narazaciclib (HX301) / Traws Pharma, HanX Biopharma - LARVOL DELTA

Preclinical anti-glioblastoma pharmacology of HX301, a novel CSF-1R inhibitor (AACR 2025) - "HX301 (Narazaciclib or ON123300) is a clinical-stage tyrosine kinase inhibitor (TKI, NCT#05731934) with great potency against CSF1R (IC50 0.285nM) and has demonstrated significant inhibition on macrophage proliferation in vitro/in vivo as well as capability of penetrating brain-blood-barrier (BBB)...HX301, Temozolomide (TMZ), or their combination were oral-administrated daily...Moreover, although HX301 and radiation combo failed to show any synergistic effects in orthotopic GL261-Red-Fluc model, HX301 in combination with TMZ exhibited significantly stronger anti-tumor activities over either HX301 alone or TMZ alone in the subcutaneous U87-MG model, suggesting a synergistic effect between the two.Conclusions. HX301 demonstrated great ability to penetrate BBB and robust anti-tumor efficacy, as well as enhanced activity when combined with TMZ, in GBM models, which warrants a further clinical investigation."

Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • IL34 • TGFB1

Development of the Pyrido[2,3-d]pyrimidin-7(8H)-one Scaffold toward Potent and Selective NUAK1 Inhibitors. (PubMed, ACS Med Chem Lett) - "Through a scaffold-optimization approach we have identified different chemotypes delivering NUAK1 inhibition with improved potency and selectivity over CDK kinases compared with ON123300. We present ADME profiling and in vivo pharmacokinetic data for these compounds."

Journal • CNS Disorders • CDK6 • NUAK1

A Phase 2 Study of HX301 in Patients with High-grade Giloma (clinicaltrials.gov) - P1/2 | N=72 | Recruiting | Sponsor: Hangzhou Hanx Biopharmaceuticals, Ltd. | Not yet recruiting ➔ Recruiting

Enrollment open • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor

a Phase 2 Study of HX301 in Patients With High-grade Giloma (clinicaltrials.gov) - P1/2 | N=72 | Not yet recruiting | Sponsor: Hangzhou Hanx Biopharmaceuticals, Ltd.

Combination therapy • New P1/2 trial • Brain Cancer • CNS Tumor • Glioma • Malignant Glioma • Oncology • Solid Tumor

ON 123300 (Narazaciclib) and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=36 | Recruiting | Sponsor: Adriana Rossi | Not yet recruiting ➔ Recruiting | Initiation date: Jun 2024 ➔ Sep 2024

Enrollment open • Trial initiation date • Hematological Malignancies • Multiple Myeloma • Oncology

Hansit announced that HX301 IND was approved by the National Medical Products Administration [Google translation] (HanX Bio Press Release) - "Hansaitai announced that the HX301 clinical trial has obtained the drug clinical trial approval notice from the National Medical Products Administration. Hansaitai's application meets the relevant requirements for drug registration and agrees to conduct clinical trials of this product in combination with temozolomide for glioblastoma."

New trial • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

THE MULTIKINASE CDK4/6 INHIBITOR NARAZACICLIB OVERCOMES BTK-I RESISTANCE IN MANTLE CELL LYMPHOMA BY TARGETING USP24-P53 SIGNALING AXIS (EHA 2024) - "Aims: Our aim was to compare the efficacy and safety profiles of narazaciclib with three health authority-approvedCDK-i (palbociclib, abemaciclib and ribociclib), as monotherapy or in combination with covalent (ibrutinib,acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTK-i, across a panel of preclinical models of MCLwith distinct sensitivity to these latter, and to determine the molecular bases of the interaction between thesetwo classes of drugs. Our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL,including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitroand in vivo, accelerating cell cycle blockade and, specifically in the BTK-resistant cases, promoting thephosphorylation of USP24, followed by the activation of P53 and the modulation of DNA repair pathway."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • Targeted Protein Degradation • CDKN1A

Traws Pharma Reports Q2 2024 Financial Results, Provides Recent Business Highlights (GlobeNewswire) - "Upcoming Milestones...Narazaciclib – our multi-kinase inhibitor, including CKD4+, with potential for use in multiple solid tumors. H2 2024: Release topline results from our Phase 1/2 study at an upcoming medical meeting. In addition, we plan to announce the recommended Phase 2 dose (RP2D) and initiate ISTs in multiple myeloma, breast cancer and other indications...Completion of Phase 1/2 dose escalation studies for narazaciclib, evaluated as a monotherapy and in combination with letrozole in patients with recurrent metastatic low-grade endometrioid endometrial cancer and other gynecologic malignancies."

