<?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 Perinatal/Infantile-Onset HPP</title>
<text>
<paragraph>Study 1 was a 24-week prospective single-arm trial in 11 patients with severe perinatal/infantile-onset HPP. In this study, 7/11 (64%) were female and 10/11 (91%) patients were white, and age ranged from 3 weeks to 39.5 months. Severe perinatal/infantile-onset HPP was defined as biochemical, medical history and radiographic evidence of HPP as well as the presence of any of the following: rachitic chest deformity, vitamin B6-dependent seizures, or failure to thrive. Ten of 11 patients completed the 24-week trial and continued treatment in the extension phase. Nine patients have been treated for at least 216 weeks (54 months) and 4 patients have been treated for over 240 weeks (60 months). Patients received subcutaneous STRENSIQ 3 mg/kg per week for the first month; subsequently, dose increases up to 9 mg/kg per week were allowed for changes in weight and/or for lack of efficacy. All 10 patients required dose increases up to 6 mg/kg per week or higher; 9 patients increased between 4 and 24 weeks after starting treatment and 1 patient increased after 70 weeks due to suboptimal clinical response. One patient's dose was decreased from 9 mg/kg per week to 6 mg/kg per week based on PK data.</paragraph>
<paragraph>Study 2 was a prospective open-label study in 59 patients with perinatal/infantile-onset HPP. In this study, 32/59 (54%) were female, 46/59 (78%) were white, and age ranged from 1 day to 78 months. Patients received subcutaneous STRENSIQ at 6 mg/kg per week for the first 4 weeks. Ten patients received dose increases higher than 6 mg/kg per week due to suboptimal clinical response, with dose increases occurring between 8 and 24 weeks after starting treatment. The recommended dosage regimen of STRENSIQ for the treatment of perinatal/infantile-onset HPP is up to 9 mg/kg per week administered subcutaneously as 3 mg/kg three times per week <content styleCode="italics">[see <linkHtml href="#S2.2">Dosage and Administration (2.2)</linkHtml>].</content>
</paragraph>
<paragraph>Forty-one patients were treated for at least 24 weeks (6 months) and 15 patients were treated for at least 96 weeks (24 months).</paragraph>
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<paragraph>
<content styleCode="underline">Survival and Ventilation-Free Survival in Perinatal/Infantile-Onset HPP</content>
</paragraph>
<paragraph>Survival and invasive ventilation-free survival were compared in STRENSIQ-treated patients (Studies 1 and 2) with a historical cohort of untreated patients with similar clinical characteristics (Table 7 and Figure 1).</paragraph>
<table ID="table7" width="75%">
<caption>Table 7: Survival and Invasive Ventilation-Free Survival in STRENSIQ-Treated versus Historical Control Patients with Perinatal/ Infantile-Onset HPP (Pooled Studies 1 and 2)</caption>
<col align="left" valign="top" width="60%"/>
<col align="center" valign="top" width="20%"/>
<col align="center" valign="top" width="20%"/>
<thead>
<tr>
<th styleCode="Lrule Rrule"/>
<th styleCode="Rrule">STRENSIQ-Treated</th>
<th styleCode="Rrule">Historical Controls</th>
</tr>
</thead>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Survival</td>
<td styleCode="Rrule">n = 68</td>
<td styleCode="Rrule">n = 48</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Alive at Point of Last Contact (%)</td>
<td styleCode="Rrule">91</td>
<td styleCode="Rrule">27</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Hazard Ratio (STRENSIQ/Historical Control), 95% Confidence Interval<footnote ID="t7f1">Adjusted for year of diagnosis.</footnote>
</td>
<td colspan="2" styleCode="Rrule">0.14<br/>(0.05, 0.39)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule" valign="middle"> Kaplan-Meier Estimate and Alive at Age 1 Year (Week 48) (%)</td>
<td styleCode="Rrule" valign="middle">97</td>
<td styleCode="Rrule" valign="middle">42</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule"> </td>
<td/>
