<?xml version="1.0" encoding="UTF-8"?><section ID="S14">
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<title>14 CLINICAL STUDIES</title>
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<section ID="S14.1">
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<title>14.1 Paroxysmal Nocturnal Hemoglobinuria (PNH)</title>
<text>
<paragraph>The safety and efficacy of ULTOMIRIS in adult patients with PNH was assessed in 2 open-label, randomized, active-controlled, non-inferiority Phase 3 studies: PNH Study 301 and PNH Study 302. Study 301 enrolled patients with PNH who were complement inhibitor naïve and had active hemolysis. Study 302 enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months. The safety and efficacy of ULTOMIRIS in pediatric patients with PNH was assessed in PNH Study 304, an open-label, Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment naïve pediatric patients with PNH.</paragraph>
<paragraph>In Study 301 and Study 302, adults with PNH were dosed with ULTOMIRIS administered intravenously in accordance with the weight-based dosing described in Section 2.3 (4 infusions of ULTOMIRIS over 26 weeks) above. Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of the studies.</paragraph>
<paragraph>Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. Prophylactic treatment with appropriate antibiotics beyond 2 weeks after vaccination was at the discretion of the provider.</paragraph>
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<text>
<paragraph>
<content styleCode="underline">Study in Complement-Inhibitor Naïve Adult Patients with PNH</content>
</paragraph>
<paragraph>The Complement-Inhibitor Naïve Study [ALXN1210-PNH-301; NCT02946463] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 246 patients naïve to complement inhibitor treatment prior to study entry.</paragraph>
<paragraph>Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to either intravenously administered ULTOMIRIS or eculizumab. The mean total PNH granulocyte clone size was 85%, the mean total PNH monocyte clone size was 88%, and the mean total PNH RBC clone size was 39%. Ninety-eight percent of patients had a documented PNH-associated condition diagnosed prior to enrollment on the trial: anemia (85%), hemoglobinuria (63%), history of aplastic anemia (32%), history of renal failure (12%), myelodysplastic syndrome (5%), pregnancy complications (3%), and other (16%). Major baseline characteristics were balanced between treatment groups. Table 22 provides the baseline characteristics for the patients enrolled in the complement-inhibitor naïve study.</paragraph>
<table ID="tab22" width="80%">
<caption>Table 22: Baseline Characteristics in the Complement-Inhibitor Naïve Study</caption>
<col align="left" valign="middle" width="35%"/>
<col align="center" valign="middle" width="15%"/>
<col align="center" valign="middle" width="25%"/>
<col align="center" valign="middle" width="25%"/>
<thead>
<tr>
<th align="center" styleCode="Lrule Rrule" valign="middle">Parameter</th>
<th styleCode="Rrule" valign="middle">Statistics</th>
<th styleCode="Rrule" valign="middle">ULTOMIRIS <br/>(N=125)</th>
<th styleCode="Rrule" valign="middle">Eculizumab<br/>(N=121)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="4">Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Age (years) at first infusion in study</td>
<td styleCode="Rrule">Mean (SD)<br/>Min, max</td>
<td styleCode="Rrule">44.8 (15.2)<br/>18, 83</td>
<td styleCode="Rrule">46.2 (16.2)<br/>18, 86</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Sex</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Male</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">65 (52.0)</td>
<td styleCode="Rrule">69 (57.0)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Race</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Asian</td>
<td rowspan="6" styleCode="Rrule Botrule" valign="middle">n (%)</td>
<td styleCode="Rrule">72 (57.6)</td>
<td styleCode="Rrule">57 (47.1)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> White</td>
<td styleCode="Rrule">43 (34.4)</td>
<td styleCode="Rrule">51 (42.1)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Black or African American</td>
<td styleCode="Rrule">2 (1.6)</td>
<td styleCode="Rrule">4 (3.3)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> American Indian or Alaska Native</td>
<td styleCode="Rrule">1 (0.8)</td>
<td styleCode="Rrule">1 (0.8)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Other</td>
<td styleCode="Rrule">4 (3.2)</td>
<td styleCode="Rrule">4 (3.3)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Not reported </td>
<td styleCode="Rrule">3 (2.4)</td>
<td styleCode="Rrule">4 (3.3)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule" valign="middle">Pre-treatment LDH levels (U/L)</td>
<td styleCode="Rrule" valign="middle">Median<br/>Min, max</td>
<td styleCode="Rrule" valign="middle">1513.5<br/>(378.0, 3759.5)</td>
<td styleCode="Rrule" valign="middle">1445.0<br/>(423.5, 3139.5)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Units of pRBC/whole blood transfused within 12 months prior to first dose</td>
<td styleCode="Rrule">Median<br/>Min, max</td>
<td styleCode="Rrule">6.0<br/>(1, 44)</td>
<td styleCode="Rrule">6.0<br/>(1, 32)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Antithrombotic agents used within 28 days prior to first dose</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">22 (17.6)</td>
<td styleCode="Rrule">22 (18.2)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Patients with a history of MAVE</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">17 (13.6)</td>
<td styleCode="Rrule">25 (20.7)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Patients with a history of thrombosis</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">17 (13.6) </td>
<td styleCode="Rrule">20 (16.5)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Patients with concomitant anticoagulant treatment</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">23 (18.4) </td>
<td styleCode="Rrule">28 (23.1)</td>
</tr>
</tbody>
</table>
<paragraph>Efficacy was established based upon transfusion avoidance and hemolysis as directly measured by normalization of LDH levels. Transfusion avoidance was defined as patients who did not receive a transfusion and did not meet the protocol specified guidelines for transfusion from baseline up to Day 183. Supportive efficacy data included the percent change from baseline in LDH levels, the proportion of patients with breakthrough hemolysis defined as at least one new or worsening symptom or sign of intravascular hemolysis in the presence of elevated LDH ≥ 2 × ULN, after prior LDH reduction to < 1.5 × ULN on therapy and the proportion of patients with stabilized hemoglobin.</paragraph>
