lanraplenib (GS-9876) / Gilead, Lakefront Biotherapeutics, Ignota Labs - LARVOL DELTA

Platelet SYK promotes solid tumor metastasis via TXA2-mediated immunosuppression. (PubMed, J Thromb Haemost) - "Taken together, our results indicate, that SYK in platelets promotes solid tumor metastasis and tumor immunosuppression. Secretion of TXA2 by platelets is SYK-dependent and can be inhibited by SYK-selective inhibitors, which release anti-tumor CD8+ T cells from TXA2-mediated suppression."

Journal • Colorectal Adenocarcinoma • Colorectal Cancer • Gastrointestinal Disorder • Melanoma • Oncology • Solid Tumor • CD8 • SYK

FC-GAMMA-RIIA-MEDIATED PROCOAGULANT PLATELETS ARE IMPORTANT DRIVERS OF IMMUNOTHROMBOSIS IN APS (EHA 2026) - "Importantly, and of potential therapeutic interest, APS AAb-induced procoagulant PLT as well as immunothrombosis were significantly abrogated in the presence of intravenous immunoglobulin (IVIG) or Lanraplenib. . Summary/Conclusion Our studies indicate that a subgroup of APS patient AAbs induce the formation of a procoagulant PLT phenotype with dramatic prothrombotic potential in a PLT Fc γ RIIA-dependent manner .The observation that the presence of IVIG or SYK inhibitor Lanraplenib rescued from APS AAb-mediated procoagulant PLT and increased thrombus formation directs towards a therapeutic potential of such Fc-gamma-receptor-targeting therapeutics to prevent the onset of thromboembolic events in APS."

Cardiovascular • Genetic Disorders • Hematological Disorders • Immunology • Obstetrics • Thrombosis • FCGR2A • SELP • SYK

Design, synthesis and biological evaluation of novel imidazo[1,2-a]pyrazine derivatives as potent SYK inhibitors for solid tumor therapy. (PubMed, Bioorg Chem) - "In vivo studies using a SKOV3 xenograft model demonstrated that B13 significantly inhibited tumor growth in a dose-dependent manner, with tumor inhibition rates of 58.62% and 66.97% at 30 and 60 mg/kg, respectively, better than Lanraplenib, while showing no obvious toxicity. Collectively, these findings identify B13 as a promising SYK inhibitor and provide valuable insights for the further development of SYK targeted therapeutics for solid tumors."

Journal • Oncology • Solid Tumor • SYK

Developing agents to target IL-8 signaling and intercept progression to esophageal adenocarcinoma (AACR 2026) - "Proof-of-concept studies conducted in BE.HGD and EAC cell lines showed that a natural product, cranberry proanthocyanidins, as well as the drug lanraplenib, both significantly inhibited IL-8 secretion, followed by potent cell death induction...Thus, we plan to screen the NCI's natural product library for agents that inhibit the IL-8-CXCR-immune signaling axis and that, in turn, may offer efficacious options to intercept BE progression to EAC. This research was supported in part by NCI 1UG3CA299397-01, along with other funding sources."

Esophageal Adenocarcinoma • Oncology • Solid Tumor • CXCL8 • CXCR1 • CXCR2

The Novel Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) Platform Identifies Synergistic Activity of Lanraplenib and Ruxolitinib in Hematological Malignancies (ASH 2023) - P1/2 | "Lanraplenib (LANRA) is a next-generation SYK inhibitor currently being evaluated in combination with gilteritinib, a FLT3 inhibitor, in patients with relapsed or refractory (R/R) FLT3–mutated acute myeloid leukemia (AML) (NCT05028751). These studies demonstrate the utility of PRISM as a platform to rapidly identify rational combination agents. Importantly, LANRA is effective in combination with ruxolitinib in AML and other hematological malignancy preclinical models. This finding is consistent with the observation that SYK can regulate STAT signaling and cooperate with other RTKs like FLT3."

Acute Myelogenous Leukemia • Fibrosis • Hematological Malignancies • Immunology • Leukemia • Oncology • FLT3 • STAT5 • SYK

KB-Lanra 1001: A Phase 1b/2 Study of Safety, PK, PD, and Preliminary Efficacy of the Selective SYK Inhibitor Lanraplenib in Combination with the FLT3 Inhibitor Gilteritinib in FLT3-Mutated R/R AML (ASH 2023) - P1/2 | "Enrollment of additional patients to dose cohort(s) previously cleared for safety and tolerability by the DEC will be allowed under specific conditions. The phase 2 component will further evaluate safety, PK, PD, and anti-leukemic activity of the combination at the LANRA RP2D"

Clinical • Combination therapy • P1/2 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3 • HOXA9 • MEIS1 • SYK