<td styleCode="Rrule"/>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Invasive Ventilation-Free Survival<footnote ID="t7f2">Alive and not initiating invasive ventilation after start of STRENSIQ treatment. STRENSIQ-treated patients on invasive ventilation at baseline were excluded from this analysis.</footnote>
</td>
<td styleCode="Rrule">n = 54</td>
<td styleCode="Rrule">n = 48</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Alive and Not on Ventilation at Point of Last Contact (%)</td>
<td styleCode="Rrule">85</td>
<td styleCode="Rrule">25</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Hazard Ratio (STRENSIQ/Historical Control), 95% Confidence Interval<footnoteRef IDREF="t7f1"/>
</td>
<td colspan="2" styleCode="Rrule">0.21<br/>(0.09, 0.51)</td>
</tr>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule"> Kaplan-Meier Estimate of Alive and Not on Ventilation at Age 1 Year (Week 48) (%)</td>
<td styleCode="Rrule">96</td>
<td styleCode="Rrule">31</td>
</tr>
</tbody>
</table>
<paragraph>In patients who required any form of respiratory support, 21 of 26 (81%) of the treated patients survived through their last assessment (median age at last assessment was 3.2 years of age), versus 1 of 20 (5%) of historical controls.</paragraph>
<paragraph>
<content styleCode="bold">Figure 1: Overall Survival in STRENSIQ-Treated versus Historical Control Patients with Perinatal/ Infantile-Onset HPP (Pooled Studies 1 and 2)</content>
</paragraph>
<paragraph>
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<text>Figure 1</text>
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<text>
<paragraph>
<content styleCode="underline">Skeletal Manifestations in Perinatal/Infantile-Onset HPP</content>
</paragraph>
<paragraph>Radiographs from 68 STRENSIQ-treated perinatal/infantile-onset HPP patients, including 64 patients in Studies 1 and 2, and 4 patients in Study 3 <content styleCode="italics">[see <linkHtml href="#S14.2">Clinical Studies (14.2)</linkHtml>]</content>, were examined to assess HPP-related rickets using the 7-point Radiographic Global Impression of Change (RGI-C) scale. Patients with a minimum RGI-C score of +2 were defined as "responders". Radiologic improvements could be seen by Month 24; at last assessment, 50/68 [74%] treated patients were rated as RGI-C responders. No comparative data were available from historical controls. The mean time interval between the baseline and last RGI-C assessment was 24 months (range was 1 month to 67 months).</paragraph>
<paragraph>Eighteen perinatal/infantile-onset HPP patients experienced fractures during the course of treatment. There were insufficient data to determine the effect of STRENSIQ on fractures.</paragraph>
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<paragraph>
<content styleCode="underline">Growth in Perinatal/Infantile-Onset HPP</content>
</paragraph>
<paragraph>Height and weight measurements (as measured by Z-scores) were available post-treatment for 72 perinatal/infantile-onset HPP patients, including 68 patients enrolled in Studies 1 and 2, and 4 patients enrolled in Study 3 (Table 8).</paragraph>
<table ID="table8" width="75%">
<caption>Table 8: Perinatal/Infantile-Onset Height and Weight Measurements as Measured by Z-Score (Studies 1 and 2)</caption>
<col align="left" valign="top" width="24%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<thead>
<tr styleCode="Botrule">
<th rowspan="3" styleCode="Lrule Rrule"/>
<th colspan="4" styleCode="Rrule">Height Z-score</th>
<th colspan="4" styleCode="Rrule">Weight Z-score</th>
</tr>
<tr styleCode="Botrule">
<th align="center" colspan="2" styleCode="Rrule">Baseline</th>
<th colspan="2" styleCode="Rrule">Last Assessment</th>
<th colspan="2" styleCode="Rrule">Baseline</th>
<th colspan="2" styleCode="Rrule">Last Assessment</th>
</tr>
<tr>
<th align="center" styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
<th styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
<th styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