<paragraph>Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the complement-inhibitor naïve treatment population described in Table 23 below.</paragraph>
<table ID="tab23" width="85%">
<caption>Table 23: Efficacy Results in the Complement-Inhibitor Naïve Study</caption>
<col align="left" valign="top" width="20%"/>
<col align="center" valign="top" width="20%"/>
<col align="center" valign="top" width="20%"/>
<col align="center" valign="top" width="20%"/>
<col align="center" valign="top" width="20%"/>
<thead>
<tr>
<th/>
<th valign="middle">ULTOMIRIS<br/> (N=125)</th>
<th valign="middle">Eculizumab<br/>(N=121)</th>
<th valign="middle">Statistic for Comparison</th>
<th valign="middle">Treatment Effect<br/>(95% CI)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="5" valign="top">For the transfusion avoidance endpoint, treatment differences (95% CIs) are based on estimated differences in percent with 95% CI. For the lactate dehydrogenase normalization endpoint, the adjusted prevalence within each treatment is displayed. <br/>Abbreviations: LDH = lactate dehydrogenase; CI = confidence interval</td>
</tr>
</tfoot>
<tbody>
<tr>
<td>Transfusion avoidance rate</td>
<td>73.6%</td>
<td>66.1%</td>
<td>Difference in rate</td>
<td>6.8<br/>(-4.66, 18.14)</td>
</tr>
<tr>
<td>LDH normalization</td>
<td>53.6%</td>
<td>49.4%</td>
<td>Odds ratio</td>
<td>1.19<br/>(0.80, 1.77)</td>
</tr>
<tr>
<td>LDH percent change</td>
<td>-76.84%</td>
<td>-76.02%</td>
<td>Difference in % change from baseline</td>
<td>-0.83<br/>(-5.21, 3.56)</td>
</tr>
<tr>
<td>Breakthrough hemolysis</td>
<td>4.0%</td>
<td>10.7%</td>
<td>Difference in rate</td>
<td>-6.7<br/>(-14.21, 0.18)</td>
</tr>
<tr>
<td>Hemoglobin stabilization </td>
<td>68.0%</td>
<td>64.5%</td>
<td>Difference in rate</td>
<td>2.9<br/>(-8.80, 14.64)</td>
</tr>
</tbody>
</table>
<paragraph>There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under- or over-estimation because patients were not blinded to treatment assignment.</paragraph>
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<text>
<paragraph>
<content styleCode="underline">Study in Eculizumab-Experienced Adult Patients with PNH</content>
</paragraph>
<paragraph>The study in eculizumab-experienced patients [ALXN1210-PNH-302; NCT03056040] was a 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months.</paragraph>
<paragraph>Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the prior 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS administered intravenously. The mean total PNH granulocyte clone size was 83%, the mean total PNH monocyte clone size was 86%, and the mean total PNH RBC clone size was 60%. Ninety-five percent of patients had a documented PNH-associated condition diagnosed prior to enrollment in the trial: anemia (67%), hematuria or hemoglobinuria (49%), history of aplastic anemia (37%), history of renal failure (9%), myelodysplastic syndrome (5%), pregnancy complication (7%), and other (14%). Major baseline characteristics were balanced between the 2 treatment groups. Table 24 provides the baseline characteristics for the patients enrolled in the eculizumab-experienced study.</paragraph>
<table ID="tab24" width="80%">
<caption>Table 24: Baseline Characteristics in Eculizumab-Experienced Adult Patients with PNH</caption>
<col align="left" valign="middle" width="35%"/>
<col align="center" valign="middle" width="15%"/>
<col align="center" valign="middle" width="25%"/>
<col align="center" valign="middle" width="25%"/>
<thead>
<tr>
<th align="center" styleCode="Lrule Rrule">Parameter</th>
<th styleCode="Rrule">Statistics</th>
<th styleCode="Rrule">ULTOMIRIS <br/>(N=97)</th>
<th styleCode="Rrule">Eculizumab<br/>(N=98)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="4">Abbreviations: LDH = lactate dehydrogenase; max = maximum; min = minimum; MAVE = major adverse vascular event; pRBC = packed red blood cell; SD = standard deviation</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule" valign="middle">Age (years) at first infusion in study</td>
<td styleCode="Rrule" valign="top">Mean (SD)<br/>Min, max</td>
<td styleCode="Rrule" valign="top">46.6 (14.41)<br/>18, 79</td>
<td styleCode="Rrule" valign="top">48.8 (13.97)<br/>23, 77</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Race</td>
<td rowspan="8" styleCode="Rrule Botrule" valign="middle">n (%)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> White</td>
<td styleCode="Rrule">50 (51.5)</td>
<td styleCode="Rrule">61 (62.2)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Asian</td>
<td styleCode="Rrule">23 (23.7)</td>
<td styleCode="Rrule">19 (19.4)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Black or African American</td>
<td styleCode="Rrule">5 (5.2)</td>
<td styleCode="Rrule">3 (3.1)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Other</td>
<td styleCode="Rrule">2 (2.1)</td>
<td styleCode="Rrule">1 (1.0)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Not reported</td>
<td styleCode="Rrule">13 (13.4)</td>
<td styleCode="Rrule">13 (13.3)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Unknown</td>
<td styleCode="Rrule">3 (3.1)</td>
<td styleCode="Rrule">1 (1.0)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Multiple</td>
<td styleCode="Rrule">1 (1.0)</td>
<td styleCode="Rrule">0</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Sex</td>
<td rowspan="2" styleCode="Rrule Botrule" valign="middle">n (%)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Male</td>
<td styleCode="Rrule">50 (51.5)</td>
<td styleCode="Rrule">48 (49.0)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Pre-treatment LDH levels (U/L)</td>
<td styleCode="Rrule">Median<br/>Min, max</td>
<td styleCode="Rrule">224.0<br/>135.0, 383.5</td>
<td styleCode="Rrule">234.0<br/>100.0, 365.5</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule" valign="bottom">Units of pRBC/whole blood transfused within 12 months prior to first dose</td>
<td styleCode="Rrule" valign="bottom">Median<br/>Min, max</td>
<td styleCode="Rrule" valign="bottom">4.0<br/>(1, 32)</td>
<td styleCode="Rrule" valign="bottom">2.5<br/>(2, 15)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule" valign="top">Antithrombotic agents used within 28 days prior to first dose</td>
<td styleCode="Rrule" valign="middle">n (%)</td>
<td styleCode="Rrule" valign="middle">20 (20.6)</td>
