Postmarketing Safety Concerns of Teprotumumab: A Real-World Pharmacovigilance Assessment

Abstract

Context

Teprotumumab, which targets the insulin-like growth factor-1 receptor, is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED).

Objective

This study aimed to identify potential safety signals of teprotumumab by analyzing postmarketing safety data from the FDA Adverse Event Reporting System (FAERS) database in 2023.

Methods

The case/noncase approach was used to estimate the reporting odds ratio (ROR) and information component (IC) with relevant 95% CI for adverse events (AEs) that numbered 3 or more.

Results

A total of 2158 cases were included in the analysis. Main safety signals identified were ear and labyrinth disorders, reproductive system and breast disorders, metabolism and nutrition disorders, and gastrointestinal disorders. Specifically, autophony (ROR [95% CI] = 4188.34 [1403.29-12500.8]), eyelid retraction (ROR [95% CI] = 2094.17 [850.69-5155.29]), permanent deafness (ROR [95% CI] = 1552.35 [789.07-3053.98]), bilateral deafness (ROR [95% CI] = 73.12 [41.14-129.97]), inflammatory bowel disease (ROR [95% CI] = 23.26 [13.46-40.19]), hyperglycemic hyperosmolar nonketotic syndrome (ROR [95% CI] = 17.75 [5.70-55.28]), and amenorrhea (ROR [95% CI] = 47.98 [36.22-63.54]) showed significant safety signals with teprotumumab.

Conclusion

This study identified ear and labyrinth disorders, and reproductive system and breast disorders, as specific safety signals of teprotumumab. Clinicians and pharmacists should be vigilant regarding these AEs. However, available data are currently insufficient, and further pharmacovigilance and surveillance are needed to fully understand this issue.

Teprotumumab is the only drug approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED), and it represents a major step forward for patients living with this chronic disease (1-3). TED is an orbital disease initiated by autoantibodies targeting the thyrotropin receptor (TSHR) and commonly associated with Graves disease. This autoimmune response results in a series of ocular symptoms, such as eyelid retraction, extraocular muscle enlargement, and optic nerve compression (4). Teprotumumab (Tepezza) is a monoclonal antibody that targets the insulin-like growth factor type I receptor (IGF-1R), which is overexpressed on orbital fibroblasts and fibrocytes. The signaling crosstalk between IGF-1R and TSHR in orbital fibroblasts plays a pathogenic role in TED. However, as IGF-1R is not specific to orbital tissues, the use of teprotumumab in clinical practice has highlighted several previously underappreciated adverse effects (5, 6). As the clinical utilization of teprotumumab continues to rise, the identification of adverse drug reactions becomes an urgent clinical challenge that needs to be addressed (7).

In real-world settings, spontaneous reporting systems play a critical role in the collection and documentation of adverse events (AEs) associated with pharmacotherapy. The FDA Adverse Event Reporting System database (FAERS) is a spontaneous reporting system for the collection of AEs and is recognized as the largest and most comprehensive publicly available pharmacovigilance database globally. FAERS is a ready-to-use data source for the early identification of safety issues related to pharmacotherapy in the real-world setting from a large population. Spontaneous reporting systems can detect the full spectrum of AEs, surpassing what can be achieved in controlled studies. Therefore, FAERS is a valuable resource for promptly identifying new associations and assessing the risk-benefit profile of drugs (8).

The objective of this study was to analyze real-world safety data regarding adverse effects induced by teprotumumab using the FAERS database. We aim to identify potential safety signals associated with teprotumumab treatment, in order to guide clinical decision-making and optimize the risk-benefit balance.

Methods

Data Source

This study collected and analyzed adverse event reports from the publicly available version of the FAERS database, covering the period from the second quarter of 2019 to the first quarter of 2023. Doctors, pharmacists, patients, pharmaceutical companies, and healthcare professionals can all report drug-related adverse events to the FEARS system. AEs were coded using the Medical Dictionary for Regulatory Activities version 25.0. The FAERS data files consist of 7 databases, including demographic and administrative information, information on adverse drug reactions, drug information, drug therapy start and end dates, report source information, and indications for use/diagnosis. To ensure data accuracy, a deduplication process was performed. The most recent FDA received date (FDA_DT) was selected among cases with the same case unique ID (CASE_ID), and if both the CASE_ID and FDA_DT were identical, the record with the higher reporting record ID (PRIMARY_ID) was chosen. Only AEs where teprotumumab was assigned as the primary suspected drug were included in the analysis.

Study Design and Statistical Analysis

The case/noncase approach, similar to a case-control study design, was adopted for this analysis (9, 10). Cases were defined as adverse event reports where TEPEZZA, TEPROTUMUMAB-TRBW, TEPROTUMUMAB, and RG-1507 were recorded, while noncases represented adverse event reports for all other drugs included in the FAERS database (10, 11). Disproportionality analysis, a key tool in pharmacovigilance research, was used to identify drug-associated AEs as signals by comparing the proportion of events occurring with a specific drug to all other drugs (12). Within this cohort, we tested for disproportionality: if the proportion of AEs of interest was found to be higher in patients exposed to teprotumumab (cases) than those not exposed (noncases), an association could be hypothesized between the drug and the AE and considered a disproportionality signal (13). Based on a 4-fold table (Table 1), 4 methods (12) were employed: reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma-Poisson shrinker (MGPS) using empirical Bayesian geometric mean (EBGM) as the signal index, and Bayesian confidence propagation neural network (BCPNN) analyses using information component (IC) as the signal index to investigate the association between teprotumumab and AEs (the formulas are shown in Table S1 in Google Drive (14)). When the lower limit of the ROR 95% CI was > 1, the proportional reporting ratio was ≥2, χ2 was ≥4, IC025 was > 0, and EBGM05 was > 2, a significant safety signal was identified. The flowchart of study population displayed in Fig. 1.

Table 1.

Four-fold table required for disproportionality measures

	Target AE	Other AEs	Total
Target drug	a	b	a + b
Other drugs	c	d	c + d
Total	a + c	b + d	a + b + c + d

Abbreviations: AE, adverse event; target drug: teprotumumab.

Figure 1.

Flowchart of study population.

The onset time was defined as the interval between the date of AE occurrence (EVENT_DT) and the start date of teprotumumab use (START_DT) (15). Input errors or inaccurate date entries were excluded from the analysis. Data processing and statistical analyses were conducted using SAS v.9.4 and SPSS v.21 software.

Results

Case Characteristics of Teprotumumab Usage

A total of 2158 cases were included in this study. Table 2 displays the sex, age, weight, report countries, and reporter role of the enrolled patients. More than 90% of the patients did not report their age, weight, or country. The proportion of female, male, and sex not reported were 38.92%, 10.57% and 50.51%, respectively; in total, cases enrolled in this study were 840 female, 228 male, and 1090 sex not reported. The basic characteristics of the subgroup of sex are also displayed in Table 2.

Table 2.

Characteristics of adverse event reports of teprotumumab as suspected drugs

		Teprotumumab, n (%)		Female, n (%)		Male, n (%)
Sex	Male	228	10.57	0	0	228	100
	Female	840	38.92	840	100	0	0
	Not reported	1090	50.51	0	0	0	0
Age (years)	18-64	13	0.60	9	1.07	4	1.75
	≥ 65	6	0.28	6	0.71	0	0
	Not reported	2139	99.12	825	98.21	224	98.25
Weight (kg)	< 80	108	5.00	97	11.55	10	4.39
	80-100	50	2.32	31	3.69	19	8.33
	> 100	31	1.44	18	2.14	13	5.70
	Not reported	1969	91.24	694	82.62	186	81.58
Country	USA	2138	99.07	830	98.81	225	98.68
	Others	2	0.09	1	0.12	0	0
	Not reported	18	0.83	9	1.07	3	1.32
Reporting year	2020	436	20.20	303	36.07	84	36.84
	2021	697	32.30	325	38.69	91	39.91
	2022	795	36.84	200	23.81	51	22.37
	2023	230	10.66	12	1.43	2	.88
Reporter role	CN	1154	53.48	430	51.19	98	42.98
	HP	272	12.60	96	11.43	37	16.23
	MD	620	28.73	254	30.24	67	29.39
	PH	81	3.75	43	5.12	12	5.26
	Not reported	31	1.44	17	2.02	14	6.14

Abbreviations: CN, customer; HP, health professional; MD, medical doctor; PH, pharmacist.

