New promising drugs for the treatment of systemic sclerosis: pathogenic considerations, enhanced classifications, and personalized medicine

ABSTRACT

Introduction: Systemic sclerosis (SSc), also known as scleroderma, is a complex orphan disease characterized by early inflammatory features, vascular hyper-reactivity, and fibrosis of the skin and internal organs. Although substantial progress has been made in the understanding of the pathogenesis of SSc, there is still no disease-modifying drug that could significantly impact the natural history of the disease.

Areas covered: This review discusses the rationale, preclinical evidence, first clinical eevidence,and pending issues concerning new promising therapeutic options that are under investigation in SSc. The search strategy was based on PubMed database and clinical trial.gov, highlighting recent key pathogenic aspects and phase I or II trials of investigational drugs in SSc.

Expert opinion: The identification of new molecular entities that potentially impact inflammation and fibrosis may constitute promising options for a disease modifying-agent in SSc. The early combinations of antifibrotic drugs (such as pirfenidone) with immunomodulatory agents (such as mycophenolate mofetil) may also participate to achieve such a goal. A more refined stratification of patients, based on clinical features, molecular signatures, and identification of subpopulations with distinct clinical trajectories, may also improve management strategies in the future.

KEYWORDS:

• Autoimmunity
• fibrosis
• investigational drugs
• macrophages
• myofibroblasts
• scleroderma
• systemic sclerosis
• vasculopathy

Article highlights

• Recent advances in the understanding of systemic sclerosis (SSc) pathogenesis have allowed the FDA approval of two drugs for the treatment of SSc-ILD (tocilizumab and nintedanib) but no drug has been approved as a disease-modifying agent in SSc so far.

• TGF-β plays a key role in fibroblast activation and myofibroblast trans-differentiation through non-canonical and canonical pathways. Selective inhibition of TGF-β1 and TGF-β3 by AVID200, showed good tolerance and safety profile (NCT03831438) fostering the relevance of future trials evaluating the efficacy of this drug in SSc.

• Considering the multiplicity of pathways involved in the pathogenesis of SSc, simultaneous targeting of multiple cytokines by the same drug may be especially promising. The concomitant targeting of the immunomodulatory and profibrotic IL-4 and IL-13 with Romilkimab has shown promising results on skin involvement in dcSSc in a phase II trial (NCT02921971)

• Considering the recent demonstration that both M1 (pro-inflammatory) and M2 (pro-fibrotic) macrophages were over-activated in the skin of patients with diffuse SSc, JAK inhibition with pan-JAK inhibitors such as Tofacitinib (NCT03274076) or Ruxolitnib may be especially promising with potential impact on IL-6 (STAT-1/3 dependent) pro-inflammatory & profibrotic signaling, and IL-4/IL-13 (STAT6 dependent) pro-fibrotic & immunomodulatory signaling.

• Combination therapies may offer the opportunity of targeting multiple pathways at the same time. In this respect, the ongoing Scleroderma-Lung-Study III, a phase III trial assessing the efficacy of Pirfenidone versus placebo, as add-on therapy with mycophenolate mofetil in patients with SSc-ILD (NCT03221257), may demonstrate the proof of concept of the combined efficacy of an immunomodulatory drug with an anti-fibrotic molecule in SSc. This may pave the way for further evaluation of combination therapies for SSc in the future.

• These potential new therapeutic options will still need to be adapted to relevant subpopulations of patients, highlighting the importance of pursuing the effort for better stratification and precise phenotyping of patients with SSc. Identification of molecular signatures that could predict treatment response as identified in the abatacept trial (NCT02161406), may constitute a promising strategy.

This box summarizes key points contained in the article.

Declaration of interest

J Varga reports consulting agreements/advisory for Boehringer Ingelheim, TeneoBio, Mitobridge, Emerald Pharma, Horizon Therapeutics, Formation Biologics, Astellas, Forbius, Abingworth and research funding from Pfizer, Bristol-Myers-Squibb, Teneo-Bio, Takeda, and Sun Bio.

M Matucci-Cerinic has received consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, and Roche. D Khanna reports the following conflicts of interest: Grant support from NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer. Consultant: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics. He also holds stocks in Eicos Sciences, Inc (less than 5%) and has Leadership/Equity positions – Chief Medical Officer, CiviBioPharma/Eicos Sciences, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Abbreviations

FAK=focal adhesion kinase, LPA= lysophosphatidic acid; LPA-R=LPA-Receptor; IL-6R=IL-6 receptor; TGF-βRI & II= TGF-β receptor I & II; PAI-1=plasminogen activator inhibitor 1; ROS=Reactive Oxygen Species; YAP=Yes Associated Protein; α-MSH =α-Melanocyte-stimulating hormone; IL-4Rα=IL-4 receptor α; IL-13Rα1= IL-13 receptor α1; ECM=Extra-cellular matrix

Additional information

Funding

A Lescoat was funded by the French network of the University Hospitals HUGO (Hôpitaux Universitaires du Grand Ouest-GIRCI) (AAP JCM2020) and by grant support from the Rennes University Hospital (CORECT Visiting Grant 2020). D Khanna was funded by grant support from the NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (K24-AR-063129)