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MIRAXION (AMR101)

MIRAXION (AMR101) FOR HUNTINGTON’S DISEASE 

INTRODUCTION

Miraxion (AMR101) is a semi-synthetic, ultra pure (~97%) derivative of (all-cis)-5,8,11,14,17-eicosapentaenoic acid (ethyl-EPA). It is a long chain highly unsaturated fatty acid (often written in short as 20:5n-3 or 20:5ω3).

Miraxion is currently in Phase III clinical development for Huntington’s disease (“HD”). HD is a genetic neurodegenerative disease characterized by movement disorder, dementia and psychiatric disturbance. Eventually, the HD sufferer is unable to care for himself or herself. Death follows from complications including choking, infection or heart failure.

HD is believed to be caused by a genetic mutation of the cytosine, adenosine and guanine ("CAG") polymorphic trinucleotide repeat. All people with a CAG repeat length of greater than 36 will develop the disease. It is believed that there is a direct link between CAG repeat length and age of onset, disease progression and clinical symptoms of HD. CAG repeat length can be measured by carrying out a blood test.

HD has been diagnosed in approximately 30,000 patients in the U.S. with a similar number in Europe. Additionally, over 200,000 persons in the U.S. alone are genetically "at risk" to developing the disease. Onset of symptoms is typically between 30-50 years of age with a typical life expectancy from diagnosis of 10-25 years. Patients with late stage disease require continuous nursing care, often in nursing homes, with an estimated annual cost to the U.S. economy of up to $2.5 billion. Presently, there is no effective treatment or cure for HD. The market for an effective treatment for HD is estimated to be in excess of $500 million in the US and Europe.

For more information on Huntington’s disease please refer to http://huntington-study-group.org/

Description

In progressive neurodegenerative diseases, it is thought that the functionality and effectiveness of affected neurons decline over time, and ultimately die. Neurons that are experiencing such neuronal dysfunction are often described as "suffering neurons". The mechanism of action of Miraxion is believed to involve (1) replenishment of the lipid bi-layer potentially restoring the functions of suffering neurons, (2) reducing the over production of enzymes (PLA2) associated with apoptosis and (3) stabilizing mitochondrial integrity of suffering neurons by acting on specific signal transduction pathways and changing cellular energy metabolism. This may prevent or slow progression from neuronal dysfunction to apoptosis. Preclinical studies have shown that in aging brains, Miraxion demonstrates neuro anti-inflammatory effects, potentially protecting the brain from inflammation, which is often associated with a number of neurodegenerative diseases such as Alzheimer's, Parkinson's and HD. Age-related learning and memory decline in the brain has also been shown to be accompanied by inflammatory changes, typified by microglial activation.

 (Click here to view animation of the role of Miraxion in neuronal cell membranes)

While there are dietary supplements available in drugstores without prescription that also contain EPA at lower concentrations, in all cases such products contain mixtures of various fatty acids and other substances. Miraxion is produced by a manufacturer authorized by the FDA through a unique, complex and patented process that reliably and consistently creates the highly purified prescription-grade medicine. The purity level of Miraxion and the absence of other fatty acids and impurities confer a number of important benefits such as:

  • enabling pure EPA to metabolize and function in the brain without potential interference from other unsaturated fatty acids (e.g., GLA, arachidonic acid and DHA) and saturated fatty acids contained in these impure dietary supplements.
  • minimizing the risk of exposing patients to unnecessary and undesirable impurities
  • enabling more readily identifiable and specific dosing for the treatment of central nervous system disorders.
Intellectual Property

Two key patent families cover the use of Miraxion for HD and extend to 2020 and 2023.

Miraxion has also received Orphan Drug designation by the FDA and EMEA for Huntington’s disease. If approved, Miraxion will receive marketing exclusivity for seven years in the US and up to 10 years in Europe.


CLINICAL DEVELOPMENT HIGHLIGHTS

US and EU Phase III Studies (>600 Patients)

Amarin recently completed one of the largest therapeutic Phase III programs ever conducted in HD, with over 600 patients recruited in total. The two Phase III trials with Miraxion (one in North America (TREND-HD), and one in Europe) were conducted under a Special Protocol Assessment ("SPA") with the FDA. The TREND-HD trial, conducted by the Huntington Study Group in the US and Canada in 316 patients, was a 6-month, double-blind placebo controlled study followed by a further 6-month extension period where all patients received Miraxion. The primary endpoint was the 6-month change in TMS-4, a scale that measures motor symptoms. The European trial was also a 6-month study, but with no 6-month extension period.

On April 24th 2007 Amarin announced top line results from the two studies. Study data showed no statistically significant difference in either study between Miraxion and placebo with regard to the primary and secondary endpoints at 6 months. These top-line findings were inconsistent with data from an earlier 12-month 135 patient clinical trial.

