<?xml version="1.0" encoding="UTF-8"?><section ID="S14">
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<title>14 CLINICAL STUDIES</title>
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<title>14.1 Infants with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life</title>
<text>
<paragraph>A multicenter, open-label, single-arm clinical study of KANUMA was conducted in 9 infants with LAL deficiency who had growth failure or other evidence of rapidly progressive disease prior to 6 months of age. The age range at entry was 1 to 6 months. Patients received KANUMA at 0.35 mg/kg once weekly for the first 2 weeks and then 1 mg/kg once weekly. Due to suboptimal clinical response, doses in all 6 surviving patients were escalated to 3 mg/kg once weekly, between 4 and 88 weeks (median 11 weeks) after starting treatment at 1 mg/kg.</paragraph>
<paragraph>The efficacy of KANUMA was assessed by comparing the survival of the 9 KANUMA-treated patients (followed in the open-label, single-arm trial) at 12 months of age to the survival in an untreated, historical cohort of 21 patients with a similar age at disease presentation and clinical characteristics. Of the 9 KANUMA-treated patients, 6 patients survived beyond 12 months of age, compared to 0 of 21 patients who survived in the historical cohort, all of whom had died by 8 months of age. The median age of the 6 surviving KANUMA-treated patients was 18.1 months (range 12 to 42.2 months).</paragraph>
<paragraph>Following initiation of treatment with KANUMA 1 mg/kg once weekly, weight-for-age (WFA) z-scores improved in 3 of 5 surviving patients with growth failure, and all 6 surviving patients demonstrated improvements in WFA z-scores following dose escalation to 3 mg/kg once weekly.</paragraph>
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<paragraph>
<content styleCode="underline">Continuation Treatment</content>
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<paragraph>Across Study 1 and another study, Study 3, in infants with rapidly progressive LAL Deficiency, 9 patients received successive dose escalations up to 5 mg/kg once weekly due to suboptimal clinical response <content styleCode="italics">[see <linkHtml href="#S2.2">Recommended Dosage (2.2)</linkHtml>]</content>. The median duration of exposure to 5 mg/kg for the 9 patients whose doses were escalated to 5 mg/kg once weekly was 33 months (range 27 to 39 months) for patients in Study 1 and 15 months (range 5 to 24 months) in Study 3.</paragraph>
<paragraph>Of the 9 patients whose KANUMA dose was escalated to 5 mg/kg once weekly, 6 were alive at their last follow up at 3 years, and 2 were alive at their last follow up at 5 years. Of these 9 patients, 6 experienced normalization of ALT and/or AST which had remained abnormal on the lower KANUMA dose.</paragraph>
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<section ID="S14.2">
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<title>14.2 Pediatric and Adult Patients with LAL Deficiency</title>
<text>
<paragraph>The safety and efficacy of KANUMA were assessed in 66 pediatric and adult patients with LAL deficiency, aged 4 to 58 years (71% were less than 18 years old), in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to receive KANUMA at a dosage of 1 mg/kg (n=36) or placebo (n=30) once every other week for 20 weeks in the double-blind period. Sixty-two of the 66 (94%) patients had LDL-c of 130 mg/dL or greater at study entry. The majority of patients (58%) had LDL-c above 190 mg/dL at study entry, and 24% of patients with LDL-c above 190 mg/dL remained on lipid lowering medications.</paragraph>
<paragraph>At the completion of the 20-week double-blind period of the trial, a statistically significant improvement in percent change from baseline in LDL-c was observed in the KANUMA-treated group as compared to the placebo group (mean difference and 95% C.I.: -22%, [-33%, -15%]; p<0.0001). LDL-c of less than 130 mg/dL was achieved in 13 of 32 (41%; 95% C.I.: [24%, 58%]) KANUMA-treated patients and in only 2 of 30 (7%; 95% C.I.: [0%, 16%]) placebo-treated patients with baseline LDL-c of 130 mg/dL or greater. A statistically significant improvement in percent change from baseline at 20 weeks was also observed in the KANUMA-treated group compared to the placebo group for other parameters related to LAL deficiency, including decreases in non-HDL-c (mean difference and 95% C.I.: -21%, [-30%, -15%]; p<0.0001) and triglycerides (mean difference and 95% C.I.: -14%, [-28%, -1%]; p=0.0375), and increases in HDL-c (mean difference and 95% C.I.: 20%, [12%, 26%]; p<0.0001). The effect of KANUMA on cardiovascular morbidity and mortality has not been established.</paragraph>
<paragraph>Patients treated with KANUMA had larger reductions from baseline in ALT values and liver fat content (measured by MRI), compared to patients treated with placebo. The significance of these findings as they relate to progression of liver disease in LAL deficiency has not been established.</paragraph>
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<paragraph>
<content styleCode="underline">Open Label Treatment</content>
</paragraph>
<paragraph>Pediatric and adult patients who participated in the randomized, placebo-controlled trial were eligible to continue treatment in an open-label extension. Sixty-five of the 66 patients entered the open-label extension and were treated with KANUMA at a dosage of 1 mg/kg once every other week. During the open-label extension, patients treated with KANUMA for up to 36 weeks demonstrated improvements in lipid parameters, including LDL-c and HDL-c levels, and ALT.</paragraph>
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<section>
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<paragraph>
<content styleCode="underline">Continuation Treatment</content>
</paragraph>
<paragraph>Across Study 2 and another study, Study 4, in children and adults with LAL Deficiency, 23 of 97 patients received dose escalations from the protocol-defined starting dose of 1 mg/kg every other week (12 patients in Study 2 and 11 patients in Study 4). The median duration of exposure to the 3 mg/kg every other week regimen was 28 months (range 6 to 33 months) for patients in Study 2 and 12 months (range 3 to 27 months) in Study 4. Before being escalated to 3 mg/kg every other week, patients were on 1 mg/kg every other week for a median of 19 months (range 6 to 33 months), and most dose escalations were initiated in response to an increase in serum transaminase levels, an increase in serum lipids, or a decrease in WFA z-scores in children.</paragraph>
<paragraph>Of the 23 patients whose KANUMA dose was escalated to 3 mg/kg every other week, 20 were children. After the dose escalation, 14 of the 23 patients experienced normalization of one or more of the following biomarkers which had remained abnormally high on the lower KANUMA dose: serum transaminases, triglycerides, and/or LDL-c.</paragraph>
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