Prometic’s PBI-4050 Plays Dual Role in Targeting New Antifibrotic Pathway, Study Says

PBI-4050, Prometic Life Sciences’ lead therapy candidate, works through a dual mechanism to target a newly discovered pathway, involving the receptors GPR40 and GPR84, that is critical to fibrosis development, a study shows.

The study, “A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84,” was published in the American Journal of Pathology.

Fibrosis occurs when there is an excessive accumulation of extracellular matrix (ECM) components in damaged or inflamed tissues, as a result of many inflammatory and metabolic diseases. There is a vital need for therapies that can effectively target biological pathways that lead to fibrosis.

PBI-4050 is an oral therapy candidate that has been shown to be safe and effective in animal models of fibrosis, including the lung, liver, heart, kidney, and pancreas.

It binds to two receptors on cells — GPR40 and GPR84 — known to be involved in diverse physiological processes related to metabolic regulation and inflammation, but their role in fibrosis has not been identified until now.

To investigate the role of these receptors in fibrotic processes, researchers developed multiple mouse models of kidney fibrosis that lacked either GPR40 or GPR84.

Using these animal models, researchers found that GPR40 has a protective role while GPR84 has a damaging role in fibrotic diseases. The same results were seen in other models of fibrosis, including the liver, heart, lung, pancreas, and skin.

In binding to cells, PBI-4050 activates the receptor GPR40, while it suppresses GPR84 activity, which researchers believe is beneficial in the context of fibrosis.

“In studying the mechanism of action of PBI-4050, we have clearly demonstrated the contribution of two fatty acid receptors, GPR40 and GPR84, in the regulation of cells involved in fibrosis, including macrophages, epithelial cells and fibroblasts,” Lyne Gagnon, the study’s lead author and Prometic’s vice president of R&D Pre-clinical, said in a press release.

“Our data show that GPR40 and GPR84 modulate fibrotic disease progression. Therefore, by targeting this novel antifibrotic pathway, PBI-4050 and its analogues have the potential to delay or even reverse the progression of fibrotic diseases,” Gagnon said.

The benefits of PBI-4050 seen in animal models also were demonstrated in Phase 2 studies (NCT02538536) in idiopathic pulmonary fibrosis (IPF), in metabolic syndrome with Type 2 diabetes, and in Alström syndrome patients.

PBI-4050 is entering pivotal placebo-controlled Phase 3 clinical trials for the treatment of IPF, for which Prometic is hoping to begin enrollment by mid-2018, and Phase 2 trials in metabolic syndrome and Type 2 diabetes.

“We have seen the benefits of PBI-4050 in the treatment of fibrotic diseases. Now, having an understanding of the unique mechanism of action of PBI-4050, we are more confident than ever in its potential to help patients suffering from fibrosis-related conditions such as IPF and Alström Syndrome,” said Pierre Laurin, CEO of Prometric.

“We look forward to initiating our Phase 3 pivotal clinical trial for PBI-4050 in IPF, expanding the program in Alström Syndrome and to advancing follow-on analogues of PBI-4050 in clinical programs targeting other large fibrosis-related unmet medical needs,” he said.