<th styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
</tr>
</thead>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">Studies 1 and 2<footnote ID="t8f1">The mean time interval between baseline and last assessment was 21 months (range was 1 month to 72 months).</footnote> (N=68)</td>
<td styleCode="Rrule">-3.3</td>
<td styleCode="Rrule">-10.1, 0.9</td>
<td styleCode="Rrule">-2.9</td>
<td styleCode="Rrule">-10.6, 0.4</td>
<td styleCode="Rrule">-3.2</td>
<td styleCode="Rrule">-23.8, 0</td>
<td styleCode="Rrule">-2.4</td>
<td styleCode="Rrule">-20.9. 1.1</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Study 3 (N=4)<footnote ID="t8f2">The mean time between baseline and last assessment was 56 months (range was 53 months to 60 months).</footnote>
</td>
<td styleCode="Rrule">-2.6</td>
<td styleCode="Rrule">-6.6, -0.7</td>
<td styleCode="Rrule">-1.5</td>
<td styleCode="Rrule">-5.8, 0.4</td>
<td styleCode="Rrule">-2.5</td>
<td styleCode="Rrule">-8.2, -1.0</td>
<td styleCode="Rrule">-1.5</td>
<td styleCode="Rrule">-5.4, 0.5</td>
</tr>
</tbody>
</table>
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<section>
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<text>
<paragraph>
<content styleCode="underline">Long-Term Extension Trials in Perinatal/Infantile-Onset HPP</content>
</paragraph>
<paragraph>Long-term data were collected in 68 STRENSIQ-treated patients with perinatal/infantile onset HPP in Studies 1 and 2 and an additional 10 patients enrolled in Study 2. The longest duration of follow-up in the 78 patients was 7 years (84 months). At point of last contact, 69/78 (88%) STRENSIQ-treated patients had survived.</paragraph>
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<section ID="S14.2">
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<title>14.2 Juvenile-Onset HPP</title>
<text>
<paragraph>Study 3 was a prospective open-label 24-week trial that included 8 juvenile-onset HPP patients and 5 perinatal/ infantile-onset HPP patients; 11/13 (85%) were male and 12/13 (92%) were white <content styleCode="italics">[see <linkHtml href="#S14.1">Clinical Studies (14.1)</linkHtml>]</content>. On study entry, patients were 6 to 12 years of age. All 8 juvenile-onset patients entered the extension study and were treated for at least 48 months. At trial entry, patients were randomized to receive subcutaneous STRENSIQ 6 mg/kg per week or 9 mg/kg per week. Two patients received dose reductions during the primary treatment period, including one patient who experienced a decrease in vitamin B6 levels and one patient who experienced recurrent injection site reactions. During the extension phase, the dosing regimen for all patients was initially changed to 3 mg/kg per week. Dosing was subsequently increased to 6 mg/kg per week, with no patients requiring doses higher than 6 mg/kg per week. The recommended dosage regimen of STRENSIQ for the treatment of juvenile-onset HPP is 6 mg/kg per week <content styleCode="italics">[see <linkHtml href="#S2.2">Dosage and Administration (2.2)</linkHtml>].</content>
</paragraph>
</text>
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<paragraph>
<content styleCode="underline">Growth in Juvenile-Onset HPP</content>
</paragraph>
<paragraph>Height and weight measurements (as measured by Z-scores) in 8 STRENSIQ-treated juvenile-onset HPP patients were compared with a historical cohort of 32 untreated patients with similar clinical characteristics (Table 9). Height and weight data for historical patients were collected from medical records.</paragraph>
<table ID="table9" width="75%">
<caption>Table 9: Juvenile-Onset Height and Weight Measurements as Measured by Z-Score (Study 3)</caption>
<col align="left" valign="top" width="24%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<col align="center" valign="top" width="8%"/>
<col align="center" valign="top" width="11%"/>
<thead>
<tr styleCode="Botrule">
<th rowspan="3" styleCode="Lrule Rrule"/>
<th colspan="4" styleCode="Rrule">Height Z-score</th>
<th colspan="4" styleCode="Rrule">Weight Z-score</th>
