Patterns of Teprotumumab‐Induced Hearing Dysfunction: A Systematic Review

Abstract

Objective

Hearing loss has been reported after administration of the monoclonal antibody teprotumumab. The purpose of this study was to review available evidence regarding the patterns of teprotumumab‐related ototoxicity.

Data Sources

PubMed, EMBASE, and Cochrane Library.

Review Methods

A systematic review was performed using standardized methodology. Studies were included if they included subjects who were prescribed teprotumumab. Exclusion criteria included non‐English articles, abstracts, letters/commentaries, case reports, and reviews. Subjects without both pre‐ and posttreatment audiometric data were also excluded. Bias was assessed using the Mixed Methods Appraisal Tool.

Results

From an initial search of 76 articles, 7 studies reporting on 109 unique patients were included. Four studies were level 4 evidence, 1 study was level 3 evidence, and 2 studies were level 2 evidence. Mean age was 55 ± 14 years with a female predominance (64%). The most commonly reported symptoms were hearing loss (22%), followed by fullness (18%) and tinnitus (14%). In total, 41% of patients with available data met criteria for ototoxicity, all exhibiting shifts in the middle frequencies or higher. Fifteen (14%) patients underwent ultrahigh frequency audiometric testing and 8 (53%, 8/15) demonstrated shifts exclusively in this range.

Conclusion

Ototoxicity may occur in patients treated with teprotumumab. Hearing loss occurs primarily in higher frequencies, and routine hearing screening with ultrahigh frequency testing may be warranted. The true incidence of ototoxicity with teprotumumab remains unknown, and more data is needed to elucidate underlying mechanisms and develop strategies to minimize risks.

The landscape of monoclonal antibody therapy has rapidly grown over the past few years. This resurgence has been driven by several factors, including advancements in engineering techniques and the expansion of antibody targets beyond cancer to include autoimmune and neurodegenerative diseases. ¹ , ² Teprotumumab is a monoclonal antibody that targets insulin‐like growth factor‐1 receptor (IGF‐1R), and has emerged as a promising treatment option for patients with thyroid eye disease (TED) or Grave's orbitopathy.

TED is a condition characterized by autoimmune‐mediated inflammation and fibrosis of extraocular muscles, orbital fat, and connective tissue, leading to symptoms of proptosis, periorbital edema, and if left untreated, permanent visual loss. ³ IGF‐1R is overexpressed in the orbital tissue of TED patients and plays a role in fibroblast proliferation, glycosaminoglycan synthesis, and adipogenesis. ⁴

The efficacy of teprotumumab for improving overall eye‐related symptoms in TED patients has been well‐documented. ⁵ , ⁶ However, increasing reports have suggested that teprotumumab carries the risk of hearing loss. In the cochlea, IGF‐1 receptors support normal homeostatic signaling pathways and sensory cell differentiation, ⁷ and inhibition of these receptors has been theorized to play a role in its ototoxicity.

The goal of this study was to perform a systematic review of existing clinical data to elucidate the frequency and patterns of hearing loss in patients treated with teprotumumab.

Methods

Search Strategy

A systematic review was performed in accordance with standardized Preferred Reporting Items for Systematic Reviews and Meta‐analyses guidelines. ⁸ A database search was performed in PubMed, EMBASE, and Scopus for relevant peer‐reviewed studies (Supplemental Appendix A, available online). The primary purpose of this review was to evaluate ototoxicity in patients treated with teprotumumab and our search strategy was designed to identify all publications that reported on hearing loss in treated with teprotumumab. Results were imported into Covidence for systematic review management. No temporal limits were applied.

Study types included clinical prospective and retrospective studies, experimental research, and case series. Articles were evaluated to meet the following inclusion criteria: patients of any age, gender, ethnicity, or health status with exposure to any teprotumumab regimen and comparison to a control or preteprotumumab hearing baseline. Exclusion criteria included review articles, non‐English articles, case reports, letters/commentaries, abstracts, and conference proceedings. Subjects with both normal hearing and hearing loss pretreatment were included. Subjects without baseline pretreatment audiometry were excluded from analysis. Two authors (P.A. and Y.S.) performed the initial review of the literature and a third (K.W.) served as an adjudicator. Full‐text articles were obtained for (1) abstracts that met inclusion criteria, (2) abstracts that did not provide sufficient information to make a screening decision, and (3) abstracts with reviewer disagreement. An additional search was also performed by reviewing reference lists for included full‐text articles to identify any additional articles. All included articles were reviewed by all authors to ensure accuracy and consistency of data, with any discrepancies resolved through discussion to reach agreement. All authors approved the final dataset.

