Tanezumab helps osteoarthritis but trials halted

After halting studies on tanezumab, a drug that is extremely good at relieving pain and improving function in patients with moderate to severe osteoarthritis, a small phase II clinical trial has reported just a few slight side effects, and considerable improvement in the condition of patients. Details of the 16-week trial have been published in the New England Journal of Medicine. Previous longer-lasting trials have revealed that tanezumab may speed up the progression of osteoarthritis – the trial was subsequently suspended until the FDA (Food and Drug Administration) could check trial data and decide on its safety. Researchers believe this occurred because the drug worked too well – some patients may have overused their joints because the pain had gone, and damaged them more.

NSAIDs (non-steroidal anti-inflammatory inhibitors) are commonly used to treat osteoarthritis symptoms, however when used long term they can lead to serious problems, such as heart attacks, strokes, gastrointestinal bleeding, kidney dysfunction and ulcers. Examples of such medications include, aspirin, naproxen, ibuprofen and COX-2 inhibitors such as Celebrex and Vioxx.

Osteoarthritis

Treatment with tanezumab, a monoclonal antibody that targets nerve growth factor, led to significant improvements in osteoarthritis knee pain, a phase II proof-of-concept study showed.

Patients who received various doses of tanezumab had significant reductions ranging from 31 to 45.2 points in knee pain while walking, as assessed on a 100-point visual analogue scale, compared with a change of 15.5 points for patients receiving placebo, according to Nancy E. Lane, MD, of the University of California Davis in Sacramento, and colleagues.

This represented reductions in pain of 45% to 62% for tanezumab versus 22% for placebo (P<0.001), the investigators reported online in the New England Journal of Medicine.

However, reports of progressively worsening osteoarthritis that emerged following completion of this study have led the FDA to put a hold on the tanezumab clinical development program.

The reports included 16 patients who had radiographic evidence of bone necrosis that required total joint replacement, according to the investigators.

Osteoarthritis

In an editorial accompanying the study, John N. Wood, DSc, of the University of London, explained that these instances of joint failure probably can be attributed to excess wear and tear on the joint when pain is absent.

“Pain has an important role in the avoidance of self-harm, but chronic inflammatory pain has generally been considered to be wholly undesirable. The study by Lane et al suggests that a complete quenching of pain in patients with osteoarthritis may not necessarily be a good thing,” Wood wrote.

The study itself included 440 patients from 46 centers in the U.S. More than half were women, and mean age was about 60 years.

The drug was given as two intravenous injections, on days one and 56, in doses of 10, 25, 50, 100, or 200 ?g per kg body weight.

Mean increases in patient global assessment (in which an increase in score indicates improvement) during 16 weeks of treatment ranged from 16.3 to 23.7 points in the active treatment groups, compared with 9.2 points in the placebo group, which represented increases of 29% to 47% compared with 19% for placebo (P?0.001).

Significant reductions also were seen on these secondary outcomes compared with placebo:

* Overall knee pain, 43% to 62% versus 23% (P<0.001)
* Mean Western Ontario and McMaster University Osteoarthritis index scores for pain, 46% to 64% versus 23% (P<0.001)
* Stiffness, 48% to 65% versus 22% (P<0.001)
* Physical function, 47% to 65% versus 22% (P<0.001)

In addition, rescue medications (acetaminophen, tramadol) were used less often by patients in the tanezumab groups (OR 0.50, 95% CI 0.24 to 1.02, P=0.05).

Osteoarthritis

The most common adverse events associated with tanezumab were headache, upper respiratory tract infection, and paresthesia, and adverse events were seen more frequently among patients on higher doses.

Mild-to-moderate paresthesias — changes in sensation in the extremities and in deep-tendon reflexes — were reported by 14% of patients on tanezumab and by 4% of those on placebo.

Mean time to onset of these sensory symptoms was 33 days, and mean duration was 18 days.

Serious adverse events, including bacterial arthritis and cellulitis, occurred in 2% of patients receiving the active treatment, and 6% withdrew because of adverse events.

Limitations of the study were the absence of a comparison group given a different active treatment, insufficient numbers to analyze efficacy according to dose, and lack of long-term data.

The investigators concluded that the efficacy profile for tanezumab was favorable, but called for more safety data.

“Longer trials involving larger samples are needed to better understand safety and tolerability issues and explore the clinical potential of tanezumab as an alternative to current pharmacologic treatments,” they wrote.