New Safety Concerns for Osteoarthritis Drug

By Pat Anson, PNN Editor

Disappointing results from a Phase 3 clinical study are raising new safety concerns about an experimental class of pain-relieving drugs once considered a promising alternative to opioids.

Pfizer and Eli Lilly say 6.3% of osteoarthritis patients taking a 5 mg dose of tanezumab experienced rapidly progressive osteoarthritis in their joints. There was significant improvement in their pain and physical function, but the patients’ overall assessment of their condition was no better than those treated with non-steroidal anti-inflammatory drugs (NSAIDs).

Patients taking a lower 2.5 mg dose of tanezumab did not have any significant improvement in their pain, quality of life or overall condition. And 3.2% experienced rapidly progressive osteoarthritis.

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“We are analyzing these findings in the context of the recent Phase 3 results as we assess potential next steps for tanezumab,” Ken Verburg, Pfizer Global Product Development, said in a statement. “We plan to review the totality of data from our clinical development program for tanezumab with regulatory authorities.”

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases as a result of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from reaching the brain.

Tanezumab was considered so promising a therapy that it was given fast track designation from the FDA in 2017, a process that speeds up the development of new therapies to treat serious conditions.

Ironically, it was the FDA that slowed the development of NGF inhibitors in 2010 because of concerns that tanezumab made osteoarthritis worse in some patients. Most clinical studies of tanezumab did not resume until 2015.

The reappearance of the same safety issue and the marginal pain relief provided by tanezumab could be the last straw for the drug, according to one analyst.

“It is hard for us to imagine how these results could have been much worse. Pfizer indicated that they ‘plan to review the totality of data’ with regulatory authorities, which suggests to us that the co-sponsors will try to find a way to resurrect the program for some subset or sub-population of patients, but recognizes that this result puts the drug’s entire future in doubt,” SVB Leerink research analyst Geoffrey Porges said in a note to clients.

A clinical study of fasinumab, another NGF inhibitor being developed by Teva and  Regeneron Pharmaceuticals, was stopped by the FDA in 2016 after a patient showed signs of severe joint disease. Regeneron and Teva are continuing to study fasinumab in patients with chronic low back pain.

Pfizer and Eli Lilly are also studying tanezumab as a treatment for low back pain, and reported promising results from a Phase 3 trial in February. Rapidly progressive osteoarthritis was also reported in a small number of patients involved in that study.

Future Pain Pills

By Roger Chriss, PNN Columnist

The Food and Drug Administration announced this week that it would require drug makers to conduct new studies on the effectiveness of opioid pain medication and whether long-term use of the drugs lead to addiction. The FDA’s unprecedented action was due in no small part to a 60 Minutes report that said the agency “opened the floodgates” to the opioid crisis by approving the use of opioids for chronic pain. 

With opioid medication coming under scrutiny again – and perhaps more regulatory action – this is a good time to assess where we stand with development of newer and safer painkillers.  

Many analgesics already on the market have too many risks or too few benefits. A recent meta-analysis in JAMA concluded that opioids “may provide benefit for chronic noncancer pain, but the magnitude is likely to be small.”

And a new Cochrane review on acetaminophen (Tylenol) for hip or knee osteoarthritis found “only minimal improvements in pain and function.”

So new analgesics, whether safer opioids or non-opioid drugs, are urgently needed. Fortunately, there has been significant progress.

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NKTR-181, from Nektar Therapeutics, is a new kind of opioid under “fast track” FDA review. It was designed with safety in mind, because it enters the nervous system slowly as a result of its unique chemical structure. NKTR-181 is the only abuse-deterrent opioid in the drug development pipeline designed to reduce the “high” and “drug liking” that can lead to addiction. Practical Pain Management recently gave it four out of five stars as a future analgesic.

Desmetramadol, from Syntrix Pharmaceuticals, is another opioid in early testing. Developed with support from the National Institute on Drug Abuse, desmetramadol is designed as a safer version of tramadol, a Schedule IV opioid. Researchers are looking at the results of a recent clinical trial to see whether the new drug “provides the safety and pain relief of tramadol without its metabolic issues.”

VX-150, from Vertex Pharmaceuticals, is a sodium channel inhibitor that late last year finished a “proof-of-concept” Phase II trial successfully. It acts specifically on sodium channels to block the pain caused by small fiber neuropathy. Because these channels are not expressed in the brain, VX-150 should have few if any cognitive side effects. Phase III clinical trials are expected to start later this year.

Tanezumab, from Pfizer and Eli Lilly, just completed a Phase III clinical study for chronic low back pain. The results showed that tanezumab injections were associated with a statistically significant improvement in low back pain compared with placebo. Tanezumab is also being studied as a treatment for osteoarthritis, although there are some lingering concerns about its side-effects.

Finally, the novel compound AT-121 from Astraea Therapeutics is showing promise as a non-addictive opioid analgesic. Researchers created AT-121 to bind to both the mu opioid receptor and the FQ peptide receptor, a combination that blocks the unwanted side effects of current opioid analgesics. Preclinical testing of AT-121 in animals found that it was more potent than morphine, but did not produce physical dependence or tolerance at high doses. The National Institute on Drug Abuse recently called AT-121 a “promising alternative to opioid pain medications.”

