bosmolisib (BR101801) / Boryung Group - LARVOL DELTA

Dual PI3Kδ/γ inhibition enhances radiotherapy-induced antitumor immunity via macrophage-dependent cGAS-STING-type I interferon signaling. (PubMed, Biochem Biophys Res Commun) - "In the syngeneic CT26 model, dual PI3Kδ/γ inhibition (BR101801 or duvelisib), unlike selective PI3Kδ inhibition (idelalisib), synergized with RT (7.5 Gy) to suppress tumor growth and induce durable immune memory. Furthermore, blockade of the IFN-I receptor abolished CD8+ T cell infiltration and M2-like macrophage suppression, abrogating antitumor efficacy and confirming the requirement for IFN-I signaling. These findings identify macrophage-driven activation of the cGAS-STING-IFN-I axis as a key mechanism by which dual PI3Kδ/γ inhibition potentiates RT, providing a strong scientific rationale for its development as an immunomodulatory radiosensitizer."

Journal • Colorectal Cancer • Oncology • Solid Tumor • CD8 • CGAS • CXCL10 • PIK3CD • PIK3CG • STING

A Novel PI3K γ/δ and DNA-PK Triple Inhibitor, BR101801, for r/r PTCL: A Phase 1a/b, Multi-Center, Open-Label Clinical Trial (ASH 2023) - P1 | "Preliminary results showed the ORR of 31.6% and a CR rate of 21.1%. Phase 2 study is warranted further investigate the safety and efficacy of BR101801 in r/r PTCL and Nodal TFH cell lymphoma at 200 mg QD orally."

Clinical • P1 data • Cough • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Oncology • Peripheral T-cell Lymphoma • Respiratory Diseases • MYC • PIK3CG

A Study of Bosmolisib (BR101801) in Participants With R/R PTCL. (clinicaltrials.gov) - P2 | N=44 | Not yet recruiting | Sponsor: Boryung Pharmaceutical Co., Ltd

Monotherapy • New P2 trial • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

BR-101801-CT-101: BR101801 in Adult Patients With Advanced Hematologic Malignancies(Phase I) (clinicaltrials.gov) - P1 | N=26 | Completed | Sponsor: Boryung Pharmaceutical Co., Ltd | Active, not recruiting ➔ Completed

Trial completion • B Cell Lymphoma • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Waldenstrom Macroglobulinemia

Radiotherapy, in conjunction with a PI3Kδ/γ inhibitor, enhances effector CD8+ T cell-mediated anti-tumor immune responses and the memory function of T cells within the tumor microenvironment by stimulating innate immunity (ESMO-IO 2024) - "However, the isolated inhibition of either PI3Kδ or γ is insufficient for the complete eradication of solid tumors.Methods We utilized BR101801, a PI3Kδ/γ inhibitor, in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor...We checked if IFNAR1 antibody administration negated the combined treatment's anticancer activity, and the result showed that only the monotherapy's effect was seen. The previously established CD8 T cell infiltration did not occur, and PMN-MDSC's immunosuppressive impact was eliminated.Conclusions Preclinical data indicates that PI3Kδ/γ suppression and irradiation can enhance systemic antitumor immunity against solid tumors, suggesting its potential as an immune-regulatory radiosensitizer."

Biomarker • Tumor microenvironment • Oncology • Solid Tumor • BATF3 • CD8 • IFNAR1 • PIK3CD

Boryung, green light to achieve KRW 1 trillion in sales this year...Effect of expansion of items such as new drug K-Cap 'knock knock' [Google translation] (consumernews.co.kr) - "Additionally, in the anti-cancer field, we are operating 12 pipelines, including the candidate substance discovery process. Among these, 'BR101801', a treatment for peripheral T-cell lymphoma, has already been designated as an orphan drug by the U.S. Food and Drug Administration (FDA) in 2022 and can receive conditional approval after completing phase 2. Boryung plans to submit a phase 2 plan this year."

New P2 trial • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma

BR-101801-CT-101: BR101801 in Adult Patients With Advanced Hematologic Malignancies( Phase I) (clinicaltrials.gov) - P1 | N=30 | Active, not recruiting | Sponsor: Boryung Pharmaceutical Co., Ltd | Recruiting ➔ Active, not recruiting

Enrollment closed • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Waldenstrom Macroglobulinemia

BR101801 enhances the radiosensitivity of p53-deficient colorectal cancer cells by inducing G2/M arrest, apoptosis, and senescence in a p53-independent manner. (PubMed, Am J Cancer Res) - "Moreover, BR101801 exerted robust synergistic effects on IR-induced cell cycle arrest, apoptosis, and tumor growth inhibition, even in radioresistant HCT116 p53 cells. Overall, these findings provide a scientific rationale for combining BR101801 with IR as a new therapeutic strategy to overcome radioresistance induced by p53 deficiency."

