ZS-9

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ZS-9 is a selective oral sorbent that traps potassium ions throughout the gastrointestinal tract. It is being developed by ZS Pharma for the treatment of hyperkalemia (elevated serum potassium levels).[1][2]

Background[edit]

Main article: Hyperkalemia

Hyperkalemia occurs in 3 to 10% of hospitalized patients[3] but is often mild. Hyperkalemia can arise from impaired renal function, potassium-sparing diuretics and renin-angiotensin system blockers (e.g., ACE inhibitors, angiotensin receptor blockers, spironolactone) and diabetes mellitus.[3][4][5][6]

There is no universally accepted definition of what level of hyperkalemia is mild, moderate, or severe.[7] However, if hyperkalemia causes any ECG change it is considered a medical emergency[7] due to a risk of potentially fatal abnormal heart rhythms (arrhythmia) and is treated urgently.[7] serum potassium concentrations greater than 6.5 to 7.0 mmol/L in the absence of ECG changes are managed aggressively.[7]

Hyperkalemia, particularly if severe, is a marker for an increased risk of death.[3] However, there is disagreement regarding whether a modestly elevated serum potassium level directly causes significant problems. One viewpoint is that mild to moderate hyperkalemia is an secondary effect that denotes significant underlying medical problems.[3] Accordingly, these problems are both proximate and ultimate causes of death,[3] and adjustment of potassium may not be helpful. Alternatively, hyperkalemia may itself be an independent risk factor for cardiovascular mortality.[8]

Several approaches are used in treatment of hyperkalemia,[7] but currently the only product approved by the U.S. Food and Drug Administration (FDA) to treat hyperkalemia is sodium polystyrene sulfonate (Kayexalate),[9] an organic ion-exchange resin that nonspecifically binds cations (e.g., calcium, potassium, magnesium) in the gastrointestinal tract. The effectiveness of sodium polystyrene sulfonate has been questioned: a study in healthy subjects showed that laxatives alone were almost as effective in increasing potassium secretion as laxatives plus Kayexalate.[10] In addition, use of sodium polystyrene sulfonate, particularly if formulated with high sorbitol content, is uncommonly but convincingly associated with colonic necrosis.[7][9][11][12]

Mechanism of action[edit]

ZS-9 is a zirconium silicate. Zirconium silicates have been extensively used in medical and dental applications because of their proven safety.[13] 12 zirconium silicates were screened by an iterative optimization process.[citation needed] ZS-9 selectively captures potassium ions by mimicking the actions of physiologic potassium channels.[citation needed] ZS-9 is an inorganic cation exchanger crystalline with a high capacity to entrap monovalent cations, specifically potassium and ammonium ions, in the GI tract. ZS-9 is not systemically absorbed; accordingly, the risk of systemic toxicity may be minimized.

Clinical studies[edit]

Phase 2[edit]

A phase 2 clinical trial in 90 patients with chronic kidney disease and mild-to-moderate hyperkalemia found a significantly greater reduction in serum potassium with ZS-9 than placebo. ZS-9 was well tolerated, with a single adverse event (mild constipation).[14]

Phase 3[edit]

A phase 3 clinical trial included 753 patients with hyperkalemia and underlying chronic kidney disease, diabetes, congestive heart failure, and patients on renin-angiotensin system blockers. Patients were randomized (1:1:1:1:1) to ZS-9 (1.25g, 2.5g, 5g or 10g) or placebo three times daily for 48 hours (acute phase), after which those with potassium levels ≤4.9 mmol/L (normokalemic) were either re-randomized 1:1 to the same dose of ZS-9 or placebo once daily; placebo-treated patients were re-randomized to ZS-9 1.25g or 2.5g once daily for Day 3-15 (extended phase).[15]

ZS-9 produced a significant dose-dependent reduction in potassium when given three times daily for 48 hours during the acute phase.[16] Subgroup analyses showed that 10g ZS-9 was effective in decreasing serum potassium during the acute phase, regardless of baseline potassium level or use of renin-angiotensin system blockers (yes/no).[17][18] 542 patients achieved normokalemia in the acute phase. During the extended phase, patients receiving 5g and 10g ZS-9 maintained normokalemia, whereas those receiving placebo generally returned to hyperkalemia.[19] Subgroup analyses of extended phase data showed that 10g ZS-9 was effective in maintaining normokalemia regardless of starting potassium level, glomerular filtration rate, chronic kidney disease status (yes/no), congestive heart failure status (yes/no), use of renin-angiotensin system blockers (yes/no), and diabetes mellitus status (yes/no).[20] 10g ZS-9 was also shown to significantly increase urinary pH and serum bicarbonate, and reduce blood urea nitrogen (compared with placebo), suggesting ZS-9 may improve acid-base balance in patients with hyperkalemia.[21] The overall incidence of adverse events (including gastrointestinal adverse events) associated with ZS-9 was similar to placebo both the acute and extended phase. [22]

References[edit]