<td styleCode="Rrule" valign="middle">13 (13.3)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Patients with a history of MAVE </td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">28 (28.9)</td>
<td styleCode="Rrule">22 (22.4)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Patients with a history of thrombosis</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">27 (27.8) </td>
<td styleCode="Rrule">21 (21.4)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule" valign="top">Patients with concomitant anticoagulant treatment</td>
<td styleCode="Rrule" valign="middle">n (%)</td>
<td styleCode="Rrule" valign="middle">22 (22.7) </td>
<td styleCode="Rrule" valign="middle">16 (16.3)</td>
</tr>
</tbody>
</table>
<paragraph>Efficacy was established based on hemolysis as measured by LDH percent change from baseline to Day 183 and supportive efficacy data was transfusion avoidance, proportion of patients with stabilized hemoglobin, and the proportion of patients with breakthrough hemolysis through Day 183.</paragraph>
<paragraph>Non-inferiority of ULTOMIRIS to eculizumab was demonstrated across endpoints in the patients with PNH previously treated with eculizumab described in Table 25 below.</paragraph>
<table ID="tab25" width="85%">
<caption>Table 25: Efficacy Results in the Eculizumab-Experienced Adult Patients with PNH Eculizumab-Experienced Study</caption>
<col align="left" valign="top" width="24%"/>
<col align="center" valign="top" width="19%"/>
<col align="center" valign="top" width="19%"/>
<col align="center" valign="top" width="19%"/>
<col align="center" valign="top" width="19%"/>
<thead>
<tr>
<th/>
<th>ULTOMIRIS<br/> N = 97</th>
<th>Eculizumab<br/>N = 98</th>
<th>Statistic for Comparison</th>
<th>Treatment Effect<br/>(95% CI)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="5" valign="top">Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase</td>
</tr>
</tfoot>
<tbody>
<tr>
<td>LDH percent change</td>
<td>-0.82%</td>
<td>8.4%</td>
<td>Difference in % change from baseline</td>
<td>9.2<br/>(-0.42, 18.8)</td>
</tr>
<tr>
<td>Breakthrough hemolysis</td>
<td>0%</td>
<td>5.1%</td>
<td>Difference in rate</td>
<td>5.1<br/>(-8.9, 19.0)</td>
</tr>
<tr>
<td>Transfusion avoidance</td>
<td>87.6 %</td>
<td>82.7%</td>
<td>Difference in rate</td>
<td>5.5<br/>(-4.3, 15.7)</td>
</tr>
<tr>
<td>Hemoglobin stabilization</td>
<td>76.3%</td>
<td>75.5%</td>
<td>Difference in rate</td>
<td>1.4<br/>(-10.4, 13.3)</td>
</tr>
</tbody>
</table>
<paragraph>There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation because patients were not blinded to treatment assignment.</paragraph>
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<text>
<paragraph>
<content styleCode="underline">Study in Eculizumab-Experienced and Complement-Inhibitor Naïve Pediatric Patients with PNH</content>
</paragraph>
<paragraph>The pediatric study, ALXN1210-PNH-304 (NCT03406507), was a multi-center, open-label Phase 3 study conducted in eculizumab-experienced and complement inhibitor treatment-naïve pediatric patients with PNH. A total of 13 pediatric patients with PNH completed intravenously administered ULTOMIRIS treatment during the Primary Evaluation Period (26 weeks). Five of the 13 patients had never been treated with complement inhibitors and 8 patients were treated with eculizumab. Eleven of the thirteen patients were between 12 and 17 years of age at first infusion, with 2 patients under 12 years old (11 and 9 years old). Table 26 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-PNH-304.</paragraph>
<table ID="tab26" width="85%">
<caption>Table 26: Baseline Characteristics for Pediatric Patients with PNH</caption>
<col align="left" valign="bottom" width="40%"/>
<col align="center" valign="bottom" width="20%"/>
<col align="center" valign="bottom" width="20%"/>
<col align="center" valign="bottom" width="20%"/>
<thead>
<tr>
<th styleCode="Lrule Rrule" valign="middle">Variable</th>
<th styleCode="Rrule" valign="middle">Complement Inhibitor Treatment-naïve Patients<br/>(N = 5)</th>
<th styleCode="Rrule" valign="top">Eculizumab-Experienced Patients<br/>(N = 8)</th>
<th styleCode="Rrule" valign="middle">All Patients<br/>(N = 13)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="4" valign="top">Note: Percentages were based on the total number of patients in each cohort, or overall.<br/>Abbreviations: LDH = lactate dehydrogenase; kg = kilogram; max = maximum; min = minimum; pRBC = packed red blood cells; SD = standard deviation</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Lrule Rrule">Sex, n (%)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Male</td>
<td styleCode="Rrule">4 (80.0)</td>
<td styleCode="Rrule">1 (12.5)</td>
<td styleCode="Rrule">5 (38.5)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Female</td>
<td styleCode="Rrule">1 (20.0)</td>
<td styleCode="Rrule">7 (87.5)</td>
<td styleCode="Rrule">8 (61.5)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Age at first infusion (years)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Mean (SD)</td>
<td styleCode="Rrule">14.4 (2.2)</td>
<td styleCode="Rrule">14.4 (3.1)</td>
<td styleCode="Rrule">14.4 (2.7)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Median (min, max)</td>
<td styleCode="Rrule">15.0 (11, 17)</td>
<td styleCode="Rrule">15.0 (9, 17)</td>
<td styleCode="Rrule">15.0 (9, 17)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Age at first infusion (years) category, n (%)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> < 12 years</td>
<td styleCode="Rrule">1 (20.0)</td>
<td styleCode="Rrule">1 (12.5)</td>
<td styleCode="Rrule">2 (15.4)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> ≥ 12 years</td>
<td styleCode="Rrule">4 (80.0)</td>
<td styleCode="Rrule">7 (87.5)</td>
<td styleCode="Rrule">11 (84.6)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Baseline weight (kg)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Mean (SD)</td>
<td styleCode="Rrule">56.3 (11.6)</td>
<td styleCode="Rrule">56.3 (12.2)</td>
<td styleCode="Rrule">56.3 (11.5)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Median (min, max)</td>
<td styleCode="Rrule">55.6 (39.5, 72.0)</td>
<td styleCode="Rrule">55.5 (36.7, 69.0)</td>
<td styleCode="Rrule">55.6 (36.7, 72.0)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Baseline weight (kg) category, n (%)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> ≥ 30 to < 40 kg</td>
<td styleCode="Rrule">1 (20.0)</td>
<td styleCode="Rrule">1 (12.5)</td>
