207078Orig1s000

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

207078Orig1s000

CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) Office of Clinical Pharmacology Integrated Review

NDA or BLA Number 207078 Link to EDR \\cdsesub1\evsprod\NDA207078\0042 Submission Date 22th Nov 2017 Submission Type Second Resubmission Brand Name LOKELMA Generic Name Sodium zirconium cyclosilicate (ZS) Dosage Form and Strength 5 g, 10 g ZS/packet for suspension Route of Administration Oral Proposed Indication Treatment of Hyperkalemia Applicant AstraZeneca Associated IND 108951 OCP Review Team Lars Johannesen, Ph.D. Sudharshan Hariharan, Ph.D. OCP Final Signatory Mehul Mehta, Ph.D. Division Director Division of Clinical Pharmacology I

Reference ID: 4246262 Table of Contents

1. EXECUTIVE SUMMARY ...... 3 1.1 Recommendations ...... 3 1.2 Post-Marketing Requirements and Commitments ...... 4 2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT ...... 4 2.1 Initial maintenance dose ...... 4

Reference ID: 4246262 1. EXECUTIVE SUMMARY

This is the second resubmission for NDA 207078 (NME) by AstraZeneca seeking approval of LOKELMA (Sodium Zirconium Cyclosilicate, ZS) for the treatment of hyperkalemia. Both the original NDA submission and the first resubmission received a complete response (CR) letter (DARRTS 05/16/2016 and 03/16/2017). Two clinical pharmacology issues were identified in the first CR letter: (i) assessment of the drug interaction liability with administration of ZS that remained unresolved at the end of original review cycle, and (ii) disagreement with the Applicant on the Agency recommended maximum maintenance dose of 15 g. The review of the first resubmission concluded that: 1) drug-interaction liability could be resolved by spacing dosing of other drugs relative to ZS and 2) that 15 g should remain the maximum dose (DARRTS 01/27/2017). Agreement was reached with the Applicant on these two issues, however, a CR was issued because of non-compliance of the manufacturing site.

In this resubmission, the Applicant (b) (4) is proposing to change the initial maintenance dose from 10 (b) (4) g qd (b) (4)

The review team disagrees with the Applicant and still considers 10 g to be a better initial maintenance dose because: i) patients with a higher serum potassium level at baseline will likely require a higher dose; ii) patients receiving ZS are more likely to have a higher serum potassium at baseline; iii) an initial maintenance dose of 10 g is likely to result in fewer titration steps and iv) no new safety concerns have been identified in the new study.

The review team therefore concludes that 10 g is a more appropriate initial maintenance dose, which is the focus of this review.

1.1 Recommendations The Office of Clinical Pharmacology, Division of Clinical Pharmacology I has reviewed the information contained in the second resubmission for NDA 207-078. This NDA is considered approvable from a clinical pharmacology perspective assuming agreement can be reached on labeling. Key review issues with specific recommendations/ comments are summarized below:

Review Issues Recommendations and Comments Initial maintenance dose The review team considers 10 g to be the appropriate initial maintenance dose.

Reference ID: 4246262 1.2 Post-Marketing Requirements and Commitments None.

2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT

2.1 Initial maintenance dose We have previously reviewed pivotal clinical studies of ZS and concluded that 10 g qd is an appropriate initial maintenance dose for all patients (DARRTS 05/09/2016). This conclusion was primarily based on data from the ZS-004 trial, which included two phases: 1) initial serum potassium correction phase (10 g tid for 48 – 72 h) and 2) double-blind 28-day maintenance phase where patients were randomized to placebo, 5, 10 or 15 g qd. The proportion of patients at the end of maintenance phase that are normo-, hypo and hyperkalemic by dose level and baseline serum potassium is shown in Figure 1. This figure shows that the proportion of patients with normal serum potassium depends on both baseline serum potassium and dose and suggests that 10 g is better initial maintenance dose than 5 g for patients with serum potassium at baseline greater than 5.5 mEq/L.

Figure 1: Potassium group by dose and baseline at end of maintenance treatment

Source: Reviewer’s analysis of ZS-004

(b) (4) ZS-005, which is a long-term open-label study and the first study to use 5 g qd as the maintenance dose. In this study, patients were titrated based on serum potassium levels. We have analyzed the proportion of patients receiving different doses over time, which is shown in Figure 2. This analysis shows that approximately 30% of the

Reference ID: 4246262 patients had their dose changed to 10 g qd from a starting dose of 5 g qd. A similar analysis of ZS-004E, which evaluated 10 g qd as the initial dose, was performed and the results of this analysis is shown in Figure 3. In contrast to the results of ZS-005, the proportion of patients that had their dose changed from 10 g qd to a lower dose was approximately 5%. This analysis suggests that 10 g qd is likely to result in fewer titration steps, although this might not be critical from a clinical perspective.

Figure 2: Proportion of patients receiving different doses by visits in ZS-005 (5 g QD initial dose)

Source: Reviewer’s analysis of ZS-005

Reference ID: 4246262 Figure 3: Proportion of patients receiving different doses by visits in ZS-004E (10 g QD initial dose)

Source: Reviewer’s analysis of ZS-004E

The review team therefore concludes that 10 g qd is a more appropriate initial maintenance dose because: 1) patients with higher serum potassium at baseline will require a higher dose to remain normokalemic; 2) 10 g qd as the initial maintenance dose is likely to result in fewer titration steps and 3) no new safety concerns have been identified to support a lower initial maintenance dose.

Reference ID: 4246262 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------

LARS JOHANNESEN 04/09/2018

SUDHARSHAN HARIHARAN 04/09/2018

MEHUL U MEHTA 04/09/2018

Reference ID: 4246262 Office of Clinical Pharmacology Integrated Review

NDA or BLA Number 207078 Link to EDR Application 207078 - Sequence 0030 - 0030 (34) 09/16/2016 ORIG-1 /Resubmission/Class 2

Submission Date 16th September 2016 Submission Type Resubmission Brand Name LOKELMA Generic Name Sodium zirconium cyclosilicate (ZS) Dosage Form and Strength 5 g, 10 g ZS/packet for suspension Route of Administration Oral Proposed Indication Treatment of Hyperkalemia Applicant ZS Pharma Associated IND 108951 OCP Review Team Ju-Ping Lai, Ph.D., Lars Johannesen, Ph.D., Jeffry Florian, Ph.D., Sudharshan Hariharan, Ph.D. OCP Final Signatory Mehul Mehta, Ph.D. Division Director Division of Clinical Pharmacology I

Reference ID: 4047831 Table of Contents

1. EXECUTIVE SUMMARY ...... 3 1.1 Recommendations ...... 3 1.2 Post-Marketing Requirements and Commitments ...... 4 2. CLINICAL PHARMACOLOGY ASSESSMENT ...... 4 2.1 Drug-drug Interaction Liability ...... 4 2.2 Dosing and Therapeutic Individualization ...... 11 2.3 Summary of Labeling Recommendations ...... 13