The Combination of Lanraplenib, a Selective SYK Inhibitor, and Gilteritinib, a FLT3 Inhibitor, Targets Aberrant Proliferation and Differentiation Blockade in Acute Myeloid Leukemia (ASH 2023) - P1/2 | "In preclinical models, LANRA demonstrates compelling anti-leukemic activity in combination with gilteritinib. By jointly targeting hyperproliferation and differentiation blockade, LANRA and gilteritinib may provide a new therapeutic approach that can be exploited in AML. Additionally, LANRA disrupts downstream signaling of key pathways often associated with resistance to gilteritinib, providing additional mechanistic support for continued testing of LANRA in combination with gilteritinib in FLT3-ITD-mutated AML patients."

Acute Myelogenous Leukemia • Hematological Malignancies • Immunology • Leukemia • Oncology • ANXA5 • CD14 • FLT3 • ITGAM • STAT3 • SYK

Combined Single Cell Flow Cytometry and Imaging Analyses Reveal Immunomodulatory Effects Exerted By Targeted Phospho-SYK Inhibitors with Elevated Sensitivity in NPM1 Mutated AML (ASH 2023) - P1/2 | "Entospletinib (ENTO) and lanraplenib (LANRA) are inhibitors of spleen tyrosine kinase (SYK); the latter is a next-generation SYK inhibitor and is currently being evaluated in combination with gilteritinib (GILT) in patients with relapsed or refractory FLT3-mutated AML (NCT05028751)...Two different AML patient cohorts were assessed by ex vivo treatment with ENTO, LANRA and combinations of LANRA (trametinib, gilteritinib (GILT), aPD-1) over a range of time points (2h, 4h, 3d and 9d) and readouts for cellular phenotype (e.g., differentiation state, immune cell populations) and functional readouts (pSYK, viability) for each cohort were analyzed by HP-FC and sc-MI and associated with available mutation information (bulk gene and single cell RNA sequencing)...These support studies investigating the use of pSYK inhibitors in combination with other therapies to reduce tumor burden, and as an improved line of treatment for AML. Acknowledgements: We are appreciative of the..."

Immunomodulating • Acute Myelogenous Leukemia • CNS Disorders • Hematological Malignancies • Leukemia • Oncology • Psychiatry • FLT3 • IDH1 • IDH2 • mTOR • MYC • NPM1 • SYK

Ignota Labs...has announced its acquisition of Kronos’s clinical assets, istisociclib, a CDK9 inhibitor, and entospletinib and lanraplenib, SYK inhibitors. (Businesswire) - "Kronos’ valuation peaked at $3.5 billion after its IPO; however, it failed to progress its assets past Phase 2 trials and subsequently ceased operations. Given the challenges relating to safety and clinical positioning, Ignota Labs saw promise in the clinical portfolio and has acquired Kronos’s clinical IP in full."

Commercial • Hematological Malignancies • Immunology • Solid Tumor

Fc-gamma-RIIA-mediated procoagulant platelets are important drivers of immunothrombosis in APS (ISTH 2025) - "Compared to controls, spike in of APS patient serum or corresponding immunoglobulin G (IgG) isolates into healthy whole blood resulted in dramatic formation of immunothrombi that were characterized by high amounts of procoagulant PLTs and high numbers of leukocytes that were recruited to the growing thrombus. Importantly, and of potential therapeutic interest, APS AAb-induced procoagulant PLT as well as immunothrombosis were significantly abrogated in the presence of intravenous immunoglobulin (IVIG) or Lanraplenib."

Cardiovascular • Genetic Disorders • Hematological Disorders • Immunology • Obstetrics • Thrombosis • FCGR2A • SELP • SYK

Anti-PF4-mediated procoagulant platelets play an indispensable role in VITT-mediated immunothrombosis (ISTH 2025) - "While dramatic multicellular thrombus was observed upon spike in of VITT patient IgG into healthy whole blood, no leukocyte recruitment or thrombus could be observed in corresponding PLT-depleted WB samples. Most importantly, and of potential therapeutic relevance, specific inhibiton of PLT spleen tyrosine kinase, an important enzyme in the PLT activating Fc-gamma-RIIA signaling pathway via Lanraplenib resulted in a near complete abrogation of anti-PF4-induced procoagulant PLT and subsequent multicellular thrombus formation ex vivo."

