Bruce Spinowitz, M.D. FACP

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1 Bruce Spinowitz, M.D. FACP Associate Director, Nephrology Vice Chairman, Medicine New York Hospital Queens Clinical Professor of Medicine Weill Medical College of Cornell University

2 McDonough et al. Am J Physiol Renal Physiol Jun;282(6):F

3 Greenlee et al. Ann Intern Med May 5;150(9):

immediate adverse consequences allows for a quick response without significant disturbances in plasma K + Meal intake over 1 h produced a kaliuresis, which occurred in the absence of change in plasma

4 immediate adverse consequences allows for a quick response without significant disturbances in plasma K + Meal intake over 1 h produced a kaliuresis, which occurred in the absence of change in plasma aldosterone and with only a small (0.5 meq/l) increase in plasma K + When the intragastric K + infusion was combined with a meal, there was markedly enhanced clearance of the K + infused Plasma K + and aldosterone can stimulate renal K + excretion only at supraphysiological levels Hypophysectomy and/or afferent nerve section diminishes reflex increase in K + excretion Testing for the role of humoral factors that could mediate the gut factor effects, (gut peptides, such as glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), guanylin, and uroguanylin, and pituitary peptides, such as AVP, α- MSH, γ-msh), were negative Rabinowitz L, Kid Int. 49: 1738, 1996 Oh KS, et al, AJP Regul Integr Comp Physio. 301: R421, 2011

5 Signals to the kidney are poorly understood Possible effector mechanism via Na-Cl Cotransporter Sorensen et al. Kidney Int May;83(5): McDonough et al. Kidney Int May;83(5):

6 Youn JH. Semin Nephrol May;33(3): Review.

Potential channels involved in luminal K secretion: Luminal KCNMA1 (BK) [Butterfield 1997, Hay-Schmidt 2003, Matos 2007, Sausbier 2006] abundance is increased by high dietary K + load, aldosterone,

7 Potential channels involved in luminal K secretion: Luminal KCNMA1 (BK) [Butterfield 1997, Hay-Schmidt 2003, Matos 2007, Sausbier 2006] abundance is increased by high dietary K + load, aldosterone, and probably also by glucocorticoids [Butterfield 1997, Lomax 1994, Sandle 1999, Binder 1989, Lam 2004] Cell model of human colonocyte (enterocyte) showing apical (Ap) localization of BK channels, Na+ channels (ENaC) and CFTR (mediating electrogenic K+ secretion, electrogenic Na+ absorption and electrogenic Cl secretion, respectively) and basolateral (Bl) localization of Na+,K+-ATPase (mediating exchange of Na+ for K+), Na+-K+-2Cl cotransporters (mediating Na+, K+ and Cl uptake into cells) and a K+ conductance (to facilitate K+ recycling across the basolateral membrane) that may reflect more than one type of K+ channel.. Sandle et al. QJM Feb;103(2):85-9. Butterfield et al. J Physiol 501: , Lomax et al. Am J Physiol Gastrointest Liver Physiol 266: G71 G82, Binder et al. J Physiol 410: , Lam et al. Biochim Biophys Acta 1667: , 2004.

Caecum Asc. Colon Trans. Colon Desc. Colon Sig.

8 Greater Potassium Concentration in the Colon of the GI Tract Sodium, Potassium, and Soluble Calcium Concentrations In the GI Tract Electrolyte Concentration (mm) Stomach Duodenum Proximal Middle Distal Caecum Asc. Colon Trans. Colon Desc. Colon Sig. Colon/ Rectum Feces Small Intestine Large Intestine Wrong et al. Proc R Soc Med Dec;58(12): Fordtran et al. Am J Dig Dis Jul;11(7):

9 Kayexalate is an Organic Polymer Cation Exchange Resin SPS Chemical Structure KAYEXALATE (SPS) Negative charge from the SO3 - groups; sodium is the counter ion Potassium exchange capacity (KEC) = ~3.1 meq/g in vitro and ~1 meq/g in vivo

