Nature was the venue (8/18/16) for the publication of a paper from academic collaborators at UCSF, Stanford, UNC, Friedrich-Alexander-Universität Erlangen-Nürnberg, and Parelcus Medical University, a paper that reported the development of a highly refined, selective mu opioid agonist that–in animal models–came close to morphine’s analgesic efficacy while not generating abuse potential on ‘liking’ measures and without morphine’s risk of respiratory depression (RD). Perhaps.
The group screened over three million molecules against a subunit of the mu opioid receptor crystal structure, parsing out those which activated beta-arrestin activity (thought responsible for RD) versus those which were biased towards Gi protein signalling at the mu opioid receptor, believed to be the basis of analgesic activity. Via a number of sophisticated optimization steps, the group developed a prototype drug, PZM21, that fit the criterion of similar efficacy with reduced side effect/abuse risk. In term of selectivity vis-vis other opioid receptor subtypes, the compound lacks nociceptin receptor activity, is a mild kappa opioid antagonist, and has very weak delta-opioid binding. In animal testing, PZM21’s effect in pain models showed efficacy similar to morphine’s; did not trigger sustained respiratory depression, though the paper’s authors failed to mention (and Nature’s peer reviewers overlooked) that the drug had the same RD effect after 15 minutes as morphine* (though morphine’s suppressive action became profound and persistent), and thus at least temporarily separated from vehicle (which raises the question of whether an overdose might in fact be potentially lethal in that timeframe); had less impact on GI motility than morphine; and was not observed to activate reward pathways and behavioral ‘liking.’ This is a unique profile, though this compound has yet to be tested in humans, and thus has a long developmental journey ahead of it. Trevena’s TRV130 is also a biased Gi opioid agonist, and is in Phase III. However, that compound differs from PZM21–it does have kappa opioid agonist activity (which can have aversive affective effects in males)–and it does briefly stimulate respiratory depression (albeit not much more than PZM21)–though there is evidence suggesting decreased abuse/risk.
Though the minefield of human testing remains ahead for PZM21, the animal models used in the analgesia context are more predictive than are models in most neuro-contexts, and the compound differentiates itself on a number of important features that would be relevant to safer, more efficient, less abuse-prone analgesia. We expect that this will be a sought-after licensing asset, though several major pharmas have deleted acute pain relief from their licensing interests; in spite of their flaws, standard opioid analgesics constitute a challenging competitive environment. PZM21 appears, at least preclinically, to address many of the shortcomings that are pervasive in the current offerings. However, the published report somehow overlooked the possibility that the compound may have a window of vulnerability to respiratory depression–a highly experienced neuroscientist suggested to NIR that an animal study be done comparing the potential lethality of PZM21 at 15 minutes post-administration to that of morphine and oxycontin (and we would add, TRV130), in order to ascertain whether the compound has a short-lived but potentially lethal Achilles Heel.
*noted by the LA Times’ Karen Kaplan
Also: TauRx Claims Posthoc Victory Prematurely
A couple weeks back, TauRx released results from the first of three clinical trials (two in AD, one in FTD) for LMTX, reporting that it failed overall in AD, but they then claimed success based on a subset of patients not receiving concurrent ChEis who appeared to outperform placebo patients (both on and off ChEis). At best, this represents an interesting hypothesis that can only be proven, or disproven, by further prospective testing. Management’s claim that this established LMTX as an efficacious monotherapy was sloppy and specious–other explanations are as likely or more so. These results for the most clinically advanced tau-targeting therapeutic will be discussed in much more detail in the upcoming September/October issue of NeuroPerspective, which covers Alzheimer’s.