SCM14: ZS-9, What Else Does It Do?

Dr. Bhupinder Singh

Dr. Bhupinder Singh

Dr. Bhupinder Singh (BS), Chief Medical Officer of Apex Research of Riverside, CA, discusses his abstract for the National Kidney Foundation’s 2014 Spring Clinical Meetings (SCM14), ZS-9, a Novel Selective Cation Trap, Does Not Significantly Increase Sodium Excretion When Used for the Treatment of Hyperkalemia in Patients with CKD, with Dr. Kenar Jhaveri (eAJKD), eAJKD Editor.

eAJKD: Why don’t you tell us a little about your research and abstract being presented at NKF 2014 Spring Meetings?

BS: The data being presented are from a 90-patient, phase 2 proof-of-concept placebo-controlled study of ZS-9 for the treatment of patients with hyperkalemia, in this case due to CKD.

Unlike the non-specific organic polymer resins SPSS (Kayexalate) and the investigational agent patiromer, ZS-9 is inorganic and has a unique crystalline lattice structure. The pores within this lattice structure utilize an energetically favorable size selectivity filter to preferentially entrap potassium (K+), over divalent cations (eg, calcium [Ca2+] and magnesium [Mg2+]) in the gastrointestinal tract. This is analogous to physiologic selectivity filter of K+ ion channels in cell membranes. So, ZS-9 was designed specifically to have both high selectivity and high capacity for K+.

At NKF we are presenting the  data on urinary sodium (Na+) excretion from the phase 2 study. The particular poster on urinary Na+ excretion is interesting because it shows that the highest dose of ZS-9 studied — 10g 3 times daily (TID) for 2 days — had no clinically relevant effect on 24-hour urine Na+ excretion, including in patients on RAAS inhibitors, relative to placebo treatment. The current standard of care, SPSS (Kayexalate), which incidentally is more selective for Ca2+ and Mg2+, as shown in the NKF poster by Yang and colleagues, uses Na+ as its counter ion. As a consequence, SPSS (Kayexalate) has been known to increase Na+ loading, which in turn may increase the risk of hypertension and potentially exacerbate heart failure symptoms.

In part due to the concern about Na+ loading, ZS-9 went through a comprehensive drug optimization process and is actually balanced with Na+ and hydrogen, the two counter ions used in the exchange with K+. This balance between Na+ and hydrogen is meant to mitigate the Na+ loading issues that have been seen with SPSS (Kayexalate). In the phase 2 trial we show that there was no significant increase in urinary Na+ excretion, compared with placebo.

eAJKD: Is efficacy of ZS-9 reduced if the patient is severely hypocalcemic or hypomagnesemic?

BS: In the phase 2 study we did not have patients with hypocalcemia or hypomagnesemia. Yang and colleagues actually show in their poster that ZS-9 is highly specific for K+ in vitro, and the compound’s ability to bind Ca2+ and Mg2+ was actually below the very sensitive level of detection employed in these preclinical experiments. So while binding of these divalent cations and the clinical risk of hypocalcemia or hypomagnesemia might be a concern with SPSS (Kayexalate) and other resins in development, it is not expected with ZS-9.

eAJKD: Where do you and your group go from here?

BS: I am also an investigator on the phase 3 placebo-controlled trial of ZS-9 that just completed, which was the largest phase 3 hyperkalemia trial to date and included both CKD and non-CKD patients, the vast majority of whom were on RAAS inhibitors during the trial. One of my co-authors, Dr. Steve Ash, gave a sneak peak at the primary results from the acute phase of this study during his late-breaker oral presentation at Kidney Week in November.  The results showed that ZS-9 produced a significant, dose-dependent reduction in serum K+ within 48 hours and was well tolerated compared with placebo.

Here at NKF, I’ll be presenting late-breaker data from both the acute (48 hr) and the extended (12-day) treatment phases of this important study showing via statistical modeling that the dose-response effect of ZS-9 allows for individualization of patient therapy. Therefore, ZS-9 doses can be titrated to individualize the absolute decline and speed of decline in serum K+ in the acute setting, as well as to maintain normokalemia in the extended treatment setting.

Beyond this, longer term studies of ZS-9 are getting underway. In fact the second phase 3 study just started enrolling patients. This study will evaluate the safety and efficacy of ZS-9 once-daily vs placebo in maintaining normokalemia over 28 days in approximately 275 patients with hyperkalemia (serum K+ >5 mEq/L), including those with CKD, heart failure, diabetes, and those on RAAS inhibitor therapy.

Click here for a full list of SCM14 abstracts of poster presentations.

Check out more eAJKD coverage of the NKF’s 2014 Spring Clinical Meetings!

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