Cannabinoid-derived Therapies Slow Fibrosis, Block Inflammation in Scleroderma, Mouse Studies Show

Emerald Health’s lead cannabinoid-derived investigational therapy, EHP-101, shows promise as a possible oral treatment for scleroderma, a mouse study shows.

A second cannabinoid-derivative, called VCE-004.3, also showed potential to enhance anti-inflammatory and anti-fibrotic responses in animal models of scleroderma.

Both EHP-101 and VCE-004.3 are derived from cannabidiol (CBD), one of the natural chemicals extracted from the cannabis plant.

EHP-101 is an oral formulation of VCE-004.8, the original cannabinoid-derivative that was previously shown to alleviate fibrosis when injected in a mouse model of skin fibrosis.

The therapies target and activate two receptors, called peroxisome proliferator-activated receptor gamma (PPAR-γ) and CB2 receptors, increasingly recognized for their potential to prevent inflammation and fibrosis.

In the study “EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis,” published in the journal Biochemical Pharmacology, researchers tested whether oral EHP-101 maintained the same therapeutic properties as VCE-004.8.

Researchers used a bleomycin-induced scleroderma mouse model, and showed that EHP-101 also had significant therapeutic effects in easing both skin and lung fibrosis in these animals. Specifically, oral EHP-101 inhibited the accumulation of collagen (a fibrous protein, which precedes fibrosis), and reduced the infiltration of inflammatory cells.

The team also performed a molecular analysis and found that EHP-101 normalized the activity of several markers of fibrosis, including tenascin C, vascular cell adhesion molecule 1 (VCAM1), and the α-smooth muscle actin (SMA).

EHP-101 also had a wide effect in halting the signaling of transforming growth factor (TGF)-beta, an established player in scleroderma development, as it promotes the transformation of fibroblast cells into collagen-forming cells called myofibroblasts.

“Scleroderma is a rare life-threatening disease that causes fibrosis of skin and internal organs. There are currently no scleroderma-specific approved drugs, and existing therapies are not effective and/or have significant toxicities,” Eduardo Muñoz, an MD and PhD, the chief scientific officer at Emerald, said in a press release.

“These findings add to the preclinical evidence that shows the potential of cannabinoid-derived medicines to serve as disease-modifying treatments for scleroderma and help us advance our lead candidate, EHP-101, into clinical trials,” Muñoz added.

Another study published in the British Journal of Pharmacology, titled “VCE‐004.3, a cannabidiol aminoquinone derivative, prevents bleomycin‐induced skin fibrosis and inflammation through PPARγ‐and CB₂ receptor‐dependent pathways,” tested the anti-inflammatory and anti-fibrotic properties of VCE-004.3 in vitro (in the lab) using human skin fibroblasts and two mouse models of bleomycin-induced fibrosis.

Like EHP-101, VCE-004.3 also targets and activates the PPAR-γ and CB2 receptors. However, this molecule carries an additional regulatory function, working as an antagonist of the cannabinoid CB1 receptor, which mediates the psychotropic effects of cannabis.

The team confirmed that VCE-004.3 activated both the PPAR-γ and CB2 receptors while it blocked the CB1 receptor. Moreover, VCE-004.3 inhibited collagen synthesis and prevented the transformation of TGF-beta-induced transition of fibroblasts into myofibroblasts.

Treatment with VCE-004.3 also reduced the activity of inflammatory and profibrotic factors. Researchers tested in parallel two routes of administration of the drug, injected into the abdomen or administered topically, and saw that both eased skin fibrosis.

“VCE-004.3 is a novel cannabinoid derivative that acts as a dual PPARγ/CB2 agonist and as a negative modulator of CB1 receptors. Because of this, it qualifies as a candidate for the development of novel therapies against different forms of scleroderma,” the team concluded.