UPDATED: Regeneron, Sanofi and Amgen shares suffer on FDA's frets about PCSK9 class

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Some of the leaders in the frenzied late-stage race to develop a PCSK9 drug watched their stock prices stumble on Friday afternoon as word of the FDA's concern about potential neurocognitive side effects in the cholesterol drug class spread like wildfire through Twitter.

Shares of Regeneron ($REGN) dropped 10% Friday afternoon, its partner Sanofi ($SNY) was off more than 1% and Amgen ($AMGN) was down more than 2% on the news, which wiped out billions of dollars in market capitalization as investors reacted nervously to the warning. But there were signs of a quick pullback on a second look, with losses softening later in the day for Regeneron. 

Sanofi got the wrecking ball swinging as it reported the FDA's position in a regulatory filing, which reiterated a note in an earlier filing from Regeneron which had evidently been overlooked. Under a detailed account of its pipeline activity, Sanofi reported:

"Sanofi and Regeneron have been advised by the FDA that it has become aware of neurocognitive adverse events in the PCSK9 inhibitor class. Neurocognitive adverse events have also been associated with the use of statins for lowering LDL cholesterol. Neither company knows the circumstances under which the FDA became aware of these adverse events or whether these adverse events were observed with a drug candidate tested as monotherapy or in combination with a statin or other cholesterol-lowering agent. The FDA has requested that Sanofi and Regeneron make an assessment of potential neurocognitive adverse events across the global development program for alirocumab, especially in the longer-term studies. Additionally, the FDA requested to be informed about the feasibility of incorporating neurocognitive testing into at least a subset of patients in the ODYSSEY OUTCOMES trial or other long-term Phase III trial(s). While neither company is aware of any neurocognitive adverse event signal relating to alirocumab, if this or another adverse event signal is detected, the further development of alirocumab may be delayed or fail, or its commercial value diminished, which could severely harm future prospects."

Analysts have been cheering on huge late-stage efforts aimed at gaining a pioneering approval for a PCSK9 drug. Amgen has posted 5 successful Phase III studies for evolocumab (AMG145) so far, with 8 more to come as Regeneron and Sanofi combined their attention on a 12-study effort of their own for alirocumab. And Pfizer is planning to spend big on a 22,000-patient outcomes program to demonstrate the long-term benefits of its drug bococizumab (RN-316).

ISI's Mark Schoenebaum says that his contacts at Amgen suggest the company got the same warning letter that Sanofi and Regeneron referred to. But they don't sound concerned.

"We spoke with AMGN this afternoon and appears that the company received a similar letter as Sanofi/Regeneron although we don't know exactly what was written in AMGN's letter," Schoenebaum says. "AMGN reports not seeing neurocognitive issues in its program and expects to present phase 3 data in ~4K subjects at ACC at the end of March. AMGN also reports that the company has been proactively looking at neurocognitive changes due to the question with statins and notes that no such changes were noted in its phase 2 long-term open label study OSLER that was presented late last year. AMGN is also not expecting a delay in its program from what it has previously said, filing in 2014."

Amgen confirmed that in a statement sent to FierceBiotech Friday afternoon.

"Similar to other companies developing PCSK9 inhibitors, Amgen has been in communication with the FDA, and we will continue to investigate the potential for cognitive impairment in our program," the company stated in an e-mail. "As previously reported in our 52 week OSLER study, amnesia and memory/mental impairment were reported uncommonly (in less than or equal to 1% of patients in any group). As such, we have not seen any such signal so far, and we will continue to monitor for these events carefully."

Cholesterol drugs have long been one of the holy grails of drug R&D, with top companies willing to invest hundreds of millions of dollars on late-stage efforts that required huge numbers of patients to satisfy regulators leery over the potential risks posed by drugs that would be marketed to a mass audience. But so far, for all the many studies already completed, this is the first sign that the class could potentially face a serious safety hurdle like this. 

According to the FDA's consumer site, regulators have been studying the neurocognitive side effects of statins for years, noting rare cases of memory loss and "fuzzy" thinking. Those effects, though, are easily reversed when the patients stop taking their drugs, making it fairly simple to deal with.

Whatever the long-term impact of the FDA's concerns prove to be, the event marks the growing importance of Twitter in spreading business news with lightning speed across large global networks.

- here's the regulatory filing

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