Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Diffuse Cutaneous Systemic Sclerosis

A Phase 2, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Diffuse Cutaneous Systemic Sclerosis

To evaluate the efficacy of MT-7117 treatment in subjects with diffuse cutaneous systemic sclerosis (dcSSc) using the American College of Rheumatology Composite Response Index in Diffuse Systemic Sclerosis (ACR CRISS) at Week 52

Additional screening criteria check may apply for qualification.

Inclusion Criteria:

• Subjects who meet all the following criteria will be considered eligible to participate in the study:

  1. Must provide signed and dated informed consent form (ICF) to participate in the study. Subjects must be able to (in the judgment of the Investigator) understand the nature of the study and all risks involved with participation in the study. Subjects must be willing to cooperate and comply with all protocol restrictions and procedures including study visits.

  2. Male or female age ≥ 18 years at screening with documented diagnosis of systemic sclerosis (SSc), as defined using the 2013 ACR/European League Against Rheumatism (EULAR) criteria.

  3. Has diffuse cutaneous form of SSc according to Leroy and Medsger's criteria.

  4. Disease duration ≤ 5 years from the first non-Raynaud's phenomenon manifestation.

  5. Has an mRSS of 15 to 45 units at screening and have clinical skin involvement proximal and distal to the elbows, knees, or both or any truncal involvement, with or without face involvement.

  6. If disease duration is > 24 months defined as time from the first non Raynaud phenomenon manifestation, subject must fulfill at least 1 of the criteria listed below that are indicatives of active disease at screening:

     1. A documentation of new skin involvement that occurred within the past 9 months, or
     2. Increase in mRSS ≥ 3 units within the past 9 months, or
     3. Presence of TFRs or,
     4. C- reactive protein (CRP) ≥ 6 mg/L, or
     5. Erythrocyte sedimentation rate ≥ 28 mm/hr, or
     6. Platelet count ≥ 330 x 10^9/L (330,000/microliter).

     NOTE: Investigator should exclude all other acute intercurrent illness if subjects fulfilling laboratory criteria (d, e, f) only.

  7. Willing to follow restrictions regarding concomitant medications that are described.

  8. Female subjects who are non-lactating and have a negative urine pregnancy test at baseline visit prior to receiving the first dose of study drug.

  9. Female subjects of childbearing potential and male subjects with partner of child-bearing potential currently using/willing to use 2 effective methods of contraception including barrier method as described.

Exclusion Criteria:

- Subjects will be excluded from the study if any of the following criteria apply:

1. Has a history or presence of rheumatic autoimmune diseases other than dcSSc unless the dominant features of the disease are dcSSc, as determined by the Investigator.

2. Has a pulmonary disease with FVC ≤ 50% of predicted at time of screening.

3. Has a diagnosis of clinically significant resting pulmonary hypertension (if exceeding estimated right ventricular systolic pressure of > 40 mmHg estimated by transthoracic echocardiography [unless the right heart catheterization is normal within the last 6 months] or mean pulmonary artery pressure > 30 mmHg as measured by right heart catheterization) and requires treatment with more than one oral medication.

4. Has a cardiac abnormality such as left ventricular failure with ejection fraction < 45%, significant arrhythmia, congestive heart failure (New York Heart Association Class II-IV), unstable angina, uncontrolled hypertension, or symptomatic pericardial effusion at screening.

5. Has a history of myocardial infarction in the last 26 weeks prior to screening.

6. Has a history of renal crisis within the past 52 weeks prior to screening.

7. Has a documented history of chronic kidney disease (stage 4-5, an estimated glomerular filtration rate [eGFR] < 30 mL/min at screening).

8. Presence or history of hepatobiliary disease at screening, determined as clinically significant by the Investigator after the discussion with the Sponsor Medical Monitor.

9. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) ≥ 2.0 × upper limit of normal (ULN), or total bilirubin > 1.5 × ULN at screening.