Reference ID: 4047831 1. EXECUTIVE SUMMARY

This is a resubmission for NDA 207078 (NME) by ZS Pharma seeking approval of LOKELMA (Sodium Zirconium Cyclosilicate, ZS) for the treatment of hyperkalemia. The original NDA submission received a complete response (CR) action. The details on the deficiencies supporting a CR action can be found in the letter dated 05/26/2016. Two clinical pharmacology issues were noted as part of the CR letter: (i) assessment of the drug interaction liability with administration of ZS that remained unresolved at the end of original review cycle, and (ii) disagreement with the applicant on the Agency recommended maximum maintenance dose of 15 g. In this resubmission, the applicant has provided completed in vivo drug interaction study reports, proposed labeling and the responses to the deficiencies identified in the CR letter, including their (b) rationale for support of a maximum maintenance dose of (4) g. Currently, there are two products available in the US for the treatment of hyperkalemia - Kayexalate®, a cation-exchange resin, and Veltassa® (patiromer), a cation-exchange polymer, which were approved in 1958 (NDA 011287) and 2015 (NDA 205739), respectively. Key issues addressed in this review include LOKELMA’s drug-drug interaction (DDI) liability and the appropriate maximum maintenance dose.

1.1 Recommendations

The Office of Clinical Pharmacology, Division of Clinical Pharmacology I and Division of Pharmacometrics, has reviewed the information contained in the resubmission for NDA 207078. This NDA is considered approvable from a clinical pharmacology perspective pending agreements on labeling to be reached with the applicant. Key review issues with specific recommendations and comments are summarized below:

Review Issues Recommendations and Comments Drug Interaction The review team identifies that ZS has an interaction Liability liability with drugs whose solubility is pH dependent. Further, the review team recommends spacing administration of other oral drugs with ZS by 2 hours (before and after) to mitigate this drug interaction liability. Maximum dose for The review team continues to assert labeling should titration permit a maximum maintenance dose of 15 g based on individual response. Inclusion of this dose allows for maximizing efficacy yet maintaining therapeutic individualization.

Reference ID: 4047831 1.2 Post-Marketing Requirements and Commitments

None.

2. CLINICAL PHARMACOLOGY ASSESSMENT

2.1 Drug-drug Interaction Liability Background ZS is a non-absorbed inorganic cation exchanger. In the original review cycle, an in vitro test system, spanning the range of pH in the gastrointestinal tract, was used to evaluate potential interaction between ZS and 39 orally administered compounds. These test compounds represented some of the commonly used concomitant medications in the target patient population. The findings from in vitro studies are summarized below.

• 30% to 99% decrease in drug concentration was observed in one or more media for the following drugs in the presence of ZS: aluminum, amlodipine, calcium carbonate, dabigatran, E- and Z-norgestimate, levothyroxine, lithium, prasugrel and warfarin. • 40% to 564% increase in drug concentration was observed in one or more media for the following drugs in the presence of ZS: atorvastatin, edoxaban, erythromycin, furosemide and valsartan. Increase in binding capacity from 26% to 50% was observed for lanthanum and sevelamer in the presence of ZS. • Inconsistent findings over different pH media was observed for the following drugs: clopidogrel, docusate, glipizide, ketoconazole and losartan.

The applicant asserted that the interactions observed in vitro were mainly attributed to the ability of ZS to elevate gastric pH affecting the solubility of drugs. However, not all interactions could be explained by pH changes alone. Some uncertainties remained, as outlined in the original clinical pharmacology review (DARRTS date: 05/09/2016), that did not allow ruling out the possibility of an interaction beyond mediated by pH change. Therefore, the applicant conducted drug interaction studies in vivo following coadministration with ZS to test their hypothesis.

In vivo DDI studies were conducted with nine drugs in healthy subjects. These drugs - losartan, warfarin, atorvastatin, amlodipine, furosemide, levothyroxine, glipizide, clopidogrel and dabigatran - represented weak acids, bases and drugs with narrow therapeutic index which showed an increase, decrease or inconsistent result in the in vitro studies.

Study Design

Study ZS-009 was a Phase 1, single-dose, open-label, single-sequence crossover study to assess the effect of ZS on the pharmacokinetics of 9 different drugs. The study consisted of 9 independent drug cohorts with each cohort consisting of 18 or 24 healthy subjects.

Reference ID: 4047831 Table 1. Drugs, Doses, and Washout Period.

[Source: ZS009-report, Table 1, page 12] The study consisted of 2 dosing periods (Dosing Period 1 and Dosing Period 2). On Study Day 1 of Dosing Period 1, subjects received a single dose of the cohort drug to which they were assigned, followed by serial blood sampling for pharmacokinetic evaluation of the coadministered drug. On Study Day 1 of Dosing Period 2, subjects received a single dose of the coadministered drug to which they were assigned with a single dose of ZS 10 g, followed by serial blood sampling for pharmacokinetic evaluation of the coadministered drug. The dosing periods were separated by a washout interval as specified for each drug cohort (Table 1). All drugs with the exception of levothyroxine were administered with food. Per the label, levothyroxine was administered 30 minutes prior to food.

The choice of the drugs selected to be further evaluated in in vivo DDI studies was discussed with the Agency and was agreed upon. The study design including doses for testing drugs, washout period and PK sampling scheme is reasonable.

Results The summary of the pharmacokinetic results are provided in Table 2.

Systemic exposures for 5 of 9 compounds (atorvastatin, clopidogrel, dabigatran, furosemide, and warfarin) were altered when administered in the presence of ZS. Specifically, among weakly acidic drugs, increase in peak concentration (Cmax) by 69 %, 66% and 38% were observed for atorvastatin, furosemide and warfarin, respectively. Amongst weakly basic drugs, decrease in both Cmax and area under the curve (AUC) by ~32-43% were observed for dabigatran and clopidogrel acid. These findings support the hypothesis that for drugs with pKa in the range of approx. 2 to 6, an increase in gastric pH caused by ZS increases solubility for acidic drugs and decreases solubility for basic drugs thereby affecting bioavailability.

The bioanalytical methods for all tested drugs were validated and the limits for quality control samples were within the specifications allowed as per the ‘FDA Guidance for Industry: Validation of Bioanalytical Reports’.

Reference ID: 4047831

exposure observed by concomitant administration with ZS is expected to be clinically significant.

Therefore, the results from this study support that there is a liability for ZS to cause significant interactions with drugs having a pKa in the range of approx. 2 to 6. There is a possibility that for drugs which were not studied, a similar or greater extent of interaction might occur which might be of clinical significance. It is important that the prescribers are informed about this potential drug interaction liability of ZS. However, it is not practical to qualify the drugs in the product insert based on their physicochemical properties (e.g., pKa, pH dependent solubility) and expect the prescribers to identify drugs that possess such properties. Hence, a pragmatic approach is required with respect to labeling and in terms of a mitigation strategy that would apply to all drugs irrespective of their physicochemical properties.

