UNI-494 DOG 28-Day Oral Toxicity Study

Orally Administered UNI-494 Is Well-Tolerated in Dogs

Guru Reddy¹, Pramod Gupta¹, Atul Khare¹, Shalabh Gupta¹

¹Unicycive Therapeutics, Inc.

Background

• Inflammation and reactive oxygen species driven mitochondrial permeability transition pore (mPTP) opening causes mitochondrial dysfunction/swelling and eventual cell death over time
• This is implicated in a wide range of acute diseases including acute kidney disease originating from ischemia reperfusion injury or delayed graft function
• Furthermore, unresolved inflammation exacerbates sustained mPTP opening, evident in chronic kidney diseases
• UNI-494 is a selective mitochondrial ATP-sensitive potassium (K_ATP) channel activator that binds to the K_ATP channels which reverses the mitochondrial dysfunction by closing the mPTP (Figure 1)

Methods and materials

• UNI-494 was administered orally to 32 Beagle dogs over 28 days with a 14-day recovery period (Figure 2)
• Dogs were assigned to 4 groups: 0 (control), UNI-494 5, 25, and 50 mg/kg/day (Figure 2)
• Each group contained 3 male and 3 female dogs, with 2 additional animals of each sex in the control and highest UNI-494 dose groups to assess recovery (Figure 2)
• Safety parameters included in-life observations and measurements (e.g., morbidity/mortality checks, clinical signs, body weight, food consumption, ophthalmological examinations), post-treatment and post-recovery ECG and respiratory parameters, clinical chemistry, urinalysis, coagulation and hematology, toxicokinetic analysis and post-treatment and post-recovery organ weights, macroscopic findings, and histopathology

Results

• No adverse UNI-494-related clinical signs, changes in body weight, food consumption, ophthalmological examinations, hematology, clinical chemistry, urinalysis, organ weight, or macroscopic observations were observed in the UNI-494 5, 25, or 50 mg/kg/day dose groups (Figure 3)
• Microscopic changes consisting of vascular wall thickening/perivascular fibroplasia in the heart, acinar cell apoptosis/necrosis in the pancreas, and tubular degeneration in the kidney were observed in the UNI-494 25 and 50 mg/kg/day groups
• There were no unscheduled deaths
• Exposure to UNI-494 (AUC_0-t and C_max) increased in a dose dependent manner over the dose range of 5 to 50 mg/kg following both single and multiple doses for both sexes
• Following both single and multiple administrations, the mean T_max for all doses of UNI-494 was <1 hour (mean T_max = 0.235 – 0.826 h).  The time to peak concentration of nicorandil was observed earlier for the 5 mg/kg dose (mean T_max = 0.487-0.997 h) when compared to the 25 and 50 mg/kg doses (mean T_max = 1.35-2.99 h)

Acknowledgments:

Writing support was provided by Xelay Acumen Group, Inc., and funded by Unicycive Therapeutics, Inc.