Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment

Douglas, Raymond S.; Kahaly, George J.; Ugradar, Shoaib; Elflein, Heike M.; Ponto, Katharina A.; Fowler, Brian; Dailey, Roger A.; Harris, Gerald J.; Schiffman, Jade S.; Tang, Rosa A.; Wester, Sara T.; Jain, Amy Patel; Marcocci, Claudio; Marinò, Michele; Antonelli, Alessandro; Eckstein, Anja; Führer-Sakel, Dagmar; Salvi, Mario; Sile, Saba; Francis-Sedlak, Megan; Holt, Robert J.; Smith, Terry J.

doi:10.1016/j.ophtha.2021.10.017

Cited by 98 publications

(97 citation statements)

References 29 publications

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“…Dysmotility is more complex with many patients responding favorably but with guarded expectations in those with large angle deviations. Maintenance of therapy up to 72 weeks is encouraging, but the durability beyond that, and the role of retreatment, remain unclear (40).…”

Section: Discussionmentioning

confidence: 99%

“…After completion of the Phase-3 clinical trial, the placebo treated patients and the 5 teprotumumab nonresponders were treated with 8 infusions of teprotumumab using the same every 3-week schedule as the Phase-3 trial (OPTIC-X) (40). Of the teprotumumab nonresponders, 2 responded, 1 had a proptosis reduction of 1.5 mm from OPTIC baseline, and 2 discontinued treatments early.…”

Section: Evolving Data On Durability Of Effect Re-treatment and Impac...mentioning

confidence: 99%

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A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface

Ugradar¹,

Kossler²,

Douglas³

et al. 2022

Journal of Neuro-Ophthalmology

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T eprotumumab is the first and only Food and Drug Administration (FDA)-approved medication for the treatment of thyroid eye disease (TED). At the time of writing, aside from the clinical information from the original trials on the safety and efficacy of teprotumumab (1-4), only a handful of clinical reports have been published (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). This review discusses the mechanism of action of teprotumumab and provides an overview of real-world experience with teprotumumab 21 months after the approval.

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Section: Discussionmentioning

confidence: 99%

Section: Evolving Data On Durability Of Effect Re-treatment and Impac...mentioning

confidence: 99%

A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface

Ugradar¹,

Kossler²,

Douglas³

et al. 2022

Journal of Neuro-Ophthalmology

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“…Although teprotumumab has proven effective and relatively safe in the treatment of TED, long-term observations, beyond those thus far reported ( 99 ) are currently unavailable. Many questions pertaining to IGF-IR, its relationship with TSHR, and how the drug might be disrupting this protein/protein interaction remain to be answered ( Fig.…”

Section: Igf-ir Bioactivitiesmentioning

confidence: 95%

It Takes Two to Tango: IGF-I and TSH Receptors in Thyroid Eye Disease

Girnita

Smith

Janssen

2022

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Thyroid eye disease (TED) is a complex autoimmune disease process. Orbital fibroblasts represent the central orbital immune target. Involvement of the TSH receptor (TSHR) in TED is not fully understood. IGF-I receptor (IGF-IR) is overexpressed in several cell types in TED, including fibrocytes and orbital fibroblasts. IGF-IR may form a physical and functional complex with TSHR. Objective Review literature relevant to autoantibody generation in TED and whether these induce orbital fibroblast responses directly through TSHR, IGF-IR, or both. Evidence IGF-IR has traditionally been considered a typical tyrosine kinase receptor in which tyrosine residues become phosphorylated following IGF-I binding. Evidence has emerged that IGF-IR possesses kinase-independent activities and can be considered a functional receptor tyrosine kinase/G-protein-coupled receptor hybrid, using the G-protein receptor kinase/β-arrestin system. Teprotumumab, a monoclonal IGF-IR antibody, effectively reduces TED disease activity, proptosis, and diplopia. In addition, the drug attenuates in vitro actions of both IGF-I and TSH in fibrocytes and orbital fibroblasts, including induction of proinflammatory cytokines by TSH and TED IgGs. Conclusions Although teprotumumab has been proven effective and relatively safe in the treatment of TED, many questions remain pertaining to IGF-IR, its relationship with TSHR, and how the drug might be disrupting these receptor protein/protein interactions. Here, we propose 4 possible IGF-IR activation models that could underlie clinical responses to teprotumumab observed in patients with TED. Teprotumumab is associated with several adverse events, including hyperglycemia and hearing abnormalities. Underpinning mechanisms of these are being investigated. Patients undergoing treatment with drug must be monitored for these and managed with best medical practices.

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“…7 One clinical study reported borderline audiometry in two patients with tinnitus, however baseline pretreatment audiometry was not obtained for comparison. 9 Multiple published cases of teprotumumab-associated hearing loss objectively demonstrated persistent and potentially permanent sensorineural hearing loss. 10–12 IGF-1 plays a significant role in the development, maintenance and protection of hearing function within the inner ear.…”

Section: Introductionmentioning

confidence: 99%

“…Subsequent literature has found the incidence of otological side effects to be as high as 30% 7. One clinical study reported borderline audiometry in two patients with tinnitus, however baseline pretreatment audiometry was not obtained for comparison 9. Multiple published cases of teprotumumab-associated hearing loss objectively demonstrated persistent and potentially permanent sensorineural hearing loss 10–12.…”

Section: Introductionmentioning

confidence: 99%

Teprotumumab-associated chronic hearing loss screening and proposed treatments

Chow

Silkiss

2022

BMJ Case Rep

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We report a case of a woman in her 50s with chronic teprotumumab-associated sensorineural hearing loss. The patient presented with chronic thyroid eye disease with proptosis and diplopia despite systemic thyroid control and orbital decompression. She was started on teprotumumab but developed tinnitus after the third dose, followed by frank hearing loss after the fifth dose. Her audiogram showed bilateral mild to moderate-severe hearing loss, which was significantly worse compared with her baseline audiogram obtained prior to treatment. Teprotumumab was immediately stopped, however repeat audiogram 6 weeks later showed no improvement. Given potentially irreversible sensorineural hearing loss, we recommend close monitoring with regular audiometric testing before, during and after teprotumumab therapy and propose potential treatment to reverse its effects in the ear.

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Teprotumumab Efficacy, Safety, and Durability in Longer-Duration Thyroid Eye Disease and Re-treatment

Cited by 98 publications

References 29 publications

A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface

A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface

It Takes Two to Tango: IGF-I and TSH Receptors in Thyroid Eye Disease

Teprotumumab-associated chronic hearing loss screening and proposed treatments

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