Mitigation strategy The mechanistic basis for drug interactions with ZS is reasonably well understood based on the results from in vitro and in vivo studies. This mechanism is similar to that of antacids that are known to elevate gastric pH affecting the solubility of drugs dependent on pH. Therefore, a literature search was conducted to understand the duration of effect of antacids and whether spacing of drugs from antacid administration alleviates a potential interaction.

In vitro studies delineating duration of antacid effect Acid neutralizing profiles of various antacids was investigated by Lin et al1 in an in vitro setting. The results of Maalox (aluminum-magnesium hydroxide) and Tums (calcium carbonate) are summarized below since they are among the strongest and also commonly used antacids.

Table 3. pH after incubation and acid-neutralizing capacity of antacids1 Acid-neutralizing capacity Dose Final pH (mEq HCl/minimum dose) Aluminum-magnesium hydroxide 0.75 g 5.72±0.13 25.75±0.19 Calcium carbonate 1 g 6.13±0.13 20.39±0.08

1 Evaluation of Buffering Capacity and Acid Neutralizing-pH Time Profile of Antacids, J Formos Med Assoc 1998, Vol 97, No 10 8

Reference ID: 4047831

In another study in healthy subjects, the range of duration of antacid activity with clinical doses of antacids (magnesium hydroxide 600 mg, aluminum hydroxide 675 mg or calcium carbonate 750 mg) was reported to be 8-121 minutes in the fasting state 3.

Comparison of acid neutralizing capacity of antacids with ZS Based on the above in vitro and in vivo studies it is reasonable to conclude that the duration of antacid effect lasts only up to about 2 hours or less even with the highest clinical dose of the strongest antacids. However, in order for these findings to be extended to ZS, the acid neutralizing capacity of ZS relative to these antacids should be understood. The acid neutralizing capacity of Maalox and Tums at their clinical dose is shown in Table 3. Although ZS is not developed as an antacid, it has been shown that addition of 10 g ZS to the incubation media increases pH from 1.2 to 3.2. Based on the potential of ZS to neutralize the hydrogen ions in the media (mEq hydrogen ions/ZS dose) to elevate pH from 1.2 to 3.2, the acid neutralizing capacity is approx. 30% to 50% of Maalox or Tums for the lowest and highest dose of ZS i.e., 5 g and 15 g, respectively. Therefore, potency of ZS to alter gastric pH, even at the highest dose of 15 g, is expected to be similar if not lower when compared to Maalox or Tums, such that findings from antacids could be extended to ZS. Hence, any dosing strategy to mitigate potential drug interaction of antacids can also be reasonably applied to ZS.

Drug interaction studies with antacids showing separation by 2 hours mitigates drug interaction For drugs with pH dependent solubility, impact of pH elevation on PK and drug bioavailability has been evaluated and the results have supported the recommendations for dosing in the package inserts. For example, dasatinib, with a pKa of 3.1 and exhibiting pH dependent solubility, showed decrease in Cmax and AUC by 58% and 55%, respectively, when coadministered with 30 mL Maalox. However, no changes in PK were observed when dasatinib was taken 2 hours after antacid administration4. Based on the results of this study, the product insert of dasatinib states that “If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of dasatinib”.

As a pH buffering agent, didanosine markedly decreased the systemic exposure of atazanavir by ~80-90% in both Cmax and AUC when coadministered together. However, when the two drugs were administered separated by at least 1 hour, there were no changes in atazanavir systemic exposures compared to atazanavir administered alone. This finding has been extended to antacids and has led to instructions for dosing atazanavir with antacids. The product insert of atazanavir states that “Reduced plasma concentrations of atazanavir are expected if antacids, including buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.”

Another example is an antacid interaction study with nilotinib. The clinical DDI study was conducted by dosing nilotinib 2 hours before or 2 hours after Maalox 20 mL. No changes in PK were observed in the study5. Similarly, based on the findings, the label of nilotinib has stated that “if necessary, an antacid may be administered approximately 2 hours before or approximately 2 hours after the dose of nilotinib”.

3 Journal of Pharmaceutical Sciences, 1976, Vol. 65, No 7 4 Clinical Pharmacology Review for NDA 21986 and NDA 22072 5 Clinical Pharmacology Review for NDA 22068 10

Reference ID: 4047831 Therefore, considering the totality of information, the duration of pH change upon administration of ZS is not expected to be beyond 2 hours. Based on interaction studies performed with antacids, a 2 hour separation with other drugs seems adequate to mitigate drug interaction.

Recommendation The drug interaction liability of ZS is a manageable risk that can be mitigated by separating the timing of administration with other orally administered drugs. A pragmatic approach is to space oral administration of other drugs with ZS by 2 hours.

2.2 Dosing and Therapeutic Individualization

In the original clinical pharmacology review for ZS (DARRTS date: 5/9/2016) a maximum dose of 15 g QD was recommended for the maintenance phase in order to maintain serum potassium levels within the normal range (defined as 3.5 to 5 mmol/L; normokalemic). Dosing would be titrated up to this amount based on inadequate response at lower doses. Dosing could be reduced if patients experienced any adverse events of concern or experienced hypokalemia. It was expected that patients with higher baseline serum potassium may require higher doses to maintain normokalemia and may benefit from the availability of a 15 g QD dosing option. This recommendation was further informed by the observed dose-dependent increase in the percentage of subjects achieving normokalemia among those subjects with serum potassium >5.5 mmol/L at baseline. It should be noted that overall experience in the Phase 3 trial with subjects with serum potassium >6 mmol/L was limited, and that such subjects may be more common in the clinical setting. The recommendation for a maximum dose of 15 g QD was communicated in the CR letter dated 5/26/2016.

The sponsor has provided a response to this issue in their resubmission (NDA 207078, Seq 0030), which is based on three additional analyses:

1. Similar reduction in serum potassium for 10 and 15 g 2. Proportion of normokalemic patients or normokalemic days by subgroup 3. Proportion of patients needing 15 g in ZS-004E and ZS-005

For the first analysis, the applicant has provided a summary of response rates by dose over the maintenance phase. The results show that all doses were effective relative to placebo and that a similar percentage of patients on 10 g QD and 15 g QD achieved normokalemia at the end of treatment. The reviewer agrees with the conclusion of a similar effect on average in the study. However, such an analysis does not contradict the observation that patients with elevated serum potassium at baseline require a higher daily dose to achieve normokalemia.

For the second analysis, the sponsor evaluates the percentage subjects achieving normokalemic subjects for 10 and 15 g QD in those patients with serum potassium between 5.5 and 6.0 and ≥6.0 mmol/L (Table 4). This is an attempt to identify the need for higher doses based on baseline serum potassium. As noted by the sponsor, some of the subgroups are rather small. While they propose separate groups of 5.5 to <6 mmol/L and ≥6 mmol/L, and it is likely more appropriate to split the subjects based on average serum potassium value at baseline ~5.5 mmol/L instead for

Reference ID: 4047831 this analysis. Using this cutoff shows a ~11% difference in percentage of normokalemic subjects (10 g: 28/32 and 15 g: 30/31) for subjects with serum potassium ≥5.5 mmol/L at baseline. Overall, the reviewer’s interpretation of the data is that some patients with higher baseline serum potassium may benefit from the availability of a higher dose. Additional analyses that support this inference are included in the original clinical pharmacology review for ZS.