<td styleCode="Rrule">2 (15.4)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> ≥ 40 to < 60 kg</td>
<td styleCode="Rrule">3 (60.0)</td>
<td styleCode="Rrule">4 (50.0)</td>
<td styleCode="Rrule">7 (53.8)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> ≥ 60 to < 100 kg</td>
<td styleCode="Rrule">1 (20.0)</td>
<td styleCode="Rrule">3 (37.5)</td>
<td styleCode="Rrule">4 (30.8)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Units of pRBC/whole blood transfused within 12 months prior to first dose</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Median (min, max)</td>
<td styleCode="Rrule">7.0 (3, 11)</td>
<td styleCode="Rrule">2.0 (2, 2)</td>
<td styleCode="Rrule">-</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Pre-treatment LDH levels (U/L)</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Median (min, max)</td>
<td styleCode="Rrule">588.5 (444, 2269.7)</td>
<td styleCode="Rrule">251.5 (140.5, 487)</td>
<td styleCode="Rrule">-</td>
</tr>
</tbody>
</table>
<paragraph>Based on body weight, patients received a loading dose of ULTOMIRIS on Day 1, followed by maintenance treatment on Day 15 and once every 8 weeks (q8w) thereafter for patients weighing ≥ 20 kg, or once every 4 weeks (q4w) for patients weighing < 20 kg. For patients who entered the study on eculizumab therapy, Day 1 of study treatment was planned to occur 2 weeks from the patient's last dose of eculizumab.</paragraph>
<paragraph>The weight-based dose regimen of ravulizumab-cwvz provided inhibition of terminal complement in all patients throughout the entire 26-week treatment period regardless of prior experience with eculizumab. Following initiation of ravulizumab-cwvz treatment, steady-state therapeutic serum concentrations of ravulizumab-cwvz were achieved after the first dose and maintained throughout the primary evaluation period in both cohorts. Three of 5 complement inhibitor treatment-naïve patients and 6 out of 8 eculizumab-experienced patients achieved hemoglobin stabilization by Week 26, respectively. Transfusion avoidance was reached for 11 out of 13 of patients during the 26-week Primary Evaluation Period. One patient experienced breakthrough hemolysis during the extension period. Table 27 presents secondary efficacy outcomes for the primary evaluation period.</paragraph>
<table ID="tab27" width="80%">
<caption>Table 27: Efficacy Outcomes from the 26-Week Primary Evaluation Period of Pediatric Patient Study in PNH (ALXN1210-PNH-304)</caption>
<col align="left" valign="middle" width="40%"/>
<col align="center" valign="middle" width="25%"/>
<col align="center" valign="middle" width="35%"/>
<thead>
<tr>
<th styleCode="Lrule Rrule">Endpoint</th>
<th styleCode="Rrule">Treatment Naïve<br/>(N = 5)</th>
<th styleCode="Rrule">Eculizumab Experienced <br/>(N = 8)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="3" valign="top">Abbreviations: FACIT = Functional Assessment of Chronic Illness Therapy; LDH = lactate dehydrogenase</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">LDH percent change from baseline (%)<footnote ID="t27fa">95% CIs for the mean obtained from t-distribution were presented.</footnote>
</td>
<td styleCode="Rrule">-47.9 (-113.4, 17.5)</td>
<td styleCode="Rrule">4.7 (-36.7, 46.0)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Transfusion avoidance (%)<footnote ID="t27fb">95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.</footnote>
</td>
<td styleCode="Rrule">60.0 (14.7, 94.7)</td>
<td styleCode="Rrule">100.0 (63.1, 100.0)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Change in FACIT-Fatigue<footnoteRef IDREF="t27fa"/>
</td>
<td styleCode="Rrule">3.4 (-4.2, 11.0)</td>
<td styleCode="Rrule">1.3 (-3.1, 5.7)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Hemoglobin stabilization (%)<footnoteRef IDREF="t27fb"/>
</td>
<td styleCode="Rrule">60.0 (14.7, 94.7)</td>
<td styleCode="Rrule">75.0 (34.9, 96.8)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Breakthrough hemolysis (%)</td>
<td styleCode="Rrule">0</td>
<td styleCode="Rrule">0<footnote>No patients experienced breakthrough hemolysis during the primary evaluation period. One patient experienced breakthrough hemolysis at 1.8 years during the extension period; however, at the time of the breakthrough hemolysis event the patient had adequate C5 inhibition (free C5 < 0.5 mcg/mL).</footnote>
</td>
</tr>
</tbody>
</table>
<paragraph>A clinically relevant improvement from baseline in fatigue as assessed by Pediatric FACIT-Fatigue (i.e., mean improvement of > 3 units for Pediatric FACIT Fatigue scores) was sustained throughout the primary evaluation period in the 5-complement inhibitor treatment naïve patients. A slight improvement was also observed in eculizumab-experienced patients. However, patient-reported fatigue may be an under- or over-estimation because patients were not blinded to treatment assignment.</paragraph>
<paragraph>The efficacy of ULTOMIRIS in pediatric patients with PNH is similar to that observed in adult patients with PNH enrolled in pivotal studies.</paragraph>
</text>
<effectiveTime value="20240924"/>
</section>
</component>
</section>
</component>
<component>
<section ID="S14.2">
<id root="6a68a0bb-f7b0-408f-97ff-6610bc57f899"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<title>14.2 Atypical Hemolytic Uremic Syndrome (aHUS)</title>
<text>
<paragraph>The efficacy of ULTOMIRIS administered intravenously in patients with aHUS was assessed in 2 open-label, single-arm studies. Study ALXN1210-aHUS-311 enrolled adult patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have a platelet count ≤ 150 × 10<sup>9</sup>/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal or required dialysis.</paragraph>
<paragraph>Study ALXN1210-aHUS-312 enrolled pediatric patients who displayed signs of TMA. In order to qualify for enrollment, patients were required to have a platelet count ≤ 150 × 10<sup>9</sup>/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level ≥ 97.5% percentile at screening or required dialysis. In both studies, enrollment criteria excluded patients presenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin <content styleCode="italics">Escherichia coli</content> related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism. Patients with confirmed diagnosis of STEC-HUS after enrollment were excluded from the efficacy evaluation.</paragraph>
</text>
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<section>
<id root="611034f6-b38f-4b82-8999-d20b57a10a4f"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<text>
<paragraph>
