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Drug May Offer New Approach Against Rheumatoid Arthritis

THURSDAY, May 18, 2023 (HealthDay News) -- An investigational drug may hit the reset button on a faulty immune system for some people with rheumatoid arthritis.

Rheumatoid arthritis, or RA, is an autoimmune disease that occurs when the body misfires against its own joints and tissues, causing joint pain, stiffness, fatigue and other symptoms.

The drug, peresolimab, is a monoclonal antibody that stimulates human programmed cell death protein 1 (PD-1), which serves as the brakes on the immune system, said study author Dr. Ajay Nirula. He's vice president of immunology for Lilly Research Laboratories in San Diego, which is developing peresolimab. It funded the new research, which was published May 17 in the New England Journal of Medicine.

PD-1 is a protein found on T cells that helps keep the body's immune responses in check.

“Some autoimmune disease like RA could be caused by an inability to push the normal brakes on the immune system,” Nirula said. The new drug hits this brake by stimulating PD-1. "We are trying to turn down the immune system by replacing a missing signal,” he added.

And so far, so good, the researchers report.

The new study included 98 people with difficult-to-treat RA. They received 700 mg of peresolimab, 300 mg of peresolimab, or a placebo intravenously once every four weeks.

Compared to folks who got a placebo, participants who took the higher dose of peresolimab had significantly less joint pain, swelling, tenderness and inflammation at 12 weeks as measured on a standard scale assessing RA symptom severity. The safety profiles were similar across all groups in the study.

“We saw a level of efficacy that was intriguing,” Nirula said.

“In the past, steroids were effective in alleviating symptoms of RA, but chronic steroid use has its toxicities, so we moved to different types of drugs that suppress the immune system,” he said.

Then came biologics such as tumor necrosis factor (TNF) alpha-blockers. These drugs target specific proteins, such as TNF, that play a role in stirring the inflammatory cascade, Nirula said.

The new study included people who had not done well on traditional immune-suppressing drugs or existing biologics.

“We saw good responses in both patient populations, and we are looking for medications that work in RA patients who have failed multiple therapeutics,” Nirula said.

PD-1 is also a target of some current cancer drugs, but in cancer, the goal is to shut this pathway down, not stimulate it. Longer studies are needed to see if peresolimab increases cancer risk in people with RA, Nirula noted.

The drug is still a few years away from the bedside, assuming further research pans out and no new safety signals emerge. Results of a phase 2 study are expected next year. If they are positive, it could set the stage for phase 3 clinical trials, which would take two to three years to complete.

Dr. Ellen Gravallese is chief of rheumatology, inflammation and immunity at Brigham and Women’s Hospital in Boston. She co-wrote an editorial that accompanied the new study.

This drug works differently from anything doctors who treat RA have in their toolbox. “It stimulates PD-1 to reset the immune system so it no longer attacks its own joints and bones,” Gravallese said.

When people with RA or other autoimmune diseases stop taking biologics or other immune-suppressing drugs, their symptoms often return, she said.

“Peresolimab might be more permanent,” she said. “If we reset the immune system with a stimulating molecule, we may get away without giving the drug forever.”

More research is needed before any firm conclusions can be drawn. This study was small, and people were followed for just three months. Longer studies are needed to see what side effects emerge, Gravallese said.

“The biggest worry would be whether it allows for cancers to become evident,” she said.

Dr. Anne Bass, a rheumatologist at the Hospital for Special Surgery in New York City, agreed.

“It’s a very interesting approach -- I am excited to see what comes up in a bigger trial,” said Bass, who has no ties to the new research.

“There is a theoretical worry about cancer risk, and that is something to be on the lookout for, but there hasn't been a signal so far,” she said.

More information

The Arthritis Foundation has more on how to treat RA.

SOURCES: Ajay Nirula, MD, PhD, vice president, immunology, Lilly Research Laboratories, San Diego; Ellen Gravallese, MD, professor, Harvard Medical School, chief, Division of Rheumatology, Inflammation and Immunity, Brigham and Women’s Hospital, Boston; Anne Bass, MD, rheumatologist, Hospital for Special Surgery, New York City; New England Journal of Medicine, May 17, 2023

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