  1. ^ "ZS Pharma Completes $55 Million Financing to Advance Its Novel Investigational Treatment for Hyperkalemia." Business Wire. March 05, 2014
  2. ^ ZS-9. ZS-Pharma. [1]
  3. ^ a b c d e Elliott, M. J.; Ronksley, P. E.; Clase, C. M.; Ahmed, S. B.; Hemmelgarn, B. R. (2010). "Management of patients with acute hyperkalemia". Canadian Medical Association Journal 182 (15): 1631. doi:10.1503/cmaj.100461.  edit
  4. ^ Stevens, M. S.; Dunlay, R. W. (2000). International Urology and Nephrology 32 (2): 177. doi:10.1023/A:1007135517950.  edit
  5. ^ Navaneethan, S. D.; Yehnert, H.; Moustarah, F.; Schreiber, M. J.; Schauer, P. R.; Beddhu, S. (2009). "Weight Loss Interventions in Chronic Kidney Disease: A Systematic Review and Meta-analysis". Clinical Journal of the American Society of Nephrology 4 (10): 1565. doi:10.2215/CJN.02250409.  edit
  6. ^ Tamirisa, K. P.; Aaronson, K. D.; Koelling, T. M. (2004). "Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure". American Heart Journal 148 (6): 971. doi:10.1016/j.ahj.2004.10.005.  edit
  7. ^ a b c d e f Taal, M.W.; Chertow, G.M.; Marsden, P.A.; Skorecki, K.; Yu, A.S.L.; Brenner, B.M. (2012). Brenner and Rector's The Kidney (Chapter 17, page 672, 9th ed.). Elsevier. ISBN 978-1-4160-6193-9. 
  8. ^ Fang, J.; Madhavan, S.; Cohen, H.; Alderman, M. H. (2000). "Serum potassium and cardiovascular mortality". Journal of General Internal Medicine 15 (12): 885. doi:10.1046/j.1525-1497.2000.91021.x.  edit
  9. ^ a b Watson, M.; Abbott, K. C.; Yuan, C. M. (2010). "Damned if You Do, Damned if You Don't: Potassium Binding Resins in Hyperkalemia". Clinical Journal of the American Society of Nephrology 5 (10): 1723–6. doi:10.2215/CJN.03700410. PMID 20798253.  edit
  10. ^ Emmett, M.; Hootkins, R. E.; Fine, K. D.; Santa Ana, C. A.; Porter, J. L.; Fordtran, J. S. (1995). "Effect of three laxatives and a cation exchange resin on fecal sodium and potassium excretion". Gastroenterology 108 (3): 752. doi:10.1016/0016-5085(95)90448-4.  edit
  11. ^ Sterns, R. H.; Rojas, M.; Bernstein, P.; Chennupati, S. (2010). "Ion-Exchange Resins for the Treatment of Hyperkalemia: Are They Safe and Effective?". Journal of the American Society of Nephrology 21 (5): 733–5. doi:10.1681/ASN.2010010079. PMID 20167700.  edit
  12. ^ Kamel, K. S.; Schreiber, M. (2012). "Asking the question again: Are cation exchange resins effective for the treatment of hyperkalemia?". Nephrology Dialysis Transplantation 27 (12): 4294. doi:10.1093/ndt/gfs293.  edit
  13. ^ Denry I, Kelly JR. State of the art of zirconia for dental applications. Dental Materials. Volume 24, Issue 3, March 2008, Pages 299–307
  14. ^ Ash SR, et al. "Safety and efficacy of ZS-9, a novel selective cation trap, for treatment of hyperkalemia in CKD patients." American Society of Nephrology 2013 conference, Late-Breaking Abstract.
  15. ^ El-Shahawy MA, Rasumssen HS, Lavin PT, Yang A, Packham DK. Acute-phase efficacy in a phase 3 multicenter, randomized, double-blind, placebo-controlled trial of ZS-9 for hyperkalaemia. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.
  16. ^ El-Shahawy MA, Rasumssen HS, Lavin PT, Yang A, Packham DK. Acute-phase efficacy in a phase 3 multicenter, randomized, double-blind, placebo-controlled trial of ZS-9 for hyperkalaemia. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.
  17. ^ Singh B, Rasumssen HS, Lavin PT, Yang A, Roger SD. Phase 3 multicenter, randomized, double-blind, placebo-controlled trial of ZS-9: acute efficacy by baseline serum potassium levels. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.
  18. ^ Roger SD, Rasumssen HS, Lavin PT, Yang A, El-Shahawy. Efficacy of ZS-9 in patients receiving RAAS therapy: a subgroup analysis of a phase 3 multicenter, randomized, double-blind, placebo-controlled trial. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.
  19. ^ Roger SD, Rasumssen HS, Lavin PT, Yang A, Qunibi W. Extended efficacy of ZS-9 in a phase 3 multicenter, randomized, double-blind, placebo-controlled trial of patients with hyperkalaemia. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.
  20. ^ Packham DK, Rasumssen HS, Lavin PT, El-Shahawy MA, Roger SD, Qunibi WY, Pergola PE, Singh B. ZS-9 once daily maintained normokalaemia across subgroups in a phase 3 multicenter, randomized, double-blind, placebo-controlled trial of patients with hyperkalaemia. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.
  21. ^ Singh B, Ash SR, Lavin PT, Yang A, Rasumssen HS. Acid-base balance in phase 2 and phase 3 trials of ZS-9 for hyperkalaemia in patients with chronic kidney disease. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.
  22. ^ Packham DK, Rasmussen HS, Lavin PT, Yang A, Qunibi W. Safety and tolerability of ZS-9 in a multicenter, randomized, double-blind, controlled trial in patients with hyperkalemia. Poster presented at the 2014 ERA-EDTA Congress, Amsterdam, The Netherlands.

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