."

Journal • Preclinical • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • CD8 • PIK3CG

Harnessing the CD16-PI3Kγ axis in peritoneal CD14hi macrophages: A transformative approach to endometriosis management. (PubMed, Int J Biol Macromol) - "Pharmacologically targeting CD16 downstream signaling, PI3Kγ inhibition via IPI-549 attenuated ESC-induced differentiation of both CD14hi and CD14low macrophages in vitro, ultimately ameliorating pathological conditions in WH-EMS mice. This cumulative evidence indicates that CD14hi macrophages promote EMS progression through CD16-dependent mechanisms. Consequently, therapeutic targeting of CD16 or its downstream effectors (e.g., PI3Kγ) represents a promising strategy for clinical EMS management."

Journal • Endometriosis • Gynecology • Women's Health • CD14 • CD80 • IL4 • PIK3CG

IPI-549 in Patients With Locally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=16 | Completed | Sponsor: Assuntina G. Sacco, MD | Recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A PHASE 1B OPEN-LABEL STUDY TO EVALUATE THE SAFETY AND TOLERABILITY OF EGANELISIB AS MONOTHERAPY AND IN COMBINATION WITH CYTARABINE IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (EHA 2025) - P1 | "Importantly, knock-out of PI3K-γ or its regulatory protein encoded by PIK3R, reversed resistance to venetoclax, indicating its potential importance in combination regimens. All patient data from the DE part will be combined with the data from the corresponding doses at the OPT part to select the Recommended Phase 2 Dose that will be studied further.Primary endpoints are safety, tolerability, determining the RDE, and evaluating the preliminary clinical activity of eganelisib administered as monotherapy and in combination with cytarabine. The pharmacokinetics and pharmacodynamics of eganelisib administration will be characterized."

Clinical • Combination therapy • Monotherapy • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • PAK1 • PIK3CG • RAC1

TRPM2 deficiency contributes to M2b macrophage polarization via the PI3K/AKT/CREB pathway in murine sepsis. (PubMed, Innate Immun) - "The 7-day mortality rate was 92% in trpm2-/- mice, compared to 42% in IPI549-pretreated trpm2-/- mice. Moreover, IPI549-treated mice exhibited improved lung wet/dry ratios, reduced lung and liver injury scores, reversed M2b polarization and decreased bacterial load.ConclusionThe PI3K/AKT/CREB pathway mediates the effect of TRPM2 by inhibiting M2b macrophage polarization and promoting bacterial clearance during sepsis."

Journal • Preclinical • Hepatology • Infectious Disease • Liver Failure • Septic Shock

Hybrid Nanocarrier Delivers Immuno-Photothermal Therapy to Modulate Pancreatic Tumor Microenvironment. (PubMed, ACS Appl Bio Mater) - "Additionally, we showed that macrophages exposed to the nanoparticles exhibited sustained antitumor activity when repeatedly put in contact with cancer cells, confirming the long-term efficacy of the treatment. This study highlights the potential of the present polymer-metal hybrid nanoparticles as a versatile platform for combined immuno- and photothermal therapy in PDAC."

Biomarker • Journal • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • PIK3CG

Eganelisib as Monotherapy and in Combination With Cytarabine in Relapsed/Refractory AML (clinicaltrials.gov) - P1 | N=125 | Recruiting | Sponsor: Stelexis BioSciences | Not yet recruiting ➔ Recruiting | Initiation date: Jan 2025 ➔ Apr 2025

Enrollment open • Monotherapy • Trial initiation date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Engineering pH-Responsive Bioscaffolds for Disrupting Myeloid Cell-Driven Immunosuppressive Niche to Enhance PD-L1 Blockade-Based Post-Neoadjuvant Immunotherapy (IGCC 2025) - "Methodology The hydrogel (aPDL1&IPI549@Gel) was designed to co-deliver IPI549, a myeloid cell-targeting agent, and an anti-PD-L1 antibody (aPDL1)...Conclusion This study introduces a novel NAC-optimized immunotherapy platform leveraging a pH-responsive hydrogel scaffold to disrupt immunosuppressive TMEs and improve GC outcomes. It offers a promising strategy for post-NAC cancer management and recurrence prevention."