Safety Signals of Teprotumumab

The significant safety signals of teprotumumab are shown in Table S2 in Google Drive (14). The most common AEs (n ≥ 10) are presented in Fig. 2. The most frequently reported AEs include muscle spasms (n = 426, ROR [95% CI] = 27.31 [1.69-2.17], IC [IC025] = 4.67 [3.00]), fatigue (n = 299, ROR [95% CI] = 3.43 [3.06-3.85], IC [IC025] = 1.73 [.07]), blood glucose increased (n = 171, ROR [95% CI] = 11.24 [9.66-13.09], IC [IC025] = 3.45 [1.79]), and alopecia (n = 171, ROR [95% CI] = 7.77 [6.67-9.04], IC [IC025] = 2.92 [1.26]), which is consistent with currently published research results. High safety signals were also observed for various AEs, especially ear and labyrinth disorders, reproductive system and breast disorders, metabolism and nutrition disorders, and gastrointestinal disorders, which will be discussed in detail below.

Figure 2.

The safety signal of AEs (n ≥ 10) of teprotumumab. Abbreviations: AEs, adverse events; IC, information component; ROR, reporting odds ratio.

Eye Disorders

There were a large number of high safety signals regarding eye disorders (Table S2 in Tencent Documents (14)), which are similar to TED symptoms. We show the top 10 RORs of AEs regarding eye disorders in Fig. 3A. As shown, the safety signals also included TED symptoms such as diplopia (n = 148, ROR [95% CI] = 70.65 [59.90-83.35], IC [IC025] = 6.07 [4.40]), eye pain (n = 46, ROR [95% CI] = 8.19 [6.12-10.94], IC [IC025] = 3.02 [1.35]), exophthalmos (n = 43, ROR [95% CI] = 220.01 [160.80-301.03], IC [IC025] = 7.64 [5.97]), vision blurred (n = 43, ROR [95% CI] = 3.50 [2.59-4.72], IC [IC025] = 1.80 [0.13]), and eyelid retraction (n = 9, ROR [95% CI] = 2094.17 [850.69-5155.29], IC [IC025] = 10.10 [8.32]).

Figure 3.

The safety signals of teprotumumab in different system organ class: (A) the safety signals of teprotumumab in eye disorders and (B) the safety signals of teprotumumab in ear and labyrinth disorders and (C) the safety signals of teprotumumab in reproductive system and breast disorders and (D) the safety signals of teprotumumab in gastrointestinal disorders and (E) the safety signals of teprotumumab in metabolism and nutrition disorders. Abbreviations: AEs, adverse events; IC, information component; ROR, reporting odds ratio.

Ear and Labyrinth Disorders

The safety signals of ear and labyrinth disorders are presented in Fig. 3B. As shown, autophony (n = 9, ROR [95% CI] = 4188.34 [1403.29-12500.8], IC [IC025] = 10.55[8.72]), deafness permanent (n = 14, ROR [95% CI] = 1552.35 [789.07-3053.98], IC [IC025] = 9.86 [8.13]), deafness (n = 87, ROR [95% CI] = 30.42 [24.59-37.64], IC [IC025] = 4.89 [3.22]), tinnitus (n = 112, ROR [95% CI] = 28.23 [23.39-34.06], IC [IC025] = 4.78 [3.11]) and hypoacusis (n = 153, ROR [95% CI] = 24.79 [21.10-29.12], IC [IC025] = 4.59 [2.92]) showed high safety signals. Other safety signals related to ear and labyrinth disorders, such as ear discomfort, neurosensory deafness, ear pain, bilateral deafness, and unilateral deafness, should also be noted.

The Reproductive System and Breast Disorders

The safety signals of teprotumumab for the reproductive system and breast disorders are shown in Fig. 3C. Statistically significant AEs include amenorrhea (n = 50, ROR [95% CI] = 47.98 [36.22-63.54], IC [IC025] = 5.55 [3.88]), delayed menstruation (n = 15, ROR [95% CI] = 22.73 [13.66-37.81], IC [IC025] = 4.49 [2.82]), and irregular menstruation (n = 10, ROR [95% CI] = 8.97 [4.82-16.70], IC [IC025] = 3.16 [1.49]). Other safety signals related to reproductive system and breast disorders included menstrual disorder, vulvovaginal pain, intermenstrual bleeding, and heavy menstrual bleeding.

Gastrointestinal Disorders

The safety signals related to gastrointestinal disorders are shown in Fig. 3D. The safety signals include gingival recession (n = 19, ROR [95% CI] = 132.16 [83.19-209.94], IC [IC025] = 6.96 [5.29]), irritable bowel syndrome (n = 17, ROR [95% CI] = 7.23 [4.49-11.65], IC [IC025] = 2.85 [1.18]), and inflammatory bowel disease (n = 13, ROR [95% CI] = 23.26 [13.46-40.19], IC [IC025] = 4.52 [2.86]).

