Treatment Of Thyroid Eye Disease Research Articles

Cyclosporin A inhibits PDGF-BB induced hyaluronan synthesis in orbital fibroblasts

Orbital connective tissue changes are contributors to the pathogenesis in thyroid eye disease (TED). Activated fibroblasts respond to immune stimuli with proliferation and increased hyaluronan (HA) production. Cyclosporin A (CsA) was reported to be beneficial in the treatment of TED. PDGF isoforms are increased in orbital tissue of TED patients and enhance HA production. We aimed to study the effect of CsA on HA production and hyaluronan synthase (HAS1, 2 and 3) and hyaluronidase (HYAL1 and 2) mRNA expressions in orbital fibroblasts (OFs). Measurements were performed in the presence or absence of CsA (10 μM) in unstimulated or PDGF-BB (10 ng/ml) stimulated OFs. The HA production of TED OFs (n=7) and NON-TED OFs (n=6) were measured by ELISA. The levels of mRNA expressions were examined using RT-PCR. The proliferation rate and metabolic activity were measured by BrdU incorporation and MTT assays, respectively. Treatment with CsA resulted in an average 42% decrease in HA production of OFs (p<0.0001). CsA decreased the expression levels of HAS2, HAS3 and HYAL2 (p=0.005, p=0.005 and p=0.002, respectively.) PDGF-BB increased HA production (p<0.001) and HAS2 expression (p=0.004). CsA could reduce the PDGF-BB-stimulated HA production (p<0.001) and HAS2 expression (p=0.005) below the untreated level. In addition, CsA treatment caused a decrease in proliferation potential (p=0.002) and metabolic activity (p<0.0001). These findings point to the fact that CsA affects HA metabolism via HAS2, HAS3 and HYAL2 inhibition in OFs. In addition to its well characterized immunosuppressant properties, CsA’s beneficial effect in TED may be related to its direct inhibitory effect on basal and growth factor stimulated HA production.

One Incremental Stride for Doxycycline, One Substantial Advancement for Thyroid Eye Disease.

The aim of this study is to assess the effectiveness of a 12-week doxycycline treatment for thyroid eye disease (TED), an autoimmune condition associated with thyroid dysfunction. In this randomized controlled clinical trial, 82 patients were randomly assigned at a 1:1 ratio to receive doxycycline (50 mg) or to undergo no treatment. Various metrics, including margin reflex distance (MRD1 and MRD2), eyelid aperture, levator muscle function, lagophthalmos, proptosis, ocular motility, diplopia, and Graves' ophthalmopathy-specific quality-of-life (GO-QOL) scale scoring were assessed. Exclusion criteria were uncontrolled systemic diseases, tetracycline allergies, pregnancy, lactation, or age below 18. The mean age was 51.6 years (SD), 87.8% of participants were female, and all were Caucasians. By week 12, the doxycycline group exhibited a significant improvement rate based on MRD2 (from 4 to 15 participants with physiological findings), clinical activity score (from 7 to 35 participants with non-active disease), and GO-QOL (from 51.22% to 70.73% of participants with a good life quality). Doxycycline showcased anti-inflammatory and immunomodulatory effects in treating TED, suggesting its potential efficacy for TED and other orbit inflammatory conditions. However, these results warrant further validation through future research involving extended follow-up periods and larger cohorts.

Change in upper eyelid position after teprotumumab treatment for thyroid eye disease

ABSTRACT Purpose Despite the high prevalence, treatment challenges, and significant impact of eyelid retraction on vision and quality of life among patients with thyroid eye disease, the effects of teprotumumab on eyelid retraction are not fully understood. This study evaluated change in upper eyelid position after teprotumumab. Methods A retrospective study of all patients who completed eight teprotumumab infusions at one institution from January 1 2020 to December 31 2022. Primary outcome was change in upper eyelid position immediately after treatment and at most recent follow-up compared to pre-treatment. Results Among 234 eyes of 118 patients, average margin reflex distance-1 (MRD1) pre-treatment was 5.25 mm (range 0–10.0, SD 1.75), 4.66 mm (1.0–9.0, SD 1.32) immediately post-treatment (p < 0.001), and 4.50 mm (0–10.0, SD 1.52) at most recent follow-up (mean follow-up duration 10.60 months). In total, 136 (58.12%) eyes of 88 patients had MRD1 reduction immediately post-treatment, averaging 1.49 mm (0.5–5.0 mm, SD 0.97). Every 1-mm increase in pre-treatment MRD1 increased the odds of MRD1 reduction by 15.03% (CI 10.52–19.72, p < 0.001) and increased the reduction amount by 0.48 mm (CI 0.39–0.57, p < 0.001). Of 154 eyes of 78 patients with most recent follow-up, 107 (69.48%) eyes had stable or further improved retraction at most recent follow-up compared to immediately post-treatment. Conclusions This study found a modest but significant reduction in MRD1 in approximately 60% of eyes, independent of proptosis change, which was sustained by most patients over longer-term follow-up. Higher pre-treatment MRD1 corresponded with greater improvement. These results suggest an overall mild benefit of teprotumumab for upper eyelid retraction.