Table 4. Percentage of subjects maintaining average serum potassium below 5.1 mmol/L

[Source: Table 5-2 in sponsors response]

The final conclusion presented by the Applicant is based on an analysis of percentage of patients requiring the 15 g dose in ZS-004E and ZS-005 to achieve a pre-specified target potassium level. Based on this analysis the sponsor concludes that it is not possible to identify the subgroup of patients who would require 15 g and that the percentage of patients requiring 15 g only represents a small subgroup (percentage of treated subjects: ZS-004E, 13%, ZS-005, 10%). However, it should be noted that the estimated percentages of patients uptitrated to 15 g is likely under estimated as the dose titration scheme in ZS-005 only permits uptitration to the 15 g dose if serum potassium exceeds 5.5 mmol/L and the subject is already receiving 10 g (Table 5). This is essentially equivalent to considering 5.0 to 5.5 mmol/L normokalemic, and it is obvious that if one extends the boundary of normokalemia that fewer patients would require a higher dose. Moreover, the position of identifying patients for the higher dose is not supported by the available data. While such subjects may not be able to be identified a priori, it would be possible to identify subjects requiring a higher dose by monitoring their serum potassium and increasing the dose to 15 g QD if the serum potassium remains elevated.

Table 5. Dose titration scheme for ZS-004E and ZS-005.

[Source: Table 5-3 in sponsors response] 12

Reference ID: 4047831 In conclusion, the additional analysis provided by the Applicant does not provide convincing evidence for why 15 g should not be approved. Moreover, the last analysis presented by the sponsor supports that at least 10-13% of patients would require a 15 g QD dose to achieve a target serum potassium level. The percentage of subjects requiring 15 g QD may be even higher than suggested by ZS-005 if a target serum potassium range of 3.5 to 5 mmol/L had been selected. Given that these patients can be identified by a readily available laboratory measure and that this represents a substantial portion of the population, the review team continues to recommend a maximum daily dose of 15 g.

2.3 Summary of Labeling Recommendations

The Office of Clinical Pharmacology recommends the following labeling concepts be included in the final package insert:

• Dose can be titrated based on serum potassium assessment to a maximum of 15 g QD. • Take other orally administered drugs at least 2 hours before or 2 hours after ZS.

Reference ID: 4047831 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------JU PING LAI 01/27/2017

LARS JOHANNESEN 01/27/2017

JEFFRY FLORIAN 01/27/2017

SUDHARSHAN HARIHARAN 01/27/2017

MEHUL U MEHTA 01/27/2017

Reference ID: 4047831 Office of Clinical Pharmacology Integrated Review

NDA or BLA Number 207078 Link to EDR Application 207078 - 1 Regional - Submission Date 26th May 2015 Submission Type Standard Brand Name LOKELMA Generic Name Sodium zirconium cyclosilicate (ZS) Dosage Form and Strength 5 g, 10 g ZS/packet for suspension Route of Administration Oral Proposed Indication Treatment of Hyperkalemia Applicant ZS Pharma Associated IND 108951 OCP Review Team Ju-Ping Lai, Ph.D., Lars Johannesen, Ph.D., Jeffry Florian, Ph.D., Rajanikanth Madabushi, Ph.D. OCP Final Signatory Mehul Mehta, Ph.D. Division Director Division of Clinical Pharmacology I

Reference ID: 3928583 Table of Contents

1. EXECUTIVE SUMMARY ...... 4 1.1 Recommendations ...... 4 1.2 Post-Marketing Requirements and Commitments ...... 5 2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT ...... 5 2.1 Pharmacology and Clinical Pharmacokinetics ...... 5 2.2 Dosing and Therapeutic Individualization ...... 5 2.2.1 General dosing ...... 5 2.2.2 Therapeutic individualization ...... 5 2.3 Outstanding Issues...... 6 2.4 Summary of Labeling Recommendations ...... 6 3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW ...... 6 3.1 Overview of the Product and Regulatory Background ...... 6 3.2 General Pharmacological and Pharmacokinetic Characteristics ...... 7 3.3 Clinical Pharmacology Questions ...... 9 3.3.1 Does the clinical pharmacology information provide supportive evidence of effectiveness? ...... 9 3.3.2 Is the proposed general dosing regimen appropriate? ...... 12 3.3.3 Is an alternative dosing regimen and management strategy required for subpopulations based on intrinsic factors? ...... 15 3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate management strategy? ...... 15 3.3.5 Is the to-be-marketed formulation the same as the clinical trial formulation, and if not, are there bioequivalence data to support the to-be-marketed formulation? ...... 19 4. Appendix ...... 20 4.1 Methods ...... 20 4.1.1 Data ...... 20 4.1.2 Analysis ...... 21 4.2 Results ...... 22 4.2.1 Dose response – acute ...... 22

Reference ID: 3928583 4.2.2 Dose response – end-of-acute phase to end-of-maintenance ...... 23 4.2.3 Time to washout ...... 24 4.2.4 Time to first hypokalemia event ...... 26 4.2.5 Comparison between i-STAT and central serum potassium ...... 26

Reference ID: 3928583 1. EXECUTIVE SUMMARY

This is an original NDA (NME) submitted by ZS Pharma on May 26, 2015 seeking approval of LOKELMA (Sodium Zirconium Cyclosilicate, ZS) for the treatment of hyperkalemia. Currently, Kayexalate®, a cation-exchange resin, and Veltassa® (patiromer), a cation-exchange polymer, are available in the US for this indication and were approved in 1958 (NDA 011287) and 2015 (NDA 205739), respectively. Key review issues include the appropriateness of the general dosing instructions and LOKELMA’s potential drug-drug interaction (DDI) liability.

