Amarin Corporation plc a clinical-stage biopharmaceutical company with a focus on cardiovascular disease, reported positive, statistically significant top-line results from the Marine study, its first phase 3 clinical trial of lead drug candidate AMR101. The Marine study, investigating AMR101 as a treatment for very high triglycerides (=500 mg/dL), met its primary efficacy endpoints as defined in the clinical trial protocol and demonstrated a positive safety profile. The company believes that AMR101 has the potential to be the best-in-class product for this indication and that the Marine study results may support additional patentable claims that could further protect the company's rights to this product through 2030.
The study's primary endpoint, the percent change in triglyceride (TG) levels from baseline to week 12, was met for both the 4 gram and 2 gram dose groups. The Marine study was required to meet a stringent level of statistical significance of 1% (p < 0.01), as agreed in the Company's SPA (Special Protocol Assessment) with the FDA. Twenty-five per cent of patients were on background statin therapy.
The patient group treated with 4 grams of AMR101 showed a significant median TG decrease of 33 % (P < 0.0001) compared to placebo, and the patient group treated with 2 grams of AMR101 showed a significant median TG decrease of 20 % (P = 0.0051) compared to placebo. The median baseline triglyceride levels were 703 mg/dL, 680 mg/dL and 657 mg/dL for the patient groups treated with placebo, 4 grams of AMR101 and 2 grams of AMR101, respectively.
In a pre-specified secondary analysis in the subgroup of patients with baseline TG > 750 mg/dL, representing 39% of all patients, the effect of AMR101 in reducing TG levels was even more pronounced. In this group, the median decrease in TG levels from placebo was 45% for 4 grams and 33% for 2 grams, both statistically significant (P= 0.0001 for 4 grams and P= 0.0016 for 2 grams, respectively).
The median baseline TG levels in this subgroup were 1052 mg/dL, 902 mg/dL and 948 mg/dL for placebo, 4 gram and 2 gram groups, respectively. In addition, the subgroup of patients on background statin therapy had much greater median reductions in TG, which were also statistically significant, than those not on statin therapy.
Importantly, AMR101 did not result in an increase in median LDL-C compared to placebo at either dose (-2.3% for the 4 gram group and +5.2% for the 2 gram group [p=NS]). This is the first and only triglyceride-lowering therapy studied in this population with very high triglyceride levels to show a lack of elevation in LDL-C. Furthermore, there was a statistically significant decrease in median non-HDL-C (total cholesterol less “good cholesterol”) compared to placebo with both of the AMR101 treated groups (-18% for the 4 gram group [p < 0.001] and -8% for the 2 gram group [p < 0.05]).
There were also statistically significant reductions in several important lipid markers, including Apo B, Lp-PLA2 (Lipoprotein-phospholipase A2), VLDL-C and total cholesterol. These results are particularly encouraging given that no other TG-lowering therapy studies have shown such results. For these achieved endpoints, p-values were <0.01 for most and <0.05 for all. Apo B (Apolipoprotein B) is a sensitive index of residual cardiovascular risk and is generally considered to be a better predictor than LDL-C. Lp-PLA2 is an enzyme found in blood and atherosclerotic plaque; high levels have been implicated in the development and progression of atherosclerosis. Furthermore, AMR101 appeared to be very well tolerated with a safety profile that appears to be both comparable to placebo and more favourable compared to other triglyceride lowering therapies. There were no treatment-related serious adverse events in the Marine study.
Commenting on the results of the study, Harold Bays, MD, Medical Director, Louisville Metabolic and Atherosclerosis Research Centre, and Principal Investigator of the study, stated, “The Marine trial included a study population of patients with very high TG levels (i.e. > 500 mg/dl). In this study, AMR101 reduced TG levels to within the range observed with common approved triglyceride-lowering drugs. Clinicians are aware, and some may have concerns, that common TG-lowering agents may raise LDL-C by 40 — 50% in patients with very high TG levels. In the Marine trial, AMR101 did not significantly increase LDL-C levels. Another surprise to me was the degree of TG-lowering efficacy in the statin-treated group, which exceeded the TG lowering in the non-statin treated group. It was also reassuring that the safety and tolerability of AMR101 was similar to placebo. Adding these favourable findings to the significant reductions in total cholesterol, non-HDL-C, Apo B, and Lp-PLA2 levels, this suggests that AMR101 may prove to represent an effective, and safe alternative treatment option to improve cardiovascular risk factors in patients with very high triglycerides. In summary, the results of the Marine trial suggest that AMR101 may prove to represent a "first in class" EPA TG-lowering agent that not only represents a new chemical entity, but a potential novel therapy with favourable lipid efficacy effects that differ from common TG-lowering agents, such as fibrates and previously approved prescription omega-3 drugs. We very much look forward to presenting the full dataset at a scientific meeting.”
Joseph S. Zakrzewski, executive chairman and chief executive officer of Amarin, added, “The Marine study was conducted in a population representative of millions of people with very high triglyceride levels, including more than 3.8 million in the US alone. We believe that these results and the overall profile of AMR101 position the drug candidate to be best in class in this market. Furthermore, the Marine study results are encouraging, especially the positive outcomes with respect to LDL-C and other lipids, as we await the results of the ongoing Anchor study. This separate Phase 3 study is designed to investigate AMR101 in patients with high triglycerides (=200 and <500mg/dL) with mixed dyslipidemia treated with statins, a patient population for which no drug in this class is currently approved. While the market for a drug labelled for treatment of triglycerides of =500 mg/dL is already proven to be a billion dollar market, there are ten times the number of patients with triglycerides of =200 and <500 mg/dL.”
Based on the timing and nature of these results, Amarin intends in 2011 to submit a New Drug Application (NDA) seeking approval to market and sell AMR101 in the US previous company guidance projected 2012 for the NDA submission. The Company further added that, based on the positive results of the Marine trial, Amarin has advanced additional patent claims to add to its growing portfolio of US and international intellectual property claims related to AMR101.
AMR101 is ethyl icosapentate (ethyl-EPA). Significant scientific and clinical evidence supports the efficacy of ethyl-EPA in reducing triglyceride levels. In addition to the Marine trial, Amarin has completed patient screening in a second Phase 3 clinical trial to investigate the efficacy of AMR101 in reducing elevated triglyceride levels in a patient population with high triglycerides (=200 and <500mg/dL) who also have mixed dyslipidemia (the Anchor trial). Top-line results for the Anchor trial are expected in mid-2011.
The Marine trial, a multi-centre, placebo-controlled, randomized, double-blind, study enrolled 229 patients with fasting triglyceride levels greater than or equal to 500 mg/dL. Patients in this trial were characterized as having very high triglyceride levels according to the National Cholesterol Education Program Adult Treatment Panel III treatment guidelines. The Marine trial is the largest controlled therapeutic study ever conducted in patients with very high triglyceride levels (=500mg/dL). The Company believes that AMR101 is positioned to be best-in-class in this patient population.
The Anchor trial is a multi-centre, placebo-controlled, randomized, double-blind, 12-week pivotal study to evaluate the efficacy and safety of 2 grams and 4 grams of AMR101 in patients with high triglyceride levels from 200 mg/dL to less than 500 mg/dL who are also on statin therapy. Patients in this trial are characterized as having high triglyceride levels with mixed dyslipidemia (two or more lipid disorders).
The trial aims to recruit approximately 650 patients into clinical sites in the US. The primary endpoint in the trial is the percent change in triglyceride level from baseline to week 12. A secondary endpoint in the Anchor trial is to show that the addition of AMR101 to statin therapy does not increase LDL-C compared to placebo in this population. The Company believes that AMR101 is positioned to be first-in-class to address this patient population.
In both the Marine and Anchor trials, prior to randomization into the 12-week double-blind treatment period, all patients underwent a six-to-eight week washout period of lipid altering drugs, as well as diet and lifestyle stabilization. Both the Marine and Anchor trials received Special Protocol Assessment (SPA) agreements in 2009 from the US Food and Drug Administration (FDA).
Amarin Corporation plc is a clinical-stage biopharmaceutical company with expertise in lipid science focused on the treatment of cardiovascular disease. The company's lead product candidate is AMR101 (ethyl icosapentate), which is presently being investigated in a second phase 3 clinical trial for the treatment of patients on statin therapy with high triglycerides (=200 and <500mg/dL) with mixed dyslipidemia.