<content styleCode="underline">Study in Adult Patients with aHUS</content>
</paragraph>
<paragraph>The adult study [ALXN1210-aHUS-311; NCT02949128] was conducted in patients who were naïve to complement inhibitor treatment prior to study entry. The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years. All patients received ULTOMIRIS administered intravenously according to their weight <content styleCode="italics">[see <linkHtml href="#S2.3">Dosage and Administration (2.3)</linkHtml>].</content>
</paragraph>
<paragraph>A total of 56 patients with aHUS were evaluated for efficacy. Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (i.e., postpartum).</paragraph>
<paragraph>Table 28 presents the demographics and baseline characteristics of the 56 adult patients enrolled in Study ALXN1210-aHUS-311 that constituted the Full Analysis Set.</paragraph>
<table ID="tab28" width="80%">
<caption>Table 28: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-311</caption>
<col align="left" valign="top" width="40%"/>
<col align="center" valign="top" width="25%"/>
<col align="center" valign="top" width="35%"/>
<thead>
<tr>
<th styleCode="Lrule Rrule" valign="middle">Parameter</th>
<th styleCode="Rrule" valign="middle">Statistics</th>
<th styleCode="Rrule" valign="middle">ULTOMIRIS <br/>(N=56)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="3" valign="top">Note: Percentages are based on the total number of patients.<br/>Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum; SD = standard deviation</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Age at time of first infusion (years)<br/>
</td>
<td styleCode="Rrule">Mean (SD)<br/>Min, max</td>
<td styleCode="Rrule">42.2 (14.98)<br/>19.5, 76.6</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Sex</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Female</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule">37 (66.1)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Race <footnote>Patients can have multiple races selected.</footnote>
</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> White</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">29 (51.8)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Asian</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">15 (26.8)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Unknown</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">8 (14.3)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Other</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">4 (7.1)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Platelets (10<sup>9</sup>/L) blood<br/>[normal range 130 to 400 × 10<sup>9</sup>/L]</td>
<td styleCode="Rrule">n<br/>Median (min,max)</td>
<td styleCode="Rrule">56<br/>95.25 (18, 473)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Hemoglobin (g/L) blood<br/>[normal range 115 to 160 g/L (female), 130 to 175 g/L (male)]</td>
<td styleCode="Rrule">n<br/>Median (min,max)</td>
<td styleCode="Rrule">56<br/>85.00 (60.5, 140)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">LDH (U/L) serum<br/>[normal range 120 to 246 U/L]</td>
<td styleCode="Rrule">n<br/>Median (min,max)</td>
<td styleCode="Rrule">56<br/>508.00 (229.5, 3249)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">eGFR (mL/min/1.73 m<sup>2</sup>)<br/>[normal range ≥ 60 mL/min/1.73 m<sup>2</sup>]</td>
<td styleCode="Rrule">n (%)<br/>Mean (SD)<br/>Median (min,max)</td>
<td styleCode="Rrule">55<br/>15.86 (14.815)<br/>10.00 (4, 80)</td>
</tr>
</tbody>
</table>
<paragraph>The efficacy evaluation was based on Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet each Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.</paragraph>
<paragraph>Complete TMA Response was observed in 30 of the 56 patients (54%) during the 26-week Initial Evaluation Period as shown in Table 29.</paragraph>
<table ID="tab29" width="80%">
<caption>Table 29: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-311)</caption>
<col align="left" valign="top" width="40%"/>
<col align="center" valign="top" width="10%"/>
<col align="center" valign="top" width="10%"/>
<col align="center" valign="top" width="40%"/>
<thead>
<tr styleCode="Botrule">
<th rowspan="2" styleCode="Lrule Rrule"/>
<th rowspan="2" styleCode="Rrule" valign="middle">Total</th>
<th colspan="2" styleCode="Rrule">Responder</th>
</tr>
<tr styleCode="Botrule">
<th align="center" styleCode="Rrule">n</th>
<th styleCode="Rrule">Proportion (95% CI)<footnote>95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.</footnote>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="4" valign="top">Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Complete TMA Response</td>
<td styleCode="Rrule">56</td>
<td styleCode="Rrule">30</td>
<td styleCode="Rrule">0.54 (0.40, 0.67)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Components of Complete TMA Response</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Platelet count normalization</td>
<td styleCode="Rrule">56</td>
<td styleCode="Rrule">47</td>
<td styleCode="Rrule">0.84 (0.72, 0.92)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> LDH normalization</td>
<td styleCode="Rrule">56</td>
<td styleCode="Rrule">43</td>
<td styleCode="Rrule">0.77 (0.64, 0.87)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> ≥ 25% improvement in serum creatinine from baseline</td>
<td styleCode="Rrule">56</td>
<td styleCode="Rrule">33</td>
<td styleCode="Rrule">0.59 (0.45, 0.72)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Hematologic normalization</td>
<td styleCode="Rrule">56</td>
<td styleCode="Rrule">41</td>
<td styleCode="Rrule">0.73 (0.60, 0.84)</td>
</tr>
</tbody>
</table>
<paragraph>One additional patient had a Complete TMA Response that was confirmed after the 26-week Initial Evaluation Period. Complete TMA Response was achieved at a median time of 86 days (range: 7 to 169 days). The median duration of Complete TMA Response was 7.97 months (range: 2.52 to 16.69 months). All responses were maintained through all available follow-up.</paragraph>
<paragraph>Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by estimated glomerular filtration rate (eGFR).</paragraph>
<paragraph>An increase in mean platelet count was observed after commencement of ULTOMIRIS treatment, increasing from 118.52 × 10<sup>9</sup>/L at baseline to 240.34 ×10<sup>9</sup>/L at Day 8 and remaining above 227 × 10<sup>9</sup>/L at all subsequent visits in the Initial Evaluation Period (26 weeks).</paragraph>
