March 18, 2017

Two cheers for genomics

PCSK9 inhibitors are one of the high-profile stories of genomics in medical research.  The gene’s function was previously unknown: it was identified as important for cholesterol metabolism by genetic studies.  People with mutations that increase the activity of the protein have high LDL cholesterol; people with mutations that destroy the activity have low LDL cholesterol. And, importantly, there’s at least one person walking around and alive and healthy with mutations breaking both her copies of the gene, so inhibiting it looked relatively safe.  It was an obvious target for drug development and a showcase for the benefits of large-scale genetic research.

Three drug companies have made injectable antibodies that block the activity of PCSK9 and dramatically lower LDL cholesterol. One dropped out last year because their drug got attacked by the patients’ immune systems.  We’re now seeing the first results of clinical trials looking at whether the LDL cholesterol reduction leads to fewer heart attacks.

From a New Zealand point of view, the results are mostly of theoretical interest. Pharmac isn’t likely to subsidise these treatments for large groups of people any time soon.  However, we do still care what the trials show, because they help answer some questions about cholesterol. The research paper is here; two good commentaries on it are here and here

Amgen’s drug, evolocumab, reduced LDL cholesterol by about two-thirds (from an average of 2.3 mmol/l to 0.78 mmol/l). The combined rate of heart attack, stroke, and death from heart disease was 20% lower; there was only a 15% reduction in the longer shopping list of bad events that the study put its money on for the primary analysis.

So, first, lowering LDL cholesterol by a different mechanism from statins has also resulted in lower heart attack rates.  That reinforces the evidence that LDL cholesterol really matters; it’s not just a marker like smoke from a fire.  Given the largely failed efforts to improve health with drugs that raise HDL cholesterol, this is good to know. Second, lowering LDL cholesterol this way seems fairly safe. There wasn’t any detectable harm (apart from the localised symptoms of the injections themselves). There could be rarer or more subtle effects, of course.

And finally, while the results are qualitatively positive, the actual scale of the benefit is a bit disappointing.  With an average 2.2 years of followup for 13784 people in the treatment group, about 200 heart attacks, strokes, or heart disease deaths were postponed or prevented.  At current US prices of $14,000 per year, that would cost over US$420 million.

So, two cheers for genomics in drug development.


Thomas Lumley (@tslumley) is Professor of Biostatistics at the University of Auckland. His research interests include semiparametric models, survey sampling, statistical computing, foundations of statistics, and whatever methodological problems his medical collaborators come up with. He also blogs at Biased and Inefficient See all posts by Thomas Lumley »