Isis Pharmaceuticals this week reported phase II data showing its antisense drug Isis 301012 significantly reduced low-density lipoprotein levels alone or in combination with two top-selling statins, Merck’s Zocor and Pfizer’s Lipitor.
According to Isis, data from one phase II trial demonstrated that weekly treatments of Isis 301012 in patients with high cholesterol who were receiving stable doses of statins cut LDL cholesterol levels by more than 50 percent and total cholesterol levels by more than 40 percent beyond the reductions observed with statin treatment alone.
In a separate phase II study, patients with high cholesterol who were treated with Isis 301012 alone for three months experienced a greater than 60-percent drop in LDL cholesterol levels and a nearly 50-percent decline in total cholesterol.
“The take-home message is … that the reduction in cholesterol [achieved with Isis 301012] is the same whether you’re on a statin or not,” Mark Wedel, Isis’ chief medical officer, told RNAi News this week. Based on earlier clinical data, “we knew we could knock [cholesterol levels] down 50 to 60 percent if you were not on a statin, but the real question was, ‘Will you be able to do the same thing when you are on a statin?’ We now can say without question, ‘Yes we can.’
“These two studies in parallel are showing a 50- to 60-percent reduction [in LDL cholesterol], which … is as good as any drug on the market,” he added. “And [the reductions] occur irrespective of whether the patient is on a statin or not, with the same safety profile in both populations.”
On news of the clinical results, which were presented at the American Heart Association Annual Scientific Sessions in Chicago, shares of Isis surged more than 20 percent to $12.50. By midday Thursday, the stock had lost much of that gain and was trading around $10.84.
“These new data demonstrate pronounced lipid-lowering effects of ISIS 301012, both as a single agent and as an add-on to statin therapy,” John Kastelein, a researcher at the Academic Medical Center in Amsterdam and the principal investigator on the studies, said in a statement.
"The guidelines for target cholesterol levels continue to be revised downward," Kastelein added. "A significant percentage of at-risk patients are simply not meeting LDL [cholesterol] targets with current lipid-lowering drugs, so there is a growing need for therapies that can be added to statins to achieve additional reductions in atherogenic lipids.”
Isis 301012 is an antisense drug that targets apolipoprotein B 100, a protein associated with LDL cholesterol synthesis and transport. It is being developed with the financial support of Symphony Capital Partners, an investment group that provided Isis with $75 million in funding earlier this year to develop Isis 301012 and two drugs for diabetes.
The first phase II study enrolled patients with LDL cholesterol levels between 100 and 220 mg/dL who have been on stable 40 mg or lower doses of either Zocor or Lipitor for at least three months. Patients were randomized to receive 30, 100, 200, 300, or 400 mg doses of Isis 301012 administered intravenously once a week for five weeks.
At five weeks, patients in the 300 mg cohort achieved median reductions of 51percent in LDL cholesterol, 42 percent in total cholesterol, 51 percent in non-high density lipoprotein cholesterol, and 41 percent in triglycerides beyond the levels they had already achieved on stable statin doses.
The findings, the company said, “are consistent with the data suggesting Isis 301012 acts through a mechanism of lipid lowering that is independent of and complementary to the statin mechanism. The data further demonstrate that when co-administered with a stable dose of statins, Isis 301012 displays a linear dose-response relationship.” Specifically, the 200 mg per week dose lowered LDL cholesterol by 30 percent while the 300 mg a week dose lowered LDL cholesterol by 51 percent.
In the second phase II study, patients with high cholesterol were treated for three months with Isis 301012 alone at weekly doses of 50 mg, 100 mg, 200 mg, and 300 mg. Patients in the highest dose group achieved median reductions of 62 percent in LDL cholesterol, 46 percent in total cholesterol, 54 percent in non-high density lipoprotein cholesterol, and 43 percent in triglycerides, demonstrating that the antisense drug causes “linearly increasing reductions of atherogenic lipids as doses are increased,” in contrast to statins, Isis said.
“We knew we could knock [cholesterol levels] down 50 to 60 percent if you were not on a statin, but the real question was, ‘Will you be able to do the same thing when you are on a statin?’ We now can say without question, ‘Yes we can.’”
The company said that Isis 301012 appeared well-tolerated in the studies, and the most common adverse event was mild injection site reactions. No clinically significant effects on liver function tests were observed, Isis added.
Both phase II trials are ongoing with patients being enrolled in 400 mg/week cohorts. Extended three-month treatment periods are planned for subsequent cohorts of 200 and 300 mg/week doses in the statin co-administration study.
Isis 301012 is also being evaluated in two phase II trials of patients with homozygous and heterozygous familial hypercholesterolemia, two different versions of a genetic disorder characterized by high cholesterol. Results from these trials, in which patients are being dosed with Isis 301012 in addition to their existing lipid-lowering therapies, are expected late this year or early next year, Isis said.
Looking ahead, Wedel said that Isis is planning on submitting Isis 301012 for US regulatory approval as a treatment for FH in combination with statin therapy sometime in 2008, with a filing for approval for polygenic hypercholesterolemia, also in combination with statins, following in 2011.
Whether the initial approval sought will be for both forms of FH or just homozygous FH, an indication for which Isis 301012 was granted orphan drug status in June, will depend on discussions with the FDA slated for the first half of next year, he noted.
Wedel noted that homozygous FH affects approximately one in 1 million people, while about one in 500 people are believed to have heterozygous FH.