Ardelyx, Inc. · NASDAQ:ARDX
Ardelyx — Technical Presentation (November 2014)
12 slides from Ardelyx's technical presentation, Nov 14, 2014
Slide 1: Tenapanor inhibits phosphorous absorption and protects against vascular calcification in nephrectomized rats
Tenapanor inhibits phosphorous absorption and protects against vascular calcification in nephrectomized rats D. Charmot, C.W. Carreras, M.R. Leadbetter, K. Kozuka, J. Kohler, S. Koo- McCoy, L.He, E. Dy, D. Black, Z. Zhong, I. Langsetmo, A.G. Spencer, N. Bell, D. Deshpande, M. Navre, J.G. Lewis, J.W.
Slide 2: Na+/H+ exchanger, isoform 3: SLC9A3 or NHE3
Na+/H+ exchanger, isoform 3: SLC9A3 or NHE3 • Apically expressed on luminal surface of the gut • NHE3 knockout phenotype: role in sodium-fluid homeostasis in gut and kidney • Major absorptive Na+/H+ exchanger in the gut (there are other paths for sodium: NHE2, NHE8, ENaC) Confocal microscopy – rat j
Slide 3: Tenapanor
Tenapanor • Minimally systemic inhibitor of NHE3 • Oral agent that reduces sodium uptake in the intestine Cl Cl O O O H H H N S O N N O N N O N N O S N H H H O O O Tenapanor Cl Cl (also known as RDX5791 and AZD1722) Cl Cl O O H H N S O N N N O O H H O O N N N O S N H H O O NTX792 (close analog of te
Slide 4: Potency and specificity of tenapanor
Potency and specificity of tenapanor Cell-based assays of selected intestinal membrane proteins Target IC50 Human NHE3 5 ± 4 nM (n>50) Rat NHE3 10 ± 7 nM (n>50) Human NHE1 > 10 µM Human NHE2 > 10 µM Human NaPi2b > 10 µM Human Pit1 > 10 µM NON-CONFIDENTIAL 4
Slide 5: Summary: Observations with tenapanor
Summary: Observations with tenapanor • Plasma drug levels normally absent, rarely detected Minimally systemic • Rodent radiolabeled ADME study confirmed minimal systemic exposure • Reduces urinary sodium excretion Reduces sodium absorption • Increases stool sodium in humans • Sodium-driven model of
Slide 6: A non-systemic NHE3 inhibitor decreases acute phosphorus (P) absorption in rats
A non-systemic NHE3 inhibitor decreases acute phosphorus (P) absorption in rats • Oral co-administration of NTX792, NTX3572, or vehicle at 10 mg/kg to rats (n=4-5) along with a phosphate meal containing [33P]orthophosphate • NTX3572 is a minimally-systemic tool compound with reduced potency & persis
Slide 7: A non-systemic NHE3 inhibitor decreases urinary Na and P in normal kidney function rats
A non-systemic NHE3 inhibitor decreases urinary Na and P in normal kidney function rats • Male Sprague-Dawley rats (n=6) were orally administered vehicle (water) or tenapanor at the indicated doses by oral gavage just before the dark phase and then placed in metabolic cages for urine collection over
Slide 8: A non-systemic NHE3 inhibitor decreases urinary P in 5/6th CKD rats
A non-systemic NHE3 inhibitor decreases urinary P in 5/6th CKD rats • 5/6th nephrectomized rats fed a 4% NaCl diet (Spencer et al, STM 2014) were dosed vehicle or tenapanor daily for 4 weeks. Weekly 24 h urine collections were measured for P • In one arm of the study (Tx paradigm) , tenapanor was gi
Slide 9: A non-systemic NHE3 inhibitor increases fecal excretion of Na and P in rats
A non-systemic NHE3 inhibitor increases fecal excretion of Na and P in rats • NTX3572, a minimally-systemic tool compound with reduced potency & persistence was used to facilitate stool collection • Rats (n=9) were fed a 0.6% bioavailable P diet for 4 days with or without NTX3572 mixed in the chow a
Slide 10: Tenapanor (5 mg/kg/d) improves uremic markers in rat CKD model
Tenapanor (5 mg/kg/d) improves uremic markers in rat CKD model • Vascular calcification model (Lopez et al., JASN 17:795 (2006)) induced by – 5/6th nephectomy – 0.9% inorganic P – 0.6% Ca diet – Calcitriol injection thrice a week • At day 27 (48 hours after the last calcitriol injection), blood was
Slide 11: Tenapanor reduces vascular calcification, heart and kidney hypertrophy in CKD rats
Tenapanor reduces vascular calcification, heart and kidney hypertrophy in CKD rats • P and Ca content were assessed in the aortic arch (A) and the stomach (B) collected from NPX rats after 28 days of calcitriol treatment. Kidney remnant and heart weights as related to body weight were also measured
Slide 12: Non-systemic NHE3 inhibitors (illustrated by tenapanor)
Non-systemic NHE3 inhibitors (illustrated by tenapanor) • Reduce intestinal absorption of Na and P • Improve uremic markers (serum P, creatinine, FGF-23) in a 5/6th Nx–vascular calcification rat model • Reduce ectopic calcification • Reduce heart and kidney hypertrophy • Therapeutic dose (5 mg/kg) i