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Nerve Growth Factor Targets Continue the Fight To Enter Market

Practitioners may soon have a new weapon in their pain care arsenal—particularly for the treatment of osteoarthritis.

With Leonard Goldstein, DDS, PhD, and Alan Kaye, MD, PhD

Until recently, the methods used to treat pain have been mainly focused on opioids and nonsteroidal anti-inflammatory drugs (NSAIDs)—neither being an ideal option due to unwanted side effects, according to Leonard B. Goldstein, DDS, PhD, assistant vice president for clinical education development at AT Still University in Mesa, AZ. 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.1 Developed in partnership by Pfizer (New York, NY) and Eli Lilly and Company (Indianapolis, IN), the medication has been fast-tracked by FDA for approval for the treatment of osteoarthritis (OA) and chronic low back pain.

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 of medications could provide an important approach 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 article3 that 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 by injection, either intravenous (IV) or subcutaneous, 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.”

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),which is “bone death caused by poor blood supply. 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 NSAID drugs 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.

Hope for the Future

Tanezumab is currently undergoing several Phase III clinical trials to assess its analgesic efficacy in the treatment of three major conditions: cystitis, osteoarthritis, and chronic lower back pain. Thus far, it has demonstrated efficacy in all three conditions with minimal side effects, according to Dr. Goldstein. Added Dr. Kaye, “There is also a small volume of work revolving around its use as a cancer pain agent, but there are few Phase III trials with data for this indication. The bulk of the efficacy data for tanezumab is from its use as an analgesic in OA of the hip and knee.” In addition, tanezumab is being studied to treat diabetic neuropathies. The medication is expected to be approved for use by patients to treat OA and lower back pain in the near future, with other indications possibly following. 

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.5  (Of note, the product’s higher dose arms faced challenges in safety trials and were removed from the company’s pipeline).5

Others include:

  • Inotersen6 (Akcea Therapeutics, Cambridge, MA and Ionis Pharmaceuticals, Carlsbad, CA), an antisense drug designed to reduce the production of transthyretin, or TTR protein, to treat hereditary ATTR amyloidosis (hATTR), a severe, rare and fatal genetic disease. Inotersen is currently under regulatory review for marketing authorization in the US and Canada, and FDA has granted Orphan Drug Designation and Fast Track Status.
  • Patisiran (Alnylam Pharmaceuticals, Cambridge, MA), an infusion for the treatment of peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR), characterized by the buildup of abnormal amyloid protein in peripheral nerves, the heart and other organs. Recently approved7 by FDA, it is the first approval of a class of drugs known as small interfering ribonucleic acid (siRNA) treatment.

This may be the beginning of a new horizon in pain management strategies (read about other analgesics on the way), and the use of NGF targets may broaden as scientists begin to better understand its efficacy, as well as any risks involved.

Both Drs. Goldstein and Kaye pointed out that additional research should continue to provide insight into those patients who may benefit from tanezumab and similar types of anti-NGF drugs to modify their pain response for a variety of diagnoses. “We need to explore different mechanistic therapeutics given the scope and prevalence of pain in our society,” Dr. Kaye said.

Last updated on: September 26, 2018
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