Poster Number-64 - ADV-502, a Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: III. Phase-1 Study

ADV-502, a Novel Dual Sigma-1 Receptor Antagonist and Mu-Opioid Receptor Agonist for the Treatment of Pain: III. Phase-1 Study

Purpose: ADV-502 was identified in a discovery program aimed at overcoming shortcomings of existing analgesic classes. The process employed a new strategy (pharmacophore-merging) to identify compounds having dual action at both the µ-opioid receptor (MOR) and the s₁ receptor (sigma-1R). The rationale was the role of sigma-1R antagonists in inhibiting central sensitization (in which opioids are not completely satisfactory) and the enhancement of opioid-induced analgesia by sigma-1R antagonists. ADV-502 (EST73502//WLB-73502) emerged as a novel compound of particular interest (García et al., 2020). It has binding affinity for both MOR and sigma-1R and behaves as a partial MOR agonist and sigma-1R antagonist. Efficacy in vivo revealed antinociceptive effects in animal models of acute pain, visceral pain, and chronic/neuropathic pain. ADV-502 displays good selectivity over other binding sites, has a good PK profile and a balanced metabolism. It also displays less respiratory and gastrointestinal (GI) MOR-related AEs, low development of tolerance and physical dependence, and a safety profile [see the accompanying poster for the Preclinical summary] that supported advancement to a Phase-1 clinical trial, summarized here.

Methods: This was an exploratory, randomized, double-blinded, placebo- and active-therapy-controlled phase I study of ADV-502 using an adaptive integrated design which assessed the safety tolerability, food effect, PK and PD of single ascending doses (SAD) and multiple doses (MD). The participants were healthy Caucasians 18 – 45 yrs. Sixty-two participants were analyzed for safety and tolerability and were sampled for PK analysis, and 51 underwent intensive cardiac assessment. ADV-502, placebo, or oxycodone were administered by oral capsules. Primary endpoints included safety and tolerability as measured by the incidence of treatment emergent adverse events (TEAEs), proportion of subjects with clinically significant changes in laboratory values, ECG, or vital signs. Secondary endpoints included PK and some ADME measures. Some exploratory endpoints (e.g., PK/PD relationship, PD effects of ADV-502 and oxycodone IR on pupil size and gastrointestinal function and symptoms) were also included.   

Results:

A total of 62 healthy volunteers were enrolled and dosed in the study. None withdrew from the study. Overall, single and multiple administrations of ADV-502 were well tolerated, no serious adverse event (SAEs) occurred during the study, and no participant was discontinued due to a TEAE. In Part I (SAD), ADV-502 demonstrated a clear dose response as the incidence of TEAEs increased with increasing single oral doses from 2.5 mg up to 30 mg, and most notably in the 20 and 30 mg doses. In Part II (food effect), the safety profile of ADV-502 was generally comparable in the fed and fasted state; however, the frequency of dizziness and headache was higher in the fed than fasted state, despite no clear relationship was observed with individual PK data. In Part III (5mg MD), the small number of subjects who received oxycodone IR translated to a relatively limited comparison with ADV-502. Despite this, the limited data showed a relatively comparable safety profile for a 5 mg dose of both oxycodone IR and EST73502 administered QID for 7 consecutive days (and a morning dose on Day 8). The most common TEAEs included somnolence, headache, nausea, euphoric mood, and dizziness, more commonly in the oxycodone and ADV-502 groups than in the placebo group. There were no ADV-502-related or clinically-significant changes in vital signs, clinical lab tests, or ECG, and no evidence of respiratory depression. QTc prolongation occurred at the highest dose (30 mg). A rapid PD effect was demonstrated by pupillometry. PK/PD relationship between reduction of pupil size and exposure to ADV-502 was observed after single oral administration of ADV-502 at dose levels equal or higher than 5 mg. In the 5 mg MD administration, QID regimen, the limited data obtained for 5 mg oxycodone IR suggested similar potency to reduce pupil size to that of ADV-502. There was a PD effect on bowel function but less than oxycodone. There was a dose-related increase in drug-liking compared to placebo. Established PK/PD models of ADV-502 predict that analgesia, measured by its potency to produce miosis, appeared at lower ADV-502 concentrations than neurological performance, measured by drug-related relative VAS.

Conclusion: ADV-502 shows dual MOR-agonism and sigma-1R antagonism that results in potent analgesic activity comparable to the MOR agonist oxycodone in animal models of pain including chronic/neuropathic pain after single and repeated administration [see accompanying poster]. These efficacy results, and reduced MOR-like AEs provided evidence that dual MOR-agonism and sigma-1R antagonism appeared to be a useful strategy for obtaining potent and safer analgesics, and were the basis for the selection of ADV-502 as a clinical candidate for the treatment of pain. This Phase-1 study explored a range of ADV-502 doses that encompass the potential anticipated therapeutic dose range. The dose of 5 mg QID seemed adequate to maintain the required plasma concentration above the predicted therapeutic threshold. Continued investigation of efficacy and safety is needed. Due to the low number of participants in the oxycodone arm, no comparative conclusions could be drawn, but the results aligned with preclinical data that showed a trend to better GI tolerability. Based on the overall results of this study (and perhaps depending on some extent of accumulation factor with dosing), the potential analgesic effect of ADV-502 appears to be achievable at the 5 mg dose without exceeding the PK and safety limits and no QT-prolongation concerns.

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