Background

1.1 Thyroid Eye Disease (TED)

Thyroid eye disease (TED) is a disabling condition that causes orbital inflammation, leading to proptosis, diplopia, and potential vision loss. It is one of the most frequently observed autoimmune inflammatory conditions of the orbit and is prevalent in individuals with hyperthyroidism or those with a history of hyperthyroidism due to Graves’ disease (GD).

1.2 TSAb can serve as the biomarker of TED

Three types of TRAb have been identified in recent decades: stimulatory (TSAb, also named as TSI), blocking (TBAb) and neutral TRAb. Although all three types of TRAb can be found in patients with GD, TSAb serve as a marker of the disease, especially for TED. In a European study, TSAb activity was observed in 93.4% of individuals with TED (P<0.001), which demonstrates the potential for TSAb levels to serve as a predictor of TED activity and severity. Treatment of GD with radioactive iodine has been associated with a rise in TSAb levels, and precipitation or worsening of TED with radioactive iodine may be mediated by the spike in TSAb levels.

1.3 TSAb is the root cause of TED

The characteristic orbital inflammation and tissue expansion in TED has its pathophysiological basis in immunohistochemical studies. These demonstrate an overexpression of TSH-Receptors (TSHR), on the orbital fibroblasts (OFs) in TED patients. The activation of these, either by excess hormone or TSAb, results in the differentiation of orbital preadipocytes, a subgroup of orbital fibroblasts, into adipocytes, with consequential increase in orbital adipose tissue.

Kumar et al.17 showed that treatment of orbital preadipocytes from patients with TED with M22, a human monoclonal TSAb, during adipocyte differentiation results in enhanced mRNA expression levels of IL-6. Furthermore, treatment of orbital cultures with M22 after adipocyte differentiation increases secretion of the IL-6 protein into the medium. These results suggest that M22 increases IL-6 expression in orbital preadipocyte fibroblasts and increases IL-6 release by mature adipocytes and that circulating TRAbs might play a direct role in the clinical activity of TED.

The Rationale for Use of WP1302 in the Treatment of TED

The aim for the treatment of TED is to reinstate self-tolerance, preferably by making treatments as specific for the disease as possible. Thus, the ideal situation would be to induce antigen-specific tolerance whilst preserving beneficial immune function. Such a therapy would be disease modifying whilst minimizing the potential for adverse drug reactions.

Treatment with WP1302 is expected to suppress TSHR antibody formation and specifically reduce TSAb in TED patients, offering a cure potential.

2.1 WP1302 eliminates the production of TRAb in vivo studies

The adenoviral Graves’ Disease animal model could also serve as our POC study models, as the mice are immunized with an adenoviral vector expressing a truncated version of the A-subunit of the TSHR (aa1-289) (Ad-TSHR), thereby inducing TSHR specific immune responses including anti-TSHR antibodies. The Sponsor investigated the potential of two mouse models in the development of WP1302: (BALB/cxDR3tg) F1 mice and HLA-DR3tg mice.

With the relevant animal model established and validated, WP1302 was tested. Pre treatment with WP1302 was followed by an Ad-TSHR immunization and subsequently an additional immunization at Week 3. The mice were terminated in Week 5, 2 weeks after last immunization, to allow the anti-TSHR antibodies to be generated. The design (A) and results for the inhibition of antigen-specific T cell proliferation (B) and the elimination of anti-TSHR antibody production (C) are shown in Figure 1.

Figure 1 WP1302 treatment reduces TSHR specific T cell proliferation and TSHR anti-TSHR antibody levels.

2.2 WP1302 ameliate GD paitents clinical symptoms including the decrease of TSAb

To date, 12 subjects have been treated with WP1302 in the Phase 1, first-in-human clinical trial, ATX-GD-59-001 (WP1302) from 2016-2018 (NCT02973802).

Clinical Trial ATX-GD-59-001 was an open-label, single arm study in male or female subjects with Graves' disease not concurrently treated with anti-thyroid therapy. 12 Twelve subjects who were HLA-DRB1*15, HLA DRB1*03 and HLA DRB1*04 positive were enrolled in sequence, with an upward titration over 5 dose levels (injection(s) of 25, 50, 100, 400 and 800 μg) of WP1302 followed by injection(s) of 800 μg injected on five occasions. All injections were administered by IDI.D. at intervals of approximately 14 +/- 3 days for 18 weeks. Subjects were periodically assessed for 12 weeks after the last dose of IMP (Investigational Medicinal Product).

This approach was translated into a Phase 1 trial of a 15 amino-acid TSHR α chain sequence and a second 21 amino-acid peptide that replaced charged amino acids to increase solubility (ATX-GD-59). This open-label, uncontrolled trial included 12 individuals with HLA-DR3 or DR4 and mild to moderate GD not previously treated with anti-thyroid medication, who received escalating i.d. doses of ATX-GD-5989 . Treatment was well-tolerated. 7/10 participants had improved thyroid function and 5/10 had reduced antibodies at the end of the study.

Reference

Pearce, S. H. S.; Dayan, C.; Wraith, D. C.; Barrell, K.; Olive, N.; Jansson, L.; Walker-Smith, T.; Carnegie, C.; Martin, K. F.; Boelaert, K.; Gilbert, J.; Higham, C. E.; Muller, I.; Murray, R. D.; Perros, P.; Razvi, S.; Vaidya, B.; Wernig, F.; Kahaly, G. J. Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves’ Hyperthyroidism: A Phase I Study. Thyroid 2019, 29 (7), 1003–1011. https://doi.org/10.1089/thy.2019.0036.

Jansson, L.; Vrolix, K.; Jahraus, A.; Martin, K. F.; Wraith, D. C. Immunotherapy With Apitopes Blocks the Immune Response to TSH Receptor in HLA-DR Transgenic Mice. Endocrinology 2018, 159 (9), 3446–3457. https://doi.org/10.1210/en.2018-00306.