However, on November 19th 2007, Amarin announced that analysis of a comprehensive review of the 12-month data from 190 patients from the TREND-HD Phase III study showed that the TMS-4 change for those originally randomized to Miraxion was significantly better than those originally randomised to placebo and then switched to Miraxion at 6-months (0.0 point change versus a 1.8 point change worsening respectively; p=0.02), especially for those with a CAG repeat of less than 45 (1.2 point improvement versus a 1.6 point worsening respectively; p=0.004)1. Treatment codes were not broken at the switching point so investigators and patients remained blinded to receipt of Miraxion or placebo in the initial 6-month period. These results suggest that there is benefit from a longer treatment period with Miraxion and are consistent with the 24-month open-label data and the 12 month blinded data from the earlier 135-patient trial completed in 2003 (see below for further information on the 2003 study).

In addition, a longitudinal analysis, which is a widely accepted and validated alternative statistical methodology, was applied to all available clinical data as part of the comprehensive review. The longitudinal methodology was applied to the US TREND-HD Phase III trial data to both the 3 and 6-month combined results as well as the 3, 6, 9 and 12-month combined results. A statistically significant difference between the Miraxion and comparator groups was identified in each of the 3-6 month and the 3, 6, 9 and 12-month analyses.

When applied to the earlier 135-patient study, the longitudinal analysis showed a statistically significant difference between Miraxion and placebo in the per protocol patient groups and, additionally, a greater degree of statistical significance in the intent to treat genetic sub-group of patients with a CAG≤44 than in the previous analysis.

Longitudinal analysis was also conducted on the 24-month open label data from the 135-patient trial, in which patients initially randomized to treatment with placebo had been switched to Miraxion and treated for 12 months. After switching to Miraxion, these patients demonstrated an effect of similar magnitude to patients randomized to treatment with Miraxion at baseline.

Following completion of a comprehensive data review from its Phase III studies, Amarin met with the U.S. Food and Drug Administration (FDA). The FDA indicated that one additional Phase III trial demonstrating robust results, in conjunction with the confirmatory evidence from the existing clinical data, may be sufficient clinical data to support a New Drug Application.

Amarin is currently seeking a US partner for the further development and commercialization of Miraxion in HD.


Initial 135 Patient Phase III Study2

In 2003, an initial placebo controlled Phase III study in 135 patients evaluating Miraxion in HD was conducted. Patients were randomized to receive two 500mg softgel capsules twice daily of Miraxion or placebo for one year. The primary endpoint of the trials was a change in the TMS-4 component of the UHDRS.

Key Results: 

  • 135 patients (the "Intent to Treat" group or "ITT" group) started the study and there were 14 patient drop-outs, one of which was believed to be related to Miraxion (gastrointestinal upset). This left 121 patients who completed the 12 months.
  • Prior to unblinding the study, 38 patients were identified as not having complied with the protocol of the trial. The remaining 83 patients completed the study without protocol violations, constituting the per protocol ("PP") group. Of the 38 protocol violators, 16 failed to be evaluated within four weeks of the protocol-specified time, 13 had not taken the correct dose, eight had taken other treatments which were excluded per the protocol and one violated the entry criteria.
  • For the primary endpoint (TMS-4) in the 135 patients in the ITT group, there was no significant difference between Miraxion and placebo.
  • In the PP group, for the primary endpoint (change in TMS-4), Miraxion was significantly better than placebo on the chi square test (p<0.05) and just missed significance on analysis of covariance (ANCOVA) (p=0.06).
  • On the secondary endpoints for the ITT group, no significant benefit of Miraxion was demonstrated.
  • In the PP group, the total motor scale of the UHDRS showed a significant benefit of Miraxion over placebo. The effects on the other secondary variables were not significant.
  • Four patients withdrew from the study due to adverse events, of which only one was believed to be related to Miraxion (gastrointestinal upset).
  • All but one of the 121 patients that completed the 12 month study opted to continue in an open label study for a further 12 months.


Initial Phase III Trial – CAG Group Analysis

It was pre-specified in the protocol for the trial that the relationship between CAG repeat length and Miraxion efficacy should be examined. Additional analysis of the clinical data from the initial Phase III study identified a group of Huntington’s patients that responded to Miraxion with clear statistical significance.

The additional analysis of the clinical data from the study found that the group of patients with a CAG repeat length of less than or equal to 44 receiving Miraxion showed a statistically significant improvement over those patients receiving placebo. In total, 67 of the 135 patients in the study had this specific gene variant. Figure 1 shows the reduction in TMS-4 at 6 months and 12 months experienced by patients taking Miraxion in the trial over the 12-month period. The data were statistically significant at 6 months and 12 months. It is estimated that patients with a CAG repeat length of less than or equal to 44 represent approximately 70% of all HD patients.

Figure 1: Time course of TMS-4 ITT (LOCF), CAG < 44 

 

Significance was also achieved with Miraxion in the per protocol (PP) with CAG ≤44 as shown in Figure 2 below. In the PP group those patients on Miraxion experienced a 22.7% reduction or improvement in their TMS-4 score compared to those patients on placebo experiencing a 5.7% increase or worsening. Therefore a 28% difference in TMS-4 response occurred between the Miraxion and placebo groups during the 12 month trial. A reduction in TMS-4 of this magnitude typically reflects an improvement in patient quality of life and independence and reduction in reliance on day care.

