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13 Articles in Volume 18, Issue #7
A Commentary on Medical Cannabis
Are Abuse-Deterrent Opioids Appropriate for Your Pain Patient?
Behind the AHRQ Report
Challenges Facing Abuse-Deterrent Formulations
Demystifying Opioid Abuse-Deterrent Technologies
Editorial: Our Clinical Pain Neighborhood
Independent Pain Practice: A Case Example
Inside Performing Arts Medicine
Letters to the Editor: ACT Therapy; Compounded Topicals
Nerve Growth Factor and Targeting Chronic Pain
Pain Control for Athletes: What Works?
Quality Training: One Center’s Experience with Pain Assessment
The Importance of Developing Professional Relationships in Pain Practice

Nerve Growth Factor and Targeting Chronic Pain

Emerging analgesics continue the fight to enter the pain management market.

Until recently, the methods used to treat pain have been mainly focused on opioids and NSAIDs—neither being an ideal option due to undesirable side effects, according to Leonard Goldstein, DDS, PhD, assistant vice president for clinical education development at AT Still University in Mesa, AZ, and PPM editorial advisor As the focus on decreasing prescribed opioid use has risen, the pain management community has been scrambling for alternative ways to safely control chronic pain, without the fear of addiction or death. Enter tanezumab, the first investigational humanized monoclonal immunoglobulin G2 antibody that prevents the binding of nerve growth factor (NGF) to its receptors, thus blocking the pain response pathway. Developed in partnership by Pfizer and Eli Lilly and Company, the medication has been fast-tracked by FDA for the treatment of osteoarthritis (OA) and chronic low back pain.

Nerve growth factor moleculeNerve growth factor targets may change pain care. (Source: 123RF)

The Potential of NGF Targets

The approach in targeting NGF, a protein involved in pain response, has been garnering attention for its positive outcomes in recent clinical trials, giving experts and patients hope for a new way to treat pain moving forward. NGF targets represent “an exciting new class of analgesics that have the potential to change the treatment of pain,” Dr. Goldstein pointed out, adding that the class may help to fill the void in pain management for those currently suffering from a number of chronic conditions.

Mechanism of Action: Alan Kaye, MD, PhD, head of the department of anesthesiology at Louisiana State University School of Medicine, is one of the lead authors of a recent article in the Jan-Mar 2018 Journal of Anaesthesiology Clinical Pharmacology, which explores the potential of anti-NGF antibodies, specifically tanezumab, for addressing pain in a novel way. “The inhibition of NGF binding to its receptors is a mechanism by which pain pathways can be interrupted,” he explained. “Tanezumab’s primary effect is to inhibit the interaction between NGF and its high-affinity receptor TrK-A and low-affinity receptor p75. The TrK-A is a tyrosine kinase receptor, while p75 is a specific receptor for the NGF ligand.” He added that, “While tanezumab has been shown to bind tightly to NGF, it is highly selective with a relative 1,000-fold decrease in affinity for other substances in the NGF family, specifically BDNF, NT-3 or NT-4/5, NTF, GDNF, and VEGF.” For patients who suffer from pain that is not responsive to other approved treatments on the market, the availability of a non-addictive medication such as tanezumab could offer a significant change.

Administration: Tanezumab may be administered via intravenous (IV) or subcutaneous injection every eight weeks. “Studies have shown that a 10 to 20 mg subcutaneous injection of tanezumab has the therapeutic equivalent of a 10 to 20 mg IV injection, with similar overall improvement in pain and function,” Dr. Goldstein said, adding that, “Cutaneous administration of NGF has led to hyperalgesia within 1 to 3 hours. The rapid nociceptor sensitization of cutaneous receptors shows NGF plays a pivotal role both in acute nociceptive responses and in chronic pain.” (Editor's Note: While previous studies looked at IV administration, the current Phase 3 trials for tanezumab are looking at subcutaneous administration only.)

While tanezumab has been quite well-tolerated by most patients in clinical trials, there had been some concern in the past around the results of studies on cancer patients who were diagnosed with osteonecrosis (ON). It is most common in the hip and shoulders but can affect other large joints,” Dr. Goldstein explained. However, further review of these patients found that the ON was from concomitant therapy for OA, with co-prescribed NSAIDs and poor underlying bone architecture, he pointed out, rather than being related to tanezumab. While similar studies have raised concern about the drug’s safety profile, most findings have been encouraging to date.

Tanezumab is currently undergoing several Phase III clinical trials to assess its analgesic efficacy in the treatment of three major conditions: osteoarthritis, chronic lower back pain, and cancer pain (due to bone metastasis). Thus far, it has demonstrated efficacy in all three conditions with minimal side effects, according to Dr. Goldstein. The bulk of the efficacy data for tanezumab is from its use as an analgesic in OA of the hip and knee.

Additional Options

In mid-August 2018, Regeneron Pharmaceuticals and Teva Pharmaceutical Industries announced positive topline results from their Phase 3, randomized, double-blind, placebo-controlled study of fasinumab, a competing antibody targeting NGF, in patients with chronic pain from knee or hip osteoarthritis. At Week 16, both co-primary endpoints and all key secondary endpoints were met, with subjects experiencing significantly less pain and significantly improved functional ability from baseline compared to placebo. (Of note, the product’s higher dose arms faced challenges in safety trials and were removed from the company’s pipeline).

Two other NFG products are also pending. Inotersen (Akcea Therapeutics and Ionis Pharmaceuticals), an antisense drug designed to reduce the production of transthyretin aims to treat hereditary ATTR amyloidosis (hATTR), has been granted FDA Orphan Drug Designation and Fast Track Status. Patisiran (Alnylam Pharmaceuticals), an infusion for the treatment of polyneuropathy caused by hATTR, was recently approved by FDA and is the first in a class of drugs known as small interfering ribonucleic acid (siRNA). Both Drs. Goldstein and Kaye pointed out that additional research may provide insight into using anti-NFG targets to modify pain response for a variety of diagnoses.

Last updated on: October 26, 2018
Continue Reading:
Tanezumab Gets Fast Track Designation From FDA for Chronic Pain Conditions
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