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.’ “
