FDA News

FDA panel declines to recommend next generation IV opioid

The FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted 8-7 against recommending approval of IV oliceridine for the management of moderate to severe acute pain in adult patients who require an IV opioid in hospital and similar controlled clinical settings.

Although the FDA is not required to follow the recommendations of advisory committee decisions, historically it almost always does.

Oliceridine injection is a new chemical entity designed to deliver the pain relief of a conventional opioid, but with fewer adverse effects, Maxine Gowen, PhD, founding president and CEO of Trevena Inc., the drug’s manufacturer, said.

“While IV opioid analgesics are needed treatment options, we recognize that we are seeking approval in the backdrop of an opioid crisis,” Gowen said. “While diversion and abuse of IV opioids in controlled settings is relatively low, we believe that any new IV opioid should not expand the population exposed to these medicines or introduce a greater risk for abuse.”

Trevena had requested that oliceridine be listed as a Schedule II product and carry the same mandatory restrictions of other IV opioids, she said.

“We don’t expect the approval of oliceridine to affect the opioid crisis because it is for short-term IV use only, use in a hospital only and will serve as a substitute for current IV opioids,” Gowen said. In the case of an accidental overdose, nonclinical data suggests that oliceridine can be reversed by naloxone, she added.

Efficacy and safety data

Researchers conducted two phase 3, multicenter, randomized, double-blind, placebo- and active-controlled studies (APOLLO-1 and APOLLO-2) to determine the efficacy and safety of oliceridine.

Mark Demitrack, MD, chief medical officer of Trevena Inc., said that their primary endpoint was focused on the sufficiency of analgesia or the improvement in pain intensity without need for rescue pain medication, early discontinuation or reaching the dosing limit.

In both phase 3 studies, all oliceridine regimens (0.1 mg, 0.35 mg and 0.5 mg) met the primary endpoint and demonstrated statistically significant analgesic efficacy and superiority over placebo, Demitrack said.

“Both studies showed that oliceridine reached a plateau in efficacy at the 0.35 mg regimen,” he said. “There was no clinically apparent advantage with the 0.5 mg dose over the 0.35 mg dose.”

The researchers also conducted an additional phase 2 study (ATHENA) in more diverse settings. The ATHENA study showed similar safety and tolerability to the APOLLO studies, Demitrack said.

Many participants were dissatisfied with the effects of placebo, but patients on oliceridine were mostly or completely satisfied.

Addressing concerns regarding oliceridine

During Trevena’s presentation, they addressed the FDA’s concerns regarding hepatic, cardiac and respiratory safety and abuse potential with oliceridine use.

Paul Watkins, MD, professor of medicine, toxicology and experimental therapeutics at the University of North Carolina, Chapel Hill, said that the current data do not suggest that oliceridine use is associated with clinically significant liver safety risk.

Similarly, Robert B. Kleiman, MD, chief medical officer and VP of global cardiology at ERT, said that there were no clinically relevant effects of oliceridine on drug-induced arrhythmia or QT prolongation in the Phase 3 studies.

Oliceridine produced significantly less opioid-induced respiratory depression, hypoventilation events and respiratory safety events than morphine, according to Jonathan Violin, PhD, co-founder and senior VP of scientific affairs at Trevena Inc. Additionally, Violin reported that oliceridine was associated with clinically relevant reductions in nausea and vomiting compared with morphine. He did acknowledge that oliceridine has a similar abuse profile to morphine.

“Oliceridine is the first IV opioid that is engineered to reduce adverse events. This is an important first step,” Gregory Hammer, MD, professor of anesthesiology, pediatric perioperative and pain and pediatrics critical care at Stanford University Medical Center, said. “At the same time, we should acknowledge that olceridine is not a perfect drug ... but we should not let the perfect be the enemy of the good. Any incremental improvement in opioid safety should be embraced.”

FDA panel vote

Many panel members expressed that they struggled with their decision on whether to approve oliceridine for commercial use. Most members agreed that oliceridine’s rapid onset was of value to patients and that it showed efficacy against placebo, but noted that placebo might not have been the best comparator because anything is likely better than placebo for pain management.

