Anavex Life Sciences Corp (AVXL)

[TrueTrades]

A2-73 could be disease-modifying in MS. Biogen just failed there again. Maybe they should stop naming drugs ___mab!

http://www.bloomberg.com/news/articles/2016-06-07/biogen-plunges-after-ms-drug-fails-in-mid-stage-trial

http://www.nationalmssociety.org/For-Professionals/Clinical-Care/Managing-MS/Disease-Modification#section-5

http://bmcneurol.biomedcentral.com/articles/10.1186/s12883-016-0609-0

A2-73 acts as a S1 agonist and NMDA antagonist, just as DM, but without the serotonin reuptake inhibitor(SRI) properties. This may overcome the dose-limiting barrier of DM. An oral, well tolerated compound that can better DM's effects will be very promising in PBA for ALS and MS.



Friday, February 19, 2016

12:30 PM - 02:00 PM
Hyatt Regency New Orleans - Storyville Hall

Background: The sigma-1 receptor (S-1R) is an endoplasmic reticulum (ER) chaperone upregulated during ER stress; the receptor also regulates calcium homeostasis through its association with inositol triphosphate (IP3) at the ER membrane-associated mitochondrial interface. Activation of S-1R by a variety of agonists has neuroprotective effects both in vitro and in vivo. Dextromethorphan (DM) is a S-1R agonist as well as a weak N-methyl-D-aspartate receptor (NMDAR) antagonist, which in combination with quinidine sulfate is approved for treatment of pseudobulbar affect in multiple sclerosis (MS) and other neurologic diseases. We have reported that DM protects oligodendrocytes (OL) in vitro from the cytotoxic effects of staurosporine (inducer of apoptosis), glutamate (excitotoxicity), reactive oxygen species (ROS, induced by hydrogen peroxide, H202) and quinolinic acid (QA, a product of tryptophan indoleamine metabolism associated with inflammation) (Lisak et al. Glia, 2014).

Objectives:

To determine if another S-1R agonist might also have OL protective properties, which might be effective in progressive MS, we examined the effects of ANAVEX2-73 on protection of OL from these cytotoxic molecules. ANAVEX2-73 is a new clinical stage compound, which is chemically unrelated to DM, and a S-1R agonist, NMDAR antagonist, also targeting muscarinic receptors, currently in a Phase 2a trial in Alzheimer’s disease (Macfarlane et al. 2015 AAIC abstract).

Methods:

Glial cultures enriched in OL were prepared from newborn rat brain and cells identified by phenotypic markers (Lisak et al. Mult Scler, 2006). Cultures were incubated with various concentrations of ANAVEX2-73, 200 nanoM (nM)-200 microM, for 24 hours to assess cell death by trypan blue uptake. Since there was no toxicity noted at 200 nM, we then incubated cultures with staurosporine, glutamate, H2O2, QA or medium (control) and determined cell death.

Results:

ANAVEX2-73 reduced OL cell death induced by all 4 molecules by over 50%.

Conclusion:

ANAVEX2-73, which like DM is a S-1R and NMDAR antagonist but differs in other activities, protects OL from cytotoxic mechanisms involved in pathogenesis of MS lesions. Studies to determine the relative roles of S-1R agonism, NMDAR antagonism and muscarinic activities are objectives for future studies. ANAVEX2-73 and DM are small molecules that enter the central nervous system and thus have potential to provide protection of OL in MS.
http://www.nationalmssociety.org/For-Professionals/Clinical-Care/Managing-MS/Disease-Modification#section-5

The 003 study is aimed squarely at long term saftey. AVXL will uproot the entire spectrum of CNSD therapies if the trend stays positive.
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