FDA panel refuses to recommend next generation opioid IV

The FDA's Anesthetic and Analgesic Drugs Advisory Committee voted 8 to 7 to recommend approval of intravenous oliceridine for the treatment of moderate to severe acute pain in adult patients requiring opioid opioid intravenous use in the hospital and in similar controlled clinical settings.

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

Oliceridine Injection is a new chemical entity designed to relieve the pain of a classic opioid, but with fewer side effects, Maxine Gowen, PhD, founding president and CEO of Trevena Inc., the drug's manufacturer, said.

"While IV opioid analgesics are necessary treatment options, we recognize that we are seeking approval for an opioid crisis," Gowen said. "Although diversion and abuse of intravenous opioids in controlled environments is relatively small, we believe that any new intravenous opioid should not increase the population exposed to these drugs or increase the risk of abuse. "

Trevena had requested that oliceridine be listed as Schedule II and had the same mandatory restrictions as other intravenous opioids, she said.

"We do not believe that the approval of oliceridine will affect the opioid crisis because it is reserved for short-term intravenous use, is only used in a hospital and will serve as a substitute for current intravenous opioids," he said. said Gowen. In case of accidental overdose, non-clinical data suggest that oliceridine can be reversed by naloxone, she added.

Efficiency and safety data

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

Mark
demitrack, MD, The Chief Medical Officer of Trevena Inc. stated that his primary endpoint was the sufficiency of analgesia or the improvement of pain intensity without the need for rescue treatment, neither the early stop nor the dosage 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 analgesic efficacy and efficacy. statistically significant superiority over placebo, explained Demitrack.

"Both studies showed that the efficacy of oliceridine reached a plateau with the diet at 0.35 mg," he said. "There was no clinically apparent benefit with the 0.5 mg dose compared to the 0.35 mg dose."

The researchers also conducted an additional phase 2 study (ATHENA) in a wider variety of settings. The ATHENA study showed that safety and tolerability were similar to APOLLO studies, said Demitrack.

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

Address concerns
In regards to
olicéridine

During Trevena's presentation, they discussed FDA's concerns regarding the safety of the hepatic, cardiac and respiratory systems and the risks of abuse associated with the use of oliceridine.

Paul Watkins, MD, A professor of medicine, toxicology and experimental therapies at the University of North Carolina, Chapel Hill, said the current data did not suggest that the use of oliceridine was associated with a risk clinically significant for liver safety.

Similarly, Robert B. Kleiman, MD, The Chief Medical Officer and Vice President of Global Cardiology at ERT, stated that there was no clinically significant effect of oliceridine on the arrhythmia of 39 drug-induced or QT interval lengthening in phase 3 studies.

Olriceridine produced much less respiratory depression, hypoventilation and opioid-induced respiratory safety than morphine, according to Jonathan Violin, PhD, Co-founder and Senior Vice President Scientific Affairs at Trevena Inc. In addition, Violin reported that oliceridine was associated with a clinically significant reduction in nausea and vomiting compared to morphine. He acknowledged that oliceridine had a profile of abuse similar to that of morphine.

"Olicridine is the first opioid IV designed to reduce side effects. This is an important first step » Gregory Hammer, MD, Professor of Anesthesiology and Pediatric and Perioperative Intensive Care at the Stanford University Medical Center, said. "At the same time, we should recognize that oléréridine is not a perfect medicine … but we should not let the perfect become the enemy of good. Any gradual improvement in the safety of opioids should be considered. "

FDA
panel vote

Many panel members said they had difficulty deciding whether to approve oliceridine for commercial purposes. Most members agreed that the rapid onset of oliceridine was helpful for patients and showed efficacy against placebo, but noted that placebo may not be the best comparator because nothing was better than placebo for the treatment of pain.

The general opinion was that oliceridine was generally relatively safe and probably not more dangerous than morphine. However, some panellists were concerned that oliceridine may be perceived as safer for patients with a history of opioid abuse, that the drug has euphoric effects, and that there is no superiority in the treatment of opioids. deterrence of abuse.

Joseph P. O'Brien, MBA, President and CEO of the National Scoliosis Foundation, voted in favor of his approval, saying that it was a first step in the fight against the epidemic. ; opioids.

"We need something different. We need a new approach. … We have a community of people stuck in this world where they have no choice but opioids and this is not a good option, "he said.

Other panelists who also voted for yes said they thought the drug was an effective painkiller with positive opioid safety and a reduced profile of adverse effects.

The majority of those who voted against a recommendation of approval were less convinced of the drug's safety profile.

"Although I like that oliceridine is an innovative molecule, I recognize that better options are needed to relieve pain. … I do not believe that dosage regimens have a positive risk / benefit profile, " Terri L. Warholak, PhD, RPh, CPHQ, FAPhA, Professor and Associate Dean of Academic Affairs and Evaluation at the College of Pharmacy of the University of Arizona, said.

Other members voting against the recommendation regarding the approval of oliceridine emphasized the need for further research on safety and potential risks to public health. They also wanted data showing more demographic variability and drug interactions.

Many panel members indicated that they appreciated the principle of the drug, were about to vote yes and would be happy to do so in the future if he had enough data on safety in the real world.

however, Steven solga, MD, Associate Professor of Clinical Medicine and Director of the Graft Hepatology Program 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.

"It would not meet the urgent need not satisfied and is not innovative. In fact, it would be potentially the opposite, so I want to be excited about these data, but I found myself unable to do so, "he said.

The new drug application for oliceridine should be the subject of a formal FDA decision by November 2nd. – by Alaina Tedesco

Disclosure: Healio internal medicine has not been able to confirm the relevant financial information at the time of publication.