Isis CEO Vows that Cholesterol Drug, Partnered With Genzyme, Will be “Remarkable” Advance

10/21/09Follow @xconomy

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human who has been tested. It works consistently across multiple measurements of heart disease, like total cholesterol, and LDL. The higher the dose goes, the lower the apoB protein level goes. The drug works in patients who are new to treatment, and provides a consistent 35 to 40 percent reduction for patients who are taking the maximum tolerated dose of statins, he says.

“I’ve never seen a drug do that,” Crooke says.

Sounds simple enough, but the development path for this drug is especially tricky. The companies hope to begin marketing this drug, in classic Genzyme style, as a treatment for a rare genetic disorder in need of a life-saving therapy. That will surely come at a high price. But the companies also plan to introduce the product in a larger population of patients with a more common genetic disorder that puts them at very high cholesterol and associated heart risks, as well as a broader population of people who just have high cholesterol that’s not thoroughly controlled by maximum statin doses.

With an eye toward eventual broader market usage, Isis and Genzyme decided to go with what Crooke called a “middle-of-the-road” dose of 200 milligrams once a week. The companies figured that dosage offered the best overall balance of effectiveness and safety, although it also meant the odds are higher that they might see less-than-stellar effectiveness in the initial group of super-tough-to-treat patients, Crooke says. “This is the study I was most worried about heading in,” he says.

He wouldn’t spill the beans about what the data really is going to say at the American Heart Association, but he suggested that the LDL reduction scores will look better when researchers look only at patients who completed the protocol. Six dropouts who are penalizing your trial normally doesn’t sound like much, but it does add up when the trial only has 51 patients to begin with.

When I asked why those patients dropped out, Crooke was clearly annoyed, saying, “there is some fatalism” among the patients with this rare disorder that causes high cholesterol. It also can be hard to stay motivated to stick with a trial that required visiting the doctor once a week for 26 weeks for blood draws, and new drug dosing. Sometimes patients had to travel long distances, Crooke says.

One patient on mipomersen dropped out after elevated liver enzymes were seen in the blood, which can be a sign of liver damage, a side effect that the FDA will surely watch out for. There also was some more variation from patient to patient in this study than was seen in earlier studies, Crooke says. But none of that outweighs the positive result in his mind, which will be presented to the world in less than a month. “When we show the data, people will be as thrilled as we are,” Crooke says.

Even beyond that, Crooke vowed that mipomersen will be the drug that, once and for all, he says, will lay to rest skepticism toward antisense technology.

“First there’s wild enthusiasm about a new technology, then comes the disappointment, cynicism, and slow, grudging acceptance,” Crooke says. “Then you start to hear people say ‘it was my idea to begin with.’ “

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  • adam feuerstein

    Luke — Crooke was “annoyed” when you asked him about the patients who dropped out of his study? Who cares about ITT results, right? I mean, let’s just get rid of all the patients who don’t respond or who have side effects so severe that they need to stop taking the drug. Brush those “annoying” patients under the rug.

    Were you able to keep a straight face when he threw this blather out there?

  • http://www.xconomy.com/author/ltimmerman/ Luke Timmerman

    Adam–He wasn’t trying to downplay the intent-to-treat analysis, that would be disingenuous. But in a trial with such small numbers, six dropouts can make a difference between an ITT and a completer analysis. I think he was annoyed at the patients themselves, or maybe his own company, for not being able to keep them on the protocol. That point wasn’t totally clear to me, but I thought it was worth noting that the six dropouts are a sore point when looking at this study result, and something worth focusing on at the American Heart Association.

  • http://mediabankers.com Roland DeSilva

    Luke,
    I have been following this company for 7yrs and its process is amazing, which is why Genzyme invested. The FDA is making the company jump thru hoops, because if effect they are now completing a 4th stage testing, all of which has and will prove out.
    Adam sounds like a short seller who is trying to make his position. Full disclosure..I am long on the stock.

  • adam feuerstein

    stanley crooke — disingenous? Never!

    Why won’t there be a large (or larger) number of dropouts in a large (or larger) trial?

    mipo will be fortunate to be approved in the homozygous patients. It’s the best and only shot this drug has, given the tiny patient population and severity of disease. I think approval in heterozygous patients or statin-intolerants/refractory is a pipe dream.

  • http://mediabankers.com Roland DeSilva

    Adam,
    You sound like a short to me or have some other agenda. You are seriously uniformed. I

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  • http://IV theodore bash

    I question AF’s ability to understand the science and the importance of this drug for a selected population that GENZ and ISIS think will be bigger than just for HoF. I’ve put my money on GENZ/ISIS, not on the person who miscalled so many other binary events. A posting of AF’s record would increase his creditiblity. t

  • Art

    Adam, the 25% reduction included the 6 dropouts so the reduction in ldl-c was actually > 30%. Some of these people live in Africa and probably don’t have use of a car. For a guy that has a paid column you sound very unprofessional, like someone with an ax to grind when it comes to Crooke. In fact you remind me of the nut case who goes by the name of darkout on Yahoo.

  • bogtalk

    Art-
    I have seen Feuerstein the columnist you refer to as a featured speaker. He was very professional and knowledgeable, not at all like the Feuerstein who is posting above. And why would a busy professional be spending his time posting on an obscure venue like this one?
    As for sounding like Dark, I think Dark was a little more sopisticated than this guy. jmo.
    Bogtalk

  • noonne

    Looks like that Mipomersen drug does exactly the same as Eprotirome, a drug in developing by the Swedish company Karo Bio.
    http://www.karobio.se/en/Research–Development/Our-RD-Portfolio2/KB2115/

  • minifesto

    Love your answer to Feuerstein or sosie. I am long on ISIS and plan to speak with Stan the man. So your interview was useful.

    Been investing for 50 years and 15 years in biotechs.

    Like ALNY ATHX CALP LGND MYRX OSIR ZGEN. Very interested in ATHM but do they have enough cash. Will speak to Tim after vacation.

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