Treatment for thyroid eye disease enters new era, shows potential for brighter future
Click Here to Manage Email Alerts
Until recently, patients with active thyroid eye disease had limited options for treatment of their condition besides observation.
Patients managed their symptoms with oral or intravenous corticosteroids that often had significant side effects. Surgical correction was reserved for patients with compressive optic neuropathy or corneal breakdown and chronic stable patients with fixed deficits.
Source: Kimberly Cockerham, MD
Patients and their families were often left frustrated by the disruptive and disfiguring condition with a heavy impact on quality of life.
In 2020, the introduction of Tepezza (teprotumumab-trbw, Horizon Therapeutics/now Amgen) changed the thyroid eye disease treatment landscape. Tepezza, a human monoclonal antibody that blocks the insulin-like growth factor type 1 receptor (IGF-1R), was the first drug approved by the FDA for the treatment of thyroid eye disease (TED), and it has proved effective in improving both the signs and symptoms of the disease.
“Already at the time of first infusion, within a half dose over 90 minutes, you can see rapid changes in the patient’s appearance and comfort. There is a dramatic reduction in the redness, the swelling, the pain and even the proptosis. With each additional dose, patients continuously improve. Most of them, by the fourth or fifth dose, are looking dramatically different and see much, much better,” Healio | OSN Neurosciences Board Member Kimberly P. Cockerham, MD, said. “What is really remarkable is that it works to restore the extraocular muscle and intraconal fat volume to pre-disease state independent of the duration or severity of the disease.”
According to Raymond S. Douglas, MD, PhD, an oculoplastic surgeon in Beverly Hills, California, Tepezza has been a revolution in the field.
“I often tell my fellows there was life before Tepezza and life after Tepezza in the landscape of thyroid eye disease,” he said. “Before Tepezza, we tried to get patients through with as few medications as possible, potentially considering surgery down the line. Now, with Tepezza, almost every patient is introduced to the option of medical therapy.”
The success of the drug, with 15,000 patients treated and more than $2 billion sales in the first 3 years, has raised the interest of several other pharmaceutical companies that have opened clinical trials to advance new products in this space. Research in the field is flourishing.
Pearls for diagnosis
Thyroid eye disease is a challenging diagnosis that often is missed by optometrists and general ophthalmologists because it might begin subtly, with symptoms that overlap with other common ophthalmic problems.
“Most thyroid eye disease patients start with symptoms that mimic dry eye syndrome or allergies. They complain of gritty eyes, tearing, redness and puffiness of their eyelids. Sometimes their intraocular pressure also goes up and doctors will place them on glaucoma medications, when all of it is really due to abnormal depositions making the muscles and the fat expand in volume,” Cockerham said.
There is one symptom that unmistakably points to the diagnosis of TED, and that is double vision upon waking.
“Almost nothing gives you double vision when you first wake up. If practitioners asked that one question, they would detect more early TED,” she said. “Ask patients if they experience double vision or blurring when they look at their cell phone when they first wake up. It typically goes away over 20 to 30 minutes.”
Other important clues are chronic conjunctival injection and chemosis in a patient with a known thyroid imbalance, and dry eye symptoms in a patient with a normal-appearing tear lake and Schirmer’s test.
“They get tearing because the tear quality is different. It’s just not as stable. Even though you can test the aqueous part of the tears and it might look normal, pursuing questions about the symptoms of TED and other signs of TED is important,” Cockerham said.
It is also helpful to have the patient look downward, she said. Eyelid retraction may not be so obvious when the patient looks straight but often becomes apparent on downgaze (lid lag and lagophthalmos). Finally, patients with ocular hypertension should have IOP tested in upgaze.
“If you measure the IOP and you find it is 24 mm Hg, have the patient look up and test it again. If the pressure goes up to 28 mm Hg or 30 mm Hg, it suggests that the inferior rectus is restricted, and it’s a nice clue to understanding that you are dealing with something more than ocular hypertension,” Cockerham said.
“When puffy eyelids are a complaint, I ask about a change in the position of the eye. I ask patients to show me photos on their phone that show their appearance prior to the onset of the swelling. If you can see that their eyes are more proptotic (aka prominent or more bulging), that’s helpful. I ask my patients to close their eyes, and then I retropulse the globe and see if there is resistance to retropulsion. If there is excessive fat or muscle behind the eyeball instead of feeling relatively soft, it can feel very, very firm,” she said.