<paragraph>Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy. The mean eGFR (+/- SD) increased from 15.86 (14.82) at baseline to 51.83 (39.16) by 26 weeks. In patients with Complete TMA Response, renal function continued to improve after the Complete TMA Response was achieved.</paragraph>
<paragraph>Seventeen of the 29 patients (59%) who required dialysis at study entry discontinued dialysis by the end of the available follow-up and 6 of 27 (22%) patients were off dialysis at baseline were on dialysis at last available follow-up.</paragraph>
</text>
<effectiveTime value="20240924"/>
</section>
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<component>
<section>
<id root="19aaeb76-d38e-4bcf-8a4e-37edd8498ea7"/>
<code code="42229-5" codeSystem="2.16.840.1.113883.6.1" displayName="SPL UNCLASSIFIED SECTION"/>
<text>
<paragraph>
<content styleCode="underline">Study in Pediatric Patients with aHUS</content>
</paragraph>
<paragraph>The Pediatric Study [ALXN1210-aHUS-312; NCT03131219] is a 26-week ongoing, multicenter, single-arm study conducted in 16 pediatric patients. All patients received ULTOMIRIS administered intravenously according to their weight <content styleCode="italics">[see <linkHtml href="#S2.3">Dosage and Administration (2.3)</linkHtml>].</content>
</paragraph>
<paragraph>A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and included in this interim analysis. The median age at the time of first infusion was 5.2 years (range 0.9, 17.3 years). The overall mean weight at Baseline was 19.8 kg; half of the patients were in the baseline weight category ≥ 10 to < 20 kg. The majority of patients (71%) had pretreatment extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline. At baseline, 35.7% (n = 5) of patients had a CKD Stage 5. Seven percent had history of prior kidney transplant and 35.7% were on dialysis at study entry.</paragraph>
<paragraph>Table 30 presents the baseline characteristics of the pediatric patients enrolled in Study ALXN1210-aHUS-312.</paragraph>
<table ID="tab30" width="80%">
<caption>Table 30: Demographics and Baseline Characteristics in Study ALXN1210-aHUS-312</caption>
<col align="left" valign="bottom" width="50%"/>
<col align="center" valign="bottom" width="25%"/>
<col align="center" valign="bottom" width="25%"/>
<thead>
<tr>
<th styleCode="Lrule Rrule" valign="middle">Parameter</th>
<th styleCode="Rrule" valign="middle">Statistics</th>
<th styleCode="Rrule" valign="middle">ULTOMIRIS <br/>(N = 14)</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="3" valign="bottom">Note: Percentages are based on the total number of patients.<br/>Abbreviations: eGFR = estimated glomerular filtration rate; LDH = lactate dehydrogenase; max = maximum; min = minimum</td>
</tr>
</tfoot>
<tbody>
<tr>
<td styleCode="Lrule Rrule">Age at time of first infusion (years) category</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Birth to < 2 years</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">2 (14.3)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> 2 to < 6 years</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">7 (50.0)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> 6 to < 12 years</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">4 (28.6)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> 12 to < 18 years</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">1 (7.1)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Sex</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule"/>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Female</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">9 (64.3)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Race<footnote>Patients can have multiple races selected.</footnote>
</td>
<td styleCode="Rrule">n (%)</td>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> White</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">7 (50.0)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Asian</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">4 (28.6)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Black or African American</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">2 (14.3)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> American Indian or Alaskan Native</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">1 (7.1)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Unknown</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule">1 (7.1)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Platelets (10<sup>9</sup>/L) blood [normal range 229 to 533 × 10<sup>9</sup>/L]</td>
<td styleCode="Rrule">Median (min, max)</td>
<td styleCode="Rrule">64.00 (14, 125)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Hemoglobin (g/L) blood [normal range 107 to 131 g/L]</td>
<td styleCode="Rrule">Median (min, max)</td>
<td styleCode="Rrule">74.25 (32, 106)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">LDH (U/L) serum [normal range 165 to 395 U/L]</td>
<td styleCode="Rrule">Median (min, max)</td>
<td styleCode="Rrule">2077.00 (772, 4985)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule" valign="top">eGFR (mL/min/1.73 m<sup>2</sup>) [normal range ≥ 60 mL/min/1.73 m<sup>2</sup>]</td>
<td styleCode="Rrule" valign="top">Mean (SD)<br/>Median (min, max)</td>
<td styleCode="Rrule" valign="top">28.4 (23.11)<br/>22.0 (10, 84)</td>
</tr>
</tbody>
</table>
<paragraph>Efficacy evaluation was based upon Complete TMA Response during the 26-week Initial Evaluation Period, as evidenced by normalization of hematological parameters (platelet count and LDH) and ≥ 25% improvement in serum creatinine from baseline. Patients had to meet all Complete TMA Response criteria at 2 separate assessments obtained at least 4 weeks (28 days) apart, and any measurement in between.</paragraph>
<paragraph>Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period as shown in Table 31.</paragraph>
<table ID="tab31" width="80%">
<caption>Table 31: Efficacy Results in aHUS during the 26-Week Initial Evaluation Period (ALXN1210-aHUS-312)</caption>
<col align="left" valign="middle" width="46%"/>
<col align="center" valign="middle" width="12%"/>
<col align="center" valign="middle" width="12%"/>
<col align="center" valign="middle" width="30%"/>
<thead>
<tr styleCode="Botrule">
<th rowspan="2" styleCode="Lrule Rrule"/>
<th rowspan="2" styleCode="Rrule" valign="top">Total</th>
<th colspan="2" styleCode="Rrule">Responder</th>
</tr>
<tr styleCode="Botrule">
<th align="center" styleCode="Rrule">n</th>