</tr>
<tr styleCode="Botrule">
<th align="center" colspan="2" styleCode="Rrule">Baseline</th>
<th colspan="2" styleCode="Rrule">Last Assessment</th>
<th colspan="2" styleCode="Rrule">Baseline</th>
<th colspan="2" styleCode="Rrule">Last Assessment</th>
</tr>
<tr>
<th align="center" styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
<th styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
<th styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
<th styleCode="Rrule">Mean</th>
<th styleCode="Rrule">Min, Max</th>
</tr>
</thead>
<tbody>
<tr styleCode="Botrule">
<td styleCode="Lrule Rrule">STRENSIQ (N=8)<footnote ID="t9f1">The mean time interval between baseline and last assessment was 55 months (range was 53 months to 60 months).</footnote>
</td>
<td styleCode="Rrule">-1.5</td>
<td styleCode="Rrule">-3.8, 0</td>
<td styleCode="Rrule">-0.9</td>
<td styleCode="Rrule">-2, 0</td>
<td styleCode="Rrule">-1.1</td>
<td styleCode="Rrule">-3.5, 2.3</td>
<td styleCode="Rrule">0</td>
<td styleCode="Rrule">-1.3, 2.2</td>
</tr>
<tr>
<td styleCode="Lrule Rrule">Control (N=32)<footnote ID="t9f2">The mean time interval between baseline and last assessment was 61 months (range was 19 months to 109 months).</footnote>
</td>
<td styleCode="Rrule">-1.1</td>
<td styleCode="Rrule">-4.9, 2.6</td>
<td styleCode="Rrule">-1.1</td>
<td styleCode="Rrule">-4.9, 1.8</td>
<td styleCode="Rrule">-1.2</td>
<td styleCode="Rrule">-5, 2.1</td>
<td styleCode="Rrule">-1</td>
<td styleCode="Rrule">-5.7, 2.1</td>
</tr>
</tbody>
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<section>
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<paragraph>
<content styleCode="underline">Skeletal Manifestations in Juvenile-Onset HPP</content>
</paragraph>
<paragraph>Radiographs from 8 STRENSIQ-treated juvenile-onset HPP patients and 32 historical controls were compared to assess HPP-related rickets using the 7-point RGI-C (Radiographic Global Impression of Change) scale. Patients who achieved a RGI-C score of 2 or higher (corresponding to substantial healing of rickets) were classified as being responders to treatment. All 8 treated patients were rated as responders by Month 54 of treatment. The mean duration between the baseline and last RGI-C assessments for control patients was 56 months (range was 8 to 95 months). At last assessment, 2/32 (6%) of control patients were rated as responders.</paragraph>
<paragraph>Eight of 20 (40%) patients with juvenile-onset HPP experienced new fractures during the course of treatment. There were insufficient data to assess the effect of STRENSIQ on fractures.</paragraph>
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<section>
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<paragraph>
<content styleCode="underline">Gait/Mobility in Juvenile-Onset HPP</content>
</paragraph>
<paragraph>Gait was assessed using a modified Performance Oriented Mobility Assessment-Gait (MPOMA-G) scale in 8 STRENSIQ-treated juvenile-onset HPP patients at 6-month intervals out to 36 months. Mobility was also assessed using the 6 Minute Walk Test (6MWT) in 7 of the 8 patients. Step length improved by at least 1 point in either foot in 6/8 patients compared to 1/6 (17%) control patients. The proportion of patients who had 6MWT percent predicted values within the normal range for age, sex, and height-matched peers increased from 0/8 patients at baseline to 6/6 patients (100%) by Month 48 and all 6 were also able to walk longer distances at this time point compared to baseline.</paragraph>
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<paragraph>
<content styleCode="underline">Long-Term Extension Trials in Juvenile-Onset HPP</content>
</paragraph>
<paragraph>Long-term data were collected in 8 patients with juvenile-onset HPP treated with STRENSIQ for at least 6 years (72 months). At last assessment, 7 patients with available 6MWT results had maintained improvements in gait/mobility.</paragraph>
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