Visual field testing and OCT are then performed to confirm the status of their optic nerve and see whether there is any evidence of compression.
“Then I send them to do other exams outside of my office, which include either MRI or CT scan of the orbit. For lab evaluation, I recommend a free T3, free T4, TSH, TPO for Hashimoto’s disease and TSI for Graves’. They provide evidence of cell-to-cell signaling between the thyroid tissue and eye tissue,” Cockerham said.
Comanagement approach
There are three subspecialized fields of ophthalmology in which TED specialists may be trained: neuro-ophthalmology, oculoplastic surgery and strabismus surgery. Who sees the patient first depends on the presenting signs and symptoms.
“If patients present with dry eye, it may be a general ophthalmologist or even an optometrist to see them first. If they pick up on something like eyelid retraction or proptosis, the patient is usually sent to an oculoplastic surgeon. If there is diplopia, it may be the neuro-ophthalmologist to see them first, and it could even be a strabismus surgeon if the patient is sent for the workup of lack of motility,” Healio | OSN Oculoplastic and Reconstructive Surgery Section Editor Wendy W. Lee, MD, MS, said.
Eye symptoms, however, may not be the first to appear, in which case the first referral from primary care would be to the endocrinologist.
“We are the first line of defense, so we should be always looking at signs or symptoms in these patients that are suggestive of any eye involvement,” David Toro-Tobon, MD, an endocrinologist at the Mayo Clinic in Rochester, Minnesota, said.
The endocrinologist may help in the diagnosis, but once identified, the disease needs comanagement and a team approach.
“It should not be primarily managed by an endocrinologist. It should not be primarily managed by an ophthalmologist. It should be a combination. And in fact, that’s what we’re trying to promote here in our department,” he said.
At the Mayo Clinic, a thyroid eye disease clinic offers a multidisciplinary approach in which the ophthalmology and endocrinology departments are equally involved.
“On the endocrinology side, other than playing a major role in the identification of the disease, we need to make sure that the thyroid disease is well controlled with medications or surgery because having normal thyroid levels is key to improving the prognosis of the thyroid eye disease. As endocrinologists, we can also guide a lot of the lifestyle modifications in these patients, from smoking cessation to selenium supplementation as an adjuvant therapy to standard thyroid medications,” Toro-Tobon said.
Endocrinologists and ophthalmologists collaborate in the planning and comanaging of medical therapies for TED.
“We can really help in the prescribing process but also in the monitoring process to deal with all of the possible adverse effects,” he said. “And for us to define whether surgery is needed, we need our ophthalmology colleagues. So, that’s why I think it is so important to collaborate in a shared decision-making process.”
The typical journey of a patient at the thyroid eye disease clinic begins with seeing the endocrinologist and the ophthalmologist in close sequence, usually in the same morning. In the afternoon, endocrinologists and ophthalmologists meet and talk about each patient, decide on a management strategy, and then bring the patients back, discuss the plan with them and answer questions.
“This initial joint consultation makes us sure that everyone’s going to be on the same page, and it has been a really good experience so far here in the clinic. I hope that this model, which I know has already been replicated in many other places, continues to grow because it really makes a difference to our patients,” Toro-Tobon said.
There is increasing awareness of the need for comanagement in TED, and Toro-Tobon anticipates that it will become the standard in the near future.
“This is what both the American Thyroid Association and the European Thyroid Association are promoting in their consensus statements. It should be a collaborative effort because the management should be multimodal,” he said.
Paradigm change
Medications that were available in the past were basically tackling inflammation in TED at a nonspecific level, Toro-Tobon said.
“We were using molecules that tackle inflammation in the whole body, and these included glucocorticoids, tocilizumab, rituximab and mycophenolate,” he said.
Tepezza acts specifically in the receptor that is mediating the inflammatory process in the eyes, so the effect is much more specific.
“In the trials, it showed a really good response in managing inflammation, but in addition, this is the first medication that leads to clinically significant improvement in proptosis and double vision. This is what makes it different from the previous options, and this is why we’re so excited about having it as a new tool when we treat our patients,” Toro-Tobon said.
Douglas was the principal investigator in the two phase 3 trials of teprotumumab that led to FDA approval and in the subsequent phase 4 trial in which the drug was evaluated in patients with a diagnosis of thyroid eye disease 2 to 10 years before enrollment.
