EHP-101’s Active Ingredient Helps Tissues Thrive in Low Oxygen

Phase 2 trial testing therapy's safety, effectiveness is still enrolling participants

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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A trio of mice climb in and around a beaker and several vials of blood in a laboratory.

The active ingredient of EHP-101, a cannabidiol-derived medicine being developed by Emerald Health Pharmaceuticals (EHP), can set in motion a tissue’s response to low oxygen or hypoxia, which backs its use for  treating systemic sclerosis (SSc) and multiple sclerosis (MS), a study in cells and mice found.

These findings “validate EHP-101’s unique ability to address key disease factors associated with the complex pathophysiology [underlying processes] of fibrotic [scarring] and demyelinating diseases such as SSc and MS through complementary specific mechanisms of action,” Alain Rolland, PhD, chief operating officer of EHP, said in a press release. Demyelination refers to loss of myelin, the protective sheath of nerve fibers.

The company has a Phase 2 clinical trial (NCT04166552) underway that’s testing how safe EHP-101 is and how well it works versus a placebo to ease symptoms of diffuse forms of SSc in adults.

The trial is halfway through its enrollment and is taking in more participants at locations in the U.S. (including Puerto Rico), Australia, and New Zealand.

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The study, “A cannabidiol aminoquinone derivative activates the PP2A/B55α/HIF pathway and shows protective effects in a murine model of traumatic brain injury,” was published in the Journal of Neuroinflammation.

Scleroderma occurs when the immune system becomes overactive and launches an attack against the connective tissue beneath the skin, causing it to thicken and scar.

In the systemic type of scleroderma, the attack also reaches the connective tissue around the blood vessels and internal organs. The thickening and scarring can make it hard for oxygen to find its way to tissues. When tissues are starved of oxygen, their cells are unable to make enough energy to keep working as they should. This is called hypoxia.

Testing EHP-101’s active ingredient

Scientists at EHP think EHP-101 may reduce the symptoms of scleroderma by activating anti-inflammatory pathways in the body. EHP-101’s active ingredient is VCE-004.8, a lab-made version of cannabidiol (a compound found in the cannabis plant).

To learn how VCE-004.8 does this, the scientists teamed up with researchers in Spain and Belgium.

In lab-grown cells, they observed that VCE-004.8 inhibits the action of an enzyme PHD2. This enzyme breaks down part of the hypoxia-inducible factor (HIF) protein complex, which helps the body’s tissues adapt to too little oxygen. By inhibiting PHD2, more HIF remains available to make the best use of the amount of oxygen that reaches the tissues.

VCE-004.8 did this by switching on B55-alpha, a subunit of a protein complex called PP2A.

Switching on B55-alpha may change how blood vessels grow or arrange themselves. To test this, a gel that mimics the matrix in which cells normally develop was injected under the back skin of mice, which were then given daily into-the-belly injections of VCE-004.8 for a week. VEGF, a protein that helps new blood vessels grow (a process called angiogenesis), was used as a positive control.

Compared to a control gel with no blood vessel growth, VEGF led to a reddish gel that indicated the presence of blood vessels. The gel of VCE-004.8-treated mice was dark red, meaning more blood vessels had grown. These vessels were not leaky, but were instead able to deliver the blood into the gel.

This “provides a new mechanism to treat diseases where vascular integrity is compromised,” the press release stated.

The research team then turned to a mouse model of traumatic brain injury (TBI) wherein inflammation follows damage caused to a specific area of the brain. This makes the mice lose weight and affects their ability to run on a rotating rod (rotarod) as early as one day after the damage.

But treating the mice with daily into-the-belly injections of VCE-004.8, starting one hour after the damage and for up to a week, significantly reduced weight loss and increased the time they could stay on the rotarod compared to no treatment.

A deeper look into the damaged area revealed more new blood vessels, less inflammation, and healthier nerve cells in VCE-004.8-treated mice than in the no-treatment group.

“This study provides new insight about the mechanism of action of VCE-004.8,” the scientists concluded. “Furthermore, we show the potential efficacy for TBI treatment.”