Development of cebranopadol, a potent dual MOP/NOP agonist, for the treatment of Opioid Use Disorder (OUD) - ABSTRACT/SUMMARY
The U.S. is experiencing a crisis of opioid misuse, addiction, and overdose; in the most recent year, there were
over 100,000 drug-related overdose deaths, 75% of which involved opioids. Current pharmacotherapies for
opioid use disorder (OUD) target mu opioid peptide (MOP) receptors, one of five classes of opioid receptors.
These therapies include the full MOP agonist methadone, the partial MOP agonist buprenorphine, and the MOP
antagonist naltrexone. There are several drawbacks in using these medications to treat OUD, which include the
potential for abuse, development of physical dependence, and risk of overdose, particularly for methadone and
buprenorphine. Buprenorphine and naltrexone also trigger severe withdrawal symptoms. There is thus an urgent
need for an improved therapeutic for the treatment of OUD. Cebranopadol (TRN-228) is a first-in-class synthetic
drug developed for its dual-action mechanism in treating pain, mediated by high affinity and potency for both
MOP and nociceptin/orphanin FQ receptor (NOP). NOP receptor activation has been associated with reduced
development of tolerance, abuse-related behavior, addiction, and physical dependence. In this UG3/UH3
proposal, Park Therapeutics is developing TRN-228 as a first-in-class dual MOP/NOP agonist that can
be used as a safe and effective treatment for OUD. Preliminary nonclinical and clinical data indicate that
cebranopadol has low potential for abuse and physical dependence and produces milder respiratory depression
compared to pure MOP agonists such as morphine and oxycodone. TRN-228 also decreases morphine, heroin,
and cocaine self-administration in rats and did not induce withdrawal when given to opioid-dependent rats. The
UG3 phase of this proposal will test whether oral TRN-228 is a safe and potentially effective alternative treatment
for OUD, based on the following Specific Aims: 1) determining the effects of TRN-228 on intravenous fentanyl
self-administration and fentanyl-induced respiratory depression in opioid-dependent rats, 2) determining the IV
abuse potential of TRN-228, and 3) assessing the ability of TRN-228 to suppress withdrawal. Upon meeting the
UG3 Go/No-Go milestones, Park will progress to the UH3 phase which will demonstrate the therapeutic efficacy
of TRN-228 in decreasing opioid use with low risk of withdrawal or abuse, which will be accomplished by 4)
determining the effects of TRN-228 on fentanyl-induced respiratory depression in opioid-tolerant participants and
5) evaluating the ability of TRN-228 to block the subjective effects of hydromorphone. These studies will
significantly advance the field by establishing the safety and preliminary efficacy of TRN-228. Successful
completion of these aims will guide future efforts to establish a clinical program for FDA approval.
