Amarantus Bioscience Holdings Inc (AMBS)

[JPetroInc]

L-Dopa-Induced Dyskinesia

On May 22, 2013, the Company (AMBS) entered into a letter of intent to in-license a Phase II drug candidate in L-Dopa-Induced Dyskinesia Parkinson's Disease from an undisclosed 3rd party. Once licensed, the Company intends to initiate a Phase IIb clinical trial within 12 months...

http://biz.yahoo.com/e/130613/ambs8-k.html

Earlier in June we wrote an article for Seeking-Alpha discussing Parkinson's Disease and the problems that exist for patients as the disease progresses, including psychosis and the development of L-Dopa-induced dyskinesia (LID).

http://scr.zacks.com/files/June%2019%202013_AMBS_Napodano_v001_n50g1c.pdf

One of the companies we highlighted in the article was Addex Therapeutics and their Phase IIb ready drug candidate, dipraglurant for LID. We encourage investors to view that article for a background on the PD-LID market opportunity.

In brief, LID is a major side effect of L-Dopa use. LID is characterized by hyperkinetic movements, including chorea (abnormal involuntary movement), dystonia (sustained muscle contraction, abnormal posture), and athetosis (involuntary convoluted movements). It is most common at times of peak L-DOPA plasma concentrations (peakdose dyskinesia), although it may also occur when plasma concentrations rise and fall (diphasic dyskinesia) or uring off-time (off-period dystonia). There are no approved treatment options for LID. Approximately 50% of PD patients will experience LID after 4 to 6 years on Levodopa therapy. The number rises to 90% after 10 to 15 years.

It is a significant problem for patients and physicians seeking treatment for PD. In fact, a survey of key opinion leaders (KOLs) in the Parkinson's treatment space showed that dyskinesia is the most important unmet medical need in the treatment of PD after a disease modifying agent (Datamonitor 2011).

A quick search of the BioMed-Tracker and ClinicalTrials.gov websites shows several candidates beyond Phase I development for LID:

1.) Amantadine: Amantadine is a generic antiviral that is used off-label for the treatment of LID. Its utility in the treatment of LID has been studied in a series of small clinical trials, many of which were open-label or lacked a control arm. A randomized double-blind trial in 18 patents with LID concluded that it reduced the duration of dyskinesia episodes by 60% and improved quality of life (1). A second study found that amantadine reduced dyskinesia symptoms by 45%, but that the duration of the effect was only 8 months and patients experienced a rebound of symptoms upon ceasing therapy (2). The utility of amantadine in the treatment of LID appears to result from its activity as an NMDA antagonist.

2.) Privately-held Adamas Pharmaceuticals recently completed an 80 subject Phase II/III trial of their extended release amantadine product Nurelin. In June 2013, they announced that the trial had met its primary endpoint of reduction in LID as measured by the MDS-Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Details will be presented at the 17th International Congress of Parkinson's Disease and Movement Disorders. Whether an extended release product will be seen by physicians and patients as adding value is difficult to assess, as the pharmacokinetics of immediate release amantadine are compatible with once daily dosing.

3.) Mavoglurant: Mavoglurant (AFQ056) is an antagonist of the glutamate receptor mGluR5 being developed by Novartis for several CNS indications, including LID. In a 31 patient Phase II trial in patients with moderate-to-severe LID, 15 patients were randomized to 25-150 mg mavoglurant twice daily and 16 patients were randomized to placebo. Patients in the active drug group experienced a significant reduction in symptoms as measured by the Lang-Fahn Activities in Daily living scale (p = 0.21) without negative impact on the effectiveness of the anti-Parkinson's efficacy of their ongoing dopaminergic therapy. Similar effects were seen in the second study, which examined the efficacy of mavoglurant in 28 patients with severe LID and used the Modified Abnormal Movement Scale to measure efficacy. According to Clinicaltrials.gov, a 234 patient Phase IIb trial (NCT01813019) has been completed but results from that trial have not yet been reported. A 140 patient Phase II trial examining a modified release formulation of mavoglurant has completed enrollment and the initiation of a Phase II trial is expected shortly after that trial completes. Novartis has guided for the filing of an sNDA in 2015.

4.) Dipraglurant: Addex Therapeutics is developing dipraglurant, an oral negative allosteric modulator (NAM) of the metabotropic glutamate receptor 5 (mGluR5), for the treatment of Parkinson's disease levodopa-induced dyskinesia (PD-LID). Dipraglurant was examined in a randomized, double blind, placebo controlled Phase IIa trial in 83 subjects with moderate-to-severe Parkinson's disease. Results show that dipraglurant was safe and well tolerated with the most important side effects being vertigo, blurred vision, and a drunk feeling but none of these was severe. Results on the modified AIMS scale showed statistically significant improvement on days 1 and 14, with clinically relevant reductions in the dipraglurant group on all three periods tested (days 1, 14, and 28). We note Addex has specifically been looking to out-license dipraglurant for the initiation of a Phase IIb study, although we suspect the
price tag is far above what Amarantus is looking to spend.

5.) Eltoprazine: Eltoprazine is being developed by privately-held Psychogenics for the treatment of LID and other CNS indications It is an agonist at the 5-HT1a and 5-HT1b receptors and an antagonist at the 5-HT2C receptor. A three arm, double-blind, randomized clinical trial compared eltoprazine 5 mg or 7 mg daily vs. placebo in 24 patients with "significant" LID symptoms. Each dose demonstrated statistically significant reduction in dyskinesia symptoms without adversely affecting levodopa efficacy. Eltoprazine was well-tolerated and there were no serious adverse events. These results were reported in mid-2012, and as a small private company mainly engaged in contract
research services, Psychogenics will need to partner this compound in order to move it forward into Phase IIb.

6.) Nuedexta: Avanir Pharmaceuticals is conducting a Phase II trial of Nuedexta (dextromorphan/quinidine) for the treatment of LID. This double-blind, randomized, placebo controlled trial will enroll 20 patients with at least moderate severity LID. The trial initiated in March 2013 and results are expected to be publicly available in the first half of 2014. This trial is co-sponsored by the Michael J. Fox Foundation for Parkinson's Research.

7.) Neu-120: Neu-120 is a selective uncompetitive NMDA receptor modulator being developed by Israeli-based Neurim Pharmaceuticals for the treatment of LID. Neu-120 also has MAO inhibitory and SDK-3B activities. A double-blind, randomized, placebo-controlled Phase II trial in 20 patients was initiated in January 2009 and completed enrollment in August 2009, but the results of this trial do not appear to have been disclosed. The compound remains listed in the Pipelinesection of the Neurim website.