MTX-474 for diffuse cutaneous systemic sclerosis (dcSSc)

A Phase 2 Randomized, Double-blind, Placebo-Controlled Study to Assess the Safety and Efficacy of MTX-474 in the Treatment of Participants With Diffuse Cutaneous Systemic Sclerosis (dcSSc)

This trial will test whether IV MTX-474 given every four weeks helps people with diffuse cutaneous systemic sclerosis compared with placebo.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 85 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Mediar Therapeutics (industry)
• Drugs / interventions: rituximab, tocilizumab, imatinib, nilotinib, chimeric antigen receptor, methotrexate, Cyclophosphamide, prednisone
• Locations: 5 sites (Newport Beach, California and 4 other locations)
• Trial ID: NCT07287670 on ClinicalTrials.gov

What this trial studies

This Phase 2, randomized, double-blind, placebo-controlled study assigns participants with dcSSc in a 3:2 ratio to receive MTX-474 or matching placebo by IV infusion every four weeks from Day 0 through Week 20, with an End of Treatment visit at Week 24 and safety follow-up at Week 28. Certain approved background dcSSc therapies (immunosuppressants, systemic glucocorticoids, or other antifibrotics) are permitted under prespecified criteria. Key measurements include modified Rodnan skin score (mRSS) at screening, baseline and each treatment visit, spirometry and DLCO for lung function, HRCT at screening and Week 24, skin biopsies at baseline and Week 12, and blood draws for safety labs, Ephrin receptor levels, and PK around the first and last doses. The design focuses on safety and signals of clinical effect on skin and lung-related markers over a 24–28 week period.

Who should consider this trial

Good fit: Ideal candidates are adults with diffuse cutaneous systemic sclerosis who meet the trial's specified disease-duration and mRSS thresholds (early or progressing disease within the protocol windows) and who can attend regular IV infusion visits, with some background therapies allowed under protocol rules.

Not a fit: Patients unlikely to benefit include those with limited cutaneous SSc, those who do not meet the trial's mRSS or disease-duration criteria, or those with severe uncontrolled organ failure or other exclusion criteria.

Why it matters

Potential benefit: If successful, MTX-474 could reduce skin thickening and slow organ-related progression in people with diffuse cutaneous systemic sclerosis.

How similar studies have performed: MTX-474 is an investigational therapy; while some immunosuppressive and antifibrotic agents have shown partial benefits in dcSSc, MTX-474's efficacy in this condition has not yet been established.

Eligibility criteria

Inclusion Criteria:

1. Diagnosis of diffuse cutaneous systemic sclerosis, classified according to 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR)
2. Participant is either:

   1. Within 2 years of their first non-Raynaud's symptom and their mRSS is \>7; OR
   2. \>2 and ≤5 years from their first non-Raynaud's symptom, their mRSS is between 10 and 30, they are negative for the RNA polymerase 3 autoantibody, and (1) they have never had any previous spontaneous improvement in skin thickening of ≥4 points by mRSS on exams performed by the same clinician, or (2) they were never clinically noted to have a meaningful spontaneous reduction in skin thickness if mRSS was never done; OR
   3. \>5 and ≤10 years from their first non-Raynaud's symptom, their mRSS is between \>15 and ≤25, they are negative for the RNA polymerase 3 autoantibody, and (1) they have never had any previous spontaneous improvement in skin thickening of ≥4 points by mRSS, or (2) were never clinically noted to have a meaningful spontaneous reduction in skin thickness if mRSS was never done.
3. Participant is ≥18 years of age at time of signing the ICF.
4. Able to understand the study and provide a signed, written ICF
5. Able to read and understand the language of the ICF and other study-related materials
6. Forced vital capacity (FVCpp) of ≥45 pp10
7. Have diffusing capacity of the lungs for carbon monoxide (DLCO) of ≥30 percent predicted at Screening
8. Willing and able to complete all protocol-required study visits and procedures
9. Participants of childbearing potential must have a negative serum pregnancy test at Screening.
10. All participants with reproductive potential must agree to use and follow medically approved, highly effective methods of contraception during treatment and until 5 half-lives or 125 days after the last dose, whichever is longer

Exclusion Criteria:

1. Concomitantly have another serious medical illness, which, in the opinion of the Investigator, would interfere with the participant's ability to complete the study
2. Participant is currently on immunosuppressive therapy, systemic glucocorticoids or other antifibrotic agents detailed as follows:

