Drug With Potential To Ease Pain in Osteoarthritis Moves to Clinical Trial

Results from an animal study published in Science Translational Medicine demonstrate that a drug compound can disrupt overactivation of inflammation and manage pain and stiffness in osteoarthritis. The drug will be tested in upcoming Phase I and IIa clinical trials.

Immune system attack

Osteoarthritis (OA) is the most common type of arthritis, affecting over 32.5 million adults in the US. Currently, there is no cure for OA and doctors may recommend physical therapy, exercise, painkillers or even joint replacement surgery to ease the pain and stiffness caused by hyperinflammation. These remedies are often not enough to restore function and eliminate the severe pain caused by the tiny bone spikes that grow on chronically inflamed joints. An estimated 3% of OA patients become addicted to opioids as a result.

GP130 is an important cell receptor in the immune system, mobilizing antibodies to attack in the event of an infection. In OA, this receptor rallies an attack on broken pieces of cartilage from our own joints. Targeting this receptor therefore shows promise for OA, but it’s not so cut and dry. Denis Evseenko, MD, PhD, professor of orthopaedic surgery, stem cell research and regenerative medicine at the Keck School of Medicine, said: “GP130 is a vital receptor. You cannot inhibit it, because it’s needed for healthy stem cells, as well as cardiovascular and immune function.”

Blocking just one of GP130’s signaling cascades, however, could prevent the hyperinflammatory response characteristic of OA without preventing its vital functions.

The drug in question

To confirm that blocking the signaling cascade could halt the cellular processes behind the hyperinflammation in OA, the Genome Modification Facility at the Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC genetically modified a mouse to prevent a specific GP130 signaling cascade from being activated. In response to this, the mouse showed signs of resistance to arthritis and superior healing and regenerative capabilities compared to other mice. “No white blood cells rushed to the scene and no hyperinflammation occurred,” Evseenko said.

Evseenko and colleagues then studied the effect of a drug compound, R805/CX-011, in mice and other animal models. The drug’s effects were tested in three different doses, then compared to a placebo control group. The compound was able to disrupt the receptor’s over-activation of inflammation while managing pain and stiffness. “We saw a profound effect on joint pain, structure and function,” said Evseenko. 

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Key Steps in Drug Development

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Future trials

The positive results gathered using animal models give researchers hope for its potential in humans and this year, the team plan to launch a combined safety and preliminary efficacy clinical trial (Phases I and IIa) of R805/CX-011 for the treatment of OA in patients.

The trials will test knee injections of R805/CX-011 in up to 70 patients.

Injections of the drug may offer a less expensive, less invasive option that could be delivered several times a year in an outpatient clinic with the potential to delay or even reduce the need for joint replacement surgery.

The researchers also intend to test the efficacy of R805/CX-011 for promoting tissue regeneration in a variety of other conditions, such as pulmonary fibrosis and bone loss as a result of chronic obesity.

Reference: Shkhyan R, Flynn C, Lamoure E, et al. Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis. Sci. Transl. Med. 2023;15(688):eabq2395. doi: 10.1126/scitranslmed.abq2395

This article is a rework of a press release issued by Keck School of Medicine of University of Southern California. Material has been edited for length and content.