Phase 2 Randomized, Double‑Blind, Placebo‑Controlled, Dose‑Ranging Study of Subcutaneous Nemolizumab in Adults with Systemic Sclerosis Assessing Skin Thickness

The primary objective is to assess the effect of nemolizumab on cutaneous thickness versus placebo after 52 weeks of treatment in adults with systemic sclerosis and to identify the dose that provides optimal therapeutic benefit, while a secondary primary aim is to characterize the safety profile of the investigational product throughout the 156‑week extension period.

Secondary objectives include:

• Evaluation of efficacy on predefined secondary endpoints compared with placebo after the 52‑week treatment period.
• Assessment of safety outcomes in the nemolizumab and placebo groups after 52 weeks.
• Characterization of pharmacokinetic parameters and immunogenicity of nemolizumab during the 52‑week treatment phase.

A total of 98 adult participants (both male and female) diagnosed with systemic sclerosis according to the 2013 ACR/EULAR classification criteria were enrolled. Eligible individuals were at least 18 years of age, with disease duration of ≤5 years for diffuse cutaneous disease or ≤2 years for limited cutaneous disease, and demonstrated a modified Rodnan Skin Score of ≥12 and <30 (diffuse) or ≥8 (limited) at both screening and baseline. Participants were required to be on stable background therapy for at least three months, which could include nintedanib, methotrexate (≤25 mg weekly) or mycophenolate derivatives (≤3000 mg daily) provided dosing restrictions were observed. Lifestyle considerations included the use of effective contraception for women of child‑bearing potential and men with female partners capable of pregnancy, with abstinence or approved contraceptive methods mandated throughout the study and for 12 weeks after the final dose. Exclusion criteria encompassed limited cutaneous disease with positive anti‑centromere antibodies, use of methotrexate in combination with mycophenolate agents, and anti‑RNA polymerase III positivity in participants with disease duration >18 months. The cohort represented a vulnerable population, encompassing patients of reproductive age, and was selected based on the outlined clinical and serologic parameters to evaluate the efficacy of nemolizumab versus placebo on cutaneous thickness and safety outcomes.

This Phase 2, multicenter study evaluates subcutaneous nemolizumab versus matching placebo in adult patients with Systemic sclerosis using a randomized, double‑blind, placebo‑controlled, dose‑ranging design. After an eligibility screening visit, participants who meet the inclusion criteria undergo a baseline visit during which they are assigned to one of the study arms and receive the first dose. Subsequent visits occur every four weeks through week 52 (the main treatment period) to assess efficacy (primary endpoint: change from baseline in modified Rodnan Skin Score at week 52) and safety, and to collect pharmacokinetic and immunogenicity samples. Following week 52, eligible participants may continue into a 156‑week extension with the same visit schedule to evaluate long‑term safety. The total participant involvement may extend up to 208 weeks from randomization. Criteria for early termination include occurrence of serious or intolerable treatment‑emergent adverse events, development of pregnancy, withdrawal of informed consent, or violation of major protocol requirements. All visits include physical examination, vital signs, laboratory assessments, pulmonary function testing, and completion of electronic patient‑reported outcome instruments.

The investigational product, Nemluvio 30 mg powder and solvent for solution for injection supplied in a pre‑filled pen, contains the monoclonal antibody nemolizumab. It is formulated as a solution for injection and is administered by the subcutaneous route. Each dose consists of the reconstituted 30 mg preparation delivered via the pen, with dosing intervals defined in the study protocol and recorded by site personnel to ensure adherence.

The comparator is a placebo consisting of lyophilized powder for solution for injection, identical in appearance to the active product. It is also administered subcutaneously using the same pre‑filled pen system and follows the same dosing schedule as the investigational arm. Participant compliance with both the active and placebo administrations is monitored through injection logs and routine study visits.

The primary efficacy assessment is the change from baseline in modified Rodnan Skin Score measured at week 52. Skin thickness is evaluated using the validated modified Rodnan Skin Score at screening (baseline) and again at the end of the 52‑week treatment period. The difference between these two time points determines the primary efficacy outcome.

Secondary efficacy evaluations include the change from baseline in forced vital capacity at week 52, assessed by standardized pulmonary function testing, and the proportion of patients achieving a response according to the revised Composite Response Index in Systemic Sclerosis at week 52. These measures are collected at baseline and at week 52, and comparative analyses between nemolizumab and placebo groups will be performed using appropriate statistical methods for continuous and categorical data.