Amgen’s PCSK9 inhibitor Repatha (evolocumab) is facing scrutiny after a reassessment of its FOURIER late-stage trial data revealed that the biologic may be associated with an increased risk of cardiovascular death.
The FOURIER trial laid the foundation for Repatha’s regulatory approval. The reanalysis, published in the BMJ, has identified several inconsistencies between the 2017 NEJM publication of FOURIER’s primary results and a more detailed Clinical Study Report (CSR). In cases of discrepancy between the sources, an independent committee blindly “readjudicated and restored” the cause of death according to the information in the CSR narratives.
- The reanalysis found that the number of deaths of cardiac origin was higher in the evolocumab group than the placebo group (113 vs. 88), although the relative increase in CV mortality was still non-significant (RR 1.20, p=0.13).
- The authors argue that the reanalysis raises the possibility that evolocumab might have specific adverse cardiac effects, a hypothesis “consistent with pharmacovigilance reports” (FAERS, Eudravigilance or VigiAccess databases), but inconsistent with the FOURIER trial finding that evolocumab decreased non-fatal myocardial infarctions.
- Specifically, the CSR contained a higher number of deaths due to myocardial infarction (36 vs. 25) and cardiac failure (31 vs. 16) than the NEJM report.
These findings have caused a stir in the medical community, with reactions ranging from confusion and surprise to others pointing out that the “readjudication and restoration” process may not have been more accurate than the original adjudication process, and did not even yield significant findings. However, authors of the reanalysis point out that the original investigation was terminated early, and had the investigation been carried out over the full 56-month follow-up, evolocumab-related CV mortality may have reached statistical significance.
This new scrutiny emerges while Amgen is in a patent fight over Repatha, arguing to revive patents protecting Repatha and to block the sale of Praluent (alirocumab), a similar PCSK9 inhibitor created by Sanofi.
Discrepancies between CSRs and peer-reviewed publications are actually fairly common, and the particular discrepancies noted in the reanalysis do not dramatically change the takeaways from the original FOURIER publication. That said, this type of scrutiny is never welcome, and at the very least, the study points to the importance of data transparency.