Great Cholesterol Drug Data From Regeneron Pharmaceuticals Inc. and Sanofi SA, but Read the Fine Print

Amgen (NASDAQ: AMGN  ) is leading the race to bring the first anti-PCSK9 cholesterol-lowering drug on the market, having submitted its application for evolocumab to the FDA last week. But Regeneron Pharmaceuticals (NASDAQ: REGN  ) and Sanofi (NYSE: SNY  ) look like they might have the better data set.

The duo might even leapfrog Amgen to get to market first in the U.S.; more on that in a bit.

First, the data
Regeneron Pharmaceuticals and Sanofi presented data from four phase 3 trials testing their PCSK9 antibody, alirocumab, at the European Society of Cardiology Congress 2014 over the weekend.

Source: "Protein PCSK9 PDB 2p4e" by Emw - Own work. Licensed under CC BY-SA 3.0 via Wikimedia Commons.

PCSK9, proprotein convertase subtilisin/kexin type 9, is responsible for breaking down the LDL receptor that removes LDL cholesterol -- that's the bad kind of cholesterol -- from the blood. If PCSK9 is inhibited, the receptor can remove more LDL cholesterol, thus lowering bad cholesterol levels. People with mutations in PCSK9 that inactivate it have abnormally low levels of LDL cholesterol, so it seems reasonable to believe that drugs that inactivate PCSK9 should do the same.

In one trial, dubbed Odyssey Long Term, after 24 weeks, LDL cholesterol was reduced by 61% in patients taking alirocumab, compared to a 1% increase in the placebo group. There was a 57% reduction in LDL cholesterol levels in the alirocumab group after a year, while the placebo group's LDL cholesterol levels rose 4%.

There were half as many major cardiovascular events -- heart attacks, strokes, chest pain so bad that it requires hospitalization -- in patients taking alirocumab as seen in patients taking the placebo. Patients in both the alirocumab and placebo groups were already on statins, which are known to decrease cardiovascular events, so it's exciting that lowering LDL cholesterol using an additional mechanism further decreased the risk of cardiovascular events. Quite a few drugs recently have looked good on laboratory tests but failed to show an effect on cardiovascular events.

But...
Unfortunately, the end point of major cardiovascular events was a post-hoc analysis. Since the measurement wasn't predefined, the FDA isn't likely to accept it as proof that alirocumab decreases heart attacks and other cardiovascular events.

Regeneron Pharmaceuticals and Sanofi are conducting a larger trial, dubbed Odyssey Outcomes, to measure the rate of major cardiovascular events prospectively. While data from the Odyssey Long Term trial are inconclusive, they should give investors confidence that the Odyssey Outcomes study will meet its primary end point of lower cardiovascular events in patients taking alirocumab.

Even more data
In addition to Odyssey Long Term, which was arguably the star of the show given the potential for better cardiovascular outcomes, three additional studies were presented at the European Society of Cardiology Congress 2014.

Alirocumab beat Merck's (NYSE: MRK  ) Zetia in a head-to-head trial comparing the two in combination with statins. Alirocumab lowered LDL cholesterol by 50% for patients on the drug for a year, compared to 21% for patients taking Zetia.

And in two trials testing patients with mutations in a gene that causes abnormally high levels of LDL cholesterol, alirocumab lowered LDL cholesterol by 47% and 50% after a year, compared to an increase of 9% and 8% in the two placebo groups.

Playing leapfrog
Having long-term data and preliminary outcomes data is great, but it won't be as valuable if Amgen beats Regeneron Pharmaceuticals and Sanofi to market, getting first shot at talking to doctors about its PCSK9 inhibitor, which lowers LDL cholesterol by a comparable amount.

To close the gap -- and probably even leapfrog Amgen -- Regeneron Pharmaceuticals and Sanofi purchased a priority review voucher, which shaves four months off the review time of the drug. The duo told investors they're shooting to submit the application to the FDA by the end of the year, which would put their decision from the agency ahead of Amgen's assuming they get it in before Dec. 28.

Tick-tock.

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  • Report this Comment On September 02, 2014, at 12:10 PM, PharmTeam wrote:

    Nice summary, Brian. Unfortunately the whole landscape could be blown up if IMPROVE_IT fails. Seems likely that all bets (both regulatory and marketing) are off if it does fail.

  • Report this Comment On September 02, 2014, at 1:09 PM, TMFBiologyFool wrote:

    @PharmTeam Agreed, it's hard to know what the FDA will do. Amarin precedence would say make them wait, but since Zetia and PCSK9 drugs work through different mechanisms and Improve-It is such a bad trial to begin with (failure doesn't really prove that lowering cholesterol further doesn't help heart), FDA might give PCSK9's a pass.

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