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Occurrence of anaphylaxis in adult incident pegvaliase-treated PKU patients in a post-marketing safety analysis in the United States

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:
Pegvaliase is a blood Phe-lowering enzyme substitution therapy approved for adults with PKU and Phe >600 μmol/L. As a bacterially-derived enzyme pegvaliase elicits an immune response. Immune-mediated adverse drug reactions including anaphylaxis were observed in clinical trials, but the real-world risk following post-marketing approval in the United States (US) is unknown.



 

Methods:
A retrospective observational cohort analysis of patients with PKU treated with pegvaliase between 24 May 2018 (FDA approval) and 31 December 2022 was conducted to estimate the incidence rate of anaphylaxis in the US using record-linkage of BioMarin’s Risk Evaluation and Mitigation Strategy (REMS), safety, and drug dispensing databases. All patients who are prescribed pegvaliase in the US are required to enroll in the REMS program.



 

Results:
As of 31 December 2022, 1986 patients have enrolled in the REMS program, and 1772 (89.2%) had at least one record of drug dispensed and were eligible for analysis. Of these pegvaliase-treated patients, 1579 (89.1%) were incident users (i.e., treatment naïve) and 193 were prevalent users (i.e., patients who switched from treatment in clinical trial to commercial drug treatment). Herein, results are reported for incident users. Among the 1579 incident users, 48.1% were female and the median age was 28 years. There were 89 patients (5.6%) who were <18 years. The total pegvaliase exposure was 2764.2 person-years; and the median exposure was 1.6 years. The crude incidence proportion of anaphylaxis was 12% (189/1579). The exposure-adjusted incidence rate of anaphylaxis was 5.5 (95% CI: 4.7-6.5) per 100 person-years; and the exposure-adjusted event rate (EAER) was 6.0 (95% CI: 5.1-7.0) per 100 person-years. To assess treatment management following the first anaphylaxis event (n=145 with known event date), the average daily dose for the prescription during the event was compared to the average daily dose in the subsequent prescription. The most common response following an anaphylactic event was to discontinue treatment (56.6%=82/145), but many remained on therapy; specifically, 24.8% remained on a stable dose, 12.4% received a lower dose, and 6.2% received a higher dose. Of the 82 incident users who discontinued treatment after experiencing an anaphylaxis event, 37.8% re-initiated treatment within 46 days following the end of the last prescription prescribed at time of the event.  

 

Conclusion:
In this real-world analysis of incident pegvaliase patients, the EAER for anaphylaxis was consistent with that observed in the 285 participants who received the I/T/M (induction/titration/maintenance) regimen in the pegvaliase clinical trial, at 6.0 vs. 5.29 events per 100 person-years, respectively. Although the most common clinical response immediately following an anaphylactic event was to discontinue treatment, one-third of these patients resumed treatment within 1.5 months, demonstrating that the majority of incident users persist with pegvaliase treatment despite experiencing an anaphylactic event.

 

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