“Both the phase 3 trials demonstrated a dramatic decrease in the proptosis, approximately 3.2 mm, as well as reduction in double vision and a very dramatic improvement in the inflammation with good safety data. In the phase 4 trial, patients with long-duration TED also had a reduction in their eye bulging. This led to Tepezza largely being considered a first-line treatment especially when proptosis and inflammation are associated with the disease,” he said.
Since its approval in 2020, Tepezza has rapidly gained traction in the U.S.
“It has been a nice addition to our armamentarium. It was the first and only FDA-approved drug and a good nonsurgical alternative for patients. I’ve definitely seen an improvement in my patients who have been on teprotumumab,” Lee said.
Some patients respond better than others, and some tolerate it better than others with fewer side effects.
“There is variability, and some of my patients did have very bad side effects. However, they experienced so much improvement that the side effects did not discourage them from continuing their treatment,” Lee said.
The side effects she has commonly seen are leg cramps, hyperglycemia, hair loss, and hearing loss or hearing issues, but more often than not, they have been temporary.
Ear plugging sensation, autophony and tinnitus are usually transient, but decreased hearing at high frequencies may be long term or even permanent, Douglas said.
“If you notice these changes, discontinue the treatment. In our studies, patients did recover, but a close follow-up and early identification are key,” he said.
Hyperglycemia occurs rarely in patients who have good control of blood sugar, but in patients with diabetes or prediabetes, the rates can be higher.
“The biggest concern would be someone with brittle diabetes or diabetes in general because if you put them on teprotumumab, there’s a risk of hyperglycemia,” Lee said. “On the other hand, if you treat them with steroids, there is also a risk of worsening hyperglycemia.”
Patients with diabetes should therefore be monitored by measuring HbA1c and blood glucose levels regularly.
Having Tepezza available as a treatment has also decreased the demand for surgery.
“We still have to do surgery in urgent cases with compressive optic neuropathy, even though Tepezza has been used in emergent cases and shown some promise in that area. But the need for cosmetic bone decompression to address proptosis has decreased, and so has the need for eyelid surgery and even strabismus surgery because Tepezza helps with diplopia,” Lee said.
“In our practice, we do about 50% to 75% less surgery. And when we do surgery, it’s typically less involved with less side effects. Tepezza usually gives about a 75% improvement. That’s what I realistically tell patients,” Douglas said, noting that if there is still an issue, surgery can be considered.
Demand and accessibility
According to the FDA label, Tepezza is administered by IV infusion every 3 weeks for a total of eight infusions. The majority of patients, up to 80% or more, have long-term improvement and do not require any additional treatment, according to Douglas.
“There can be reactivations of the disease, but it is not a lifelong or continuous treatment,” he said.
Thyroid eye disease has active phases and quiescent phases, and reactivation may occur even in successful treatment cases, Toro-Tobon said.
“Maybe patients will need to be treated again or may need additional strategies. That’s something that we are starting to navigate now because it hasn’t been long enough since Tepezza was released,” he said.
What has already become apparent is that after the approval of Tepezza, the number of patients being referred to his clinic for TED has almost tripled.
“Now that we have options, patients are much more interested in actively treating their disease, and physicians are becoming much more aware because the company has done a pretty strong job at advertising their medication,” he said.
However, the cost of Tepezza is high, and not all insurance companies cover it.
“Unfortunately, the first question I ask my patients is: What kind of insurance do you have? If they say Medicare or PPO, that’s great, I can get them Tepezza. But if they have Medicaid, Obamacare or HMO, it is very challenging to get an authorization. So, the insurance definitely drives my discussion with the patient,” Cockerham said.
More in the pipeline
The success of Tepezza has raised the interest of several other pharmaceutical companies and has stimulated research in this field.
A variety of treatments are in the pipeline, three of which are targeting IGF-1R, with various ways of administration.
VRDN-001 (Viridian Therapeutics), a monoclonal antibody administered intravenously, has reached phase 3 with the THRIVE-1, THRIVE-2 and OLE clinical trials. They include patients with short-term disease as well as chronic patients and a third cohort of nonresponders.
Linsitinib (Sling Therapeutics) is an oral IGF-1R inhibitor, and batoclimab (Immunovant) is meant for subcutaneous injection. Meanwhile, a phase 1 pharmacokinetic trial to explore subcutaneous administration of Tepezza is in progress.
“The IGF-1 receptor is co-located and co-acting with the TSH receptor, and so by blocking it, you are splitting up the team. You disrupt the cell signaling, which disrupts the cytokine cascade that had produced the inflammation and all the downstream effects,” Cockerham said.
