cudetaxestat (BLD 0409) / Blade Therap - LARVOL DELTA

Discovery of Novel Autotaxin Inhibitors Bearing the 4,5,6,7-Tetrahydro-7H-Pyrazolo[3,4-c]Pyridine-7-One Core for Pulmonary Fibrosis Therapy. (PubMed, Arch Pharm (Weinheim)) - "Furthermore, predictive analyses of drug-like properties and toxicity uncovered that 19 demonstrated comparable safety to PAT-409 while exhibiting significantly superior drug-like characteristics. This study provides a promising ATX inhibitor for PF therapy."

Journal • Immunology • Pulmonary Disease • Respiratory Diseases

Development of Tricyclic 4,5-Dihydro-3H-pyrrolo[2,3-c]quinolin-4-ones as Potent Autotaxin Inhibitors for Pulmonary Fibrosis Treatment In Vivo. (PubMed, J Med Chem) - "Herein, a hydrophilic amide linker and sp3-rich bicyclic 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one scaffold were employed to modify the lead compound PAT-409, followed by benzene ring fusion to generate novel tricyclic 4,5-dihydro-3H-pyrrolo[2,3-c]quinolin-4-one ATX inhibitors...Significantly, in bleomycin-induced pulmonary fibrosis mouse models, both compounds markedly improved respiratory function and reduced fibrotic lesions. Mechanistic studies revealed that 45 suppressed the TGF-β/Smad signaling pathway, downregulating α-smooth muscle actin (α-SMA) and extracellular matrix components (ECM). Overall, the identification of 45 and 46 for pulmonary fibrosis therapy provides a featured tricyclic scaffold for further development of novel ATX inhibitors."

Journal • Preclinical • Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • TGFB1

Development of potent indole-3-carboxamide autotaxin inhibitors with preferred lipophilicity for in vivo treatment of pulmonary fibrosis. (PubMed, Eur J Med Chem) - "Notably, compounds 4 and 29 exhibited excellent in vitro metabolic stability (t1/2 > 170 min) and negligible cytotoxicity. Furthermore, oral administration of either compound 4 or 29 (60 mg/kg) exhibited comparable anti-pulmonary fibrosis effects to PAT-409 (60 mg/kg) in a bleomycin-induced pulmonary fibrosis mouse model, suggesting their potential as promising anti-pulmonary fibrosis agents for further development."

Journal • Preclinical • Immunology • Pulmonary Disease • Respiratory Diseases

Discovery of Novel 4,5,6,7-Tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one Derivatives as Orally Efficacious ATX Allosteric Inhibitors for the Treatment of Pulmonary Fibrosis. (PubMed, J Med Chem) - "Herein, starting from PAT-409 (Cudetaxestat), a series of novel ATX inhibitors bearing 1H-indole-3-carboxamide, 4,5,6,7-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one, or 4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine cores were designed based on the structure of ATX hydrophobic tunnel...In a bleomycin-induced mouse PF model, both compounds significantly reduced fibrosis by regulating the TGF-β/Smad signaling pathway and downregulating collagen deposition...Notably, 35 was characterized by favorable pharmacokinetic properties (F = 69.5%) and excellent safety in vivo. Overall, 35 turned out to be a well-characterized potent and safe ATX inhibitor warranting further investigation for the treatment of PF."

Journal • Fibrosis • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • TGFB1

Anti-fibrotic Effects of MT-5562, a Novel Potent Selective Autotaxin Inhibitor, in Preclinical Studies: Roles of Lysophosphatidic Acid in Autoimmune Diseases and Clues to Treat Skin and Lung Fibrosis in Systemic Sclerosis (ACR Convergence 2023) - " We examined the inhibitory effects of MT-5562 and its free form (MT-5562F) in comparison to other autotaxin inhibitors such as ziritaxestat and cudetaxestat on ATX activity using the choline assay...The effects of MT-5562F on skin and lung fibrosis were evaluated using murine SSc models induced by bleomycin (BLM) and the plasma concentrations of MT-5562F and LPA were also determined... Our results suggest that multiple LPA species are elevated in plasma of SSc patients and that MT-5562 is a selective and potent ATX inhibitor with a good preclinical safety and efficacy profile. It may offer a good option to treat lung and skin fibrosis in SSc, which has to be analyzed in clinical trials. H."