<th styleCode="Rrule">Proportion (95% CI)<footnote>95% CIs for the proportion were based on exact confidence limits using the Clopper-Pearson method.</footnote>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="4" valign="middle">Note: One patient withdrew from study after receiving 2 doses of ravulizumab-cwvz.<br/>Abbreviations: CI = confidence interval; LDH = lactate dehydrogenase; TMA = thrombotic microangiopathy</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Complete TMA Response</td>
<td styleCode="Rrule">14</td>
<td styleCode="Rrule">10</td>
<td styleCode="Rrule">0.71 (0.42, 0.92)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Components of Complete TMA Response</td>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
<td styleCode="Rrule"/>
</tr>
<tr>
<td styleCode="Lrule Rrule"> Platelet count normalization</td>
<td styleCode="Rrule">14</td>
<td styleCode="Rrule">13</td>
<td styleCode="Rrule">0.93 (0.66, 0.99)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule"> LDH normalization</td>
<td styleCode="Rrule">14</td>
<td styleCode="Rrule">12</td>
<td styleCode="Rrule">0.86 (0.57, 0.98)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> ≥ 25% improvement in serum creatinine from baseline</td>
<td styleCode="Rrule" valign="top">14</td>
<td styleCode="Rrule" valign="top">11</td>
<td styleCode="Rrule" valign="top">0.79 (0.49, 0.95)</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Hematologic normalization</td>
<td styleCode="Rrule">14</td>
<td styleCode="Rrule">12</td>
<td styleCode="Rrule">0.86 (0.57, 0.98)</td>
</tr>
</tbody>
</table>
<paragraph>Complete TMA Response during the Initial Evaluation Period was achieved at a median time of 30 days (range:15 to 88 days). The median duration of Complete TMA Response was 5.08 months (range: 3.08 to 5.54 months). All responses were maintained through all available follow-up.</paragraph>
<paragraph>Other endpoints included platelet count change from baseline, dialysis requirement, and renal function as evaluated by eGFR.</paragraph>
<paragraph>An increase in mean platelet count was observed after commencement of ULTOMIRIS treatment, increasing from 60.50 × 10<sup>9</sup>/L at baseline to 296.67 × 10<sup>9</sup>/L at Day 8 and remained above 296 × 10<sup>9</sup>/L at all subsequent visits in the Initial Evaluation Period (26 weeks). The mean eGFR (+/- SD) increased from 28.4 (23.11) at baseline to 108.0 (63.21) by 26 weeks.</paragraph>
<paragraph>Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment. No patient started dialysis during the study.</paragraph>
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<component>
<section ID="S14.3">
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<title>14.3 Generalized Myasthenia Gravis (gMG)</title>
<text>
<paragraph>The efficacy of ULTOMIRIS for the treatment of gMG was demonstrated in a randomized, double-blind, placebo-controlled, multicenter study (ALXN1210-MG-306; NCT03920293). Patients were randomized 1:1 to either receive ULTOMIRIS (n=86) or placebo (n=89) for 26 weeks. ULTOMIRIS was administered intravenously according to the weight-based recommended dosage <content styleCode="italics">[see <linkHtml href="#S2.3">Dosage and Administration (2.3)</linkHtml>].</content>
</paragraph>
<paragraph>Patients with gMG with a positive serologic test for anti-AChR antibodies, Myasthenia Gravis Foundation of America (MGFA) clinical classification class II to IV, and Myasthenia Gravis-Activities of Daily Living (MG-ADL) total score ≥ 6 were enrolled. Baseline and disease characteristics were similar between treatment groups (including age at first dose [mean of 58 years for ULTOMIRIS versus 53 years for placebo], gender [51% female for ULTOMIRIS versus 51% female for placebo], race as White, Asian, and Black or African American [78%, 17%, and 2% for ULTOMIRIS versus 69%, 18%, and 5% for placebo, respectively], and duration of MG since diagnosis [mean of 10 years, ranging from 0.5 to 39.5 years, for ULTOMIRIS versus mean of 10.0 years, ranging from 0.5 to 36.1 years, for placebo].</paragraph>
<paragraph>Over 80% of patients were receiving acetylcholinesterase inhibitors, 70% were receiving corticosteroids, and 68% were receiving non-steroidal immunosuppressants (ISTs) at study entry. Patients on concomitant medications to treat gMG were permitted to continue on therapy throughout the course of the study.</paragraph>
<paragraph>The primary efficacy endpoint was a comparison of the change from baseline between treatment groups in the MG-ADL total score at Week 26. The MG-ADL is a categorical scale that assesses the impact on daily function of 8 signs or symptoms that are typically affected in gMG. Each item is assessed on a 4-point scale where a score of 0 represents normal function and a score of 3 represents loss of ability to perform that function. The total score ranges from 0 to 24, with the higher scores indicating more impairment.</paragraph>
<paragraph>The secondary endpoints, also assessed from baseline to Week 26, included the change in the Quantitative MG total score (QMG). The QMG is a 13-item categorical scale assessing muscle weakness. Each item is assessed on a 4-point scale where a score of 0 represents no weakness and a score of 3 represents severe weakness. A total score ranges from 0 to 39, where higher scores indicate more severe impairment.</paragraph>
<paragraph>Other secondary endpoints included the proportion of patients with improvements of at least 5 and 3 points in the QMG and MG-ADL total scores, respectively.</paragraph>
<paragraph>Treatment with ULTOMIRIS demonstrated a statistically significant change in the MG-ADL and QMG total scores from baseline at Week 26 as compared to placebo (Table 32).</paragraph>
<table ID="tab32" width="80%">
<caption>Table 32: Efficacy Results in Patients with gMG</caption>
<col align="left" valign="middle" width="20%"/>
<col align="center" valign="middle" width="20%"/>
<col align="center" valign="middle" width="20%"/>
<col align="center" valign="middle" width="20%"/>
<col align="center" valign="middle" width="20%"/>
<thead>
<tr>
<th styleCode="Lrule Rrule">Efficacy Endpoints: Change from Baseline at Week 26</th>
<th styleCode="Rrule">Placebo<br/>(n = 89)<br/>LS Mean</th>
<th styleCode="Rrule">ULTOMIRIS <br/>(n = 86)<br/>LS Mean</th>
<th styleCode="Rrule">Treatment Effect<br/>(95% CI)</th>
<th styleCode="Rrule">p-value<footnote>p-value calculated using mixed effect model for repeated measures</footnote>
</th>
</tr>
</thead>
<tfoot>
<tr>
<td align="left" colspan="5" valign="middle">Abbreviations: CI = confidence interval, LS = least squares; MG-ADL = Myasthenia Gravis Activities of Daily Living profile; QMG = Quantitative Myasthenia Gravis score for disease severity</td>
