Enhanced Urinary Phosphorous Reduction: Comparative Study of Oxylanthanum Carbonate and Tenapanor in Rats

S. MEDICHERLA¹, G. REDDY¹, P. GUPTA¹, S. GUPTA¹

1 Unicycive Therapeutics, Inc.

Background

• End-stage renal disease (ESRD) affects >7M people worldwide¹ and ~70% of patients with ESRD have hyperphosphatemia²
• Current hyperphosphatemia treatment options are dietary phosphate (P) restriction, dialysis, and P binders. However, not only are these hyperphosphatemia treatment options not highly effective for P control, they also negatively impact patient quality of life
• Thus, there is an unmet need for novel therapeutic innovations that maintain efficacy while reducing the required number of tablets and adverse effects, thereby increasing adherence and potentially improving clinical outcomes
• Tenapanor is a sodium hydrogen exchanger inhibitor used to reduce serum P in adults with chronic kidney disease (CKD) on dialysis as an add-on therapy with P binders³. Tenapanor has a unique mechanism of action that blocks paracellular absorption, thus reducing intestinal P absorption
• Combination treatments, especially those employing therapies with distinct mechanisms of action, may improve P control while reducing the negative characteristics of current P binders
• A previous study conducted by King et al.⁴ found that when administered together, tenapanor and sevelamer decreased urinary P excretion significantly more than either tenapanor or sevelamer alone across all sevelamer dose levels
• Oxylanthanum carbonate (OLC) is a novel nanotechnology product that combines lanthanum, which has highest binding capacity vs other P binders, with smaller pill size that is swallowed with water vs chewed⁵

Methods

• In our study, we utilized the study design and dosage regimen from King et al.⁴ involving sevelamer and tenapanor
• The study consisted of acclimatization, randomization, in vivo study period, and termination (Figure 1)
• 40 male Sprague Dawley rats fed standard chow 1 week prior to study start and then spiked with an additional 0.4% inorganic phosphate [1:1 sodium:potassium salt, 1.1% (wt/wt) total phosphate content] for rest of   the study⁴
• On study Day -1, rats were randomized into study groups (n = 8): 1) Vehicle, 2) tenapanor 0.15 mg/kg, 3) Vehicle + OLC 0.75%, 4) Vehicle + OLC 1.5%,
• 5) Vehicle + OLC 3% (Figure 1)
• From 11 days, Vehicle and tenapanor were dosed orally (PO) twice/day via oral gavage whereas OLC was incorporated into the diets
• Food intake was measured daily from study Day -3 until study Day 11, when the animals were euthanized
• 24-hour urine samples were collected using metabolic cages on Days 9, 10, and 11 for urinary P measurements
• Mean urine P excretion concentrations for each animal from Days 9 to 11 were averaged by treatment group

Results

• Reduction of urinary P excretion with tenapanor was not significantly different compared to Vehicle (Figure 2)
• Compared to Vehicle alone (group 1), tenapanor demonstrated 8.5 mg/day less urinary P excretion while OLC demonstrated 25.3 mg/day less urinary P excretion, a significantly greater reduction in urinary P excretion with OLC compared to tenapanor (p<0.05) (Figure 2)

References:

1.Lv JC, et al., Adv Exp Med Biol. 2019. Aug.
2.K/DOQI clinical practice guidelines. Am J Kidney Dis. 2003. Oct.
3.XPHOZAH (tenapanor) tablets, for oral use [prescribing information]. Ardelyx. 2023.
4.King AJ, et al., Am J Physiol Renal Physiol. 2021. Jan. Arenas MD, et al., Nefrologia. 2010. May.

Acknowledgments:

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