Assessment of Bias

Publication bias for each article was assessed using the Mixed Methods Appraisal Tool (MMAT). ⁹ Evaluated domains included: participant selection, randomization, assessor blinding, adherence to intended intervention, completeness of data, and outcome measurement. The series of questions to assess bias within the tool were answered based on article type for each included study.

Data Collection

Information obtained from each article included study title, authorship, country, publication year, publication journal, study design, and total subjects. Level of evidence was determined using established guidelines (1 = randomized controlled trial; 2 = prospective cohort study; 3 = retrospective/chart review; 4 = case series; 5 = expert opinion/commentary). ¹⁰

In subjects with teprotumumab‐associated ototoxicity and/or hearing loss, information recorded included age, gender, indications for teprotumumab use, dosage, length of treatment, follow‐up timeline, concurrent medications, co‐morbidities, pre‐ and posttreatment audiometric data at low, middle, high, and ultrahigh frequencies when available, tympanometry, word recognition score (WRS), speech recognition threshold, and treatment for ototoxicity (if observed). Frequency ranges were defined as follows: low (250‐500 kHz), middle (1‐3 kHz), high (4‐8 kHz), and ultrahigh (>8 kHz).

Medication‐induced ototoxicity was determined usually established guidelines by the American Speech‐Language‐Hearing Association (ASHA): 20 dB threshold decrease at any frequency, 10 dB decrease at any 2 consecutive frequencies, or no response at 3 consecutive frequencies when responses were previously present. ¹¹

A quantitative synthesis was performed using pooled samples. Given the heterogeneity of studies and results reporting, a standard meta‐analysis for comparing studies with paired samples and a weighted average was not feasible.

Results

Search Results

In total, 7 studies met inclusion criteria. ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ The initial search generated 37 unique results, of which 10 were excluded after initial screening and 20 articles were excluded after full‐text review (Figure 1). Among the 7 included articles, 273 total subjects were described, of which 109 had both baseline and post‐treatment hearing assessments reported and were thus included for analysis.

Figure 1.

Disposition of preferred reporting items for this systematic review.

Assessment of Bias

All of the studies included in this review were considered to have a clear research question and relevant data collection process (screening questions 1 and 2 of MMAT, respectively). The largest proportion of included papers (57%) reported on quantitative descriptive studies (Table 1). The distribution of affirmative responses to the MMAT categories indicate an acceptable quality within the limitations of their study designs.

Table 1.

Mixed Methods Appraisal Tool (MMAT)

Study	Yes on 5, MMAT criteria	Yes on 4, MMAT criteria	Yes on 3, MMAT criteria	Yes on 2, MMAT criteria	Yes on 1, MMAT criteria	Yes on 0, MMAT criteria
Quantitative nonrandomized studies 43% (3)	33% (1)	33% (1)	33% (1)	0% (0)	0% (0)	0% (0)
Quantitative descriptive studies 57% (4)	50% (2)	50% (2)	0% (0)	0% (0)	0% (0)	0% (0)

Abbreviation: MMAT, Mixed Methods Appraisal Tool.

Bibliometrics

A description of the participants, interventions, comparisons, outcomes, timing, and study design of included publications is shown in Table 2. The majority of studies (57%, 4/7) were published between 2022 and 2023 with a range from 2021 to 2024. All studies originated from the United States. Four studies were level 4 evidence, 1 study was level 3 evidence, and 2 studies were level 2 evidence.

Table 2.

Participants, Interventions, Comparisons, Outcomes, Timing, and Study Design

Study	Year	Journal	Population	Intervention	Comparator	Outcome	Timing	Study design
Shah et al	2024	Ophthalmology	Patients across 6 tertiary care centers who received teprotumumab	Teprotumumab	Pure‐tone audiometry	Hearing loss	Variable	Retrospective cohort
Douglas et al	2024	Thyroid	Patients who received teprotumumab and underwent audiology testing	Teprotumumab	Mobile audiometry	Hearing loss	6 mo follow‐up	Prospective cohort
Keen et al	2023	Ophthalmology	Patients who received teprotumumab and underwent audiology testing	Teprotumumab	Pure‐tone audiometry	Hearing loss	5 mo follow‐up	Case series
Belinsky et al	2022	Ophthalmic Plast Reconstr Surg	Patients who experienced hearing loss after treatment with teprotumumab	Teprotumumab	Pure‐tone audiometry	Hearing loss	7 mo follow‐up	Case series
Kay‐Rivest et al	2022	Otolaryngol Head Neck Surg	Adults treated with teprotumumab between May 2020 and January 2022	Teprotumumab	Pure‐tone audiometry Tympanometry DPOAE	Hearing loss	6 mo follow‐up	Prospective cohort
Sears et al	2022	Am J Ophthalmol	Patients with TED treated with temprotumumab between February 2020 and May 2021	Teprotumumab	Pure‐tone audiometry PET tympanometry	Hearing loss	14 mo follow‐up	Prospective cohort
Yu et al	2021	Am J Ophthalmol Case Rep	Patients who experienced hearing changes after treatment with teprotumumab	Teprotumumab	Pure‐tone audiometry	Hearing loss	6 mo follow‐up	Case series

Abbreviations: DPOAE, distortion product otoacoustic emissions; mo, months; PET, patulous eustachian tube; TED, thyroid eye disease.

Patient Characteristics

Patient characteristics are described in Table 3. Across studies, a total of 109 patients met inclusion criteria. Mean age was 55 years with a range from 31 to 84 years. There was a female predominance (64%). Exactly half of the included subjects (47/94) had normal hearing on pretreatment audiograms (15 subjects from Key‐Rivest et al and Shah et al were excluded from this figure due to amassed reporting).

Table 3.

Clinical Characteristics ^a

Characteristic	Na (%)
Age, y	55 ± 14 (31‐84)
Female	53 (64%)
Clinical symptoms
Hearing loss	24 (22%)
Fullness	20 (18%)
Tinnitus	15 (14%)
Autophony	5 (5%)
Popping	3 (3%)
Vertigo/dizziness	2 (2%)
Otalgia	1 (1%)
Timing of initial symptoms	3.6 ± 1.3 infusions
Ototoxicity (ASHA)	40 (41%)
Unilateral hearing loss	6 (40%)

Abbreviation: ASHA, American Speech‐Language‐Hearing Association.

^a Sum does not equal total sample size due to incomplete reporting.

The most commonly reported symptoms during teprotumumab treatment were hearing loss (22%), followed by fullness (18%) and tinnitus (14%). On average, initial symptom onset occurred after 3.6 infusions (SD 1.4) with a range from after the first infusion to after completion of all infusions. Two patients experienced dizziness or vertigo without exam findings demonstrating peripheral weakness.

Indication for teprotumumab was TED in all patients, and the dosing schedule was most commonly a 10 mg/kg intravenous initial dose, followed by 20 mg/kg infusions every 3 weeks for a total of 8 infusions (Table 4). Average treatment length was 19 weeks with a range from 11 to 24 weeks. Average follow‐up length was 8 months with a range from 5 to 16 months.

Table 4.

Teprotumumab Treatment

Study	Indication	Dose	Dosing interval	Treatment length	Last follow‐up
Shah et al	TED	10 mg/kg (first) 20 mg/kg (subsequent)	q3 wk	21 wk	Variable
Douglas et al	TED	10 mg/kg (first) 20 mg/kg (subsequent)	q3 wk	24 wk	6 mo
Keen et al	TED	10 mg/kg (first) 20 mg/kg (subsequent)	q3 wk	21 wk	5 mo
Belinsky et al	TED	‐	‐	8 infusions	7 mo
Kay‐Rivest et al	TED	10 mg/kg (first) 20 mg/kg (subsequent)	q3 wk	21 wk	6 mo
Sears et al	TED	10 mg/kg (first 2) 20 mg/kg (subsequent)	q3 wk	21 wk	14 mo
Yu et al	TED	‐	‐	11 wk	6 mo

Abbreviations: kg, kilogram; mg, milligram; q, every; TED, thyroid eye disease; ‐, not reported.

Ototoxicity Outcomes

Among 97 patients with reported pre‐ and posttreatment audiometric data, 40 (41%) experienced hearing threshold shifts on pure‐tone audiometry meeting criteria for ototoxicity per ASHA guidelines. Shah et al reported the other 12 patients, of which 8 (67%) had posttreatment hearing loss. The specific degree of hearing loss was not reported in this study so ototoxicity criteria could not be determined. Laterality was reported in 15 patients, of which 6 (40%) demonstrated a unilateral hearing loss. Douglas et al reported unilateral hearing loss in 4 patients with ototoxicity, however, the laterality of the remaining 7 subjects was not reported. Among those with normal pretreatment audiograms, 30% (14/47) experienced ototoxicity; among those with pre‐existing hearing loss, more than half (57%, 27/47) experienced ototoxicity.

