Experimental Therapies

Systemic sclerosis (SSc) is a connective tissue disease that is characterized by immune dysregulation, vascular damage, and fibrotic changes occurring in multiple organs.^1,2

Treatments available for SSc are currently insufficient to cure the disease or prevent its progression. However, there are new experimental therapies in the pipeline, and several agents are now being studied as potential therapies. Several agents, such as lenabasum and Adempas® (riociguat), have also failed to demonstrate benefit when used in patients with SSc.³

Romilkimab

Romilkimab is a humanized immunoglobulin G4 (IgG4) antibody that prevents fibrosis by binding and neutralizing interleukin (IL)-4 and IL-13. IL-4 and IL-13 are released by T-helper cells, a type of T cell, which are activated following endothelial injury in SSc. Patients with diffuse cutaneous SSc (dcSSc) were randomized during a clinical study to receive either romilkimab or a placebo for 24 weeks. The decline in the modified Rodnan Skin Score (mRSS) was reportedly higher in patients receiving the investigational drug than in those receiving the placebo.³

Read more about SSc clinical trials

Rituximab

Rituximab is a humanized chimeric anti-CD20 monoclonal antibody that leads to the depletion of peripheral B cells. A meta-analysis performed on 24 studies showed that this drug improves both mRSS and quality of life and is effective in stabilizing the involvement of internal organs in patients with the disease.⁴

DESIRES, a clinical study conducted in Japan involving patients with SSc, has shown a greater absolute change in mRSS from baseline in patients treated with rituximab than in patients receiving the placebo. Rituximab was also well tolerated. A different clinical trial is assessing rituximab’s efficacy compared to Cytoxan® (cyclophosphamide) in patients with interstitial lung disease (ILD).³

Uplizna

Uplizna® (inebilizumab, MEDI-551) is a humanized, anti-CD19 monoclonal antibody that binds to CD19, leading to antibody-dependent, cell-mediated cytotoxicity of B cells.^2,5 CD19 is involved in B-cell signaling, intervening in the balance between humoral, antigen-induced response and tolerance induction.² This monoclonal antibody is also being developed for the treatment of other diseases, such as neuromyelitis optica spectrum disorders (NMOSD) and relapsing multiple sclerosis (MS).⁵

A phase 1 randomized, placebo-controlled, single-dose escalation clinical trial has reported that 96% of patients with SSc receiving Uplizna experienced treatment-emergent adverse events. The most common were nausea and fatigue.⁵ Additionally, in a double-blind, randomized, placebo-controlled phase 2/3 clinical trial in patients with SS, MS, and NMOSD, treatment with Uplizna led to the effective depletion of peripheral B cells by more than 99%.⁶

Read more about SSc pathophysiology

Orencia

Orencia® (abatacept) is a recombinant fusion protein that binds to both CD80 and CD86, which prevents T-cell costimulation by CD28.² In a multicenter, double-blind, randomized, placebo-controlled phase 2 clinical trial, patients were randomized to receive either Orencia or a placebo. Changes in mRSS and safety were the primary endpoints of the trial. Results of the study reported that there was no significant difference in the mRSS between the Orencia and placebo groups, however, improvements in health quality were observed for patients receiving the experimental treatment.⁷

Adcetris

Adcetris® (brentuximab vedotin) is an experimental treatment targeting the CD30 protein. This protein is expressed on activated immune cells such as lymphocytes and is found in patients with dcSSc. Two clinical trials (phase 1/2 and phase 2) are ongoing for the evaluation of the therapeutic efficacy of Adcetris in patients with dcSSc.⁸

Read more about SSc therapies

SAR100842

SAR100842 is a selective oral antagonist of the lysophosphatidic acid receptor 1 (LPA 1 receptor). LPA is responsible for stimulating cell division and the differentiation of lung fibroblasts to myofibroblasts. Patients with SSc exhibit a higher level of LPA 1 than healthy individuals. A phase 2a, open-label extension clinical trial provided insights into the efficacy and treatment tolerance of SAR100842 in patients with dsSSc. Greater reductions in mRSS and LPA-related genes were observed in the treatment group than in the placebo group.⁸

Pradaxa

Pradaxa® (dabigatran) is a direct thrombin inhibitor that irreversibly binds to thrombin’s active site. This is a therapy used for the primary prevention of venous thromboembolic events, the prevention of stroke, and the treatment of deep vein thrombosis and pulmonary embolism.⁹

Pradaxa was able to attenuate pulmonary fibrosis in a mouse model of SSc. A phase 1, prospective, single-center, open-label study was also performed in patients with SSc who presented with ILD to determine the therapy’s safety profile.²

Read more about SSc treatment

Allogeneic Bone Marrow-Derived Multipotent Mesenchymal Stromal Cells

The use of mesenchymal stromal cells (MSCs) in patients with dcSSc has been recently evaluated in an open-label phase 1/2 clinical trial. In this trial, patients received an infusion of allogeneic bone marrow-derived MSCs, which proved to be safe and well tolerated over the short- and long-term follow-up. In this study, an improvement in mRSS was observed and maintained at 12 months, while forced vital capacity was also stable at 12 months.³

Read more about SSc prognosis

References

Ebata S, Yoshizaki-Ogawa A, Sato S, Yoshizaki A. New era in systemic sclerosis treatment: recently approved therapeutics. J Clin Med. 2022;11(15):4631. doi:10.3390/jcm11154631
Campochiaro C, Allanore Y. An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years. Arthritis Res Ther. 2021;23(1):155. doi:10.1186/s13075-021-02536-5
Bukiri H, Volkmann ER. Current advances in the treatment of systemic sclerosis. Curr Opin Pharmacol. 2022;64:102211. doi:10.1016/j.coph.2022.102211
Moradzadeh M, Aghaei M, Mehrbakhsh Z, Arab-Bafrani Z, Abdollahi N. Efficacy and safety of rituximab therapy in patients with systemic sclerosis disease (SSc): systematic review and meta-analysis. Clin Rheumatol. 2021;40(10):3897-3918. doi:10.1007/s10067-021-05698-4
Yan L, Kimko H, Wang B, Cimbora D, Katz E, Rees WA. Population pharmacokinetic modeling of inebilizumab in subjects with neuromyelitis optica spectrum disorders, systemic sclerosis, or relapsing multiple sclerosis. Clin Pharmacokinet. 2022;61(3):387-400. doi:10.1007/s40262-021-01071-5
Cree BAC, Bennett JL, Kim HJ, et al; N-MOmentum study investigators. Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): a double-blind, randomised placebo-controlled phase 2/3 trial. Lancet. 2019;394(10206):1352-1363. doi:10.1016/S0140-6736(19)31817-3
Khanna D, Spino C, Johnson S, et al. Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol. 2020;72(1):125-136. doi:10.1002/art.41055
Bohdziewicz A, Pawlik KK, Maciejewska M, et al. Future treatment options in systemic sclerosis-potential targets and ongoing clinical trials. J Clin Med. 2022;11(5):1310. doi:10.3390/jcm11051310
Khanna D, Tashkin DP, Denton CP, Lubell MW, Vazquez-Mateo C, Wax S. Ongoing clinical trials and treatment options for patients with systemic sclerosis-associated interstitial lung disease. Rheumatology (Oxford). 2019;58(4):567-579. doi:10.1093/rheumatology/key151

Reviewed by Hasan Avcu, MD, on 4/19/2023.

Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.

Systemic Sclerosis (SSc)

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