New trial • P1/2 data • Trial status • Breast Cancer • Endometrial Cancer • Gynecologic Cancers • Hematological Malignancies • Multiple Myeloma • Oncology • Solid Tumor

The Tolerability and Pharmacokinetics of HX301 Monolactate Capsules in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Hangzhou Hanx Biopharmaceuticals, Ltd. | Active, not recruiting ➔ Completed

Metastases • Trial completion • Gastrointestinal Cancer • Oncology • Solid Tumor • PD-L1

A phase I clinical trial investigating the safety, tolerability, and pharmacokinetics of HX301 (narazaciclib), a novel multi-kinase inhibitor targeting CSF1R, CDK 4/6, and ARK5, in patients with advanced solid tumors. (ASCO 2024) - P1 | "HX301 at dose levels ranging from 40mg to 160mg was tolerable with a manageable toxicity profile. Further clinical studies are needed to explore the drug's anti-tumor activity, particularly in combination settings. Clinical trial information: NCT05731934."

Clinical • Metastases • P1 data • PK/PD data • Breast Cancer • Diabetes • Dyspepsia • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • CDK4 • CSF1R

Traws Pharma Reports First Quarter 2024 Financial Results and Provides Business Update (GlobeNewswire) - "Narazaciclib: CDK 4+ to treat solid tumors: Phase 1/2....A dose escalation study to define the recommended Phase 2 dose (RP2D) recently enrolled the last cohort. A review of the clinical and PK/PD data is underway. We intend to utilize these data to define the clinical strategy, including selection of a lead indication and next steps in its development....Research and development (R&D) expenses were $1.9 million for the first quarter of 2024, compared with $4.1 million for the same period in 2023. The decrease was primarily caused by lower costs related to narazaciclib drug substance and drug product manufacturing, a reduction in clinical development and consulting costs and lower personnel expenses due to lower bonus accrual."

Commercial • Trial status • Hematological Malignancies • Oncology • Solid Tumor

HanxBio announces the publication of a research paper in Scientific Reports on preclinical evaluation of Narazaciclib for the treatment of acute myeloid leukemia (AML) (PRNewswire) - "HanxBio today announced that it has published a research article...in the Nature Portfolio online journal Scientific Reports...The report demonstrated the strong anti-leukemia activity of HX301 along with potential mechanism of actions (MOAs), including the inhibition of FLT3-ITD/TKD and potentially the inhibition of CSF1R, which is demonstrated in a robust experimental system beyond inv(16) subset for the first time. This report also studied the pharmacodynamics and pharmacokinetics of HX301, including the relationship between drug exposure and efficacy, which can be used to assist clinical dosage selection. Some of these works were conducted in collaboration with Crown Bioscience, Inc. and Kyinno Biotech, Ltd."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Genomic profiling of leukemic cell lines, responders vs. non-responders to Narazaciclib (HX301 or ON123300), a novel kinase inhibitor with activity against CSF1R and FLT3 (AACR 2024) - "The biomarker analysis has been performed on gene expression, mutation and copy number variation levels, and the data been presented using common methodologies, including principal component analysis, differential expression analysis, correlation analysis, Gene Ontology enrichment analysis, gene set variation analysis, somatic gene mutation analysis, and copy number variation analysis, etc. Some of the observations have been made: 1) differential expression analysis on all leukemic cell lines shows that 254 genes have been positively associated with the responders; while expression of 191 genes are negatively correlated with AUC, i.e. positively associated with response, as revealed by Spearman correlation analysis; 2) Gene Ontology enrichment analysis revealed these response related genes are mostly involved in myeloid leukocyte activation and defense response; 3) all FLT3-ITD AML lines are responders, presumably due to the FLT3i activity of HX301; 4) CSF1R expression..."

Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CSF1R • FLT3 • IL7 • STAT5

Narazaciclib, a novel multi-kinase inhibitor with potent activity against CSF1R, FLT3 and CDK6, shows strong anti-AML activity in defined preclinical models. (PubMed, Sci Rep) - "Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants."

