Romilkimab shows potential for early diffuse cutaneous systemic sclerosis

Romilkimab – a novel engineered, humanized immunoglobulin(Ig)-G4 antibody – delivers significant skin benefits for individuals with early diffuse cutaneous systemic sclerosis (dcSSc), a subtype of SSc, a phase II proof-of-concept study has shown.

“SSc is an orphan disease with no current treatments that can prevent disease progression … Overall prognosis remains poor,” said the researchers. “[Our study is] the first to highlight the potential of romilkimab in patients with dcSSc … [which] has a 10-year mortality rate of ~20 percent.”

Anti-interleukin(IL)-4 and anti-IL-13 antibodies are reportedly capable of inhibiting the development of dermal fibrosis. [J Invest Dermatol 2001;116:136-143; Inflamm Res 2015;64:151-159] Given their probable involvement in the pathology of SSc, the IL-4/IL-13 pathways may represent a new avenue for fibrosis treatment, the researchers pointed out. Romilkimab – a bispecific IgG4 antibody that binds and neutralizes IL-4/IL-13 – may be a promising option that could be explored, they said.

Ninety-seven patients (mean age 49.7 years, 79 percent female) diagnosed with dcSSc with or without immunosuppressive background therapy were randomized 1:1 to receive SC romilkimab 200 mg or placebo QW for 24 weeks. [Ann Rheum Dis 2020;79:1600-1607]

At week 24, the reduction in mRSS* was greater with romilkimab vs placebo (least-squares [LS] mean change, –4.76 vs –2.45; p_one-sided=0.0291), implying significant skin improvements with romilkimab. “The impact on skin met the prespecified endpoint; [this] is the first time this has been achieved in a phase II study in dcSSc,” said the researchers.

Subgroup analysis also reflected the greater efficacy of romilkimab vs placebo among patients with the most severely affected skin at baseline (mRSS ≥15; LS mean change, –5.25 vs –1.83; p=0.0083). “[Romilkimab was also] effective in patients at the earliest disease stages of <20 months,” they added.

Romilkimab also appeared to have an additive effect among those who were receiving background immunosuppressive therapy vs those who were not, as reflected by the week-24 changes in mRSS (‒5.81 vs ‒3.64).

“[T]here was an initial improvement of mRSS up to week 12 in both arms, followed by slight worsening of mRSS up to week 24 in the placebo arm, which may reflect the initial impact of background therapy,” they explained. “However, the study was not designed to examine prior medication use in detail. Nevertheless, allowing background immunosuppressant in a study looking primarily at skin outcomes was novel.”

Romilkimab was also more favourable than placebo in terms of lung outcomes, as reflected by the reductions in DL_CO** (haemoglobin corrected; LS mean change, –0.12 vs –0.27; p=0.14) and FVC*** (LS mean change, –10 vs –80 mL; p=0.10). While the differences were not significant, the 80-mL loss for FVC in the placebo arm correlates with evidence suggesting that patients with early dcSSc may develop significant lung disease, noted the researchers.

Overall incidence of treatment-emergent adverse events (TEAEs) was high (>80 percent), but most were mild-to-moderate in intensity. Overall treatment discontinuation rate due to TEAEs was low (n=3). Romilkimab was generally well-tolerated with no cardiac safety signals observed.

“[Despite the] relatively short treatment duration, … [our findings] are consistent with a meaningful benefit of romilkimab on skin involvement … [These data] provide further validation of the role that IL-4 and IL-13 may play in dcSSc,” said the researchers.

However, given the phase II nature of the study, this warrants further verification in longer and more in-depth phase III trials to establish the clinical relevance of the study drug, they pointed out.

And although recent trials on potential therapies did not meet their mRSS endpoints, skin score assessments remain clinically relevant as these may augment patient-reported or organ-specific outcomes in ascertaining the clinical benefit of a potential therapeutic alternative for SSc. “Future studies may use combined composite endpoints to more robustly evaluate efficacy in SSc,” said the researchers.