LB-003 - A PHASE I, RANDOMIZED, OPEN-LABEL, CROSSOVER, FIXED-SEQUENCE STUDY TO EVALUATE THE PK, D0SE-PROPORTIONALITY, BIOAVAILABILITY, AND TOLERABILITY OF SUBCUTANEOUS LEVOTHYROXINE SODIUM (XP-8121) IN HEALTHY ADULT SUBJECTS.

V. Conoscenti, R. Huang, R. Fitch, D. Harper; Xeris Pharmaceuticals, Chicago, IL, United States.

Background: Daily oral levothyroxine is standard of care for hypothyroidism but can be limited by malabsorption due to gastrointestinal disorders or poor medication adherence. XP-8121 is a novel ready-to-use liquid formulation of levothyroxine sodium intended to address these limitations.

Methods: This Phase 1, randomized, open-label, crossover study evaluated the pharmacokinetics, dose proportionality, safety and tolerability of 600 μg, 1200 μg, and 1500 μg of XP-8121 given subcutaneously (SC) and the relative bioavailability of 600 μg SC XP-8121 versus 600 μg oral (PO) levothyroxine (Synthroid®).

Results: Among 60 healthy adult volunteers, peak thyroxine exposure was highest for subjects given Synthroid 600 µg (mean [SD] Cmax: 47.6 [10.20] ng/mL) versus all doses of XP-8121 (mean [SD] Cmax: 21.6 [7.85] ng/mL for 600 µg XP-8121, 37.1 [14.92] ng/mL for 1200 µg XP-8121, and 46.9 [14.92] ng/mL for 1500 µg XP-8121). The overall mean [SD] AUCs0-last of 600 μg XP-8121 (5392 [3054.6] ng•hr/mL), 1200 μg XP-8121 (8980 [3048.9] ng•hr/mL), and 1500 μg XP-8121 (12720 [4469.6] ng•hr/mL) were greater than 600 µg Synthroid (4005 [2032.6] ng•hr/mL). Dose-proportionality was concluded based on a power model of AUC0-last and Cmax. The incidence and severity of adverse events were similar across treatment groups, with no deaths or serious adverse events.

Conclusion: In healthy adults, baseline-adjusted plasma thyroxine levels showed that subjects given XP-8121 SC versus 600 µg Synthroid PO had slower systemic absorption, lower peak plasma concentration, and longer exposure to thyroxine. XP-8121 SC was generally well-tolerated and had dose-proportionality across all doses. These results support further development of XP-8121 for patients who require thyroid hormone replacement therapy.