Preclinical • Fibrosis • Immunology • Inflammatory Arthritis • Lupus • Respiratory Diseases • Rheumatoid Arthritis • Rheumatology • Scleroderma • Sjogren's Syndrome • Systemic Lupus Erythematosus • Systemic Sclerosis • CTGF • IL6

ANTI-FIBROTIC EFFECTS OF MT-5562, A NOVEL POTENT SELECTIVE AUTOTAXIN INHIBITOR, IN PRECLINICAL STUDIES: CLUES TO TREAT SKIN AND LUNG FIBROSIS IN SYSTEMIC SCLEROSIS (EULAR 2023) - "The effects of MT-5562F on skin and lung fibrosis were evaluated in murine SSc models induced by bleomycin (BLM). Results MT-5562F, ziritaxestat, and cudetaxestat inhibited the enzyme activity of human ATX with IC50s of 0.45, 49.3, and 2.77 nmol/L, respectively...Conclusion Our results suggest that MT-5562 is a selective and potent ATX inhibitor. It is expected to be a safer compound comparing other ATX inhibitors under development, and it may offer a good option to treat lung and skin fibrosis in SSc."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • Scleroderma • Systemic Sclerosis • CRP • CTGF • EGFR • IL6R • POSTN • TGFB1

Cudetaxestat, a differentiated phase 2-ready investigational treatment for idiopathic pulmonary fibrosis (ICLAF 2022) - P1, P1a | "Introduction:Cudetaxestat is a differentiated, non-competitive small molecule inhibitor of autotaxin being developed as a daily oral treatment for IPF, SSc-ILD, and other fibrotic diseases.A battery of preclinical in vitro and ex vivo biochemical assays and pharmacokinetic (PK) and pharmacology studies (mouse bleomycin model) were used to assess the potency and activity of cudetaxestat...When dosed concomitantly with either nintedanib or pirfenidone, the total exposure for these SOC therapeutics was not significantly altered. Cudetaxestat is a first-in-class non-competitive (allosteric) autotaxin inhibitor with robust preclinical anti-fibrotic activity and good PK/PD correlations in Phase 1 clinical trials. This body of data provides a dose rationale for Phase 2 clinical development of cudetaxestat in IPF with or without SOC."

P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Cudetaxestat, a differentiated phase 2-ready investigational treatment for idiopathic pulmonary fibrosis (ERS 2022) - P1, P1a | "A battery of preclinical in vitro and ex vivo biochemical assays along with pharmacokinetic (PK) and pharmacology studies (mouse bleomycin model) were used to assess the potency and activity of cudetaxestat...When dosed concomitantly with either nintedanib orpirfenidone, the total exposure for each of these SOC therapeutics was not significantly altered...Cudetaxestat is a first-in-class non-competitive (allosteric) autotaxin inhibitor with robust preclinical anti-fibrotic activity and good PK/PD correlations in Phase 1 clinical trials. This body of data provide a dose rationale for Phase 2 clinical development of cudetaxestat in IPF with or without SOC"

P2 data • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Blade Therapeutics Presents Analyses from Phase 1 and Preclinical Studies of Cudetaxestat at the European Respiratory Society International Congress 2022 (Businesswire) - "Blade Therapeutics...announced the presentation of positive data from Phase 1 and preclinical studies of cudetaxestat, an investigational non-competitive autotaxin inhibitor in clinical development for IPF and other fibrotic diseases. The data were featured in a poster (abstract #PA459) presented today at the European Respiratory Society (ERS) International Congress 2022, which is taking place in Barcelona, Spain, from September 4-6, 2022."

P1 data • Preclinical • Idiopathic Pulmonary Fibrosis

Blade Therapeutics to Participate in “Drug Development in Pulmonary Medicine” Panel Discussion at 2022 BTIG Biotechnology Conference (Businesswire) - "Blade Therapeutics...announced that Wendye Robbins, M.D., president and CEO, will participate in the 'Drug Development in Pulmonary Medicine: Emerging Trends and a Review of the Unmet Need' panel discussion on Tuesday, August 9, 2022, 1:00 pm (ET), during the 2022 BTIG Biotechnology Conference, August 8 – 9, in New York City. Blade’s lead investigational medicine is cudetaxestat, a non-competitive autotaxin inhibitor with direct anti-fibrotic activity and differentiating characteristics that is expected to enter a planned phase 2 clinical trial in patients with idiopathic pulmonary fibrosis."

Clinical data • Idiopathic Pulmonary Fibrosis

Blade Therapeutics Presents Data from Phase 1 and Preclinical Studies of Cudetaxestat at the American Thoracic Society 2022 International Conference (Businesswire) - P1 | N=86 | NCT04939467 | Sponsor:Blade Therapeutics | "Company on track to start phase 2 clinical trial of cudetaxestat dosed either as monotherapy or co-administered with pirfenidone or nintedanib in patients with IPF in second quarter of 2022...Neither nintedanib nor pirfenidone significantly alter the exposure of cudetaxestat; Cudetaxestat does not affect the PK of pirfenidone; Cudetaxestat does not significantly increase the exposure of nintedanib (AUC(0-12)); Most common treatment-related adverse events were mild gastrointestinal upset (diarrhea and nausea); and There were no treatment-related serious adverse events."

