6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In clinical trials, a total of 106 patients received treatment with KANUMA. The data described below reflect exposure to KANUMA in 75 patients who received KANUMA at dosages up to 3 mg/kg once weekly in clinical trials:

Nine patients (5 males, 4 females) who had growth failure or other evidence of rapidly progressive LAL deficiency presenting within the first 6 months of life received KANUMA for up to 165 weeks (median 60 weeks) at escalating doses ranging between 0.35 mg/kg and 5 mg/kg once weekly [see Clinical Studies (14.1)].
66 pediatric and adult patients with LAL deficiency aged 4 to 58 years (33 males, 33 females) received KANUMA 1 mg/kg every other week for up to 36 weeks.

Table 2 summarizes the most common adverse reactions occurring in >30% of patients with rapidly progressive LAL deficiency presenting within the first 6 months of life receiving KANUMA in Study 1.

Table 2: Adverse Reactions in ≥30% of Infants with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life Receiving KANUMA
Adverse Reactions	KANUMA N=9
Adverse Reactions	n (%)
Diarrhea	6 (67)
Vomiting	6 (67)
Fever	5 (56)
Rhinitis	5 (56)
Anemia	4 (44)
Cough	3 (33)
Nasopharyngitis	3 (33)
Urticaria	3 (33)

Other less common adverse reactions reported in patients with rapidly progressive disease presenting within the first 6 months of life who received KANUMA included hypotonia, decreased oxygen saturation, retching, sneezing, and tachycardia.

For infant patients within Study 1 and Study 3 (n = 19), the following additional adverse reactions were reported in ≥ 30% of infants who received KANUMA since the time of marketing authorization, including patients who received an escalated dose to 5 mg/kg qw: hypersensitivity, respiratory distress, and tachycardia.

Table 3 summarizes the most common adverse reactions that occurred in ≥8% of pediatric and adult patients with LAL deficiency receiving KANUMA in Study 2.

Table 3: Adverse Reactions in ≥8% of Pediatric and Adult Patients with LAL Deficiency Receiving KANUMA
Adverse Reactions	KANUMA N = 36	Placebo N = 30
Adverse Reactions	n (%)	n (%)
Headache	10 (28)	6 (20)
Fever	9 (25)	7 (23)
Oropharyngeal pain	6 (17)	1 (3)
Nasopharyngitis	4 (11)	3 (10)
Asthenia	3 (8)	1 (3)
Constipation	3 (8)	1 (3)
Nausea	3 (8)	2 (7)

Other less common adverse reactions reported in pediatric and adult patients who received KANUMA included anxiety and chest discomfort.

For pediatric and adult patients (n = 106), the following additional adverse reactions were reported in ≥ 8% of pediatric and adult patients who received KANUMA since the time of marketing authorization, including patients who received an escalated dose to 3 mg/kg qw: hypersensitivity, diarrhea, abdominal pain, and dizziness.

Hyperlipidemia

Increases in circulating LDL-cholesterol (LDL-c) and triglycerides above pre-treatment values were observed in 29 of 36 (81%) and 21 of 36 (58%) patients, respectively, at 2 and 4 weeks following initiation of KANUMA [see Clinical Pharmacology (12.2)]. The maximum mean percentage increase was 18% for LDL-c at Week 2 and 5% for triglycerides at Week 4.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other sebelipase alfa products may be misleading.

Approximately 8% (9/106) of pediatric and adult patients with LAL deficiency developed antibodies to sebelipase alfa (anti-drug antibodies or ADA) following treatment with KANUMA across all clinical studies. Among the 9 patients who developed ADA, 2 patients were positive for neutralizing antibodies (NAb). Approximately 53% (10/19) of infants with rapidly progressive LAL deficiency developed ADA following treatment with KANUMA across all clinical studies. Among the 10 patients who developed ADA, 9 patients were positive for NAb.

Study 1: Patients with Rapidly Progressive LAL Deficiency Presenting within the First 6 Months of Life

Seven of the 9 infants with rapidly progressive disease had at least one post-treatment ADA assessment, and 4 of these 7 (57%) patients developed ADA during treatment with KANUMA. All of the 4 ADA-positive patients were determined to be positive for neutralizing antibodies that inhibit in vitro enzyme activity and/or cellular uptake of the enzyme. At the time of initial ADA positivity, 3 patients were receiving a dosage of 1 mg/kg once weekly and 1 patient was receiving a dosage of 3 mg/kg once weekly. Three of the 4 ADA-positive patients had ADA titers monitored from the initiation of treatment and developed measurable ADA titers within the first 2 months of exposure. Persistent ADA was observed in all 4 patients.

Hypersensitivity reactions occurred in all 4 of the ADA-positive patients, whereas they occurred in only 1 of the 3 ADA-negative patients. None of the patients discontinued treatment. In 1 patient, decreased growth velocity in a setting of neutralizing antibodies to KANUMA was observed.

Study 2: Pediatric and Adult Patients with LAL Deficiency

Five of 35 (14%) KANUMA-treated pediatric and adult patients who completed the 20-week double-blind period of study treatment developed ADA. All patients were receiving 1 mg/kg once every other week. All 5 ADA-positive patients first developed measurable ADA titers within the first 3 months of exposure. Two of the 5 ADA-positive patients had a measurable ADA titer at only one time point. In the 3 patients with measurable ADA titers at multiple time points, ADA titers decreased to undetectable levels during continued treatment. Two patients developed in vitro neutralizing antibodies during the open-label extension phase after 20 weeks and 52 weeks of treatment with KANUMA, respectively. There is no clear association between the development of ADA and decreased efficacy in pediatric and adult patients treated with KANUMA.