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March 20, 2017 no comments

Anti-PCSK9 Drugs: An Ingenious Solution For A Problem That’s Mostly Already Solved

Anti-PCSK9 Drugs


On Friday, for the first time, we saw the full data from the FOURIER clinical trial of Amgen’s cholesterol-lowering antibody, evolocumab (Repatha). Depending on who you listen to, it was either “the most important study in at least 20 years” or a damp squib. So what does FOURIER really tell us? And how will it change management of patients with cardiovascular disease?

First the background:


What is evolocumab?  It is an antibody against an enzyme called PCSK9. Since PCSK9 is a protease that breaks down the LDL receptor, itself the major clearance mechanism for cholesterol from the blood, blocking PCSK9 increases the level of LDL receptor and therefore dramatically reduces circulating cholesterol, and in particular the triglyceride-rich lipoproteins, such as LDL, that are implicated in causing cardiovascular disease.


Anti-PCSK9 antibodies are the jewel in the crown of modern genomic medicine, illustrating what many hope will be a paradigm for future drug discovery. People with naturally occurring mutations in the gene encoding PCSK9 have lower levels of LDL cholesterol and are protected from heart disease, strongly suggesting that an antibody against the PCSK9 protein should have the same beneficial effects–a story that remains the poster child for exploiting human genetics to understand the biology of common diseases (such as heart disease) in the same way it revolutionized the discovery of new treatments for rare diseases a decade earlier.


The first part of the story has already been proven–lots of trials in various groups have demonstrated powerful reductions in LDL cholesterol following treatment with anti-PCSK9 antibodies, with reductions of more than half routinely observed even among patients with stubbornly high cholesterol resistant to other lipid-lowering medications.


This was enough to convince the FDA to approve the drug, albeit with a limited label. But use of these expensive antibodies has been rather limited while clinicians and payers alike waited for proof they actually reduce heart attacks and strokes. FOURIER was designed to answer that question.


What was the design of FOURIER? It was a conventional clinical trial design, in which more than 27,000 people who had previously suffered a heart attack, but who had been unable to achieve optimal LDL cholesterol with dietary advice and existing medications (including statins), were randomized to receive either evolocumab or a placebo regularly for just over two years. The participants were then followed to see who suffered cardiovascular events (which ranged from hospitalization for a worsening of their angina symptoms through to death).


Compared to previous studies in similar populations, such as those used to prove the benefits of the statins, FOURIER was a large study, which gave it lots of statistical power to detect even a relatively small benefit, but it was also rather short, with a median follow-up of only 2.2 years. The short duration was likely driven by commercial considerations, as evolucumab’s owner, Amgen, sought to gain a head start over Regeneron and Sanofi, who have an essentially identical product candidate, called alirocumab (Praluent). But it was also a gamble–the benefit of lipid-lowering agents typically increases with the duration of treatment.


What did FOURIER tell us? As expected, the effect of evolocumab on LDL cholesterol levels was impressive–reducing from over 90mg/dl at baseline to 30mg/dl. To put that into context, a maximal dose of the most potent statin (80mg atorvastatin) reduced LDL cholesterol from a similar baseline to only around 60mg/dl in the PROVE-IT trial. Anti-PCSK9s lower LDL cholesterol to a greater extent than any other therapeutic intervention.


We also already knew that evolocumab lowered cardiovascular events in FOURIER, but until the paper was published in New England Journal of Medicine on Friday, the magnitude of the effect was unknown. We now know that evolocumab reduced cardiovascular events from 11.3% in the group receiving only statins to 9.8% in the group also receiving evolocumab–a 15% reduction in events, which, due to the large size of FOURIER, was highly statistically significant.


So the PCSK9 story is complete–not only do the anti-PCSK9s reduce LDL cholesterol, they reduce cardiovascular events, too.


Both the accompanying NEJM editorial and Amgen itself, as well as many independent observers, trumpeted the importance of this finding. By contrast, the Amgen share price dipped just over 5%, suggesting a degree of disappointment among investors, concerned sales may not be boosted by the FOURIER data as much as they had previously hoped. Why such different takes on the same data?


Several factors, at least superficially, look disappointing. The magnitude of the reduction in cardiovascular events was smaller than had been predicted based on the dramatic reduction in LDL cholesterol levels. If the well-established correlation between LDL cholesterol levels and cardiovascular disease had been maintained down to 30mg/dl LDL cholesterol, the event rate would have been as much as 30% lower.


