Premier Research

1. Males and females at least 18 years of age who give voluntary written informed consent to participate in the study.
2. Patients with a diagnosis of ILD based on computed tomography imaging, including:
   • Idiopathic interstitial pneumonia, including idiopathic pulmonary fibrosis
   • Connective tissue disease-associated ILD with FVC <70%
   • Hypersensitivity pneumonitis
   • Scleroderma-related ILD
   • Autoimmune ILD
   • Nonspecific interstitial pneumonia
   • Occupational lung disease
   • Combined pulmonary fibrosis and emphysema
3. Patients must meet a total of 2 or more criteria from at least 2 distinct categories below (ie, Category 1, Category 2, Category 3) based on the Investigator’s clinical judgment, within 180 days of Screening.

Category 1: Clinical tests

a. PFTs with at least 1 of the following results:

• DLCO <40%
• DLCO decline of ≥15% based on 2 most recent assessments
• Worsening DLCO (decline >10%) with stable FVC (decline <5%) (ie, worsening FVC/DLCO ratio) based on 2 most recent assessments

b. Historical HRCT with any of the following findings:

• Right ventricle enlargement: RV:LV ratio >1
• Pulmonary artery enlargement
• Pulmonary artery/aorta ratio >1.0
• Ventricular septal flattening
• Enlarged pulmonary arteries in the lung periphery

Category 2: Symptoms, oxygenation, exercise capacity, and BNP/NT-proBNP

• Symptoms disproportionate to ILD severity or changes in symptoms not explained by ILD progression
• Desaturation on 6MWT disproportionate to ILD severity in the opinion of the Investigator
• 6-Minute Walk Distance decline of ≥15% based on 2 more recent assessments
• Worsening desaturation requiring more supplemental oxygen
• Recent worsening desaturation
• BNP >200 pg/mL or NT-proBNP >395 pg/mL
• Physical exam findings (at least 1 of the following): syncope, jugular venous distension, ankle swelling/peripheral edema, ascites, loud P2 or S2 heart sound, or hepatomegaly

Category 3: Echocardiography

• RV systolic pressure >35 mmHg
• Any RV dilation or enlargement
• Other RV abnormalities in the clinician’s judgment
• Tricuspid annular plane systolic excursion <2 cm

Patients are excluded from the study if any of the following criteria apply:

1. Prior RHC with mPAP >20 mmHg
2. Currently on a Food and Drug Administration (FDA)-approved pulmonary arterial hypertension medication
3. Diagnosed with chronic obstructive pulmonary disease
4. Uncontrolled or untreated sleep apnea
5. Pulmonary embolism within the past 3 months
6. History of ischemic heart disease or left-sided myocardial dysfunction within 12 months of Screening, defined as LV ejection fraction <40% or pulmonary capillary wedge pressure >15 mmHg
7. Any other clinical features that, in the opinion of the Investigator, might adversely affect interpretation of study data or study safety, or make the patient unsuitable for RHC

1. Patient 40 Years or Older at the time of signed informed consent
2. IPF diagnosis:
   • Satisfying the 2022 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/ Latin American Thoracic Association(ATS/ERS/JRS/ALAT) diagnostic criteria (Raghu 2022) confirmed by the investigator
   • UIP or probable UIP based on chest HRCT obtained within 12 months of Day 0, or historical lung biopsy consistent with UIP
3. If receiving antifibrotic agents pirfenidone or nintedanib, patients must be receiving a stable dose for > 2 months prior to Day 0 and planning to stay on stable background therapy; if not receiving pirfenidone or nintedanib, patients must be naive to both drugs or not have received either for at least four weeks prior to Day 0 and remain off background therapy with no intention to start or re-start. (combination of nintedanib and pirfenidone not allowed)
4. If receiving monotherapy for the treatment of pulmonary hypertension (eg, phosphodiesterase 5 inhibitors, endothelin receptor antagonists, or inhaled or oral prostanoid therapy), patients must be receiving a stable dose for > 4 weeks prior to Day 0 and planning to remain on a stable dose throughout the study
5. FVC > 40% of predicted normal according to Global Lung Initiative (GLI) (Appendix B)
6. DLCO (corrected for hemoglobin) > 25% to <80% of predicted normal (Appendix B)
>

