Second time around, something else for PCSK9 class to worry about

The strangest thing about the latest scare to hit the anti-PCSK9 class is that it had in fact first been disclosed three weeks ago; apparently no one had noticed.

If doubts about the acceptability of LDL lowering as a way to anything other than modest sales were not enough, the class now has to contend with a possible risk of neurocognitive adverse events. Still, there is plenty to suggest that this will amount to nothing, though in a jittery market environment Regeneron Pharmaceuticals fell 10% at one point on Friday, before ending the day off 3%.

The company had actually disclosed in a February 13 filing with the SEC that the US FDA had “become aware of neurocognitive events in the PSCK9 inhibitor class”. As a result the agency requested an assessment of such adverse events across the global development programme of alirocumab, the anti-PCSK9 Regeneron is developing with Sanofi.

But it was only on Friday, when Sanofi filed a document with the SEC with virtually the same wording, that the market sat up and took note. The FDA has asked the two companies to assess neurocognitive effects, especially in longer-term studies, and to look at incorporating neurocognitive testing into a subset of patients in a long-term phase III trial like Odyssey Outcomes.

Class effect?

Attention immediately turned to other late-stage developers of PCSK9 inhibitors, and analysts were quick to play down the possible fallout – not entirely without reason.

For instance, Regeneron and Sanofi say they do not know how the FDA became aware of adverse events, implying that this did not come from a trial of alirocumab. They do not know even whether the agency’s concerns were prompted by monotherapy or use of a PCSK9 inhibitor with a statin.

Rare reports of reversible neurocognitive changes have been seen with statin use, for instance, and indeed this is specified on statin labels. If the FDA’s concern resulted from a trial of an anti-PCSK9 and a statin, it would be logical to blame it on the latter part of this combination.

Credit Suisse analysts went further, stating that Regeneron had confirmed that the events seen were not in an alirocumab programme. Those at ISI Group said Amgen, whose anti-PCSK9 evolocumab is neck and neck with Sanofi/Regeneron, had received a similar FDA letter. Pfizer, the third group with a phase III project in this class, has not disclosed such a request in regulatory filings.


Although speculation is premature it is understandable given the current bull market, and the fear is that the FDA is having yet more doubts about this drug class.

The agency does still view LDL reduction as an approvable endpoint, on the strength of which both Amgen and Sanofi/Regeneron plan to file over the next year or so. However, there are growing demands to show that these agents actually reduce heart attacks and strokes, and all three front runners are conducting huge outcomes studies (AHA vantage point – Taking stock in PCSK9 class following new cholesterol guidelines.)

Clinical-stage anti-PCSK9 projects
Status  Project Type Company 2018e sales ($m) NPV ($m) CV outcomes studies Trial ID Enrollment
Phase III evolocumab Monoclonal antibody (MAb) Amgen/Astellas  365 1,699 Fourier NCT01764633 22,500
alirocumab MAb Sanofi/Regeneron 346 3,200 Odyssey Outcomes NCT01663402 18,000
bococizumab MAb Pfizer 67 27 Spire-1
Phase II LY3015014 MAb Eli Lilly - 0 - - -
RG7652 MAb Roche - 0 - - -
Phase I ALN-PCS RNAi therapeutic Alnylam/The Medicines Company - 12 - - -

As such, the truly lucrative indication – hypercholesterolaemia – probably depends on the demonstration of a cardiovascular benefit in outcomes studies, and is thus years away. It is logical for the FDA to be especially risk averse in a broad use, and this is why it might be putting up an additional hurdle in longer-term trials.

Of course, the agency might have even bigger doubts about the class, and it might want to wait for outcome study results to disprove the neurocognitive risk before granting any approval, though for now that looks like the worst-case scenario.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobEPVantage on Twitter

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