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US FDA scientists raise concerns over safety, efficacy of Trevena IV opioid

Scientists from the U.S. Food and Drug Administration raised concerns about the safety and efficacy of Trevena Inc.'s intravenous opioid oliceridine, particularly its high potential for abuse.

Shares of Trevena were trading down 61% at $1.16 as of 2:27 p.m. ET.

Trevena's plea to the FDA to market oliceridine as a treatment to manage moderate to severe acute pain in adults for whom an intravenous opioid is warranted comes at the height of the U.S. addiction crisis — an epidemic that killed 72,000 Americans in 2017.

Just last week, the Senate agreed with the House on a massive package of legislation to address the crisis, a bill that is awaiting enactment by the White House.

The FDA's review documents of oliceridine, released ahead of an Oct. 11 meeting of the agency's Anesthetic and Analgesic Drug Products Advisory Committee, also revealed that Trevena may have misled investors about what regulators told the company in 2016 about its studies of the drug.

In a May 2, 2016, statement, Trevena called the meeting it held with the FDA a little over a month earlier "successful" and said it had reached a general agreement with regulators on key elements of oliceridine's phase 3 program to support a new drug application for the drug.

Then-CEO Maxine Gowen, who was replaced as company chief Oct. 1 with Carrie Bourdow, said she was "very pleased with the outcome of our end-of-phase 2 discussion with the FDA."

But the FDA told a different story in its Oct. 9 documents.

At the March 29, 2016, meeting at the end of phase 2, the FDA told Trevena that the agency did not agree with the proposed dosing in the company's phase 3 studies, according to the agency's account.

The FDA also said it did not agree with Trevena's proposed primary endpoint, nor did regulators agree with the company's proposed noninferiority margin for comparing morphine to oliceridine.

FDA analysis

Trevena hypothesized that the drug's mechanism of action will result in less respiratory depression, less slowing of gastrointestinal motility and less sedation versus morphine.

The company studied oliceridine in three phase 3 studies, known as 3001, 3002 and 3003.

Studies 3001 and 3002 were randomized, double-blind, placebo- and morphine-controlled key efficacy studies, while 3003 was an open-label safety trial in surgical and medical patients.

The FDA's analysis of 3001 found that all three doses of oliceridine evaluated — 0.1 milligram, 0.35 milligram and 0.5 milligram — demonstrated a statistically greater reduction in pain intensity than placebo.

But regulators determined that morphine demonstrated a greater reduction in pain intensity than all three doses of oliceridine, which was statistically significant.

In addition, the FDA's analysis of 3002 found that two of the three doses of oliceridine — 0.35 milligram and 0.5 milligram — demonstrated a statistically greater reduction in pain intensity than placebo, but the 0.1-milligram dose did not.

In 3002, morphine demonstrated a greater reduction in pain intensity relief than oliceridine at the 0.1-milligram and 0.35-milligram doses, which was statistically significant, the FDA reviewers said.

While the reduction in pain intensity by morphine was not greater than oliceridine at 0.5 milligram, Trevena is not seeking approval of that higher dose.

Regulators noted that a secondary objective of Trevena's studies was to demonstrate the superiority of oliceridine to morphine in terms of respiratory safety burden.

But the FDA said it did not agree with that endpoint due to concerns with its clinical meaningfulness.

"When evaluating this endpoint in both studies, none of the oliceridine treatment arms demonstrated a significant reduction in the expected cumulative duration of respiratory safety events compared to morphine," regulators said. "Further, any numeric trends in terms of respiratory safety must be considered in the context of the observed efficacy. A conclusion of benefit in a dose-related safety outcome cannot be made without a demonstration of similar efficacy."

Safety concerns

The FDA reviewers also raised issues with the complex dosing for oliceridine in the hospital setting.

In Trevena's studies, the oliceridine dosing regimen included a clinician-administered loading dose; a patient-delivered, as-needed dosing via a patient-controlled analgesia pump; a clinician-administered as-needed supplemental dosing; or some combination of those.

The FDA said that resulted in a wide range of patient exposures and added complexity to the safety analyses.

The variability in doses administered also led to Trevena and the FDA scientists analyzing safety in a variety of ways.

"An overall assessment of the abuse-related data from preclinical and clinical studies leads to the finding that oliceridine is a mu opioid agonist with an abuse potential, overdose potential and ability to produce physical dependence that is similar to other mu opioid agonists," the FDA said.

In separate documents, Trevena said the approval of oliceridine "would not be expected to affect the ongoing opioid overdose epidemic" and would "offer the potential to provide a new option which may improve care for patients who require IV opioid therapy."

The FDA scientists also highlighted safety concerns in the oliceridine studies of adverse liver events and a heart rhythm disorder known as QT prolongation.

They also questioned whether Trevena's safety database for oliceridine was adequate to support the proposed dosing.

At the Oct. 11 meeting, the FDA wants its outside panel of advisers to discuss whether Trevena's data provided substantial evidence for the effectiveness of oliceridine and whether the drug's safety profile was sufficient.

It also wants the committee to weigh in on the abuse potential of oliceridine and any concerns the panelists may have about the impact of the product, if approved, on the nation's public health.

The committee will ultimately vote on whether to approve the drug or if more data are needed.