UNI-494 Phase I Safety, Tolerability and Pharmacokinetics: Trial in Progress

G. REDDY¹, S. MOURYA¹, S. HASAL¹, S. GUPTA¹

¹ Unicycive Therapeutics, Inc.

Background

• Acute kidney injury (AKI) is a clinical syndrome defined by the sudden loss of kidney function¹, resulting in an inability to maintain electrolyte, acid-base and water balance^2,3
• Currently, there are no effective treatments for AKI approved by the US Food and Drug Administration or the European Medicines Agency (EMA); management of the condition is primarily supportive^2,4
• The most common cause of AKI was thought to be ischemia³
• However, more recently the focus has shifted from clinical causes to the underlying cellular processes inherent in these situations, in particular the dysfunction of mitochondria in AKI⁴
• Inflammation and reactive oxygen species (ROS) driven 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 (AKI) originating from ischemia reperfusion injury (IRI) or delayed graft function (DGF)
• Furthermore, unresolved inflammation exacerbates sustained mPTP opening, evident in chronic kidney diseases (CKD)
• Nicotinamide adenine dinucleotide (NAD+) can suppress the frequency and duration of mPTP opening
• UNI-494 is a novel nicotinamide ester derivative and selective mitochondrial ATP-sensitive potassium channel activator that binds to the ATP-sensitive potassium (KATP) channels, which reverses the mitochondrial dysfunction by closing mPTP pore (Figure 1)

Methods

• This is a single-center, double-blind, placebo-controlled, randomized single ascending dose (SAD) (Part 1) (Figure 2) and multiple ascending dose (MAD) (Part 2) (Figure 3) study in healthy male subjects and female subjects of non-childbearing potential
• Part 1 will enroll up to approximately 40 subjects in 5 cohorts of 8 subjects each (randomized to a ratio of 6 active and 2 placebo per cohort) (Figure 2)
• Main inclusion criteria were healthy males and WONCBP, aged 18 to 55 inclusive at the time of signing informed consent
• Body mass index (BMI) of 18.0 to 32.0 kg/m2 as measured at screening
• There will be an interim decision meeting after each cohort/period, to review the safety, tolerability, and pharmacokinetics (PK) data up to 48 hours post-dose in order to decide the dose level for the subsequent cohort
• Part 2 will enroll approximately 20 subjects in 2 cohorts of 10 subjects each, randomized to a ratio of 8 active treatment to 2 placebo who will be dosed for 5 days (Figure 3)
• The dose level for the Part 2 Cohort 1 (80 mg BID) was selected based on the safety, tolerability, and PK data from Part 1
• Pharmacokinetic assessments included collecting blood samples for PK analysis at regular time intervals, and analysis of the plasma concentration-time data for UNI-494, nicorandil and 1-cyclohexylethylamine
• The safety assessments included adverse events monitoring, ECG, vital signs, clinical laboratory tests (clinical chemistry, hematology, and urinalysis), and physical examinations

Results

• We intend to present results elucidating safety, tolerability, and pharmacokinetics of UNI-494 in healthy subjects by 2H 2024

References:

1. Kellum JA. et al., Nat Rev Dis Primers. 2021. July.
2.Mercado MG. et al., Am Fam Physician. 2019. Dec.
3.Makris K. et al., Clin Biochem Rev. 2016. May.
4.Szeto HH, J Am Soc Nephrol. 2017. Oct.

Acknowledgments:

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