United States

Clinical manifestations of thyroid eye disease (TED) are mainly caused by the binding of immunoglobulin G (IgG) thyrotropin receptors (TSHR) autoantibodies (TSHR-Ab) on orbital fibroblasts. Batoclimab (IMVT-1401) is an anti-neonatal Fc receptor (FcRn) human monoclonal antibody that prevents normal IgG recycling, leading to reduced levels of circulating IgG. Thus, batoclimab may provide benefit for patients with TED by reducing pathogenic anti-TSHR-Ab. In this Phase 2b, double-blind, randomized study (NCT03938545), subjects with active and moderate-to-severe TED received weekly subcutaneous (SC) injections of batoclimab (680mg, 340mg, 255mg) or placebo for 12-weeksSixty-five subjects were randomized and received batoclimab (680mg [n=18], 340mg [n=19], 255mg [n=10]) or placebo (n=18). Recruitment and treatment were stopped because of an unanticipated increase in LDL cholesterol levels, not included in subject informed consent. Hence, forty-five of 77 planned subjects completed the 12-week treatment period. Serum IgG and anti-TSHR-Ab were reduced from baseline to Week-12 with batoclimab (680mg [-77.9%; -65.5%], 340mg [-65.8%; -70.1%], 255mg [-56.6%; -42.1%]) versus placebo (-4.67%; -3.23%), respectively. Substantial reductions were also observed at Week-12 in stimulatory anti-TSHR-Ab. Fifty-one of 65 subjects had proptosis ≥ upper level of normal at baseline. At Week-12 (primary outcome), greater proportions of 680mg (30%; p=0.2197) and 340mg (30.8%; p=0.1311) subjects were proptosis responders (≥2mm reduction) versus placebo (8.3%). Absolute risk reduction (ARR [95% CI]) versus placebo was 21.4 (-11.3, 54.1) for 680mg and 24.2 (-4.8, 53.2) for 340mg at Week 12. Earlier proptosis responses were statistically different from placebo for 680mg at Weeks-four (35.7%; ARR [95% CI] 36.0 [10.9, 61.1]), five (42.9%; 43.0 [17.1, 68.9]), and 11 (41.7%; 34.5 [3.4, 65.6]) and for 340mg at Weeks-five (29.4%; 29.6 [7.9, 51.3]), nine(35.7%; 30.6 [3.0, 58.2]), and 11 (46.2%; 40.2 [10.2, 70.1]) (all p&lt;0.05). Changes in clinical activity at Week-12 were not significantly different from placebo.The proportion of subjects with an adverse event (AE) were similar across treatment groups; most were mild or moderate in severity. Two subjects reported serious AEs not related to treatment (optic neuropathy, autoimmune encephalitis [occurring after treatment period]). No subjects withdrew from the study due to an AE during the 12-week treatment period. There was a reversible dose-dependent reduction in serum albumin during the treatment period. Post-hoc lipid analysis demonstrated a reversible increase in mean serum LDL during treatment (680-mg: 58.7%; 340-mg: 30.8%; 255-mg: 19.0%) vs placebo (-3.9%),.In conclusion, batoclimab reduced circulating IgG and especially the pathogenic anti-TSHR-Ab. Although the proptosis response was not statistically significant at the primary endpoint, significance was seen at earlier time points. This is probably related to early study termination which reduced the numbers of patients available for efficacy assessment at the primary endpoint.

ENDO 2022

Double-Blind, Randomized, Placebo-controlled, Multicenter, Phase 2b Study of Batoclimab in Active and Moderate-to-Severe Thyroid Eye Disease

**Program**
ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

This year’s education program features:
more than 100 in-person and virtual sessions with another 70+ in-person only sessions;
six plenary sessions including plenaries on Envisioning Future Therapies for Type 1 Diabetes and Addressing Challenges in Fertility and Reproduction;
over 20 Meet the Professor sessions presented both in-person and live-streamed virtually and another 20+ presented live in Atlanta;
four Basic Science Pathways, including Diabetes and Metabolism; Neuroendocrinology; Nuclear Receptors and Signaling; and Reproductive Endocrinology; and
more than 30 oral sessions and a robust virtual poster hall for accepted scientific abstracts.

**What Programming Is Included in My Virtual Meeting Registration?**
As you build your schedule during the conference, you can select the sessions that are tagged with 'Livestreamed', so you can view virtually. These sessions are being livestreamed, so they are available in real time to our virtual audience. In addition, our in-person and livestreamed sessions will be recorded, so you can access them on demand after 72 hours. We will have over 200 hours available on demand for Standard and Premium pass registrants.

Product theaters and the Communications and Career Center will also include hybrid content delivery.

**Plenaries**
Spanning the spectrum of science, clinical care, and social implications, an outstanding slate of world-renowned speakers will showcase the most cutting-edge advances on research and medicine.