Journal • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CDK6 • CSF1R • FLT3

Preclinical pharmacology modeling (pharmacokinetics/efficacy) of narazaciclib (HX301 or ON123300) to predict its clinical effective dose (AACR 2024) - "Narazaciclib at 160 mg/d is predicted to be an effective dose in AML patients."

PK/PD data • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • CSF1R • ETV6

ON 123300 (Narazaciclib) and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=36 | Not yet recruiting | Sponsor: Adriana Rossi

New P1/2 trial • Hematological Malignancies • Multiple Myeloma • Oncology

Onconova Therapeutics, Inc. and Trawsfynydd Therapeutics, Inc. Announce Business Combination to Form Traws Pharma, Inc, a Best-in-Class Virology and Oncology Company (GlobeNewswire) - "Onconova Therapeutics, Inc...and Trawsfynydd Therapeutics, Inc...announced that the companies have entered into a definitive merger agreement to combine in an all-stock transaction (the 'Merger'). Under the terms of the agreement, Onconova acquired 100% of Trawsfynydd’s outstanding equity interests....In connection with the Merger, Traws announced that it will raise $14 million in a committed private placement financing by OrbiMed and Torrey Pines, expected to close on April 3, 2024....These proceeds will be used to advance the Traws’ programs through multiple clinical data catalysts and complete the dose ranging study for narazaciclib....Define the RP2D and development strategy for LGEEC/other indications."

M&A • Endometrial Cancer • Gynecologic Cancers • Oncology • Solid Tumor

Narazaciclib, a Differentiated CDK4/6 Antagonist, Prolongs Cell Cycle Arrest and Metabolomic Reprogramming, Enabling Restoration of Ibrutinib Sensitivity in Btki-Resistant Mantle Cell Lymphoma (ASH 2023) - "We compared the efficacy and safety profiles of narazaciclib with three health authority-approved CDKi (palbociclib, abemaciclib or ribociclib) in association with covalent (ibrutinib, acalabrutinib) and non-covalent (pirtobrutinib, ARQ-531) BTKi, across a panel of 10 MCL cell lines with distinct sensitivity to the first-in-class BTKi, ibrutinib. In conclusion, our findings demonstrate that narazaciclib is safe and effective as a single agent in preclinical models of MCL, including BTKi-resistant cases. Its combination with ibrutinib achieved a synergistic tumoricidal effect in vitro and in vivo, accelerating cell cycle blockade and reverting the metabolic reprogramming characterizing MCL refractoriness to BTKi therapy."

Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Oncology • CDK4 • CDKN1A

Narazaciclib's differential targets and kinase inhibitory activity contribute to the enhanced inhibition of tumor growth in preclinical models (SABCS 2023) - P1, P1/2 | "Narazaciclib is in Ph I trials; NCT04739293 and CXHL1900340; studying different administration regimens and in endometrial cancer in combination with letrozole (NCT05705505)...Kd values of CDK4/cyclinD1 binding show similar trends; abemaciclib (0.08 nM), narazaciclib (0.18 nM), palbociclib (0.75 nM) and ribociclib (1.3 nM)...Our findings identify important differences generated from assay models studying kinase inhibition, binding and pathway engagement. Understanding the role of the differential targets engaged by narazaciclib, the potential enhanced antitumor immunity and the sensitization by autophagy inhibitors to cell death, will guide future clinical studies."

IO biomarker • Preclinical • Breast Cancer • HER2 Breast Cancer • Oncology • Triple Negative Breast Cancer • AURKA • B2M • BUB1 • CCND1 • CHEK1 • CSF1R • CXCL10 • HER-2 • NUAK1 • PD-L1

Onconova Therapeutics’ Narazaciclib ASH Poster Highlights Activity in Treatment Resistant Mantle Cell Lymphoma (GlobeNewswire) - "Narazaciclib showed safety and efficacy as a single agent in preclinical MCL models, including ibrutinib-resistant settings, with significant reductions in cell viability. Combination Synergy: The narazaciclib plus ibrutinib combination showed synergy in vitro and in vivo, especially in ibrutinib-resistant models, with overall greater synergy, measured by lower 'Combination Index' values, versus ibrutinib-sensitive cells....'Looking ahead, we are enthusiastic to advance the clinical program for narazaciclib in 2024 and to update our stakeholders regarding our progress, including the planned completion of dose escalation studies, definition of an RP2D, and development of our registrational trial plans for LGEEC'."

