FDA arthritis advisory panel votes to continue anti-NGF clinical trials

An FDA Arthritis Advisory Committee voted 21-0 to continue development trials for the anti-nerve growth factor class of drugs developed as pain relief treatments for conditions such as osteoarthritis, chronic lower back pain, vertebral fractures, diabetic peripheral neuropathy, post-herpetic neuralgia, endometriosis and cancer due to a lack of data on how the drugs specifically affect bone health.

Despite FDA concerns that the anti-nerve growth factor (anti-NGF) drugs could cause osteonecrosis, avascular necrosis, rapidly progressing osteoarthritis (OA) and other joint-related adverse events, the panel unanimously voted to continue development of the drugs in order to further investigate potential neurological processes triggered by these drugs and whether the drugs caused osteonecrosis or rapidly progressing osteoarthritis.

The panel also voted 20-1 for the continuation of trials designed to help manage pain in patients with conditions that have no current treatments with analgesic efficacy, such as interstitial cystitis or chronic pancreatitis.

In his dissenting vote on this issue, David Blumenthal, MD, assistant professor of medicine at Case Western Reserve University in Cleveland said, “I guess I see this as a two-stage process where I would prefer to get better data on how much of a problem the bone and joint disease is going to be and whether the risk/mitigation strategies that sponsor has suggested are actually going to work before I have people who do not yet need a joint replacement taking the risk of possibly getting a joint replacement. I would have wanted to see phase one before moving on to this, which would be phase two.”

The committee’s recommendation will be considered by the FDA in its review of the drugs tanezumab (Pfizer Inc.), fulranumab (Janssen Pharmaceuticals Inc.) and REGN475 (Regeneron Pharmaceuticals Inc.). The FDA has the option of seeking the advice of its advisory committees when it is reviewing a new drug or device for approval, although it is not obliged to follow the recommendations.

Risks of anti-NGF agents

The FDA ordered a clinical hold on these drugs in December of 2010 due to these safety issues and scheduled a meeting for September 2011. The meeting was delayed until March 12, 2012 after the manufacturers requested to continue to analyze results of their clinical trials.

Panel members discussed five questions from the FDA about the anti-NGF drugs. All were in agreement that rapidly progressing OA was an adverse event in the tanezumab and fulranumab programs; a combination of tanezumab and NSAIDs to treat patients was not favorable compared to treatment with NSAIDS or tanezumab alone; and that rapidly progressing OA type two, an OA subclassification presented by Pfizer, represented a distinct finding in the studies.

Controversy over clinical definition

Panel members noted discrepancies in the definitions of osteonecrosis used between the sponsor and FDA adjudicators assigned to examine the clinical studies. However, the panel decided that due to insufficient data, the clinical trials should continue to reach a future conclusion on the agents.

John D. Kelly, IV

In summarizing his viewpoint on the efficacy of these drugs, orthopedic surgeon and temporary voting committee member John D. Kelly IV, MD, said that the panel could not “throw the baby out with the bathwater” and suggested that changing the vehicle of the agents from an intravenous method to a slow release, locally administered mode could hold potential.

He added, “Of all the things presented here today, I think that the thing that disturbs me most is the remote site of arthritis progression of joints that had no native OA. That is worrisome. However, if this could be crafted in a more locally administered and timely [way], there is a potential niche and that is many patients who are not surgical candidates who could benefit from this. I do not think that we should totally dismiss this as a potential promising agent.”

The panel members recommended that the companies investigate aspects of the anti-NGF drugs in future clinical trials, such as vascular and neurological effects of the agents, potential bone markers for OA and fracture development in patients taking these drugs.

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