INTRAVENOUS CORTICOSTEROID EFFECTS ON SUPERIOR AND INFERIOR RECTUS MUSCLE IN THYROID EYE DISEASE

Abstract&#x0D; Introduction &amp; Objectives : Intravenous corticosteroid has been used in management of Thyroid Eye Diseases (TED) which was an autoimmune inflammatory disease of the orbital tissues and the eyes. Previous study has shown benefits of intravenous corticosteroid therapy on TED but there was need of quantitative measure to assess the effect of intravenous corticosteroid therapy on extraocular muscle. This study aimed to report the effect of high-dose intravenous corticosteroid pulse therapy on superior and inferior rectus muscle and providing data distribution of active TED before and after therapy&#x0D; Methods : Retrospective analyses were used in the data collection of patients with active TED underwent high- dose intravenous methylprednisolone pulse therapy regiment 500mg every week for six consecutive weeks at Sardjito Eye Centre between January and December 2022. Ophthalmological investigation and quantitative computed tomography (CT) scan of the orbit were performed before and after corticosteroid pulse therapy and demographics data were presented in tables and graphs&#x0D; Results : This study included 62 eyes of 31 patients (61,3% female) with mean age of 37.8±13.47 years old. The mean thickness of Superior Rectus (SR) muscle before therapy were 4.12±2.20 mm and decreased to 3.64±1.50 mm post therapy. The mean thickness of Inferior Rectus (IR) muscle before therapy were 4.45±1.80 mm and decreased to 4.26±1.63 mm post therapy. There was significant difference in mean ΔSR -0.47±1.84 mm (p=0.046) but not in ΔIR -0.18±1.69 (p=0.381)&#x0D; Conclusion : The treatment of Thyroid Eye Disease (TED) with high dose intravenous corticosteroid is safe and effective in reducing extraocular muscle tissue thickness with minimal side effects.

INTRAVENOUS METHYLPREDNISOLONE EFFECTS ON RECTUS MUSCLES IN THYROID EYE DISEASE

Introduction &amp; Objective:&#x0D; Intravenous methylprednisolone has been used in management of Thyroid Eye Diseases (TED) which was an autoimmune inflammatory disease of the orbital tissues and the eyes. Previous study has shown benefits of intravenous methylprednisolone therapy on TED but there was need of quantitative measure to assess the effect of intravenous methylprednisolone therapy on extraocular rectus muscles. This study aimed to report the effect of high-dose intravenous methylprednisolone pulse therapy on inferior, medial, superior, and lateral rectus muscles and providing data distribution of active TED before and after therapy.&#x0D; Methods:&#x0D; Retrospective analyses were used in the data collection of patients with active Thyroid Eye Disease (TED) underwent high-dose intravenous methylprednisolone pulse therapy regiment 500mg every week for six consecutive weeks at Sardjito Eye Centre between January 2022 and December 2022. Ophthalmological investigation and quantitative computed tomography (CT) scan of the orbit were performed before and after methylprednisolone pulse therapy and demographics data were presented in tables and graphs.&#x0D; Results:&#x0D; This study included 62 eyes of 31 patients (61,3% female) with mean age of 37.8±13.47 years old. The mean thickness of Superior Rectus (SR) muscle before therapy were 4.12±2.20 mm and significantly decreased to 3.70±1.54 mm post therapy. There was no significant difference in delta mean Inferior Rectus (?IR) -0.18±1.69 (p=0.381), Medial Rectus (?MR) -0.34±1.68 (p=0.116), and Lateral Rectus (?LR) -0.33±1.94 (p=0.188)&#x0D; Conclusion:  &#x0D; The treatment of Thyroid Eye Disease (TED) with high dose intravenous corticosteroid is safe and effective in reducing extraocular muscle tissue thickness with minimal side effects.&#x0D; Keywords:&#x0D; Thyroid Eye Disease, Extraocular Muscle, Intravenous Methylprednisolone Therapy.