On top of that, the reduction in cardiovascular events that was seen was not accompanied by any reduction in either cardiovascular mortality or all-cause mortality.


These “negatives” might not have mattered much, given the clear reduction in cardiovascular events, but the price of the drug (at more than $14,000 for a year) throws them into very sharp focus. After all, with such a modest reduction in event rates, more than 70 patients would have to be treated for two years to eliminate one myocardial infarction event (at a cost, therefore, of just under $1 million).


First, the simple conclusions: there’s a stubborn rump of cardiovascular events that don’t result from elevated LDL cholesterol (at least in the short term), and preventing these will need new approaches.  And secondly, anti-PCSK9s may be the most powerful way to lower LDL cholesterol, but their price will restrict their use to patients at very high risk of a cardiovascular event who have exhausted all other, cheaper, strategies for lowering LDL cholesterol.


Now some crystal ball gazing: it is very unlikely that the reduction in cardiovascular events seen with evolocumab will not eventually translate into a mortality benefit. In this regard, context from other studies is helpful. The overall MI rate, even in the placebo group, was much lower than in older studies in similar populations (it was over 50% lower than in the PROVE-IT trial, for example), suggesting that we are getting better at managing patients at risk of MI. In addition, in the large statin trials, such as 4S, mortality benefit took longer to emerge than a reduction in MI rates, suggesting that milder (and hence survivable) MIs are prevented quicker than the larger, potentially fatal, ones. At two years, many trials with statins showed reduction in MI without much effect on mortality, but in longer studies the mortality benefit becomes apparent (and continues to grow with extended usage)–although it is worth noting that in PROVE-IT high-dose atorvastatin already showed a mortality benefit at two years, despite a much smaller reduction in LDL cholesterol than was achieved with evolocumab.


Such an analysis is encouraging for anti-PCSK9s, since there is no reason to doubt that a similar pattern will emerge as with statins. But it must be disconcerting for Amgen investors, since there must now be a very real risk that while equivalent cardiovascular event data for alirocumab will not be available until 2018, it will be for patients with longer exposure. We may very well, therefore, see a mortality benefit for alirocumab that was missed for evolocumab due to the shorter treatment duration. The early bird may have caught the worm, but it may be the tortoise rather than the hare that proves to be the ultimate winner in this multibillion-dollar race.


And what does this mean for other approaches to lowering LDL cholesterol, such as Esperion, who are developing ETC-1002, an inhibitor of ATP citrite lyase (ACL)? Again, it seems to be a double-edged sword. On the one hand, FOURIER proves that lowering LDL cholesterol is associated with reduced cardiovascular events irrespective of the mechanism of lowering (there are now drugs with three different molecular mechanisms that lower LDL cholesterol that have been shown to reduce cardiovascular events). It seems ever more likely, therefore, hat lowering LDL cholesterol with ETC-1002 will have similar benefit.


On the other hand, the relatively modest magnitude of the reduction seen in FOURIER suggests that for agents with quantitatively less impact on LDL cholesterol (ETC-1002 is only about half as powerful as evolocumab at lowering LDL) even larger, longer trials may still lack the power to detect this benefit.


With FOURIER, the PCSK9 story–15years in the making–is complete. We should not focus on the lack of effect on mortality, which almost certainly simply reflects the short duration of the study–although this may yet be very relevant in the fight between evolocumab and alirocumab for supremacy (and the lack of a mortality effect may rightly negatively impact the Amgen share price for this reason). Similarly, the size of the benefit likely reflects how good we have become in managing high-risk patients with existing drugs, rather than a lack of impact of the anti-PCSK9s themselves. Make no mistake, these agents are triumph for genomic science.


Equally clearly, they will not yield the economic returns once hoped for–not because of any disappointment with their therapeutic profile, but because the treatment landscape into which they are being launched is very different from when development started and their cost is unavoidably high due to the frequent, large doses that are required for efficacy. We should see their use expand significantly among high-risk, poorly managed patients, yielding a healthy income for owners of this class of drugs, but fears of statin-like sales bankrupting our healthcare system now look unlikely, only because too few patients are left who can benefit that still need these new miracle drugs.


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