The initial screening hit, ORC-0001 (also formerally known as BPN-0001 and PROTO-1), was effective in zebrafish and rats in protecting hair cells from the toxic effects of aminoglycosides (AGs), but ADMET testing and especially hERG tests showed that the safety margin of ORC-0001 was not adequate to progress it as a medicinal candidate.
Funding provided by NIDCD, the Life Sciences Discovery Fund and the NINDS Blueprint Neurotherapeutics Program (NIH BPN) allowed development of an extensive SAR (structure activity relationship) program. In all, 329 analogs of ORC-0001 were synthesized and tested, and 50 analogs found that were 10 times more potent and 10 analogs that were 100 times more potent than the initial lead in protecting zebrafish hair cells. Additional testing and analysis established that five compounds had the selectivity (based on broad screening), potency, efficacy, pharmacokinetic and physiochemical properties along with chemical novelty to advance the project to late lead optimization. In parallel, it was confirmed that none of these compounds interfere with the bactericidal efficacy of AGs.
ORC-13661 is a new chemical entity discovered and patented (US 9416141 and US 9493482 ) by University of Washington with grant assistance from NIH, and is exclusively licensed to Oricula Therapeutics LLC.
Preclinical testing of ORC-13661 has lead to the following findings:
· At an oral dose of 5mg/kg/day, it provides 100 percent protection of hearing for rats treated for 10 days with amikacin at 320 mg/kg/day administered subcutaneously and almost complete hearing protection for rats treated for 12 days at the same dose of amikacin
· Oral bioavailability in mice, rats and dogs are in the 40 – 60 % range
· Linear pharmacokinetics in a range of 0.2 mg/kg - 100 mg/kg
· A half-life of 4-6 hours, providing adequate coverage for once/day oral therapy
· Microsomal and Hepatocyte clearance consistent with the half-life in serum
· A metabolic profile similar in rat, dog, monkey and human with no unique human metabolites
· No interference with aminoglycoside bactericidal effect in Pseudomonas aeruginosa, E. coli, or M. tuberculosis.
After devising an efficient synthesis, 3.2 kg of cGMP material was manufactured. GLP Safety Studies reveal:
· ORC-13661, administered orally to rats at 30, 80, and 200 mg/kg, does not produce mortality, clinical observations, or effects on the evaluated respiratory parameters.
· ORC-13661, administered orally to rats at 30, 80, and 200 mg/kg, does not produce behavioral or neurological observations.
· The IC50 for the inhibitory effect of ORC-13661 on hERG potassium current was 0.6 µM, the IC20 was 0.1 µM. The hERG inhibition was confirmed in a dofetilide evaluation which found the IC50 was 1.1 µM.
· ORC-13661, administered orally to beagle dogs at 10, 30, and 80 mg/kg, did not produce mortality or adverse effects.
· A human derived pluripotent stem cell cardiomyocyte study revealed no significant alteration of action potentials at concentrations up to 3 µM.
GLP toxicology studies reveal:
· AMES and Micronucleus studies were negative showing no evidence of mutagenicity.
· Dogs dosed for 28 days at 10, 30 and 60mg/kg/day had a No Adverse Effect Level (NOAEL) of 10mg/kg/day. The major findings at higher doses was liver toxicity which was completely reversible after cessation of treatment.
· Rats dosed for 28 days at 30, 80 and 200mg/kg/day had a NOAEL of 80mg/kg/day. The major findings at higher doses included: inflammation of skeletal and cardiac muscles and vacuolation in macrophages and/or epithelial cells in a wide array of tissues (consistent with phospholipidosis). The recovery animals showed no signs of these problems. There was no evidence of liver toxicity in the rats at any dose.
An Investigation New Drug application was submitted to the FDA, and Oricula has been approved to move forward into human testing.