The general consensus was that oliceridine was relatively safe overall and likely not more dangerous than morphine. However, some panel members were worried that there might be a perception that oliceridine is safer for patients with a history of opioid misuse, that the drug showed euphoric effects and that there was no superiority regarding abuse deterrence.

Joseph P. O’Brien, MBA, president and CEO of the National Scoliosis Foundation, voted to recommend approval because he saw it as a first step to breaking the opioid epidemic.

“We need something different. We need a new approach. ... We have a community of people who are stuck in this world where they have no other option than opioids and that’s not a good option,” he said.

Other panel members who also voted yes mentioned that they believed the drug was an effective analgesic with a positive opioid-related safety and reduced adverse events profile.

The majority voting against a recommendation for approval were less convinced about the drug’s safety profile.

“Although I do like that oliceridine is an innovative molecule and I recognize that better options are needed for pain relief. ... I do not believe that the dose regimens have a positive risk/benefit profile,” Terri L. Warholak, PhD, RPh, CPHQ, FAPhA, professor and assistant dean of academic affairs and assessment at the College of Pharmacy at the University of Arizona, said.

Additional members who voted against recommendation for approval of oliceridine expressed the need for more research on safety and potential public health risk. They also wanted data with more demographic variability and drug-drug interactions.

Many panel members noted that they appreciated the principle behind the drug and were close to voting yes and would be happy to in the future if there was enough real-world safety data.

However, Steven Solga, MD, associate professor of clinical medicine and transplant hepatology program director at the Perelman School of Medicine at the University of Pennsylvania, was firmer in his decision to vote no, comparing oliceridine to a lower dose of morphine.

“This would not meet the urgent unmet need and is not innovative. In fact, it would potentially be the opposite, so I want to be excited about these data, but I found myself unable to be so,” he said.

The New Drug Application for oliceridine is expected to have a formal decision by the FDA by Nov. 2. – by Alaina Tedesco

Disclosure: Healio Internal Medicine was unable to confirm relevant financial disclosures at the time of publication.

 

 

The FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted 8-7 against recommending approval of IV oliceridine for the management of moderate to severe acute pain in adult patients who require an IV opioid in hospital and similar controlled clinical settings.

Although the FDA is not required to follow the recommendations of advisory committee decisions, historically it almost always does.

Oliceridine injection is a new chemical entity designed to deliver the pain relief of a conventional opioid, but with fewer adverse effects, Maxine Gowen, PhD, founding president and CEO of Trevena Inc., the drug’s manufacturer, said.

“While IV opioid analgesics are needed treatment options, we recognize that we are seeking approval in the backdrop of an opioid crisis,” Gowen said. “While diversion and abuse of IV opioids in controlled settings is relatively low, we believe that any new IV opioid should not expand the population exposed to these medicines or introduce a greater risk for abuse.”

Trevena had requested that oliceridine be listed as a Schedule II product and carry the same mandatory restrictions of other IV opioids, she said.

“We don’t expect the approval of oliceridine to affect the opioid crisis because it is for short-term IV use only, use in a hospital only and will serve as a substitute for current IV opioids,” Gowen said. In the case of an accidental overdose, nonclinical data suggests that oliceridine can be reversed by naloxone, she added.

Efficacy and safety data

Researchers conducted two phase 3, multicenter, randomized, double-blind, placebo- and active-controlled studies (APOLLO-1 and APOLLO-2) to determine the efficacy and safety of oliceridine.

Mark Demitrack, MD, chief medical officer of Trevena Inc., said that their primary endpoint was focused on the sufficiency of analgesia or the improvement in pain intensity without need for rescue pain medication, early discontinuation or reaching the dosing limit.

In both phase 3 studies, all oliceridine regimens (0.1 mg, 0.35 mg and 0.5 mg) met the primary endpoint and demonstrated statistically significant analgesic efficacy and superiority over placebo, Demitrack said.

“Both studies showed that oliceridine reached a plateau in efficacy at the 0.35 mg regimen,” he said. “There was no clinically apparent advantage with the 0.5 mg dose over the 0.35 mg dose.”

