Future Projections in Thyroid Eye Disease

Abstract

Background and Aims This review aims to summarize current and emerging therapies for treatment of thyroid eye disease (TED), in the light of novel understanding of pathogenetic mechanisms, leading to new treatment options and clinical trials. Methods We reviewed and analyzed peer-reviewed literature reporting recent translational studies and clinical trials in the treatment of TED. Searches were made at www.pubmed.gov with keywords “thyroid eye disease,” “Graves’ ophthalmopathy,” “thyroid orbitopathy,” and “Graves’ orbitopathy.” Results Surgery is reserved for rehabilitation in chronic TED or for emergent compressive optic neuropathy. Oral and intravenous glucocorticoid therapy has been used for decades with variable efficacy in acute TED, but results may be temporary and side effects significant. Nonsteroidal oral immunosuppressive agents offer modest benefit in TED. Several immunomodulatory monoclonal antibodies, including rituximab and tocilizumab, have shown efficacy for inactivating TED. Recently, teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) inhibitor, has demonstrated significant improvement in proptosis, clinical activity score, diplopia, and quality of life in patients with active TED, with good tolerability. Newly proposed TED therapies, currently in preclinical and clinical trial phases, include thyroid-stimulating hormone (TSH) receptor inhibitory drugs, RVT-1401, local anti-vascular endothelial growth factor therapy, IGF-1R drugs delivered subcutaneously and orally, and desensitization to the TSH receptor with modified TSH receptor peptides. Conclusion New, albeit incomplete, understanding of the molecular mechanisms of TED has led to new promising therapies and offered improved outcomes in TED patients. Their full role and their relationship to classical immune suppression should be clarified over the next few years.

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…In 2019, the compound S37a with seven centers of chirality was developed, which one of the stereoisomers at micromolar concentrations suppressed the AC activity and the cAMP accumulation in HEK293 cells with expressed TSHR when they were treated with TSH and stimulatory monoclonal antibodies TSAb M22 and KSAb1, oligoclonal stimulatory antibodies TSAb characteristic of patients with Graves’ disease, as well as a small C2 agonist [ 323 ]. S37a, when administered orally to mice, had a high bioavailability (53%) and was not toxic [ 323 ], which indicates the prospects for its clinical trials, especially since there are currently no effective and safe approaches for the treatment of Graves’ disease and Graves’ ophthalmopathy [ 352 ].…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…In 2019, the compound S37a with seven centers of chirality was developed, one of the stereoisomers of which, at micromolar concentrations, suppressed the AC activity and the cAMP accumulation in HEK293 cells with expressed TSHR when they were treated with TSH and stimulatory monoclonal antibodies TSAb M22 and KSAb1, oligoclonal stimulatory antibodies TSAb, characteristic of patients with Graves' disease, as well as a small C2 agonist [322]. S37a, when administered orally to mice, had a high bioavailability (53%) and was not toxic [322], which indicates the prospects for its clinical trials, especially since there are currently effective and safe approaches for the treatment of Graves' disease and Graves' ophthalmopathy not developed [351,352].…”

Medical Management of Thyroid Eye Disease

“…Moreover, several studies are in progress to evaluate TSH receptor inhibitors and modified TSH receptor peptides, which may hold multiple advantages through the alteration of both TED and hyperthyroidism activity. Also, investigations of both novel drugs and drug delivery, such as subcutaneous and oral administration, targeting IGF1 receptor inhibition are also underway 37. VRDN-001, an anti-IGF1 receptor monoclonal antibody similar to teprotumumab, is the subject of an ongoing phase 1/2 clinical trial assessing its safety, tolerability, and efficacy in healthy volunteers and in individuals with TED 40…”

“…Also, investigations of both novel drugs and drug delivery, such as subcutaneous and oral administration, targeting IGF1 receptor inhibition are also underway. 37 VRDN-001, an anti-IGF1 receptor monoclonal antibody similar to teprotumumab, is the subject of an ongoing phase 1/2 clinical trial assessing its safety, tolerability, and efficacy in healthy volunteers and in individuals with TED. 40…”

“…Emerging therapies targeting diverse mechanisms of TED pathophysiology are currently being investigated in preclinical and clinical research. 37 RVT-1401, a fully human antineonatal Fc receptor monoclonal antibody that potentiates immunosuppression through disruption of immunoglobulin intracellular recycling, showed promise in a phase 2a study but was the subject of a terminated phase 2b study. 38,39 In addition, delivery of antivascular endothelial growth factor to the orbit, with hypothesized attenuation of angiogenesis and orbital edema, is currently under consideration.…”