The association of race with thyroid eye disease presentation and outcomes

IntroductionClassification of thyroid eye disease (TED) is largely based on guidelines developed in Europe and North America. Few studies have investigated the presentation and treatment of TED in Black populations. The objective is to examine the manifestations of TED in secondary and tertiary care center-based populations with a significant proportion of Black patients.Materials and methodsRetrospective chart review identifying patients with a reported race/ethnicity and a presenting clinical diagnosis of TED at Kings County Hospital and SUNY Downstate Medical Center and affiliated clinics from January 1, 2010 through July 31, 2021. Main outcome measures include age of disease onset, sex, smoking status, insurance status, postal code of residence, clinical exam features, number of follow-up visits, length of follow-up, and treatments received.ResultsOf the 80 patients analyzed, 49 were Black (61.2%) and 31 were White (38.8%). Between Black and White patients, there were differences in the mean age of presentation (48.1 [range 21-76] vs 56.8 [range 28-87] years, P=0.03), insurance status (51.0% vs 77.4% private insurance, P=0.02), and mean follow up length among those with multiple visits (21.6 [range 2-88] vs 9.7 [range 1-48] months, P=0.02). The distribution of EUGOGO scores were not significantly different between Black and White patients. On initial presentation, fewer Black patients had chemosis (OR 0.21, 95% CI, 0.08 to 0.57, P=0.002), and caruncular swelling (OR 0.19, 95% CI, 0.06 to 0.59, P=0.002) compared to White patients. During the overall disease course, fewer Black patients had subjective diplopia (OR 0.20, 95% CI, 0.07 to 0.56, P=0.002), chemosis (OR 0.24, 95% CI, 0.09 to 0.63, P=0.004), and caruncular swelling (OR 0.18, 95% CI, 0.07 to 0.51, P=0.001) compared to White patients. Black patients received oral steroids (42.9% vs 67.7%, P=0.03), intravenous steroids (18.4% vs 16.1%, P=0.8), orbital decompression surgery (16.7% vs 6.5%, P=0.19), and teprotumumab (22.9% vs 22.6%, P=0.99) at similar rates.DiscussionBlack patients presented with fewer external exam findings suggestive of active TED compared to White patients, but the rate of compressive optic neuropathy and decompression surgery were similar in the two groups. These differences may be due to disease phenotypes, which warrant further study.

Data mining and analysis of adverse event signals associated with teprotumumab using the Food and Drug Administration adverse event reporting system database.

Teprotumumab was approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease in 2020. However, its adverse events (AEs) have not been investigated in real-world settings. This study aimed to detect and evaluate AEs associated with teprotumumab in the real-world setting by conducting a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database. Reporting odds ratio (ROR) was used to detect risk signals from the data from January 2020 to March 2023 in the FAERS database. A total of 3,707,269 cases were retrieved, of which 1542 were related to teprotumumab. The FAERS analysis identified 99 teprotumumab-related AE signals in 14 System Organ Classes (SOCs). The most frequent AEs were muscle spasms (n = 287), fatigue (n = 174), blood glucose increase (n = 121), alopecia (n = 120), nausea (n = 118), hyperacusis (n = 117), and headache (n = 117). The AEs with strongest signal strengths were autophony (ROR = 14,475.49), deafness permanent (ROR = 1853.35), gingival recession (ROR = 190.74), deafness neurosensory (ROR = 129.89), nail growth abnormal (ROR = 103.67), onychoclasis (ROR = 73.58), ear discomfort (ROR = 72.88), and deafness bilateral (ROR = 62.46). Eleven positive AE signals were found at the standardized MedDRA queries (SMQs) level, of which the top five SMQs were hyperglycemia/new-onset diabetes mellitus, hearing impairment, gastrointestinal nonspecific symptoms and therapeutic procedures, noninfectious diarrhea, and hypertension. Age significantly increased the risk of hearing impairment. This study identified potential new and unexpected AE signals of teprotumumab. Our findings emphasize the importance of pharmacovigilance analysis in the real world to identify and manage AEs effectively, ultimately improving patient safety during teprotumumab treatment.