Metabolic and Nutritional Disorders

The safety signals related to metabolism and nutrition disorders are shown in Fig. 3E. As shown, safety signals include diabetes mellitus (n = 126, ROR [95% CI] = 17.51 [14.67-20.90], IC [IC025] = 4.10 [2.43]), hyperglycemia (n = 51, ROR [95% CI] = 15.33 [11.63-20.21], IC [IC025] = 3.92 [2.25]), diabetic ketoacidosis (n = 23, ROR [95% CI] = 10.06 [6.67-15.16], IC [IC025] = 3.32 [1.65]), and type 2 diabetes mellitus (n = 23, ROR [95% CI] = 8.92 [5.92-13.45], IC [IC025] = 3.15 [1.48]).

Discussion

To the best of our knowledge, this is the largest pharmacovigilance study to analyze real-world data on the safety profile of teprotumumab. Our findings highlight the safety concerns related to the use of teprotumumab.

First, we found that the safety signals of teprotumumab were focused on the ear and labyrinth, eye, reproductive system and breast, metabolism and nutrition, and musculoskeletal and connective tissue disorders. Muscle spasms, fatigue, increased blood glucose, alopecia, hypoacusis, diplopia, diabetes mellitus, and tinnitus had the highest number of reports, which is consistent with the information provided in the teprotumumab product label and clinical trial reports (16-18). The majority of safety signals in eye disorders were similar to symptoms of TED, such as diplopia, eye pain, exophthalmos, vision blurred, dry eye, eye swelling, ocular hyperemia, and photophobia. Differentiating between AEs related to teprotumumab and those attributable to TED itself, especially in real-world settings, can be challenging. This emphasizes the importance of continued pharmacovigilance and surveillance to better understand the safety profile of this drug.

The findings regarding AEs related to ear and labyrinth disorders are particularly serious. Previous clinical trials of teprotumumab used in TED have reported several reversible changes in hearing, ranging from mild ear pressure change to hearing loss (19-21). Our results showed that teprotumumab had a significant number of ear and labyrinth-related safety signals, especially serious ototoxicity such as permanent deafness, deafness, and ear pain. Teprotumumab specifically targets IGF-1R, which is not only found in muscle and fat adjacent to the eye but also in the cochlea. Activation of IGF-1R triggers the MEK/ERK and PI3K/AKT pathways, leading to the expression of Netrin1 and Gap43. These molecules play a crucial role in the survival of inner ear hair cells and support cells, suggesting that this may be the mechanism behind hearing damage caused by teprotumumab (20). However, it is perplexing that previous oncological studies with IGF-1R inhibitors, including teprotumumab, did not report any hearing changes (22-26). It is possible that the lack of hearing changes in cancer studies is due to the fact that teprotumumab is often administered to patients with advanced cancer who already have a poor quality of life. Detecting hearing changes in such cases may be more challenging. In addition, ototoxicity may also be the specific safety signal of teprotumumab in TED (27-31). Given the potential for serious ototoxicity, including permanent deafness, further clinical research is warranted to determine the risk of teprotumumab-induced ototoxicity and explore strategies for its prevention and treatment. Clinicians should pay greater attention to the ototoxicity of teprotumumab and include it in patient education materials and perform necessary hearing tests before and after medication to take necessary measures, such as discontinuing the medication or other actions in the early stages of ototoxicity.

Additionally, we observed notable AEs related to the reproductive system and breast disorders, such as amenorrhea, delayed menstruation, and irregular menstruation. Menstrual changes may represent a new safety concern associated with teprotumumab in patients with TED, requiring further investigation. Although the manufacturer of teprotumumab did not mention menstrual changes, one study on adverse effects of teprotumumab reported a 23% incidence of combined amenorrhea, metrorrhagia, and dysmenorrhea in menstruating women (20). Furthermore, subgroup analysis indicated that erectile dysfunction is a potential safety risk signal of teprotumumab in males. However, it is important to note that the FAERS system lacks comprehensive information regarding the characteristics of these cases, such as the severity of effects on the reproductive system, reversibility, and impact on reproduction. Therefore, additional research is necessary to assess the safety profile of teprotumumab in relation to the reproductive system. For young or fertile patients, doctors should be cautious of the potential AEs of teprotumumab on the reproductive system.

