Is a third cycle of Tepezza (teprotumumab) indicated for a patient with thyroid eye disease (TED) who has already completed two cycles?

Third Cycle of Tepezza for Thyroid Eye Disease

A third cycle of teprotumumab can be considered for patients with recurrent or persistent active thyroid eye disease after two prior cycles, provided they have documented active inflammation (CAS ≥3), demonstrated prior response to treatment, and no contraindications such as significant hearing loss.

Evidence for Retreatment Beyond Two Cycles

While the FDA approval and pivotal trials evaluated single 8-infusion courses of teprotumumab, expert consensus and emerging clinical experience support retreatment in appropriate circumstances:

• Expert consensus from 2022 recommends retreatment for patients who experience relapses after initial therapy, establishing the principle that multiple courses can be medically appropriate 1
• The consensus panel agreed that treatment can be considered even beyond 16 months following initial TED diagnosis, indicating no strict time limitations on subsequent courses 1
• Long-term follow-up data through 72 weeks post-treatment showed that 82% of patients did not require additional TED treatment, but importantly, 17.9% did receive additional therapy during extended follow-up, suggesting some patients benefit from retreatment 2

Critical Prerequisites Before Third Cycle

Disease Activity Assessment

• Document current Clinical Activity Score (CAS) with a threshold of ≥3 indicating active inflammation warranting treatment 3
• Patients with CAS ≥5 combined with documented symptoms demonstrate active moderate-to-severe disease that clearly satisfies medical necessity 3
• Measure baseline proptosis by exophthalmometry to establish objective metrics for response monitoring 3

Safety Screening

• Establish baseline audiometry before any retreatment, as hearing loss is a critical adverse event that may be permanent and can worsen with repeated exposure 3
• The American Academy of Ophthalmology guidelines emphasize particular caution in patients with pre-existing hearing loss 3
• Screen for optic neuropathy with comprehensive evaluation including visual acuity, color vision, visual fields, pupillary examination, and fundus examination 3

Response History

• Prior positive response to teprotumumab strongly predicts benefit from retreatment, as patients who responded initially are likely to respond again 3
• Assess whether disease reactivation occurred after prior courses or if there was incomplete initial response 4

Expected Outcomes with Third Cycle

Real-world evidence from recalcitrant TED patients (those who failed prior therapies) demonstrates robust responses:

• Proptosis response rate of 85.9% with mean reduction of 3.1 mm in patients with recalcitrant disease 4
• CAS response rate of 93.8% with mean improvement of 3.8 points 4
• Diplopia response rate of 69.1% overall, though significantly lower (46.7%) in patients with prior orbital decompression surgery 4
• These response rates in recalcitrant patients are comparable to treatment-naïve patients from pivotal trials, suggesting maintained efficacy with repeated courses 4

Important Caveats and Pitfalls

Prior Surgical Decompression

• Patients with prior orbital decompression surgery show statistically significant decreases in both diplopia response (46.7% vs. 77.5%, p=0.014) and proptosis response (75.0% vs. 90.9%, p=0.045) compared to surgery-naïve patients 4
• Set realistic expectations for patients with prior decompression, as mechanical changes from surgery may limit teprotumumab's effectiveness 4

Hearing Risk with Multiple Courses

• Four patients in the recalcitrant disease study reported serious adverse events related to persistent hearing loss 4
• Cumulative exposure across multiple cycles may increase hearing loss risk, making audiometric monitoring essential before and during each course 3

Disease Chronicity

• No significant differences in response rates were found between acute (disease duration <1 year) versus chronic (≥1 year) TED, indicating that disease duration alone should not preclude retreatment 4

Treatment Algorithm for Third Cycle Decision

Proceed with third cycle if:

• CAS ≥3 (preferably ≥5) with documented active inflammation 3, 1
• Prior positive response to teprotumumab 3
• Baseline audiometry shows acceptable hearing or patient accepts risk after counseling 3
• No evidence of optic neuropathy requiring urgent decompression 3

Exercise caution or consider alternatives if:

• Pre-existing significant hearing loss is present 3
• Prior orbital decompression surgery was performed (lower response rates expected) 4
• Patient did not respond to previous teprotumumab courses 4

Complete all 8 infusions once started, as expert consensus recommends continuing therapy for the full course despite lack of response by the fourth infusion 1