AFSTYLA SIDE EFFECTS

SIDE EFFECTS

The most common adverse reactions (>0.5% of subjects) reported in clinical trials were dizziness and hypersensitivity.

Clinical Trials Experience

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

The safety, efficacy and pharmacokinetics of AFSTYLA have been evaluated in 258 previously treated patients (PTPs) with severe hemophilia A (<1% endogenous Factor VIII activity) who received at least one dose of AFSTYLA as part of either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management in two completed clinical trials (an adult/adolescent study [≥12 to 65 years of age] and a pediatric study [<12 years of age]), and an ongoing extension study (0 to ≤65 years of age). Patients with a history of, or current FVIII inhibitors, or any first order family history of FVIII inhibitors, patients with known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein, and patients with evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months prior to Day 1 of the study were excluded from study participation.

Eighty-four (32.6%) subjects were children <12 years of age (35 [13.6%] 0 to <6 years and 49 [19.0%] ≥6 to <12 years), 14 (5.4%) were adolescents (≥12 to <18 years), and 160 (62.0%) were adults (≥18 to ≤65 years). There have been a total of 28,418 exposure days (EDs), with at least 28,492 injections of AFSTYLA administered. In the completed studies, a total of 185 subjects achieved at least 50 EDs, of whom 60 subjects achieved ≥100 EDs.

Adverse reactions (ARs) (summarized in Table 1) were reported for 14 of 258 (5.4%) subjects in all studies. An adverse reaction of hypersensitivity resulted in the withdrawal of one subject. No subject developed neutralizing antibodies (inhibitors) to Factor VIII or antibodies to host cell proteins. No events of anaphylaxis or thrombosis were reported.

Table 1. Adverse Reactions Reported for AFSTYLA (N=258)

Immunogenicity

All subjects were monitored for inhibitory and binding antibodies to AFSTYLA, and binding antibodies to chinese hamster ovary (CHO) host cell proteins prior to the first infusion of AFSTYLA, at defined intervals during the studies and at the end of study visit.

Preliminary data from an ongoing clinical trial in previously untreated patients (PUPs) aged ≤5 years indicate that 12 of 23 treated subjects (52% with a 95% confidence interval of 31%, 73%) developed an inhibitor. Of these, 6 subjects (26%) had peak inhibitor values in the high titer range, and 6 subjects (26%) had peak values in the low titer range. Of the 12 subjects who tested positive for inhibitors, 11 subjects have remained in the trial; 8 experienced successful eradication of the inhibitor; three subjects with high titer inhibitors remain inhibitor positive and have continued treatment with AFSTYLA.

No PTPs developed neutralizing antibodies (inhibitors) to Factor VIII or antibodies against CHO host cell proteins at any time during the completed clinical studies. Four subjects in the adult/adolescent study and 10 subjects in the pediatric study were negative for non-neutralizing anti-drug antibodies (ADAs) at screening and turned positive during the clinical study. Two of the adult/adolescent subjects and 3 of the pediatric subjects who developed ADAs were negative at end of study visit. No adverse events were associated with the development of ADAs. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to AFSTYLA with the incidence of antibodies to other products.

Postmarketing Experience

The following adverse reaction has been identified during post-approval use of AFSTYLA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic systems disorders: Factor VIII inhibitor development