‘Opioid of the Future’ Abandoned

By Pat Anson, PNN Editor

A promising new pain medication once touted as the “opioid of the future” because of its low risk of abuse is being abandoned.

Nektar Therapeutics withdrew its new drug application for NKTR-181 (oxycodegol) after two FDA advisory committees voted 27 to 0 against approval of the drug because of lingering concerns about the potential for addiction.

“The Company is disappointed in the Committees' vote regarding oxycodegol and believes it is also disappointing for patients suffering from chronic pain and the physicians that treat those patients who are currently relying on existing opioid therapies,” Nektar said in a statement. “The Company has decided to withdraw the NDA for oxycodegol and to make no further investment into the program.”

The molecular structure of oxycodegol is designed so the drug enters the brain slowly, providing pain relief without the euphoria or “high” that can lead to abuse.

In clinical studies, recreational drug users reported less “drug liking” of oxycodegol compared to oxycodone. Patients with chronic back pain also reported significant pain relief taking the drug twice daily.  

The research was so promising the FDA gave oxycodegol “fast track” designation in 2017 to speed its development.

All that changed, however, when the FDA came under a wave of public and political pressure to tighten its regulation of opioids.  A 60 Minutes report last year claimed the FDA “opened the floodgates” to the opioid crisis by approving the use of OxyContin. The agency also received a petition from Public Citizen calling for a moratorium on new opioid approvals because the agency “can no longer be trusted” due to its “poor record” of regulating opioids.

The FDA advisory committees had concerns about oxycodegol being snorted or injected by drug abusers and its potential for liver toxicity. A staff briefing document also questioned whether Nektar’s clinical studies were adequate.

While the panels’ unanimous recommendation isn’t binding on the FDA, Nektar decided to withdraw its new drug application rather than invest further resources in oxycodegol. That will save the company $75 to $125 million in 2020, according to a news release.

Drug Distributor Stops Opioid Sales

Nektar’s decision came the same day a New York based drug distributor announced it will no longer sell opioid medications. The Rochester Drug Co-Operative (RDC) is the nation’s sixth-largest pharmaceutical wholesaler. It buys medicines directly from drug manufacturers and sells them to 1,300 pharmacies in the Northeast.

"The ever-increasing expenses associated with the legal and regulatory compliance for this segment of drugs are simply not sustainable," RDC said in a statement. "While these specific drugs represent a relatively small percent of total sales, they account for significant legal and compliance expenses." 

Two former RDC executives were charged last year with illegally distributing opioids and conspiring to defraud the government. The company paid a $20 million fine and accepted independent monitoring under a five-year deferred prosecution agreement with the government.

An RDC spokesman said the decision to stop selling opioids was a business decision and not related to the legal case.

‘Opioid of the Future’ Postponed

By Pat Anson, PNN Editor

The U.S. Food and Drug Administration is tapping the brakes on NKTR-181, an experimental opioid pain medication that has less abuse potential than traditional opioids like oxycodone or hydrocodone.

In an SEC filing, Nektar Therapeutics said it received a letter from the FDA on July 23 saying the agency was postponing all advisory committee meetings for opioid analgesics, including one scheduled for August 21 to discus Nektar’s new drug application for NKTR-181.

The FDA was due to make a final decision on NKTR-181 eight days later, but that too is apparently being postponed while the agency considers “a number of scientific and policy issues relating to this class of drugs.”

Nektar called NKTR-181 the “opioid of the future” because it is the first full mu-opioid agonist that can provide pain relief without the euphoria or “high” that can lead to abuse and addiction.

The molecular structure of NKTR-181 is designed to have low permeability across the blood-brain barrier, which slows its rate of entry into the brain.

In a Phase III clinical study, patients with chronic back pain reported that their pain scores dropped an average of 65% when taking NKTR-181 twice daily. Safety studies also found that recreational drug users had significantly less “drug liking” of NKTR-181 when compared to oxycodone.

NEKTAR IMAGE

The research was so promising the FDA gave NKTR-181 “fast track” designation to speed its development. Nektar executives told PNN two years ago they were hopeful the drug would be approved in late 2018, with a commercial launch early this year.

Obviously that didn’t happen. And the FDA’s fast track has turned into a slow walk.

Two FDA advisory committees met last month and decided “much better-quality data” was needed before approving any new opioids — even ones with low risk of abuse.  

