The March 12, 2012 meeting of the Arthritis Advisory Committee (AAC) of the Food and Drug Administration (FDA) focused on the safety of the anti-nerve growth factor (anti-NGF) drug class. Anti-NGF agents are being developed primarily for the treatment of chronic pain associated with osteoarthritis (OA).
There are three anti-nerve growth factor monoclonal antibodies in clinical development including:
- Tanezumab (Pfizer) in phase III
- Fulranumab (Janssen) in phase II
- REGN475 (Regeneron) in phase II
In June 2010, the FDA became aware of a potential safety signal based on reports of joint-related adverse events (osteonecrosis and avascular necrosis) in Tanezumab treated patients. All the patients with these AEs ended up with joint replacement. No patients in the placebo or active comparator arm experienced these problems.
Following additional safety reports, in December 2010 the FDA placed a clinical hold on the IND’s of the three anti-nerve growth factor drugs, in light of the suspicion that what was observed was possibly an anti-NGF class effect.
The sponsors presented data to the AAC that proposed rapidly progressing osteoarthritis (RPOA), and not osteonecrosis, as the safety signal in the clinical development programs of Tanezumab and Fulranumab.
The scale of the issue can be seen in the data presented in Pfizer’s FDA briefing document, in which they reported the following number of joint replacements in the Phase 3 OA studies and Phase 2 chronic low back pain studies:
| ||No. of Joint Replacements (%)|
|Placebo (n=1300) ||11||(0.84%)|
|Tanezumab Monotherapy (n=5183)||143||(2.76%)|
|Tanezumab + NSAID (n=3400)||259||(7.62%)|
|Active Comparator (n=1653)||32||(1.94%)|
Unfortunately due to other conflicts, I did not attend the meeting, although my colleague and co-blogger Dr. Andy Dzik-Jurasz was able to attend. The recommendation from the advisory panel is that if anti-NGF clinical trials are allowed to continue by the FDA, then they will require intensive monitoring of patients for joint destruction and RPOA. This recommendation is still to be confirmed by the FDA formally.
The pathology associated with OA can be assessed by radiographic review of osteophytes, joint space narrowing, and sclerosis, but the challenge remains that there is no standard definition for rapidly progressive OA (RPOA).
Sponsors will need to agree with the FDA what is an acceptable definition of OA, and then determine how to monitor this effectively. Because of cost and availability, radiographs (plain film x-ray) will be the initial modality of choice. This will require 6 radiographs: bilateral knees, hips, and shoulders. One of the challenges will therefore be the doses of radiation that some patients may receive, if there is the need to take radiographs at baseline and thereafter at regular intervals. Magnetic resonance imaging (MRI) is likely to play a key role in further elucidating the RPOA etiology, but I suspect this will not be available for all patients. I anticipate the clinical trial protocols will need careful consideration of cumulative radiation dosages.
Anti-nerve growth factor drugs appear to offer significant pain benefits. Reducing the potential risk of RPOA and monitoring the safety of patients in trials will be key to further phase III clinical development.
Dr. Miller will attend the 19th International Bone Densitometry Workshop, August 20– 24, 2012 in Breckenridge, Colorado. BioClinica is proud to sponsor this event.
Slides for the March 12, 2012 meeting of the Arthritis Drugs Advisory Committee available at: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ucm301253.htm