Opioid Dropped After Unanimous Thumbs Down From FDA Advisory Panel Pauline Anderson January 15, 2020
Following a unanimous vote by US Food and Drug Administration (FDA) advisory committee members against recommending approval of a new opioid (oxycodegol, Nektar Therapeutics), the company has withdrawn its new drug application and announced it will make no further investment in the drug's development.
In a statement, the company expressed its disappointment in the vote as well as that of patients suffering from chronic low back pain (CLBP) and the physicians who treat these patients.
The company also said it developed the drug to help patients with CLBP and physicians, and to help mitigate the US opioid abuse epidemic. The development program for oxycodegol included over 2000 patients and volunteers.
Oxycodegol is a full mu-opioid receptor (MOR) agonist designed to have slower movement across the blood–brain barrier and a slower rate of MOR binding compared with other MOR agonists.
The drug's manufacturers claim oxycodegol has a slower onset of euphoric effects compared with other opioids and, therefore, would be less attractive as a drug of abuse.
Members of the FDA's Drug Products Advisory Committee and its Drug Safety and Risk Management Advisory Committee convened a day-long meeting to discuss Nektar's application.
The proposed indication for the new agent was for the management of CLBP in adults who require daily around-the-clock long-term opioid treatment and have failed all other treatment options.
Although many committee members said the new agent has a lot of potential, they were unconvinced by the evidence presented that its benefits outweigh its risks.
"I heard a lot of ambiguity all day long, no matter what we talked about, and this is just too important an issue to approve a drug for chronic low back pain when there's just so much ambiguity about safety and efficacy," said committee chair Ronald Litman, MD, professor of anesthesia and pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia. Less Abuse Potential?
Some committee members questioned the wisdom of adding yet another opioid to the market, especially without robust data to support it.
Meeting attendees heard that low back pain is one of the most common causes of chronic pain in the United States. About 25 million adults suffer from CLBP, defined as pain occurring on a frequent or daily basis over 3 months or more. The condition impairs the ability to perform basic activities of daily living and is the leading cause of disability.
Treatments include nondrug interventions such as ice, heat, acupuncture, exercise, and cognitive behavioral therapy. Opioids are an important component of pain management, but they often have side effects, including central nervous system-mediated adverse events such as sedation and cognitive impairment, and the potential for withdrawal symptoms.
Opioids also pose significant public health risks, including abuse, misuse, addiction , and overdose. However, according to the FDA, the number of opioid prescriptions has been declining since 2012 even though new opioid analgesics, and generic versions of older opioid analgesics, have received FDA approval.
The new drug was to be available as an immediate-release oral tablet in doses of 100 and 200 mg. The company noted that the 14-hour half-life of the new molecule makes it long acting, eliminating the need for an extended-release formulation.
The company conducted a single pivotal efficacy study (07), a multicenter trial in 610 patients with moderate to severe CLBP. The study had enriched enrollment and a double-blind placebo-controlled randomized withdrawal design. Enriched enrollment involves identifying a responder population to randomize in a controlled study.
Such a strategy increases the chance of detecting a treatment effect in a study, which is useful when only a portion of a population responds to a drug. There have been high rates of early discontinuation from traditional parallel-arm designed trials of opioids in chronic pain conditions.
After an open-label titration phase, participants in the efficacy study were randomized to oxycodegol or placebo. The two groups had similar demographics and disease characteristics.
The primary efficacy endpoint was mean change in weekly pain score. The study showed the least-squares mean versus placebo was –0.55 (95% CI, –0.86 to 0.23; P = .0019) at week 1, an effect that was maintained to week 12. Liver Safety Concerns
The 30% or greater responder rate, and the 50% or greater responder rate, were consistently higher for the active drug than placebo, Margit Tagliaferri, MD, vice president, clinical development, Nektar Therapeutics, told FDA panel members.
Participants receiving active drug also experienced greater improvements in sleep and patient global impression of change (PGIC) scores, she said.
Many committee members were unconvinced of the drug's benefit and some took issue with the study's patient selection.
