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<title>14 CLINICAL STUDIES</title>
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<title>14.1 Study 1</title>
<text>
<paragraph>The effectiveness of LOKELMA in lowering serum potassium was demonstrated in a two-part, double-blind, randomized, placebo-controlled clinical trial (NCT01737697) in patients with hyperkalemia (5 to 6.5 mEq/L, mean potassium 5.3 mEq/L), Study 1.</paragraph>
<paragraph>In the first phase of the trial (the acute phase), 753 patients were randomized to receive one of four doses of LOKELMA (1.25, 2.5, 5 or 10 g) or placebo, administered three times daily for the initial 48 hours with meals.</paragraph>
<paragraph>The mean age of patients was 66 years, 59% of patients were men, and 86% were Caucasian. Approximately 60% of patients had chronic kidney disease, 10% had heart failure, 62% had diabetes mellitus and 67% were on renin angiotensin aldosterone system (RAAS) inhibitor therapy at baseline.</paragraph>
<paragraph>The primary endpoint in the acute phase was the difference in the exponential rate of change in serum potassium levels during the initial 48 hours of study drug treatment, comparing placebo-treated patients and LOKELMA-treated patients. The study met its primary endpoint demonstrating a greater reduction in serum potassium levels for the 2.5, 5 and 10 g (three times a day) dose groups compared to the placebo group (<content styleCode="italics">p</content><0.001). As displayed in Table 1 for the secondary endpoint of potassium change from baseline, LOKELMA showed dose-dependent reductions in serum potassium at 2.5, 5 and 10 g. In patients administered 10 g TID, the mean serum potassium reduction was -0.7 mEq/L at 48 hours. Patients with higher starting potassium levels had a greater response to LOKELMA. LOKELMA was effective in lowering potassium levels in patients with chronic kidney disease, heart failure, diabetes mellitus and those taking RAAS inhibitor therapy.</paragraph>
<table styleCode="Noautorules" width="100%">
<caption>Table 1: Study 1 - Potassium Change from Baseline to 48 hours</caption>
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<col width="13%"/>
<col width="13%"/>
<col width="12%"/>
<col width="11%"/>
<col width="12%"/>
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<tr>
<th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<content styleCode="bold">Mean Serum Potassium Change mEq/L<br/>(95% Confidence Intervals)<br/>Sample Size</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">Placebo</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">1.25 g TID</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">2.5 g TID</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">5 g TID</content>
</th>
<th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle">
<content styleCode="bold">10 g TID</content>
</th>
</tr>
</thead>
<tbody>
<tr>
<td styleCode="Rrule Lrule Botrule " valign="top">
<paragraph>
<content styleCode="bold">All Patients</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-0.2<br/>(-0.3, -0.2)<br/>n=158</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-0.3<br/>(-0.4, -0.2)<br/>n=150</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-0.5<br/>(-0.5, -0.4)<br/>n=137</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-0.5<br/>(-0.6, -0.5)<br/>n=152</paragraph>
</td>
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top">
<paragraph>-0.7<br/>(-0.8, -0.7)<br/>n=140</paragraph>
</td>
</tr>
<tr>
<td styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>
<content styleCode="bold">Baseline Serum Potassium</content>
<br/>
<content styleCode="bold">>5.5 mEq/L</content>
</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>-0.4<br/>(-0.6, -0.3)<br/>n=40</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>-0.3<br/>(-0.5, -0.2)<br/>n=40</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>-0.6<br/>(-0.7, -0.4)<br/>n=37</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>-0.9<br/>(-1.0, -0.7)<br/>n=29</paragraph>
</td>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top">
<paragraph>-1.1<br/>(-1.3, -0.9)<br/>n=22</paragraph>
</td>
</tr>
</tbody>
</table>
<paragraph>Patients who achieved a potassium level between 3.5 and 5 mEq/L after receiving LOKELMA during the acute phase were re-randomized to receive once daily placebo or 1.25, 2.5, 5 or 10 g of once daily LOKELMA for 12 days together with breakfast.</paragraph>
<paragraph>The primary endpoint in the maintenance phase was the difference in the exponential rate of change in serum potassium levels over the 12-day treatment interval, comparing patients receiving LOKELMA and patients receiving placebo. The study met the primary efficacy endpoint at the 5 and 10 g doses when compared with their respective placebo groups (<content styleCode="italics">p</content><0.01 and <content styleCode="italics">p</content><0.001).</paragraph>
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<title>14.2 Study 2</title>
<text>
<paragraph>The efficacy of LOKELMA was also demonstrated in a two-part trial with an open-label acute phase and a month-long randomized, double-blind, placebo-controlled withdrawal phase (Study 2; NCT02088073).</paragraph>