New P2 trial • P1 data • Trial status • Idiopathic Pulmonary Fibrosis

Differentiating Characteristics of Cudetaxestat (BLD-0409), a Non-Competitive Autotaxin Inhibitor Under Development to Treat Idiopathic Pulmonary Fibrosis (ATS 2022) - "Cudetaxestat and GLPG-1690 were dosed daily (3, 10 and 30 mg/kg) and therapeutically starting 7 days after bleomycin lung injury. Non-competitive ATX inhibition by cudetaxestat provides a differentiated profile that will maintain potency in the presence of elevated LPC concentrations, which may improve target coverage in vivo. Cudetaxestat displays clear efficacy advantages on multiple biomarkers in a preclinical lung fibrosis model supporting its potential for differentiated therapeutic outcomes."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Oncology • Pulmonary Disease • Respiratory Diseases • ACTA2 • COL1A1

Preclinical Evaluation of Cudetaxestat for Potential Drug-Drug Interactions (ATS 2022) - "Cudetaxestat was proven to be neither a substrate nor an inhibitor of P-gp at physiologically relevant concentrations. No significant change in plasma concentration of nintedanib was observed when cudetaxestat was co-administered in rats. A phase 1 clinical DDI study evaluating cudetaxestat co-administration with nintedanib and pirfenidone in healthy human volunteers is underway."

Preclinical • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Clinical Evaluation of Cudetaxestat for Safety,Tolerability, Pharmacokinetics, Pharmacodynamics, and Potential Drug-Drug Interactions (ATS 2022) - P1, P1a | "A standard drug-drug interaction (DDI) study (NCT04814498) determined the effect of cudetaxestat on the PK of probe substrates for CYP450 enzymes and evaluated its safety and tolerability when administered alone and with a cocktail of CYP450 probe substrates (Geneva cocktail less fexofenadine). Results from the SAD/MAD study demonstrated that single and multiple ascending doses of cudetaxestat oral solution were generally well-tolerated with only transient, mild, gastrointestinal (GI) treatment emergent adverse events (TEAE). These results indicate cudetaxestat is safe and well-tolerated, with an improved GI tolerability profile of oral tablet formulation, and minimal potential for CYP450 substrate interactions."

Clinical • PK/PD data • Fibrosis • Gastrointestinal Disorder • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases • CYP19A1 • CYP1A2 • CYP2C9 • CYP3A4

RESPIRARE Phase 2 Study of Efficacy and Safety of Cudetaxestat in Patients With Idiopathic Pulmonary Fibrosis (IPF) (clinicaltrials.gov) - P2 | N=200 | Not yet recruiting | Sponsor: Blade Therapeutics

New P2 trial • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

Blade Therapeutics Presents Data from Phase 1 and Preclinical Studies of Cudetaxestat at the American Thoracic Society 2022 International Conference (Businesswire) - "Preclinical Evaluation of Cudetaxestat (BLD-0409) for Potential Drug-Drug Interactions The preclinical study was designed to understand whether the plasma concentration of nintedanib, which is a P-glycoprotein (P-gp) substrate, is altered when co-administered at steady state with either cudetaxestat or GLPG-1690 (ziritaxestat), an investigational competitive inhibitor of autotaxin. Results of the study conducted in a rat model showed: Ziritaxestat is a potent inhibitor (single-digit micromolar IC50 values) of P-gp when either quinidine or nintedanib is used as a substrate, and cudetaxestat is a weak P-gp inhibitor under similar conditions; Ziritaxestat significantly increased nintedanib exposure when co-administered in vivo in rats. Cudetaxestat did not alter nintedanib exposure when co-administered in vivo in rats."

Preclinical • Idiopathic Pulmonary Fibrosis

Blade Therapeutics Presents Preclinical Data Highlighting Differentiating Characteristics of Cudetaxestat at the American Thoracic Society 2022 International Conference (Businesswire) - "Blade Therapeutics...announced new data from preclinical studies that highlight the differentiating characteristics of cudetaxestat, an investigational non-competitive autotaxin inhibitor in clinical development for IPF and other fibrotic diseases. These data were featured in a poster presentation at the American Thoracic Society (ATS) 2022 International Conference, taking place May 13-18, 2022, at the Moscone Center, in San Francisco....Non-competitive autotaxin inhibition with cudetaxestat maintained biochemical potency in the presence of elevated LPC concentrations; In a mouse model of lung fibrosis, cudetaxestat displayed direct anti-fibrotic activity (reduced αSMA, Col1A1 expression, reduced fibrosis, and assembled collagen); and Inhibition of the autotaxin/lysophosphatidic acid pathway by cudetaxestat significantly reduced activation (gene expression) of several key pro-fibrotic pathways."

