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Pain Treatment Oliceridine Wins Breakthrough Therapy Status

Pivotal studies expected to start in mid 2016

The FDA has granted breakthrough therapy status to intravenous (IV) oliceridine (TRV130) for the management of moderate-to-severe acute pain. After two successful phase 2 studies, oliceridine is now in phase 3 development. The ATHENA-1 safety and tolerability study is ongoing in approximately 900 patients, with pivotal studies expected to begin in the second quarter of 2016.

According to the drug’s developer (Trevena, Inc.), phase 2 study data for oliceridine showed “encouraging differentiation” from morphine.

Oliceridine was previously granted a fast track designation by the FDA. It is the first m receptor G protein pathway-selective modulator (mGPS)––a biased m opioid receptor ligand that in preclinical studies activated pathways associated with analgesia while avoiding pathways that can promote respiratory depression and gastrointestinal dysfunction and limit analgesia.

In preclinical studies, oliceridine activated the mu opioid G protein receptor pathway in a manner similar to that of strong opioids, such as morphine and fentanyl, and like those drugs, oliceridine was a powerful analgesic in rodents. Unlike those drugs, in cell-based studies oliceridine did not engage the beta-arrestin pathway, which was shown in mice to inhibit morphine analgesia and to promote mediate morphine-induced constipation, respiratory depression, and analgesic tolerance.

In rodent studies, oliceridine was more potent than morphine, and it reached peak analgesia faster. In mice, oliceridine caused less gastrointestinal dysfunction than morphine at equivalent analgesic doses. In rats, oliceridine also had an improved therapeutic index for analgesia to respiratory depression compared with morphine. This suggested that oliceridine may offer improved pain relief compared with currently approved opioid analgesics.

In phase 2 trials, IV oliceridine demonstrated analgesic efficacy with a reduced frequency of opioid-related adverse events, including nausea, vomiting, and hypoventilation, compared with IV morphine. Trevena anticipates that the initial market opportunity for oliceridine will be in the acute care settings, with a focus on moderate-to-severe acute pain in the hospital.

Despite the development and adoption of guidelines for the management of postoperative pain and the extensive use of current treatments, a significant unmet need remains, according to Trevena. In a 2003 national survey of surgical patients in the U.S., more than 70% of the patients undergoing in-hospital procedures reported pain during the postoperative period before hospital discharge.

Currently available mu-opioid agonists, such as morphine and fentanyl, are the most effective class of analgesics for moderate-to-severe acute postoperative and medical pain, but their efficacy is limited by severe adverse events, such as respiratory depression, nausea, vomiting, constipation, and postoperative ileus.

Sources: Trevena; February 22, 2016; How TRV130 Works; 2016; and About Postoperative Pain; 2016.

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