Kalytera Therapeutics, Inc. (TSX VENTURE: KLY and OTC: KALTF) (the “Company” or “Kalytera”) today announced proof-of-concept data demonstrating that R-107 reduces tissue damage and increases survival in a lethal rodent model of chlorine inhalational lung injury (“CILI”) that mimics the pulmonary damage of chlorine exposure in humans.
Kalytera to Acquire Salzman Group
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 are Strongly Positive
Salzman Group studied the effectiveness of R-107 in a murine model of overwhelming lung injury, designed to mimic life-threatening human CILI. This model is characterized by a 50% mortality rate within 21 days, accompanied by the development of profound levels of inflammation and tissue injury in the lung. The pulmonary damage resembles the human clinical presentation of CILI following acute exposure to high levels of chlorine gas released during warfare and terrorism, or from industrial and transportation accidents. R-107, or its active payload R-100, were introduced two hours after the exposure to chlorine, in order to mimic real world conditions in the civilian community and on the far-forward battlefield where the onset of therapy would not be made available at the earliest until a few hours after chlorine exposure.
Results from this study were strongly positive, with injection of R-107 or its active payload R-100 each increasing survival from 50% to 90% over 21 days of follow-up after chlorine exposure. The improvement in survival was supported by the results of tissue microscopy, which revealed a 50% reduction in both histologic damage and the level of inflammatory white cells in the lung. The salutary effect of both these agents was dose-dependent, allowing for a minimal dose to be identified that provided optimal protection of the lung. The improvement in survival and in the reduction in tissue damage will be correlated with the plasma concentrations of R-107 and R-100, in order to create a pharmacodynamic relationship, paving the way for future studies in large animals to be designed with optimized dosing regimens.
Professor Salvatore Cuzzocrea, President of the University of Messina and former President of the European Shock Society conducted this study.
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.
R-107 Mechanisms of Action in CILI
R-107 is a first-in-class small molecule redox agent that acts in two independent ways to protect the lung from CILI:
- CILI diminishes the concentration of the free radical nitric oxide within the lung, resulting in an increase in the tone of pulmonary blood vessels and a rise in the blood pressure of arterial blood coursing through the lungs. When nitric oxide is released by R-107, or its active payload R-100, it releases the constriction of the pulmonary vasculature, thereby diminishing the blood pressure throughout the lung and permitting blood to travel more easily through the lung without exiting the vasculature and entering the lung tissue. By maintaining the blood within the vascular compartment, and preventing its egress into lung tissue, R-107 ensures that the lung tissue remains free of edema, so that oxygen from the air may be readily exchanged with circulating blood.
- CILI directly damages the inner lining of the blood vessels (the “endothelium”) within the lung, so that circulating white cells are trapped, and can then transit into the tissue, causing inflammatory injury. In the presence of R-107, or its active payload R-100, nitric oxide is released and is able to protect the endothelium, ensuring that white cells transit the pulmonary circulation without attaching to the endothelium and entering the lung tissues.
“We are excited by the results of this study which unequivocally demonstrate the potential of R-107, and its active payload R-100, to stop lung damage in an aggressive and clinically-predictive model of chlorine inhalational lung injury in the mouse,” said Robert Farrell, President and CEO of Kalytera Therapeutics, Inc.
Development of R-107 for CILI Funded Under Contract with BARDA
The development of R-107 for the treatment of CILI has been funded in whole or in part with federal funds under Contract No. HHSO100201600016C from The Biomedical Advanced Research and Development Authority (“BARDA”). BARDA is a division of the Office of the Assistant Secretary for Preparedness and Response at the U.S. Department of Health and Human Services. In 2016, BARDA awarded Salzman Group a USD $15.9 million contract to develop R-107 as a treatment for CILI as part of ongoing preparedness efforts to protect the nation from potential health security threats. An additional USD $69.9 million could be released to Salzman Group over the next 36 months, as developmental milestones are achieved. The results of the murine study presented above were obtained in 2016 prior to BARDA funding.
Planned IND Submission
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 Phase 1 clinical study of R-107 in healthy middle-aged volunteers in order to establish that the drug is safe and well tolerated. This study is intended as a prelude to a definitive large animal investigation to prove the safety and efficacy of R-107 in a clinically relevant model of CILI.
Phase 2 and Phase 3 human clinical studies of R-107 will not be required for FDA approval for treatment of CILI under the FDA’s “Animal Rule” (21 CFR Part 314.600) that allows a drug to be registered without such studies if it is not ethical or feasible to test its efficacy in humans. Testing R-107 for clinical efficacy in CILI will not be possible because it is not feasible to evaluate the drug’s effectiveness in patients exposed to potentially fatal levels of chlorine gas. Instead, FDA approval for CILI will be based on a demonstration of safety in a Phase 1 study in human volunteers, and two efficacy studies of R-107 in the treatment of CILI in sheep. The in vivo portion of the first study in sheep has been completed, with positive survival data.
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.
Kalytera Therapeutics, Inc. (“Kalytera”) is committed to developing new treatments for a variety of diseases and disorders, by discovering, developing, manufacturing and delivering innovative human therapeutics. Kalytera focuses on areas of unmet medical need, and leverages its expertise to find solutions that will improve health outcomes and dramatically improve people’s lives.
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