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Teprotumumab and hearing loss: hear the warnings

To the Editor, Thyroid eye disease (TED) is a disfiguring and debilitating autoimmune condition of the orbit and periorbital tissues. Teprotumumab, sold under the brand name Tepezza (Horizon Therapeutics, Dublin, IRL), is a human monoclonal antibody and targeted inhibitor of insulin-like growth factor-1 receptor (IGF-1 R). This novel orphan drug has recently been FDA-approved for treatment of adults with TED, making it the first and only medicine approved for treatment of this condition. Two randomized, doublemasked, placebo-controlled studies demonstrated benefits of this drug, including improvements in proptosis, diplopia, Clinical Activity Score, and quality of life compared to placebo. Among the various side effects noted in these studies, eight patients receiving teprotumumab infusions reported changes in hearing (vs. 0 patients in the placebo group). In Smith et al. hearing impairment was reported in 3 of 43 patients (7%) who received teprotumumab: one experienced unilateral hearing loss (16 weeks after the end of therapy), one had bilateral hearing loss (resolved), and one developed tinnitus (in the setting of previous history of tinnitus; resolved). Douglas et al. reported otologic symptoms in five patients receiving teprotumumab: two experienced hypoacusis (resolved), one had deafness (resolved), one had autophony (bilateral intermittent echoing of the patient’s voice; resolved), and one had mild patulous eustachian tube (resolved). This unexpected side effect profile may have its underpinnings in a more basic understanding of insulinlike growth factor-1 (IGF-1). IGF-1 has been implicated in inner ear development, as well as in the maintenance and protection of hearing function. Genetic IGF-1 deficiency has been associated with devastating hearing loss in a human and in mouse studies. Animal models of sound trauma have shown that IGF-1 application to the round window appears to confer significant protective effects. Moreover, IGF-1 is on the therapeutic horizon as a biological therapy for sensorineural hearing loss. It has been used as a salvage therapy via direct placement on the round window in a Phase 1 study of patients with sudden hearing loss refractory to standard corticosteroid treatment; at 24 weeks post-treatment, 56% of the 24 treated patients demonstrated hearing improvement. Decreased IGF-1 in aging mice has also been associated with presbycusis. Although clear causal relationships have not been established, it is reasonable to consider IGF-1 R inhibition as a risk factor for hearing changes due to the strong relationship between IGF-1 and otologic health. Notably, hearing loss is associated with many disabling conditions, including cognitive decline, dementia, and depression. Given the reported incidence of hearing loss and other otologic symptoms, clinicians prescribing teprotumumab should consider monitoring patients in conjunction with an audiologist and otolaryngologist.