Kalytera Therapeutics, Inc. (TSX VENTURE: KLY and OTC: KALTF) (the “Company” or “Kalytera”) today announced new proof-of-concept data demonstrating that R-107 reduces tissue damage and preserves organ function in a lethal rodent model of sepsis that resembles the circulatory shock seen with COVID-19 associated lung disease.
Kalytera announced on May 19, 2020 that it has entered into a binding Letter of Intent to acquire Salzman Group, Inc., a privately held company located in West Tisbury, MA (“Salzman Group”). Salzman Group is the owner of R-107, a proprietary drug with issued and pending composition of matter and method of use patents in approximately 40 countries, including the U.S., Australia, Brazil, China, Europe, India, Japan, Russia and South Korea.
Data from Rodent Study are Strongly Positive
Salzman Group studied the effectiveness of R-107 in a rodent model that is very severe, and is designed to mimic life-threatening COVID-19 infection. It is characterized by a 90% mortality rate within 7 days, with development of tissue injury in the lung, kidney, pancreas, intestine, and liver. This model correlates closely with the human clinical presentation of circulatory shock and multiple organ failure, and thus has served for many decades as a key benchmark in the initial assessment of novel candidate therapeutics for treatment of human sepsis and circulatory shock.
Results from this study were strongly positive, with the active moiety of R-107 demonstrating increased survival from 10% to 90% in septic mice over a week of follow-up. This extraordinary improvement in survival was reflected in the results of blood tests and microscopy showing full tissue protection in all the organs examined, including the liver, lung, and small intestine.
The study was conducted by Professor Salvatore Cuzzocrea, President of the University of Messina, and former President of the European Shock Society. A sepsis-like syndrome was created in mice by inoculation with bacterial endotoxin, thereby producing a massive release of pro-inflammatory signaling molecules (“cytokines”) such as interleukin-1 beta and tumor necrosis factor alpha, which together are able to trigger the full hemodynamic, hematologic, and immunologic manifestations typical of the lethal human circulatory shock caused by COVID-19 infection.
R-107 is a Nitric Oxide Prodrug
R-107 is a liquid prodrug of nitric oxide that can be administered by injection, unlike nitric oxide gas, which requires a special type of delivery device, and complex administration by trained respiratory therapists. When administered by injection, R-107 is slowly hydrolyzed, releasing its active moiety, R-100, which in turn steadily and slowly releases nitric oxide into the lung tissue. This depot-like action of R-107 results in a sustained delivery of nitric oxide, allowing for a smooth delivery of the active drug over several days following a single dose of R-107.
Put simply, following injection, R-107 is metabolized, and releases R-100, which in turn releases nitric oxide into the tissues of the lung. R-100 is the payload of R-107.
The Potential of Nitric Oxide in Treatment of COVID-19 Associated Lung Disease
There are currently no approved treatments for lung disease caused by the COVID-19 virus, which is a severe form of lung failure called acute respiratory distress syndrome (“ARDS”). ARDS is the leading cause of death in COVID-19.
Nitric oxide is a gas that improves blood flow in areas of the lungs that are getting air, increasing the amount of oxygen in the blood stream.1
Along with being used to treat failing lungs, nitric oxide has also been found to have antiviral properties against coronaviruses.2
The Company is not making any express or implied claims that its product has the ability to eliminate, cure or contain the COVID-19 (or SARS-2 coronavirus) at this time.
R-107 Mechanisms of Action
R-107 is a first-in-class small molecule redox agent that has dual mechanisms of action:
First, the nitric oxide released by R-107 protects blood vessels in the lung in multiple ways:
- When nitric oxide is released, it dilates blood vessels, lowering blood pressure in the lung and allowing blood to travel more easily through the lung without spilling over into the lung tissue. Preventing fluid from building up in the lung tissue is important to health. Excess fluid that spills into the lung tissue makes the lungs stiff and hard to expand with each breath. Excess fluid also clogs up the air spaces in the lung so that air cannot enter the lung properly and oxygen cannot be absorbed into the blood. Nitric oxide released by R-107 prevents this unhealthy build-up of fluid in the lung.