New trial • Preclinical • Trial status • Endometrial Cancer • Mantle Cell Lymphoma

Onconova Therapeutics’ Preclinical Narazaciclib Data at SABCS Highlights Differentiated Anti-Tumor Activity v. Other CDK4/6i’s (GlobeNewswire) - "Onconova Therapeutics...announced preclinical data highlighting narazaciclib’s multi-kinase profile, broad anti-tumor activity and increased anti-tumor immunity, compared to palbociclib and other CDK4/6 inhibitors, in a poster presented at the San Antonio Breast Cancer Symposium (SABCS)....Treatment with narazaciclib/metabolite produced more profound reductions in cell viability in PYMT murine breast cancer cells, compared to palbociclib and other CDK4/6i’s (combined with autophagy inhibitors)....These data support the potential use of narazaciclib in patients with breast and ovarian cancer, as well as its potential in LGEEC....Narazaciclib progressing towards RP2D and preparation for registrational studies, with a planned update in H1 2024."

Clinical • Preclinical • Breast Cancer • Endometrial Cancer • Ovarian Cancer

Study of ON 123300 in Patients With Advanced Cancer (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Onconova Therapeutics, Inc. | Trial completion date: Oct 2023 ➔ Oct 2024 | Trial primary completion date: Oct 2023 ➔ Oct 2024

Metastases • Trial completion date • Trial primary completion date • Oncology • Solid Tumor

Onconova Therapeutics Reports Corporate Update and Announces Third Quarter 2023 Financial Results (GlobeNewswire) - "Near Term Narazaciclib Milestones: Onconova intends to: (i) present preclinical data at two December medical meetings: the San Antonio Breast Cancer Symposium (SABCS) and the annual meeting of the American Society of Hematology (ASH); (ii) continue the dose escalation segment of the Phase 1/2 program which may bring us into the first quarter of 2024; (iii) provide a read-out on narazaciclib’s safety and pharmacology in the first half of 2024; (iv) provide an update on our registrational trial-readiness over the next few quarters, including the definition of our recommended Phase 2 dose, engagement with the FDA on the pivotal trial design..."

FDA event • P1/2 data • Preclinical • Trial status • Breast Cancer • Endometrial Cancer • Hematological Malignancies

Onconova Therapeutics’ ASH Poster To Focus on Narazaciclib in MCL (GlobeNewswire) - "Onconova Therapeutics, Inc...today announced that Onconova and collaborators will present a preclinical poster related to its lead program, narazaciclib, at the 65th American Society for Hematology Annual Meeting & Exposition (ASH), taking place in San Diego, California from December 9 to 12, 2023....'The poster that we and researchers from the Josep Carreras Leukaemia Research Institute in Barcelona, Spain are presenting at ASH 2023 shows that the study of narazaciclib, either as a single agent or in combination with ibrutinib, effectively controls tumor growth in preclinical models of mantle cell lymphoma (MCL), including those that are resistant to Bruton’s tyrosine kinase inhibitors (BTKis), a mainstay of care for this aggressive and difficult to treat cancer.'"

Preclinical • Hematological Malignancies • Lymphoma • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology

Promising Preclinical Narazaciclib Data Presented at MCL Meeting (GlobeNewswire) - "Onconova Therapeutics, Inc...today announced that one of the Company’s scientific collaborators...made a podium presentation during the European MCL Network Annual Meeting in Dublin, Ireland on October 7, 2023 regarding promising ongoing preclinical studies of narazaciclib, in combination with ibrutinib and other targeted therapies used in the treatment for mantle cell lymphoma....Onconova’s proprietary multi-kinase inhibitor, narazaciclib, has nanomolar potency across a range of targets including CD1....Onconova plans to provide an update on the Phase 1/2a clinical program with narazaciclib in patients with low grade endometriod endometrial cancer (LGEEC), including topline safety, pharmacology data, and selection of a recommended Phase 2 dose, in Q4 2023."

P1/2 data • Preclinical • Trial status • Endometrial Cancer • Hematological Malignancies • Mantle Cell Lymphoma • Non-Hodgkin’s Lymphoma • Oncology