FOURIER Analysis: Evolocumab Delivers Consistent LDL Cholesterol-Lowering

The PCSK9 inhibitor evolocumab seems to robustly reduce LDL cholesterol levels among nearly all treated patients, according to a new analysis of the FOURIER trial. These findings put to bed the notion that many who receive the expensive drug might be nonresponders, the authors say.

Given the finding from the SPIRE trials that many patients treated with the now defunct monoclonal antibody bococizumab developed antibodies to the drug, there has been apprehension that patients might react similarly to treatment with the two US Food and Drug Administration-approved PCSK9 inhibitors evolocumab (Repatha; Amgen) and alirocumab (Praluent; Sanofi/Regeneron).

“The medical community has thought that ‘Okay, maybe we should be giving these drugs to people who really respond to these drugs,’ and because of that there has been concern that maybe there is a lot of variation in terms of how patients respond to these medications,” lead study author Arman Qamar, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD, adding that insurers often require proof of patient response for reauthorization as well.

But looking at data from more than 27,000 individuals from the FOURIER trial, Qamar and colleagues found that 94.7% of the cohort had at least a 50% reduction in LDL cholesterol over 1 year, 97.9% had at least a 30% reduction, and 99.5% saw at least some reduction. Their results were published online last week ahead of print in JAMA Cardiology.

This should reassure both patients and physicians that prescribing evolocumab leads to a “consistent reduction in LDL cholesterol,” Qamar said. Payers should also be confident enough to know that when a physician prescribes evolocumab, “no formal checking for responder status to LDL cholesterol needs to be done,” he added.

‘Confirmatory’ Findings

Commenting on the study for TCTMD, Michael Blaha, MD (Johns Hopkins Medical Institute, Baltimore, MD), said it is “confirmatory to what we all suspected, which is that these drugs—which don't seem to generate neutralizing antibodies, allergic response, et cetera—just provide an incredibly consistent LDL lowering response with very, very few nonresponders.” Although the analysis did not include patients treated with alirocumab, he added that he would “suspect that both PCSK9 inhibitors on the market would look very similar.”

Blaha also agreed with Qamar that payers should not require proof of responder status to reauthorize a prescription based on these findings, calling this practice an “artificial barrier” to approval. “The idea of needing to check it to make sure that they respond at all is kind of ridiculous because so few people don't respond, but I think inevitably you're going to end up checking an LDL anyway to figure out how low they got to make sure they're receiving your nominal goals,” he said.

As for why the 0.5% of patients in FOURIER showed no response to evolocumab, Qamar said there is no known reason and this should be researched further. Poor compliance and inaccurate drug administration might be to blame, but there could also be some patients in whom the PCSK9 inhibitor clears too quickly, he suggested.

“Even though [nonresponse is] exceedingly rare, it's extremely interesting,” Blaha said, adding that from a biology standpoint, investigating this mechanism might unearth some new facet of PCSK9 inhibition that is not yet known.

Going forward, Qamar said he would like to see a similar analysis done for alirocumab “so that the same reassurance could be there both for patients, physicians, and payers.” Also, he called for studies examining “how to maximize LDL cholesterol-lowering with PCSK9 inhibitors” by increasing compliance and potentially making tweaks to patient education materials about drug delivery.