- When nitric oxide is released, it protects the inner lining of the blood vessels (“the endothelium”). This protection ensures that white cells in the blood pass through the lung without sticking to the endothelium. White cells that stick to the endothelium can not only damage the blood vessel itself but they can also pass through the blood vessels and enter the lung tissue where they can cause vast damage from toxins they release. Nitric oxide released by R-107 prevents white cells from entering the lung.
Second, R-107 directly eliminates the toxins produced by white cells that are able to breach the endothelium and enter the lung. These free radicals are oxidizing agents, acting like bleach, and can severely damage lung tissue. Removal of these oxygen-centered free radicals is critical to good health of the lung because:
- These oxidants inactivate nitric oxide, so that it is no long available to protect blood vessels in the lung.
- These oxidants are toxic in their own right, directly destroying lung tissue.
Taken together, these dual mechanisms of action of R-107 allow for the release of nitric oxide into the lung tissues where it can protect blood vessels and lung tissue. These effects translate into a healthier lung that is able to easily expand and allow oxygen to enter the bloodstream.
“We are highly encouraged by the results of this study which demonstrate the potential of R-100, the active payload of R-107, to block tissue injury in an aggressive and clinically-predictive model of lethal sepsis in the mouse. We plan to clinically explore its efficacy in COVID-19 pulmonary infection and acute lung injury. We are also exploring its potential in other forms of acute lung injury, such as chlorine inhalation lung injury, smoke inhalation injury, and bacterial sepsis,” said Robert Farrell, CEO of Kalytera Therapeutics, Inc.
Kalytera plans to submit an Investigational New Drug Application (IND) to the Australian Therapeutic Goods Administration (TGA) and the U.S Food and Drug Authority (FDA) for a clinical study of R-107 in patients with COVID-19 associated pneumonia, and to initiate the trial immediately following clearance by these regulatory bodies.
Through its proven leadership, drug development expertise, and intellectual property portfolio, Kalytera seeks to establish a leading position in the development of novel medicines for a range of important unmet medical needs.
The Salzman Group is a privately held GMP and GCP compliant pharmaceutical development firm located in West Tisbury, MA. Based on over two decades of drug development experience and a strong track record, Salzman Group continues to generate groundbreaking pharmaceutical opportunities.
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This press release may contain certain forward-looking information and statements (“forward-looking information”) within the meaning of applicable Canadian securities legislation, that are not based on historical fact, including without limitation in respect of its product candidate pipeline, planned clinical trials, regulatory approval prospects, intellectual property objectives, success of any funding initiatives, and other statements containing the words “believes”, “anticipates”, “plans”, “intends”, “will”, “should”, “expects”, “continue”, “estimate”, “forecasts” and other similar expressions. Readers are cautioned to not place undue reliance on forward-looking information. Actual results and developments may differ materially from those contemplated by these statements depending on, among other things, the risk that future clinical studies, licensing and acquisition transactions, and/or any private placement or public offering may not proceed as expected or may produce unfavorable results, or that any financing may not proceed as planned, and the risk of the contemplated transactions not proceeding or closing on the terms initially contemplated. Kalytera undertakes no obligation to comment on analyses, expectations or statements made by third parties, its securities, or financial or operating results (as applicable). Although Kalytera believes that the expectations reflected in forward-looking information in this press release are reasonable, such forward-looking information has been based on expectations, factors and assumptions concerning future events which may prove to be inaccurate and are subject to numerous risks and uncertainties, certain of which are beyond Kalytera’s control. The forward-looking information contained in this press release is expressly qualified by this cautionary statement and is made as of the date hereof. Kalytera disclaims any intention and has no obligation or responsibility, except as required by law, to update or revise any forward-looking information, whether as a result of new information, future events or otherwise.