10 SPS Affinity for Other Cations Kayexalate (SPS) Ion Binding Potassium, Calcium, and Magnesium Concentration Ratio (1:1:1) K+ Ca2+ Mg2+ Selectivity Ratio* 0.2 KEY OBSERVATIONS Kayexalate is more selective for Ca 2+ than K + Kayexalate is more selective for Mg 2+ than K + *Selectivity Ratio = [K+] / [Ca+2] + [Mg+2] **Exchange capacity of Ca2+ and Mg2+ was below the set detection limit of 0.05 meq/g; therefore, 0.05 meq/g assumed for calculation purposes. Singh et al., AHA Annual Scientific Meeting Chicago, IL

11 Non-Specific Polymer Resin Action in GI Tract Stavros et al. PLoS One Dec 22;9(12):e

12 questionable efficacy

13 Lack of Clinical Evidence of Efficacy and Safety Before Ruled Effective by FDA First used in the early 1950s FDA Approval in 1958 Report of 30 cases of hyperkalemia treatment with SPS published in g of SPS in water was given per day for 2-6 days. K declined by 0.4 meq/l in 23 out of 30 patients. 2 patients developed significant hypokalemia In 1962, FDAs DESI program ruled SPS 'effective' based upon the above mentioned study Sterns et al. J Am Soc Nephrol May;21(5):733-5.

14 Scherr et al 1961 used Kayexalate mixed in ml of water in 32 patients, two of whom were treated with Kayexalate for 35 to 280 days (remaining treated for 1-6 days) Scherr et al. N Engl J Med Jan 19;264:115-9.

15 Emmett et al. Gastroenterology Mar;108(3): SPS Combined with Sorbitol Observed to Have No Greater Effect on K + Removal Total Soluble Potassium in Feces (meq/12h) Sorbitol alone Sorbitol + SPS 60g Sorbitol 60g Sorbitol + 30g SPS 120g Sorbitol 120g Sorbitol + 30g SPS

16 Kessler et al. J Hosp Med Mar;6(3):

18 Kayexalate Combined with SPS have Reports of Causing Colonic Necrosis 2009 FDA Safety Alert: Cases of colonic necrosis and other serious gastrointestinal adverse events (bleeding, ischemic colitis, perforation) have been reported in association with Kayexalate use. The majority of these cases reported the concomitant use of sorbitol... Concomitant administration of sorbitol is not recommended.

19 Kayexalate Combined with Sorbitol has been Reported to Cause Colonic Necrosis H&E H&E PAS Acid Fast Rashid et al. Am J Surg Pathol Jan;21(1):60-9.

(~100µm) Calcium exchanged for potassium 4.

20 Patiromer Background and MOA Patiromer (RLY5016) Non-absorbed K + binding organic polymer Free-flowing powder of small spherical beads (~100µm) Calcium exchanged for potassium 4.2 g of sorbitol incorporated in beads per 8.4 g of Patiromer Binds potassium predominantly in colon

Acute Treatment in Phase 1 (RLY5016-103) KEY OBSERVATIONS First significant decrease in serum potassium observed at 7 hours Mean reduction of serum

22 Acute Treatment in Phase 1 (RLY ) KEY OBSERVATIONS First significant decrease in serum potassium observed at 7 hours Mean reduction of serum K + of 0.75 meq/l over 48 hours No serum K + reduction below 5.0 meq/l Bushinsky et al., Poster Presentation at ASN Kidney Week Philadelphia, PA

23 PEARL-HF Trial Phase patients with heart failure and a history of hyperkalemia resulting in discontinuation of RAAS inhibitors and/or beta-adrenergic blockers or CKD with GFR < 60 ml/min were randomized to receive 30 g/day of RLY5016 or placebo for 4 weeks Spironolactone was initiated at 25 mg/day and titrated to 50 mg/day if K was 5.1 at Day 15 RLY5016 significantly reduced serum K levels with a difference of approximately meq/l versus placebo

24 n = 306 Poster Presentation at ASN Kidney Week Atlanta, GA

25 Poster Presentation at ASN Kidney Week Atlanta, GA

26 Poster Presentation at ASN Kidney Week Atlanta, GA

27 Phase 3 (Parts A and B) 237 patients with serum K 5.1 to < 6.5 meq/l received 4.2 g or 8.4 g of RLY5016 BID for 4 weeks 107 of 237 patients were randomized to either RLY5016 or placebo for 8 weeks Weir et al. N Engl J Med Jan 15;372(3):