Figure 2: Time course of TMS-4 PP (LOCF), CAG < 44


Initial Phase III Trial – Centre by Centre Analysis

The initial Phase III trial was conducted in six centres, Hammersmith Hospital in the UK, Johns Hopkins University, Harvard University and Emory University in the U.S., and the University of British Columbia in Canada and Monash University in Melbourne.

An analysis of the data on a centre by centre basis illustrated that Miraxion’s effectiveness in the CAG ≤ 44 group was consistent across each centre as shown in Figure 3 below, i.e. Miraxion worked better in patients with a CAG ≤ 44 than in patients with a CAG > 44, and that Miraxion worked better than placebo in patients with CAG ≤ 44. Values above the line show superiority versus placebo, values below the line inferiority. Consistently over the centres Miraxion has a superior effect in the groups with lower CAG repeats in comparison to the group with higher CAG repeats. (The sixth centre had 8 patients, only 4 of which had recorded CAG repeat lengths of which only 2 complied with the Protocol. Thus, there were not enough patients in centre 6 to generate any meaningful data.)

Figure 3: CAG ≤44 versus CAG >44 by Centre (PP Group at 12 Months)

Initial Phase III Trial – Two Year Follow-Up3

After 12 months double-blind therapy, patients were given the option to continue with open-label treatment: those previously treated with placebo were switched to Miraxion. Patients were followed up after 18 and 24 months. Efficacy was measured using the TMS-4.

From 135 patients randomized in the original study, 121 completed 12 months double-blind treatment. Of these, 120 elected to continue treatment. 110 patients completed a further 12 months of treatment (53 received Miraxion throughout and 57 switched from placebo to Miraxion). Progressive improvements from baseline of up to 11.2% were seen in TMS-4 over 24 months of Miraxion treatment with no evidence of a deterioration of response over this timescale. Placebo-treated patients showed no significant change in TMS-4 over 12 months. However, once switched to Miraxion, these patients demonstrated an improvement (8.9%) similar to that of the group treated with Miraxion throughout. The response seen in placebo patients after switching to Miraxion, support earlier findings in this initial Phase III study that Miraxion improves motor function within 6 to 12 months.

The promising data from this initial Phase III study of Miraxion supported further evaluation of Miraxion in the larger Phase III studies in the US and Europe, as described above.


REFERENCES 
  1. Miraxion abstract as presented at the Inaugural HSG Clinical Research Symposium December 2007 on the 12 month data from the US Phase III trial (TREND HD) with Miraxion in Huntington’s Disease – “A Randomised, Controlled Trial of Ethyl-EPA for the Treatment of Huntington’s Disease: 12 Month Data”. Available upon request from Amarin
  2. Puri et al – Neurology 2005;65:286-292 – “Ethyl-EPA in Huntington’s Disease. A Double Blind, Randomised, placebo-controlled trial”
  3. Miraxion poster and abstract as presented at the 11th International Congress of The Movement Disorders Society conference in Istanbul, Turkey, 2007 – “Miraxion Treatment for Huntington's Disease – A Two Year Follow-Up”. Available upon request from Amarin.
FURTHER READING
  • Ethyl EPA Poster as presented at the ASENT meeting in Washington, 2003 – “Ethyl EPA in Huntington’s Disease: A Randomised, Placebo-Controlled Trial”. Available upon request from Amarin.
  • JJ Clifford et al - Phospolipid Spectrum Disorders in Psychiatry and Neurology, Chapter 46 – “Transgenic and Other Models of Huntington’s Disease: Focus on Lipid Modulation”
  • K. Vaddadi – Nutrition, Volume 20, Issue 10, Pages 942-947 – “Essential Fatty Acids in the Treatment of Huntington’s Disease”
  • B. Puri – Phospholipid Spectrum Disorders in Psychiatry and Neurology Chapter 48 - “A Randomised Trial of Ethyl Eicosapentaenoate in Patients with End-stage Huntington’s Disease”
  • Wheelcock et al – Neurology 2003;60:998-1001 – “Predictors of Nursing Home Placement in Huntington’s Disease”
  • Brinkman et al – Am J Hum. Genet 1997;60:1202–1210 – “The Likelihood of Being Affected with Huntington’s Disease by a Particular Age, for a Specific CAG Size“
  • Langbehn et al – Clin Genet 2004;65:267-277 – “A New Model for Prediction of the Age of Onset and Penetrance for Huntington’s Disease Based on CAG length”
  • Marder et al – Neurology 2002;59:1622– 624 – “Relationship Between CAG Repeat Length and Late-Stage Outcomes in Huntington’s Disease”
  • Mahant et al – Neurology 2003;61:1085-1092 – “Huntington’s Disease: Clinical Correlates of Disability and Progression”
  • Puri et al – NeuroReport 2002;13:123-126 – MRI and Neuropsychological Improvement in Huntington’s Disease Followed by Ethyl-EPA Treatment”