• Patient 40 Years or Older at the time of signed informed consent
• In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
• Known significant PAH, defined as previous clinical or echocardiographic evidence of significant right heart failure, history of right heart catheterization showing a cardiac index >2 L/min/m, or PAH requiring combination of PAH-specific therapies or any PAH parenteral therapy.
• Emphysema > 50% on HRCT assessed by the investigator, or the extent of emphysema is greater than the extent of fibrosis according to reported results from the most recent chest HRCT.
• Acute IPF exacerbation within six weeks prior to screening and/or during the screening period (investigator-determined).
• ILD associated with other known causes.
• Lower respiratory tract infection requiring antibiotics within four weeks prior to Day 0 and/or during the screening period.
• Major surgery (major according to the investigator’s assessment) performed within six weeks prior to Day 0 or planned during the course of the trial. (Being on a transplant list is allowed).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x ULN, Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula
• Underlying chronic liver disease (Child Pugh A, B, or C hepatic impairment).
• Cardiovascular diseases, and of the following:
  • Severe hypertension, uncontrolled despite treatment (>160/100 mmHg)
  • Myocardial infarction within six months of Day 0
  • Unstable cardiac angina
• Bleeding risk, any of the following:
  • Known genetic predisposition to bleeding
  • Patients who require:
    • Fibrinolysis, full-dose therapeutic anticoagulation
    • High dose antiplatelet therapy
• History of hemorrhagic central nervous system event within 12 months of Day 0
• Any of the following within three months of Day 0:
  • Hemoptysis or hematuria
  • Active gastro-intestinal bleeding needing hospitalization/intervention or peptic ulcer disease
• Coagulation parameters: International normalized ratio (INR) >2, prolongation of
prothrombin time and activated partial thromboplastin time by >1.5 x ULN
• History of thrombotic event within 12 months of Day 0
• Use of disease-modifying antirheumatic drugs, B-cell depleting therapies or immunosuppressive medications, within six months of Day 0
• Use of systemic corticosteroids equivalent to prednisone > 15mg/day within two weeks of Day 0
• Simultaneous use of pirfenidone and nintedanib at screening
• Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
• Any documented active or suspected malignancy or history of malignancy within five years prior to Day 0, except appropriately treated basal cell carcinoma of the skin, in situ squamous cell carcinoma of the skin, in situ carcinoma of uterine cervix or “under surveillance” prostate cancer.
• Evidence of active infection based on clinical exam or laboratory findings
• The patient has a confirmed infection with Severe Acute Respiratory Syndrome-Coronvirus-2 within the four weeks prior to Day 0 or during the screening period
• Women who are pregnant, nursing, or who plan to become pregnant while in the trial
• Women of childbearing potential not willing or able to use highly effective methods of birth control per ICH M3 that result in a low failure rate of less than 1% per year when used consistently for 28 days prior to and three months after IMP administration
• In the opinion of the Investigator, active alcohol or drug abuse
• Patients not able to understand or follow trial procedures including completion of self-administered questionnaires without help.

1. Participant is 18 years of age inclusive, or older at the time of signing the informed consent.
2. Documented diagnosis of SSc as defined by the American College of Rheumatology classification criteria
3. Diffuse cutaneous disease, defined as presence of thickened skin with mRSS >0 over at least one skin area proximal to elbows and/or knees in addition to distal areas involvement on Day 1
4. Total mRSS >15 on Day 1
5. Evidence of interstitial lung disease on centrally read screening HRCT
6. Anticentromere antibodynegative on central test at screening
7. Evidence for active or progressive disease, defined by at least one of the following criteria
   • Disease duration <24 month on Day 1
   • Disease duration >24 months but <5 years on Day 1 AND one of the following
     • Anti-topoisomerase I antibody positive on central test at screening, OR
     • Absolute decline in FVC >5% predicted as determined by a comparison of the screening lung function test and a previous lung function test done within 12 months prior to screening AND worsening respiratory symptoms, OR
     • Absolute decline in DLco >10% predicted as determined by a comparison of the screening lung function test and a previous lung function test done within 12 months prior to screening AND worsening respiratory symptoms, OR
     • Progressive ILD on HRCT, as assessed by the investigator comparing the screening scan and a previous scan done within 12 months prior to screening.
   • Disease duration >5 but <7 years on Day 1 AND anti-topoisomerase I antibody positive on central test at screening, AND one of the following:
     • Absolute decline in FVC >5% predicted as determined by a comparison of the screening lung function test and a previous lung function test done within 12 months prior to screening AND worsening respiratory symptoms, OR
     • Absolute decline in DLco >10% predicted as determined by a comparison of the screening lung function test and a previous lung function test done within 12 months prior to screening AND worsening respiratory symptoms, OR
     • Progressive ILD on HRCT, as assessed by the investigator comparing the screening scan and a previous scan done within 12 months prior to screening.
8. Participant has an area of uninvolved or mildly thickened skin that, in the opinion of the investigator, would allow SC injection at the abdomen or the front, middle region of the thigh
9. Participant is capable and willing to self-administer the study medication or has a caregiver who is capable and willing to administer the study medication throughout the study
10. Female participants eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:
    • Is a WONCBP
    • Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1% during the study intervention period and for at least 4 months after the last dose of study intervention.