28 Weir et al. N Engl J Med Jan 15;372(3):

29 Hyperkalemia recurred in 60% of patients on placebo compared to 15% receiving RLY5016 at Week 8 Weir et al. N Engl J Med Jan 15;372(3):

30 Weir et al. N Engl J Med Jan 15;372(3):

Maintenance of Normokalemia During Phase 3 Study of Patiromer Recurrence of HK in Patients During the Withdrawal Phase Percent of Patients KEY OBSERVATIONS 43% of patients treated with

31 Maintenance of Normokalemia During Phase 3 Study of Patiromer Recurrence of HK in Patients During the Withdrawal Phase Percent of Patients KEY OBSERVATIONS 43% of patients treated with Patiromer experienced recurrence of hyperkalemia 10% of patients treated with Patiromer experienced recurrence of hyperkalemia within a week Weir et al. N Engl J Med Jan 15;372(3):

32 Adverse Events In Treatment and Withdrawal Phase of Patiromer Treated Patients Weir et al. N Engl J Med Jan 15;372(3):

33 ZS-9 Is a Highly Selective Potassium Trap Stavros et al. PLoS One Dec 22;9(12):e

34 Cation Unhydrated Ionic Diameter Hydrated Ionic Diameter H 3 O K + NH + 4 Na + Ca 2+ Mg 2+ Zn Published radiuses of hydrated ions are statistical averages of a population on ions Volkov et al. Bioelectrochemistry and Bioenergetics. 42(2),

35 ZS-9: In Vitro Ion Exchange Capacity and Selectivity Potassium, Calcium, and Magnesium Concentration Ratio (1:1:1) ZS-9 Ion Binding Selectivity Ratio* 96 2** 2** K+ Ca2+ Mg K+ Ca2+ Mg2+ >25 ** Kayexalate Ion Binding Selectivity Ratio* 0.2 KEY OBSERVATIONS ZS-9 has 9.3 times more K + binding capacity than Kayexalate (SPS) ZS-9 is >125 times more selective for K + than Kayexalate Kayexalate is more selective for Ca 2+ than K+ *Selectivity Ratio = [K+] / [Ca+2] + [Mg+2] **Exchange capacity of Ca2+ and Mg2+ was below the 0.05 detection limit; therefore, 0.05 assumed for calculation purposes.

36 ZS-9 is thought to begin working immediately in the small intestine ILLUSTRATIVE Stavros et al. PLoS One Dec 22;9(12):e

37 ZS-9 Development Program Overview

38 ZS-9 Demonstrates Dose Dependent Efficacy Over 48 Hours Packham et al. N Engl J Med Jan 15;372(3):

39 Pre-Specified Subgroup Effects in ZS003 Singh et al., Oral Presentation at. NKF Spring Clinical Meetings Las Vegas, NV

40 5g and 10g Once Daily Maintain Normokalemia in ZS003 Packham et al. N Engl J Med Jan 15;372(3):

41 Kosiborod et al. JAMA Dec 3;312(21):

42 ZS-9 Demonstrates Onset of Action As Soon As 1 Hour in HARMONIZE Kosiborod et al. JAMA Dec 3;312(21):

43 Achieves Primary Endpoint, Mean K+ Maintenance on Days 8-29 for All Doses in HARMONIZE Kosiborod et al. JAMA Dec 3;312(21):

44 Maintenance of K + Compared to Placebo Over 4 weeks in HARMONIZE Kosiborod et al. JAMA Dec 3;312(21):

45 HARMONIZE Randomized Phase: Proportion of Patients with Mean K <5.1 meq/l during Days 8-29 Kosiborod et al. JAMA Dec 3;312(21):

46 HARMONIZE Randomized Phase: Efficacy Consistent in All Subgroups Kosiborod et al. JAMA Dec 3;312(21):

47 ZS003 Induction Safety and Tolerability was Comparable to Placebo Packham et al. N Engl J Med Jan 15;372(3):

48 HARMONIZE Trial Safety and Tolerability Kosiborod et al. JAMA Dec 3;312(21):

Conflict of interest

Conflict of interest Hyperkalemia in Heart and Kidney patients: Rescue is here Wajeh Qunibi, MD, FACP Professor of Medicine University of Texas Health Science Center San Antonio, TX CARDIORENAL CONNECTION April 28, 2017 Conflict