Tanezumab, Tulranumab Trials Approved by FDA

That same year, after similar problems emerged with other anti-NGFs in clinical trials — like REGN475, being developed by Regeneron Pharmaceuticals Inc in cooperation with Sanofi-Aventis and fulranumab by Johnson & Johnson. In December that year the FDA put a research hold on all drugs in the class, halting studies by both Johnson & Johnson and Regeneron. Last year, the agency lifted the stay on a trial for fulranumab for cancer pain — but studies for osteoarthritis still remain on hold.

“Physicians and patients are in need of options for difficult-to-treat pain conditions and the panel’s vote is an important step toward helping us more fully understand the benefit-risk profile of this important new class of medicines,” says Steve Romano, a senior vice president at Pfizer. Before the trials were halted, analysts had projected peak global sales for tanezumab above US$1 billion a year.

Mission: find out why this happens
The resumed trials should also find out if anti-NGF cause damage and if so, why.

Some rheumatologists speculate that the pain medication is so effective that people tend to be more active and overuse their damaged joints. A patient on anti-NGFs “is able to sense traumatic damage like small fractures due to a lack of sensation, and therefore keep using the joint, adding to the damage, until it’s an end-stage joint requiring joint replacement,” the magazine Arthritis Today quotes Dr. Amanda Nelson as saying.

Dr. Nelson is a practicing rheumatologist and researcher in osteoarthritis and epidemiology at the Thurston Arthritis Research Center at the University of North Carolina at Chapel Hill. While she hasn’t conducted any study on anti-NGFs, she has helped analyze data from patients with osteoarthritis as background material for Janssen Pharmaceuticals.

Another possibility is that anti-NGFs affect the blood supply to the joint. “The idea regarding blood supply is that the NGF also has a role in the process of angiogenesis — or new blood vessel formation — and somehow by blocking NGF, there’s a loss of blood flow to the joint, leading to bone death,” Dr. Nelson says.

Renewed trials should first try to rule out whether the adverse events were evidence of osteonecrosis — or bone death caused by poor blood supply — or if patients’ osteoarthritis naturally progressed to a point where bone and cartilage deteriorated. Could some of the patients who experienced side effects be predisposed to bone fractures that exacerbate arthritis?

Another issue that needs to be clarified is the muddling of data by patients using anti-NGFs with older painkillers.

This is the main industry argument, and Pfizer points out that accelerated osteoarthritis has been reported with anti-inflammatory drugs since the 1960s — but an exact causal relationship has never been established.

A higher rate of joint problems among patients taking nerve-inhibitors and NSAIDs at the same time also showed up in data analyses by the FDA. But patients taking the newer anti-NGFs alone also showed bone deterioration. To isolate the reason, future studies shouldn’t allow the new drugs to be mixed with older medications, the FDA said.

And while their research is at different stages, all three companies present at the March 12 public meeting agreed that the problems were likely connected combining the anti-NGFs with NSAIDs — as well as to the size of the dose.

What the FDA and drugmakers agreed on was this: They’d restart the drug trials on the anti-NGFs alone, making sure that all participants are off NSAIDs during the study. Trials will also be done on limited doses of the new nerve-inhibitors and patients with advanced osteoarthritis will be excluded from the study.

Dr. Nancy E. Lane, a professor of medicine and rheumatology at the University of California, Davis, and one of the authors of the trial that tested Pfizer’s tanezumab applauded the FDA panel’s recommendation to continue with the research.

“The early stages show it can be quite effective, and I think if it’s shown to be safe in additional studies, it will be a useful medication to treat pain for our patients,” she says.

“Anything that has the hope of helping pain patients is worth pursuing,” says Susan Broyles, the patient representative on the panel.

Drugmakers often abandon research on experimental drugs when safety issues crop up, but Pfizer, Johnson & Johnson and Regeneron had all asked the FDA to lift the moratorium on testing of their drugs.

With more than 50 million U.S. adults diagnosed with arthritis — one in five — the potential multibillion dollar market opportunity may be too big to ignore. Analysts expect the medicines, once approved, to generate as much as US$11 billion a year.

The FDA released its safety analysis to the public on March 8, ahead of Monday’s public meeting.

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