"I didn't have a crystal clear image in my mind of which patients were appropriate for this medication," said Kevin Zacharoff, MD, faculty and clinical instructor, course director, pain and addiction, State University of New York.
There was also concern about lack of data on the use of alcohol and other drugs while taking the new agent.
Results from this and other studies demonstrated an acceptable overall safety profile with a low rate of CNS-mediated side effects and opioid withdrawal effects.
There was an early and transient elevation of liver enzymes, which the company maintained could potentially be mitigated with gradual titration.
However, many committee members expressed concern about hepatic safety, saying they didn't have enough data to make an accurate assessment.
The FDA typically requires two main efficacy trials for drug approvals. However, company representatives noted MOR agonists have proven robust analgesia and that this new molecule has similar analgesic effects as other MOR agonists. Lower Abuse Potential Uncertain
Several committee members took issue with having just one pivotal efficacy trial. As one explained, it's not clear how, on the one hand, the company can say this new drug is the same as other MOR agonists and so a second study isn't needed but, on the other hand, claim it's different enough that it doesn't carry the same abuse liability.
Information on abuse was included in two oral human abuse potential (HAP) studies conducted by the company. According to its background document, these demonstrated diminished "drug liking", "drug high", and "take drug again" ratings for the new molecule compared with oxycodone .
Committee members were generally unconvinced of the drug's potential for abuse deterrence.
"I don't think the data could clearly demonstrate an advantage with respect to abuse, which doesn't mean that that advantage isn't there, just that the data could not show it," said Maria E. Suarez-Almazor, MD, Barnts Family Distinguished Professor, Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston.
Although Mary Ellen McCann, MD, associate professor of anesthesia, Harvard Medical School, Boston, Massachusetts, also wants to see more data, she said she's "actually kind of optimistic" about the drug. "I think if I were to abuse drugs, this would not be the drug I'd go to; I'd go to another drug. I would encourage the sponsor to do more studies and then come back."
Many meeting delegates expressed concern about the lack of assessment of abuse potential of the new agent through intranasal and intravenous routes — two common means of opioid abuse. Some also took issue with the lack of diversity in terms of gender and race in the HAP studies.
There also seemed to be some confusion about whether the doses of oxycodegol and oxycodone used in these studies were equivalent, raising the question of whether it was a fair comparison.
Company representatives also provided data on maintenance of analgesic efficacy from a phase 3 open-label 52-week study in 638 patients. These were patients rolled over from study 07 as well as de novo patients with CLBP or noncancer pain.
This study showed a consistent reduction in pain intensity over time.
According to the FDA's assessment, the effect size from the efficacy study was generally comparable to that of many opioid analgesic studies. A Safer Alternative to Other Opioids?
FDA representatives noted that oxycodone and hydrocodone remain the most commonly misused and abused prescription opioids in the general population.
Although heroin is a more common drug of abuse in patients entering treatment for opioid use disorder, overall oxycodone misuse and abuse remains a significant public health burden in terms of morbidity and mortality.
During discussions, committee members expressed concern that, if this drug were approved, the public would perceive it as being a safer alternative to currently available opioids.
If that message was successful, "this could be one of those billion-dollar-a-year kinds of blockbuster drugs, and if you're going to have a billion-dollar blockbuster drug, you better darn well have the data to support that the benefit outweighs the risks, and we heard none of that today," said Steven Meisel, PharmD, an expert in medication safety.
Meisel said he heard "a lot of speculation" during the presentations that because the drug crosses the blood–brain barrier more slowly, it has some benefit, but did not hear "facts". "You can't approve a blockbuster drug in the middle of a public health crisis on the basis of speculation," he said.
Despite these concerns, many committee members believe the agent holds some promise.
"I agree with the idea that increased time to cross the blood–brain barrier is probably a very good step in the right direction, so with the right amount of data and the right amount of information, this could have been a yes for me," in terms of recommending approval, said Zacharoff.
However, in the end, all 27 joint committee members unanimously agreed that more studies are needed, especially larger efficacy studies that perhaps include patients with a variety of conditions, not just low back pain.
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