Summary of the safety profile The majority of the related adverse events in the clinical trials were classified as infusion-associated reactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years) and 35% of the patients in the under 5 study (up to 1 year of treatment).
Some of the IARs were severe. Over time the number of these reactions decreased. The most frequent adverse drug reactions (ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity, flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased, tachycardia and chills.
Post-marketing experience of infusion-associated reactions revealed reporting of cyanosis, hypoxia, tachypnoea, pyrexia, vomiting, chills and erythema, in which some of these reactions were severe. Tabulated list of adverse reactions ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age 5 years and older and treated up to 4 years are listed below using the following categories of frequency: 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).
Due to the small patient population, an ADR reported in a single patient is classified as common. 7 MedDRA System Organ Class Very common Common Not known Immune system disorders Anaphylactic reaction Hypersensitivity Psychiatric disorders Restlessness Nervous system disorders Headache Paraesthesia, dizziness Cardiac disorders Tachycardia Bradycardia Vascular disorders Flushing Hypotension, pallor, peripheral coldness Hypertension Respiratory, thoracic and mediastinal disorders Respiratory distress, dyspnoea, cough Cyanosis, hypoxia, tachypnoea, bronchospasm, respiratory arrest, laryngeal oedema, respiratory failure, pharyngeal swelling, stridor, obstructive airways disorder Gastrointestinal disorders Nausea, abdominal pain Vomiting, diarrhoea Lip swelling, swollen tongue Skin and subcutaneous tissue disorders Rash Angioedema, swelling face, urticaria, pruritus, cold sweat, alopecia, hyperhidrosis Erythema, facial edema, Musculoskeletal and connective tissue disorders Arthropathy, arthralgia, back pain, pain in extremity Musculoskeletal pain General disorders and administration site conditions Pyrexia, infusion site reaction* Chills, feeling hot, feeling cold, fatigue, influenza like illness, injection site pain Extravasation, oedema peripheral Investigations Body temperature increased, oxygen saturation decreased Drug specific antibody, neutralizing antibodies, blood pressure increased * During clinical trials and post-marketing experience, infusion/injection site reactions notably included: swelling, erythema, oedema, discomfort, urticaria, pallor, macule, and warmth.
A single patient with pre-existing airway compromise developed a severe reaction three hours from the start of the infusion (at week 62 of treatment) consisting of urticaria and airway obstruction, requiring tracheostomy. This patient tested positive for IgE.
4). Paediatric population ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of age and mainly of the severe phenotype, treated up to 12 months are listed below. ADRs were all mild to moderate in severity.
8 MedDRA System Organ Class MedDRA Preferred term Frequency Cardiac disorders tachycardia Very common General disorders and administration site conditions pyrexia Very common chills Very common Investigations blood pressure increased Very common oxygen saturation decreased Very common In a phase 4 study 33 MPS I patients received 1 of 4 dose regimens: 100 U/kg IV every week (recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks or 300 U/kg IV every 2 weeks.
The recommended dose group had the fewest number of patients who experienced ADRs and IARs. The type of IARs was similar to those seen in other clinical studies. Description of selected adverse reactions Immunogenicity Almost all patients developed IgG antibodies to laronidase.
Most patients seroconverted within 3 months of initiation of treatment; although seroconversion in patients under 5 years old with a more severe phenotype occurred mostly within 1 month (mean 26 days versus 45 days in patients 5 years and older).
By the end of the Phase 3 study (or at time of early study withdrawal), 13/45 patients had no detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had never seroconverted. Patients with absent to low antibody levels showed a robust reduction in urinary GAG level, whereas patients with high antibody titres showed variable reduction in urinary GAG.
In addition, higher ADA titres were also observed in MPS I Registry patients with severe disease. Patients with persistently high ADA titres tended to have less reduction in urinary GAG. In the Phase 2 and 3 studies, 60 patients were tested for in-vitro neutralising effects.
Four patients (three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitro inhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/or urinary GAG reduction.
In patients with clinical decline, assessing urinary GAGs, ADA and neutralising antibodies should be considered. The presence of antibodies was not consistently related to the incidence of IARs, although the onset of IARs typically coincided with the formation of IgG antibodies.
Clinical trials and observational studies show only a small number of patients have tested positive for IgE antibodies. The development of IgE antibodies may be associated with hypersensitivity or anaphylactic […]