10. Has a history or presence of clinically significant disease not related to SSc [neurologic, renal, endocrinal, gastrointestinal cardiovascular, hepatic, dermatologic, hematological, musculoskeletal, genitourinary, thromboembolic, advanced arteriosclerosis, hyperthyroidism, moderate to severe hypertension, immunologic disease, pulmonary (e.g., uncontrolled asthma, emphysema, chronic obstructive pulmonary disease) or any other disorder] as determined by the Investigator at screening. Conditions deemed not-clinically significant according to the Investigator's discretion are acceptable.

11. Has a history or presence of psychiatric disease judged to be clinically significant by the Investigator and which may interfere with the study evaluation and/or safety of the subject.

12. Has any clinically significant disease or laboratory abnormality judged to be clinically significant by the Investigator and which may interfere with the study evaluation and/or safety of the subject at screening. Laboratory abnormalities include but not limited to any of the followings: Hemoglobin < 9 g/dL; WBC < 3,000/mm3 (< 3 x 10^9/L); platelets < 100,000/mm3 (<100 x 10^9/L).

13. Has a history of positive hepatitis B surface antigen, hepatitis C antibody, except for documented cure for the hepatitis B virus (HBV), defined as sustained, undetectable HBsAg and HBV DNA in serum and adequately treated hepatitis C virus (HCV) with documentation of sustained virologic response defined as undetectable HCV RNA at least 12 weeks after the end of treatment.

14. Has a history of positive human immunodeficiency virus (HIV)

15. Has a history of melanoma, familial melanoma (defined as having 2 or more first-degree relatives, such as parent, sibling, and/or child), or presence of melanoma and/or lesions suspicious for melanoma at screening.

16. Has a presence of squamous cell carcinoma, basal cell carcinoma, or other malignant skin lesions. Any suspicious lesions or nevi (Melanocytic Lesions) will be evaluated. If the suspicious lesion or nevi (Melanocytic Lesions) cannot be resolved through biopsy or excision, the subject will be excluded from the study.

17. Has history of any other malignancy(ies) in the last 5 years with the exception of cervical carcinoma in situ.

18. Has a history or planning to receive cell-depleting therapy or bone marrow transplantation during study treatment period.

19. Has a history of ultraviolet (UV) phototherapy within 6 weeks prior to screening or planning to receive UV phototherapy during study treatment period.

20. Treatment of SSc disease with

    1. Cyclophosphamide, rituximab, or cyclosporine received within 26 weeks prior to screening.

    2. Small molecules such as JAK inhibitors (e.g., tofacitinib) received within 12 weeks prior to screening.

    3. Pirfenidone received within 12 weeks prior to screening.

    4. Infliximab, certolizumab, golimumab, adalimumab, abatacept, tocilizumab within 10 weeks prior to screening.

    5. Etanercept within 4 weeks prior to screening.

    6. Oral, intravenous, or intramuscular corticosteroids (prednisone > 10 mg/day or equivalent) received within 30 days prior to screening

    7. Nintedanib within 12 weeks prior to screening.

    8. More than 1 of the immunosuppressant therapy listed below as concomitant therapy with study drug, has changed one of the medication below within 12 weeks prior to screening, or not on a stable dose of the same medication for at least 12 weeks prior to screening.

       • i. Mycophenolate (up to 3 g/day), or
       • ii. Mycophenolic acid (up to 2.14 g/day), or
       • iii. Methotrexate (up to 25 mg/Week), or
       • iv. Leflunomide (up to 20 mg/day), or
       • v. Azathioprine (up to 3 mg/kg/day).

21. Treatment with afamelanotide or other MC1R agonist within 12 weeks before screening (Visit 1).

22. Treatment with any drugs or supplements which, in the opinion of the Investigator, may interfere with the objectives of the study or safety of the subject.

23. Has previously exposed to MT 7117 (this does not include placebo treated subjects).

24. Has previously treated with any investigational agent within 12 weeks prior to screening OR 5 half-lives of the investigational product (whichever is longer).

25. Female subjects who are pregnant, lactating, or intending to become pregnant during the study.

26. Has a positive autoantibody status of anti-centromere antibody.