Efficiency and Safety of Tocilizumab for the Treatment of Thyroid Eye Disease: A Systematic Review.

To review existing literature concerning the effectiveness and safety of tocilizumab (TCZ) for managing thyroid eye disease. A systematic search was conducted across the PubMed and Embase databases to identify studies on TCZ therapy, from inception to May 2023. The search included the keywords "Graves orbitopathy," "thyroid ophthalmopathy," "thyroid eye disease," "thyroid-associated orbitopathy," "thyroid-associated ophthalmopathy," "Graves ophthalmopathy," "endocrine ophthalmopathy," and "Tocilizumab." Only articles written in English, Spanish, or French were considered. Among the 1,013 articles initially screened, a total of 29 fulfilled the eligibility criteria and were selected. Most studies were case reports or case series, and only one randomized clinical trial was found. TCZ has been used mainly in glucocorticoid-resistant or relapsing cases, with a dosage ranging from 4 or 8 mg/kg every 4 weeks when intravenous or a weekly subcutaneous dose of 162 mg. Treatment duration is usually adjusted to the clinical response. TCZ is mostly effective in reducing inflammatory signs during the active phase of thyroid eye disease, with an improvement of at least 3 points in clinical activity score and an overall relapsing rate of 8.2%. Numerous studies have shown marked reductions in proptosis; although the only available randomized controlled trial reported a nonstatistically significant improvement 6 months after treatment, a recent meta-analysis indicated that TCZ seems to be the most effective treatment for reducing proptosis. No severe side effects related to intravenous or subcutaneous TCZ administration were reported. Despite these promising findings, randomized clinical trials to directly compare the efficacy and safety of TCZ and other currently available therapeutic options are needed.

Computed tomography and magnetic resonance imaging approaches to Graves' ophthalmopathy: a narrative review.

Graves' ophthalmopathy (GO) affects up to 50% of patients with Graves' disease (GD) ranging from mild ocular irritation to vision loss. The initial diagnosis is based on clinical findings and laboratory tests. Orbital imaging, such as magnetic resonance imaging (MRI) and computed tomography (CT), is an important tool to assess orbital changes, being also useful for understanding disease progression and surgical planning. In this narrative review, we included 92 studies published from 1979 to 2020 that used either MRI and/or CT to diagnose and investigate GO, proposing new methods and techniques. Most of the methods used still need to be corroborated and validated, and, despite the different methods and approaches for thyroid eye disease (TED) evaluation, there is still a lack of standardization of measurements and outcome reports; therefore, additional studies should be performed to include these methods in clinical practice, facilitating the diagnosis and approach for the treatment of TED.

[Bony orbital decompression in thyroid eye disease].

This article summarizes the results of research on the morphological and functional features of different types of orbital bone decompression in thyroid eye disease (TED) and presents an analysis of surgical anatomy of the lateral orbital wall in the context of performing deep lateral bone decompression of the orbit was carried out. The study includes an analysis of the results of orbital bone decompression with resection of the greater wing of the sphenoid bone using ultrasound osteodestructor in comparison with osteodestruction using a high-speed drill, description of transethmoidal orbital decompression with endonasal access both as a single method of surgical treatment of TED and in combination with lateral bone decompression of the orbit, including the advantages and disadvantages of the method, and presents a morphological description of the pathological changes in the medial orbital wall bone fragments obtained during endonasal transethmoidal orbital decompression in patients with TED.

A Prospective Study Examining Audiometry Outcomes Following Teprotumumab Treatment for Thyroid Eye Disease.

N/A.

Immunological Processes in the Orbit and Indications for Current and Potential Drug Targets.

Thyroid eye disease (TED) is an extrathyroidal manifestation of Graves' disease (GD). Similar to GD, TED is caused by an autoimmune response. TED is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, swelling, redness, conjunctivitis, and bulging eyes. The pathophysiology of TED is complex, with the infiltration of activated T lymphocytes and activation of orbital fibroblasts (OFs) and autoantibodies against the common autoantigen of thyroid and orbital tissues. Better understanding of the multifactorial pathogenesis of TED contributes to the development of more effective therapies. In this review, we present current and potential drug targets. The ideal treatment should slow progression of the disease with as little interference with patient immunity as possible. In the future, TED treatment will target the immune mechanism involved in the disease and will be based on a strategy of restoring tolerance to autoantigens.

Thyroid Eye Disease and Its Association With Diabetes Mellitus: A Major Review.

Thyroid eye disease (TED) associated with diabetes mellitus (DM) presents unique challenges. DM is a risk factor for TED. Standard management of TED with glucocorticoids (GC), orbital radiation, or teprotumumab can cause adverse events in poor glycemic control. The authors reviewed the literature on the relationship between TED and DM and the management of co-existing diseases. The authors searched PubMed with keywords "thyroid eye disease," "diabetes mellitus," and similar terms from 2013 to 2022. The authors included relevant studies after screening the abstracts. Additional references to the selected studies were included where applicable. Data were extracted from the final articles according to the preplanned outline of the review. The initial search yielded 279 abstracts. The final review included 93 articles. TED and DM interact at multiple levels-genetic, immunologic, cellular, nutritional, and metabolic. Both DM and thyroid dysfunction exacerbate the morbidity caused by the other. Metabolic factors also affect the inflammatory pathway for TED. Patients with DM develop TED with greater frequency and severity, necessitating interventions for vision salvage. Agents (GC, teprotumumab, or radiation) used for TED are often unsuitable for treatment with DM, especially if there is poor glycemic control or diabetic retinopathy. There were no studies on using steroid-sparing agents in TED with DM. TED and DM co-exist because of multiple intersections in the pathophysiology. Challenges in the treatment include increased TED severity and risk of hyperglycemia and retinopathy. Multidisciplinary teams best undertake treatment of TED with DM.

Graves’ disease – management of Graves’ orbitopathy and thyrotoxicosis, including new therapies

Graves' disease (GD) is the most common cause of hyperthyroidism in countries with adequate iodine supply, and its main extrathyroid manifestation is thyroid orbitopathy. For many years, thyrotoxicosis has been treated with antithyroid drugs, radioactive iodine therapy and thyroidectomy, and glucocorticoids have remained the standard treatment of thyroid eye disease (TED). Currently, there is a growing trend of using targeted therapies in the treatment of thyroid orbitopathy (TO). The significant development of immunobiology, a better understanding of the pathophysiology of the disease and a multitude of studies on new therapies give hope for better treatment results and an improvement in the quality of life of patients. The aim of the paper is to discuss the current principles of management of Graves' disease, including thyroid orbitopathy, with particular emphasis on new therapeutic methods. The potent role of K1-70TM and small molecule thyroid stimulating hormone (TSH) receptor antagonists in the treatment of hyperthyroidism is indicated. Not only do we point out the promising outcomes of combining glucocorticoids with mycophenolates, but also highlight the use of teprotumumab, rituximab, cyclosporin A, azathioprine, methotrexate, tocilizumab and sirolimus in the therapy of active moderate to severe form of orbitopathy. The protective and supportive effect of statins in the treatment of TED is noted. The limitations of the research results mentioned in the paper are remarked and the need for further randomized studies of long-term safety and efficacy in a larger group of patients is underlined.

Predictive model for the progression of inactive thyroid eye disease: a retrospective study.

This study aimed to develop a model for predicting the progression of inactive thyroid eye disease (TED). We retrospectively analyzed 107 patients with inactive TED, who did not receive any TED treatment during the follow-up period of 3-6 months. A multivariable regression analysis was employed to examine the clinical risk factors influencing the progress of TED and a predictive model based on risk factors was established. Seventeen (15.9%) patients had progressed at the last observation. Male (p = 0.024), having smoking history (p = 0.009), compound indicator combined the duration of TED and immunosuppressive treatment history before 3 months (p = 0.026) and more severe diplopia (p = 0.015) were found to be the potential risk factors for progression. Among the subset of patients who exhibited progression, there was a notable escalation in the severity of proptosis (p = 0.021), margin reflex distance-1 (p = 0.031), and clinical activity score (p = 0.011). The multivariable stepwise regression analysis identified positive smoking history as well as untreated and having a duration of TED > 12 months as independent risk factors of TED progression. A predictive model including these risk factors was built, with the AUC (Area Under Curve) score of 0.783. The predictors of TED progression include smoking history and composite indicators of duration time and treatment history. Our model may provide recommendations for immunosuppressive therapy and prognostic predictions for inactive TED patients preparing for surgery.

Elevated serum thyroid stimulating immunoglobulin linked to failure of first-line intravenous methylprednisolone monotherapy in moderate-to-severe thyroid eye disease.

