ADV502

Bispecific Sigma-1 Antagonist and Mu-Opioid Partial Agonist

Candidate Profile:

  • ADV502 is a pure enantiomer with one chiral center 
  • Non-opioid structure
  • Good physicochemical profile, as indicated by its low basicity (pKa7.89), its low lipophilicity (logP2.66, logD2.04) and good water solubility(classified as soluble in water).
  • Solution stability has been demonstrated in pH 2 and 7.4 media buffer for 24 hours
  • The compound shows a good profile regarding Lipinski’s rule compliance
  • Fumarate salt with good thermal behavior and robust crystalline polymorph selected after salt screening​
  • Synthesis has 7-step process with ca 45% yield​
  • The process is suitable for scale-up. 
  • Good stability in neutral and acidic conditions and suitable solubility
  • Good affinity for σ1 receptor, Ki = 118 nM
  • Good affinity for µ-opioid receptor Ki = 64 nM
  • Partial µ-opioid agonist (lower binding versus strong opioids) 
  • Selective vs 181  targets panel (inhib.<50% at 10 µM)
  • Non relevant responses on Adrenergic α2B and α2C, Histamine H1, and Serotonin 5-HT7
  • No alerts on genotoxicity: SOS/umu, in vitro micronucleus and Ames tests negative​
  • Cardiac hERG potassium channel: IC50 > 10 µM​
  • Irwin’s test: no relevant effects on CNS at 70 mg/kg po. (rat & mouse)
  • No alerts on in vitro cytotoxicity (up to 100 µM) and genotoxicity​
  • Good in vitro metabolic stability in human and rodent species​
  • Metabolic Stability at 1 μM in liver microsomes was high in humans and dogs, moderate in monkeys, and moderate-low in rats, mini-pigs and mice.
  • Liver microsomes HRMMpDoMo=93/76/69/74/89/94)​
  • Acceptable permeability (human Caco-2 cells)​
  • Not a P-gp substrate​
  • Low potential for metabolism-based drug-drug interactions​
  • Fast brain absorption in rodents​. Brain-to plasma AUC ratio 2.6
  • Similar oral exposure in rodents: AUC > 500 ng·h/m
  • Max NonLethal Dose in rat:​ 50 mg/kg M & F
  • Not relevant alert in 7-day oral rat toxicity (RDT) at 10 mg/kg/d by subcutaneous route
  • ADV502 is an enantiomerically pure chiral compound
  • Drug-like NCE complying with Lipinski rules and BCS (Biopharmaceutics Classification System) Class I properties: high solubility and permeability
  • Good physicochemical profile, as indicated by its low basicity (pKa7.89), its low lipophilicity (logP2.66, logD2.04), and good water solubility
  • Suitable kinetic solubility >10 µM
  • Good stability in neutral and acidic conditions.
  • Drug substance highly stable both in forced and long-term stability conditions
  • Maximum solubility in water of 44 mg/mL, which allows it to be classified as soluble in water. The compound can be classified as soluble at pH < 5 (37 mg/mL), sparingly soluble at pH 5-8 (8 mg/mL) and slightly soluble at pH > 8, with an intrinsic solubility of 4.6 mg/mL.
  • Is not hygroscopic
  • Fumarate salt with good thermal behavior and robust crystalline polymorph selected after salt screening​
  • Synthesis has 7-step process with ca 45% yield​
  • Scale-up completed.
  • Good affinity for σ1 receptor, Ki = 118 nM
  • Good affinity for µ-opioid receptor Ki = 64 nM
  • Partial µ-opioid agonist (lower binding versus strong opioids)
  • Selectivity vs 5-HT1A, 5-HT2B, α1A, α2A, H1, α2δ–1, α2δ–2, DAT, NET, SERT, δ-opioid, κ-opioid, µ-opioid (inhib.<50% at 1 µM)​
  • Selective vs 181 targets panel (inhib.<50% at 10 µM)
  • No alerts on genotoxicity in vitro: SOS/umu, Ames, and CHO micronucleus tests negative​
  • No alerts on mitochondrial toxicity
  • No alerts on phospholipidosis
  • No alerts on in vitro cytotoxicity (up to 100 µM)
  • Cardiac hERG potassium channel: IC50 > 10 µM​
  • Irwin’s test: no relevant effects on CNS (GLP 70 mg/kg po, rat & mouse)
  • Metabolic Stability at 1 μM in liver microsomes was high in humans and dogs, moderate in monkeys, and moderate-low in rats, mini-pigs, and mice
  • Metabolic Stability in liver microsomes HRMDoMoMp=92/61/33/91/76/45% (1h)
  • Metabolic Stability in mouse t½=38 min​ at 1μM
  • Time-dependent CYP2D6 inhibition and CYP3A4 induction in vitro. Not a P-gp substrate​
  • Acceptable drug-drug interaction potential of ADV502 and/or metabolites for CYP2D6 based on P-gp inhibition
  • High permeability (human Caco-2 cells): Papp 349.5 nm/s. ER 2.5
  • Similar plasma protein binding in all species tested: 65% in rats, 60% in mice, 74% in humans, 67% in monkeys, 75% in dogs and 69% in minipigs
  • Fast absorption, low exposure, very fast elimination, high distribution and high clearance in rodents
  • Fast brain absorption in rodents​. Brain-to plasma AUC ratio 2.6
  • The oral bioavailability of ADV502 was moderate in dog
  • PK was characterised by a medium hepatic extraction and a good distribution
  • The metabolism of ADV502 in dog took place mainly through the formation of one main metabolite
  • Max Non Lethal Dose in mouse:​ 50 mg/kg (M) & 150 mg/kg (F)
  • Genotoxicity in vivo (micronuclei): Negative (rat)
  • The maximum repeatable dose when given once a day for 14 days was considered ≥ 50 mg/kg/day.
  • The no observed adverse effect level (NOAEL) was considered to be 50 mg/kg/day (p.o. gavage) after the 6-week treatment period.
  • ADV502 did not induce micronuclei in peripheral blood reticulocytes in rats treated up to 50 mg/kg/day.
  • Genotoxicity, in vitro & in vivo studies: Ames test, Mouse Lymphoma assay & Rat Micronucleus test
  • Safety pharmacology studies: CNS, Respiratory, CV, Gastrointestinal and Urinary functions
  • 6-week Repeated Dose Oral Toxicity studies in rats and minipigs
  • Embryofetal Development Toxicity studies in rats (oral) and rabbits (s.c.)
  • Toxicokinetic assessment conducted in all pivotal studies, confirm adequate exposure to parent & relevant metabolites Overall, good tolerability to ADV502 administrations, with a favorable safety profile and adequate safety margins to human exposure.
  • Clinical phase 1 study,  SIMU-101, showed a favorable safety profile in healthy adult Caucasian subjects.

Current Indications: