Clinical Trials

Inclusion Criteria:

• Written informed consent.
• Male or female between the ages of 18 and 75 years, inclusive, at Screening.
• Meets the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc with a total score of ≥ 9 (Van den Hoogen et al., 2013).
• Classified as having skin involvement proximal to the elbow and knee (diffuse cutaneous SSc subset by LeRoy and Medsger, 2001).
• At the time of enrollment, less than 36 months since the onset of the first SSc manifestation, other than Raynaud's phenomenon.
• Based on data available through medical history and/or medical records, the subject should have at least 1 of the following:
  • disease duration ≤ 18 months;
  • increase ≥ 3 in mRSS units compared with the last visit within the previous 1 month to 6 months;
  • involvement of 1 new body area with ≥ 2 mRSS units or 2 new body areas with ≥1 mRSS unit;
  • documentation of worsening skin thickening for subjects who did not have mRSS performed during the previous visit;
  • presence of tendon friction rub at Screening.
• Presence of at least 1 of the following features of elevated acute phase reactants at Screening:
  • high-sensitivity C-reactive protein (hsCRP) ≥0.6 mg/dL (≥ 6 mg/L);
  • erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr;
  • platelet count ≥ 330 × 10^9/L (330,000/μL).
• Skin thickening from SSc in the forearm suitable for repeat biopsy.
• mRSS units ≥ 15 at Screening.
• FVC ≥ 45% predicted at Screening, as determined by spirometry.
• Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

Exclusion Criteria:

• Positive for anti-centromere antibodies.
• Diagnosed with sine scleroderma or limited cutaneous SSc.
• Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogren's syndrome.
• Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.
• Any of the following cardiovascular diseases:
  • uncontrolled, severe hypertension (≥ 160/100 mmHg) or persistent low blood pressure (systolic blood pressure < 90 mmHg) within 6 months of Screening,
  •  myocardial infarction within 6 months of Screening,
  •  unstable cardiac angina within 6 months of Screening.
• DLCO < 40% predicted (corrected for hemoglobin). If severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider using a DLCO up to 6 months before the Screening Visit.
• Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with more than 1 oral PAH-approved therapy or any parenteral therapy. Treatment is allowed for erectile dysfunction and/or Raynaud's phenomenon/digital ulcers.
• Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids for dermatological conditions and inhaled/intranasal/intra-articular steroids are allowed).
• Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or anti-fibrotic drug within 4 weeks of Screening, including cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxic medication. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and low-dose prednisone, as follows: use of CellCept ≤ 3 g/day, Myfortic ≤ 2.14 g/day, methotrexate ≤ 15 mg/week and prednisone ≤ 10 mg/day (or equivalent dosing of glucocorticoids) is allowed. Subjects taking CellCept, Myfortic or methotrexate must have been doing so for ≥ 6 months and the dose must have been stable for ≥ 16 weeks prior to the Day 1 Visit. Prednisone must have been at a stable dose for ≥ 8 weeks prior to the Day 1 Visit. It is acceptable to be on background low-dose prednisone and anti-malarial drug along with CellCept, Myfortic or methotrexate. Rituximab must not have been used within 6 months of the Day 1 Visit.
• Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed).
• Use of a United States Food and Drug Administration-approved agent for SSc or an investigational agent for any condition within 90 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial. 12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
•  Women of childbearing potential or male subjects not agreeing to use highly effective method(s) of birth control throughout the trial and for 1 month after last dose of trial drug. Male subjects must refrain from sperm donation and females from egg/ova donation for this same time period.
• Pregnant or lactating women.
• Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the subject.
• Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842 clinical trial.
• Known history of positive test for human immunodeficiency virus.
• Active hepatitis (hepatitis B: positive hepatitis B surface antigen and positive anti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B surface antibody [HBsAb] or positive for HBcAb with a positive test for HBsAb and with presence of hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitis C virus [anti-HCV] and positive RNA HCV).
• Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis.
• Previous organ transplant (including allogeneic and autologous marrow transplant).
• International normalized ratio > 2, prolonged prothrombin time > 1.5 × the upper limit of normal (ULN) or partial thromboplastin time > 1.5 × ULN at Screening.
• Alanine aminotransferase or aspartate aminotransferase > 2 × ULN.
• Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 at Screening.
• Total bilirubin > 2 × ULN. Subjects with documented diagnosis of Gilbert's syndrome may be enrolled if their total bilirubin is ≤ 3.0 mg/dL.
• Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial.