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The Current Status of Imaging in Anti-NGF Clinical Trials

Miller, C.G. PhD, Roemer, F.W. MD, Hoover, K.B. MD, PhD, Yu, H.J. PhD, Guermazi, A. MD, PhD, BioClinica, Inc., Newtown, PA, Alacrita LLC, Cambridge, MA, Department of Radiology, Boston University, Boston, MA, Department of Radiology, University of Erlangen-Nuremberg, Erlangen, Germany, Department of Radiology, VCU Health Systems, Richmond, VA

PURPOSE
Nerve Growth Factor (NGF) is a neurotrophin that regulates the structure and function of responsive sensory neurons and is a regulator of pain sensitivity and processing. The concept of targeting NGF to target chronic pain syndromes has been gaining momentum since 1990.

There have been a significant number of trials conducted or being initiated.  This abstract provides a review of the studies that have evaluated a-NGF compounds and focuses on joint adverse events (AE)  that were observed during those studies.

METHODS
A thorough review was performed on the web site www.clinicaltrials.gov to identify all a-NGF studies that have been conducted. The terms anti-NGF, and a-NGF only return a limited number of results so the individual compounds had to be identified either by their generic name or compound number. 48 studies (2008 – Present) were identified and although 2 studies had been withdrawn prior to randomization, a total of 15,664 subjects have been enrolled in studies with the aNGF mAbs. Seven of these trials have been published in peer-reviewed journals.

RESULTS
While the majority (26) of studies have been conducted by Pfizer with Tanezumab, there have been 11 with Fulranumab previously known as JNJ-42160443 (Johnson & Johnson Pharmaceutical Research & Development), and 9 with Fasinumab previously known as REGN475 (Regeneron pharmaceuticals/Sanofi). Many of the studies have been either terminated (24), or completed (16) but there is one currently active (not recruiting) in cancer-related pain (Fulranumab).  4 new studies in the Fulranumab program have been registered as starting in January 2015 in knee and hip OA. 3 studies will enroll 450 subjects and 1 will enroll 900 subjects. The number of indications that have been studied are comprised of osteoarthritis (21), which includes either the knee, hip or both; low back pain (4), and a variety of pain syndromes (11) including neuropathic pain from diabetes (2), plus three in cancer pain of which one is on-going.

In the Tanezumab program 249 subjects were adjudicated for AEs related to the joints. Of these 68 had Rapidly Progressing Osteoarthritis (RPOA), 67 in the Phase III program and 1 in the Phase 1 program for chronic back pain.  The advisory board noted that 13 of the 68 subjects had definite evidence of (Subchondral Insufficiency Fracture) SIF at enrollment.  This program had the largest number of enrolled subjects at the time of FDA cessation of the program in 2010 (13310 subjects of the 15,664 enrolled in aNGF studies or 85%).  While these subjects were identified post hoc, SIF, RPOA and joint destruction was not an AE that was anticipated a priori and therefore nothing pro-actively built into the studies to evaluate the true incidence of these events.

CONCLUSION
As a result of previous aNGF studies with unexpected joint-related AEs, medical imaging and the thorough radiological evaluation of the major articulating joints for all subjects in future aNGF studies will be required at eligibility and during the course of the studies. The first step will be to rule out possible pathology or those at high risk of going onto a catastrophic joint failure. Then secondly, close monitoring of the subjects during the treatment phase with radiography, and if inconclusive also with magnetic resonance imaging, to ensure that any possible AE will be identified early and the subject managed to prevent any further bone or joint damage.  Finally, the Phase III programs are re-starting, with a press release in March from Pfizer-Lilly for Tanazumab and the details on Clinicaltrials.gov about Fulranumab.

SPONSOR: BioClinica, Inc. CORRESPONDENCE ADDRESS: colin.miller@bioclinica.com

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