A Multicenter Trial to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of HZN-825 in Patients With Diffuse Cutaneous Systemic Sclerosis

Inclusion Criteria:

1. Written informed consent.

2. Male or female between the ages of 18 and 75 years, inclusive, at Screening.

3. Meets the 2013 American College of Rheumatology/European League Against Rheumatismclassification criteria for SSc with a total score of ≥9 (Van den Hoogen et al., 2013).

4. Classified as having skin involvement proximal to the elbow and knee (diffusecutaneous SSc subset by LeRoy and Medsger, 2001).

5. At the time of enrollment, less than or equal to 72 months (6 years) since the onsetof the first SSc manifestation, other than Raynaud's phenomenon.

6. Skin thickening from SSc in the forearm suitable for repeat biopsy.

7. mRSS units ≥15 at Screening.

8. FVC ≥45% predicted at Screening, as determined by spirometry.

9. Willing and able to comply with the prescribed treatment protocol and evaluationsfor the duration of the trial.

Exclusion Criteria:

1. Positive for anti-centromere antibodies with the exception that subjects who arepositive for both anti-centromere and anti-topoisomerase 1 antibodies may beenrolled.

2. Diagnosed with sine scleroderma or limited cutaneous SSc.

3. Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia,scleroderma-associated myopathy and secondary Sjogren's syndrome.

4. Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.

5. Any of the following cardiovascular diseases:

6. uncontrolled, severe hypertension (≥160/100 mmHg) or persistent low bloodpressure (systolic blood pressure <90 mmHg) within 6 months of Screening,

7. myocardial infarction within 6 months of Screening,

8. unstable cardiac angina within 6 months of Screening.

9. DLCO <40% predicted (corrected for hemoglobin). If severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, considerusing a DLCO up to 6 months before the Screening Visit.

10. Pulmonary arterial hypertension (PAH) by right heart catheterization requiringtreatment with more than 1 oral PAH-approved therapy or any parenteral therapy.Treatment is allowed for erectile dysfunction and/or Raynaud's phenomenon/digitalulcers.

11. Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids for dermatological conditions andinhaled/intranasal/intra-articular steroids are allowed).

12. Use of any other non-steroid immunosuppressive agent, small biologic molecule,cytotoxic or anti-fibrotic drug within 4 weeks of Screening, includingcyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxicmedication. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and low-dose prednisone, as follows: use of CellCept ≤3g/day, Myfortic ≤2.14 g/day, methotrexate ≤20 mg/week and prednisone ≤10 mg/day (orequivalent dosing of glucocorticoids) is allowed. Subjects taking CellCept, Myforticor methotrexate must have been doing so for ≥6 months and the dose must have beenstable for ≥4 weeks prior to the Day 1 Visit. Prednisone must have been at a stabledose for ≥8 weeks prior to the Day 1 Visit. It is acceptable to be on backgroundlow-dose prednisone and anti-malarial drug along with CellCept, Myfortic ormethotrexate. Rituximab must not have been used within 6 months of the Day 1 Visit.

13. Known active bacterial, viral, fungal, mycobacterial or other infection, includingtuberculosis or atypical mycobacterial disease (fungal infections of nail beds areallowed) at the time of randomization.

14. Use of a United States Food and Drug Administration-approved agent for SSc or aninvestigational agent for any condition within 90 days or 5 half-lives, whichever islonger, prior to Screening or anticipated use during the course of the trial.

15. Malignant condition in the past 5 years (except successfully treated basal/squamouscell carcinoma of the skin or cervical cancer in situ).

16. Women of childbearing potential or male subjects not agreeing to use highlyeffective method(s) of birth control throughout the trial and for 1 month after lastdose of trial drug. Male subjects must refrain from sperm donation and females fromegg/ova donation for this same time period.

17. Pregnant or lactating women.

18. Current drug or alcohol abuse or history of either within the previous 2 years, inthe opinion of the Investigator or as reported by the subject.

19. Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842clinical trial.

20. Known history of positive test for human immunodeficiency virus (HIV). HIV testingis optional based on Investigator assessment, institutional practices or localguidelines to rule out suspected HIV or potential for a positive HIV result. Subjectconsent is required prior to HIV testing.

21. Active hepatitis (hepatitis B: positive hepatitis B surface antigen and positiveanti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B surfaceantibody [HBsAb] or positive for HBcAb with a positive test for HBsAb and withpresence of hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitisC virus [anti-HCV] and positive RNA HCV).

22. Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosingcholangitis.

23. Previous organ transplant (including allogeneic and autologous marrow transplant).

24. International normalized ratio >2, prolonged prothrombin time >1.5 × the upper limitof normal (ULN) or partial thromboplastin time >1.5 × ULN at Screening.

25. Alanine aminotransferase or aspartate aminotransferase >2 × ULN.

26. Estimated glomerular filtration rate <30 mL/min/1.73 m^2 at Screening.

27. Total bilirubin >2 × ULN. Subjects with documented diagnosis of Gilbert's syndromemay be enrolled if their total bilirubin is ≤3.0 mg/dL.

28. Any other condition that, in the opinion of the Investigator, would precludeenrollment in the trial.