1.1 Recommendations The Office of Clinical Pharmacology, Division of Clinical Pharmacology I, has reviewed the information contained in NDA 207-078. This NDA is considered approvable from a clinical pharmacology perspective pending the review of the in vivo DDI studies, which were submitted late in the review cycle, and assuming agreement can be reached on labeling. Key review issues with specific recommendations and comments are summarized below:

Review Issues Recommendations and Comments Supportive evidence of Substantial evidence of effectiveness was effectiveness demonstrated by the registration trials. Dose- response information for acute and maintenance treatment provide supportive evidence. Potassium binding in vitro under simulated intestinal conditions provide additional evidence of effectiveness, as does data from healthy volunteers demonstrating dose-dependent increases in mean daily fecal potassium excretion with concomitant decreases in mean daily urinary potassium excretion following administration of ZS. General dosing The recommended starting dose is 10 g three times instructions a day for 48 hours followed by 10 g a day with an option for dose titration to a maximum of 15 g once daily or a minimum of 5 g every other day based on serum potassium. Dosing in patient Dosing instructions for mitigating drug interaction subgroups (intrinsic and potential are pending review of in vivo DDI study extrinsic factors) reports that were recently submitted by the applicant. Bridge between the “to-be- Based on the potassium exchange capacity, the to- marketed” and clinical be-marketed product is similar to the pivotal trial. trial formulations

Reference ID: 3928583

1.2 Post-Marketing Requirements and Commitments None.

2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT

2.1 Pharmacology and Clinical Pharmacokinetics ZS is a non-absorbed inorganic cation exchanger. Hence, conventional absorption, distribution, metabolism and elimination (ADME) aspects do not apply. The potassium exchange capacity (KEC) is (b) (4) mEq/g. In aqueous media, ZS has the ability to exchange Na+ for H+ (protons) thereby causing an increase in pH. This change in pH has the potential for drug interaction liability for concomitantly administered drugs, especially those with pH-dependent solubility. Of the 39 drugs tested in vitro for interaction potential, 21 showed at least a 30% change in their solubility. At this time, the contribution of a non-pH related interaction cannot be ruled out for some of the tested drugs. In healthy volunteers, ZS demonstrated a dose-dependent increase in fecal potassium excretion with a corresponding decrease in urinary excretion. In patients, ZS showed a dose-dependent decrease in serum potassium in the acute and maintenance phases of treatment over the range of doses studied. The time course of the effect is characterized by a fast onset of effect, as early as 1 hour post first dose. After stopping the treatment, washout of the treatment effect is observed by days 11- 14.

2.2 Dosing and Therapeutic Individualization

2.2.1 General dosing The proposed dosing in patients with hyperkalemia is 10 g three times a day (TID) for the first 48 hours followed by a maintenance dose of 10 g once daily (QD) (b) (4) Monitor serum potassium and adjust the dose based on the serum potassium level and desired target range. The dose may be titrated at (b) (4) or longer interval in 5 g increments between a maximum of 15 g once daily (QD) to a minimum of 5 g every other day (QOD).

2.2.2 Therapeutic individualization The general dosing instructions, along with the proposed strategy to assess and titrate based on serum potassium levels, address the need for therapeutic individualization.

Reference ID: 3928583 There is no clear information pertaining to the effect of drug-food interactions. In the clinical trials, ZS was always administered with food, thus forming the basis for administering ZS with food. The results of in vitro interaction studies raise concern that ZS may have a significant DDI liability with concomitantly administered drugs. The interaction is mainly attributed to the ability of ZS to elevate the gastric pH. However, the possibility of an interaction beyond pH cannot be ruled out at this time. This may be a manageable risk that can be mitigated by separating the timing of administration. See Section 2.3 for more details.

2.3 Outstanding Issues In an attempt to resolve the drug interaction potential, the applicant has conducted in vivo DDI studies with some of the drugs that demonstrated an interaction in vitro. Some of the DDI reports were submitted very late in the review cycle. The review team believes that this information constitutes a major amendment that should result in a review clock extension; however, because of CMC issues, it may not be possible to approve the product during this review cycle. At this time, the product’s drug interaction potential is an outstanding issue, and labeling instructions to mitigate this interaction potential cannot be provided at this time. If a decision is made to extend the review clock, an updated Executive Summary along with the results of the DDI studies will be documented.

2.4 Summary of Labeling Recommendations The Office of Clinical Pharmacology recommends the following labeling concepts be included in the final package insert: • Treatment should be initiated with 10 g TID for 48 hours followed by a maintenance dose of 10 g QD. • Dose can be titrated at (b) (4) or longer intervals based on serum potassium assessment to a maximum of 15g QD or minimum of 5 g QOD. • (b) (4) • Instruction for mitigating the potential risk of drug interactions cannot be provided at this time (See Section 2.3).

3. COMPREHENSIVE CLINICAL PHARMACOLOGY REVIEW

3.1 Overview of the Product and Regulatory Background The clinical development program comprises six studies: one Phase 1 study, one Phase 2 study, and four Phase 3 studies. A total of 1,592 subjects participated in these clinical studies as of July 15th, 2015, including healthy volunteer subjects and patients with hyperkalemia associated with chronic kidney disease, heart failure, diabetes mellitus, and use of renin-angiotensin-aldosterone system inhibitors. These studies provide information supporting proof-of-concept (i.e.,

Reference ID: 3928583 potassium binding in the gastrointestinal tract), dose-response (for serum potassium lowering) in the acute and maintenance phase, and the efficacy and safety of ZS in the target population for the treatment of hyperkalemia. Traditional Phase 1, clinical pharmacology studies of the pharmacokinetics of ZS in healthy subjects were not conducted as ZS is not systemically absorbed. An in vitro test system (spanning the range of pH in the gastrointestinal tract) was used to evaluate potential interactions between ZS and 39 orally administered compounds, which represent some of the commonly used concomitant medications in the target patient population. During the development of the product and the review of this submission, there were a number of communications between the applicant and the Agency pertaining to the DDI issue. The regulatory history regarding these communications is summarized below:

Dates Meeting type Key communication points 7/21/2010 Pre-IND meeting Advice to conduct in vitro drug-drug interaction studies was provided during the meeting. 7/28/2015 Filing A recommendation to repeat the in vitro studies under communication physiologically relevant conditions was conveyed to the applicant. 10/15/2015 Response to IR In vitro interaction screening report submitted; results indicate the potential for drug-drug interactions between ZS and co-administered medications. 11/12/2015 Post-mid-cycle The Agency pointed out that not all of the solubility communication changes can be explained solely by pH changes. The applicant proposed to conduct additional in vitro and in vivo experiments to address this issue. 11/20/2015 Follow-up post Discussion pertaining to the in vivo drug interaction study mid-cycle proposal occurred. 3/23/2016 Late-cycle Drug-drug interaction potential remains an issue for communication weakly basic drugs. The applicant plans to submit four final in vivo DDI study reports in late March/early April. The applicant was informed that the submission would likely be considered a major amendment and result in a clock extension.

3.2 General Pharmacological and Pharmacokinetic Characteristics • ZS is a non-absorbable, insoluble, inorganic cation exchanger. Hence, conventional pharmacokinetic evaluation does not apply. • The pH of an aqueous suspension of ZS is 7 – 9.

