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

Issue: April 2012

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.

Perspective from Chris H. Evans, PhD, DSc

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 E. 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 I 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 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.

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. – by Jeff Craven

Perspective

Chris H. Evans, PhD, DSc

Patients typically become aware of their osteoarthritis (OA) because of chronic articular pain. This correlates poorly with structural changes to the joint and, in the continued absence of disease-modifying OA drugs (DMOADs), pain becomes a legitimate drug target in its own right. Standard analgesics are often of limited effectiveness in treating the stubborn pain of OA.

Anti-NGFs could represent the first effective new treatment for OA in decades. The decision of the FDA to hold public discussion at this stage is highly unusual and demonstrates the importance it assigns to the issue of pain in OA. All parties agree that the use of anti-NGFs is effective, but associated with an unique, rapidly progressing form of OA; of note, this often occurs in non-index joints. We can only speculate as to its causes. Its incidence is higher with concomitant use of NSAIDs; whether use of anti-NGFs is also associated with osteonecrosis, remains unresolved.

That the FDA advisory panel voted so overwhelmingly for continued development of anti-NGFs and the continuation of clinical trials is a striking endorsement. The FDA is not bound to follow the advice of this panel, but the lop-sided votes suggest that it will. With the clinical hold lifted, we can expect to see trials in OA resume in a modified fashion; as Dr. Kelly suggested, local delivery is certainly worth looking into. Orthopedists should watch this space.

Chris H. Evans, PhD, DSc

Maurice Müller Professor of Orthopaedic Surgery

Harvard Medical School

Boston

Disclosures: Evans is on the board of directors for Orthogen AG and is on the scientific advisory board for TissueGene Inc.