MON-390 - XP-8121: Once-Weekly Subcutaneous Levothyroxine Bypassing GI Interactions and Reduced Dose Requirements - Insights from A Phase 2 Study

Subcutaneous (SC) levothyroxine (LT4) may overcome challenges of oral LT4 therapy in patients taking medications that impair gastrointestinal (GI) absorption. This post hoc analysis evaluated dose-titration patterns of weekly SC XP-8121 among adults with hypothyroidism receiving concomitant agents known to interfere with oral LT4 uptake. Data were derived from a Phase 2, multicenter, non-randomized, open- label, single-arm study in adults on stable oral LT4 for ≥3 months with normal TSH (thyroid stimulating hormone) at and least 3 months prior to screening and free thyroxine (fT4) levels at screening. The XP- 8121 target dose was four times the participant’s daily oral LT4 dose. Treatment began at 50% of the calculated LT4 dose and titrated every 2 weeks for up to 8 weeks using fT4 trough concentrations (Titration Weeks = TW); participants then remained at the achieved dose during a 4-week maintenance period (Maintenance Days = MD).

Concomitant medications were not exclusionary. Several participants taking agents known to alter oral LT4 bioavailability, such as antacids, supplements, phosphate binders, and bisphosphonates required XP- 8121 dose down-titration. One participant receiving carafate, omeprazole, semaglutide, and zinc exhibited elevated fT4 at TW5 (72 hours post-dose) and normalized after reduction to 75% of target. Another participant taking magnesium, zinc, vitamin D3, and fluoxetine required reduction at MD15 due to suppressed TSH. They completed at 75% with rising but still low TSH. A third participant receiving iron and alendronate required down-titration to 75% of the target dose after elevated fT4 at MD1, finishing with normal thyroid labs. A fourth participant taking iron, pantoprazole, calcium, magnesium, and escitalopram showed suppressed TSH during MD15 but remained at full dose per investigator’s discretion; TSH neared the lower limit of normal by MD29. There was note of one participant taking semaglutide who discontinued early due to inability to reach a tolerable dose.

Although limited in number, these cases demonstrate that individuals taking agents that reduce oral LT4 absorption may still undergo dose reduction during conversion to SC therapy. This pattern is consistent with the higher effective bioavailability associated with the SC route, independent of GI interactions. These findings support individualized titration when transitioning from oral to SC LT4 and warrant further confirmation in larger controlled studies.

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