</tr>
</tfoot>
<tbody>
<tr styleCode="Botrule">
<td colspan="5" styleCode="Lrule Rrule">
<content styleCode="bold">Primary Endpoint</content>
</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">MG-ADL</td>
<td styleCode="Rrule">-1.4</td>
<td styleCode="Rrule">-3.1</td>
<td styleCode="Rrule">-1.6 (-2.6, -0.7)</td>
<td styleCode="Rrule">< 0.001</td>
</tr>
<tr styleCode="Botrule">
<td colspan="5" styleCode="Lrule Rrule">
<content styleCode="bold">Secondary Endpoint</content>
</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">QMG</td>
<td styleCode="Rrule">-0.8</td>
<td styleCode="Rrule">-2.8</td>
<td styleCode="Rrule">-2.0 (-3.2, -0.8)</td>
<td styleCode="Rrule">< 0.001</td>
</tr>
</tbody>
</table>
<paragraph>The proportion of QMG responders with at least a 5-point improvement at week 26 was greater for ULTOMIRIS (30.0%) compared to placebo (11.3%) p = 0.005. The proportion of MG-ADL responders with at least a 3-point improvement at week 26 was also greater for ULTOMIRIS (56.7%) compared to placebo (34.1%). The proportion of clinical responders at higher response thresholds (≥ 4-, 5-, 6-, 7-, or 8-point improvement on MG-ADL, and ≥ 6-, 7-, 8-, 9-, or 10-point improvement on QMG) was consistently greater for ULTOMIRIS compared to placebo.</paragraph>
<paragraph>
<content styleCode="bold">Figure 1: Change from Baseline in MG-ADL Total Score (A) and QMG Total Score (B) Through Week 26 of the Randomized Controlled Period of ALXN1210-MG-306 (Mean and 95% CI)</content>
</paragraph>
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<paragraph>Note: *p<0.001 versus placebo</paragraph>
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<text>Figure 1</text>
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<reference value="ultomiris-01.jpg"/>
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<section ID="S14.4">
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<title>14.4 Neuromyelitis Optica Spectrum Disorder (NMOSD)</title>
<text>
<paragraph>The efficacy and safety of ULTOMIRIS in adult patients with anti-AQP4 antibody positive NMOSD was assessed in an open-label multicenter study, Study ALXN1210-NMO-307 (NCT04291262). Patients participating in Study ALXN1210-NMO-307 received ULTOMIRIS intravenously in the Primary Treatment Period that ended when the last enrolled patient completed (or discontinued prior to) 50 weeks on study, representing a median study duration of 73.5 weeks (minimum 13.7, maximum 117.7). Efficacy assessments were based on a comparison of patients in Study ALXN1210-NMO-307 with an external placebo control group from another study (Study ECU-NMO-301, NCT01892345) composed of a comparable population of adult patients with anti-AQP4 antibody positive NMOSD.</paragraph>
<paragraph>Study ALXN1210-NMO-307 enrolled 58 adult patients with NMOSD who had a positive serologic test for anti-AQP4 antibodies, at least 1 relapse in the last 12 months prior to the Screening Period, and an Expanded Disability Status Scale (EDSS) score ≤ 7. In the external placebo control group, eligibility criteria were similar except patients were required to have at least 2 relapses in last 12 months or 3 relapses in the last 24 months with at least 1 relapse in the 12 months prior to screening. Prior treatment with immunosuppressant therapies (ISTs) was not required for enrollment. However, patients on selected ISTs (i.e., corticosteroids, azathioprine, mycophenolate mofetil, methotrexate, and tacrolimus) were permitted to continue on therapy, with a requirement for stable dosing until they reached Week 106 in the Study. Similar IST use was permitted in the external placebo control group.</paragraph>
<paragraph>ULTOMIRIS was administered intravenously according to the weight-based recommended dosage <content styleCode="italics">[see <linkHtml href="#S2.3">Dosage and Administration (2.3)</linkHtml>].</content>
</paragraph>
<paragraph>The demographics were similar between the ULTOMIRIS treatment group from Study ALXN1210-NMO-307 and the placebo treatment group from Study ECU-NMO-301 (including age [median of 46.0 years for ULTOMIRIS versus 44.0 years for placebo] and sex [89.7% female for ULTOMIRIS versus 89.4% female for placebo]). The majority of patients were White or Asian. The median time from diagnosis to first dose was 0.9 years for ULTOMIRIS and 2.0 years for placebo. The median annualized relapse rate (ARR) in the last 24 months was 1.4 for ULTOMIRIS versus 1.9 for placebo, and the median number of historical relapses was 2 for ULTOMIRIS versus 4 for placebo. The median baseline EDSS score was 3.3 for ULTOMIRIS versus 4.0 for placebo. At baseline, 48% of patients in the ULTOMIRIS group received concomitant IST, including corticosteroids, versus 72% of subjects in the placebo group.</paragraph>
<paragraph>The primary endpoint of Study ALXN1210-NMO-307 was the time to first adjudicated on-trial relapse as determined by an independent adjudication committee. No adjudicated on-trial relapses were observed in ULTOMIRIS-treated patients during the Primary Treatment Period, representing a statistically significant difference between the ULTOMIRIS and placebo treatment arms in time to first adjudicated on-trial relapse (p < 0.0001). The hazard ratio (95% confidence interval [CI]) for ULTOMIRIS compared with placebo was 0.014 (0.000, 0.103), representing a 98.6% reduction in the risk of relapse (Figure 2). ULTOMIRIS-treated patients experienced similar improvement in time to first adjudicated on-trial relapse with or without concomitant treatment.</paragraph>
<paragraph>
<content styleCode="bold">Figure 2: Kaplan-Meier Survival Estimates for Time to First Adjudicated On-Trial Relapse in Study ALXN1210-NMO-307 and Comparative Placebo Arm of Study ECU-NMO-301</content>
</paragraph>
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<paragraph>Note: The placebo group data were collected as part of Study ECU-NMO-301. Patients who did not experience an adjudicated on-trial relapse were censored at the end of the study period. If a patient in the placebo group was followed longer than any of the patients in the Ultomiris group, then that patient was censored at the longest Ultomiris follow-up time.</paragraph>
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<text>Figure 2</text>
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<reference value="ultomiris-02.jpg"/>
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