The agency has been under growing public and political pressure to tighten its regulation of opioids. In February, a 60 Minutes report claimed the FDA “opened the floodgates” to the opioid epidemic by approving the use of OxyContin for chronic pain. The following month, the agency received a petition from Public Citizen calling for a moratorium on new opioid approvals because the agency “can no longer be trusted” due to its “poor record” of regulating opioids.

On July 25, Howard Robin, Nektar’s President and CEO, sold 100,000 shares of Nektar for $3.1 million. A spokesman said the sale was previously scheduled due to expiring options. The company’s chief financial officer and a director also sold shares this month. Nektar shares (NASDAQ: NKTR) lost about 10% of their value after the SEC filing was made public.

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.

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.  

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 Treatments on Horizon for Chronic Pain

By Steve Weakley

Patients and doctors have long complained that there are few new treatments for chronic pain. And those that do come along are often reformulations of old medications or have unwelcome side effects.

Two developments this week suggest that trend may be changing. A new drug application has been submitted to the Food and Drug Administration for an “opioid of the future” that is less addictive, and research has uncovered a new way to treat neuropathic pain long term with a single injection.

In experiments on laboratory mice, researchers at the University of California at San Diego discovered a new method to block the root cause of pain with the injection of a naturally occurring protein, apolipoprotein A-I binding protein (AIBP). 

AIBP “turns off” a receptor called TLR4 that sits on the surface of nerve cells and searches for signs of infection or tissue damage.  Researchers say turning off the receptor prevents and even reverses inflammation and other cellular processes that create the sensation of pain.

A single spinal injection of AIBP relieved neuropathic pain associated with chemotherapy in the mice for two months with no side effects, according to findings published in the journal Cell.

“What’s so special about our new approach, inhibiting the TLR4 receptor with AIBP, is that it actually modifies the pain processing systems themselves," says study co-author Tony Yaksh, PhD, a professor and vice chair for research in the Department of Anesthesiology at UCSD School of Medicine.

"So, if you think of neuropathic pain as a disease, then we see this as truly disease-modifying. We’re blocking the underlying mechanism that causes pain, not just masking the symptoms.”

Neuropathic pain is a common side effect of chemotherapy treatments for cancer. Chemotherapy not only inhibits the growth of cancer cells, it can permanently damage nerve cells and make people sensitive to even the slightest touch. Opioids and other medications such as gabapentin (Neurontin) are commonly prescribed for neuropathy, but both have unwelcome side effects.

“If it comes down to a choice between living with chronic pain or getting a spinal injection once every few months, we think most people would take the injection," said co-author Yury Miller, MD, a professor in the UCSD Department of Medicine. “As it stands now, AIBP could be developed as therapy for unremitting severe pain that only responds to high dose morphine. AIBP would remove the need for opioids, and reduce the potential for drug abuse.

"We're not saying we shouldn't use opiates to treat chronic pain, or in particular cancer pain—that would be a tragedy.” Yaksh said. "But it would also be a greater tragedy if we didn't support work to find a substitute for systemic opiates.”

“Opioid of the Future”

While AIBP is still in its experimental phase and could be years away from being available for treatment, Nektar Therapeutics’ so-called “opioid of the future” is one step closer to market.  Nektar has completed over a dozen clinical trials on NKTR-181 and applied to the FDA for approval of the drug as a treatment for chronic low back pain.

PNN has previously reported on NKTR-181, a new type of opioid that shows promise in relieving moderate to severe pain with less risk of abuse and addiction of traditional opioids like oxycodone or hydrocodone.

Because of its slow rate of entry into the central nervous system, NKTR-181 significantly reduces the “high” or euphoric effect that recreational drug users crave. Many pain sufferers don't feel that high when taking opioid medication, they just get pain relief.

In trials, NKTR-181 showed a 65% reduction in low back pain vs. placebo in tablets taken twice a day. Safety studies found recreational drug users had significantly less “drug liking” of NKTR-181 -- even at high doses -- when compared to oxycodone. Participants also had less daytime sleepiness and fewer withdrawal symptoms.

nektar therapeutics

If it receives FDA approval, Nektar hopes to launch the drug commercially as early as next year. The company has yet to announce a partnership with a larger pharmaceutical company to help produce and commercialize NKTR-181 -- which is when the no-name "opioid of the future" will get a makeover with a branded name to make it more marketable.

Is This the Opioid of the Future?

By Pat Anson, Editor

What do you call a pain reliever that doesn't have a name yet, is not FDA approved and may not be available for years?

Nektar Therapeutics calls it the "opioid of the future."

