Did the gene-drug revolution just arrive?

Did the genomic revolution arrive last week, or was that just the snowstorm?

The answer depends on whom you listened to and what they thought of a study published on March 17 that showed a gene-based drug called Repatha reduced cardiovascular risk by 15%. Some called the study a triumph because it showed a drug developed through gene discovery could directly control a faulty gene’s output to therapeutic effect.

Others offered that the 15% reduction of cardiovascular risk was rather modest, being lower than the 20–25% predicted and not impressive next to existing drugs; opined that the drug is “an ingenious solution for a problem that’s mostly already solved; and noted that the the death rate itself didn’t change.”

It’s messy. My own quick take is that it’s a bit early to say Repatha settles the growing debate over whether we’re placing outsized bets on gene-based drug development. I’ve too many other commitments at present to get into this in any detail. Fortunately, Derek Lowe did get into it, three times. Amid the gush about the study’s results, his multiple examinations of this question remind us of how fraught and difficult these questions are.

Here are three snips from three his posts. I highly recommend reading all three in toto.

His quick first take, on March 17

This morning we have three-year data from Amgen and their drug Repatha (evolocumab), an announcement that has been eagerly awaited. And it’s honestly not all that impressive. There’s a 15% relative reduction in cardiovascular risk (heart attack, stroke, etc.) relative to placebo, but investors were looking for something more over 20%. Insurance companies were probably looking for that, too, and given the price they’d have been happier to see something more like 25%. Amgen is defending the data (as quotes in this Adam Feuerstein piece show), but I don’t think that’s going to do the job. The numbers shouldn’t have to be interpreted and spun; in a three-year study with over 13,000 patients in each arm, the numbers should be able to speak for themselves, and they don’t.

His March 20 post provides a thorough explanation — and then some perspective-taking:

The Amgen study, while successful, was not all that compelling. Yes, the relative risk for the composite cardiovascular endpoints used in the study went down, but not by as much as observers were hoping for (15% reduction versus 20 or 25%). And when you get down to overall mortality, there was no change at all, which has to be a disappointment. Amgen has been arguing that this was a relatively short study, and that the first measurements were also taken at a relatively early point in the treatment, and that the overall trend is for better numbers as the treatment goes on (which may well continue). But while these points may be valid, it’s a little rich for Amgen to be making them, because they designed this trial themselves, presumably to generate the most compelling results in the shortest amount of time. The fact that they’re having to make such arguments at all is a sign that the trial definitely did not come out the way that they’d hoped – you can be sure that the plan was not to have to say “Well, gosh, it’s really not bad if you look closely”.


What does this tell us, then, about genomics-based drug discovery? PCSK9 is about as compelling a story as we’re likely to see in this space, and if it has indeed come up a bit short, that’s food for thought. To be fair to Amgen, they may well be right about the continued improvements over longer-term therapy, in which case this story may have a better ending. But the slam-dunk game-winning ending is already gone. That may be the main lesson we can draw for now – here’s a terrific case, and it still didn’t blow everyone away when it finally got to multiyear human therapy. Everyone who’s following genetic-based clues to human therapy (a big crowd indeed) should keep this in mind.

In that second, longest post, he gives a hat-tip to the observer who called the study a triumph, saying that “PCSK9 is indeed the real thing, and just what people were expecting” back around 2000 when we sequenced the genome and thought it’d cure everything. It’s a conciliatory post. And yet…

So there’s a case to be made that this target really is the dawn of the era that we all thought was dawning years ago. I can appreciate the celebratory tone of Plenge’s post, but at the same time, if you’d told people back in 1999 how things had worked out, they would likely have been (at some level) horrified that (a) it took until the mid–2010s for something like this to happen and (b) that this is the main example that we can point to, and that the landscape is not littered with similar stories. That brave new world is not the one we live in, though, and for the one we’re in, this is a good result and we should make the most of it.