An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis

Vugler, Alex; O’Connell, James P.; Nguyễn, Mai Ánh; Weitz, Dietmar; Leeuw, Thomas; Verbitsky, Alexander; Ying, Xiaoyou; Rehberg, Markus; Carrington, Bruce; Merriman, Mark; Moss, Andrew R.; Nicholas, Jean-Marie; Stanley, Phil; Wright, S. Kirk; Bourne, Tim; Foricher, Yann; Brookings, Daniel C.; Horsley, Helen; Herrmann, Matthias; Rao, Srinivas; Kohlmann, Markus; Florian, Peter

doi:10.3389/fphar.2022.1037983

Cited by 11 publications

(4 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years, the concept of using small molecules to interfere with intracellular targets has emerged in both immunology and in immuno-oncology, as exemplified by JAK inhibitors for rheumatoid arthritis or orally available small molecule targeting sTNF (SAR441566) or inhibitors of various intracellular negative regulators of the antitumor immune response (MAP4K1, DGKα, EP4, ...), , ERAP enzymes involved in antigen presentation pathway, may become the target for small molecule drugs in immunology and immuno-oncology upstream of the current interventions.…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

Fougiaxis,

He,

Khan

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

Endoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases that trim antigenic precursors and generate antigens presented by major histocompatibility complex class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immuno-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors. We describe the chemical and pharmacological space explored by medicinal chemists to exploit the potential of these targets given their localization, biological functions, and family depth. Specific emphasis is put on the binding mode, potency, selectivity, and physchem properties of inhibitors featuring diverse scaffolds. The discussion provides valuable insights for the future development of ERAP inhibitors and analysis of persisting challenges for the translation for clinical applications.

show abstract

Section: Discussion and Perspectivesmentioning

confidence: 99%

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

Fougiaxis,

He,

Khan

et al. 2024

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…Sanofi is currently working on SAR441566, an oral TNF inhibitor [ 65 , 66 ]. A randomized, double-blind, placebo-controlled phase I trial with 38 participants evaluated the efficacy and safety of SAR441566 in patients with moderate to severe psoriasis (NCT05453942).…”

Section: Emerging Oral Treatments For Psoriasismentioning

confidence: 99%

New and Emerging Oral/Topical Small-Molecule Treatments for Psoriasis

Carmona-Rocha,

Rusiñol,

Puig

2024

Pharmaceutics

View full text Add to dashboard Cite

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on the development of oral therapies with improved efficacy and safety compared with available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate to severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways such as AhR, PDE-4, and Jak-STAT. Tapinarof (an AhR modulator) and roflumilast (a PDE-4 inhibitor) have exhibited favorable efficacy and safety outcomes and have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis, especially those that are currently under evaluation and development for the treatment of psoriasis.

show abstract

“…SAR441566 (Sanofi) is a small molecule inhibitor of the TNF cytokine in early phase development for psoriasis [ 35 , 36 ]. It acts by stabilizing the asymmetrical form of the soluble TNF trimer, preventing its interaction with TNFR1 and inhibiting proinflammatory cytokine production [ 35 ]. Results from a phase I, double-blind, placebo-controlled, randomized trial (NCT05453942) were recently reported [ 36 ].…”

Section: Tumor Necrosis Factor Inhibitorsmentioning

confidence: 99%

“…Oral small molecules with a similar mechanism of action are currently under investigation. SAR441566 (Sanofi) is a small molecule inhibitor of the TNF cytokine in early phase development for psoriasis [35,36]. It acts by stabilizing the asymmetrical form of the soluble TNF trimer, preventing its interaction with TNFR1 and inhibiting proinflammatory cytokine production [35].…”

Section: Tumor Necrosis Factor Inhibitorsmentioning

confidence: 99%

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents

Drakos,

Torres,

Vender

2024

Pharmaceutics

View full text Add to dashboard Cite

The introduction of biologic agents for the treatment of psoriasis has revolutionized the current treatment landscape, targeting cytokines in the interleukin (IL)-23/IL-17 pathway and demonstrating strong efficacy and safety profiles in clinical trials. These agents however are costly, are associated with a risk of immunogenicity, and require administration by intravenous or subcutaneous injection, limiting their use among patients. Oral therapies, specifically small molecule and microbiome therapeutics, have the potential to be more convenient and cost-effective agents for patients and have been a focus of development in recent years, with few targeted oral medications available for the disease. In this manuscript, we review pipeline oral therapies for psoriasis identified through a search of ClinicalTrials.gov (30 June 2022–1 October 2023). Available preclinical and clinical trial data on each therapeutic agent are discussed. Small molecules under development include tumor necrosis factor inhibitors, IL-23 inhibitors, IL-17 inhibitors, phosphodiesterase-4 inhibitors, Janus kinase inhibitors, A3 adenosine receptor agonists, and sphingosine-1-phosphate receptor 1 agonists, several of which are entering phase III trials. Oral microbials have also demonstrated success in early phase studies. As new oral therapies emerge for the treatment of psoriasis, real-world data and comparative trials are needed to better inform their use among patients.

show abstract

An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis

Cited by 11 publications

References 88 publications

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights

New and Emerging Oral/Topical Small-Molecule Treatments for Psoriasis

Emerging Oral Therapies for the Treatment of Psoriasis: A Review of Pipeline Agents

Contact Info

Product

Resources

About