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

Boryung’s cancer drug gets 'developmental orphan drug' designation (Korea Biomedical Review) - "Boryung, formerly Boryung Pharmaceutical, said Monday that its new anticancer drug, BR101801, has been designated as a developmental orphan drug by the Korean Ministry of Food and Drug Safety. The designation was made to address the unmet medical needs of peripheral T-cell lymphoma (PTCL), a rare cancer....BR101801 is a first-in-class anticancer drug that inhibits the three key growth regulators of cancer cells - PI3K gamma (γ), PI3K delta (δ), and DNA-PK- simultaneously and is being developed for relapsed or refractory PTCL after treatment....Boryung is conducting a phase 1b trial of BR101801 in relapsed or refractory patients for completion later this year."

Non-US regulatory • Trial completion date • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

A phase 1a/b study of BR101801, a PI3K γ/δ and DNA PK triple inhibitor, in adult patients with advanced hematologic malignancies. (ASCO 2023) - P1 | "The results for the phase 1a study evaluated the safety, efficacy results and pharmacokinetic characteristics, 200 mg QD was shown to provide target exposure for clinical efficacy with the tolerable and safe profile. BR101801 showed of antitumor activity, especially in R/R PTCL patients. Hence, the phase 1b study of BR101801 is warranted in R/R PTCL patients and we expect BR101801 would become a promising therapeutic option for these patients."

Clinical • Metastases • P1 data • Chronic Lymphocytic Leukemia • Dermatology • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • MYC • PIK3CG

An oral triple inhibitor of PI3Kδ/γ and DNA-PK elicits anticancer immunity and potentiates therapeutic efficacy of immune checkpoint blockade (AACR 2023) - "Our study demonstrates that BR101801, an oral triple inhibitor of PI3Kδ/γ and DNA-PK, effectively elicited anticancer immune responses within the TME and potently inhibited tumor progression in combination with immune checkpoint blockade."

Checkpoint block • Checkpoint inhibition • Clinical • IO biomarker • Colon Cancer • Gastrointestinal Cancer • Oncology • CD4 • CD8 • FOXP3 • IL2RA • PIK3CD • PIK3CG

A Phase 1a Study of BR101801; PI3Kγδ and DNA PK Triple Inhibitor; in Adult Patients with Advanced Hematologic Malignancies (ICKSH 2023) - "In phase 1a clinical study; 200mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 showed signs of preliminary activity; especially in relapsed or refractory(R/R) PTCL patients. Hence we expect BR101801 would become a promising therapeutic option for R/R PTCL patients."

Clinical • Metastases • P1 data • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • MYC • PIK3CG

A combination of BR101801 and venetoclax enhances antitumor effect in DLBCL cells via c-Myc/Bcl-2/Mcl-1 triple targeting. (PubMed, Am J Cancer Res) - "Double hit diffuse large B-cell lymphoma (DLBCL) with rearrangement and overexpression of both c-Myc and Bcl-2 responds poorly to standard R-CHOP therapy. Furthermore, BR101801 exhibited a significant synergistic antitumor effect even in late xenograft models when combined with Venetoclax. Our data strongly suggest that c-Myc/Bcl-2/Mcl-1 triple targeting through a combination of BR101801 and Venetoclax could be a potential clinical option for double-hit DLBCL."

IO biomarker • Journal • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • ANXA5 • BCL2 • MYC

BR101801 in Adult Patients With Advanced Hematologic Malignancies( Phase I) (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Boryung Pharmaceutical Co., Ltd | N=90 ➔ 30

Enrollment change • Metastases • Chronic Lymphocytic Leukemia • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Lymphoplasmacytic Lymphoma • Marginal Zone Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma • Waldenstrom Macroglobulinemia

A Phase 1 Dose Escalation Study of Dual PI3K and DNA PK Inhibitor, BR101801 in Adult Patients with Advanced Hematologic Malignancies (ASH 2021) - P1 | "200 mg QD of BR101801 was shown to provide target exposure for clinical efficacy with the tolerable and safe profiles. BR101801 was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory hematologic malignancies. The phase Ib/II study of BR101801 is warranted in relapsed/refractory NHL."

Clinical • P1 data • Cutaneous T-cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Disorders • Hematological Malignancies • Hepatology • Oncology • Thrombocytopenia • MYC • PIK3CG

FDA assigns Boryung’s new anticancer candidate as orphan drug (Korea Biomedical Review) - "Boryung said on Wednesday that its new anticancer drug candidate, BR101801, for treating peripheral T cell lymphoma (PTCL) has been designated as an orphan drug by the U.S. Food and Drug Administration (FDA)....BR101801 is a first-in-class lymphoma treatment substance that simultaneously triples the main growth and regulators of cancer cells namely, phosphatidylinositol-3-kinases like PI3K gamma (γ) and PI3K delta (δ), as well as in DNA-dependent protein kinases like DNA-PK."

Orphan drug • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Peripheral T-cell Lymphoma • T Cell Non-Hodgkin Lymphoma

PI3Kδ/γ inhibitor BR101801 extrinsically potentiates effector CD8 T cell-dependent antitumor immunity and abscopal effect after local irradiation. (PubMed, J Immunother Cancer) - "Our data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer."

