Science

AgoneX Biopharmaceuticals, Inc. is a clinical stage biopharmaceutical company developing and commercializing safe and effective therapeutics for migraine headaches. The company plans to develop both a product (AGX-201) and an industry unique proprietary technology for the treatment and prevention of migraine headaches.

Migraine is an extraordinarily common neurological disease, affecting 39 million men, women and children in the U.S. and 1 billion worldwide. Migraine is the 3rd most prevalent illness and the 6th most disabling illness in the world. (source: https://migraineresearchfoundation.org/about-migraine/migraine-facts/). The National Headache Foundation estimates that US businesses lose $50 billion each year because of absenteeism, reduced employee productivity, and medical expenses caused by headaches. (JD Bartleson, Treatment of Migraine Headaches, Mayo Clin. Proc. 1999; 74; 702-708). Neurologists agree that safer and more effective prophylactic agents represent the most critical unmet need in the treatment of both episodic and chronic migraine.

Histamine

Histamine is the primary compound released from basophils and tissue mast cells during an allergic reaction. There are four other causes of histamine release:

1) a reaction to certain drugs, peptides, venom, and other “liberators”;

2) a physical insult (thermal, vibratory, radiant, or exertional);

3) stress (chemical, traumatic, or osmotic); and

4) spontaneous basophil release, which is higher in atopic individuals (Clemis JD., 1995).

Histamine has a broad spectrum of activities in various physiological and pathological conditions including cell proliferation, differentiation hematopoiesis, embryonic development, regeneration, wound healing, aminergic neurotransmission and various brain functions (sleep, nociception, food intake and aggressive behaviour), secretion of pituitary hormones, regulation of gastrointestinal and cardiovascular systems.  It also regulates inflammatory reactions, modulation of the immune response, functioning of the endocrine system and homeostasis (Shahid et al. 2009).

Histamine’s physiologic actions are mediated by four types of cell receptors: H1, H2, H3 and H4. The principal receptors throughout the body are the H1 and H2 receptors. The H3 receptors help regulate the synthesis and release of histamine from central nervous system histaminergic nerve endings.

Histamine H1 Receptor

The histamine H1 receptor is a unique G-protein coupled receptor because the stimulation of the receptor induced and the receptor up-regulation through increase of gene expression.  Correlation between symptom and histamine H1 receptor mRNA level was observed, and the data strongly suggest that histamine H1 receptor gene is an allergic disease sensitive gene.  Histamine through H1R excites neurons in most brain regions, including brain stem, hypothalamus, thalamus, amygdala, septum, hippocampus and cortex.

Histamine H2 Receptor

The human H2R is mostly involved in suppressive activities of histamine, while stimulatory effects are mediated through H1R.  The activation of H2R regulates various functions of histamine including heart contraction, gastric acid secretion, cell proliferation, differentiation and immune response. H2Rs have been shown to downregulate the release of histamine in basophils and mast cells.

Histamine H3 Receptor

The H3R was discovered in 1983 by the group of J.C. Schwartz in Paris.  They mediate synthesis of histamine and inhibition of histamine release from histaminergic neurons.  The activation of H3 receptors can inhibit histamine synthesis and release. Histaminergic dysregulation has been found in different Central Nervous System (CNS) disorders.  Additionally, loss of H3R function is associated with behavioral state abnormalities, reduced locomotion, late-onset obesity, and an increased severity of neuroinflammatory diseases.

Histamine H4 Receptor

The last of the four histamine receptors, H4 receptor (H4R), was identified in the year 2000. Since that time, H4R has been implicated in cellular mechanisms related to immune systems, inflammatory processes, and allergic reactions. H4 receptors are expressed in bone marrow, spleen, peripheral blood, small intestine, heart, colon, lung, etc.

MIGRAINE: In 2003, Gazerani, et al. demonstrated a correlation between migraine, histamine, and immunoglobulin E.   Serum samples were collected (for histamine levels and Immunoglobulin E levels) from 70 patients (18 – 58 years) with migraine during an attack and during remission and from 45 healthy volunteers. The migraine patients were divided into two groups according to their history of allergies (60% having a history of allergies and 40% without a history of allergies).  Plasma histamine levels were significantly elevated (P ≤ 0.0001) in patients with migraine both during symptom-free periods and during migraine events when compared to the control group.

From Gazerani et al., 2003
During symptom free-states, the histamine levels were up to 70% higher in migraine patients than in healthy individuals.

From Gazerani et al., 2003
During a migraine event, the histamine levels were up to 200% higher in migraine patients than in healthy individuals.

Histamine levels in migraine patients are higher than in healthy individuals due to premature mast cell degranulation.

Nerve and mast cells both contain histamine receptors (H1R-H4R) and there is bidirectional interactions between nerve and mast cells

Mast cells are the main source of natural histamine in the body. They can be imagined as small “eggs”; the strength of the “shell” of the mast cell “egg” depends on the level of histamine in the body. In migraine-susceptible individuals, the “shell” is weakened by elevated levels of histamine. When a stressor/trigger (heat or cold, sleep pattern changes, weather changes, intense physical exertion, specific foods, etc.) is introduced in the body of a susceptible individual, mast cells degranulate (break open) and release histamine.  This “rush” of histamine triggers a reaction in adjacent nerve cells and manifests as a painful migraine headache.

AgoneX Biopharmaceuticals’ proprietary product (AGX-201) and proprietary technology modulate the activity of histamine receptors on the mast cells. Histamine receptor modulation creates more balanced levels of histamine in the body by making the shell of the mast cell “eggs” stronger and more resistant to degranulation.  As a result, susceptibility to migraine headaches is greatly reduced. The treatment consists of subcutaneous injections of AGX-201.

Drawing a parallel between the CGRP Receptor Antagonist approach and the Histamine Receptor Modulation approach, as shown below, one can see why the CGRP approach works in approximately 50% of patients:  the CGRP receptor antagonists inhibit mast cell degranulation DOWN-STREAM, while the Histamine Receptor Modulation approach (AGX-201, with AgoneX Biopharmaceuticals’ proprietary technology) prevents mast cell degranulation UP-STREAM.

We believe AgoneX Biopharmaceuticals’ technology will prove to be superior to CGRP antibody migraine products at all levels: safety, efficacy and cost. AgoneX Biopharmaceuticals has filed an Investigational New Drug (IND) application with the FDA.

The FDA agreed the company can start its development with Phase II clinical trial; Phase III may not be required if our Phase II trial and its results are sufficiently compelling.

AgoneX Biopharmaceuticals, Inc. intends to advance its industry unique technology in order to provide patients with a safe and effective treatment for migraine headaches.