The new coronavirus was first confirmed to infect people in Japan on January 15, 2020, and the cumulative number of people infected and those who have died so far is estimated to be 31 million and 62,000, respectively. The new coronavirus has mutated repeatedly since its infection began, and the spread of the mutated “Delta strain” caused progression to acute respiratory distress syndrome (ARDS), in which patients suffer from pneumonia and have difficulty in breathing, and the medical system has therefore been strained by many patients who have become severely ill. Patients with mild illnesses were treated at home or by staying hotels, but the existence of some patients with mild illnesses at the onset of the disease who rapidly became severely ill became a problem.

“Omicron strain” was highly infectious and the number of patients increased rapidly, but there were few cases of respiratory complications, many patients were asymptomatic or had mild illnesses, and the number of patients who became severely ill decreased dramatically as a result of vaccination. In May 2023, the classification of novel coronavirus under the Infectious Diseases Control Law was downgraded from “Class 2” to “Class 5,” and the infection control measures were relaxed. However, the novel coronavirus have not been contained, and there are still concerns about the emergence and spread of new mutant viruses that are highly infectious or cause severe illness. Therefore the situation should be monitored carefully.

The number of patients receiving treatment at home or as outpatients is expected to further increase. Therefore, it is expected that oral medications that can be easily and safely taken at home and prevent serious illnesses due to respiratory diseases will become increasingly important. Another problem is that the treatment for the sequalae of novel coronavirus infection (long COVID) has not significantly progressed.

Characteristics of Our Solution

We have learned valuable lessons from the past three years of novel coronavirus pandemics. The lungs are made up of numerous small botryoid-shaped sacs called alveoli. The interstitium, which is the wall of the alveoli, is the exchange pathway for oxygen and carbon dioxide. In interstitial pneumonia caused by novel coronavirus infection, this interstitium becomes thickened by inflammation, and the thickened interstitium becomes hard and remains fibrotic, making it difficult to take in oxygen. In novel coronavirus lung injury, microthrombi, in which blood vessels are clogged with a protein called fibrin in the lungs, were also a characteristic feature. Our RS5614 inhibits inflammation, fibrosis, and vascular damage, and may be effective in “interstitial lung disease” caused by novel coronavirus.

RS5614 can be a therapeutic drug that prevents interstitial lung disease from becoming more severe, especially a safe and convenient preventive and therapeutic drug (oral drug) that can be prescribed on an outpatient basis and taken at home.

In addition, while antiviral drugs and vaccines require repeated research and development to combat ever-mutating viruses, the action of RS5614 against interstitial lung disease does not require repeated research and development due to viral mutations. In addition, RS5614 could be used for interstitial lung disease associated with other diseases. Although the novel coronavirus infection has currently settled down, we would like to continue research and development of RS5614 for interstitial lung disease to not only prolong patients’ lives, but also to contribute to reducing the burden on the medical field and effectively utilizing limited medical resources.

Results to date

Early Phase II trial

An exploratory Phase II investigator-initiated clinical trial was conducted at seven medical institutions in Japan to evaluate the efficacy to prevent the aggravation and the safety of the PAI-1 inhibitor in the treatment of novel coronavirus lung injury. The first subject was enrolled in October 2020, when the “Delta strain” was prevalent, and the trial was completed in March 2021, making it a fast and efficient trial (the clinical study report was completed in June 2021). Although it was difficult to confirm the efficacy of the drug in the study without a placebo group, the results were summarized in the report as suggesting the efficacy and safety of RS5614, since all 26 subjects were considered “no deterioration” in the primary endpoint of “whether or not the patient deteriorated to the point of requiring ventilator management”, and since there were no serious adverse drug reactions that could not be denied as causally related to RS5614.

Late phase II study

Based on the results of the early Phase II investigator-initiated clinical trial, we conducted a placebo-controlled Phase II investigator-initiated clinical trial in 100 patients with novel coronavirus lung injury (moderate disease, hospitalized patients) in collaboration with 20 universities and other major medical institutions in Japan including Tohoku University, Kyoto University, Tokyo Medical and Dental University, and Tokai University. The trial started in June 2021 after the implementation plan was finalized based on a preliminary meeting with the Pharmaceuticals and Medical Devices Agency in April 2021. Due to a period of sharp decline in the number of infected patients and a decrease in the number of target patients with novel coronavirus lung injury (moderate disease, hospitalized patients) due to the emergence of the “Omicron strain”, the trial was extended until the end of October 2022 (75 enrolled cases), and the clinical trial summary report was completed in April 2023.

Although the primary efficacy endpoint showed no statistically significant difference between the RS5614 and placebo groups due to the small number of patients enrolled (75), there was a reduction in worsening lung injury in the RS5614 group versus the placebo group, and in particular, the reduction of the need for oxygen therapy in Moderate I patients (relatively mild disease who have pneumonia and dyspnea on admission but do not require oxygen therapy) has been observed. In addition, the proportion of patients requiring oxygen treatment among all the subjects was lower in the RS5614 group during the first 3 to 5 days after hospitalization, suggesting the effectiveness of RS5614 in early treatment. The RS5614 group also showed improvement in pneumonia by CT imaging, unlike the placebo group. The incidence of side effects was similar in the RS5614 and placebo groups, confirming the safety of RS5614 in patients with lung injury associated with novel coronavirus infection. The results of this study summarized that the expected effectiveness of RS5614 for Moderate I patients was suggested, and that further study is required, including the effectiveness of RS5614 for patients with mild disease at home, who are at high risk of developing severe disease. The results of the early and late phase II investigator-initiated clinical trials were published in the scientific journal “Scientific Reports” in January 2024.

Future Plans

RS5614 has a completely different mechanism of action than antiviral drugs and is an oral drug for interstitial lung disease. Although new coronavirus infection has now settled down, the number of patients receiving treatment at home or as outpatients is expected to increase with the lowering of the classification of novel coronavirus from “Class 2” to “Class 5” under the Infectious Disease Control Law. We are preparing to conduct the next phase of the clinical trial as soon as possible in the event of an outbreak of a new strain that causes interstitial lung disease.