The researchers also conducted an additional phase 2 study (ATHENA) in more diverse settings. The ATHENA study showed similar safety and tolerability to the APOLLO studies, Demitrack said.

PAGE BREAK

Many participants were dissatisfied with the effects of placebo, but patients on oliceridine were mostly or completely satisfied.

Addressing concerns regarding oliceridine

During Trevena’s presentation, they addressed the FDA’s concerns regarding hepatic, cardiac and respiratory safety and abuse potential with oliceridine use.

Paul Watkins, MD, professor of medicine, toxicology and experimental therapeutics at the University of North Carolina, Chapel Hill, said that the current data do not suggest that oliceridine use is associated with clinically significant liver safety risk.

Similarly, Robert B. Kleiman, MD, chief medical officer and VP of global cardiology at ERT, said that there were no clinically relevant effects of oliceridine on drug-induced arrhythmia or QT prolongation in the Phase 3 studies.

Oliceridine produced significantly less opioid-induced respiratory depression, hypoventilation events and respiratory safety events than morphine, according to Jonathan Violin, PhD, co-founder and senior VP of scientific affairs at Trevena Inc. Additionally, Violin reported that oliceridine was associated with clinically relevant reductions in nausea and vomiting compared with morphine. He did acknowledge that oliceridine has a similar abuse profile to morphine.

“Oliceridine is the first IV opioid that is engineered to reduce adverse events. This is an important first step,” Gregory Hammer, MD, professor of anesthesiology, pediatric perioperative and pain and pediatrics critical care at Stanford University Medical Center, said. “At the same time, we should acknowledge that olceridine is not a perfect drug ... but we should not let the perfect be the enemy of the good. Any incremental improvement in opioid safety should be embraced.”

FDA panel vote

Many panel members expressed that they struggled with their decision on whether to approve oliceridine for commercial use. Most members agreed that oliceridine’s rapid onset was of value to patients and that it showed efficacy against placebo, but noted that placebo might not have been the best comparator because anything is likely better than placebo for pain management.

The general consensus was that oliceridine was relatively safe overall and likely not more dangerous than morphine. However, some panel members were worried that there might be a perception that oliceridine is safer for patients with a history of opioid misuse, that the drug showed euphoric effects and that there was no superiority regarding abuse deterrence.

Joseph P. O’Brien, MBA, president and CEO of the National Scoliosis Foundation, voted to recommend approval because he saw it as a first step to breaking the opioid epidemic.

PAGE BREAK

“We need something different. We need a new approach. ... We have a community of people who are stuck in this world where they have no other option than opioids and that’s not a good option,” he said.

Other panel members who also voted yes mentioned that they believed the drug was an effective analgesic with a positive opioid-related safety and reduced adverse events profile.

The majority voting against a recommendation for approval were less convinced about the drug’s safety profile.

“Although I do like that oliceridine is an innovative molecule and I recognize that better options are needed for pain relief. ... I do not believe that the dose regimens have a positive risk/benefit profile,” Terri L. Warholak, PhD, RPh, CPHQ, FAPhA, professor and assistant dean of academic affairs and assessment at the College of Pharmacy at the University of Arizona, said.

Additional members who voted against recommendation for approval of oliceridine expressed the need for more research on safety and potential public health risk. They also wanted data with more demographic variability and drug-drug interactions.

Many panel members noted that they appreciated the principle behind the drug and were close to voting yes and would be happy to in the future if there was enough real-world safety data.

However, Steven Solga, MD, associate professor of clinical medicine and transplant hepatology program director at the Perelman School of Medicine at the University of Pennsylvania, was firmer in his decision to vote no, comparing oliceridine to a lower dose of morphine.

“This would not meet the urgent unmet need and is not innovative. In fact, it would potentially be the opposite, so I want to be excited about these data, but I found myself unable to be so,” he said.

The New Drug Application for oliceridine is expected to have a formal decision by the FDA by Nov. 2. – by Alaina Tedesco

Disclosure: Healio Internal Medicine was unable to confirm relevant financial disclosures at the time of publication.

 

 

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