Description
Teprotumumab-trbw (TEPEZZATM) is a fully human IgG1 monoclonal antibody that binds to insulin-like growth factor-1 receptors (IGF-IR) and blocks activation and signaling. Teprotumumab-trbw is to be used for the treatment of adult patients with thyroid eye disease (TED). 

Thyroid eye disease is an autoimmune disease of the retroocular tissues occurring in patients with Grave’s disease. TED, also called Graves’ orbitopathy, causes inflammation and tissue expansion behind the eye leading to proptosis. It is often accompanied by pain, double vision, facial disfigurement and in severe cases blindness. About 90% of patients with TED have Graves’ disease. Approximately 20 – 40% of patients with Graves’ disease will develop TED and will be classified as mild or moderate to severe. It is estimated that 5% of TED patients will develop moderate to severe symptoms. These include inflamed eyes, increasing diplopia, proptosis > 3mm above the upper limit of normal for race and gender, and corneal irritation. TED is a self-limiting disease. Patients experience an active progressive period that moves to an inactive (fibrotic) phase within one to three years. It is important to identify and treat patients early to minimize damage caused in the active phase of the disease.

Teprotumumab-trbw is the first FDA-approved drug for the treatment of TED. Prior management of TED involved reversal of hyperthyroidism, saline eye drops to reduce surface irritation, and glucocorticoids for inflammation in the periorbital tissues. More severe cases are managed with surgical procedures including strabismus correction, eyelid repair, and orbital decompression.

The IGF-IRs are overexpressed by orbital fibroblasts and B and T cells in Graves’ disease and TED. IGF-IRs form a physical and functional complex with thyrotropin receptors, which play a crucial role in Graves’ disease. This complex results in inflammation, edema, and expansion of extraocular muscle and adipose tissue. Teprotumumab-trbw diminishes signaling at either receptor and blocks the pathologic immune responses in active TED. 

Regulatory Status
Teprotumumab-trbw (TEPEZZATM) was approved by the U.S. Food and Drug Administration (FDA) on Jan. 21, 2020 for the treatment of thyroid eye disease.

Policy 
The initial use of this drug requires documentation of direct physician involvement and signature in the ordering and evaluation as documented in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.

The use of Teprotumumab-trbw meets is considered MEDICALLY NECESSARY when ALL of the following criteria are met:

1. Individual is 18 years of age or older.
2. Prescriber must be an ophthalmologist with experience in the treatment of patients with thyroid eye disease.
3. Photographs of individual's eyes must be submitted for review.
4. Individual is euthyroid (verified by submission of current laboratory value, defined as 0 – 90 days from date of lab draw). Note: mild hypo- or hyperthyroidism is permitted, defined as free thyroxine (FT4) and free triiodothyronine (FT3) levels less than 50% above or below the normal limits.
5. Individual is to be monitored and every effort should be made to remain euthyroid (i.e. levothyroxine, armour thyroid, etc.) throughout Teprotumumab-trbw treatment.
6. Individual is diagnosed with moderate to severe Graves orbitopathy (at least one of the following):
   • Proptosis ≥ 3mm above the upper limit of normal for race and gender
     1. Upper limit of normal for patients:
        • African American Female — 23mm
        • African American Male — 24 mm
        • White Female — 19 mm
        • White Male — 21 mm
        • Asian Female — 16 mm
        • Asian Male — 17 mm
   • Lid retraction of ≥ 2mm
   • Moderate to severe soft-tissue involvement
   • Periodic or consistent diplopia
7. Ocular symptoms began in individual within the past 12 months.
8. Individual has a Clinical Activity Score ≥ 4 (see policy guidelines) in the more proptotic eye.
9. Attestation that the patient is not pregnant and been informed that appropriate forms of contraception should be implanted prior to initiation, during treatment and for 6 months following the last dose of Teprotumumab-trbw.
10. Patient has failed an adequate trial of prior treatment with oral or IV glucocorticoids.

*Clinical Activity Score (CAS)
CAS is a 7-point scale commonly used in assessing disease activity in patients with TED. Add 1 point for each finding:

• Painful feeling behind the globe
• Pain with eye movement
• Redness of the eyelids
• Swelling of the eyelids
• Redness of the conjunctiva
• Chemosis (edema of the conjunctiva)
• Swollen caruncle (flesh body at medial angle of the eye)

Dosage and Administration

Teprotumumab-trbw is administered by intravenous infusion over 60 to 90 minutes. Recommended dose is 10mg/kg for the first infusion, followed by 20mg/kg every 3 weeks for 7 additional infusions. Teprotumumab-trbw is available as a 500mg lyophilized powder in a single-dose vial for reconstitution.   

