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Brevenal

Brevenal

Brevenal is being developed as a disease modifying agent for the treatment of mucociliary dysfunction in patients with cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).

Brevenal was discovered serendipitously in Karenia brevis, a single cell oceanic algae.
When in bloom (Red Tide) K. brevis, which synthesizes numerous ladder frame polyether compounds, is responsible for fish, shellfish and marine mammal death. The toxic compounds isolated from K. brevis, the brevetoxins, are toxic due to their activating effect on voltage-sensitive sodium channels (VSSC, Nav) at pico-molar concentrations.

Multiple roles for these compounds were described in K. brevis. A recent report describes an increase in brevetoxin and brevenal production in K. brevis in response to sudden changes in salinity, which implicates a role in osmoregulation or osmotic sensing. Brevetoxins were shown to localize to the chloroplast of K. brevis where it binds to the light-harvesting complex II (LHCII) and thioredoxin. A culture of K. brevis producing low levels of toxin was shown to be deficient in non-photochemical quenching (NPQ) and produced reactive oxygen species at twice the rate of the toxic culture, implicating a role in NPQ for the brevetoxins.

Curiously, the organism synthesizes brevenal, which acts on VSSC in an opposite manner to the brevetoxins, inhibiting rather than activating sodium current.

In airway epithelium VSSC, Nav 1.7, localizes near the endothelia reticulum (ER) in the cytosol. Brevenal binds to a novel site on the receptor. Brevenal treatment results in intracellular calcium release, which activates the calcium activated chloride channels (CaCC) resulting in chloride secretion. In CF airway epithelial cells, it elicits the secretion of airway surface liquid (ASL) as well as in inhibition of inflammation mediated ASL absorption, thereby restoring airways homeostasis.

Brevenal reverses cystic fibrosis transmembrane conductance regulator inhibitor (CFTRinh-172) inhibition of pulmonary mucociliary clearance (MCC). Brevenal also inhibits the bronchoconstrictive effect of the inflammatory mediator, neutrophil elastase (NE), found in high concentrations in CF and COPD airways. Due to these effects, brevenal exerts a disease modifying effect for the treatment of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD).

In in vitro and in vivo studies brevenal is additive to CFTR therapies. Brevenal can act as an adjuvant to CFTR therapies, as well as a sole therapy for patients with mutations not previously exploited by any other therapeutic agent. Improving normal lung function, clearing mucus and inhibiting inflammation will result in prevention of exacerbations, improved quality of life and possibly in prolongation of life.

Brevenal (C39H60O8; MW 656.4043) is manufactured from a proprietary strain of K. brevis in a biotechnology facility, under photosynthetic conditions. The compound is isolated from the cultured organism. This manufacturing process gives Silurian a unique competitive advantage; a well characterized small molecule, in a cell culture biotech environment.

Cystic Fibrosis

Initial indication to be pursued for brevenal will be the treatment of patients with cystic fibrosis. CF is an inherited genetic disorder resulting in life-shortening disease. CF is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. There are approximately 2000 known mutations, which are now classified into 5 classes of pathological outcomes to the function of the CFTR gene/ protein. All mutations result in dysfunctional sodium/ chloride transport across the cell membranes. Sodium/ chloride transport is crucial for the control of water in tissues. Normal function results in the production of thin, free-flowing mucus that lubricates the airways, digestive tract and reproductive organs. More so, normal physiological functions of the lung and pancreas are dependent on proper sodium transport.

Patients with CF encounter many and persistent infections and inflammatory conditions, which can be life threatening. Currently CF patients are most often treated with antibiotics and steroidal anti-inflammatory drugs to help control infections and persistent inflammation to the tissues.

Several new drugs, targeting the CFTR gene or protein, are either approved (Ivacaftor/Kalydeco) or are under development. They provide an exciting new era for CF patients. Yet, they have limited efficacy, and so far limited utility to the majority of CF patients. More so, there is already concern that they will result in acquired resistance and negative drug/drug interactions.

In 2012 the CF market was a $629M market, and is expected to grow to $4.5B by 2019.

CF patient's life expectancy has grown significantly in the past 4 decades. This results in longer use of chronic therapies, especially normal lung function.

With current price of Ivacaftor/ Kalydeco (Vertex) at >$300,000/ year, treating ~5% of CF patients, Brevenal sales can exceed $1B/year.

The company aims to enter Phase 1 clinical testing, for the treatment of Cystic Fibrosis, following the completion of pre-clinical work and IND filing.