**Symposia**
Our ENDO 2022 lineup of sessions offers a unique opportunity to dive into topics from nearly every major therapeutic area of endocrinology and hormone science. Listen, learn, and be inspired by world-class faculty who are at the forefront of scientific discovery and high-quality health care.

**Basic Science Pathways**

These special “meeting-within-a-meeting” tracks integrate focused discussions, poster sessions, and networking opportunities to provide you with the latest research in:
Diabetes and Metabolism
Neuroendocrinology
Nuclear Receptors and Signaling
Reproductive Endocrinology

**Meet the Professor & Meet the Scientist**
Discover insights from experts on treating a variety of endocrine conditions and emerging science in the field of endocrinology, and learn the latest in patient care and scientific research.

ENDO’s comprehensive program provides attendees the opportunity to learn about the latest developments in hormone science and medicine from renowned investigators, expert clinicians, and educators from all over the world. 

Clinical manifestations of thyroid eye disease (TED) are mainly caused by the binding of immunoglobulin G (IgG) thyrotropin receptors (TSHR) autoantibodies (TSHR-Ab) on orbital fibroblasts. Batoclimab (IMVT-1401) is an anti-neonatal Fc receptor (FcRn) human monoclonal antibody that prevents normal IgG recycling, leading to reduced levels of circulating IgG. Thus, batoclimab may provide benefit for patients with TED by reducing pathogenic anti-TSHR-Ab. In this Phase 2b, double-blind, randomized study (NCT03938545), subjects with active and moderate-to-severe TED received weekly subcutaneous (SC) injections of batoclimab (680mg, 340mg, 255mg) or placebo for 12-weeksSixty-five subjects were randomized and received batoclimab (680mg [n=18], 340mg [n=19], 255mg [n=10]) or placebo (n=18). Recruitment and treatment were stopped because of an unanticipated increase in LDL cholesterol levels, not included in subject informed consent. Hence, forty-five of 77 planned subjects completed the 12-week treatment period. Serum IgG and anti-TSHR-Ab were reduced from baseline to Week-12 with batoclimab (680mg [-77.9%; -65.5%], 340mg [-65.8%; -70.1%], 255mg [-56.6%; -42.1%]) versus placebo (-4.67%; -3.23%), respectively. Substantial reductions were also observed at Week-12 in stimulatory anti-TSHR-Ab. Fifty-one of 65 subjects had proptosis ≥ upper level of normal at baseline. At Week-12 (primary outcome), greater proportions of 680mg (30%; p=0.2197) and 340mg (30.8%; p=0.1311) subjects were proptosis responders (≥2mm reduction) versus placebo (8.3%). Absolute risk reduction (ARR [95% CI]) versus placebo was 21.4 (-11.3, 54.1) for 680mg and 24.2 (-4.8, 53.2) for 340mg at Week 12. Earlier proptosis responses were statistically different from placebo for 680mg at Weeks-four (35.7%; ARR [95% CI] 36.0 [10.9, 61.1]), five (42.9%; 43.0 [17.1, 68.9]), and 11 (41.7%; 34.5 [3.4, 65.6]) and for 340mg at Weeks-five (29.4%; 29.6 [7.9, 51.3]), nine(35.7%; 30.6 [3.0, 58.2]), and 11 (46.2%; 40.2 [10.2, 70.1]) (all p<0.05). Changes in clinical activity at Week-12 were not significantly different from placebo.The proportion of subjects with an adverse event (AE) were similar across treatment groups; most were mild or moderate in severity. Two subjects reported serious AEs not related to treatment (optic neuropathy, autoimmune encephalitis [occurring after treatment period]). No subjects withdrew from the study due to an AE during the 12-week treatment period. There was a reversible dose-dependent reduction in serum albumin during the treatment period. Post-hoc lipid analysis demonstrated a reversible increase in mean serum LDL during treatment (680-mg: 58.7%; 340-mg: 30.8%; 255-mg: 19.0%) vs placebo (-3.9%),.In conclusion, batoclimab reduced circulating IgG and especially the pathogenic anti-TSHR-Ab. Although the proptosis response was not statistically significant at the primary endpoint, significance was seen at earlier time points. This is probably related to early study termination which reduced the numbers of patients available for efficacy assessment at the primary endpoint.

