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|Data from Mipomersen Phase 3 Trial in hoFH Patients Presented at AHA|
Study Meets Primary Endpoint with 25 Percent LDL Reduction in Very High-Risk Patient Population
This phase 3 study in hoFH patients, one of the largest trials to date in this rare population, was designed to test the efficacy and safety of adding mipomersen to substantial lipid-lowering therapy. Patients’ average LDL-C at baseline was greater than 400 mg/dL. All but one of the patients were being treated with lipid-lowering therapy (50/51, 98 percent), of whom 11 (22 percent) were taking a statin alone and 39 (78 percent) were taking a statin in combination with at least one other lipid-lowering agent, most commonly ezetimibe (37/50, 74 percent). The LDL-C reductions observed in the study were in addition to those achieved with the patients’ existing therapeutic regimen.
“These results are good news for patients with hoFH,” said Professor
The trial met all of its secondary and tertiary endpoints, suggesting that mipomersen may offer potential benefits to patients beyond LDL-C reduction. Patients treated with mipomersen experienced a 27 percent reduction in apolipoprotein B vs. 3 percent for placebo; a 21 percent reduction in total cholesterol vs. 2 percent for placebo; and a 25 percent reduction in non-HDL cholesterol vs. 3 percent for placebo (all p<0.001).
Reductions were observed in other atherogenic lipids, including: Lp(a) by 31 percent and VLDL-C by 17 percent (both p<0.01 vs. placebo); and triglycerides by 18 percent (p=0.013 vs. placebo). Apo B, Lp(a) and triglycerides are all generally accepted risk factors for cardiovascular disease.
Mipomersen patients’ HDL-C levels increased 15 percent (p=0.035 vs. placebo), which combined with the LDL-C reductions observed, resulted in improved LDL/HDL ratios, a ratio considered an important measure of cardiovascular risk. Mipomersen patients’ LDL/HDL ratios decreased by 34% (p<0.001 vs. placebo).
“Mipomersen could represent a significant advance for hoFH patients, who
are in great need of new treatment options,” said
Consistent with previous studies evaluating mipomersen, the most commonly observed adverse events were injection site reactions (77 percent for mipomersen vs. 24 percent for placebo), flu-like symptoms (29 percent for mipomersen vs. 24 percent for placebo) and elevations in liver transaminases (12 percent ≥ 3 X ULN for mipomersen vs. none for placebo.)
Of the 34 patients treated with mipomersen, 28 completed the study. Reasons for withdrawal from the mipomersen group were: injection site reactions (2), elevations in liver transaminases (1), rash (1), personal reasons (1), and non-compliance (1).
Four patients had elevations in liver transaminases above 3 X ULN (three times the upper limit of normal), three of whom reached between 5 and 8 X ULN. None of these patients, including the patient who discontinued the study, had changes in other laboratory tests to indicate hepatic dysfunction, i.e., Hy’s Law. In all cases, transaminases returned to entry criteria by the end of planned clinical observations.
“Mipomersen continues to provide an exciting example of the potential of
Isis’ antisense technology platform to create potent and specific drugs
that could play an important role in the treatment of disease,” said
Genzyme’s initial U.S. and E.U. regulatory filings for mipomersen will seek marketing approval for the treatment of patients with hoFH. These two filings may also include patients with severe hypercholesterolemia. A phase 3 study of mipomersen in patients with severe hypercholesterolemia is fully enrolled with 58 patients and data are anticipated in mid-2010.
With the completion of enrollment of this study, the last of the four
phase 3 studies that will form the basis for the first regulatory
The companies have also completed enrollment in a phase 3 trial of mipomersen in patients with heterozygous FH; there are 124 patients in this study and results are expected in the first quarter of 2010. In addition, a phase 3 trial in hypercholesterolemic patients at high risk for coronary heart disease is now fully enrolled with 158 patients, and data are anticipated in mid-2010.
Data from these and other ongoing studies of mipomersen will inform the design of an outcome study to support mipomersen’s use in a broader group of at-risk, high cholesterol patients.
About the phase 3 study in hoFH patients
The trial was a randomized, double-blind, placebo-controlled study that
enrolled 51 hoFH patients, aged 12 and older. Seven patients were aged
12 to 17. Patients were randomized 2:1 to receive a 200 mg dose of
mipomersen or placebo via weekly injections for 26 weeks. The trial was
conducted at 10 sites in seven countries in
Professor Raal presented the overall study results at AHA. Study
All study participants had the option of enrolling in an open-label extension trial. The extension study’s efficacy measurements include percent reduction of LDL-C, apo-B and non-HDL-C at various points through at least 52 weeks of treatment. Of the 28 patients treated with mipomersen who completed the initial trial, 23 enrolled in the extension study; of the 17 placebo patients, 16 enrolled in the extension.
About Familial Hypercholesterolemia
FH is a genetic disorder in which patients are unable to properly metabolize LDL cholesterol, resulting in elevated LDL-C levels. FH patients experience a markedly increased risk of premature cardiovascular disease (CVD) and CVD-related death. There are two forms of FH: homozygous (hoFH), where the same defective gene is inherited from both parents, or heterozygous (heFH), where the defective gene is inherited from only one parent so that some function is preserved.
The homozygous form of FH is a very rare condition estimated to affect approximately one in a million people. HoFH patients can have LDL-C levels greater than 600 mg/dL and are at very high risk for early coronary events and sudden death. Because many patients are resistant to the lipid-lowering effects of currently available therapies, effective treatment of hoFH patients is difficult. HeFH is a more common form of the disorder, with a prevalence of approximately one in 500, and results in untreated LDL cholesterol levels of approximately 300 mg/dL, double those of the general population.
Lp(a) is a lipoprotein particle that is found in atherosclerotic plaques and appears to play a role in complications at these plaque sites. Studies have shown that increased levels of Lp(a) are associated with increased vascular risk due to the proatherogenic and prothrombotic effects of the lipoprotein. Lp(a) is now generally recognized as an independent cardiovascular risk factor. In view of observed associations of high levels of Lp(a) with vascular disease, research suggests that treatments to reduce Lp(a) levels could be clinically beneficial.
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Isis is exploiting its expertise in RNA to discover and develop novel
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and cancer. Isis' partners are developing antisense drugs invented by
Isis to treat a wide variety of diseases.
Genzyme Safe Harbor Statement
This press release contains forward-looking statements regarding
Genzyme’s business plans and strategies including, without limitation,
statements about the potential uses and benefits of mipomersen; the
expected timing of regulatory filings for mipomersen; and the design of
future clinical studies of mipomersen and the expected timing of such
studies. These statements are subject to risks and uncertainties that
could cause actual results to differ materially from those forecasted.
These risks and uncertainties include, among others: the actual efficacy
and safety of mipomersen; the actual timing and results of the clinical
Isis Safe Harbor Statement
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In this press release, unless the context requires otherwise, “Isis”