This is a 2-Part study with Part A, a double-blind, randomized, placebo-controlled, PoC study to evaluate the efficacy, safety, and tolerability of efzofitimod in patients with SSc-ILD. The primary objective of the study is to evaluate the PoC for efficacy in a population with SSc-ILD. While improvement of ILD is the outcome of interest, the study will also evaluate changes in the skin. After initial screening (up to 4 weeks), approximately 25 eligible participants will be randomized 2:2:1 to 1 of 2 active (experimental) dose arms or placebo, administered every 4 weeks up to and including Week 20. Part B is an optional open-label extension to Part A in which participants can receive 450 mg efzofitimod every 4 weeks for 6 doses.

Inclusion Criteria:

1. Diagnosis of SSc based on ACR/ EULAR criteria (2013)
2. Overall duration of SSc < 84 months from the first non-Raynaud symptom manifestation prior to Day 1
3. HRCT obtained at the Screening Visit or within the 3 months prior to Screening consistent with SSc-ILD (adjudicated by a central reader) AND with pulmonary involvement > 10%
4. Clinical presentation at Screening consistent with lcSSc (up to 40% of patients) or dcSSc
5. MMF of ≥ 2 gm/day (or equivalent doses of other mycophenolate based compounds) for 3 months prior to Day 1 OR When documented intolerance to mycophenolates (in discussion with the Medical Monitor): treatment with maximum tolerated dose of MMF is acceptable, if < 2 gm/day, provided the cumulative duration of dosing has exceeded 3 months, OR An adequate dose and duration of an alternate immunosuppressant with a stable dose for the 4 weeks prior to baseline is also allowed.

Exclusion Criteria:

1. Pulmonary disease with FVC %pred ≤ 45% OR DLco %pred ≤ 30%; FEV1/FVC ratio < 0.7
2. Participants with pulmonary artery hypertension on parenteral therapy or with clinical evidence of right heart failure
3. HRCT obtained in the 3 months prior to Screening consistent with other confounding pathology.
4. Treatment with corticosteroids (> 10 mg/day of prednisone or equivalent) within 2 weeks prior to Day 1
5. Treatment with more than 1 immunosuppressant (e.g., MMF, methotrexate [MTX], azathioprine [AZA], or leflunomide)
6. Any treatment in the 12 months prior to Day 1 with any of the following: rituximab, intravenous immune globulin (IVIG), tocilizumab, cyclophosphamide, pirfenidone, tyrosine-kinase inhibitors (e.g., imatinib, nilotinib, dasatinib)
7. Rheumatic autoimmune disease other than SSc, Is an active, heavy smoker of tobacco/nicotine-containing products
8. History of (anti-Jo-1) anti-synthetase syndrome or Jo-1 positive at Screening