Thyroid eye disease (TED) is an autoimmune condition commonly associated with Graves' disease; it is alternatively called Graves' orbitopathy or Graves' ophthalmopathy (GO). In TED, autoantibodies termed Graves' disease IgG's (GD-IgG) interact with autoantigens on orbital tissues triggering an autoimmune response that results in erythema, swelling, proptosis (protruding eyeballs), pain and upper eyelid. Importantly, the condition is associated with multiple potentially sight-threatening ocular morbidities, including conjunctivitis, corneal lesion, optic nerve compression and diplopia. It also causes disfiguring and highly distressing changes in facial appearance. TED is not a secondary symptom of Graves' hyperthyroidism and is not prevented by anti-thyroid drugs or thyroid-ablative procedures. Multiples lines of evidence indicate that the primary cellular target for the autoimmune response involve orbital fibroblasts. The activation and proliferation of orbital fibroblasts trigger a cascde of events resulting in increases in tissue volume within the confined anatomy of the orbit, forcing the eyes out of their sockets. TED progresses through an active (dynamic) phase, lasting between 1.5 to 3 years and is characterized by a strong inflammatory response in the orbital tissues, tissue proliferation and remodeling. Unlike most autoimmune disorders, the active phase spontaneously transitions into a stable (static) phase where the inflammation resolves and further tissue expansion stops, however, the expanded tissue mass remains becoming fibrotic and essentially permanent.
The aim of this proposal is to execute a well-designed, randomized, double-masked, placebo-controlled Phase 2 study (TED01RV) that will: (i) Determine whether RV 001 produces clinically-meaningful efficacy in improving the symptoms of TED; i.e. improvements in clinical activity score (pain and inflammation), proptosis (protrusion of eyeballs) and ductions (ability to move eyes); (ii) To assess the safety and tolerability of RV 001 in TED patients; (iii) To measure the pharmacokinetics of RV 001 in TED patients to further clarify pharmacokinetic/pharmacodynamic (PK/PD) relationships; (iv) To better understand disease mechanisms underlying TED, and the mechanism of action of RV 001, through measuring plasma disease biomarkers; e.g. thyroid stimulating hormone receptor (TSHR) activating immunoglobulins, cytokines, and IGF-1R and TSRH expression levels on plasma T cells, B cells and fibrocytes. If the TED01RV study shows a clear efficacy signal and good tolerability this will trigger Phase 3 development of RV 001 for TED.
The project has the potential to demonstrate a novel, efficacious and well-tolerated therapy to treat thyroid eye disease (TED); a painful, sight-threatening and disfiguring orphan condition that has no approved therapy and for which there is major unmet medical need.