SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Blade Therapeutics, Inc. (Blade or the Company), a biopharmaceutical company focused on developing cutting-edge treatments for fibrotic and neurodegenerative diseases, today announced positive preliminary data from a new preclinical study of cudetaxestat, an investigational non-competitive autotaxin inhibitor in clinical development for IPF. This preclinical study was designed to understand whether the plasma concentration of nintedanib is altered when co-administered at steady state with either cudetaxestat or GLPG-1690 (ziritaxestat).
In an in vivo pharmacokinetics study, co-administration of cudetaxestat with nintedanib at a steady state resulted in no significant changes (p=ns) in either maximal plasma concentration (Cmax) or area under the concentration-time curve (AUC) for nintedanib. Study results also showed that GLPG-1690, an investigational competitive autotaxin inhibitor from Galapagos NV, significantly increased plasma concentration of nintedanib when co-administered at a steady state, with a 1.8-fold increase (p ≤ 0.05) in Cmax and a 2.8-fold increase (p ≤ 0.001) in AUC. Nintedanib was shown in this study to not affect plasma concentrations of either cudetaxestat or GLPG-1690. Nintedanib, a medicine from Boehringer Ingelheim, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of IPF.
“We believe that these are important data that help inform our step-wise approach to advance the clinical development program for cudetaxestat,” said Wendye Robbins, M.D., president and CEO of Blade. “Based on preclinical in vivo and in vitro studies conducted to date with cudetaxestat, we believe there is low potential risk for drug-drug interactions with either of the approved drugs for IPF – pirfenidone or nintedanib.”
In the preclinical study, 18 male rats received daily oral administration with nintedanib only during study days one through four. During study days five through 11, one group of nine subjects received daily oral co-administration of nintedanib and GLPG-1690, and a second group of nine subjects received daily oral co-administration of nintedanib and cudetaxestat. The study was conducted by an independent laboratory. Blade plans to further analyze data from this study and intends to submit study data for potential publication in a peer-reviewed scientific journal.
Blade also recently completed a phase 1 clinical study in healthy volunteers investigating the relative bioavailability of a new tablet formulation of cudetaxestat to the oral solution formulation (NCT04814472). Study findings showed comparable pharmacokinetics and pharmacodynamics profile for the two formulations and a favorable tolerability profile with no severe adverse events or drop-outs due to adverse events.
The Company is currently conducting an ongoing phase 1 study of cudetaxestat in healthy volunteers to evaluate the effect of cudetaxestat on the pharmacokinetics of a combination of probe substrates for CYP450 enzymes (NCT04814498). The study remains on track and is expected to complete in the second half of 2021.
Blade plans to initiate a phase 1 clinical study (NCT04939467) in healthy volunteers to assess the effect of cudetaxestat on the pharmacokinetics of nintedanib and pirfenidone. This study is projected to start in the second half of 2021 and complete in the first half of 2022. Study results will be used to inform the design of a planned phase 2 clinical trial to evaluate the efficacy and safety of cudetaxestat in patients with IPF, which is anticipated to start in the first half of 2022.
Cudetaxestat (BLD-0409), a non-competitive, reversible inhibitor of autotaxin, has demonstrated direct anti-fibrotic activity and differentiating pre-clinical and biochemical characteristics which support the potential for a treatment profile in lung and liver fibrosis. Available data from a completed phase 1 study (NCT04146805) showed that cudetaxestat was well tolerated with a demonstrated pharmacokinetic/pharmacodynamic correlation and biomarker activity, and a supportive clinical safety profile. Orphan drug designation for cudetaxestat in the treatment of IPF was granted by the FDA in February 2021. Cudetaxestat is an investigational medicine that is not approved for commercial use by the FDA or any other regulatory authority.
Pro-fibrotic processes are stimulated by autotaxin, a key enzyme responsible for generating the potent signaling lipid lysophosphatidic acid (LPA). Excessive autotaxin levels and activity play a central role in various fibrotic diseases and occur in response to epithelial cell/tissue damage, leading to elevated levels of LPA. Lysophosphatidic acid binds to LPA receptors on myofibroblasts, thereby triggering a signaling cascade that leads to myofibroblast activation/differentiation. Activated myofibroblasts produce extracellular matrix proteins that make up the fibrotic lesion (organ/tissue scarring). Increased autotaxin levels and activity are associated with liver, lung, kidney, and skin fibrosis. In addition, autotaxin levels correlate with fibrosis severity in various liver diseases (e.g., nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH)). Inhibition of the autotaxin pathway has been clinically validated in IPF.
Fibrosis is a complex, pathologic process involving the development of organ/tissue scarring characterized by deposition of extracellular matrix proteins that develop in response to aberrant cell/tissue damage. Excessive fibrosis disrupts normal architecture and function of organs/tissues. Later-stage fibrotic disease is marked by poor outcomes and high morbidity and mortality. Diseases characterized by uncontrolled, progressive fibrosis include IPF, interstitial lung disease, and NASH. New well-tolerated therapies that provide robust attenuation of disease progression are needed to address the high burden of fibrotic and neurodegenerative diseases.
Blade Therapeutics, Inc. is a biopharmaceutical company focused on developing cutting-edge treatments for fibrotic and neurodegenerative diseases that impact millions of people worldwide. The Company is a leader in novel biological pathways – including autotaxin/LPA and calpain biology – that are foundational to cell- and tissue-damage responses for diseases that result from protein deposition (fibrosis) or protein aggregation (neurodegeneration) that disrupt normal cellular, tissue or organ function. Blade is advancing a differentiated pipeline of oral, small-molecule therapies that include a non-competitive autotaxin inhibitor and multiple inhibitors of dimeric calpains designed for potential treatment of lung, liver and cardiac fibrosis or neurodegenerative diseases. The Company’s focused approach offers the potential to produce disease-modifying, life-saving therapies.