Thyroid Eye Disease: Navigating the New Treatment Landscape

Chrysoula Dosiou; Andrea Lora Kossler

Disclosures

J Endo Soc. 2021;5(5) 

In This Article

An Eye to the Future: Upcoming Therapies

Emerging biologic targeted therapies are promising but will need to prove substantial benefit, a low side effect profile, or a more cost-effective alternative to enter the TED therapeutic landscape.

Thyrotropin Receptor Antagonists

Small-molecule TSHR antagonists have been tested in preclinical models. These could attenuate orbital fibroblast activation by TSI, as allosteric inhibition of the TSHR G protein signaling has been shown to silence the TSHR.[62] A small-molecule TSHR antagonist (ANTAG3) has been shown to inhibit TSI-induced signaling and TSHR activation in the thyroid gland of mice and could thus potentially inhibit TSHR signaling in orbital fibroblasts.[63] Additional animal studies have reported new small-molecule TSHR antagonists that are highly selective TSHR inhibitors.[64] While these studies are still in preclinical development, their potential as targeted therapeutic options for TED is exciting.

Enhancement of Immunoglobulin G Catabolism

IMVT-1401 is a fully human monoclonal antibody inhibiting FcRn-mediated recycling of immunoglobulin G (IgG). FcRn is the primary protein preventing the degradation of IgG antibodies, thereby prolonging their half-life. IMVT-1401 disrupts the IgG-FcRn interaction to increase catabolism of IgG and is thought to remove pathogenetic autoantibodies against the TSHR and IGF-1R. In an open-label, single-arm phase 2a clinical trial (NCT03922321), 7 patients with moderate/severe active TED were treated weekly for 6 weeks. Initial results demonstrated a 65% reduction in total IgG, 57% of patients had ≥ 2 point improvement in CAS, and 67% of patients with baseline diplopia improved, with no serious adverse events.[65] A larger phase 2b double-blind study is under way with a plan to enroll 77 patients with moderate/severe active TED. IMVT-1401 is being developed as a subcutaneous injection for the treatment of TED and other autoimmune disorders.

Other Therapies

Belimumab (monoclonal antibody against B-cell activating factor) is under investigation in a European RCT in patients with TED (EudraCT 2015-002127-26). Immunomodulators such as fingolimod (a sphingosine-1-phosphate receptor antagonist)[66] and iscalimab (an anti-CD40 antibody),[67] antibodies that block the TSHR, as well as microbiome manipulation are other novel therapies under investigation.

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