Cardiovascular • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Thrombocytopenia • Thrombosis • FCGR2A • SELP

Platelet antibodies induce distinct platelet and megakaryocyte phenotypes in ITP (ISTH 2025) - "Methods We conducted a comprehensive investigation using multiple approaches: (1) Megakaryocytes differentiated from CD34+ cells were treated with monoclonal antibodies (mAbs) targeting CD41 (GPIIb), CD61 (GPIIIa), CD42a (GPIX), and CD42b (GPIbα); (2) Washed platelets were treated with these mAbs and assessed for various phenotypes including activation, aggregation, procoagulant activity, and apoptosis using flow cytometry; (3) Signaling pathway analysis was performed using specific inhibitors including IV.3 (FcγRIIA-blocking antibody) and Syk inhibitors (Lanraplenib and R406). Notably, the signaling pathways differed between antibody specificities. In the clinical context, 16% of ITP patient sera induced similar patterns of platelet activation, apoptosis, and procoagulant phenotype."

Hematological Disorders • Immune Thrombocytopenic Purpura • Immunology • Thrombocytopenia • Thrombocytopenic Purpura • ANXA5 • CD34 • ITGA2B • ITGB3 • SYK

Kronos Bio Enters into Agreement to Be Acquired by Concentra Biosciences for $0.57 in Cash per Share Plus a Contingent Value Right (The Manila Times) - "Kronos Bio, Inc...announced that it has entered into a definitive merger agreement (the 'Merger Agreement') with Concentra Biosciences, LLC ('Concentra'), whereby Concentra will acquire Kronos Bio for $0.57 in cash per share of Kronos Bio common stock ('Kronos Bio Common Stock'), plus one non-tradeable contingent value right ('CVR'), which represents the right to receive: (i) 50% of the net proceeds in the case of a disposition of the Company's product candidates known as KB-9558 and KB-7898 that occurs within 2 years following closing; (ii) 100% of the net proceeds in the case of a disposition of the Company's product candidates known as KB-0742, lanraplenib and entospletinib that occurs prior to closing..."

M&A • Breast Cancer • Graft versus Host Disease • Lupus • Multiple Myeloma • Non Small Cell Lung Cancer • Non-Hodgkin’s Lymphoma • Ovarian Cancer • Prostate Cancer • Rheumatoid Arthritis

KB-LANRA- 1001: A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants With FLT3-mutated Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P1/2 | N=24 | Terminated | Sponsor: Kronos Bio | Trial completion date: Oct 2024 ➔ Apr 2024 | Active, not recruiting ➔ Terminated; Sponsor decision

Combination therapy • Trial completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

The ABCB1 and ABCG2 efflux transporters limit brain disposition of the SYK inhibitors entospletinib and lanraplenib. (PubMed, Toxicol Appl Pharmacol) - "This transporter-mediated restriction of brain penetration for both drugs could be almost fully inhibited by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, without signs of acute toxicity. This interaction was, however, unlikely to be mediated through any of the studied transporters or CYP3A. The obtained insights may perhaps help to further improve the safety and efficacy of entospletinib and lanraplenib."

Journal • Breast Cancer • CNS Disorders • Hematological Malignancies • Oncology • Solid Tumor • ABCB1 • ABCG2 • CYP3A4 • SYK

Orphan Designation: Treatment of Acute Myeloid Leukemia (AML) (FDA) - Date Designated: 01/29/2024

Orphan drug • Acute Myelogenous Leukemia

Novel Signaling Pathway and NSC689534 as a Potential Drug Candidate for Cutaneous Squamous Cell Carcinoma. (PubMed, Front Biosci (Landmark Ed)) - "NSC689534 might be a candidate drug for cSCC targeting TPX2 and KIF11, which are hub genes in cSCC."

Journal • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CDK1 • KIF11

Platelet Factor 4 Mediates Procoagulant Platelet and Increased Thrombus Formation in Vaccine-IndUced Thrombotic Thrombocytopenia Via Syk Signaling Pathway (GTH 2024) - "Conclusion Taken together, our data indicate that PF4 is the key mediator of anti-PF4 VITT Ab-induced procoagulant PLT and thrombus formation ex vivo . The observation that SYK inhibition in PLTs via Lanraplenib prevents from VITT Ab-mediated prothrombotic conditions directs towards a therapeutic potential of SYK inhibitors in prothrombotic conditions observed in anti-PF4-mediated disorders."

