Isis Pharmaceuticals' New Cholesterol Drug Might Be a Hit, But It Won't Be Soon

Isis Pharmaceuticals has big hopes for its novel drug mipomersen, which it wants to use for treating high cholesterol in otherwise difficult-to-treat patients. But liver-related side effects and the fact that the drug requires injections -- as opposed to rival cholesterol pills -- could make it a tough sell, potentially limiting its market-share prospects.

Mipomersen, a first-in-class apo-B synthesis inhibitor, works by decreasing the production of apo-B, a protein critical to the synthesis and transport of LDL and VLDL cholesterol -- the "bad" lipids involved in the buildup of plaque in the arteries and the development of heart disease -- through the bloodstream.

Whether mipomersen rises to $1 billion-plus blockbuster status or remains a niche drug with $250 million peak sales will depend on how the FDA feels about approving the drug for use in a broad pool of high-risk patients with uncontrolled LDL, despite taking maximum doses of lipid-lowering drugs such as statins like Pfizer's Lipitor. There are about a million patients refractory to statin-therapy in the U.S. and Europe who are likely candidates for this indication, according to Isis chief executive officer Stan Crooke.

In January 2008, Isis sold development and marketing rights of mipomersen to Genzyme, receiving an up-front payment of $300 million ($150 million for Isis stock at $30 per share and a $175 million license fee). Isis also has the opportunity to receive from Genzyme up to $825 million in development and regulatory milestone payments plus significant commercial payments -- contingent on an agreed-on, stepwise plan that gets mipomersen to market(s) for treatment in a variety of at-risk population groups refractory to current therapies, such as the popular "statin" drugs (like Crestor and Lipitor).

Genzyme intends to first seek approval in the U.S. and Europe for mipomersen in those patients with homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder affecting one in a million people, in the first half of 2011. HoFH patients have extremely high cholesterol levels (greater than 500 mg per deciliter) and exhibit early signs of cardiovascular disease in all major arterial beds (including the neck, heart, and legs), resultant from defective LDL-c receptors in the liver that are unable to remove LDL-c from circulation. Ergo, a therapy aimed at reducing LDL production at its source could be an attractive option.

Assuming successful submissions, Genzyme plans a second submission in Europe for the more common heterozygous form of the disease (HeFH), which affects one in 500 people.

Stan Crooke told analysts on the fourth-quarter 2009 earnings call that (according to Genzyme) there are 25,000 to 30,000 patients with HoFH who could use mipomersen in the U.S. and Europe and an additional 25,000 HeFH-patients (in Europe) for therapy.

Late-stage studies assessing the efficacy of mipomersen (weekly injection of 200 mg dose), when added to existing lipid-lowering drugs, showed success in meeting primary endpoints: LDL-c reductions of 25 percent and 28 percent in cohorts of HoFH and HeFH- treated patients.

Isis and Genzyme may want to keep that celebratory champagne on ice for now, as new safety data from the HoFH study (published in Lancet) connected the drug to elevated liver enzymes and fat deposits in the liver: four patients (12 percent) of mipomersen-treated patients had increases in liver enzymes (ALT) of three times (or more) the upper limit of normal and showed increases in hepatic fat, too.

Responding to repeated queries on the safety of mipomersen, chief executive Cooke stressed to analysts on the earnings call that the collective body of data to date shows mipomersen to be a safe drug:

With mipomersen, we have no drug-drug interactions, we have no central nervous system toxicity that we've identified, no cardiovascular toxicity and no muscle toxicity. So in that sense, mipomersen is an ideal drug to be added to patients who are typically taking 10 to 15 drugs on top of mipomersen.

Nonetheless, before the companies can get to the lucrative lipid-lowering markets, they must fix the potholes on the current road: addressing likely FDA and European concerns of liver safety issues in FH patients. Genzyme is enrolling patients in an alternate dosing study. Although formal guidance on trial endpoints haven't been issued to analysts, investigators are probably focused on two salient outcomes: Would variable dosing -- as opposed to labeled dosing of be 200 mg in once-weekly shot -- reduce risk of ALT elevations and increases in hepatic fat? And, would temporarily lowering the dose be advisable (following a dramatic reduction in lipid markers, such as apo-B)? To date, late-stage studies have been blinded and protocols didn't offer this flexibility of dosing.

With almost $575 million in the bank, and other promising compounds in its pipeline, Isis can weather a likely delay -- and pushback -- of Genzyme's initial regulatory filing date for mipomersen (planned for mid-2011).

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