lanraplenib (GS-9876) / Gilead, Galapagos, Kronos Bio - LARVOL DELTA

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

The Novel Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) Platform Identifies Synergistic Activity of Lanraplenib and Ruxolitinib in Hematological Malignancies (ASH 2023) - P1b/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 Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • FLT3 • STAT5 • 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) - P1b/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

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

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) - P1b/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 Disorders • 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) - P1b/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

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

KB-LANRA 1001: A PHASE 1B/2 STUDY ON 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 (EHA 2023) - P1b/2 | "Eligible pts must have documented FLT3 mutation from a reference lab, and can have received prior therapy with a FLT3 inhibitor (including midostaurin, gilteritinib, quizartinib, or ceronlanib). Accrual is ongoing."

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

Responses in patients with AML and treated with entospletinib monotherapy. (ASCO 2023) - P1b/2 | "Sponsored by Pharmaceutical/Biotech Company, Kronos Bio. Based on the results from these three patients, the clinical activity of SYK inhibition should be explored further in AML. We are testing Lanraplenib, a next-generation SYK inhibitor with enhanced selectivity, and more favorable pharmacologic properties in combination in genetically defined subsets of AML (NCT05028751). Clinical trial information: NCT02343939."

Clinical • Monotherapy • Acute Myelogenous Leukemia • HOXA9 • KMT2A • MEIS1 • NPM1 • SYK

Immunohistological pattern-stratification opens the door for reliabletargeted treatment strategies in cutaneous lupus erythematosus (ISID 2023) - "This IHC-screening algorithm identified 92% (n=109) patients who expressed atleast one on these IHC-markers. 28% expressed all 3 markers at the same time, 17% MxA& CD20, 5% CD123 & CD20, 9% CD123 & MxA, 18% MxA, 7% CD20 and 9% CD123. This study demonstrates that > 90% of CLE patients might be prone to betreated with at least one targeted drug, which were developed for the treatment of SLE oris in clinical studies for CLE. These drugs include belimumab (anti-Blys/ B cells) andanifrolumab (anti-IFNabR), which have already been approved for the treatment of SLEby FDA and EMA, but also anti-pDCs drugs (BIIB059 (anti-BDCA2); Daxdilimab (AntiILT7)) and inhibitors of the JAK/STAT pathway (Tofacitinib (JAK), Lanraplenib &Filgotinib (JAK/SYK), Deucravacitinib (TYK2), which block IFN-mediatedinflammatory pathways."

Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • CD123 • CD20 • IFNAR2 • SYK • TYK2

SYK INHIBITION DRIVES DEEP RESPONSES IN A BIOMARKER GUIDED SUBSET OF AML ALONE AND IN RATIONAL COMBINATIONS (EHA 2022) - P1b/2, P3 | "The selective, orally bioavailable SYK inhibitor entospletinib (ENTO) has demonstrated clinical activity and tolerability in HOXA9/MEIS1- driven AML...Lanraplenib (LANRA) is a next-generation SYK inhibitor with similar potency and selectivity to ENTO but with more favorable pharmacologic properties that is currently being evaluated in combination with gilteritinib in patients with relapsed or refractory (R/R) FLT3 -mutated AML (NCT05028751)...Results Kinase selectivity profiling found >10-fold higher selectivity of ENTO and LANRA for SYK vs other kinases with improved potency and selectivity compared with the approved first-generation agent, fostamatinib...Combinations with AML standard-of-care and investigational agents, including azacytidine, showed at least additive effects. Strong synergy with the JAK inhibitor ruxolitinib was consistent mechanistically with a reporter model that demonstrated the ability of LANRA to block activation of STAT5 in..."

Biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology • FLT3 • HOXA9 • MEIS1 • NPM1 • STAT5 • STAT5AWqe • SYK

SYK Inhibitors, Entospletinib and Lanraplenib, Show Potent Anti-Leukemic Activity in Combination with Targeted Agents (ASH 2022) - P1b/2, P3 | "Introduction: Spleen tyrosine kinase (SYK) acts as a key integrator of cellular signaling from surface contact and receptor tyrosine kinase receptors containing an immunoreceptor tyrosine-based activation motif (ITAM). SYK is a promising therapeutic target for genetically defined subsets of AML. Two highly selective SYK inhibitors are currently undergoing clinical testing in different but complementary clinical settings. Given its central role as a modulator of leukemogenic signaling, SYK inhibition has the potential to synergize with other targeted therapies in AML."

Combination therapy • IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD14 • FLT3 • HOXA9 • ITGAM • KMT2A • MEIS1 • NPM1 • SYK

Kronos Bio Reports Recent Business Progress and Fourth-Quarter and Full-Year 2022 Financial Results (GlobeNewswire) - "Kronos Bio anticipates sharing initial data from the Phase 1b/2 study of lanraplenib in combination with gilteritinib in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia (AML), along with a recommended Phase 2 dose (RP2D), in the fourth quarter of 2023 or first quarter of 2024."

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

Influence of efflux and uptake transporters on the pharmacokinetics of the SYK inhibitors entospletinib and lanraplenib (ESMO-TAT 2023) - "Conclusions ABC transporters play an important role in the brain disposition of entospletinib and lanraplenib, although they have only a slight impact on the plasma exposure of entospletinib. The role for the OATP uptake transporters seems to be less prominent for both drugs, but they might be involved in the tissue disposition of lanraplenib, but not of entospletinib."

PK/PD data • Breast Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • SYK

PHARMACOLOGICAL INHIBITION OF SYK CONFERS ANTI-PROLIFERATIVE AND NOVEL ANTI-TUMOR IMMUNE RESPONSES IN AML (EHA 2022) - P1/2, P1b/2, P3 | "The selective, orally bioavailable SYK inhibitor entospletinib (ENTO) has demonstrated clinical activity and tolerability in HOXA9/MEIS1- driven AML...Lanraplenib (LANRA) is a next-generation SYK inhibitor with similar potency and selectivity to ENTO but with more favorable pharmacologic properties that is currently being evaluated in combination with gilteritinib in pts with relapsed or refractory FLT3 -mutated AML (NCT05028751)...Our studies illustrate that ENTO and LANRA may restore T-cell proliferation in a subset of AML pts with dysfunctional T-cell responses, suggesting a novel mechanism of action. Additional studies are required to fully understand the mechanism of SYK-mediated antitumor immune responses in AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Inflammation • Leukemia • Lymphoma • Oncology • FLT3 • HOXA9 • MEIS1 • NPM1 • SYK