Isis Pharmaceuticals Inc. (ISIS) and Genzyme Corp. (GENZ) reported the success of two late-stage clinical trials of mipomersen in lowering cholesterol in patients with extremely high levels, but concerns about the drug's side effects remain.

The companies said Wednesday that mipomersen significantly cut levels of LDL, so-called bad cholesterol, in patients with a rare genetic disorder that were already on the maximum level of standard therapy. The data continued mipomersen's success over four Phase III clinical trials, but elevations of liver enzymes, a potential signal of liver damage, has persisted and may raise questions from regulators as well as limit sales to a small patient population.

Shares of Isis recently fell 5.4% to $9.46, while Genzyme dropped 1.7% to $69.

Mipomersen is Isis's most significant pipeline product. Genzyme, reported to be in takeover talks with Sanofi-Aventis SA (SAN.FR SNY), has highlighted mipomersen as a key product for its future.

"Overall, we think the efficacy data from this study appears solid, but the safety profile creates significant regulatory risk," JPMorgan analyst Geoffrey Meacham said.

He said that Mipomersen will likely need to be priced at more than $200,000 a year to be "commercially meaningful," and he has "a difficult time" projecting more than $100 million in annual sales, if approved.

In the past, the companies have downplayed the liver effects as normal and possibly exaggerated because it is being monitored so closely, but Wednesday acknowledged that only a very limited population would likely get the drug.

"We believe that these effects appear to be manageable...based on the evidence we have today, we believe that mipomersen could be appropriate for the highest risk patients," said Joanne Donovan, vice president of clinical research at Genzyme.

The companies acknowledged that the drug will likely need a risk management plan to monitor the liver issues if it is approved for marketing.

Genzyme expects to file for Food and Drug Administration approval in the first half of next year. Initially, it will seek to use the drug in patients with homozygous familial hypercholesterolemia and severe forms of heterozygous familial hypercholesterolemia, both genetic diseases that cause extremely high cholesterol levels.

In U.S. and top five European Union countries, there are 30,000 such patients that have exhausted the use of existing therapies.

The latest data show mipomersen cut LDL by 36% in patients with severe hypercholesterolemia compared with a 13% increase from placebo. In a second study of hypercholesterolemia patients with high cardiovascular risk, mipomersen reduced LDL by 37% compared with a 5% reduction for placebo.

A large number of patients using the drug dropped out because of side effects, amounting to 21% in the first trial and 25% in the second trial.

The chief concern surrounding the future of the drug is that it continues to show elevated liver alanine transaminases, or ALT, which can be a signal of liver damage, as one of its most common side effects. In one of the studies, 15% of the patients on the drug had "persistent elevations in ALT greater than three times the upper limit of normal." That level was higher than previous studies.

In the call, the companies said the increased ALT levels are associated with rapid and substantial reductions in cholesterol and such changes could be monitored by physicians in a "real world" setting.

Despite the elevations, the company stressed that there have been no cases of liver toxicity and they are consistent with the companies' expectations. Regardless, they are studying how to deal with these cases, which may include halting use or decreasing dosing.

Notably, the company said they haven't spoken to the FDA about whether the data from the four studies is substantial enough to access the safety of the drug, which would be used by patients for extended periods. All four studies spanned 26 weeks.

Genzyme said it plans to meet with regulators before filing for approval, but it hinted that more work may be needed.

"We will make determination after we look at these two studies and the four studies overall as what additional work may or may not be warranted in terms of both of pre- and post-filing," said Pam Williamson, senior vice president of global regulatory affairs at Genzyme.

-By Thomas Gryta, Dow Jones Newswires; 212-416-2169; thomas.gryta@dowjones.com
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