Clinical • Gastric Cancer • Oncology • Solid Tumor

Highly selective and oral bioavailable PI3Kγ inhibitor for cancer immunotherapy by targeting myeloid-derived suppressor cells in tumor (AACR 2025) - "The lead PI3Kγ inhibitors were further evaluated in vivo using MC38 colon cancer model and MMTV-PyMT breast cancer model, in both monotherapy (p.o.) and combination therapy with paclitaxel (PTX) or anti-PD-1 antibody (aPD-1). The PI3Kγ inhibitors SH-315 and SH-327 demonstrated superior anti-tumor efficacy compared to IPI-549. Treatment with SH-315 and SH-327 reduced immunosuppressive MDSCs and increased cytotoxic CD8+ T cell activity, highlighting their potential to drive anti-tumor responses through targeted immune modulation and supporting their further development for cancer immunotherapy."

IO biomarker • Myeloid-derived suppressor cells • Breast Cancer • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • CD8 • ITGAM • PIK3CA • PIK3CB • PIK3CD • PIK3CG

Janus Silica Nanoparticle Based Tumor Microenvironment Modulator for Restoring Tumor Sensitivity to PD-L1 Immune Checkpoint Blockade Therapy (APASL 2025) - "The IUIPC we developed can release IPI549 in the tumor's mildly acidic microenvironment, where it targets MDSCs, reducing their levels along with Tregs in the TME. Under the high-concentration GSH conditions within tumor cells, the CXCL9 gene is released, allowing tumor cells to continuously secrete the chemokine CXCL9 into the surrounding TME, thereby recruiting CD8+ T cells and NK cells to infiltrate the tumor. Compared to the use of PD-L1 antibody alone, the combination of IUIPC with PD-L1 antibody more effectively eliminates the primary tumor, inhibits distal tumor growth, and prevents tumor recurrence."

Biomarker • Checkpoint block • Checkpoint inhibition • Tumor microenvironment • Hepatology • Liver Cancer • Oncology • Solid Tumor • CD8 • CXCL9

The Role of PI3k-Gamma Modulation in Bacterial Infection: A Review of the Literature and Selected Experimental Observations. (PubMed, Antibiotics (Basel)) - " We observed that knockout of PI3kγ in murine macrophages alongside pharmacological inhibition through IPI549 treatment in THP-1 cells led to an NF-κB-driven suppression in transcription and release of inflammatory cytokines upon infection with methicillin-resistant Staphylococcus aureus. We were also able to confirm that this suppression of NF-κB translocation and subsequent decrease in inflammatory cytokine release did not compromise and even slightly boosted the bacterial killing ability. PI3k is primarily targeted for cancer therapies, but further exploration can also be carried out on its potential roles in treating bacterial infection."

Journal • Review • Infectious Disease • Oncology • PIK3CG

Macrophage-targeting combination therapy enhances T-DXd-induced tumor regression. (PubMed, Int Immunopharmacol) - "Our results demonstrated that the combination of T-DXd, anti-SIRPα, and IPI-549 significantly inhibited tumor growth compared to monotherapies, with no major weight loss, indicating a favorable tolerability profile. Importantly, previously treated mice developed durable immunological memory, completely rejecting subsequent challenges with HER2-expressing tumors. Overall, these findings highlight the therapeutic potential of combining T-DXd with macrophage-targeting strategies as a robust approach to improve the efficacy of immunotherapy in HER2-positive cancers, presenting a promising avenue for clinical development."

Journal • Oncology • HER-2 • PIK3CG • SIRPA

STING agonists and PI3Kγ inhibitor co-loaded ferric ion-punicalagin networks for comprehensive cancer therapy. (PubMed, Int J Biol Macromol) - "The therapeutic effect of various nanohybrids were validated in the mice with spontaneous tumor in the colorectal area and tumor-bearing mice, which lead to the increase of ferroptosis, the activation of STING signaling pathway, and the repolarization of macrophages. Collectively, the cGAMP and IPI-549 co-loaded nanohybrids effectively reshaped the tumor immune microenvironment, and exhibited prominent treatment effect of anti-colorectal cancer in vitro, patient-derived organoids, and in vivo."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • PIK3CG

Eganelisib combined with immune checkpoint inhibitor therapy and chemotherapy in frontline metastatic triple-negative breast cancer triggers macrophage reprogramming, immune activation and extracellular matrix reorganization in the tumor microenvironment. (PubMed, J Immunother Cancer) - P1, P2 | "This is the first report of translational analyses including paired tumor biopsies from a phase 2 clinical study of the first-in-class PI3K-γ inhibitor eganelisib in combination with atezolizumab and nab-paclitaxel in frontline mTNBC. These results support the mechanism of action of eganelisib as a TAM-reprogramming immunotherapy and support the rationale for combining eganelisib with ICI and chemotherapy in indications with TAM-driven resistance to ICI."

