Preclinical data presented by Kadmon showed that the Rho-associated coiled-coil kinase (ROCK) pathway is a key player in the development of pulmonary fibrosis (PF), supporting the hypothesis that ROCK inhibition has therapeutic potential for the disease.
The data was shown in a poster presentation at the 2017 Keystone Symposia on Injury, Inflammation and Fibrosis, running from March 26 to 30 in Snowbird, Utah.
Research teams at Kadmon and elsewhere have demonstrated that ROCK signaling influences the development of PF, a disease marked by scarring of the lungs. Specifically, the ROCK pathway works by mediating the signaling of a molecule called transforming growth factor-β (TGF-β) — a master regulator of healing responses that is fundamental to the proper function of numerous tissues.
Targeting ROCK signaling, for this reason, could hold therapeutic potential in fibrosis.
To explore this potential, Kadmon researchers formulated a series of potent small molecule ROCK inhibitors and evaluated their ability to modulate cellular mechanisms that cause aberrant signaling in PF.
Findings showed that ROCK inhibition blocks the expression of α-smooth muscle actin (α-SMA), the central component of myofibroblast cells — cells responsible for the development of fibrosis.
Blocking the ROCK pathway was also seen to reduce endothelial cell and epithelial cell activity, known to contribute to fibrosis-associated progressive organ injury.
“These data demonstrate that ROCK inhibition blocks multiple cell signaling mechanisms that drive pulmonary fibrosis, including α-SMA expression and endothelial and epithelial cell function,” Masha Poyurovsky, PhD, vice president and head of molecular signaling at Kadmon, said in a press release. “By targeting ROCK, we can disrupt fundamental aspects of the TGFβ signaling pathway to potentially treat pulmonary fibrosis.”
Harlan W. Waksal, MD, president and chief executive officer of Kadmon, added, “Through our ROCK research platform, we continue to establish the importance of ROCK signaling in fibrotic disease … These findings further support the clinical development of our ROCK inhibitor KD025, for which we have three ongoing Phase 2 clinical trials, including in idiopathic pulmonary fibrosis (IPF).”
The Phase 2 clinical trial, (NCT02688647), is a randomized and open-label, 24-week U.S. study evaluating the safety, tolerability, and activity of KD025 (400 mg) in IPF patients who were already treated with either Esbriet (pirfenidone) or Ofev (nintedanib). It is expected to conclude shortly.