We believe APPA is now ready to apply for regulatory approval to start formal human trials now that required preclinical toxicology studies have been completed.
There is a considerable body of evidence behind the efficacy, safety, tolerability and mode of action of APPA. Consistent with data in the public domain, the studies undertaken indicate that the toxicity potential of orally administered APPA is low.
In vitro genotoxicity panel with a clean outcome for both molecules. APPA also completed in vivo preclinical toxicology studies with no clinical signs of toxicity or out-of-range laboratory or pathological parameters:
Maximum Tolerated Dose (MTD) study – dose escalation up to 1000mg/kg APPA followed by fixed dose phase of 1000mg/kg. No dose limiting findings, no obvious chemistry or haematological findings. Overall APPA was well tolerated.
In-life 28-day oral administration followed by 2-week treatment free, observations and results were as expected. The report concluded that “Daily administration oral (gavage) administration of APPA at 200, 500 and 1000 mg/kg/day for 28 days was well tolerated and there were no adverse toxicological findings. The No Observed Adverse Effect Level (NOAEL) is therefore identified at 1000 mg/kg/day”.
As a point of reference, based on FDA guidanceI that dosage is 14.5X the recommended single dose and 7.25X the recommended daily therapeutic dose for humans, which is presumed to be 800 mg (11.5 mg/kg) twice a day, for a total daily dose of 1,600 mg (23 mg/kg/day).
I Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, U.S. Department of Health and Human Services, Food and Drug Administration July 2005.