14 CLINICAL STUDIES

TEPEZZA was evaluated in 2 randomized, double-masked, placebo-controlled studies in 171 patients with Thyroid Eye Disease: Study 1 (NCT01868997) and Study 2 (NCT03298867). Patients were randomized to receive TEPEZZA or placebo in a 1:1 ratio. Patients were given intravenous infusions (10 mg/kg for first infusion and 20 mg/kg for the remaining 7 infusions) every 3 weeks for a total of 8 infusions. Patients had a clinical diagnosis of Thyroid Eye Disease with symptoms and were euthyroid or had thyroxine and free triiodothyronine levels less than 50% above or below normal limits. Prior surgical treatment for Thyroid Eye Disease was not permitted. Proptosis ranged from 16 to 33 mm and 125 patients (73%) had diplopia at baseline.

A total of 84 patients were randomized to TEPEZZA and 87 patients were randomized to placebo. The median age was 52 years (range 20 to 79 years), 86% were White, 9% were Black or African-American, 4% were Asian and 1% identified as Other. The majority (73%) were female. At baseline, 27% of patients were smokers.

The proptosis responder rate at week 24 was defined as the percentage of patients with ≥2 mm reduction in proptosis in the study eye from baseline, without deterioration in the non-study eye (≥2 mm increase) in proptosis. Additional evaluations included signs and symptoms of Thyroid Eye Disease including pain, gaze evoked orbital pain, swelling, eyelid erythema, redness, chemosis, inflammation, clinical activity score and assessments of functional vision and patient appearance. Results for proptosis are found in Table 2.

Table 2. Efficacy Results in Patients with Thyroid Eye Disease in Study 1 and 2
	Study 1			Study 2
	Teprotumumab (N=42)	Placebo (N=45)	Difference (95% CI)	Teprotumumab (N=41)	Placebo (N=42)	Difference (95% CI)
* Difference and its corresponding 95% Confidence Interval (CI) is based on a weighted average of the difference within each randomization stratum (tobacco user, tobacco non-use) using CMH weights. † Results were obtained from an MMRM with an unstructured covariance matrix and including treatment, smoking status, baseline value, visit, treatment by visit, and visit by baseline value interaction as fixed effects. A change from Baseline of 0 was imputed at the first post-Baseline visit for any subject without a post-Baseline value.
Proptosis responder rate at week 24, % (n) *	71% (30)	20% (9)	51% (33, 69)	83% (34)	10% (4)	73% (59, 88)

Proptosis (mm) average change from baseline through week 24, LS Mean (SE) †	-2.5 (0.2)	-0.2 (0.2)	-2.3 (-2.8, -1.8)	-2.8 (0.2)	-0.5 (0.2)	-2.3 (-2.8, -1.8)

In Study 2, improvement of proptosis as measured by mean change from Baseline was observed as early as 6 weeks and continued to improve through week 24 as shown in Figure 1. Similar results were seen in Study 1.

Figure 1. Change from Baseline in Proptosis over 24 Weeks in Study 2

P<0.01 at each timepoint

TEPEZZA also led to improvement in the less severely impacted "fellow" eye.

Diplopia (double vision) was evaluated in a subgroup of patients that had diplopia at baseline in Study 1 and 2. Results are shown in Table 3.

Table 3. Diplopia in Patients with Thyroid Eye Disease in Study 1 and 2
Parameter	TEPEZZA (n=66)	Placebo (n=59)
P<0.01
* Diplopia was evaluated on a 4-point scale where scores ranged from 0 for no diplopia to 3 for constant diplopia. A diplopia responder was defined as a patient with baseline diplopia >0 and a score of 0 at week 24.
Diplopia
Responder rate* at week 24, % (n)	53% (35)	25% (15)

Following discontinuation of treatment in Study 1, 53% of patients (16 of 30 patients) who were proptosis responders at week 24 maintained proptosis response 51 weeks after the last TEPEZZA infusion. 67% of patients (12 of 18) who were diplopia responders at week 24 maintained diplopia response 51 weeks after the last TEPEZZA infusion.

Subgroups

Examination of age and gender subgroups did not identify differences in response to TEPEZZA among these subgroups. Reduction in proptosis was similar between smokers and non-smokers in both studies.