Improved understanding of the nervous system and of chronic painful disorders is also contributing to drug development. A recent review in Frontiers in Pharmacology looks at emerging “safer opioids” that provide effective pain relief with fewer side effects. The review explains that the new goal of drug developers is to target opioid receptors in injured or diseased tissues, while avoiding the brain to reduce cognitive side effects and minimize risk of abuse, addiction and overdose.

And new genetic research is identifying genes involved in painful neuropathies. For instance, a recent case report found that a variant in the gene PMP22 is linked to painful peripheral neuropathy in Charcot-Marie-Tooth Disease.

With the prevalence of chronic pain increasing as the population ages, the development of safer, more effective analgesics is critical. Advances in drug development techniques and better understanding of painful disorders should accelerate the process.  

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Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.

New Non-Opioid Drug Effective in Treating Low Back Pain

By Pat Anson, PNN Editor

Pfizer and Eli Lilly have announced positive results from a large Phase 3 study evaluating an experimental non-opioid pain reliever as a treatment for chronic low back pain.

Patients receiving 10 mg injections of tanezumab showed statistically significant improvement in back pain at 16 weeks compared to placebo. A lower dose of tanezumab 5 mg was not as effective. Over 1,800 people with chronic low back pain in North America, Europe and Asia participated in the study.

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases in the body because of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from muscles, skin and organs from reaching the brain.

"This study demonstrates the potential of tanezumab to treat individuals suffering from moderate-to-severe chronic low back pain who have been unable to achieve relief with currently available medicines," said Ken Verburg, Pfizer’s tanezumab development team leader.

“This is one of the longest studies conducted to date in chronic low back pain. We look forward to further analyzing these results, and believe the data from this study will support our planned future global regulatory submissions in chronic low back pain."

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Pizer and Eli Lilly have also reported positive findings in evaluating tanezumab for the treatment of osteoarthritis. The Food and Drug Administration granted “fast track” designation to tanezumab in 2017 to help speed its development.

Tanezumab has a history of safety concerns. Clinical studies were halted in 2010 after Pfizer reported some osteoarthritis patients receiving the drug had worse symptoms and needed joint replacement surgery. Another safety issue arose in 2012 when tanezumab caused adverse changes in the nervous system of animals.  Most clinical studies of tanezumab did not resume until 2015.

In the current study, rapidly progressive osteoarthritis (RPOA) was observed in 1.4 percent of patients receiving tanezumab and 0.1 percent of patients in the other treatment groups. Joint fractures and total joint replacements were experienced in 0.4 percent and 0.7 percent of tanezumab-treated patients, respectively, while none were observed in the other treatment groups.

In addition to back pain, the ongoing Phase 3 program for tanezumab includes studies in osteoarthritis pain and cancer pain due to bone metastases.

Positive Results for New Osteoarthritis Drug

By Pat Anson, Editor

Two pharmaceutical companies have announced positive results from a Phase 3 study of an experimental non-opioid pain reliever that has a history of safety concerns.

Teva and Regeneron are jointly developing fasinumab as a treatment for chronic pain from osteoarthritis of the knee and hip. The companies say patients treated for 16 weeks with fasinumab injections had significantly less pain and improved function compared to a placebo.

"We are encouraged by these data and look forward to advancing our pivotal Phase 3 fasinumab program in patients with osteoarthritis of the knee or hip, who currently have very limited therapeutic choices to treat their chronic pain, other than with non-steriodal anti-inflammatory drugs or opioids," said George Yancopoulos, MD, President and Chief Scientific Officer of Regeneron.

Fasinumab is a humanized antibody that targets nerve growth factor (NGF), a protein that increases in the body because of injury, inflammation or chronic pain. Fasinumab binds to NGF and inhibits pain signals from muscles, skin and organs from reaching the brain.

Teva and Regeneron say fasinumab was “generally well tolerated” in the Phase 3 study, with similar adverse events (AEs) as in previous trials. Treatment was discontinued due to AEs in 6 percent of the fasinumab patients, about the same as the placebo group. The companies plan to present further details at an upcoming medical conference.

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Regeneron recently halted high-dose trials of fasinumab because the risk of harm outweighed the benefits of the drug. There is some concern that NGF antibodies work too well and encourage osteoarthritis patients to become more active, which accelerates joint deterioration. No cases of joint damage were observed in the current study.

Regeneron and Teva are currently enrolling osteoarthritis patients in three additional Phase 3 clinical trials, including one assessing the long-term safety of fasinumab and two trials comparing fasinumab to standard pain therapies.

There is intense competition about drug companies to develop non-opioid pain relievers that don’t have the risk of addiction and overdose. Pfizer and Eli Lilly are jointly developing a similar NGF inhibitor called tanezumab, which was given fast track designation by the FDA in 2017 to speed its development.

Like fasinumab, there are safety concerns about tanezumab. The FDA ordered a partial halt to clinical studies of tanezumab in 2010 after Pfizer said a small number of osteoarthritis patients taking the drug needed joint replacements. Another safety issue arose in 2012 because the drug caused “adverse changes in the sympathetic nervous system of mature animals.”  Most clinical studies of tanezumab did not resume until 2015.