As expected, teprotumumab had significant AEs related to metabolism and nutrition disorders. Glucose fluctuates greatly in people with diabetes who use teprotumumab. The underlying mechanism involves the inhibition of IGF-1R, which reduces the negative feedback of growth hormone secretion. This leads to elevated growth hormone levels, resulting in increased glucose production and insulin resistance (32). As reported, approximately 70% of clinical use of IGF-1R inhibitors is associated with hyperglycemia, which can be relatively easily controlled with oral antidiabetic agents (20). However, one of the serious acute complications of hyperglycemia, diabetic ketoacidosis, was identified as a potential safety risk signal of teprotumumab in TED cases. Research reports that the probability of severe hyperglycemia occurring with IGF-1R inhibitors is approximately 2%, with patients who have diabetes mellitus or insulin resistance being at higher risk (20, 33). The subgroup analysis reveals that male individuals show a high safety signals of hyperglycemia and diabetes mellitus. It is necessary to closely monitor the blood glucose levels in patients using teprotumumab, especially among male patients. However, further research is needed to explore strategies for preventing the occurrence of severe blood sugar complications.

The present study has several limitations that need to be acknowledged. First, it is important to note that the bias of FAERS database is unavoidable and cannot be eliminated, including underreporting bias, reporting bias (demographic groups, healthcare settings or regions/races and so on), detection bias, and temporal bias. The underreporting bias and reporting bias may lead to an underestimation or overestimation of certain AEs, particularly those that are less severe or more common in underrepresented demographic groups. Detection bias could result in an overrepresentation of AEs that are easier to diagnose in certain settings, affecting the perceived safety profile of the drug. Temporal bias, reflecting the changes in reporting over time, could skew the results if not properly accounted for, particularly in a rapidly evolving therapeutic area like thyroid eye disease. Meanwhile, the observed safety signals on teprotumumab in this study can be influenced by various missing data, such as previous treatment, underlying disease, drug co-administration, start or end dates, smoking, and working environment. These biases are common limitations in voluntary incident reporting systems. Therefore, the safety signals indicated by the ROR value or IC value should be considered relatively reliable.

Generally, safety signals can be influenced by unmeasured confounding factors, such as height, weight, concomitant medication use, or the knowledge and attitudes of healthcare professionals (11). Unfortunately, most basic patient characteristics are not reported in the FAERS database. Furthermore, teprotumumab is a newly approved drug as of January 2020, and the quantity of reports in this specific population is insufficient to draw robust conclusions. The safety signal on eye disorders could be compromised by the symptoms of TED itself, which may mask the safety signal of teprotumumab. Finally, due to the small sample size and wide confidence interval, further research with a larger sample size is needed to study the safety of teprotumumab more comprehensively. Overall, although the FAERS database provides safety signals for teprotumumab, additional postmarket safety analyses and clinical trials should be conducted in the future. Moreover, considering the mechanism of teprotumumab's side effects, individual differences, and potential drug-drug interactions, further research in pharmacokinetics, pharmacology, and pharmacogenomics could be valuable.

Conclusion

In summary, this postmarketing analysis of teprotumumab based on FAERS has revealed important safety signals that clinicians and pharmacists should be aware of. Our study identified specific safety signals associated with teprotumumab, including ear and labyrinth disorders and reproductive system and breast disorders. Diabetic ketoacidosis, a serious acute complication of hyperglycemia, was also highlighted as a potential AE that healthcare professionals should monitor in patients using teprotumumab. Because the available data are currently insufficient, further research is necessary to gain a better understanding of the risks associated with teprotumumab use in this particular population.

Abbreviations

AE

adverse event

FAERS

FDA Adverse Event Reporting System

FDA

US Food and Drug Administration

IC

information component

IGF-1R

insulin-like growth factor type 1 receptor

ROR

reporting odds ratio

TED

thyroid eye disease

TSHR

thyrotropin receptor

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 82304629].

Author Contributions

Z.L., W.Z., and J.H. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Z.L., J.H., and W.Z. Acquisition, analysis, or interpretation of data: W.Z. and J.Y. Drafting of the manuscript: J.H. and A.S. Critical revision of the manuscript for important intellectual content: Z.L., J.H., and W.Z. Statistical analysis: J.H. and W.Z. Supervision: Z.L., J.H., and W.Z.

Disclosures

The authors have nothing to disclose.

Data Availability

The data ar e openly available in the FDA Adverse Event Reporting System Public Dashboard at: https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Ethics Statement

The present pharmacovigilance study was conducted using a public database of spontaneous reports. Given the use of deidentified data, ethical approval was not considered necessary.