Xenpozyme Adverse Reactions

Summary of the safety profile: Serious adverse reactions reported in patients treated with Xenpozyme were an event of extrasystoles in the context of a history of cardiomyopathy in 1 (2.5%) adult patient, and anaphylactic reaction, urticaria, rash, hypersensitivity, and alanine aminotransferase level increase, each in 1 (5%) paediatric patient. The incidence of serious hypersensitivity-related IARs were higher in paediatric patients compared to adults. One adult patient discontinued due to recurrent adverse events of rash.
The most frequently reported adverse drug reactions (ADRs) were headache (31.7%), urticaria (26.7%), pyrexia (25%), nausea (20%), abdominal pain (16.7%), vomiting (16.7%), pruritus (13.3%), myalgia (13.3%), rash (11.7%), abdominal pain upper (10%), erythema (10%), and C-reactive protein increased (11.7%).
Tabulated list of adverse reactions: The pooled safety analysis from 4 clinical studies (a tolerability study in adult patients, ASCEND, ASCEND-Peds, and an extension study in adult and paediatric patients) included a total of 60 patients (40 adult and 20 paediatric patients) treated with Xenpozyme at doses up to 3 mg/kg every 2 weeks.
Adverse reactions reported in the pooled safety analysis of clinical studies are listed in Table 12 per System Organ Class, presented by frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to <1/100), rare (≥1/10 000 to <1/1 000), very rare (<1/10 000) and not known (cannot be estimated from the available data). (See Table 12.)

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Description of selected adverse reactions: Infusion-associated reactions (IARs), including hypersensitivity/anaphylactic reactions: IARs were reported in 57.5% of adult and 65% of paediatric patients. IAR symptoms reported most frequently in adult patients were headache (25%), nausea (17.5%), urticaria (17.5%), myalgia (12.5%), arthralgia (10%), pyrexia (10%), pruritus (10%), vomiting (7.5%), abdominal pain (7.5%), erythema (7.5%) and fatigue (7.5%). IAR symptoms reported most frequently in paediatric patients were pyrexia (40%), urticaria (40%), vomiting (30%), C-reactive protein increased (20%), headache (20%), nausea (20%), erythema (15%), rash (15%), serum ferritin increased (15%), abdominal pain (10%), and pruritus (10%). IARs typically occurred between the time of infusion and 24 hours after infusion end.
Hypersensitivity-related IARs, including anaphylaxis, occurred in 30% patients, 22.5% adult and 45% paediatric patients in clinical studies. The most frequently reported hypersensitivity-related IAR symptoms were urticaria (25%), pruritus (10%), erythema (10%), and rash (8.3%).
One paediatric patient in the clinical studies incurred a severe anaphylactic reaction. Also, independent of the clinical study program, a 16-month-old patient with ASMD type A treated with Xenpozyme experienced 2 anaphylactic reactions. Anti-olipudase alfa IgE antibodies were detected in both patients.
In 2 adults and 3 paediatric patients, IAR symptoms were associated with changes in laboratory parameters (e.g C-reactive protein, ferritin value) indicative of acute phase reaction.
Transaminase elevations: Transient transaminase (ALT or AST) elevations within 24 to 48 hours after an infusion occurred in some patients treated with Xenpozyme during the dose escalation phase in the clinical studies. These elevations generally returned to the previous pre-infusion transaminase levels by the next scheduled infusion.
Overall, after 52 weeks of treatment with Xenpozyme, mean ALT decreased 46.9% and mean AST decreased 40.2%, compared to baseline. In adult patients, all 16 patients with an elevated baseline ALT had an ALT within the normal range and 10 of 12 patients with an elevated baseline AST had an AST within the normal range.
Immunogenicity: Overall, 19 out of 40 (47.5%) adult patients and 15 out of 20 (75%) paediatric patients treated with Xenpozyme developed treatment-emergent anti-drug antibodies (ADA). The median time to seroconversion from first Xenpozyme infusion was approximately 52 weeks in adults and 12 weeks in paediatric patients. The majority of ADA-positive patients ( 16 out of 19 adult and 10 out of 15 paediatric patients) had a low ADA response (peak titer ≤400) or reverted to ADA-negative. Three adult ADA-positive patients and 4 paediatric ADA-positive patients developed intermediate ADA responses (peak titer ranged 800-6400). Eight out of the 19 adult ADA-positive patients and 9 out of the 15 paediatric ADA-positive patients had Neutralizing Antibodies (NAb) that inhibited the olipudase alfa activity. Only 2 adult patients and 3 paediatric patients had NAb at more than one timepoint. One paediatric patient experienced an anaphylactic reaction and developed IgE ADA, and IgG ADA with a peak titer of 1600.
No effect of ADA was observed on pharmacokinetics and efficacy of Xenpozyme in adult and paediatric populations. There was a higher percentage of patients with treatment-emergent IARs (including hypersensitivity reactions) in patients who developed treatment-emergent ADA versus those who did not (70.6% versus 46.2%).
Paediatric population: Except for a higher incidence of hypersensitivity-related IARs in paediatric patients compared to adults, the safety profile of Xenpozyme in paediatric and adult patients was similar.
Long-term use: The median exposure duration was 4.95 years (range: 0.4 to 9.6 years) in adult patients and 6.15 years (range: 4.3 to 8.2 years) in paediatric patients. Overall, the pattern of adverse events observed in adult and paediatric patients in longer term use was consistent with that observed during the first year of treatment.