Inflammatory Response Research, Inc. (IRR) is a drug development company focused on pharmaceutical products for the treatment of inflammatory disorders and conditions. Given the COVID-19 pandemic our current focus is on a safe and effective therapeutic for use in the global treatment paradigm. In parallel development is a dose-pak for the common cold and a ‘First Response’ injectable to treat acute inflammation associated with traumatic brain injury.
Marketed commercially as Xyzal® in the United States by Sanofi-Aventis, levocetirizine is indicated for the relief of symptoms associated with allergic rhinitis and chronic idiopathic urticaria. The small molecule is considered an ideal, ‘insurmountable’ antihistamine by pharmacologists.
Marketed commercially as Singulair® in the United States by Merck, montelukast is approved for the treatment of allergy, asthma, and exercised induced bronchoconstriction.
The novel coronavirus presenting in Wuhan, China in late 2019 has been characterized as the seventh discrete coronavirus species capable of causing human disease. This virulent organism, responsible for the global pandemic, efficiently spreads from person to person veiled by a long incubation period of up to fourteen days. Addressing the COVID-19 therapeutic challenge is IRR401, a safe and effective combination therapeutic to decrease the inflammatory response elicited by the virus.
The Common Cold
The common cold is the most common infectious disease in humans. The number of cold treatment eligible patients in the US alone is expected to grow to approximately 170 million by 2020 (Mirubi Group). Presently there is no FDA approved product to simultaneously treat the symptoms and shorten the duration of the disease.
Traumatic Brain Injury
Traumatic brain injury represents a staggering cost to society of $80 billion / year and remains the US military’s #1 medical unmet need. To date there is no safe and effective product to actively treat inflammation following a head injury.
Levocetirizine + montelukast can be used in existing treatment paradigms to safely reduce morbidity and mortality in acute brain and lung injury without the side effects associated with steroids. Steroids were removed from the CNS treatment guidelines in 2004 due to an 18% relative increase in two-week mortality.
Synergy to Significantly Reduce Inflammation / Shorten the Course of the Clinical Presentation
Acting at multiple targets within both the innate and adaptive divisions of the immune system, oral dose and duration specific formulations for COVID-19 / common cold as well as an injectable ‘First Response’ medication for the treatment of traumatic brain injury (TBI) will be ideal therapeutics to treat inflammation in the 21st Century.
A detailed examination of the pharmacokinetics of levocetirizine at the cell level illuminates the unique anti-inflammatory properties that extend beyond the IgE mediated release of histamine. Most important are its low volume of distribution (0.4 L/kg; ideal drug ≤ 0.6 L/kg), prolonged dissolution time from the H1 receptor in an acidic ph, enhanced receptor affinity as the pure isomer of cetirizine, fastest onset (0.9 hour), fastest to steady state, (approximately 40 hours), and the highest receptor occupancy at 24 hours of any currently available antihistamine. Such parameters impart an anti-inflammatory effect by down regulating the signaling proteins: IL-4, IL-6, IL-8, and TNF-alpha as well as cellular adhesion molecules. The latter are a homogeneous group of inducible immunoglobulins, integrins and selectins involved in cell-to-cell adhesion, cellular recruitment, homing and healing.
Levocetirizine has been shown in a laboratory model to decrease ICAM-1, IL-6, IL-8, TLR3 expression and NF-kappa B activation resulting in decreased human rhinovirus (HRV) titers by log-2. Levocetirizine inhibits rhinovirus-induced ICAM-1 and cytokine expression and viral replication in airway epithelial cells. Separate research has shown that many rhinovirus serotypes share the same cellular receptor identifying ICAM-1 as the portal of entry into the cell. Independently, a one-log reduction in viral shedding results in a significant clinical benefit in HRV-infected patients. Safe and effective, levocetirizine is the only antihistamine in the world to independently improve quality of life across all domains (global health status SF-36; P<0.05 for all scales) as well as decrease overall health-care costs in a series of 551 patients with allergy / asthma treated for six months. Bachert C, et. al. J Allergy Clin Immunol. 2004;114(4);838-844.
Montelukast acts at the CysLT1 receptor to inhibit the physiologic action of leukotriene D4 (LTD4). Leukotrienes are protein mediators of inflammation similar to histamine; however, 100-1000x more potent on a molar basis than histamine in the lung. LTD4 is the most potent cysteinyl leukotriene in contracting smooth muscle, thereby producing bronchoconstriction. Contemporary cell and animal science underscore the potential use in patients with acute respiratory distress syndrome. Moreover, both montelukast and levocetirizine are known to reduce the quantity of neutrophils, eosinophils and their migration to the site of inflammation.
Clinical data to date generated over the past 10 years suggests the combination levocetirizine + montelukast has the ability to significantly reduce the inflammatory response / duration of disease across a spectrum of ssRNA viruses: Influenza A, Influenza B, and the common cold. Like influenza and the common cold, COIVD-19 is also a ssRNA virus. Existing cell and animal data support the therapeutic concepts.