Approximately half of patients meeting ototoxicity criteria reported otologic symptoms (59%, 17/29). Conversely, 4 out of 13 (31%) patients who did not meet ototoxicity criteria endorsed symptoms (data excluding Kay‐Rivest et al, Shah et al, and Douglas et al with amassed reporting). The majority of symptomatic patients (92%, 12/13) who underwent standard audiometry did not undergo ultrahigh frequency testing. Only 4 subjects had WRS reported ¹⁷ , ¹⁸ ; in 3 subjects, WRS declined 10% to 56% lower than pretreatment levels. In the fourth subject, WRS remained stable.

A summary of deleterious hearing effects is presented in Table 5. Among patients with proven ototoxicity, all exhibited shifts in the middle frequency range or higher. There was no change in the lower frequency range. Fifteen (33.3%, 15/45) patients underwent ultrahigh frequency audiometric testing; among these 15 patients, 8 (53%) demonstrated threshold shifts only in the ultrahigh frequency range with no shifts on standard audiometry.

Table 5.

Summary of Study Findings Demonstrating Deleterious Hearing Effects

Study	Included sample	Frequency range affecteda	ASHA ototoxicity	Percent symptomaticb
Shah et al.	12	‐	‐	‐
Douglas et al.	52	Middle High	11	‐
			(21%)
Keen et al.	22	Middle High	11	5/11
			(50%)	(45%)
Belinsky et al.	1	Ultrahigh	1	1/1
			(100%)	(100%)
Kay‐Rivest et al.	14	Middle High Ultrahigh	11	6/11
			(78.6%)	(54.5%)
Sears et al.	6	Middle High	5	5/5
			(83.3%)	(100%)
Yu et al.	2	Middle High	1	0/1
			(50%)	(0%)

Abbreviations: ASHA, American Speech‐Language‐Hearing Association; ‐, not reported.

^a Frequency ranges: Low (250‐500 kHz), middle (1‐3 kHz), high (4‐8 kHz), ultrahigh (>8 kHz).

^b Any audiovestibular symptoms among those with ototoxicity.

Predictors of Ototoxicity

Four studies investigated risk factors for teprotumumab‐related hearing dysfunction. Sears et al and Douglas et al found that baseline hearing loss was correlated with teprotumumab‐related ototoxicity. Shah et al identified 5 patients in their study who discontinued teprotumumab therapy early due to ototoxicity, of which 4 had pretreatment hearing loss. Keen et al found that greater baseline PTA and older age were individually predictive of ototoxicity; however, this relationship did not hold on multivariate logistic regressions. Authors did not find any other association between demographics, medical history, prior ototoxic medication use, or prior Grave's treatment (antithyroid medication, thyroidectomy, or radioactive iodine) on the presence or absence of teprotumumab‐related SNHL.

Long‐Term Outcomes

Three studies reported on treatment of teprotumumab‐related hearing loss. Keen et al and Belinksy et al recorded the use of oral steroids (prednisone) in a pooled 4 patients at a starting dose of 60 mg for a target period ranging from 7 to 10 days, with no improvement in any patient. ¹⁴ , ¹⁵ Shah et al reported the use of systematic steroids in 1 patient for the treatment hearing loss without outcome measures. Five studies reported on the long‐term resolution of symptoms after cessation of teprotumumab, with 22/34 (65%) reporting improvement of hearing back to baseline. In their prospective study, Douglas et al found that more than half of patients (6/11, 55%) demonstrated resolution of ototoxicity by 6 months follow‐up.

Discussion

Since its Food and Drug Administration approval in January 2020, the monoclonal antibody teprotumumab has gained attention as an effective treatment option for TED. However, warnings of potential ototoxicity have existed for several years. In a phase 2 clinical trial published in 2017, Smith et al evaluated 42 patients treated with teprotumumab and reported 1 patient with unilateral hearing impairment, 1 with bilateral hearing impairment, and 1 with subjective tinnitus after treatment initiation. In the subsequent phase 3 trial, 5 of 41 patients in the teprotumumab cohort experienced otologic symptoms ranging from hypoacusis to autophony and hearing loss. ⁵ In the past year, scattered reports have increasingly suggested a link between teprotumumab and hearing loss. As teprotumumab shows promise as a treatment for TED, understanding the ototoxic side effect profile becomes increasingly important to guide patient counseling and informed decision‐making.