Cardiovascular • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Thrombocytopenia • Thrombosis • FCGR2A • SELP • SYK

KB-LANRA- 1001: A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants With FLT3-mutated Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P1/2 | N=24 | Active, not recruiting | Sponsor: Kronos Bio | Recruiting ➔ Active, not recruiting | Phase classification: P1b/2 ➔ P1/2 | N=100 ➔ 24 | Trial primary completion date: Nov 2023 ➔ May 2024

Combination therapy • Enrollment change • Enrollment closed • Phase classification • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Kronos Bio Announces Pipeline Update and p300 KAT Inhibitor Development Candidate (GlobeNewswire) - "After a review of data from the phase 1b portion of its phase 1b/2 trial of lanraplenib in combination with gilteritinib in FLT3-mutated relapsed/refractory acute myeloid leukemia (AML), the Company has decided not to proceed to phase 2. The Company is open to further development of lanraplenib, a SYK inhibitor, with a partner. Kronos Bio also announced the designation of a new development candidate, KB-9558, which targets the lysine acetyltransferase (KAT) domain of p300, a critical node of the IRF4 transcription regulatory network (TRN). IRF4 is a key driver in multiple myeloma. KB-9558...is currently in IND-enabling studies, which are expected to be completed in the fourth quarter of 2024."

New molecule • Trial status • Acute Myelogenous Leukemia • Multiple Myeloma

Kronos Bio Announces Plan to Optimize Resource Allocation, Restructure and Contain Costs Following Positive Preliminary Clinical Data from its KB-0742 Phase 1/2 Study (GlobeNewswire) - "Kronos Bio...announced a plan to optimize its resource allocation, restructure, and contain costs in light of the positive preliminary safety and efficacy clinical data from its Phase 1/2 study of KB-0742. This plan positions the company to maximize the potential of KB-0742 while continuing to advance the development of lanraplenib, currently in the dose escalation portion of a Phase 1b/2 study. The company will also focus its discovery efforts on maturing projects and its Genentech collaboration activities. Kronos Bio expects that these restructuring efforts, which include a 19% reduction in force, will extend its cash runway into 2026."

Commercial • Acute Myelogenous Leukemia • Oncology • Solid Tumor

Kronos Bio Reports Recent Business Progress and Second-Quarter 2023 Financial Results (GlobeNewswire) - "Lanraplenib is currently in the dose escalation portion of a Phase 1/2 trial in combination with gilteritinib in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia. Three patients have cleared the 28-day safety window at each of the 20 mg and 40 mg dose levels. The Company is now enrolling at the 60 mg dose....Kronos Bio anticipates achieving the recommended phase 2 dose in Q4 2023/Q1 2024 and expects to share data from this study in mid-2024."

P1/2 data • Trial status • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

KB-LANRA- 1001: A Study to Evaluate Lanraplenib (LANRA) in Combination With Gilteritinib in Participants With FLT3-mutated Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - P1b/2 | N=100 | Recruiting | Sponsor: Kronos Bio | N=55 ➔ 100

Combination therapy • Enrollment change • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • FLT3

Impact of spleen tyrosine kinase inhibition on vaccine-induced thrombotic thrombocytopenia antibody-induced procoagulant platelet and thrombus formation (ISTH 2023) - "Background: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare but life-threatening prothrombotic syndrome observed in individuals following vaccination with vector-based SARS-CoV-2 (ChAdOx1 CoV-19) vaccine. VITT patient sera induced significant changes in healthy PLTs, namely the formation of a procoagulant PLT (CD62p/PS double positive) phenotype compared to controls (p=0.0006). These changes were observed in the presence or absence of exogenous PF4 (p=0.0582) and most importantly were markedly reduced in the presence of different Syk inhibitors. Interestingly, the pretreatment of PLTs with the clinically approved Syk inhibitor Fostamatinib prior to VITT serum incubation resulted only in a slight reduction of VITT Ab-induced procoagulant PLT formation (p=0.0625)."

Hematological Disorders • Immunology • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • Thrombocytopenia • Thrombosis • SELP • SYK

The impact of spleen tyrosine kinase-inhibition on 5B9 HIT antibody-induced procoagulant platelet formation (ISTH 2023) - "5B9 induced a significant formation of procoagulant PLTs (CD62p/PS double positive) in the presence of low- (0.2 IU/mL) dose heparin whereas these changes were absent under buffer conditions or in the presence of high-dose heparin (p=0.0009 and 0.0011, respectively). Formation of Ab-induced procoagulant PLTs seem to be mainly mediated by PLT FcγRIIA as the inhibition of PLT protease activated receptor-1 (PAR-1) with a specific PAR-1 inhibitor did not affect procoagulant PLT formation. Additionally, experiments with the Syk inhibitors Fostamatinib (R406), PRT-060318 and Lanraplenib revealed that procoagulant PLT formation seems to be dependent on Syk-mediated signaling mechanisms as the pretreatment with these inhibitors resulted in a marked reduction of Ab-induced procoagulant PLTs (IC50:14.35±1.27μM; 0.14±1.1μM; and 0.22±1.29μM, respectively).Conclusion(s): Findings of our study suggest that 5B9 HIT Ab induces procoagulant PLTs via the engagement of PLT..."

Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis • FCGR2A • SELP • SYK