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Phase IIa Clinical Development of EN101 for the Treatment of Myasthenia Gravis

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Introduction/Background

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 signalling. 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.

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 10 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.

Aims/Hypothesis

EN101 is undergoing clinical development for the treatment of MG.

Research

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.

A Phase Ib clinical trial was conducted by Ester to assess the safety, efficacy and pharmacokinetics of oral EN101 in MG patients. This study was a multicentre (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 (10¼g/kg, 50¼g/kg and 150¼g/kg) were given in the first day, followed by a daily dose of 500¼g/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.

Ester commenced a Phase IIa dose finding randomized double blind study in MG patients. 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. 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. 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. 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).

Conclusion

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.

Relevance/Opportunity

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. Please enquire regarding licensing or codevelopment partnerships.

Development status

Preclinical

Patent information

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.

http://investor.amarincorp.com/releasedetail.cfm?ReleaseID=504699

June 10, 2009

Amarin Announces Results From Exploratory Phase 2a Study Of EN101 In Myasthenia Gravis

Amends Ester Neurosciences Acquisition Agreement

DUBLIN, Ireland, June 10, 2009 – Amarin Corporation plc (NASDAQ: AMRN) today announced encouraging top line results from an exploratory Phase 2a multi-centre, dose-ranging, cross-over clinical study of EN101 in patients with myasthenia gravis, a chronic autoimmune disease characterized by muscle weakness which can be life-threatening.

Thomas Lynch, Chairman and Chief Executive Officer of Amarin, commented “We are pleased to announce this update regarding the EN101 program. EN101 is one of our CNS assets that we plan to partner as a consequence of the Company’s recent focusing of development efforts on cardiovascular disease programs. We expect this data will be of interest to any future potential partners.”

Dr. Declan Doogan, Head of Research and Development of Amarin, added “The results from this exploratory Phase 2a study support the further clinical evaluation of EN101 in myasthenia gravis.”

The primary objective of the exploratory study, for which interim results had previously been announced, was to assess the efficacy and safety of three doses of EN101 each given orally once daily for one week in patients with myasthenia gravis. The final results of the study indicate that 10mg, 20mg and 40mg of EN101 resulted in a statistically significant reduction in Quantitative Myasthenia Gravis (QMG) score from baseline of 11.8% (p=0.001), 16.8% (p<0.001) and 20.3% (p<0.001), respectively. Importantly, EN101 was also shown to be safe and well tolerated.

The 31-patient study was performed in six centers in the U.K., Israel and Serbia. Each dose of EN101 was administered to patients for one week and was separated by a one week wash-out on pyridostigmine, often the first-line treatment for myasthenia gravis. Efficacy was assessed by evaluating changes in the QMG score, an established questionnaire that evaluates signs and symptoms of myasthenia gravis.

Amarin also announced that it has amended the Ester Neurosciences Limited (“Ester”) acquisition agreement entered into in December 2007. The amendments, which reflect Amarin’s intention to seek a partner for EN101, provide for the release of Amarin from research and development diligence obligations contained in the original agreement, with remaining contingent milestones only being payable from fees and milestones received from any future partners. As part of the amended agreement, Amarin will issue 1,315,789 ordinary shares to the former Ester shareholders.

About EN101
EN101 is an orally delivered oligonucleotide with complementary mechanisms of action. As an antisense agent it preferentially suppresses the "read-through" or "R" isoform (AChE-R) of acetylcholinesterase (AChE). This is believed to enhance neuromuscular functioning while avoiding the negative cholinergic effects currently observed with conventional, non-selective acetylcholinesterase inhibitors. EN101 also acts on re-balancing innate immunity features, which are often impaired by conventional acetylcholinesterase inhibitors. By elevating acetylcholine levels EN101 further reduces circulating pro-inflammatory cytokines through the "cholinergic anti-inflammatory reflex".

EN101 and its underlying technology are protected by a number of issued patents and pending applications in a number of territories worldwide, including the U.S. and Europe. EN101 has been granted orphan drug designation for the treatment of myasthenia gravis by the U.S. Food and Drug Administration and by the European Medicines Agency.

About Myasthenia Gravis
Myasthenia gravis (MG) is the most common primary disorder of neuromuscular transmission. It is a chronic autoimmune neuromuscular disease characterized by varying degrees of weakness of the skeletal (voluntary) muscles of the body. About 10% of MG patients develop a life-threatening weakness of the respiratory muscles needed for breathing, a condition called myasthenic crisis. MG occurs in all races, both genders and at all ages. According to the Myasthenia Gravis Foundation of America, the prevalence of MG is estimated at 14 to 20 per 100,000 population, with up to 60,000 cases in the U.S.

About Amarin
Amarin is a late-stage biopharmaceutical company with a focus on cardiovascular disease. The Company’s lead product candidate is AMR101, a prescription grade Omega-3 fatty acid comprising not less than 96% ultra-pure ethyl eicosapentaenoic acid (EPA), which is entering Phase 3 clinical trials for the treatment of hypertriglyceridemia under a Special Protocol Assessment (SPA) agreement with the U.S. Food and Drug Administration (FDA). Amarin recently established its research and development headquarters in Mystic, Connecticut with an experienced research and development team. Amarin’s programs capitalize on its lipid science expertise and the known therapeutic benefits of Omega-3 fatty acids in treating cardiovascular disease. The pipeline also includes proprietary next-generation lipid candidates, currently at preclinical stages of development.

Amarin has a range of clinical and preclinical stage compounds to treat central nervous system (CNS) disorders, including Huntington’s disease, myasthenia gravis, Parkinson’s disease and epilepsy, all of which are available for partnering. Amarin is listed in the U.S. on the NASDAQ Capital Market (“AMRN”). For more information please visit http://www.amarincorp.com

Contacts:
Amarin +353 (0)1 669 9020
Thomas Lynch, Chairman and Chief Executive Officer
Alan Cooke, President and Chief Operating Officer
Darren Cunningham, EVP Strategic Development and Investor Relations
investor.relations@amarincorp.com

Disclosure Notice
The information contained in this document is as of June 10, 2009. Amarin assumes no obligation to update any forward-looking statements contained in this document as a result of new information or future events or developments. This document contains forward-looking statements about Amarin's results of operations, business prospects and products in research that involve substantial risks and uncertainties. You can identify these statements by the fact that they use words such as "will", "anticipate", "estimate", "expect", "project", "forecast", "intend", "plan", "believe" and other words and terms of similar meaning in connection with any discussion of future operating or financial performance or events. Among the factors that could cause actual results to differ materially from those described or projected herein are the following: Amarin's ability to maintain sufficient cash and other liquid resources to meet its operating and debt service requirements; the success of Amarin's research and development activities; decisions by regulatory authorities regarding whether and when to approve Amarin's drug applications, as well as their decisions regarding labeling and other matters that could affect the commercial potential of Amarin's products; the speed with which regulatory authorizations, pricing approvals and product launches may be achieved; whether and when Amarin will be able to enter into and consummate strategic collaborations with respect to its products or product candidates on acceptable terms; the success with which developed products may be commercialized; Amarin's ability to protect its patents and other intellectual property; and claims and concerns that may arise regarding the safety or efficacy of Amarin's products or product candidates. A further list and description of these risks, uncertainties and other matters can be found in Amarin's Form 20-F for the fiscal year ended December 31, 2007, filed with the SEC on May 19, 2008 and Amarin's Form 20-F/A for the fiscal year ended December 31, 2007 filed with the SEC on September 24, 2008.