Journal • Immunology • Oncology • Solid Tumor • PIK3CD

Synergistic radiosensitizing effect of BR101801, a specific DNA-dependent protein kinase inhibitor, in various human solid cancer cells and xenografts. (PubMed, Am J Cancer Res) - "In addition, combination BR101801 and IR suppressed tumor growth compared with IR alone by reducing phosphorylation of DNA-PK in human solid cancer xenografts. Our findings suggested that BR101801 is a selective DNA-PK inhibitor with a synergistic radiosensitizing effect in human solid cancers, providing evidence for clinical applications."

Journal • Oncology • Solid Tumor • BRCA2

BR101801 stimulates anti-tumor immunity and enhances the efficacy of radiation in a syngeneic model (SITC 2021) - "Conclusions BR101801 demonstrated an anticancer immune effect by changing the tumor microenvironment and showed synergistic effects with radiation combination therapy. We will confirm the anticancer immunity effect in ongoing clinical trials."

Clinical • Breast Cancer • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CD8 • PIK3CG

[VIRTUAL] Combination of BR101801 and Radiation Demonstrates Synergistic Activity in Solid tumors (EACR 2021) - "Introduction The DNA-dependent protein kinase (DNA-PK) plays a critical role in the overall survival and proliferation of cells. The in vivo efficacy of the combination with IR or doxorubicin was assessed in MDA-MB-231 models. Conclusion These data indicate that DNA-PK might be an effective target for chemo- and radio-potentiation in cancer cell lines and suggest that a clear rationale of DNA-PK inhibitors for clinical investigation."

Oncology • Solid Tumor • PIK3CG

[VIRTUAL] Combination of BR101801 and Radiation Demonstrates Synergistic Activity in Solid tumors (EACR 2021) - "Introduction The DNA-dependent protein kinase (DNA-PK) plays a critical role in the overall survival and proliferation of cells. The in vivo efficacy of the combination with IR or doxorubicin was assessed in MDA-MB-231 models. Conclusion These data indicate that DNA-PK might be an effective target for chemo- and radio-potentiation in cancer cell lines and suggest that a clear rationale of DNA-PK inhibitors for clinical investigation."

Oncology • Solid Tumor • PIK3CG

[VIRTUAL] Combination of BR101801 and Radiation Demonstrates Synergistic Activity in Solid tumors (EACR 2021) - "Introduction The DNA-dependent protein kinase (DNA-PK) plays a critical role in the overall survival and proliferation of cells. The in vivo efficacy of the combination with IR or doxorubicin was assessed in MDA-MB-231 models. Conclusion These data indicate that DNA-PK might be an effective target for chemo- and radio-potentiation in cancer cell lines and suggest that a clear rationale of DNA-PK inhibitors for clinical investigation."

Oncology • Solid Tumor • PIK3CG

[VIRTUAL] Combination of BR101801 and Radiation Demonstrates Synergistic Activity in Solid tumors (EACR 2021) - "Introduction The DNA-dependent protein kinase (DNA-PK) plays a critical role in the overall survival and proliferation of cells. The in vivo efficacy of the combination with IR or doxorubicin was assessed in MDA-MB-231 models. Conclusion These data indicate that DNA-PK might be an effective target for chemo- and radio-potentiation in cancer cell lines and suggest that a clear rationale of DNA-PK inhibitors for clinical investigation."

Oncology • Solid Tumor • PIK3CG

[VIRTUAL] BR101801: A first-in-class triple-inhibitor of PI3K gamma/delta and DNA-PK targeting non-Hodgkin's lymphoma (AACR-II 2020) - "A tumor mouse xenograft model was established by subcutaneously implanting human derived B-cell lymphoma cell line, SU-DHL-10 (Bendamustine, Rituximab) or DOHH-2 (Venetoclax) into female SCID mice. In vitro selectivity and target potency of BR101801 on different PI3K subtypes including DNA-PK were studied in cell-free systems in which the biochemical IC50 values of BR101801 for PI3K-α, -β, -γ, -δ and DNA-PK were 106 nM, 171 nM, 15 nM, 2 nM and 6 nM, respectively. BR101801 is a first-in-class triple inhibitor of PI3K γ/δ and DNA-PK, and has shown highly potent effects to block cellular proliferation of NHL cell lines including both the indolent and aggressive subtypes. Therefore, the strategy of triple targeting against PI3K γ/δ and DNA-PK suggests rationale for BR101801 as innovative therapeutics for NHL patients."

Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • MYC • PARP1 • PIK3CG

[VIRTUAL] BR101801: A potent and selective inhibitor of DNA-PK, potentiates the activity of topoisomerase II inhibitor in vitro and causes tumor inhibition in cancer models (AACR-II 2020) - "These data confirm that DNA-PK inhibition of BR101801 enhanced the efficacy of rage of DSB inducing agent in vitro and in vivo, providing a clear rationale for its clinical use."

Preclinical • Colon Cancer • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • AGER