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Friday, October 22, 2021

New painkiller may work dangerously well

A study released Sept. 29 found positive results for “wonder drug” tanezumab[ta-NEZ-oo-mab], Pfizer’s new medication for osteoarthritic pain.

The study appeared in the New England Journal of Medicine just months after the Food and Drug Administration called off tanezumab’s clinical trials. Patients who had tried the drug reported progressively worsening pain that required surgery.

“The need to find new drugs to treat osteoarthritis is critical,” said Nancy Lane, professor of internal medicine and director of the UC Davis Center for Healthy Aging. Lane was the principal investigator on the study. “We really don’t have anything that slows [osteoarthritis], and most people with severe disease end up dependent on narcotic analgesics while waiting to have a joint replaced.”

Pfizer put trials on hold in June, responding to concerns that tanezumab may accelerate osteoarthritis. After being taken off the drug, a number of patients experienced dramatically worse pain than before. Sixteen of them required total joint replacement surgery. Another side effect was paresthesia – a pins and needles sensation.

One alternate explanation is that the drug works too well. Freedom from pain may have made the patients more active than normal, causing extra wear on the joint. Lane’s study may provide clues as to how this happened.

“The study by Lane et al. suggests that a complete quenching of pain in patients with osteoarthritis may not necessarily be a good thing,” wrote John Wood, a biomedical researcher from the University of London, in an editorial published alongside the study.

“The most problematic issue – which has emerged during the Phase 3 study and has resulted in the FDA putting the Phase 3 study and two other studies of tanezumab on hold – has been joint failure, which was most likely caused by excessive wear and tear in the absence of joint pain.”

The problems with tanezumab have recently become a hot topic online.

“I was in the study,” a user named Jacquie commented on an About.com article. “I briefly improved, but [was no more active than usual], and now I am waiting for a joint replacement at age 52. This is ridiculous – tanezumab did not work ‘too well.’ I had some nasty paresthesia, swelling in both of my legs and now cannot walk a city block without severe difficulty.”

Tanezumab is an antibody that prevents pain by attacking nerve growth factor (NGF), a protein that plays a crucial role in pain signaling. NGF is a protein that binds with nerve cells, sending pain signals to the brain.

NGF is sent out from hormone-manufacturing “target tissues,” so named because they’re targeted and switched on by certain hormones. Normally, once it’s released from the target-tissue factory into the bloodstream, NGF diffuses out of the blood, travels through the fluid between body cells and finally lands on nerve cells, where it helps detect and send pain signals. As more NGF is released, a person feels more pain.

But with tanezumab in the patient’s bloodstream, the NGF never makes it to the neurons. Tanezumab has two binding sites on the ends of its Y-shaped branches that are specially configured to catch NGF and keep it locked away.

With NGF largely disabled by the new drug, patients in the study reported significant relief: 45 to 62 percent less pain while walking, with the optimal 10 mg dose. For comparison, the placebo group reported a 22 percent improvement by the end of the 16-week trial.

But, says Lane, more research is clearly needed before trials can progress further.

The study from Nancy Lane’s group was funded by Rinat Neuroscience Corporation, a subsidiary of Pfizer.

EMILY GOYINS can be reached at science@theaggie.org.

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