Promising New Opioid Has Novel Mechanism

Pauline Anderson

September 14, 2015

LAS VEGAS — An investigational opioid with a novel mechanism of action produced rapid pain relief in a new study.

Results of a double-blind, phase 2 study of the drug (TRV130, Trevena Inc) showed that it was superior to placebo in terms of reducing pain intensity in patients undergoing a bunionectomy, relieving pain within 5 minutes of administration and without causing serious adverse events.

Franck Skobieranda, MD, vice president, clinical development, Trevena, the company that funded the research, presented the findings at a poster session here at PAINWeek 2015.

Conventional opioids bind to the mu-opioid receptor and activate G protein–mediated analgesia, but they also recruit β-arrestin. TVR130 is a protein-biased ligand of the mu-opioid receptor that also activates G protein, "but with relatively little β arrestin recruitment," Dr Skobieranda told Medscape Medical News.

"We believe that that differential activation can result in a better therapeutic index, either increased general analgesia, better tolerability, or some mix of both."

The study, conducted at four US centers, compared three doses of TRV130 (1, 2, and 3 mg), morphine (4 mg), and placebo. Patients entered into the study with a numeric rating scale (NRS) pain score of about 7, indicating severe pain.

"Profound" Relief

The primary endpoint was the time-weighted average NRS change with TRV130 vs placebo over 48 hours. For this measure, the 2-mg and 3-mg TRV130 doses were significantly better than placebo, as was morphine.

"TRV130 provided really robust, profound pain relief," commented Dr Skobieranda.

Another efficacy endpoint was the level of reduction of pain intensity with TRV130 vs morphine. The researchers found that the 3-mg dose had significantly more analgesic effect than morphine (P = .0144).

Dr Skobieranda plotted results on a graph displaying pain intensity over time. The 4-mg dose of morphine produced about a 2-point change in NRS pain intensity that took about 30 minutes to produce.

"For TRV130, in a very dose-responsive way, we were able to show up to a 6-point decrease in pain intensity and this occurred at the first measurement time at 5 minutes," said Dr Skobieranda. "So this is really a remarkable magnitude of pain intensity reduction."

Dr Skobieranda highlighted other results suggesting superior analgesia efficacy. This included "categorical pain relief" where patients were asked about their level of pain relief compared with when they started the study.

"Not surprisingly," the placebo patients had "none, little, or at most only some pain relief" with the first dose of placebo, he said. With morphine, patient responses ranged widely, from none to complete, which Dr Skobieranda said reflects the "interpatient variability" in response to morphine.

"But with TRV130, one sees a very nice migration of the population with increasing dose to increasing categorical pain relief. So by the 3-mg dose, every patient in the treatment group reported either very much or complete pain relief with the first dose."

Another measure of efficacy was the median time to meaningful pain relief with the first dose of drug. Here, as doses of TRV130 increased to 3 mg, so did the number of patients achieving meaningful relief.

"The time that it took for patients to achieve that meaningful pain relief decreased as the dose increased; at the 2- and 3-mg doses it was under 5 minutes."

Respiratory Safety

Researchers also looked at respiratory safety by monitoring oxygen saturation for the first 24 hours. They found a "very modest dose-related effect of TRV130 both in the short term and long term," said Dr Skobieranda.

Adverse events were dose related and were typical for an opioid; the most common events included nausea, dizziness, headache, vomiting, somnolence, and constipation. No serious adverse events occurred.

Dr Skobieranda noted that the drug is an intravenous product that would be used in a controlled hospital environment. An oral formulation of the drug is being developed for acute pain.

A limitation of the study was that it used "fixed forced dosing," so patients received a drug whether or not they were in pain. "That's not the best way to tease out tolerability differences," said Dr Skobieranda.

Poster session co-moderator Joseph Pergolizzi Jr, MD, chief operating officer, NEMA Research, Bonita Springs, Florida, commented that new chemical entities to treat pain, such as TRV130, "are definitely needed."

"The promise with this drug is that we may be able to have an opioid that has a longer therapeutic index. It may confer better versatility and it may also confer better safety for our patients."

He was impressed with the potential effect on respiratory depression for surgery patients. "Hospitals are struggling with opioid-induced respiratory depression, and this drug may allow us to mitigate that."

But Dr Pergolizzi noted that TRV130 is not the only new product in development. "There are other interesting molecules on the horizon," he said, including a new class of opioids called kappa opioid agonists (KORAs).

The study was funded by Trevena. Dr Skobieranda is an employee of Trevena. Dr Pergolizzi has disclosed no relevant financial relationships.

PAINWeek 2015. Poster 117. Presented September 11, 2015.


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