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EN101

EN101 FOR MYASTHENIA GRAVIS

INTRODUCTION

In December 2007, Amarin acquired Ester Neurosciences Limited (Ester), a private research and development company based in Israel. As a result of the acquisition, Amarin gained access to EN101 and its underlying platform technology.

EN101 is an orally available antisense oligonucleotide, specifically targeting the “read-through” or “R” isoform (AChE-R) of acetylcholinesterase (AChE). The molecule suppresses the production of the AChE-R protein without the negative cholinergic effects currently observed with conventional inhibitors.

Myasthenia gravis (MG) is the first target indication for which EN101 is undergoing clinical development. MG is a chronic disease characterized by fatigable weakness of muscles due to autoimmune attack on acetylcholine receptors at the neuromuscular junction, and the resulting interference with nerve-to-muscle signaling. Since acetylcholine action is regulated by AChE, and since MG is characterized by under stimulation of the muscles, drugs blocking the activity of AChE have proven an effective palliative treatment for this disease. The prevalence of myasthenia gravis in the United States is estimated at 14-20 per 100,000 population, approximately 42,000 to 60,000 cases in the United States (more on Myasthenia Gravis).

The current standard of care for MG includes a combination of AChE inhibitors (neostigmine, pyridostigmine, physostigmine), steroids, immunosuppressants, plasmapheresis, intravenous immunoglobulins and thymectomy. However, as EN101 is intended primarily for use as a first line of treatment in MG, direct competition to EN101 is represented by the currently available AChE inhibitors for MG.

According to our research, one of the main drawbacks of the AChE inhibitors is their side effect profile e.g. drooling, loose stools, hypersalivation. Excessive medication of such AChE inhibitors in MG can lead to cholinergic crisis characterized by severe generalized weakness and respiratory failure. Another drawback of current AChE inhibitors is their dosing regimen - require multiple daily dosing (up to 15 pills a day in some cases). AChE inhibitors also appear to be only moderately effective, wearing off in the majority of patients after a few months. After this time patients are typically given corticosteroids and / or immunosuppressants, both of which are associated with long term side effects.

For more information on myasthenia gravis please refer to http://www.myasthenia.org/

Intellectual Property

EN101 and its underlying platform messenger RNA silencing technology are protected by a number of granted patents and pending applications in a number of territories worldwide, including the US and Europe. EN101, specifically, is protected by a granted composition of matter patent in the US which extends to 2022.

EN101 has been designated an orphan drug in both the US and Europe, which means it will have seven years marketing exclusivity post its approval in the US, and up to 10 years in Europe. 

DEVELOPMENT TO DATE IN MYASTHENIA GRAVIS

To date, EN101 has demonstrated safety and efficacy in a Phase Ib clinical trial and is undergoing further safety and efficacy evaluation in an ongoing Phase IIa clinical trial, where interim data analysis suggests EN101 is more efficacious and has an improved side effect profile over current AChE inhibitors.

Preclinical Development

In order to evaluate the potential therapeutic use of EN101 in improving muscle activity in MG patients, a set of in-vivo studies with EAMG animal model were designed.

Experimental Autoimmune Myasthenia Gravis (EAMG) shares many characteristic features of human MG: (a) muscle weakness (aggravated by exercise and relieved by cholinesterase inhibitors) (b) decrementing compound muscle action potentials and low amplitude miniature endplate potentials (c) simplification of the postsynaptic membrane at neuromuscular junctions (d) circulating autoantibodies to nicotinic AChR (e) T-cell responding to AChR.

In EAMG, electromyographic (i.e. electrical properties of skeletal muscle) abnormalities were alleviated by nanomolar doses of EN101. Whereas animals treated with placebo or conventional anticholinesterases continued to deteriorate. A four week daily oral administration of EN101 improved survival, neuromuscular strength and clinical status in moribund EAMG rats.1

EN101 Phase Ib Clinical Study

A Phase Ib clinical trial was conducted by Ester in 2002 to assess the safety, efficacy and pharmacokinetics of oral EN101 in MG patients.2,3

This study was a multicenter (Israel and UK), open label, non-placebo controlled trial conducted in 16 patients with stable MG receiving at least 180mg of pyridostigmine daily. For assessment of myasthenia status, the Quantitative MG (QMG) score was used. The QMG score is used commonly in MG studies and measures the strength of 13 different muscle groups. Escalating oral doses of EN101 (10μg/kg, 50μg/kg and 150μg/kg) were given in the first day, followed by a daily dose of 500μg/kg for three days. Patients were monitored for one month thereafter.

Baseline QMG score was 14.9 (±7.25 SD). Of the 15 patients evaluated for efficacy, all showed an improvement in QMG score on day four as compared with baseline. The overall mean QMG change from baseline was 6.13 (±4.5 SD), a mean 46.5% improvement (p< 0.01).

EN101 was well tolerated with no major adverse events. Four patients participated in a four week extension study and no adverse events related to EN101 were reported.

EN101 Phase IIa Clinical Study (Ongoing)

In 2004, Ester commenced a Phase IIa dose finding randomized double blind study in MG patients. Interim analysis from this study were announced in May 2007.

This ongoing study is a randomized double blind study evaluating the safety and efficacy of three different doses of oral EN101; 10, 20 or 40 mg administered once daily to patients with MG. Each dose is administered for one week followed-up by one week of treatment with Mestinon (pyridostigmine) and a follow-up period of 4 weeks after the third EN101 treatment.

Efficacy is being measured by the QMG score; at different time points, without any treatment, during EN101 treatment and during Mestinon treatment. The percent improvement is defined as the difference between QMG score measured without any treatment (12-18 hours without Mestinon) and after treatment with Mestinon or EN101.

Safety parameters include blood, urine and ECG tests and reporting of adverse reactions.

To date this study has been conducted mainly in the UK and Israel.

An interim analysis on 16 of the 18 patients enrolled showed that the treated group with EN101 in all three doses exhibited an improvement in the mean QMG score when compared to treatment with Mestinon. The EN101 groups showed an average 20 to 25% improvement compared to baseline QMG score as shown in Figure 1 below. Furthermore, the percent change from baseline QMG score was statistically significant in all EN101 groups. While treatment arms (EN101 and Mestinon) were unblinded for the purposes of the interim analysis, the three EN101 doses remained blinded.

Figure 1. 

The efficacy of EN101 compared to Mestinon was also demonstrated in specific muscle group/functions that are mostly affected in myasthenia as shown in Figure 2 below.

Figure 2.

Ocular components (i.e. double vision and ptosis (drooping eyelids)) are among the more important components in the QMG score and were affected in some of the patients. In this study (and the Phase Ib study), EN101 showed an encouraging effect on these components, particularly double vision, compared to Mestinon. These are objective parameters that are generally considered difficult to influence by the patient or the physician.

There was also a substantial difference between the Mestinon and EN101 treatment in the swallowing and speech components. These components contribute greatly to the quality of life as they enable the patients to eat, drink and speak more easily.

The overall percent improvement in the hands and legs muscles was also much higher in the EN101 treatment group compared to Mestinon.

Safety analysis showed EN101 to be safe.

The above interim analysis is encouraging especially due to the relatively small number of patients evaluated. Based on these results and the results of the Phase Ib study, EN101 appears to have a more favourable safety and efficacy profile, as well as a more favourable dosing regimen compared to the current standard of care, Mestinon (pyridostigmine).

Amarin plans to complete the Phase IIa study and other non-clinical studies before conducting further trials.

REFERENCES

  1. Brenner et al - FASEB J. 17, 214–222 (2003) - “The role of readthrough acetylcholinesterase in the pathophysiology of MG”.
  2. Argov et al – Neurology 2007;69:699-700 – “Treatment of Human Myasthenia Gravis with Oral Antisense Suppression of Acetylcholinesterase”;
  3. Kaminski – Neurology 2007;69:629-630 – “Restoring the Balance at the Neuromuscular Junction”.

 

FURTHER READING

  • Admec et al – Behavioural Brain Research 2008 - “The Role of the Read Through Variant of Acetylcholinesterase in Anxiogenic Effects of Predator Stress in Mice”
  • Evron et al – Neurodegenerative Dis 2005;2:16-27 – “RNA-Targeted Suppression of Stress Induced Allostasis in Primate Spinal Cord Neurons”
  • Pollak et al – Ann Neurol 2005;57:741-745 – “Acetylcholinesterase Inhibitors Reduce Brain and Blood Interleukin-1beta Production”
  • Soreq et al - J Mol Med 2000;78:228-236 – “Antisense Approach to Isoform Specific Blockade of Acetylcholinesterase”
  • Nijholt et al – Molecular Psychiatry 2004;9:174-183 – “Stress Induced Alternative Splicing of Acetylcholinesterase Results in Enhanced Fear Memory and Long-term Potentiation”
  • Shohmai et al – J Mol Med 2000;78:228-236 – “Antisense Prevention of Neuronal Damages Following Head Injury in Mice”
  • Gillboa-Geffen et al – Blood, 109, 4383-4391 (2007) - “The Thymic Theme of Acetylcholinesterase Splice Variants in Myasthenia Gravis”
  • Perry et al – Neoplasia 2004;6:279-286 – “CREB Regulates AChE-R-Induced Proliferation of Human Glioblastoma Cells”