Teprotumumab effective, safe after 1 year in clinical use
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Teprotumumab was approved for the treatment of thyroid eye disease in January 2020. As real-world experience with teprotumumab increases, several clinical reports describing patient responses, safety and effectiveness are now appearing.
The FDA approval, based on the successful completion of two pivotal clinical trials, made teprotumumab-trbw (Tepezza, Horizon Therapeutics) the only approved medical therapy for thyroid eye disease. The rollout was followed shortly by the onset of the COVID-19 pandemic. Despite the inherent challenges associated with any drug rollout during a crisis, physician and patient uptake of teprotumumab was brisk in the months immediately after approval. To date, thousands of patients with thyroid eye disease have been treated successfully with this monoclonal anti-insulin-like growth factor I receptor antibody.
In late 2020, the U.S. government mandated that COVID-19 vaccine production be prioritized, resulting in a manufacturing pause of teprotumumab beginning in late December. This resulted in a supply disruption until early April, which has been fully restored. I have taken this opportunity to review briefly the effectiveness and safety of teprotumumab and provide information emerging from recent real-world experience with the drug.
Effectiveness of teprotumumab
Among recent reports concerning teprotumumab’s effectiveness are those describing its use in chronic, stable disease, well after clinical signs of inflammation and periocular edema have subsided. It is becoming clearer that the underlying molecular mechanisms of thyroid eye disease involving the IGF receptor pathway persist well-beyond the clinical signs of disease activity.
Furthermore, the disease duration of patients enrolled in the open-label OPTIC X study, the majority of whom were proptosis responders while being treated with teprotumumab, was 11.7 months. Data from that study reveal that most patients experienced an at least 2 mm proptosis reduction at week 24.
Important indicators of sustained effectiveness in less inflammatory, more chronic (“white eye”) disease are revealed in reports suggesting teprotumumab may be effective in longer-duration disease than that studied in the clinical trials. A case report from Ozzello and colleagues described a patient with a 2-year history of nonprogressive thyroid eye disease who responded with substantial reduction in proptosis.
Other case reports suggest the rapid reversal of vision-threatening optic neuropathy after treatment with teprotumumab.
Refractory pretibial myxedema, not currently indicated by the FDA for teprotumumab, was reported recently to have improved dramatically in a 49-year-old patient being treated with teprotumumab for thyroid eye disease. Thus, evolving evidence suggests broadening clinical circumstances in which clinically important responses to teprotumumab in patients with thyroid eye disease may be achieved.
No new adverse effect signals
Adverse events occurring during the treatment period of the two clinical trials in 63 of 67 patients (94%) receiving teprotumumab and 59 of 60 (98%) of those receiving placebo were mild to moderately severe (grade 1 or 2). Importantly, none of these resulted in study discontinuation. Of the most commonly reported adverse events with teprotumumab (> 5%), muscle spasm (18%), hearing loss (10%) and hyperglycemia (8%) had the greatest risk difference from placebo.
Updated information concerning adverse events being reported to the FDA adverse event reporting system can be accessed at www.fda.gov/drugs/questions-and-answers-fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard. While the reports appearing in the dashboard do not establish causation, have not been verified and cannot be used to determine the rates of occurrence of any adverse event, availability of this information to the public is important as we manage our patients on teprotumumab. Importantly, no new common side effect signals have appeared materially differing from those encountered during either the two pivotal clinical trials.
Three adverse events being observed with clinical use are below.
Muscle spasm
These were among the most common adverse events detected from the clinical trials. They most frequently involve the lower legs, are transient, and have not resulted in the interruption of teprotumumab therapy. They can appear at any time during the 24-week course of infusion, but in our experience, commonly first develop after the second or third dose. They do not appear to be associated with any electrolyte imbalance.
Increased blood glucose
Hyperglycemia may occur in patients treated with teprotumumab. In the clinical trials, 10% of patients — two-thirds of whom had preexisting diabetes or impaired glucose tolerance — experienced hyperglycemia. I have typically assessed HbA1c and postprandial blood glucose at baseline and 1 to 2 weeks after the first and second infusions of teprotumumab. Hyperglycemic events should be managed with medications for glycemic control, if necessary. Patients should be monitored for elevated blood glucose and symptoms of hyperglycemia while undergoing treatment with teprotumumab. Those with preexisting diabetes should be under appropriate glycemic control before receiving teprotumumab.
Hearing impairment
Several hearing abnormalities were detected in approximately 10% of patients receiving teprotumumab during the clinical trials, including deafness, tinnitus, autophony, eustachian tube dysfunction, hyperacusis or hypoacusis. In an abstract presented at the 2021 annual meeting of the Endocrine Society, Kossler and colleagues reported that 17 of 26 patients (65%) treated at their institution with teprotumumab complained of hearing abnormalities, including six cases of subjective hearing loss, seven patients with new-onset tinnitus, six with “ear plugging” sensation and three with autophony. Four patients experienced new or worsening sensorineural hearing loss while patulous eustachian tube, which was documented in three of these patients.
Findings in that report are inconsistent with those observed in the two multicenter, randomized, placebo-controlled trials, in which 84 patients received teprotumumab. A longer-term follow-up of the findings reported by Kossler and colleagues will be necessary to determine the reversibility of those effects on hearing. Further, the identification of mechanisms underlying these effects must await further studies.
Real-world experience similar to clinical trials
Teprotumumab remains the only FDA approved medical therapy for thyroid eye disease. Since its introduction into clinical practice more than 1 year ago, clinical responses to the drug have closely resembled those observed in the two clinical trials.
In addition, reports have appeared describing the efficacy of teprotumumab in thyroid eye disease of considerably longer duration than that studied in the trials. Other reports have described rapid and substantial improvement of vision-threatening optic neuropathy with teprotumumab.
Since its approval, no new safety signals have been reported in the thousands of patients receiving the full recommended eight-infusion treatment course of teprotumumab over 24 weeks. The most common adverse events occurring during the clinical trials continue to be the most frequently reported in real-world clinical use. As with the use of all medications, careful monitoring of patients receiving teprotumumab is strongly advised.
References:
Chern A, et al. Otolaryngol Head Neck Surg. 2021;doi:10.1177/01945998211004240.
Chiou CA, et al. Am J Ophthalmol Case Rep. 2021;doi:10.1016/j.ajoc.2021.101075.
Diniz SB, et al. Ophthalmic Plast Reconstr Surg. 2021;doi:10.1097/IOP.0000000000001959.
Douglas RS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1910434.
Hwang CJ, et al. Eur J Ophthalmol. 2021;doi:10.1177/1120672121991042.
Kahaly GF, et al. Lancet Diabetes Endocrinol. 2021;doi:10.1016/S2213-8587(21)00056-5.
Kossler A, et al. J Endocr Soc. 2021;doi:10.1210/jendso/bvab048.1713.
Markham A. Drugs. 2020;doi:10.1007/s40265-020-01287-y.
Ozzello DJ, et al. Am J Ophthalmol Case Rep. 2020;doi:10.1016/j.ajoc.2020.100744.
Sears CM, et al. Ophthalmic Plast Reconstr Surg. 2021;doi:10.1097/IOP.0000000000001831.
Slentz DH, et al. JAMA Ophthalmol. 2021;doi:10.1001/jamaophthalmol.2020.5296.
Smith TJ, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614949.
Ugradar S, et al. Eye (Lond). 2020;doi:10.1038/s41433-020-01297-w.
Varma A, et al. JAAD Case Rep. 2020;doi: 10.1016/j.jdcr.2020.09.003.
For more information:
Terry J. Smith, MD, is an endocrinologist specializing in thyroid eye disease. He is the Frederick G.L. Huetwell Professor in Ophthalmology and Visual Sciences, professor of internal medicine, and a member of the Program on Cell and Molecular Biology at the University of Michigan Medical School. Reach him at terrysmi@med.umich.edu.
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