To assess factors associated with failure of intravenous methylprednisolone (IVMP) monotherapy as the first-line treatment for thyroid eye disease (TED) and to identify patients who might benefit from supplementing mycophenolate mofetil (MMF) to IVMP. Data for all patients with TED treated with IVMP according to the EUGOGO protocol in our center between 2016-2021 were retrospectively analysed. Forty-seven patients (mean age 51.32 ± 14 years, 27 females) were enrolled. The mean time from first reported symptoms to first IVMP treatment was 12.1 ± 5.59 months (range 0-120). The mean clinical activity score (CAS) before treatment and at a mean of 5 and 12.2 weeks after treatment initiation was 6.00, 2.96, and 1.81, respectively (P < 0.01). Twenty-one patients (44.68%) were recommended second-line treatment: nine due to no response or worsening of CAS, six due to partial response, four with good response but early relapse after completion of treatment, and one due to late relapse. Eighteen of those 21 patients received second-line treatment which included rituximab (n = 7), MMF (n = 6), a second course of IVMP (n = 4), and tocilizumab (n = 1). Serum thyroid-stimulating immunoglobulin (TSI) levels were higher in patients who received second-line treatment compared with patients who responded well to first-line IVMP monotherapy at presentation (2135% vs 1159%, P = 0.05) and after completion of first-line treatment (2201% vs. 986%, P = 0.043). TED patients requiring second-line treatment after failed IVMP monotherapy had higher baseline and post-first-line treatment serum TSI levels. Those with elevated TSI may benefit from dual therapy (IVMP and MMF) and require closer monitoring.

FRI546 VRDN-001, A Full Antagonist Antibody To IGF-1 Receptor In Development For Thyroid Eye Disease (TED): Pharmacodynamic Responses In Healthy Volunteers And Patients With Active TED

Abstract Disclosure: K. Foster: Employee; Self; Viridian Therapeutics Inc. B.A. Dickinson: Employee; Self; Viridian Therapeutics Inc. R.M. Summerfelt: Employee; Self; Viridian Therapeutics Inc. A. She: Employee; Self; Viridian Therapeutics Inc. V. Bedian: Employee; Self; Viridian Therapeutics Inc. B. Katz: Employee; Self; Viridian Therapeutics Inc. Introduction: VRDN-001, a full antagonist antibody to IGF-1 receptor (IGF-1R), is in development for the treatment of thyroid eye disease (TED). Clinical and preclinical evidence demonstrate IGF-1R antagonism reduces the inflammation and proptosis that occur in TED. We provide pharmacodynamic (PD) results in healthy volunteers and TED patients from our ongoing phase 1/2/3 clinical trial (NCT05176639) evaluating VRDN-001. Methods: Healthy volunteers (HVs) and patients with active, moderate-to-severe TED were randomized 3:1 to receive 2 intravenous infusions 3 weeks apart (i.e., at week 0 and week 3) of either VRDN-001 (at 3-20 mg/kg) or placebo. PD parameters (IGF-1 serum levels) were assessed through 7 weeks. Results: Thirteen HVs received either placebo (n=3) or VRDN-001, 3 mg/kg (n=3), 10 mg/kg (n=3), or 20 mg/kg (n=4). Additionally, 16 TED patients received either placebo (n=4), 10 mg/kg of VRDN-001 (n=6), or 20 mg/kg of VRDN-001 (n=6). Baseline characteristics were similar across all TED cohorts. All VRDN-001 doses (3-20 mg/kg) elicited rapid, sustained, and similar increases in IGF-1 serum levels, a biomarker for target engagement and IGF-1R inhibition. In HVs receiving VRDN-001 (n=10), IGF-1 serum levels increased within a day of the first infusion for all doses, reaching 4-6-fold above baseline; levels continued to increase after the second infusion, ultimately reaching 4-9-fold above baseline. In TED patients receiving VRDN-001 (n=12), IGF-1 serum levels increased for both doses 2-6-fold above baseline after the first infusion, and further increased after the second infusion, ultimately reaching levels 4-9-fold above baseline. No increases in IGF-1 serum levels occurred for placebo. Conclusions: Two infusions of VRDN-001 in healthy volunteers as well as TED patients elicited rapid and sustained increases in IGF-1 serum levels that were similar across groups, indicating maximal target engagement at all doses tested. Results from an additional ongoing cohort of 3 mg/kg in TED patients will further inform optimal VRDN-001 dosing and potential treatment regimens to balance efficacy and safety and minimize treatment burden in TED. Presentation: Friday, June 16, 2023

