Kalytera Therapeutics, Inc. (TSX VENTURE: KLY and OTC: KALTF) (the “Company” or “Kalytera”) today announced new proof-of-concept data for R-107, its liquid nitric oxide donor, in treatment of pulmonary arterial hypertension (“PAH”) in the setting of acute respiratory distress syndrome (“ARDS”). These results were obtained from a classic rodent model designed to mimic life-threatening COVID-19 lung disease.
Professor Salvatore Cuzzocrea, President of the University of Messina and former President of the European Shock Society, carried out the study.
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.
Strongly Positive Data from Animal Model of COVID-19 Associated Lung Disease
Salzman Group studied the effectiveness of R-107 in a rodent model that mimics life-threatening COVID-19 infection, triggered by injection of the plant alkaloid monocrotaline. This model is characterized by progressive fibrosis of lung tissue and the pulmonary vasculature that culminates in a tripling of pulmonary arterial blood pressure and a doubling of right ventricular heart size consistent with excessive strain on the right side of the heart. This rodent model correlates closely with the human clinical presentation of lung failure during COVID-19 associated ARDS and PAH.
R-107 is a donor of nitric oxide, a gas that is naturally present in the lung and which improves blood flow in areas of the lungs that participate in gas exchange. The natural role of nitric oxide is to modulate pulmonary vascular resistance and pulmonary blood pressure, matching blood flow in the lung to areas rich in oxygen. During lung infection, however, it is common to observe a deficiency of nitric oxide, triggering a rise in pulmonary blood pressure to dangerous levels that cause the right heart to fail. The combination of the high pressure in the vasculature and the leakiness of blood vessels during lung infection drives fluid through the blood vessel wall into the lung tissue, rendering the lung edematous and unable to efficiently absorb oxygen into the blood circulation. These deleterious effects of infection often require mechanical ventilation to prevent death from acute respiratory failure.
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 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.
Animal Data Also Strongly Positive in Animal Model of PAH
Proof of concept data in PAH were strongly positive, with R-107 preserving vascular function and restoring normal pulmonary arterial blood pressure in rats. These data demonstrated a return of pulmonary arterial blood pressure to normal baseline within 20 minutes after dosing with R-107, with no adverse impact on heart rate or peripheral arterial blood pressure. This extraordinary improvement was sustained for the full period of four hours of observation after dosing. Treatment with R-107 was not associated with apparent side effects: R-107 did not lower peripheral arterial blood pressure and it had no effect on heart rate. Taken together, these data signify that R-107 selectively lowered PAH and did not compromise peripheral hemodynamics. These preclinical findings are significantly superior in both their potency and duration of activity compared to results of currently marketed agents evaluated in the same animal models of PAH.
“There are currently no approved treatments for PAH caused by the COVID-19 virus, which is in fact a severe form of ARDS. Thus, we are highly encouraged by the results of this study, which demonstrate the potential of R-100, the active payload of R-107, to selectively lower blood pressure in the lung while leaving peripheral blood pressure unchanged. The absolute selectivity of R-107 in reducing the pulmonary but not the peripheral blood pressure is unprecedented for a systemically administered drug. These exciting findings have prompted us to explore the efficacy of R-107 in COVID-19 pulmonary infection and acute lung injury where the requirement for selectivity of the blood pressure lowering effect is obligatory for reasons of safety. In addition, we are exploring its potential in other forms of PAH, where selectivity of the blood pressure lowering effect is also essential, such as chlorine inhalation lung injury, smoke inhalation injury, idiopathic pulmonary fibrosis, persistent pulmonary hypertension of the newborn, bacterial sepsis, and other forms of ARDS,” said Robert Farrell, President and CEO of Kalytera Therapeutics, Inc.
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 clinical study of R-107 in patients with COVID-19 associated pneumonia, and to initiate the trial immediately following clearance by these regulatory bodies.
PAH associated with COVID-19 Infection is an Unmet Medical Need
Acute PAH, as occurs in the setting of COVID-19 associated ARDS, is generally treated in the intensive care unit where an injectable form of R-107 would be utilized, given the difficulty in administering oral drugs to intubated and mechanically ventilated patients. Accordingly, R-107 is currently under development as an intramuscular injectable agent.
Chronic PAH, in contrast, is a lethal condition that inexorably progresses to end-stage heart failure and death within 5-10 years. Current therapies have marginally improved the quality of life and decreased symptoms of PAH, but are not a cure, and do not alter long-term prognosis. All of the currently registered agents have significant side effects that limit their acceptability. A novel therapy for PAH that halts disease progression and is well tolerated would address this important unmet medical need. R-107 is orally bioavailable and thus may be given in chronic PAH on an outpatient basis in the form of an ingestible soft gel capsule.
Kalytera’s Option to Acquire Ex-U.S. Rights R-107 for Treatment of PAH
Salzman Group owns all rights under U.S. issued patents covering the use of R-107 in the treatment of PAH. Other companies affiliated with Salzman Group own all rights under EU, Australian, and other issued patents covering the use of R-107 in the treatment of PAH. These affiliates of Salzman Group have agreed to grant to Kalytera an option (the “Option”) for Kalytera to acquire all rights for the use of R-107 in the treatment of PAH under the EU, Australian, and other patents. The Option exercise price is USD $5 million payable in cash or shares of Kalytera’s common stock on or prior to expiration of the Option on December 31, 2020. If Kalytera exercises this option and acquires R-107 for the treatment of PAH in the EU, Australia, and other jurisdictions, Kalytera will become obligated to pay additional milestone payments to the affiliates on achievement of certain milestone events, including regulatory approvals of R-107 for treatment of PAH.
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.
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.
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