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April 12, 2012

FDA: Committee Recommends Exploring Anti-NGF Biologics for Chronic Pain Management

Lower back pain

In 2011, an Institute of Medicine report found that chronic pain affects 116 million Americans and costs the U.S. as much as $635 billion each year.  Moreover, common conditions like low back pain and osteoarthritis, or damage to the joints caused by wear and tear affect about 27 million adults in the United States and are a common cause of chronic disability.  

While there are numerous pain products on the market, such as opioids, these drugs have significant risks and costs associated with them.  Hundreds of thousands of people each year suffer from complications associated with painkillers, including death, overdose, and poisoning. Others become addicted.  Alternative solutions to painkillers, such as physical therapy and surgery are available, but neither has proven to solve this colossal problem. 

Earlier this month, however, the millions of Americans suffering from chronic pain received good news when the Food and Drug Administration’s (FDA) Arthritis Advisory Committee voted 21-0 that the investigational anti-nerve growth factor (anti-NGF) drug class should continue to be developed and research conducted for pain treatment, despite the drug class's link to joint-related adverse events.  

Background of Anti-NGF’s 

Anti-NGFs, which are injectable, work by blocking a protein called nerve growth factor, which is thought to cause an increased sensitivity to pain.  The mechanism is a novel approach to treating pain, and drug companies, the FDA, and patients who suffer from chronic pain all agree that new pain treatments are sorely needed. 

There are no anti-NGF drugs currently approved, but three companies are deep into their development programs, testing the safety and efficacy of the drug class to treat a variety of pain, including pain associated with osteoarthritis, chronic lower back pain, diabetic peripheral neuropathy, post-herpetic neuralgia, chronic pancreatitis, endometriosis, interstitial cystitis, vertebral fracture, thermal injury, and cancer.  The drugs have also been tested in narrower groups, like people with bladder pain syndrome. 

Pfizer, Johnson & Johnson and Regeneron Pharmaceuticals all began trails for Anti-NGF drugs several years ago.  Pfizer is in phase III of its development for a drug called tanezumab; Jansen is developing fulranumab; and Regeneron Pharmaceuticals is developing REGN472.  "Physicians and patients are in need of options for difficult-to-treat pain conditions and the panel's vote today is an important step towards helping us more fully understand the benefit-risk profile of this important new class of medicines," said Steve Romano, a senior vice president at Pfizer. 

In 2010, however, the FDA halted the development of most anti-NGF drugs after unexpected reports from clinical trials surfaced that the drugs may cause adverse joint-related events, including osteonecrosis and avascular necrosis, which all led to the patient having joint replacement surgeries.  Only trials testing anti-NGF drugs in terminal cancer patients were allowed to continue. 

According to Medpage Today, “The companies all agree there is a signal linking the use of anti-NGF drugs and deterioration of the joints, but they say it's caused by patients using anti-NGF drugs along with nonsteroidal anti-inflammatory drugs (NSAIDs) and have recommended that if the drugs are marketed patients not use them alongside NSAIDs.” 

Interestingly, however, the Food and Drug Administration (FDA) recently held an advisory meeting regarding the anti-NGF’s—an unusual move given that this class of drugs is not even approved yet.  However, Medpage noted that FDA “wanted guidance on whether the potential benefits of having a new analgesic available outweigh the risks observed in clinical trials.” 

For Monday's meeting of the Arthritis Advisory Committee, FDA researchers reviewed data from the three drug companies and concurred with earlier findings that anti-NGF drugs do appear to cause rapid joint destruction.  In patients who already had osteoarthritis, the joint deterioration was more severe than if their disease had progressed naturally, and, in some cases, patients who did not have osteoarthritis developed rapidly progressing joint deterioration during the trial. 

Lower doses and less frequent administration of anti-NGF agents as well as placebo were both associated with naturally progressing osteoarthritis, while higher doses of anti-NGF drugs and use of an NSAID was linked to rapidly-progressing osteoarthritis as well as osteonecrosis. 

An FDA reviewer and an outside academic reviewer performed separate analyses on 355 cases where patients receiving anti-NGF drugs underwent joint replacement surgery.  Of those cases, 21% were determined to be rapidly-progressing osteoarthritis, and 7% were determined to be osteonecrosis. 

The advisory committee members agreed that the class of drugs is linked to joint destruction but said the evidence is not well-understood on whether anti-NGF drugs cause osteonecrosis and how they interact with other drugs. 

Panelists also called for testing anti-NGF drugs in patients with no other options for analgesics, including patients with interstitial cystitis and chronic pancreatitis.

There is an “enormous need” for new types of analgesics with novel mechanisms of action, said Bob Rappaport, MD, director of the FDA's division of Anesthesia, Analgesia and Addiction Productions.  “We need more [pain] drugs that are broadly effective and well-tolerated,” he told MedPage Today

"I think we can't close the door ... for this class of drugs because it is unique, and it has been shown to be effective," said Susan Broyles, the patient representative on the panel.

Current widely used painkillers, including NSAIDs and opioids, have their own sets of side effects which can include nausea and vomiting, gastrointestinal bleeding and ulceration, constipation, hepatotoxicity, cardiovascular events, renal toxicity, and potential for abuse and dependence. 

FDA's Rappaport said the companies must now present a plan on how to move forward with their studies in a way that minimizes the osteoarthritis risk for patients.  Panelists suggested performing radiographic scans of patients before administering the drug as well as often during treatment to monitor bone loss.

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The nerve grouth factor (NGF), protein discovered by Rita Levi-Montalcini, was found for first time in patients with knee osteoarthritis by us in 1992 (Arthritis and rheumatism 35, 3: 351-355). Since then we have done studies and found that the NGF has a anti-inflammatory activity (Clinical and experimental rheumatology 1997, 15: 433-438)and effect repairer skin ulcers (Lancet 2000, 356:1739-1740). These effects are mediated by lymphocytes Th2 and by mastcells that release cytokines such as IL-4 and IL-10.
The joint destruction and osteonecrosis by tanezumab are due to blockage of anti-inflammacory activities and angiogenesis of the NGF.
The NGF is a potent anti-inflammatory and promotes healing of skin ulcers.

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