SAT471 Hearing-Related Adverse Events in Teprotumumab Oncology Clinical Trials

Abstract Disclosure: T.J. Smith: Consulting Fee; Self; Horizon Therapeutics plc, Viridian, Lundbeck. Other; Self; US patents covering the use of IGF-1 receptor inhibitors in TED which are held by UCLA and the Lundquist Institute. Q. Fu: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. R.J. Holt: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. Background: Teprotumumab was originally developed for the treatment of a variety of cancers; however, the development program was terminated due to lack of efficacy although no major safety concerns were observed. Teprotumumab was eventually approved by the FDA for the treatment of thyroid eye disease (TED). Hearing-related adverse events (AEs) with insulin-like growth factor-I receptor inhibitors have been reported in clinical trials. Methods: The incidence and severity of hearing-related AEs, as classified by the Medical Dictionary for Regulatory Activities, in teprotumumab-treated patients (N=633) receiving monotherapy (N=362) or in combination with anti-neoplastic therapy (N=271) from oncology clinical trials was evaluated. The relation of events to teprotumumab, severity, and drug exposure up to time of each event was calculated. Results: A total of 8 oncology clinical trials were included with 8.1% (N=51) of patients reporting any Ear and Labyrinth Disorder AEs, and 2.1 % (N=13) reporting events considered teprotumumab-related by the investigators. 3.8% of patients (N=24) reported hearing impairment or tinnitus-related events with 1.3% (N=8) ascribed to teprotumumab. Approximately 80% of reported AEs were considered mild, with Ear Discomfort being the most common. More than half of AEs were reported within 60 days of therapy initiation. The majority of patients (74%) had teprotumumab exposures consistent with the current FDA-recommended dosing regimen of teprotumumab for TED (150 mg/kg). Findings were consistent regardless of relatedness to teprotumumab or whether given as monotherapy or in combination with anti-neoplastic agents (some of which have been reported to cause hearing-related events). Of the teprotumumab-ascribed hearing AEs, two were considered moderate (deafness and hypoacusis) and one as severe (bilateral deafness). The moderate hypoacusis event occurred in a patient exposed to nearly twice the total dose of the recommended regimen of teprotumumab for TED. The severe event occurred in a patient exposed to almost 7 times the expected exposure with the recommended TED dosing. Conclusions: Hearing-related AE type and incidence were similar in patients who received teprotumumab as monotherapy or in combination with other agents in this sizeable oncology trial program. The most severe events reported were at higher drug exposures than used in the TED clinical trials. The types of AEs and incidence were also comparable to those reported in the TED clinical trial program and as reported in the current FDA-approved prescribed labeling for teprotumumab in the United States. Presentation Date: Saturday, June 17, 2023

OR26-02 VRDN-001, A Full Antagonist Antibody To IGF-1 Receptor In Development For Thyroid Eye Disease (TED), Binds To A Distinct Epitope From Teprotumumab

Abstract Disclosure: V. Bedian: Employee; Self; Viridian Therapeutics Inc. J.C. Tsai: Employee; Self; Viridian Therapeutics Inc. R.N. Newell: Employee; Self; Viridian Therapeutics Inc. Y. Zhao: Employee; Self; Viridian Therapeutics Inc. Introduction: VRDN-001, a full antagonist antibody to IGF-1 receptor (IGF-1R), is under development for the treatment of thyroid eye disease (TED). Clinical and preclinical evidence confirm IGF-1R antagonism reduces the inflammation and proptosis that occur in TED. As different anti-IGF-1R antibodies may have distinct characteristics, we compared the binding epitope and in vitro antagonist properties of VRDN-001 with teprotumumab. Methods: We generated a panel of IGF-1R extracellular domain point mutants of 40 potential IGF-1 interacting residues and 3 N-terminal truncations and assessed the binding pattern of the 2 antibodies to these variants by bio-layer interferometry (Octet). Antagonist characteristics were determined by dose-responses of inhibition of biotinylated IGF-1 binding to IGF-1R expressing FreeStyle™ 293-F cells by flow cytometry and inhibition of IGF-1 mediated signaling in primary human ocular choroidal fibroblasts. Results: VRDN-001 binding was affected by the same domain deletions/truncations as teprotumumab but was not affected by the same point mutations; while teprotumumab binding was reduced or abolished by 2 of the mutations, VRDN-001 binding was not affected by any of the 40-point mutations. These results are consistent with overlapping binding sites but distinct receptor interactions. In antagonism studies, at ≥50 nM, VRDN-001 nearly completely inhibited IGF-1 binding, while teprotumumab only partially inhibited IGF-1 binding through 300 nM. Similarly, VRDN-001 more completely antagonized IGF-1 mediated signaling (phosphorylation of IGF-1R and AKT) than teprotumumab. Conclusion: Despite having overlapping epitopes, VRDN-001 is distinct from teprotumumab in both its mutational signature and its more complete antagonism of IGF-1 mediated signaling. VRDN-001’s unique binding and functional antagonism characteristics may contribute to the robust pharmacodynamic responses observed in healthy volunteers and favorable efficacy signals observed in early clinical trials of TED patients. Presentation: Saturday, June 17, 2023