Reference ID: 3928583 • Mechanism of action: The applicant states that ZS has the ability to exchange potassium for hydrogen and sodium contained in its microporous crystalline structure. The potassium binding leads to an increase in fecal excretion, eventually leading to lowered serum potassium. The potassium exchange capacity of the product is (b) (4) (b) (4) mEq/g. • ZS is also reported to have selectivity for ammonium ions, which can translate in vivo to increases in serum bicarbonate. Pharmacodynamics • Over a dose range of 5 g/day to 10 g/day administered once daily for four days in healthy subjects on standardized diet (40 mEq/day Na+ and 128 mEq/day K+), ZS demonstrates a dose-dependent increase in mean daily fecal potassium excretion and a concomitant decrease in mean daily urinary potassium excretion. A numerical trend towards a dose-dependent increase in mean daily fecal sodium excretion and a decrease in mean daily urinary sodium excretion was also observed in the study. • Onset: The onset of action at doses greater than 5 g is relatively rapid. One hour after starting ZS 10 g, an average decrease in serum potassium of 0.1 – 0.2 mEq/L is observed. Following a TID regimen, the maximum decrease in serum potassium is observed at the end of the acute phase (48 hours). • Offset: Upon cessation of the treatment, wash-out of treatment occurs with a half-life of 2.8 days (see Appendix 4.2.3 for details). Near complete washout (4 – 5 half-lives) of the effect is observed in 11 – 14 days. • A dose-dependent increase in serum bicarbonate was observed in the maintenance phase. • The drug interaction potential of ZS was evaluated in vitro and in vivo. The in vivo study reports were submitted late in the review cycle and are not addressed in this review (see Section 2.3). For in vitro testing, thirty nine drugs identified by the applicant or the Agency as commonly co-administered medications in the target population were screened for interactions. The interactions described below represent the percentage change in exposure for the co-administered medication.

o 30% to 99% decrease in drug concentrations was observed in one or more media for the following drugs: aluminum, amlodipine, calcium carbonate, dabigatran, E- and Z-norgestimate, levothyroxine, lithium, prasugrel and warfarin.

o 40% to 564% increase in drug concentrations or binding capacity was observed in one or more media for the following drugs: atorvastatin, edoxaban, erythromycin, furosemide, lanthanum, sevelamer and valsartan.

o Inconsistent findings over different pH ranges in different media were observed for the following drugs: clopidogrel, docusate, glipizide, ketoconazole and losartan.

Reference ID: 3928583 3.3 Clinical Pharmacology Questions

3.3.1 Does the clinical pharmacology information provide supportive evidence of effectiveness? Yes. The data from three short-term studies (Studies ZS-002, ZS-003 and ZS-004) and one long- term study (ZS-004E) provide substantial evidence of effectiveness of ZS in reducing serum potassium levels in patients with hyperkalemia (See Clinical Review by Dr. Xiao; 04/07/2016). In addition, several clinical pharmacology aspects in the submission provide supportive evidence of effectiveness for ZS as a potassium binder for the treatment of hyperkalemia. They are as follows:

• Mechanistic basis:

The mechanistic basis for ZS as a potassium binder was demonstrated in vitro. ZS (1g) when incubated in a 500 mL solution containing 2500 – 3500 ppm K+ at pH 6.8 (simulated large intestinal fluid at 37°C with constant agitation) demonstrated a rapid uptake of K+ during the first 10 minutes followed by continued but slower uptake over the next hour (Table 1). At pH 4.5 (simulated small intestinal fluid), there was also an immediate uptake followed by a small release with equilibrium achieved in about 20 minutes. At pH 1.2 (simulated gastric fluid, minus enzymes), there was minimal uptake. These results indicate that at this concentration of ZS (2 mg/mL), little potassium exchange is likely to occur in highly acidic environments such as the stomach. However, potassium exchange is expected to occur at higher pH levels found in the latter parts of the gastrointestinal tract.

Table 1: K+ concentrations over time in when ZS is incubated in simulated intestinal conditions

Source: Applicant’s Pharmacology Written Summary (Table 2.6.2-3; page 10/18)

In another in vitro study (Report Number: TR-113010-P0020) conducted over a wide range of pH values (1.2 – 6.8), ZS over a range of 0.5 mg/mL to 50 mg/mL incubated in the presence of a known concentration of potassium for 3 hours at ambient temperature and constant agitation showed a concentration proportional increase in potassium exchange capacity (KEC). There was no significant effect of pH on the KEC of ZS at 50 mg/mL (2.4 – 2.6 mEq/g). However, at ≤ 5

Reference ID: 3928583 mg/mL, a dose dependent decrease in KEC with decreasing pH was observed. These results suggest that potassium binding is likely to occur throughout the gastrointestinal tract with a higher concentration of ZS.

• Proof of concept in healthy volunteers:

In healthy subjects (ZS-006), two dose levels of ZS administered once a day for 4 days (5 g/day and 10 g/day) showed an increase in mean daily fecal potassium excretion and a corresponding decrease in mean daily urinary potassium excretion (Table 2). While there was no placebo group, it should be noted that the effects were dose dependent. The highest dose group also showed a lowering of serum potassium.

Table 2: Mean (±SD) Daily Fecal and Urinary K Excretion (mg/day) and Serum K (mmol/L). Samples were collected in 24 hour intervals from Day 3 to Day 4 as baseline and from Day 7 to Day 8 as endpoint. ZS 5 g QD ZS 10 g QD Variable/Time Point (N=15) (N=15) Fecal Potassium (mg) Baseline 880 ± 455 946 ± 442 Endpoint 1244 ± 552 1641 ± 797 Change from Baseline to Endpoint 364 ± 585 696 ± 716 p-value <0.05 <0.05 Urinary Potassium (mmol/24 hour) Baseline 84 ± 19 85 ± 22 Endpoint 74 ± 21 64 ± 17 Change from Baseline to Endpoint -9.7 ± 18 -21 ± 21 p-value 0.06 <0.05 Serum Potassium (mmol/L) Baseline 4.5±0.29 4.6±0.26 Endpoint 4.5±0.30 4.3±0.35 Change from Baseline to Endpoint -0.06±0.24 -0.25±0.24 p-value 0.36 <0.05 Source: Table generated from study report ZS-006, Tables 11-3, 11-4, 11-6, pages 42, 43, 45

• Dose-response in patients: The registration trials clearly demonstrated dose-dependent lowering of serum potassium. In the Phase 3 clinical studies (Study ZS-003 and ZS-004), ZS was given three-times-a-day (TID) for the first 48 hours (acute phase) followed by once-daily dosing in the maintenance phase.

As shown in Figure 1 below, in the acute phase (Study ZS-003), there is a dose-dependent decrease in serum potassium over the range of 0 to 10 mg TID. A linear relationship with a slope of -0.056 mEq/L/g (95% CI: -0.065 to -0.047) adequately described the dose response (see Appendix 4.2.1 for details).

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Figure 1: ZS (0 g - 10 g administered TID for 2 days) exhibits a dose dependent decrease in serum potassium in patients with mild to moderate hyperkalemia. Negative numbers represent a decrease in serum potassium from the respective baseline. Error bars represent 95% Confidence Intervals.

In study ZS-004, a similar dose-dependent change in serum potassium (slope: -0.038 mEq/L/g [95% CI: -0.046 to -0.029]) was observed (see figure 2 below) when patients receiving 10 mg TID for 2 days were randomized to placebo or 5 – 15 g QD for 29 days (see Appendix 4.2.2 for details).