Biomarker • Checkpoint inhibition • IO biomarker • Journal • Metastases • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PIK3CG

Eganelisib as Monotherapy and in Combination With Cytarabine in Relapsed/Refractory AML (clinicaltrials.gov) - P1 | N=125 | Not yet recruiting | Sponsor: Stelexis BioSciences

Combination therapy • Monotherapy • New P1 trial • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

Targeting PI3K-gamma in myeloid driven tumour immune suppression: a systematic review and meta-analysis of the preclinical literature. (PubMed, Cancer Immunol Immunother) - "The predominant PI3Kγ inhibitors were IPI-549 and TG100-115, demonstrating favourable specificity for the gamma isoform. The combination of PI3Kγ inhibition with other therapeutic modalities demonstrated enhanced antitumour effects, suggesting a synergistic approach to overcome immune suppression. These findings support the potential of PI3Kγ-targeted therapies, particularly in combination regimens, as a promising avenue for future clinical exploration in diverse solid tumour types."

Clinical • Journal • Preclinical • Retrospective data • Review • Gastric Cancer • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • PIK3CG

PI3Kγ inhibition circumvents inflammation and vascular leak in SARS-CoV-2 and other infections. (PubMed, Sci Transl Med) - "PI3Kγ deletion and inhibition with the clinical PI3Kγ inhibitor eganelisib promoted survival in models of infectious diseases, including SARS-CoV-2 and MRSA, by suppressing inflammation, vascular leak, organ damage, and cytokine storm. These results demonstrate essential roles for PI3Kγ in inflammatory lung disease and support the potential use of PI3Kγ inhibitors to suppress inflammation in severe infectious diseases."

Journal • Fibrosis • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • PIK3CG

PI3K signaling controls metabolic adaptations in pancreatic cancer (EACR 2024) - "Under gemcitabin chemotherapeutic regimen, PI3Klow PDAC cells were less flexible than PI3Khigh PDAC cells. In vitro and in vivo, pancreatic tumour cells treated with the combination of BYL-719 and IPI-549 were more sensitive to the combination of gemcitabine + metabolic modulators (CPI-613, a lipoic acid analogue that blocks the activity of α-KG and PDH.Conclusion Inhibiting PI3Ks is a proposed way to force pancreatic cancer tumour cells into a metabolism state sensitive to combinations of chemotherapy drugs and metabolic inhibitors."

Gastrointestinal Cancer • Hepatology • Metabolic Disorders • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • KRAS • PIK3CA • PIK3CG

Electrically activated polymetallic nanocrystals for long-term tumor suppression via oxygen-independent ROS generation and electro-immunotherapy. (PubMed, J Control Release) - "Additionally, the immunomodulatory effects of IPI549, in synergy with the immunogenic cell death (ICD) induced by EDT, reversed the immunosuppressive microenvironment contributing to tumor resistance. In summary, EDT transiently killed tumor cells while simultaneously generating antigen release, instigating an adaptive immune response for electro-immunotherapy, resulting in a potent and long-lasting tumor inhibition effect."

Journal • Oncology

Targetable leukaemia dependency on noncanonical PI3Kγ signalling. (PubMed, Nature) - "In addition, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukaemia xenografts with low baseline PIK3R5 expression, as residual leukaemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Together, our study reveals a targetable dependency on PI3Kγ-PAK1 signalling that is amenable to near-term evaluation in patients with acute leukaemia."

Journal • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CDKN1A • PAK1 • PIK3CG • RAC1

Oral administration of IPI549 protects mice from neuropathology and an overwhelming inflammatory response during experimental cerebral malaria. (PubMed, Int J Parasitol Drugs Drug Resist) - "Treating the infected mice with IPI549 three days after parasite inoculation improved the murine blood brain barrier (BBB) integrity and helped the mice pass the onset of ECM. Together, these data indicate that oral administration of the PI3Kγ inhibitor IPI549 has a suppressive role in host inflammation and alleviates cerebral pathology, which supports IPI549 as a new malaria treatment option with potential therapeutic implications for cerebral malaria."

Journal • Preclinical • Infectious Disease • Inflammation • Malaria • PIK3CG

OPM-116, a highly potent and specific PI3Kγ inhibitor to enhance antitumor immunity (AACR 2024) - "Tumor-associated macrophages are an integral part of the tumor microenvironment. Mario-3 phase II study safety run-in evaluating a novel triplet combination of eganelisib, atezolizumab, and nab-paclitaxel as first-line therapy for locally advanced or metastatic TNBC. AACR, Cancer Res 2021."

IO biomarker • Oncology • Triple Negative Breast Cancer • IL4 • PD-L1 • PIK3CG