Length of Authorization
Teprorutumumab-trbw will be covered for one course of therapy per lifetime.

The use of Teprotumumab-trbw is investigational and/or unproven and therefore NOT MEDICALLY NECESSARY when the above requirements are not met and for all other conditions.

Rationale 
In a randomized, double-masked, placebo-controlled, phase 3 multicenter trial, patients with active TED were assigned in a 1:1 ratio to receive intravenous infusion of Teprotumumab-trbw or placebo once every 3 weeks for 21 weeks. Teprotumumab-trbw was administered as 10mg per kilogram of body weight for the first infusion and 20mg per kilogram for subsequent infusions. Patients were eligible for the trial if they were 18 to 80 years of age, had received a diagnosis of Graves’ disease, had active, moderate-to-severe TED, had ocular symptoms that began within 9 months before the baseline assessment, and had a CAS of at least 4. Moderate-to-severe TED was defined as patients having at least one of the following: lid retraction of ≥ 2 mm, moderate to severe soft-tissue involvement, proptosis of ≥ 3 mm above the normal values for race and sex, and periodic or constant diplopia. Patients were required to be euthyroid throughout trial. Exclusion criteria included previous orbital irradiation or surgery for TED, decreasing visual acuity or a visual-field or color vision defect from optic nerve involvement within the previous 6 months, glucocorticoid use, and any previous treatment with rituximab or tocilizumab.  

A total of 41 patients were assigned to the Teprotumumab-trbw group and 42 patients to the placebo group. At week 24, the percentage of patients with a proptosis response (a reduction in proptosis of ≥ 2 mm) was higher with Teprotumumab-trbw at 83% (34 patients) than with placebo at 10% (4 patients). All secondary outcomes were significantly better with Teprotumumab-trbw than with placebo at week 24. This included an overall response (a reduction of ≥ 2 points in the CAS plus a reduction in proptosis of ≥ 2 mm) of 78% in patients receiving Teprotumumab-trbw versus 7% in patients receiving placebo, a CAS of 0 or 1 in 59% of patients receiving Teprotumumab-trbw versus 21% in patients receiving placebo, a mean change in proptosis across trial visits of -2.82 mm in the patients receiving Teprotumumab-trbw versus -0.54 mm in patients receiving placebo, a reduction in diplopia of ≥ 1 grade in 68% of the Teprotumumab-trbw patients versus 29% of the placebo patients, and the mean change in overall score on the Graves’ ophthalmopathy-specific quality-of-life questionnaire across trial visits was 13.79 points in the patients receiving Teprotumumab-trbw versus 7.43 points in the patients receiving placebo. Most adverse events were mild or moderate in severity. Two serious events occurred in the Teprotumumab-trbw group, of which one (an infusion reaction) led to treatment discontinuation.

Teprotumumab-trbw resulted in better outcomes with respect to proptosis, CAS, diplopia, and quality of life than placebo in patients with active TED.

References 

1. Davies T, et al.(2020) Treatment of Graves’ Orbitopathy (Ophthalmopathy). Ross D, ed. UpToDate. https://www.uptodate.com. Accessed February 2020.
2. de Juan E Jr, Hurley DP, Sapira JD.(1980) Racial differences in normal values of proptosis. Arch Intern Med 1980; 140:1230.
3. Douglas RS, et al. 2020.(2020) Teprotumumab for the Treatment of Active Thyroid Disease. New Engl J Med. 382:341-352. doi: 10.1056/NEJMoa1910434.
4. Mamoojee Y, Pearce SHS.(2017) Natural History. In: Wiersinga WM, Kahaly GJ (eds): Graves’ Orbitopathy: A Multidisciplinary Approach – Questions and Answers. Basel, Karger. 2017:93-104.
5. Mourits MP, Koornneef L, Wiersinga WM, et al.(1989) Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: A novel approach. Br J Ophthalmol 1989; 73:639.
6. Smith TJ, et al. 2017.(2017) Teprotumumab for Thyroid-Associated Ophthalmopathy. New Engl J Med. 376: 1748-1761. doi: 10.1056/NEJMoa1614949
7. TEPEZZA (teprotumumab-trbw) (prescribing information) Horizon Therapeutics; January 2020.

Coding Section  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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