Figure 2: ZS (0 g - 15 g administered as QD for 28 days following 10 g TID for 2 days) exhibits a dose dependent effect on serum potassium in patients hyperkalemia. The positive numbers represent an increase in serum potassium from the respective baseline. Error bars represent 95% Confidence Intervals.

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Figure 3: Percentage of patients with potassium concentrations falling above, below, or within the target range based on baseline serum potassium at the end of the acute treatment phase (48 hours) for ZS 5 g TID and 10 g TID (Study ZS-003).

Maintenance dose: The general recommended maintenance dose is10 g QD. Further dose (b) adjustment to a maximum of 15 g QD or a minimum of 5 g QOD can be made at an interval (4) or longer.

• In patients with lower baseline serum potassium (≤ 5.5 mEq/L), all three doses provide reasonably similar efficacy. However, in patients with higher baseline serum potassium (> 5.5 mEq/L), there is a clear dose-dependent increase in the proportion of patients achieving the target range of 3.5 – 5.0 mEq/L (see Figure below). It should be noted that with 5 g QD, ~40% patients achieve the target, suggesting the need for a higher dose in these patients.

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Figure 4: Percentage of patients in different categories based on baseline serum potassium concentration over time during the maintenance phase for placebo (pbo), 5, 10 and 15 g QD of ZS (Study ZS-004). Top panel: Hyperkalemia patients with baseline serum K+ ≤ 5.5 mEq/L. Bottom panel: Hyperkalemia patients with baseline serum K+ > 5.5 mEq/L. The solid horizontal line represents the percent of patients in the target range of 3.5 – 5.0 mEq/L at the end of the acute phase i.e., 10 g TID for 2 days).

• None of the patients receiving 5 g QD developed hypokalemia, while a numerical trend for a dose-dependent increase in patients developing hypokalemia was noted for 10 g (14%) and 15 g (20%) doses. It should be noted that all cases were mild and asymptomatic. Furthermore, the proposed down titration to 5 g QD or 5 g QOD at an interval of (b) (4) or longer will allow for managing patients who develop hypokalemia. As such, the utility of 5 g QD as the general maintenance dose is limited. The 5 g dose could be useful as part of the titration strategy.

• In the long-term study, 15 g QD was associated with a numerically increased incidence of edema (see clinical review by Dr. Xiao for further discussion) and also showed numerical trends for an increase in body weight and blood pressure. The

Reference ID: 3928583 target population includes patients with heart failure; hence, a general maintenance dose of 10 g QD with an option to titrate up to 15 g QD should allow for maximizing the benefit without appreciably increasing the risk.

(b) (4)

3.3.3 Is an alternative dosing regimen and management strategy required for subpopulations based on intrinsic factors? Intrinsic factors are not expected to impact either the availability of ZS or its ability to bind potassium in the gastrointestinal tract.

3.3.4 Are there clinically relevant food-drug or drug-drug interactions and what is the appropriate management strategy? ZS is not expected to have systemic absorption. The focus of the review was on the potential for ZS to change the pH of the GI tract which could affect the solubility of concomitantly administered oral drugs, thereby resulting in a reduction or increase in the bioavailability of the concomitantly administered drug and potentially altering the efficacy or safety of the drug. Underlying conditions that are common in patients with hyperkalemia include chronic kidney disease, heart failure, and diabetes mellitus. Hyperkalemia often develops in these patients in the setting of renin-angiotensin-aldosterone system inhibitor therapy. This patient population is large and is often prescribed multiple medications; hence the potential for drug interactions represents a significant safety issue.

Reference ID: 3928583

Drug-Drug Interactions

At the filing of the NDA submission, the in vitro test conditions were identified to be inadequate (incubation in organic solvent). A request for repeating the experiment in physiologically relevant conditions was conveyed to the applicant. The in vitro studies were repeated under conditions which mimic the pH in different regions of the gastrointestinal tract and were submitted on 10/15/2015. Testing was conducted in aqueous solutions of pH 1.2 (Simulated Gastric Fluid, SGF), 4.5 (Acetate Buffer solution) and 6.8 (Phosphate Buffer) with incubation at 37°C with constant agitation (200 rpm) for 2 hours without the presence of ZS and then incubation for an additional 2 hours after adding ZS. Each test drug was evaluated in three replicates. The amount of the concomitant drug remaining at the end of the 2-hour and 4-hour incubation was measured to evaluate the extent of interaction with ZS. The results of the in vitro screening are summarized in the tables below. Table 3: Drugs that showed decreased concentrations with ZS in in vitro studies % change from control Drugs pH in drug concentrations

Aluminum 1.2 -77% Amlodipine 6.8 -47% CaCO3 1.2 -46% 4.5 -82% 1.2 -40% Dabigatran 4.5 -99% 6.8 -49% E-Norgestimate 1.2 -53% Levothyroxine 1.2 -70% 4.5 -30% 6.8 -37% Lithium 4.5 -39% Prasugrel 4.5 -85% Warfarin 1.2 -74% Z-Norgestimate 1.2 -74%

Table 4: Drugs that showed increased concentrations with ZS in in vitro studies

% change from control Drugs pH in drug concentrations 4.5 102% Atorvastatin 6.8 40% Edoxaban 6.8 68%

Reference ID: 3928583 Erythromycin 6.8 63% 1.2 69% Furosemide 4.5 564% Lanthanum 6.8 126% Sevelamer 6.8 150% Valsartan 4.5 263%

Table 5: Drugs that showed inconsistent effect on drug concentrations with ZS in in vitro studies

% change from control Drugs pH in drug concentrations

4.5 -47% Clopidogrel 6.8 +56% 4.5 -32% Docusate 6.8 +49% 1.2 -31% Glipizide 4.5 +101% 6.8 -46% 4.5 -78% Ketoconazole 6.8 +84% 1.2 -43% Losartan 4.5 +75%

It was observed that ZS changed the pH of the test media. The applicant therefore tested drugs which showed greater than a 10 % change in concentration in a second experiment in which the pH of the test media was adjusted but ZS was not added. Based on the results, the applicant stated that all the concentration changes were due to pH- mediated solubility changes. Although this statement seems to be true for most drugs, there are still drugs which showed concentration changes that cannot be explained only by pH changes (see Table below). When asked to explain this finding, the applicant responded that solubility comparisons across experiments are complex and dependent on a number of factors including the following: starting drug state, crystal phase, particle size, common ion effects, salt effects, pH, ionic strength of the media, temperature, pressure, precipitation rate, dissolution rate, and the presence of nucleating surfaces and the rates of change in any of these factors. Thus, the applicant concluded that the reasons for the discrepancies between experiments could be multifactorial, difficult to elucidate, and different for each agent.