    A WOCBP must have a negative highly sensitive pregnancy test within 24 hours before the first dose of study intervention

    • If a urine test cannot be confirmed as negative, a serum pregnancy test is required
11. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol

1. Systemic sclerosis-like illness, including but not limited to localized scleroderma, eosinophilic fasciitis, sclerodermoid graft-versus-host disease, fibro mucinous conditions, scleroderma-like conditions that are associated with environmental chemical and drug exposure
2. Primary diagnosis of a rheumatic autoimmune disease other than dcSSc, including but not limited to rheumatoid arthritis, systemic lupus erythematosus, polymyositis, dermatomyositis, systemic vasculitis, Sjogren’s syndrome, antisynthetase syndrome, or mixed connective tissue disease
3. FVC <45% of predicted, or a DLco <40% of predicted or requiring supplemental oxygen at screening
4. Pulmonary arterial hypertension prior to first day of dosing
5. SSc renal crisis within 6 months prior to the first day of dosing
6. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention or interfering with the interpretation of data
7. Obstructive pulmonary disease
8. Significant emphysema on screening HRCT
9. Significant allergies to human or murine proteins, humanized monoclonal antibodies, or contrast agents
10. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions
11. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years
12. Breast cancer within the past 10 years
13. ALT>2 x ULN
14. Total bilirubin >1.5 x ULN
15. Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice
16. QTc >450 msec or QTc >480 msec in participants with bundle branch block
17. Major surgery within 3 month prior to screening or planned during the duration of the study
18. An active infection, or a history of infections as follows:
    • History of opportunistic infections that have not resolved by 6 month prior to the first day of dosing or recurrent infection as determined by the investigator
    • A serious infection requiring treatment with IV antibiotics and/or hospitalization, if the last dose of antibiotics or the hospital discharge date was within 60 days of the first day of dosing
    • An acute or chronic infection requiring treatment with oral antibiotics or antiviral medications, if the last doe was received within 30 days of the first day of dosing. Prophylactic anti-infective treatment is allowed
    • Any active or unresolved bacterial, viral or fungal infection present on the first day of dosing, whether requiring treatment or not. This does not include fungal nail infections
    • Active or past osteomyelitis, unless fully resolved in the opinion of the investigator
19. Symptomatic herpes zoster within 3 month prior to screening
20. Evidence of active or latent TB as documented by medical history and examination, chest X-rays, and TB testing: either a positive TST or a positive TB test such as QuantiFERON-TB Gold Plus test
21. Confirmed PML or unexplained new-onset or deteriorating neurologic signs and symptoms
22. Have evidence of serious current suicide risk, defined as PHQ-9 score >10, or any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who in the investigator’s judgment, poses a significant suicide risk
23. Previous or planned major organ transplant or bone marrow transplant
24. Treatment with biologic agents, such as intravenous immunoglobulin or monoclonal antibodies, including marketed drugs, within 3 month or 5 half-lives (whichever is longer) prior to dosing
25. Treatment with rituximab within 6 months prior to Day 1
26. Treatment with non-biologic systemic immunosuppressive medication, other than mycophenolate, methotrexate or azathioprine within 3 months prior to Day 1
27. Treatment with cyclophosphamide within 6 months prior to Day 1
28. Use of anti-fibrotic agents including colchicine, D-penicillamine, pirfenidone or tyrosine kinase inhibitors within 4 weeks prior to Day 1
29. Cytotoxic drugs such as, chlorambucil, nitrogen mustard, or other alkylating agents within 6 months of Day 1
30. Treatment with IM or IV corticosteroids within 1 month prior to Day 1