Toronto-based Revive Therapeutics Ltd today announced positive results from the second half of its Phase 2a proof-of-concept study of REV-001 targeted for the treatment and/or prevention of opioid-induced respiratory depression for patients with sleep apnea in a postoperative setting.

The purpose of the study is to determine the effect of an oral dose of REV-001 on alfentanil-induced respiratory depression and analgesia. The results indicate that a single dose of REV-001 may treat and/or prevent opioid-induced respiratory depression in a postoperative setting, without affecting analgesia. The 16-patient, placebo-controlled, double-blind, randomized two-way crossover trial was performed by Professor Albert Dahan, MD, PhD, at the Leiden University Medical Center in The Netherlands. Full results of the study will be published.

The data from the second half of the study in eight patients yielded the following key findings:

  • Treatments with REV-001 were safe and well tolerated at the 50 mg dose, were not associated with serious adverse events, and there were no treatment-related discontinuations
  • A significant increase in respiratory drive as measured by inspired minute ventilation at an elevated expired PCO2 (VE55) of 36% (p = 0.039) by REV-001 as compared to placebo during high-dose alfentanil infusion-induced respiratory depression
  • Treatments with REV-001 did not affect the opioid’s analgesic properties
  • Treatments with REV-001 did not affect sedation.

“Overall, this is a successful study showing the respiratory stimulatory effects of REV-001, that now seems to have a novel target, that is reversal of opioid-induced respiratory depression and a unique solution in a postoperative setting,” says Dahan in a release.

Fabio Chianelli, Revive CEO, says, “I am very pleased with the successful completion of our first human clinical trial and that we met our milestone for REV-001 on time and on budget. The positive results of the REV-001 human clinical trial now position the drug for partnering discussions. This achievement not only validates our ability to successfully repurpose drugs for new indications, but also provides us with the opportunity to advance our business development activities via licensing and acquisitions.”

About Postoperative Pain and Sleep Apnea

According to the National Center for Health Statistics, there are over 100 million surgeries performed annually in the United States with approximately 50% of those requiring postoperative pain medication such as opioids. However, opioids are known to raise serious concerns such as respiratory depression, oxygen desaturation, and other side effects such as constipation, nausea, and vomiting. Patients who have obstructive sleep apnea (OSA) are at a particular risk of experiencing such negative side effects from opioids.

According to an article titled “A Rude Awakening-The Perioperative Sleep Apnea Epidemic” published in the New England Journal of Medicine in June 2013, the risk of perioperative complications increases substantially with those who have OSA. Hospitals must take into consideration the financial implications that may become prevalent for patients who have OSA in order to reduce the risk of adverse events, such as opioid-induced respiratory depression.

Currently, there are no approved drugs for OSA and the only drug treatments to counter opioid-induced respiratory depression are to administer opiate receptor antagonists such as naloxone (Narcan). However, those antagonists eliminate the analgesic activity of the opioid drug and thus are rarely used by hospitals and healthcare facilities to prevent or treat opioid-induced respiratory depression.

About REV-001

REV-001 is the repurposing of the drug tianeptine, an old but unique antidepressant drug, which is marketed in Asia, parts of Europe, and South America. Despite its narrow geographic scope, the decades-long clinical experience of tianeptine suggests much about its safety, the manufacturer says. Tianeptine has been shown to have substantial cardiovascular and other safety at both normal doses and in overdose. (Source: Wilde MI,  Benfield P. Drugs. 1995;49:411-439.) More recently, in animal studies conducted by Revive, tianeptine was shown for the first time to prevent opioid (morphine)-induced respiratory depression in an animal model. The novel findings in Revive’s animal studies enabled Revive to apply for intellectual property protection covering the use of tianeptine to treat respiratory depression.