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4. Appendix

4.1 Methods

4.1.1 Data

4.1.1.1 ZS-003 ZS-003 is a multicenter, two-phase (acute/maintenance), multi-dose, double-blind and placebo- controlled study to evaluate the safety and efficacy of ZS-9 in subjects with mild to moderate hyperkalemia. During the initial phase (48 h), subjects were randomized to: placebo or 1.25, 2.5, 5.0 or 10.0 g ZS-9 TID. Following the acute phase, there was a randomized withdrawal phase or randomization to 1.25 or 2.5 g ZS (for subjects receiving placebo during the acute part) which was administered for 12 additional days (Figure 1).

Figure 1: Overview of treatment groups for ZS-003, source: Clinical overview page 18

4.1.1.2 ZS-004 ZS-004 is a multicenter, multiphase (acute and maintenance), multi-dose, double-blind placebo- controlled phase 3 study to evaluate the safety and efficacy of patients with hyperkalemia. During the acute part of this trial all patients received 10 g ZS for 48 h open-label. After the end of the acute phase, patients were randomized into: placebo or 5, 10, or 15 g ZS QD, which was administered for an additional 28 days (Figure 2). Patients having a serum potassium value between 3 and 3.4 mEq/L during the maintenance phase would have their dose reduced to every other day (QOD) for the remainder of the study.

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Figure 2: Overview of treatment groups for ZS-004, source: Clinical overview page 18

4.1.2 Analysis Unless written otherwise in all the analyses described below the central serum potassium measurements for the ITT population were used. Only exception is analysis of maintenance data from ZS-004, from which patients switching from QOD to QD were excluded.

4.1.2.1 Dose response The dose-response relationship was evaluated for the acute and maintenance phase separately. The end of the acute phase was defined as the morning of day 3 (48 h). The end of the maintenance phase was selected as the day closest to day 15 post initiation (ZS-003: Day 15, ZS- 004: Day 14), and the measurement on this day would reflect the new maintenance steady state value (see section 4.2.3).

The relationship between the change from baseline serum potassium and dose as a continuous covariate was evaluated using for both phases with a linear model. Changes from baseline serum potassium were selected as the dependent variable and dose, study, and baseline serum potassium were evaluated as independent variables. In addition, interactions between the baseline serum potassium and dose as well as the study and baseline serum potassium were evaluated during model development. Study (ZS-004 versus ZS-003) was included in the analysis due to a difference in binding capacity between the batches used in the two studies (ZS- 003: (b) (4) mEq/g, ZS-004(b) (4) mEq/L). It is hypothesized that this difference in binding capacity could function as a ‘higher’ dose. In both analyses the baseline term was centered on the mean baseline serum potassium (5.4 mEq/L) or the mean end-of-acute-phase serum potassium (4.6 mEq/L). The model was fitted to the data using ‘lm’ in R 3.2.2. The appropriateness of model fit was determined by evaluating the normality of the residuals, the

Reference ID: 3928583 relationship between predicted values and residuals, and the relationship between residuals and fixed-effects in the model.

4.1.2.2 Time to washout Time to washout of the drug was evaluated using data from ZS-004 during the maintenance phase for patients switching from 10 g TID to placebo. The change from baseline was modeled using a nonlinear mixed effects model:

~ ( ) + offset+ − 훽 ∗푑푑푑 Random effects were included 퐶onℎ푔 fixed푎 -∗effects푒 ‘a’ and offset.ɛ From this model, the time to ( ) washout was quantified as five half-lives . The model was fit to the data using the β log 2 ‘nlmer’ function from the lme4 package (1.1-12) in R 3.2.2. The appropriateness of model fit � � was determined by evaluation of the normality of the residuals and the relationship between predicted values and residuals.

4.1.2.3 Time to first hypokalemia event Eighteen patients experienced hypokalemia in ZS-004. The time to the first hypokalemia event analysis was conducted to characterize the timing of hypokalemia. Cumulative percentage of events were grouped by treatment and visualized versus time. In addition, the relationship between baseline or end-of-acute-phase serum potassium and event occurrence was explored to assess factors that may predispose patients to experiencing hypokalemia.

4.1.2.4 Comparison between i-STAT and central serum potassium The difference between i-STAT and central serum potassium was evaluated using a Bland- Altman plot. While central serum potassium was used for the endpoint analyses, clinical practice may make determinations based on point-of-care devices similar to i-STAT. This analysis assesses agreement between the two methods and informs whether the observed results are generalizable to a clinical setting.

4.2 Results

4.2.1 Dose response – acute A dose-response relationship was identified between change from baseline to the end-of-the acute phase (48 h), which was adequately described with a linear model (Figure 3) with a slope of -0.056 mEq/L per g (Table 1). The remaining model parameters are provided in Table 1. In addition, a fixed effect for study was included in the model to evaluate the difference between the two studies, which may in part be due to differences between drug batches and associated binding capacity used in the two studies. From the model parameters (Table 1) a slightly significant effect (p=0.03) of study was identified, which translates into a difference of -0.094 (95%CI: 0.009 to 0.178) mEq/L.

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4.2.4 Time to first hypokalemia event In ZS-004, 18 cases of hypokalemia were observed during the maintenance phase in the 10 g QD arm (n=7) and the 15 g QD arm (n=11). The cumulative percentage of hypokalemia events are shown in Figure 7 by dose in the maintenance phase. In both the 10 and 15 g arm, the median time to hypokalemia was 14 days. In addition, there were no differences between those patients experiencing hypokalemia and those without an event in terms of baseline serum potassium (+hypokalemia [median, range]: 5.7 (5.1 to 6.2) mEq/L; -hypokalemia: 5.5 (4.1 to 7.1) mEq/L) and serum potassium at end of the acute phase (+hypokalemia: 4.2 (3.8 to 5.2) mEq/L; - hypokalemia: 4.5 (3.5 to 5.7) mEq/L).

Figure 7: Cumulative percentage of hypokalemia events in ZS-004 by treatment allocation in the maintenance phase. Note that the y-axis is cut at 50%.

4.2.5 Comparison between i-STAT and central serum potassium In both studies, serum potassium was measured using i-STAT and central measurements. However, only central serum potassium measurements were used for the primary analysis. The difference between the two measurements was evaluated using a Bland-Altman plot (Figure 8), which shows a constant difference of ~0.13 mEq/L in both studies with no apparent relationship to the average of i-STAT and central measurement.

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Figure 8: The relationship between serum potassium measurements from i-STAT and central measurements was compared in a Bland-Altman plot (top: ZS-003, bottom: ZS-004). The solid and dashed lines represent the average difference ± 2 standard deviations (ZS-003: 0.13±0.28 mEq/L, ZS-004: 0.15±0.30 mEq/L), and the blue line and shaded area represent the results of a loess regression between the average (x-axis) and the difference (y-axis).

Reference ID: 3928583 ------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. ------/s/ ------JU PING LAI 05/09/2016

LARS JOHANNESEN 05/09/2016

JEFFRY FLORIAN 05/09/2016

RAJANIKANTH MADABUSHI 05/09/2016

MEHUL U MEHTA 05/09/2016

Reference ID: 3928583