Preclinical • Idiopathic Pulmonary Fibrosis

Drug-Drug Interaction (DDI) Study in Healthy Volunteers (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: Blade Therapeutics | Active, not recruiting ➔ Completed

Trial completion

Blade Therapeutics Presents Data from Phase 1 and Preclinical Studies of Cudetaxestat at the American Thoracic Society 2022 International Conference (Businesswire) - "Toby Maher, MD, PhD...said, 'There is a huge unmet need for new antifibrotic therapies which can complement current treatments and potentially provide greater benefit for patients in need of new treatment options. I look forward to collaborating with Blade as it advances the clinical development of this investigational therapy.'"

Media quote • Idiopathic Pulmonary Fibrosis • Pulmonary Disease • Respiratory Diseases

Dedicated Drug-Drug Interaction (DDI) Study in Healthy Volunteers (clinicaltrials.gov) - P1 | N=86 | Completed | Sponsor: Blade Therapeutics | Recruiting ➔ Completed

Trial completion

Blade Therapeutics Announces Feedback from FDA on End-of-Phase 1 Data Package (Businesswire) - "Blade Therapeutics...announced receipt of feedback from the FDA regarding the company’s end-of-phase 1 data package for cudetaxestat, an investigational non-competitive autotaxin inhibitor in clinical development for treatment of IPF and other fibrotic diseases. The FDA response letter outlined requirements for a proposed phase 2 PoC/dose ranging study for use of cudetaxestat in patients with IPF. Based on the FDA feedback, Blade plans to advance cudetaxestat into a 26-week global phase 2 trial in patients with IPF in the second quarter of 2022, pending completion of preclinical toxicology studies."

FDA event • New P2 trial • Preclinical • Idiopathic Pulmonary Fibrosis

Nucleotide pyrophosphatase/phosphodiesterases (NPPs) including NPP1 and NPP2/ ATX as important drug targets: A patent review (2015-2020). (PubMed, Expert Opin Ther Pat) - "In addition to IOA-289 which has passed Phase Ia clinical trials; potent ATX inhibitor compounds such as BLD-0409, IPF and BBT-877 have been placed in phase I clinical studies. Some of the most promising ATX inhibitors in recent years are closely related analogs of previously known inhibitors, such as PF-8380. Knowledge of the structure activity relationship of such promising inhibitors can potentially translate into the discovery of more potent and effective inhibitors of NPP with a variety of structural characteristics and favourable therapeutic activities."

Journal • Review • CNS Disorders • Dermatology • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Inflammation • Multiple Sclerosis • Oncology • Pruritus • Pulmonary Disease • Respiratory Diseases

Blade Therapeutics to Present Data from Preclinical and Phase 1 Studies of Cudetaxestat at the American Thoracic Society 2022 International Conference (Businesswire) - "Blade Therapeutics...today announced that the company will present data for cudetaxestat in three posters at the American Thoracic Society (ATS) 2022 International Conference, May 13-18, 2022, The Moscone Center, in San Francisco. The poster presentations will include new data from a phase 1 drug-drug interaction clinical study of cudetaxestat, an investigational non-competitive autotaxin inhibitor in clinical development for IPF and other fibrotic diseases. The company will also present data from preclinical drug-drug interaction studies of cudetaxestat."

P1 data • Preclinical • Idiopathic Pulmonary Fibrosis

Blade Therapeutics Announces Successful Completion of Phase 1 Clinical Study that Evaluated Co-Administration of Cudetaxestat with Either of Two Approved Therapies for Idiopathic Pulmonary Fibrosis (Businesswire) - P1, N=83; Blade Therapeutics (NCT04939467); "Toby Maher, M.D., Ph.D....said, 'Existing treatments slow, but do not prevent, progression of fibrosis and the development of respiratory failure. There is a huge unmet need for new antifibrotic therapies which can complement current treatments and provide greater benefit for patients. This phase 1 study of cudetaxestat provides a clear path to proceed into a phase 2 study that addresses this need for novel therapeutics that may be administered together with current anti-fibrotic drugs.'"

Media quote • P1 data • Idiopathic Pulmonary Fibrosis • Pulmonary Disease • Respiratory Diseases

Blade Therapeutics Announces Successful Completion of Phase 1 Clinical Study that Evaluated Co-Administration of Cudetaxestat with Either of Two Approved Therapies for Idiopathic Pulmonary Fibrosis (Businesswire) - "Blade Therapeutics, Inc...announced the successful completion of a phase 1 drug-drug interaction clinical study of cudetaxestat, an investigational non-competitive autotaxin inhibitor in clinical development for IPF and other fibrotic diseases...Blade expects to submit an end-of-phase 1 data package to the FDA in the first quarter of 2022 prior to planned discussions with regulatory authorities to further inform the clinical development program for cudetaxestat. The company plans to start a phase 2 clinical study of cudetaxestat in patients with IPF in the second quarter of 2022."

New P2 trial • Trial completion • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology