An Israeli company is in the advanced stages of developing an effective treatment for Myasthenia Gravis (MG).

MG is a chronic and debilitating disease, which affects about 100,000 people worldwide, characterized by muscle weakness especially inability to open one's eyes, and hand and leg muscle problems. The body's immune system attacks acetylcholine receptors at the neuromuscular junction, interfering with normal muscular function. In severe cases the disease can involve the respiratory muscles, causing potentially life-threatening respiratory failure.

Ester Neurosciences, based in Herzliya, has recently completed a successful Phase Ib trial for its drug Monarsen - an orally-administered anti-sense therapy for the neurological disease. As a result, The U.S. Food and Drug Administration has granted Orphan Drug Designation status for Monarsen, (formerly known as EN101).

"Obtaining orphan drug designation marks an important step in our regulatory strategy for Monarsen," said Dr. Eli Hazum, CEO of Ester Neurosciences. "Current MG treatments which include anti-cholinesterases, steroids and immunosuppressants, offer limited efficacy and often cause unpleasant and sometimes dangerous side effects. Monarsen offers the prospect of an efficacious and safe product that can address a very large market," added Hazum.

Orphan drug designation is granted by the FDA for treatments that might provide significant benefit to patients with serious, life-threatening diseases that affect less than 200,000 persons in the United States. The Orphan Drug Act was created by Congress to provide assistance and incentives for sponsors to develop drugs judged to be of potential benefit for a qualifying disease.

Orphan Drug Designation status gives Ester, upon marketing approval, the exclusive right to market a drug of this kind for MG in the US for seven years. In addition to marketing exclusivity, the advantages of the designation include eligibility for research grants to conduct clinical trials, certain tax benefits, and an exemption from certain user fees at the time of submission for marketing approval of a new drug application. A similar Orphan Drug application has been made to European regulatory authorities.


The prevalence of myasthenia gravis in the United States is estimated at 14/100,000 population, approximately 36,000 cases in the United States. However, myasthenia gravis is probably under diagnosed and the prevalence is probably higher. Previous studies showed that women are more often affected than men. The most common age at onset is the second and third decades in women and the seventh and eighth decades in men. As the population ages, the average age at onset has increased correspondingly, and now males are more often affected than females, and the onset of symptoms is usually after age 50.

Ester's Phase Ib results for Monarsen were presented at a special session of the National Academy of Neurology earlier this year. The breakthrough study was the first demonstration of the safe and effective use of an orally-administered anti-sense therapy for a neurological disease.

This study, where sixteen patients received oral liquid Monarsen, demonstrated significant improvement in MG symptom severity, with no cholinergic effects, nor significant adverse events. Fourteen out of sixteen patients had better scores on the Quantitative Myasthenia Gravis (QMG) scale on the last day of dosing as compared to the initial baseline. Improvement of total QMG score for these days ranged from 27.8% to 53.4% (p less than 0.01). The Phase Ib trial results showed that Monarsen appears to have superior efficacy, longer duration of action and a more favorable side effects profile than currently used medications. Patient recruitment for extended clinical trials with Monarsen is underway.

Neurologist Jon Sussman, lead investigator at the Greater Manchester Neuroscience Centre, a UK trial site told Bio World, "We were very impressed with the striking improvement in the condition of our patients. Monarsen even enabled some patients with limited mobility to regain their ability to stand and to walk without aids."

The current means for treating MG is mainly a drug called Mestinon. While Mestinon is effective it deals only with symptoms of the disease and it has a short span of effectiveness. Mestinon works for only about two hours which means it must be administered up to six times a day by injection. It also has side affects such as diarrhea.

Monarsen on the other hand, is an antisense drug and works completely differently. Antisense technology was first developed about 10 years ago but first generation drugs started coming out only about four years ago. Monarsen is a third generation antisense drug and the first able to be administered orally instead of injected into the vein.

Antisense drugs have better penetration of the blood-brain barrier which many conventional drugs find difficult to cross. Thanks to its antisense technology, Monarsen need be administered only once a day, is more effective than Mestinon and has no known side affects.

According to Hazum, the same technology used in Monarsen can eventually be used to treat much more widespread diseases like Alzheimers and Multiple Sclerosis (MS). The company chose to target MG at first, because in US, drug markets of less than 100,000 potential patients, companies get exclusivity and the approval time is faster.

In addition, Alzheimers and MS are more complicated diseases which require testing on thousands of patients requiring tens of millions of dollars. In addition, approval takes longer - in this case up to three years more. Ester decided to initially target their concept on treating MG and then eventually partner with bigger companies for Alzheimers and other more widespread diseases.

"The next step is the Phase II study which we're preparing for, in which we'll compare head to head the efficiacy of Monarsen versus Mestinon. The studies will likely be held in the U.S. and Europe beginning at the end of the first quarter of 2004," Hazum told ISRAEL21c. According to Hazum, if testing continues to go well in the second and third phases the drug could be ready for market by 2005

Monarsen is based on pioneering research carried out by Prof. Hermona Soreq of the Hebrew University. Ester Neurosciences was established in 1997 by Medica Venture Partners, to commercialize discoveries pioneered by Soreq, who is the company's Chief Scientific Advisor.

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. 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).