Isis Pharmaceuticals CEO Stanley Crooke is a man who knows how to make a grand gesture. The market may have been underwhelmed by what Isis and its partner, Genzyme, had to say about their first-of-a-kind cholesterol-lowering drug back in May, but to him that just means they’re missing the point.
When I stopped by to visit Crooke at the company’s (NASDAQ: [[ticker:ISIS]]) Carlsbad, CA, headquarters a few weeks ago to ask about his lead drug in development, mipomersen, he didn’t just offer up the usual optimistic platitudes. He said it’s going to be historic.
“In 30-plus years in drug discovery and development, I’ve been involved with 19 drugs that have made it to the market and 200 to 300 that haven’t,” Crooke says. “I’ve encountered two in my career that were amazing.”
One was cisplatinum chemotherapy for cancer. The other was cimetidine (Tagamet) for heartburn, Crooke says. “Mipomersen is the third one that’s remarkable.”
That’s a strong statement given that investors drove down Isis shares by 10 percent on heavy volume on May 20, after seeing their first glimpse of data from a pivotal trial of mipomersen. Expectations have been sky-high for this drug for a couple years now, as the next big thing for cholesterol after the invention of multi-billion dollar statin drugs such as Pfizer’s atorvastatin (Lipitor). Cambridge, MA based Genzyme (NASDAQ: [[ticker:GENZ]]) was said to outmaneuver more than a dozen rivals that wanted to co-develop mipomersen. In January 2008 Genyzme paid the princely sum of $325 million in upfront cash, plus $1.9 billion in potential milestone payments, (and potentially much more in future profit-sharing), to get a piece of ownership in this drug.
Mipomersen has generated so much interest for at least a couple big reasons—the need for more powerful cholesterol-lowering drugs for patients who can’t get those levels under control with conventional statins, and because it represents a potential standard-bearer for Isis’ antisense technology. It’s designed to use specially engineered strands of RNA drugs to block a problematic protein in the body, which often can’t be hit by conventional small-molecule drugs. In this case, mipomersen is engineered to block the production of a protein called apoB that carries the so-called “bad” LDL cholesterol in the bloodstream.
In May, Isis and Genzyme declared victory in a press release that announced the first pivotal clinical trial of mipomersen. The companies said that of 51 patients with a rare genetic abnormality called homozygous familial hypercholesterolemia that causes high cholesterol, the drug was a success. Patients on mipomersen had a 25 percent reduction in their LDL cholesterol counts, compared with a 3 percent drop for those on a placebo. The drug also reached its secondary goals, including showing an apoB protein reduction which correlated with the cholesterol-lowering—an important point for scientists and physicians.
But the market didn’t see it as reason to cheer. Patients with this genetic abnormality are seriously ill, with LDL cholesterol scores at an eye-popping 400 milligrams per deciliter of blood when they entered the study. (Anything below 200 is considered desirable, according to the Mayo Clinic).
So simple math says that a 25 percent reduction from 400 takes those patients down to about 300, which might be good, even unprecedented for such sick patients, but it’s still not what most patients and doctors would consider healthy. Plus, there were six patients who didn’t complete their course of treatment after they were enrolled in the study, which certainly didn’t help.
So why was Crooke so enthused? He walked me through some of the context around the data that will be presented next month at the American Heart Association’s scientific sessions in Orlando, FL.
What’s remarkable, Crooke says, is that mipomersen works in every animal, and in every