technical paper

A 71-year-old male presented to the endocrine clinic for evaluation of hypothyroidism which has recently been difficult for his primary care physician to control.  He initially developed hypothyroidism in 1990 after neck radiation for squamous cell carcinoma of his sternocleidomastoid muscle. He was previously controlled for many years on levothyroxine 150mcg daily with TSH readings in the normal reference range.  Patient was infected with COVID-19 in 2020 and was hospitalized for 10 days. He was treated with 5 days of Remdesivir and 10 days of Decadron. 6 months after the infection he received mRNA COVID-19 vaccination.  Upon his first visit to the endocrine clinic post COVID-19 infection and vaccination, his TSH was elevated at 90 uIU/mL with a free thyroxine that was elevated at 1.8 ng/dL even after multiple attempts by his primary care physician to increase his Levothyroxine which was up to 225 mcg daily before he was referred to endocrinology. He is compliant with his levothyroxine and takes it on an empty stomach first thing in the morning without any of his other medications. He is not taking iron supplements, biotin or any other supplements or new medications. TSH values had been normal 1 month prior to his COVID-19 infection and was first noted to be abnormal 8 months after his COVID-19 infection and 2 months after his mRNA COVID-19 vaccine.  There was no TSH drawn between when he had COVID-19 and when he received his vaccine. It was suspected that he may have a factitious elevation in his TSH due to antibody interference.  Labs were drawn for a TSH with human anti-mouse antibodies (HAMA) treatment which resulted with a markedly suppressed TSH at 0.007 uIU/mL with an elevated free thyroxine of 1.94 ng/dL.  HAMA antibodies came back elevated at 552 ng/mL.
Reference:
Klee, G., 2000. Human Anti-Mouse Antibodies. Archives of Pathology & Laboratory Medicine, 124(6), pp.921-923.
Koshida, S., Asanuma, K., Kuribayashi, K., Goto, M., Tsuji, N., Kobayashi, D., Tanaka, M. and Watanabe, N., 2010. Prevalence of human anti-mouse antibodies (HAMAs) in routine examinations. Clinica Chimica Acta, 411(5-6), pp.391-394.

A Case of COVID-19 Infection; COVID-19 mRNA-Based Vaccine Induced Human Anti-Mouse Antibodies (HAMA) Interfering With TSH Testing

Background: In 2011, Shoenfeld and Agmon-Levin described a distinct clinical entity called the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Adjuvants are primarily used in vaccines for directing the adaptive immune response. However, adjuvants sometimes trigger undesirable autoimmune effects, especially in genetically predisposed individuals such as those with DRB1 allele mutations. The mRNA vaccine may exert "self-adjuvant" properties through activation of tumor necrosis factor, interferon-alpha and other cytokines secreted by immune cells or cross reactivity of mRNA targeting CoV-2 spike protein with thyroid tissue antigens. With the recent widespread use of SARS-CoV-2 mRNA vaccine, cases of vaccine associated thyroid disorders are becoming more apparent.Case Summary: A 45-year-old male with well controlled hypertension and type 2 diabetes mellitus was evaluated for abnormal thyroid function tests with a TSH of 0.078 uIU/mL and Free T4 of 2.17 ng/dl. He reported a history of Hashimoto's chronic thyroiditis. He received the second dose of mRNA COVID-19 vaccine one month prior to presentation. He denied any change in the size of his thyroid gland. He also reported no local neck symptoms, dysphagia, odynophagia or change in voice. A nuclear thyroid uptake and scan showed mildly asymmetric thyroid lobes with markedly decreased 24-hour uptake of 0.7 %.  Based on his clinical presentation, labs and nuclear imaging he was diagnosed with painless thyroiditis. His thyroid function normalized to a TSH of 0.96uIU/ml and Free T4 of 1.29 ng/dl within 2 months without any intervention. There is a strong possibility that the SARS-CoV-2 vaccine accentuated his underlying Hashimoto's chronic thyroiditis enough to cause this transient episode of painless thyroiditis, particularly considering the close interval between the vaccine and onset of his thyroid abnormalities.Conclusion: Autoimmune thyroid abnormalities induced by vaccines have been historically associated with protein vaccines for protection from HPV, HBV, seasonal influenza, etc. The spectrum of these disorders can potentially manifest as a transient side effect or even years later with non-specific findings. The SARS-CoV-2 mRNA vaccine may incite similar immunogenicity though yet unestablished, and physicians should be mindful of this phenomenon. Due to limited data, more rigorous studies are needed to fully understand the underlying pathogenesis of thyroiditis following SARS-CoV-2 vaccine in future. As there have been minimal cases of thyroiditis reported, SARS-CoV-2 vaccine should still be strongly recommended.References
Bragazzi NL, Hejly A, Watad A, Adawi M, Amital H, Shoenfeld Y. ASIA syndrome and endocrine autoimmune disorders. Best Pract Res Clin Endocrinol Metab. 2020 Jan;34(1): 101412. doi: 10.1016/j.beem.2020.101412. Epub 2020 Mar 11. PMID: 32265102.
Watad A, David P, Brown S, Shoenfeld Y. Autoimmune/Inflammatory Syndrome Induced by Adjuvants and Thyroid Autoimmunity. Front Endocrinol (Lausanne). 2017 Jan 24;7: 150. doi: 10.3389/fendo.2016.00150. PMID: 28167927; PMCID: PMC5256113.

Double-Blind, Randomized, Placebo-controlled, Multicenter, Phase 2b Study of Batoclimab in Active and Moderate-to-Severe Thyroid Eye Disease

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A Case of COVID-19 Infection; COVID-19 mRNA-Based Vaccine Induced Human Anti-Mouse Antibodies (HAMA) Interfering With TSH Testing

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