Positive Findings for New Osteoarthritis Drug

By Pat Anson, Editor

Pfizer and Eli Lilly have announced positive findings in treating osteoarthritis pain with an experimental non-opioid drug that has a history of safety concerns.  

Tanezumab is a humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases in the body because of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from muscles, skin and organs from reaching the brain.

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In the 16-week clinical study, osteoarthritis patients who were given two injections of tanezumab had significant improvement in their pain, physical function and assessment of their symptoms compared to a placebo. Osteoarthritis is a joint disorder that leads to thinning of cartilage and progressive joint damage.

“There is a substantial need for innovative new treatment options for osteoarthritis, as many patients are unable to find relief with currently available medicines and continue to suffer,” Ken Verburg of Pfizer Global Product Development said in a statement.

“We are encouraged by these results, which speak to the potential of tanezumab as a non-opioid treatment option for pain reduction and improvement in physical function.”

Preliminary safety data showed that tanezumab was generally well tolerated, with about 1% of patients discontinuing treatment due to adverse events. Rapidly progressive osteoarthritis was observed in about 1.5% tanezumab-treated patients, but none in the placebo arm.

The U.S. Food and Drug Administration granted “fast track” designation to tanezumab last year to help speed its development as a new treatment for osteoarthritis and chronic low back pain.

Ironically, it was the FDA that slowed the development of NGF inhibitors in 2010 after Pfizer reported some osteoarthritis patients receiving tanezumab experienced worsening of their disease and needed joint replacements. Another safety issue arose in 2012 because the drug caused “adverse changes in the sympathetic nervous system of mature animals.”  Most clinical studies of tanezumab did not resume until 2015.

“We look forward to continuing to advance tanezumab in our ongoing global Phase 3 development program, which includes six studies in approximately 7,000 patients with osteoarthritis, chronic low back pain and cancer pain,” said Christi Shaw, senior vice president of Eli Lilly. In studies to date, tanezumab has not demonstrated a risk of addiction, misuse or dependence.

Regeneron recently halted high-dose trials of fasinumab, another NGF inhibitor, because the risk of harm outweighed the benefits of the drug. There is some concern that NGF antibodies work too well and encourage osteoarthritis patients to become more active, which accelerates joint deterioration.

FDA Gives Fast Track Designation to New Pain Med

By Pat Anson, Editor

The U.S. Food and Drug Administration has granted “fast track” designation to a new, non-opioid pain medication for patients with osteoarthritis and chronic low back pain -- even though the drug has a history of safety issues.

Tanezumab is an investigational humanized monoclonal antibody that targets nerve growth factor (NGF), a protein that increases in the body as a result of injury, inflammation or chronic pain. Tanezumab binds to NGF and inhibits pain signals from reaching the spinal cord and brain.

Tanezumab is the first NGF inhibitor to receive fast track designation from the FDA, a process that speeds up the development and review of new therapies to treat serious conditions with unmet medical needs.

“If approved, tanezumab would be the first in a new class of non-opioid chronic pain medications,” said Ken Verburg, Chief Development Officer, Neuroscience & Pain, Pfizer Global Product Development. “We believe it would represent an important medical advance in the treatment of debilitating osteoarthritis and chronic low back pain for patients who do not experience adequate pain relief or cannot tolerate currently available pain medications.”

Pfizer is jointly developing tanezumab with Eli Lilly. The two drug makers are currently recruiting patients for Phase 3 studies of tanezumab in 7,000 patients with osteoarthritis, low back pain or cancer pain. Participants will be injected with tanezumab once every eight weeks for treatment periods ranging from 16 to 56 weeks, followed by a 24-week safety follow-up period.  Results from the clinical trials are not expected until next year.

"It is estimated that there are more than 27 million Americans currently living with osteoarthritis and 23 million living with chronic low back pain, many of whom fail to achieve adequate pain relief despite treatment with various types of pain medications,” said Christi Shaw, Senior Vice President and President, Lilly Bio-Medicines.

“We are committed to offering innovative solutions to people suffering from chronic pain conditions, and look forward to working closely with the FDA to facilitate the development of tanezumab.”

Ironically, it was the FDA that slowed the development of NGF inhibitors in 2010 because of safety concerns. The agency ordered a partial halt to clinical studies after Pfizer said a small number of osteoarthritis patients receiving tanezumab experienced worsening of their disease and needed joint replacements. Another safety issue arose in 2012 because the drug caused “adverse changes in the sympathetic nervous system of mature animals.” 

Most clinical studies of tanezumab did not resume until 2015. Pfizer says the current Phase 3 studies include risk mitigation measures for joint safety and sympathetic nervous system safety.

A clinical study of fasinumab, another nerve growth factor drug being developed by Teva and  Regeneron Pharmaceuticals, was stopped by the FDA last year after a patient showed signs of severe joint disease. Regeneron and Teva said they would redesign the study of patients with chronic low back pain to exclude participants with advanced osteoarthritis.