A 13-Week Oral Gavage Toxicity Study of OLX-07010 in Beagle Dogs Followed by a 4-Week Recovery Period

PROJECT SUMMARY This SBIR Ph I (R43)/Ph II (R44) Fast-Track application is for a 13-week GLP, toxicity study of OLX-07010 in dogs with a 4-week recovery to support the continued clinical development of OLX-07010 in patients. This 13- week study in dogs will be conducted both to de-risk a planned 39-week toxicology study that is required by FDA for our phase 1b clinical studies, and to alleviate any safety concerns for Alzheimer’s disease (AD) patients that will be dosed in future phase 1b studies, the duration of which could be anywhere from 3 to 18 months long. As we are presently conducting a 26-week GLP toxicity study in rats, completion of the 13-week study in dogs will enable us to extend the dosing duration allowable in our clinical evaluations to 3 months. OLX-07010 is a highly differentiated small molecule drug targeting the formation and growth of tau aggregates in AD and related tauopathies by inhibiting tau self-association. It has the potential to have a tremendous impact on the more than 6.7 million Americans who currently have AD projected to be 13.8 million by 2060) and their caregivers. It holds the promise to help reduce the current cost of AD ($345 billion; projected to be $1.1 trillion by 2050) to our nation (Alzheimer's Association 2023 Alzheimer's Disease Facts and Figures). Orally administered OLX-07010 is an economically viable alternative to costly immunotherapeutics targeting tau that require infusion and has potential to complement FDA approved drugs targeting amyloid beta. It has the potential to provide a global solution as it can be widely distributed even in regions that lack significant healthcare infrastructure. Results of the preclinical studies have shown that OLX-07010 demonstrated pharmacologic activity in preventive and therapeutic studies in two mouse models of tauopathy, htau, representing tau aggregation in AD, and P301L tau JNPL3, representing four-repeat tau tauopathies. IND enabling studies were completed in 2022 and a first-in-human clinical trial was initiated in 2023. A supplemental 28-day study in rats at higher doses was requested by FDA to support further dose escalation in humans, has been completed. Preliminary results from this study showed that higher doses of 500 and 1,000 mg/kg were associated with liver (target organ) toxicity (hepatocellular necrosis) and are consistent with 300 mg/kg, the highest dose tested in the original 28-day study, as the true NOAEL. These data are anticipated to address FDA requests and to enable higher dosing in the clinic to achieve clinical dose levels predicted to have a maximal effect based on our pharmacodynamic studies. A complete response will be submitted to FDA, and we anticipate a response letter in June. The milestone of Ph I (R43) is to synthesize 15 kg of non-clinical safety study (NCSS) drug substance to conduct the dog study. During Ph II (R44), a stability study on this batch will be conducted, and the 13-week toxicology study will be performed in beagle dogs. Dose levels will be determined using an ascending dose-range finding study, already supported by NIH award (AG066384).