Phase 2 Randomized, Double‑Blind, Placebo‑Controlled Study of IV MTX‑474 for Safety and Efficacy in Diffuse Cutaneous Systemic Sclerosis (dcSSc)

The primary objective is to evaluate the change from baseline in skin thickening in participants with diffuse cutaneous systemic sclerosis, providing a direct measure of therapeutic efficacy on the disease’s hallmark fibrotic manifestation. Secondary objectives include:

• assessment of the safety and tolerability of MTX-474, addressing potential adverse events and overall tolerability profile;
• evaluation of the impact of MTX-474 on the disease‑associated gene expression signature, offering insight into molecular mechanisms of response;
• characterization of the pharmacokinetic profile of MTX-474, informing dose optimization and exposure‑response relationships.

The trial enrolled 42 adult participants diagnosed with Diffuse Cutaneous Systemic Sclerosis according to the 2013 ACR/EULAR classification criteria. Both male and female subjects were included, with all participants aged 18 years or older; the study did not specify an upper age limit. Eligibility required a forced vital capacity (FVCpp) of at least 45 % and a diffusing capacity for carbon monoxide (DLCO) of at least 30 % of predicted values. Participants were selected based on disease duration and skin involvement measured by the modified Rodnan Skin Score (mRSS): individuals within two years of their first non‑Raynaud’s symptom needed an mRSS > 7; those between two and five years required an mRSS of 10–30, negativity for the RNA polymerase 3 autoantibody, and no prior spontaneous skin improvement of ≥4 points; those between five and ten years required an mRSS > 15–≤ 25 with similar antibody and improvement constraints. Additional inclusion criteria mandated the ability to provide informed consent, comprehension of study materials, and completion of all protocol visits. Women of childbearing potential had to present a negative pregnancy test and use highly effective contraception throughout treatment and for a defined post‑treatment period. No specific dietary or physical‑activity requirements were described, and the trial allowed enrollment of vulnerable individuals as defined by the protocol.

The study is a Phase 2, randomized, double‑blind, placebo‑controlled trial evaluating the safety and efficacy of a 4 mg/kg intravenous infusion of MTX‑474 compared with a matching placebo (0 mg/kg NaCl and dextrose solutions) in participants with diffuse cutaneous systemic sclerosis. Eligible individuals are screened, then randomized 1:1 to receive study drug on Day 0, with subsequent infusions administered according to the protocol schedule. Participants attend a screening visit to confirm eligibility, a baseline visit for randomization and first infusion, and follow‑up visits at Weeks 2, 4, 8, 12, 16, 20, and 24, the final visit serving as the end‑of‑study assessment. The primary efficacy endpoint is the mean change from baseline to Week 24 in the modified Rodnan skin score; secondary endpoints include safety assessments, laboratory evaluations, gene‑signature response at Week 12, and pharmacokinetic profiling. Each participant’s involvement spans approximately 24 weeks plus the initial screening period. Early termination may occur for reasons such as serious adverse events, protocol non‑compliance, pregnancy, or investigator discretion based on safety or efficacy concerns.

The investigational product MTX-474 is supplied as a sterile IV infusion solution for infusion. Each dose consists of 4 mg/kg administered intravenously as a single infusion per dosing cycle. The formulation is a solution for infusion prepared for intravenous administration.

The control arm receives a placebo comprising two separate infusion solutions: a 0.9 % sodium chloride solution (NaCl 0.9 % B. Braun) and a 5 % dextrose (DEXTROSE/VIOSER) solution, both provided as solutions for infusion with no active pharmaceutical ingredient (dose 0 mg/kg). Both placebo solutions are administered intravenously in the same volume and schedule as the active product to maintain blinding.

All study treatments are delivered via peripheral or central venous access according to the protocol‑specified infusion rate. Infusions are performed on day 1 of each treatment cycle and repeated at predefined intervals throughout the study period. Compliance with the dosing schedule is monitored by documenting infusion start and end times, infusion volumes, and any deviations in the electronic case report form. Adverse events and infusion‑related reactions are recorded for each administration.

Efficacy will be assessed primarily by measuring the mean change from baseline to Week 24 in skin thickness using the modified Rodnan skin score (mRSS) for each treatment arm.

The mRSS will be performed by trained evaluators using the validated scoring system at baseline and at the Week 24 visit. Changes in scores will be compared between the MTX‑474 and placebo groups.

Secondary efficacy evaluation includes the proportion of participants achieving a predefined gene‑signature response on skin biopsy specimens obtained at Week 12. Biopsy samples will be collected at baseline and at Week 12 and analyzed for the target gene expression profile.