With Positive Early Findings, Phase 2 Cudetaxestat Trial Expected Soon
Blade Therapeutics’ experimental oral therapy, Cudetaxestat (BLD-0409), was found to significantly reduce lung scarring (fibrosis) and the levels of fibrotic markers and pro-fibrotic molecules in a mouse model of pulmonary fibrosis.
“Cudetaxestat displayed direct anti-fibrotic effects on multiple biomarkers in a preclinical lung fibrosis model,” Blade said in a press release, adding that the company is now “on track to start [a] Phase 2 clinical trial of cudetaxestat in patients with idiopathic pulmonary fibrosis (IPF) in [the] second quarter of 2022.”
Notably, the observed effects of cudetaxestat — which blocks an enzyme called autotaxin — were dose-dependent. That contrasts with the linear effects of ziritaxestat (GLPG1690), an autotaxin suppressor whose development for IPF was discontinued last year due to a non-favorable benefit-risk profile.
These differences may be related to the fact that ziritaxestat, contrary to cudetaxestat, competes with autotoxin’s substrate — the underlying substance on which the enzyme normally acts — for the same enzymatic region. That means its suppressing effects may be particularly limited when the substrate is present at high levels.
“We are encouraged by the profile of cudetaxestat, which we believe is a clearly differentiated molecule based on its direct anti-fibrotic activity and non-competitive inhibition of autotaxin,” said Wendye Robbins, MD, Blade’s president and CEO.
These preclinical findings were presented at the American Thoracic Society (ATS) 2022 International Conference, held in San Francisco, May 13–18. The poster presentation was titled “Differentiating Characteristics of Cudetaxestat (BLD-0409), a Non-Competitive Autotaxin Inhibitor Under Development to Treat Idiopathic Pulmonary Fibrosis.”
Based on these new data, and positive safety findings in previous Phase 1 trials in healthy volunteers, the company is planning to launch a Phase 2 trial in the upcoming months. That trial will evaluate cudetaxestat in people with IPF.
“We look forward to advancing cudetaxestat into the next phase of clinical development as we execute on our mission to bring life changing treatments to people with fibrotic diseases,” Robbins added.
Cudetaxestat is an orally available molecule designed to block the activity of autotaxin, an enzyme that transforms lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a pro-fibrotic signaling molecule.
Notably, “tissue levels of ATX [autotaxin] and LPA are elevated in fibrotic disease states including idiopathic pulmonary fibrosis (IPF),” the researchers wrote. Therefore, that makes the suppression of the ATX-LPA pathway “a compelling therapeutic strategy” for IPF, they said.
In Phase 1 trials with healthy volunteers, cudetaxestat showed favorable safety and pharmacological profiles both alone and in combination with either Ofev (nintedanib) or Esbriet (pirfenidone) — two approved oral treatments for IPF.
Now, Blade presented new preclinical data further supporting the therapy’s differentiating features.
When looking at the mechanisms of action of cudetaxestat and ziritaxestat — known as a competitive, oral suppressor of autotaxin — the researchers found that their experimental therapy exerts a reversible, non-competitive suppression of autotaxin. This means that cudetaxestat blocks the enzyme by binding to a distinct region rather than interacting with its LPC substrate.
As such, and contrary to ziritaxestat, cudetaxestat’s potency was maintained in the presence of high LPC levels — similar to those found in fibrotic tissues. Notably, Blade’s experimental therapy was found to have a 160-times greater potency relative to ziritaxestat.
In addition, daily treatment with cudetaxestat significantly reduced lung fibrosis and the levels of fibrotic markers, such as collagen and alpha-smooth muscle actin, in a mouse model of pulmonary fibrosis.
Suppression of the ATX-LPA pathway with cudetaxestat also was found to significantly lower, and generally normalize, the levels of several key pro-fibrotic molecules in these animals.
These findings supported the therapy’s direct anti-fibrotic effects.
Notably, these effects “were dose-dependent while [ziritaxestat] did not display dose-dependence at the same doses tested,” the researchers wrote.
While both therapies “showed similar reductions of [blood] LPA levels, efficacy differences may be reflective of non-competitive vs. competitive inhibition as well as differences in tissue penetration and pathway modulation,” the team wrote.
“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,” the researchers wrote.
“Cudetaxestat displays clear efficacy advantages on multiple biomarkers in a preclinical lung fibrosis model supporting its potential for differentiated therapeutic outcomes,” they wrote.
In an open letter to the lung disease community, Robbins stressed Blade’s “commitment to find new pharmacologic options to improve patient outcomes.”
“Blade has deep expertise in novel biological pathways that are foundational to cell- and tissue-damage responses that [underlie] fibrosis,” Robbins said. “We believe that our focused approach offers the potential to produce disease-modifying, life-saving therapies.”