Poster Number-63 - ADV-502, a Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: II. Tolerance and Opioid-Induced Hyperalgesia

ADV-502, a Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: II. Tolerance and Opioid-Induced Hyperalgesia

Purpose: Pharmacological activation of opioid receptors, particularly the µ-opioid receptor (MOR), is one of the main options for the treatment of moderate-to-severe pain. However, the use of opioids is associated with a wide range of side effects as well as opioid-induced tolerance and hyperalgesia, that result in a diminished effectiveness, potentially leading to the use of higher doses that increase the abuse potential and over-dose risk. If tolerance develops, drug potency decreases. If opioid-induced hyperalgesia (OIH) is expressed, pain sensitivity increases. Thus, tolerance and OIH are pharmacologically distinct phenomena, but both tolerance and OIH become apparent as an increased requirement of opioid dose to keep pain controlled. ADV-502 (EST73502, WLB-73502, is a bispecific, dual µ-opioid receptor (MOR) partial agonist and σ1 receptor (S1R) antagonist, selective against a panel of other 180 molecular targets (receptors, transporters, ion channels, and enzymes) (García et al., 2013). Potentiation of opioid analgesia but not of opioid-related adverse events (AEs) by S1R blocking results in an improved efficacy of ADV-502 and reduced AEs compared to opioid monotherapy [see accompanying poster]. Here we investigated the development of tolerance and hyperalgesia following administration of ADV-502 in comparison with strong opioids.

Methods: The efficacy over time and thus eventual development of pharmacodynamic tolerance was investigated following repeated administration of ADV-502 and opioid comparators in a rat model of osteoarthritis (OA) pain induced by intraarticular knee injection of monoiodoacetate (MIA) and in a rat model of bone cancer pain induced by injecting MRMT-1 rat mammary gland carcinoma cells into the intramedullar cavity of the proximal tibia. Mechanical allodynia was assessed using von Frey filaments. The presence and duration of OIH was assessed following acute administration of compounds.

Results:

Systemic b.i.d. administration of SDV-502 induced a dose-dependent reduction of MIA-induced mechanical hypersensitivity. The effect of ADV-502 remained unchanged throughout the 28-d treatment period, with a slight tendency to increase efficacy over time, thus suggesting absence of tolerance to its analgesic effect after 4 weeks of repeated administration. Although morphine and oxycodone also reduced mechanical hypersensitivity, their antinociceptive effect diminished progressively throughout the treatment period (i.e., pharmacodynamic tolerance developed), the effect being almost completely lost after 3 weeks of treatment. Similar results were obtained in the bone cancer pain model: the antinociceptive effect of ADV-502 remained unchanged after daily administration for14 days, whereas the effect of morphine did not.

 With regards to OIH, single administration of fentanyl induced OIH lasting for several days. The OIH was blocked when fentanyl was co-administered with naloxone (MOR antagonist) or with S1RA, a selective S1R antagonist, indicating that OIH involves MOR activation and that S1R blocking prevents OIH. In contrast to fentanyl and other MOR agonists, including the biased MOR agonist TRV-130, all of which induced long-lasting OIH, administration of ADV-502 did not induce OIH. Interestingly, co-administration of ADV-502 with the pure S1R agonist PRE-084 did result in OIH, indicating that the bispecific ability of ADV-502 to antagonize S1R is a key distinctive mechanism to counteract MOR agonist-mediated OIH.

Conclusion: ADV-502 is a bispecific S1R antagonist/MOR partial agonist that demonstrates antinociceptive potency and efficacy comparable to, or better than (in neuropathic pain models), mono-mechanistic full MOR agonists, but unlike such drugs ADV-502 does not induce tolerance or OIH at antinociceptive doses. These results provide further evidence that dual MOR agonism and S1R antagonism may be a useful strategy for obtaining potent and safer analgesics, and they were the basis for the selection of ADV-502 as a clinical candidate for the treatment of pain [see accompanying poster].

References: García et al. (2020) J Med Chem 63:15508-26.