SAT459 Teprotumumab Pooled Efficacy From The European Study Sites Participating In The Phase 2, OPTIC (Phase 3) And OPTIC-X Pivotal Trials

Abstract Disclosure: G.J. Kahaly: Research Investigator; Self; Horizon Therapeutics plc. Q. Fu: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. R.J. Holt: Employee; Self; Horizon Therapeutics plc. Stock Owner; Self; Horizon Therapeutics plc. Background: The pivotal clinical trial program for the formal approval of teprotumumab for the treatment of thyroid eye disease (TED) in the United States (US) has previously reported excellent overall results.1 These results included data from 9 unique European Union (EU) study sites. Teprotumumab is not currently approved in the EU. Here we report pooled efficacy results from the participating EU sites. Methods: Data from the EU sites in the integrated randomized, double-masked, placebo-controlled 24-week phase 2 and 3 trials and open-label OPTIC-X trial were analyzed for the primary outcome of proptosis reduction of ≥2 mm from baseline (BL). Secondary outcomes were diplopia response (a reduction from BL in diplopia of ≥1 grade [Gorman scale]), Clinical Activity Score (CAS) of 0 or 1, an Overall response (a reduction of ≥2 in CAS plus a reduction in proptosis of ≥2 mm), the least squares (LS) and mean BL change in proptosis (mm) and the LS and mean change in overall score on the Graves’ ophthalmopathy-specific quality-of-life (GO-QOL). Tobacco exposure was controlled for using a mixed-model repeated-measures analysis with an unstructured covariance matrix. Results: In the Integrated EU phase 2 and 3 trials, a total of 35 patients were assigned to the teprotumumab group and 39 to the placebo group. Tobacco use was 44.6% compared with 13.4% in US. Months since diagnosis of Graves’ disease was longer in EU than US (48.8 vs. 26.3). Fewer EU patients had constant diplopia (grade 3) at BL than US (13.5% vs. 25.8%). At week 24, the percentage of EU patients with a proptosis response was higher with teprotumumab than with placebo (77% [27] vs. 13% [5], P&amp;lt;0.001). All secondary outcomes were significantly better with teprotumumab than with placebo, respectively, including diplopia response (63% [17 of 27] vs. 22% [6 of 27], P&amp;lt;0.001), CAS 0/1 (71% [25] vs. 26% [10], P&amp;lt;0.001), Overall response (77% [27] vs. 13% [5], P&amp;lt;0.001), LS mean change in proptosis of −2.76 mm vs. −0.28 mm, P&amp;lt;0.001, BL line mean change in proptosis of -3.18 mm vs.-0.39 mm and LS mean change in GO-QOL overall score of 14.84 points vs. 4.16 points, P&amp;lt;0.001 with BL mean change in GO-QOL of 18.66 vs. 3.75. In the open-label OPTIC-X trial, a total of 19 EU OPTIC study placebo patients received teprotumumab for the first time. After 24 weeks of treatment, the percentage of patients with a proptosis response was 95% (18 out of 19), diplopia response was 54% (7 of 13), CAS 0/1 was 69% (11 out of 16), Overall response was 81% (13 out of 16), mean change in proptosis was −3.29 mm, and mean change in GO-QOL overall score was 11.71 points, indicating robust improvements. Conclusions: Among EU patients with TED, teprotumumab resulted in better outcomes with respect to proptosis, CAS, diplopia, and quality of life as compared with placebo.