A Phase 2 Study of XP-8121: Once-Weekly Subcutaneous Levothyroxine Sodium for the Treatment of Hypothyroidism in Adults

Background: The standard of care for hypothyroidism treatment worldwide is daily oral levothyroxine (LT4) sodium. Limitations associated with daily oral administration highlight the need for alternative formulations to address challenges in maintaining euthyroidism. XP-8121 (LT4 sodium for subcutaneous [SC] administration) is a ready-to-use, liquid formulation of LT4 intended for once-weekly administration, offering an alternative hormone replacement approach by bypassing the gastrointestinal tract. This study assessed the safety, tolerability, and target dose conversion factor from oral LT4 to XP-8121 SC in adult participants. Participants and Methods: This Phase 2, multicenter, nonrandomized, open-label, single-arm, self-controlled study (NCT05823012) evaluated XP-8121 SC in 46 adults with hypothyroidism receiving a consistent dose of oral LT4 for at least 3 months prior to screening, with documented normal thyrotropin (TSH) levels at least 3 months prior to screening and normal free thyroxine (fT4) at screening. The weekly XP-8121 SC dose was initiated at 50% of the target dose and titrated every 2 weeks for up to 8 weeks based on individual response using fT4 trough concentrations. Following titration, participants continued the established dose during a 4-week maintenance period. Results: Of the 46 participants enrolled, 39 completed the study. The majority were female (37; 80.4%) and identified as White (44; 95.7%). The final dose conversion factor point estimate ranged from 4.02 (90% confidence interval [CI]: 3.79–4.27) to 4.24 (90% CI: 4.06–4.42), supporting a conversion factor of approximately four times the daily oral LT4 dose when transitioning to XP-8121 SC. Although participants were initially underdosed during titration, TSH normalization was observed in 79.5% and fT4 normalization in 100% among those who completed the study on a consistent dose (unchanged for 6 weeks) at the end of maintenance. Overall, 78 treatment-emergent adverse events (TEAEs) were reported in 30 participants (65.2%) who received at least one dose of XP-8121 SC; fatigue (21.7%) and injection-site pain (10.9%) were the most common TEAEs. A majority of participants who completed the study reported higher satisfaction, convenience, and perceived effectiveness with once-weekly XP-8121 SC and expressed preference over daily oral LT4. Conclusions: Once-weekly XP-8121 SC was generally well-tolerated in all treated participants and supported a dose conversion factor of four times the daily oral LT4 dose.