Prompt Agalsidase Alfa Therapy Initiation is Associated with Improved Renal and Cardiovascular Outcomes in a Fabry Outcome Survey Analysis

Abstract

Background

The timing of enzyme replacement therapy initiation in patients with Fabry disease is hypothesized to be critical. In this study, we used Fabry Outcome Survey data to assess the impact of prompt versus delayed initiation of treatment with agalsidase alfa on cardiovascular and renal events in patients with Fabry disease.

Methods

Available genetic data at baseline were used to define patients with mutations associated with classical versus late-onset Fabry disease. Time to cardiovascular or renal events, from treatment initiation until 120 months, was compared for patients in prompt versus delayed groups. “Prompt” was defined as treatment initiation <24 months from symptom onset (analysis A) or diagnosis (analysis B), and “delayed” was defined as ≥24 months from symptom onset (analysis A) or diagnosis (analysis B). Kaplan–Meier curves and Log rank tests compared event-free probabilities and time to first event. Multivariate Cox regression estimated hazard ratios (HRs).

Results

Analysis by time from symptom onset included 1374 patients (172 prompt, 1202 delayed). In a multivariate Cox regression analysis, prompt versus delayed treatment initiation significantly reduced the probability of cardiovascular (HR=0.62; P<0.001) and renal (HR=0.57; P=0.001) events. History of cardiovascular or renal events was associated with increased risk of respective events. Analysis by time from diagnosis included 2051 patients (1006 prompt, 1045 delayed). In a multivariate Cox regression analysis, prompt treatment initiation significantly reduced the probability of cardiovascular events (HR=0.83; P=0.003) after adjusting for history of cardiovascular events, sex, and age at treatment initiation. Univariate analysis showed that the probability of renal events was significantly lower in the prompt group (P=0.018); this finding was attenuated in the multivariate Cox regression analysis.

Conclusion

This analysis suggests that prompt treatment initiation with agalsidase alfa provided better renal and cardiovascular outcomes than delayed treatment in patients with Fabry disease.

Keywords:

• cardiomyopathies
• nephrology
• mutation
• therapeutics
• early diagnosis

Acknowledgments

Jaco Botha, employee of Takeda Pharmaceuticals International AG, provided additional statistical support. Under the direction of the authors, Latoya M. Mitchell, PhD, CMPP, employee of Excel Medical Affairs, provided writing assistance for this article. Editorial assistance in formatting, proofreading, copy editing, fact-checking, and preparation of the manuscript for submission was provided by Excel Medical Affairs. Takeda Development Center Americas, Inc., provided funding to Excel Medical Affairs for support in writing and editing this article and participated in data collection and analysis. Portions of these data were previously presented at the 16th Annual WORLDSymposium 2020, February 10–13, 2020, Orlando, FL, USA; the 13th Annual WORLDSymposium 2017, February 13–17, 2017, San Diego, CA, USA; the European Society of Cardiology (ESC) Annual Congress, August 26–30, 2017, Barcelona, Spain; and the Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, September 6–9, 2016, Rome, Italy.

Abbreviations

CI, confidence interval; eGFR, estimated glomerular filtration rate; ERT, enzyme replacement therapy; FOS, Fabry Outcome Survey; HR, hazard ratio; ICF, informed consent form; LVH, left ventricular hypertrophy; LVM, left ventricular mass; LVMI, left ventricular mass index.

Data Sharing Statement

The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participant data supporting the results reported in this article, will be made available within three months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its de-identification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.

Ethics Approval and Informed Consent

FOS was approved by the ethics institutional review boards of the participating centers. Further, this registry was compliant with relevant global and local regulations and best practices: Good Pharmacoepidemiological Practice and Good Research for Comparative Effectiveness principles. The relevant principles of the International Council for Harmonisation Good Clinical Practice (ICH GCP) guidelines (ICH E6) were followed as appropriate for an observational registry, consistent with the Declaration of Helsinki. All participants gave written informed consent.

Patient Consent for Publication

Patient consent for publication was not required.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Disclosure

DH reports personal fees from Takeda, Sanofi Genzyme, Amicus Therapeutics, Idorsia, Protalix Biotherapeutics, and Freeline Therapeutics, outside the submitted work. AL reports personal fees from Amicus Therapeutics, Avrobio, Sanofi Genzyme, and Takeda, outside the submitted work. AG and VK were employees of Takeda at the time of the study. DJ is an employee of Takeda and is a stockholder of Takeda Pharmaceuticals Company Limited. SF reports personal fees from Takeda, Sanofi Genzyme, and Amicus Therapeutics, outside the submitted work. The authors report no other conflicts of interest in this work.

Additional information

Funding

The Fabry Outcome Survey (FOS) is funded by Shire Human Genetic Therapies, a Takeda Company.