Notice of Phase II Trial for Interstitial Lung Disease in Patients with Systemic Scleroderma

On March 15, 2023, we disclosed the “Notice of Adoption in AMED Practical Research Program for Intractable Diseases in FY2023”. This news is a supplemental explanation of Systemic Scleroderma and the phase II study of our RS5614.

Systemic scleroderma (SSc, designated intractable disease 51) is a systemic autoimmune disease (*1) characterized by vasculopathy and fibrosis of the skin and many organs, the etiology of which is still unknown. It is an intractable disease that causes symptoms such as skin hardening, interstitial lung disease (ILD), gastroesophageal reflux disease, cardiac involvement, and hand ulcers. ILD is a serious disorder that accounts for more than 30% of deaths among SSc patients in Japan, and even when ILD is not the direct cause of death, fibrosis impairs lung function, resulting in severe coughing and dyspnea that severely limits daily life. Current therapies are not effective enough, and even with advances in the treatment of autoimmune diseases, disease-related deaths account for 70% of deaths in SSc, while disease-related deaths are less than 10% of all deaths in rheumatoid arthritis and systemic lupus erythematosus. The development of effective therapies is therefore strongly desired for SSc and SSc-ILD.

Our RS5614 inhibits the activity of plasminogen activator inhibitor 1 (PAI-1) and suppresses inflammation, fibrosis, and vascular damage. The pathogenesis of SSc is primarily inflammation, fibrosis, and vasculopathy associated with autoimmunity, suggesting that RS5614 may inhibit the progression of SSc symptoms. In fact, RS5614 inhibited the lung fibrosis in the animal model of SSc (*2). RS5614 has fewer side effects than current SSc treatments such as steroids and immunosuppressive drugs (*3).

A phase II study (investigator-initiated clinical trial) will be conducted from fiscal 2023 to fiscal 2025 with a support of Practical Research Program for Intractable Diseases of the Japan Agency for Medical Research and Development (AMED). This is a placebo-controlled double-blind study (*4) to verify the safety and efficacy of RS5614 in 50 patients with SSc-ILD who are being treated with immunosuppressive drugs. The clinical trial will be conducted at 12 medical institutions in Japan, including Tohoku University Hospital and The University of Tokyo Hospital.

(*1) Autoimmune diseases: Our body has an immune system that recognizes pathogens such as bacteria and viruses that have entered the body and cancer cells that have formed in the body as foreign substances and attacks them. Immunity is an important mechanism for protecting the body, but autoimmune diseases occur when parts of the body that would not normally be recognized as foreign are recognized as foreign and attacked by the immune system.

(*2) Efficacy in SSc animal model: The efficacy of RS5614 was examined in a mouse model of systemic scleroderma, in which continuous subcutaneous administration of the anticancer drug bleomycin (subcutaneous administration model) causes inflammation and fibrosis in the skin and lungs. Mice were orally administered 1 or 5 mg/kg of RS5614 or 10 or 50 mg/kg of the control drug nindetanib daily from the same day that bleomycin was started. The results showed that RS5614 reduced the amount of hydroxyproline, a biomarker for fibrosis in the lung, more than nindetanib on day 28. In a model in which bleomycin is administered via the airway, RS5614 also significantly reduced lung hydroxyproline levels.

(*3) Safety of RS5614: RS5614 has been administered to more than 150 patients (chronic myeloid leukemia, novel coronavirus lung injury) to date, and 180 mg/day for 48 weeks in chronic myeloid leukemia (33 patients), and no serious adverse events attributable to RS5614 have been reported. It has a good safety profile.

(*4) Double-blind study: A clinical trial method in which eligible patients are randomly divided into two groups, one to receive the investigational drug (RS5614) and the other to receive a control drug (placebo with no effect), and both groups receive the drug simultaneously under conditions in which neither the physician nor the patient knows which drug will be administered. This is a method to avoid intentional intervention by physicians and any preconceptions of patients.

(Reference)

About AMED Adopted Projects

Name of the Program: Practical Research Program for Intractable Diseases in FY2023 (Drug Discovery, Regenerative/Cell Medicine, Gene Therapy)”

Name of the Project: Phase II Investigator-Initiated Clinical Trial of PAI-1 Inhibitor RS5614 for Interstitial Lung Disease Associated with Systemic Scleroderma (SSc-ILD)

Representative Research Organization: Tohoku University Graduate School of Medicine (Principal Investigator: Professor Yoshihide Asano)

Sharing Research Organizations: The University of Tokyo Graduate School of Medicine; Osaka University Graduate School of Medicine; University of Fukui School of Medical Sciences; Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University; Wakayama Medical University; Gunma University Graduate School of Medicine; Renascience Inc.

Q&A

question	Answer.
When will the clinical trial begin?	Preparations for the clinical study, including the Institutional Review Board at the clinical study institutions and the notification of the clinical trial plan, are underway, and the clinical trial is scheduled to start in the next fiscal year.
When did you file for approval of this drug?	The exploratory phase II study will be completed by the end of March 2026, after which a confirmation study will be required to apply for approval.
We expect that this drug has a new mechanism of action and is safer than existing drugs, but is the medical cost high?	The official price, the NHI drug price, is determined by the Ministry of Health, Labour and Welfare after regulatory approval, so the price is unknown at this moment. However, since it is a low-molecular-weight drug manufactured by chemical synthesis, the medical cost is expected to be lower than that of biopharmaceuticals such as antibodies. In addition, the drug does not require hospitalization and can be taken at home.
What other drugs are available for the treatment of interstitial lung disease associated with systemic scleroderma?	The efficacy and safety of nintedanib for idiopathic pulmonary fibrosis was confirmed in interstitial lung disease associated with systemic scleroderma and approved by the regulatory authorities in 2019. The drug is a tyrosine kinase inhibitor that targets key receptors, including signaling pathways that lead to fibrosis in the lungs. Nintedanib is taken orally twice daily.
Can RS5614 be taken at the same time as other systemic scleroderma medications?	Since our PAI-1 inhibitor has a different mechanism of action from existing drugs and has an extremely high safety profile, it may possibly show additive or synergistic effects when taken concomitantly with other medicines. We hope to clarify the safety and efficacy of such combination in this exploratory phase II study.