Among molecules with different targets, LASN01 (Lassen Therapeutics), a novel fully human antibody directed against IL-11 receptor, has shown to be tolerated in phase 1 studies. Other molecules with different mechanisms of action are in earlier stages of development. Immunovant, Tourmaline and Roche all have TED clinical trials, according to Cockerham.
“It is wonderful to be in the forefront of some of these emerging therapies,” Douglas said. “The next hurdle is understanding the long-term use of these therapies and how they impact the disease but also making them more widely available and accessible.”
“The most important thing is to get the word out to general ophthalmologists who might have patients who they think are not going to get authorized for Tepezza and let them know that there are phase 3 clinical trials recruiting in their area. Visit ClinicalTrials.gov, and the open trials are all there,” Cockerham said.
There is no reason today to tell a patient, “Sorry, there is nothing I can do for you,” due to insurance issues or because they have long-standing disease refractory to previous treatments, she said.
“These medications (Tepezza and early data from VRDN-001) appear to be working independent of severity or duration, and chronic stable patients 10 to 15 years out with ongoing symptoms, patients with optic neuropathy and TED refractory to all the prior therapeutics, are responding. It’s getting the word out to the patients so that they know that there are options but also getting it out to the general ophthalmologist who may not realize these trials are going on,” she said.
- References:
- Amarikwa L, et al. J Clin Endocrinol Metab. 2023;doi:10.1210/clinem/dgac627.
- Barbesino G, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac252.
- Belinsky I, et al. Ophthalmic Plast Reconstr Surg. 2022;doi:10.1097/IOP.0000000000001995.
- Douglas RS, et al. JAMA Ophthalmol. 2022;doi:10.1001/jamaophthalmol.2021.6284.
- Douglas RS, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa1910434.
- Douglas RS, et al. Ophthalmology. 2022;doi:10.1016/j.ophtha.2021.10.017.
- Horizon Therapeutics plc reports second-quarter 2023 financial results. https://www.businesswire.com/news/home/20230805951260/en/Horizon-Therapeutics-plc-Reports-Second-Quarter-2023-Financial-Results. Published Aug. 8, 2023. Accessed Oct. 23, 2023.
- Jain AP, et al. Clin Exp Ophthalmol. 2021;doi:10.1111/ceo.13899.
- Kahaly GJ, et al. Lancet Diabetes Endocrinol. 2021;doi:10.1016/S2213-8587(21)00056-5.
- Kang J, et al. J Infus Nurs. 2021;doi:10.1097/NAN.0000000000000446.
- Kossler AL, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac168.
- Landsberger H, et al. Facial Plast Surg Clin North Am. 2021;doi:10.1016/j.fsc.2021.02.004.
- Smith TJ. J Neuroophthalmol. 2020;doi:10.1097/WNO.0000000000000890.
- Smith TJ, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614949.
- Stan MN, et al. J Clin Endocrinol Metab. 2023;doi:10.1210/clinem/dgad213.
- Tepezza FAQs. https://www.tepezza.com/about-tepezza/frequently-asked-questions. Accessed Oct. 23, 2023.
- Toro-Tobon D, et al. Thyroid. 2023;doi:10.1089/thy.2023.0167.
- Ugradar S, et al. Eye (Lond). 2022;doi:10.1038/s41433-021-01593-z.
- Ugradar S, et al. Eye (Lond). 2023;doi:10.1038/s41433-022-02186-0.
- Ugradar S, et al. J Neuroophthalmol. 2022;doi:10.1097/WNO.0000000000001515.
- Winn BJ, et al. Ophthalmology. 2021;doi:10.1016/j.ophtha.2021.04.024.
- For more information:
- Kimberly P. Cockerham, MD, in private practice in San Diego, can be reached at cockerhammd@gmail.com.
- Raymond S. Douglas, MD, PhD, can be reached at raymonddouglasmd@gmail.com.
- Wendy W. Lee, MD, MS, of Miller School of Medicine, Bascom Palmer Eye Institute, can be reached at wlee@med.miami.edu.
- David Toro-Tobon, MD, of the division of endocrinology, diabetes, metabolism and nutrition, Mayo Clinic, can be reached at torotobon.david@mayo.edu.
Click here to read the Point/Counter to this Cover Story.
Collapse
Read more about
Click Here to Manage Email Alerts