Tag Archives: PCSK9

PCSK9: The canine that escalates Your LDL

Yes. PCSK9 is a factor in escalating LDL cholesterol levels. The point was brought home as I rode the escalator up from the first to the top pcsk9floor of the San Diego Convention Center at this year’s American College of Cardiology meetings. I suspsect if I had taken an elevator I would have seen a sign proclaming that PCSK9 is a factor in elevating cholesterol levels.
And PCSK9 signage is everywhere in this meeting.

 

 

Proprotein convertase subtilisin/kexin type 9, also known as PCSK9, is an enzyme that appears to degrade LDL receptors.

If you are born with a mutation that produces less active PCSK9 you have more LDL receptors and consequently more LDL is taken out of circulation leading to lower LDL levels.

Mutations leading to gain of PCSK9 function result in lower LDL receptors, higher LDL levels and substantial clinical evidence for premature atherosclerosis.

Amgen has produced all the PCSK9 signs that abound at the ACC meetings because they have produced a fully humanized monoclonal antibody (utilizing Chinese hamster ovaries) that inhibits PCSK9 and does a great job of lowering LDL without significant adverse effects.

At a late-breaking clinical trial session, results of longer term follow up of the company’s Osler randomized trials were presented and simultaneously published here.

The results were remarkably good. Not only did evolocumab drop LDL by 61% (from 120 down to 48) it showed significant improvement in cardiovascular outcomes.

“The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003).”

According to the biotech website fiercebiotech:

“The antibody is expected to win FDA approval by Aug. 27, trailing Sanofi ($SNY) and Regeneron’s ($REGN) alirocumab, which, thanks to some regulatory opportunism, is likely to hit the market a month or so before. Pfizer ($PFE) is in third place, working through Phase III with its bococizumab. Analysts say each treatment could bring in more than $3 billion a year at its peak…”

More study is needed of these drugs before approval in my opinion for a number of reasons. There is evidence of a small, but significant increase in neurocognitive side effects for one.

Although with evolocumab these were not related to the level of LDL achieved, there are concerns that extremely low LDL levels may interfere with neural development and such effects may not manifest for years.

The study authors did a good job of pointing out other limitations including small number of events, open-label design and patients selected who were free of adverse events. Hopefully, the FOURIER study will resolve these issues.

This post was also posted at SERMO, the physician social network. I would encourage physicians to join in the robust discussions on medicine and other topics at this site.

Skeptically Yours,

ACP