   1. Immunosuppresive agents: Cyclophosphamide (IV or oral if used in the 6 months prior to Screening), calcineurin inhibitors (if used in the 30 days prior to Screening), azathioprine (if used in the 30 days prior to Screening), Janus-kinase inhibitors (if used in the 30 days prior to Screening), rituximab (if used in the 6 months prior to Screening), tocilizumab (if used in the 60 days prior to Screening) or any other biologic Disease-Modifying Antirheumatic Drugs (DMARD, if used in the last 30 days or 3 half-lives prior to Screening, whichever is longer)
   2. Antifibrotic agents: nintedanib or pirfenidone (if used in the 30 days prior to Screening). Also, exclusionary if used within 3 months of Screening are tyrosine-kinase inhibitors with recognized anti-fibrotic activity (imatinib, nilotinib, etc.)
   3. Systemic glucocorticoids: equivalent doses of prednisone greater than 10 mg/day (≤10 mg/day allowed). Has received any pulse intramuscular (IM) or intravenous (IV) steroid within 1 month of Screening
   4. Other agents:

   i. mycophenolate mofetil unless on a stable dose for at least 6 months prior to Screening and there are no plans to adjust the dose during the study; ii. mycophenolic acid unless on a stable dose for at least 6 months prior to Screening and there are no plans to adjust the dose during the study; iii. hydroxychloroquine unless on a stable dose for at least 3 months prior to Screening and there are no plans to adjust the dose during the study; and iv. methotrexate unless on a stable dose for at least 3 months prior to Screening and there are no plans to adjust the dose during the study.
3. Previous or planned hematopoietic stem cell or solid organ transplantation
4. Previous treatment with chimeric antigen receptor (CAR)-T/CAR-NK therapy
5. Clinically significant PAH as determined by the Investigator at, or prior to first day of dosing (Baseline)
6. Current use of PAH medication (endothelin receptor antagonists, prostacyclin analogues, soluble guanylate cyclase stimulators) excluding calcium channel blockers and phosphodiesterase-5 inhibitors
7. Pregnant or currently breastfeeding
8. Aspartate transaminase (AST) or alanine transaminase (ALT) \>2.0 upper limit of normal
9. Creatinine clearance \<45mL/min
10. History of myocardial infarction, angina or congestive heart failure
11. International normalized ratio \>2 or partial thromboplastin time \>1.5 × upper limit of normal
12. Active infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C
13. History of clinically significant thrombotic event within 12 months prior to Screening
14. Positive anticentromere antibody
15. Systemic sclerosis renal crisis within 12 months prior to Screening
16. Confirmed diagnosis of overlap syndrome, systemic lupus erythematosus with anti-double strand (ds)DNA antibody, rheumatoid arthritis with anti-cyclic citrullinated peptide (anti-CCP) antibody, or systemic sclerosis mimics (eosinophilic fasciitis, scleromyxedema) at the time of inclusion in the study
17. Known malignancy or history of malignancy within 5 years of Screening other than non-melanoma skin cancer and in situ cervical cancer
18. Major surgery within 8 weeks prior to Screening or planned surgery during study period
19. Unable to routinely access veins for blood draws and IV infusions
20. Currently receiving another experimental agent or participating in another clinical trial. If a participant has recently received another experimental agent, then the last dose must have been at least 5 half-lives or 30 days (whichever is longer) prior to Screening
21. History of myocardial infarction, angina or congestive heart failure

Where this trial is running

Newport Beach, California and 4 other locations

• EncompaSSc site in Newport Beach, CA 92663 — Newport Beach, California, United States (RECRUITING)
• EncompaSSc site in Clearwater, FL 33765 — Clearwater, Florida, United States (RECRUITING)
• EncompaSSc site in Tampa, FL — Tampa, Florida, United States (RECRUITING)
• EncompaSSc site in Baltimore, MD — Baltimore, Maryland, United States (RECRUITING)
• EncompaSSc site in Boston, MA — Boston, Massachusetts, United States (RECRUITING)

Study contacts

• Study coordinator: Jeffrey Bornstein, MD

Conditions: Diffuse Cutaneous Systemic Sclerosis, MTX-474-S201, MTX-474, dcSSc participants, dcSSc, Adult, mRSS, EncompaSSc