Nektar is a research-based pharmaceutical company that has developed a new type of opioid medication that shows promise in relieving moderate to severe pain, but without the risk of abuse and addiction of traditional opioids like oxycodone or hydrocodone.

The experimental pill -- which for the time being is called NKTR-181 --  has recieved “fast track” designation  from the Food and Drug Administration, but is at least a couple of years away from full FDA approval and a commercial launch.

That hasn't stopped Nektar from promoting NKTR-181. This week it hosted a lunch symposium on the drug at PainWeek -- an industry trade show underway in Las Vegas -- a sign of just how confident the company is that NKTR-181 will receive final approval from the FDA.

"We think we could see approval as early as the end of next year," says Steve Doberstein, PhD, Chief Scientific Officer of Nektar. "So we could see a launch of this product in the first part of 2019. That would be my aspiration. If we have to do more clinical trial work, it would be delayed."

The FDA usually requires at least two "Phase 3" clinical studies to prove a new drug's effectiveness. Nektar has only completed one -- a Phase 3 study of over 600 patients with chronic back pain who reported that their pain scores dropped by an average of 65% when taking NKTR-181 twice daily.

Nektar has also completed smaller safety studies that found recreational drug users had significantly less “drug liking” of NKTR-181 -- even at high doses -- when compared oxycodone. Participants also had less daytime sleepiness and fewer withdrawal symptoms.

"NKTR-181 is quite boring as far as abuse metrics go. Boring is good. That was our goal. It doesn't appear to cause euphoria," says Doberstein.

NKTR-181 is "boring" because of its slow rate of entry into the brain's central nervous system – which significantly reduces the “high” or euphoric effect that recreational users seek. Many pain sufferers don't feel that high when taking opioid medication, they just get pain relief. But in the current regulatory and political climate, the only way a new opioid will be approved by the FDA is if it has a low or non-existent abuse potential.

"We're very focused on the fact that one of the building blocks of solving this problem is going to be a safe pain medication for chronic pain patients to take," Doberstein told PNN. "The things that work best are opioids. But the existing conventional old-fashioned opioids -- oxycodone is 100 years old -- come with an unacceptable side effect profile for many patients. And we think we've made something that is legitimately better. It's the first time in a very long time that a new opioid molecule has been developed."  

Doberstein thinks NKTR-181 has such low potential for abuse that it will not need to come in an abuse deterrent formula that would make it harder to crush or liquefy. The FDA could still require one, however, which would delay the drug's commercialization even longer. The agency is currently reviewing the effectiveness of all drugs with abuse deterrent formulas.

The FDA also has a new opioid policy steering committee that is examining whether the agency sufficiently considers the risk of abuse during its evaluation of new opioids.  That could result in rule changes that Nektar would have to address. Anti-opioid activists and politicians could also pressure the FDA to require more clinical studies on the safety and potential abuse of NKTR-181.

Another potential obstacle is that Nektar still needs to partner with a larger pharmaceutical company to help produce and commercialize NKTR-181 -- which is when the no-name "opioid of the future" will likely get a makeover with a branded name to make it more marketable.

"This is the kind of medicine that we think could be quite significant. It could really change medical practice. That means we need a lot of education, and a lot of outreach to physicians, hospitals, payers, patient advocates and law enforcement. We have a lot to do. And its probably beyond us to do it ourselves. So we'll have a commercialization partner of some kind," said Doberstein, who told PNN he expects Nektar to announce its new partnership by the end of the year.

New Opioid Painkiller Has Less Abuse Potential

By Pat Anson, Editor

A new opioid medication being developed by Nektar Therapeutics for the treatment of moderate to severe chronic pain has significantly less abuse potential than oxycodone -- even at high doses – according to the results of a new clinical study.

The investigational oral drug – known as NKTR-181 -- is the first analgesic opioid designed to reduce side effects such as euphoria, which can lead to abuse and addiction.

In a small study involving 54 recreational drug users, NKTR-181 had significantly less “drug liking” than oxycodone in the first hours of use. The dosage given to the study participants ranged from a maximum therapeutic dose of 400mg of NKTR-181 to a “supratherapeutic” dose that was 3 to 12 times higher than common doses of oxycodone.

"It is clear from our new study results that NKTR-181 is highly differentiated in this respect from oxycodone, which is a choice drug of abuse.  Further, and critically important in the context of this public health emergency, NKTR-181's less rewarding properties and strong analgesia are inherent to its novel molecular structure and independent of any abuse-deterrent formulation,” said Ivan Gergel, MD, Senior Vice President and Chief Medical Officer of Nektar. 