<paragraph>In the open-label acute phase of Study 2, 258 patients with hyperkalemia (baseline mean 5.6 mEq/L, range 5.1 to 7.4 mEq/L) received 10 g of LOKELMA administered three times daily with meals for 48 hours. As shown in Figure 3, <content styleCode="italics">left</content>, average serum potassium levels decreased from 5.6 to 4.5 mEq/L during treatment with LOKELMA in the acute phase.</paragraph>
<paragraph>Following the acute phase of the study, there was a double-blind randomized withdrawal phase where patients who achieved potassium levels between 3.5 and 5 mEq/L were randomized to one of three doses of LOKELMA administered once-daily for 28 days, or placebo just before breakfast. Of the patients enrolled in the acute phase, 92% achieved a potassium level within this range and were enrolled into the second phase of the trial.</paragraph>
<paragraph>The primary endpoint in the randomized withdrawal phase was the mean serum potassium value over the period from Day 8 to Day 29, comparing LOKELMA-treated and placebo-treated patients. All three doses (5, 10 and 15 g) of once daily LOKELMA maintained mean potassium at lower levels than placebo (mean serum potassium was 4.8, 4.5, and 4.4 mEq/L for the 5, 10 and 15 g dose groups, respectively, vs. 5.1 mEq/L in the placebo group, <content styleCode="italics">p</content>≤0.001 for all doses, Figure 3, <content styleCode="italics">right</content>). A greater proportion of patients had mean serum potassium levels in the normal range (3.5 to 5 mEq/L) while on LOKELMA than while on placebo (80%, 90% and 94% at the 5, 10 and 15 g doses, respectively, vs. 46% on placebo).</paragraph>
<paragraph>
<content styleCode="bold">Figure 3: Study 2 - Mean Serum Potassium Levels in the Acute and Randomized Withdrawal Phases</content>
</paragraph>
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<paragraph>Intent-to-Treat population includes subjects with at least one valid serum potassium measurement on or after Day 8</paragraph>
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<title>14.3 Eleven-Month Extension Study</title>
<text>
<paragraph>Patients who completed the 28-day randomized withdrawal phase had the option to continue treatment with LOKELMA, taken just before breakfast, in an open-label extension phase for up to 11 months (n=123; NCT02107092). Figure 4 shows that the treatment effect on serum potassium was maintained during continued therapy.</paragraph>
<paragraph>
<content styleCode="bold">Figure 4: 11-Month Open-Label Extension Phase of Study 2 - Mean Serum Potassium (mEq/L)</content>
</paragraph>
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<text>Figure 4</text>
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<title>14.4 Study 3 </title>
<text>
<paragraph>LOKELMA was evaluated in an open-label 12-month study in 751 hyperkalemic patients (NCT02163499). The mean baseline potassium level in this study was 5.6 mEq/L. Following the acute phase treatment of LOKELMA 10 g three times a day, patients who achieved normokalemia (3.5-5.0 mEq/L) within 72 hours (n=746; 99%) entered the maintenance phase. For maintenance treatment, the initial dosage of LOKELMA was 5 g once daily and was adjusted to a minimum of 5 g every other day up to maximum of 15 g once daily, based on serum potassium level. The treatment effect on serum potassium was maintained during continued therapy.</paragraph>
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<title>14.5 Study 4 </title>
<text>
<paragraph>The effectiveness of LOKELMA in lowering serum potassium was studied in a double-blind, placebo-controlled trial of 196 chronic hemodialysis patients (mean age 58 years, range 20 to 86 years) with persistent pre-dialysis hyperkalemia (mean baseline potassium 5.8 mEq/L) who were randomized to receive LOKELMA 5 g or placebo once daily on non-dialysis days (NCT03303521). During the dose adjustment period (initial 4 weeks), the dose was adjusted weekly in 5 g increments up to 15 g once daily based on pre-dialysis serum potassium measurement after the long inter-dialytic interval to achieve a pre-dialysis serum potassium level between 4.0-5.0 mEq/L. The dose reached at the end of the dose-adjustment period was maintained throughout the subsequent 4-week evaluation period.</paragraph>
<paragraph>The primary endpoint in the trial was the proportion of responders, defined as patients who maintained a pre-dialysis serum potassium between 4.0 and 5.0 mEq/L on at least 3 out of 4 dialysis treatments after the long inter-dialytic interval and who did not receive rescue therapy during the evaluation period. A greater proportion of patients were responders in the LOKELMA arm as compared to placebo (41% vs 1%, respectively; p<0.001). The treatment effect on mean pre-dialysis serum potassium levels was maintained during continued treatment. Mean pre-dialysis serum potassium levels during the study are presented in Figure 5.</paragraph>
<paragraph>
<content styleCode="bold">Figure 5: Mean Pre-Dialysis Serum Potassium Levels Over Time in Patients on Chronic Hemodialysis</content>
</paragraph>
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<paragraph>F/U - follow-up period</paragraph>
<paragraph>The displayed error bars correspond to 95% confidence intervals.</paragraph>
<paragraph>n = Number of patients with non-missing potassium measurements at a particular visit.</paragraph>
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