The History of Dual Opioids

Morphine was first purified from the opium poppy over 200 years ago, and since then there has been a quest by chemists around the world to find an opioid with fewer side effects. The pain management “Holy Grail” is to deliver opioid-like efficacy with fewer and less severe side effects. Opioid-related adverse effects significantly limit their effectiveness and reduce patient quality of life. Side effects include respiratory depression, constipation, sedation and drowsiness, nausea and vomiting, psychological dependence and addiction. While many combination products such as an NSAID plus an opioid (e.g., Vicodin® or Percocet®) have been developed and are widely used, these dual modality products present significant clinical problems in addition to opioid-related side effects, such as their potential for producing acute liver failure due to the acetaminophen or gastrointestinal bleeding due to ibuprofen.

Chemical Structures of Morphine and Oxycodone

Chemical differences accounting for unique properties are highlighted by circles.

In the early 1990s, scientists at the University of Queensland in Australia postulated that oxycodone acted through a different set of neural receptors than other opioids like morphine or fentanyl. The Queensland scientists published findings that sub-analgesic doses (i.e., below traditional pain relief) of oxycodone have a synergy with sub-analgesic doses of other opioids such as morphine. The scientists postulated when combined together in low doses at the proper proportion, a “dual opioid” could produce synergistic pain relief with fewer side effects. Evidence from the University of Queensland’s discovery has now been observed in both animal and human trials, and published in many peer-reviewed research papers.

The Company has conducted an extensive clinical program with the Dual Opioids®, morphine and oxycodone. These studies were conducted under FDA authorised Investigational New Drugs (INDs) authority designed to support a 505(b) 2 application that relies in part on the Agency’s finding of safety and effectiveness of previously approved products. The New Drug Application (NDA) for Moxduo, resubmitted in November, 2013 by QRxPharma, summarised data from nine clinical studies (4 Phase 1, 2 Phase 2, and 4 Phase 3 studies) in acute post-surgical pain and healthy volunteers including over 1,700 patients. The NDA highlighted the results of Study 022 demonstrating what QRxPharma believes to be less severe risk of respiratory depression as measured by oxygen desaturation with Moxduo than equi-analgesic doses of morphine or oxycodone. These important findings were presented to an Advisory Committee in a meeting in April 2014. The Committee concluded that additional clinical safety data would be required for approval. The FDA has confirmed that Moxduo has been shown to be effective with no safety signals of concern, but the Agency has agreed with the Committee that stronger evidence of a meaningful clinical benefit is necessary.

On 14 August 2014 the Company announced that it is halting all further development work on the Moxduo portfolio of products.