“Many patients do not receive adequate pain relief because they fear taking conventional opioids, including abuse-deterrent formulations, because of their potential for abuse and addiction.  We believe NKTR-181 is a transformational pain medicine that should significantly advance the treatment of chronic pain and could be a fundamental building block in the fight against prescription opioid abuse.”

nektar therapeutics

In March, NKTR-181 received “fast track” designation from the Food and Drug Administration -- a status that allows for an expedited review of the drug – after Nektar reported positive results from a Phase 3 study of over 600 patients with chronic back pain.  Pain scores dropped by an average of 65% in patients taking NKTR-181 twice daily.

The molecular structure of NKTR-181 is designed to have low permeability across the blood-brain barrier, which slows its rate of entry into the brain – thus reducing the “high” or euphoric effect. Many pain sufferers say they do not get high or experience euphoria from opioid medication, but drug makers and regulators are working to develop painkillers with less risk of abuse and addiction.  

"Getting very high, very fast, is a mark of conventional high-risk, abused opioids," said Jack Henningfield, PhD, vice president at Pinney Associates and adjunct professor at The Johns Hopkins University School of Medicine. "NKTR-181 represents a meaningful advance in the treatment of pain as the first opioid analgesic with inherent brain-entry kinetics that avoids this addictive quality of traditional opioids. This prevents the rapid 'rush' that abusers seek during the critical period immediately after dosing. Importantly, these properties of NKTR-181 are inherent to its molecular structure and are not changed through tampering or route of administration." 

Because NKTR-181 produces less euphoria, Nektar believes it should be scheduled as a Class III or Class IV controlled substance, a less restrictive schedule than Class II medications, a category that includes oxycodone, hydrocodone and many other opioids.

Nektar is a research-based biopharmaceutical company that discovers and develops new drugs for which there is a high unmet medical need. It has a pipeline of new investigational drugs to treat cancer, auto-immune disease and chronic pain.

New Opioid Relieves Pain Without the ‘High’

By Pat Anson, Editor

Nektar Therapeutics has announced positive results from Phase III study showing that a new opioid medication significantly reduces pain without the high levels of euphoria that can lead to abuse and addiction.

The company also said the Food and Drug Administration has given the medication – known as NKTR-181 – “fast track” designation for the treatment of moderate to severe chronic pain, a status that allows for an expedited review of the drug.

Many pain sufferers say they do not get "high" or experience euphoria from opioid pain medication. But drug makers and government regulators are seeking to develop painkillers with less risk of abuse and addiction.  

"The data from this efficacy study are extremely important because they demonstrate that NKTR-181 produces strong analgesia in patients suffering from chronic pain while NKTR-181 has also demonstrated significantly lower abuse potential than oxycodone in a human abuse potential study," said clinical investigator Martin Hale, MD, medical director of Gold Coast Research.

"While standard opioid analgesics, including abuse-deterrent formulations, have been the most effective way to treat chronic pain, they are associated with serious safety concerns and many opioid-naïve patients fear taking them because of the potential for abuse and addiction.  The data for NKTR-181 suggest that it is a transformational pain medicine that could fundamentally change how we treat patients with chronic pain conditions."

The placebo controlled study involved 610 patients with moderate to severe chronic low back pain who had not taken opioids before. During the open-label phase of the study, pain scores dropped by an average of 65% in patients taking NKTR-181 twice daily.

The company said over half the patients (51.5%) on NKTR-181 reported their general overall status and quality of life "improved" or "very much improved" compared to patients taking a placebo. 

They also reported better overall quality of sleep, with less sleep disturbance and fewer sleep problems. There were no differences in daytime sleepiness on NKTR-181 versus placebo. The drug was generally well-tolerated, although some patients reported nausea, constipation and somnolence.

Nektar is currently conducting another Phase III study to evaluate the safety and tolerability of NKTR-181 in 638 patients with chronic low back pain or chronic non-cancer pain.

The company says NKTR-181 is the first opioid molecule to provide pain relief without high levels of euphoria and sedation. The molecular structure of NKTR-181 is designed to have low permeability across the blood-brain barrier in order to slow its rate of entry into the brain.

Nektar is a research-based biopharmaceutical company that discovers and develops new drugs for which there is a high unmet medical need. It has a pipeline of new investigational drugs to treat cancer, auto-immune disease and chronic pain.