A pain drug discovery success story: anti-NGF therapy for osteoarthritis

ResearchBlogging.orgWith all the recent layoffs in Pharma, coupled with the axing of many analgesic drug development programs within these institutions, its nice to finally see a success (albeit of potentially short longevity — more on that later). The treatment is Tanezumab. Tanezumab is a humanized antibody against nerve growth factor (NGF). The biologic effectively blocks NGF interaction with its receptors, TrkA and p75. Basic researchers in the pain field have been working on the idea of blocking NGF function as a pain treatment for some time now. In fact, I’ve written about this before:

[in response to a question from Whimple] On your other question, are there examples where the clinical never would have been possible without the preclinical the answer is also yes. My example is not a good one because I likely would have been able to instigate a trial but it would have been much more difficult without the preclinical. On the other hand, the anti-NGF treatments for chronic pain are an excellent example of where it would not have been possible. We have known for a long time that NGF is involved in preclinical pain models and in human pain. We have also known that genetic mutations in humans that block NGF signaling (mostly receptor mutations) cause a terrible disease wherein people with the mutation have profound mental retardation, total lack of pain and inability to sweat. While it was the view of most researchers that this was due to a developmental issue, it was not known if blocking NGF signaling later in life would lead to similar deficits and this made any trial on anti-NGF therapies impossible due to very serious safety issues. After decades of preclinical work it is now known that anti-NGF treatments later in life do not cause similar problems and this animal work has made the safety issue a much smaller issue. So, due to literally thousands of papers on NGF signaling in animal models we have a good idea that these treatments will not cause devastating side effects in humans and these therapies are now late in clinical development. If they gain FDA approval I expect that they will become important treatments for chronic pain disorders. That is but one of several examples wherein animal work was absolutely neccessary to develop new pain treatments.

Onto the trial… (Lane et al. 2010 NEJM) The idea was to see if tanezumab would have efficacy for osteoarthritic knee pain. Rather than looking for efficacy in a currently treatable population, the investigators went for the gold and chose to study the effect of tanezumab in advanced osteoarthritis of the knee patients that did not receive pain relief from analgesics (mainly opiates) that are generally used in this patient population. They recruited about 450 patients and broke them into 6 groups: placebo and escalating doses of tanezumab. Treatment was given over 16 weeks and after that time frame they moved to open label. The results are striking:

They looked at 3 major endpoints: 1) pain while walking, 2) patient assessment of global response and 3) WOMAC score, which is basically a functionality assessment. For the endpoints, all but the lowest dose of tanezumab showed efficacy in all 3 measures.

For knee pain while walking:

As compared with placebo, tanezumab, at all the doses studied, was associated with an improvement in the primary efficacy measures. The mean reduction from baseline in the score on the visual-analogue scale for knee pain while walking, averaged over weeks 1 through 16, ranged from 31.0 to 45.2 points with various doses of tanezumab, as compared with 15.5 points with placebo (a reduction of 45 to 62% with tanezumab vs. 22% with placebo, P<0.001 for the comparison of all doses of tanezumab with placebo) (Fig. 2A). We observed significant improvements among patients receiving tanezumab as compared with those receiving placebo by the end of the first week, and significant improvements continued to be seen throughout the remainder of the treatment period. The mean increase from baseline in the score on the patient’s global assessment of response to therapy, averaged over weeks 1 through 16, ranged from 16.3 to 23.7 points with various doses of tanezumab, as compared with 9.2 points with placebo (an increase of 29 to 47% with tanezumab vs. 19% with placebo, P≤0.001 for the comparison of all doses of tanezumab with placebo) (Fig. 2B). By week 2, the scores on the patient’s global assessment had improved in the group receiving 25 μg of tanezumab per kilogram, as compared with placebo (P = 0.002); by week 4, the scores had improved in the groups receiving 50 μg, 100 μg, and 200 μg of tanezumab per kilogram, as compared with placebo (P = 0.01, P<0.001, and P<0.001 for the three comparisons, respectively); and during weeks 10 and 12, the scores improved in the group receiving tanezumab at a dose of 10 μg per kilogram, as compared with placebo (P = 0.008).

Here’s the graph:

WOMAC scores also looked very good (here is the table):

I think this is pretty remarkable as it suggests that, in addition to pain, some of the other major complaints of knee osteoarthritis were also markedly improved by tanezumab. It so happens that I have osteoarthritis in my left knee (one of the many gifts that my previous life as a football player left me) and that stiffness measure is a big one (at least for me).

Unfortunately, all the news is not good. Some adverse events were associated with treatment, and as many people in the field predicted, paresthesias were the most common. I suppose when it comes down to it this is going to be a trade-off issue for the patient. Its also going to be important to see if these paresthesias get worse with continuing treatment. This trial went for 16 weeks so it may be reasonable to assume that the paresthesia events will get worse with longer treatments… then again, you never know. But that’s not the end of the bad news. Rumors have been flying about FDA suspension of other tanezumab trials but there is more detail in this paper than I have seen before:

Since the completion of this study and through May 24, 2010, progressively worsening osteoarthritis associated with radiographic evidence of bone necrosis developed in 16 subjects participating in 1 of 13 phase 3 studies of tanezumab for osteoarthritis of the hip and knee; all 16 subjects
required total joint replacements. The affected joints were the knee, hip, or shoulder (predominantly
unilateral involvement), with more than half the cases occurring in a joint other than the index joint under evaluation in the study. These 16 events led the Food and Drug Administration (FDA) on June 22, 2010, to put the osteoarthritis clinical program for tanezumab on clinical hold until more information can be obtained to determine the true incidence and the causality of these events. More recently, the FDA requested the suspension of two additional trials of tanezumab, one involving patients with low back pain and the other involving patients with diabetic neuropathy.

That’s not good, anyway you cut it. We’ll see what happens with this. I understand that cancer pain trials are also ongoing with tanezumab and there is no mention of those trials here. Nevertheless, I’ll take some potentially good news and run with it. While there may be issues with this particular drug that will prevent FDA approval, it is pretty clear that the approach (NGF blockade) is viable for the treatment of severe osteoarthritis pain in humans. If you’re having trouble thinking of another treatment that is effective for severe osteoarthritis pain you should be, there are none. Maybe, just maybe, we just got one step closer.

Lane, N., Schnitzer, T., Birbara, C., Mokhtarani, M., Shelton, D., Smith, M., & Brown, M. (2010). Tanezumab for the Treatment of Pain from Osteoarthritis of the Knee New England Journal of Medicine, 363 (16), 1521-1531 DOI: 10.1056/NEJMoa0901510

2 responses to “A pain drug discovery success story: anti-NGF therapy for osteoarthritis

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