This systematic review showed that some patients receiving teprotumumab may experience ototoxicity. These data suggest an association between teprotumumab and hearing impairment that warrants further investigation, particularly in those with preexisting hearing loss where there appears to be an increased risk. ¹⁷

A notable finding from this review was that hearing loss was unilateral in slightly less than half of reported cases. From a physiological standpoint, IGF‐I is involved in cochlear cell differentiation, ⁷ proliferation, ¹⁹ and synapse regeneration. ²⁰ Teprotumumab—which acts to antagonize IGF‐1 receptors—may disrupt these neurotrophic signals, leading to downstream pathways of inner ear dysfunction and SNHL. To this end, the presence of unilateral hearing loss is intriguing, and could indicate variable tissue resistance to IGF‐1 blockade or a specific pattern of damage that is yet unknown to the auditory system.

Another important observation was that almost half of patients with hearing loss did not report any symptoms. Meanwhile, about a third of patients without hearing loss did still endorse otologic symptoms. This discordance between subjective symptoms and objective audiometric findings has been noted in the past with teprotumumab. ¹⁷ , ¹⁸ We hypothesize this may be explained by changes in hearing thresholds at ultrahigh frequencies (>8 kHz) that are outside the range of testing on standard audiometry.

Medication‐induced ototoxicity has long been known to manifest at ultrahigh frequencies (>8 kHz). For example, studies on platinum‐based chemotherapeutics and aminoglycoside antibiotics have demonstrated ototoxic affects in these higher frequency ranges, and in some cases, preferentially target these regions. ²¹ , ²² Only 15 patients in this review underwent ultrahigh frequency testing, of which approximately half experienced hearing loss in the ultrahigh frequency range, only. The presence of hearing loss at these ultrahigh frequencies may explain why a third of patients without hearing loss on standard audiometry endorsed otologic symptoms. Together, these results suggest a role for extended high‐frequency audiometry as part of routine monitoring in patients taking teprotumumab.

There is no guideline on the ideal timing or frequency of audiologic monitoring, however, given the fact that symptom onset can start as early as after the first infusion or as late as after the last infusion, 2 crucial timepoints to include are prior to initial treatment, and after the last dose. An additional timepoint to consider is several months after medication cessation to identify spontaneous recovery.

We found that treatment with oral steroids did not yield significant improvements in hearing loss among affected individuals. Despite this, a reassuring finding was that most patients, regardless of treatment, noted a subjective return to baseline hearing status and resolution of audiovestibular symptoms by about 6 months after last treatment. The reversibility of drug‐induced ototoxicity suggests spontaneous recovery in a substantial proportion of affected patients. These findings underscore the importance of further studies to elucidate the underlying disease mechanisms and redefine optimal treatment strategies.

The primary limitation of this study was inconsistent reporting and pooled outcomes that precluded a meta‐analysis between heterogeneous study populations and designs. Although we found that a large portion of patients in our pooled sample experienced ototoxicity, this inflated value does not represent the true incidence of teprotumumab‐associated ototoxicity given that the denominator does not represent the total number of patients treated with teprotumumab by the included authors. Another limitation was variability in long‐term follow‐up of included patients, therefore limiting our understanding of the persistence or resolution of symptoms and hearing loss over time. Finally, only subjects with both baseline and posttreatment audiometric testing were included in this review. This excluded 164 subjects from an initial pool of 273 patients. However, this criteria was determined a priori and was set to limit the confounding possibility that hearing loss attributed to teprotumumab was in fact present at baseline.

Conclusion

The presence of ototoxicity exists in patients receiving teprotumumab for TED. Hearing loss occurs primarily at high and ultrahigh frequencies. Formal screening protocols with baseline and posttreatment audiologic assessments in collaboration with audiologists may be warranted, with an emphasis on ultrahigh frequency testing. The prevalence of unilateral cases, a subclinical course, and variability in outcomes underscores the complexity of this disease process and the need for further research to elucidate underlying mechanisms.

Author Contributions

Kevin Wong, conception, design, data acquisition, analysis, drafting, final approval; Priya Arya, data acquisition, analysis, drafting, final approval; Yansy Salmeron, data acquisition, analysis, drafting, final approval; Douglas C. Bigelow, conception, design, analysis, drafting, final approval; Michael J. Ruckenstein, analysis, drafting, revisions, final approval; Shubhasree Banerjee, design, analysis, critical appraisal, revisions, final approval; Madhura Tamhankar, analysis, drafting, revisions, final approval; Jason A. Brant, conception, design, critical appraisal, revisions, final approval; Tiffany P. Hwa, conception, design, critical appraisal, revisions, final approval.

Disclosures

Competing interests

None.

Funding source

None.

Supporting information

Supporting information.