Endocrinology · Medical Literature
A Phase 2 Study of XP-8121: Once-Weekly Subcutaneous Levothyroxine Sodium for the Treatment of Hypothyroidism in Adults.
Abstract
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. 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. 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. 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.
Clinical relevance
In adults with hypothyroidism who are stably maintained on daily oral levothyroxine, does once-weekly subcutaneous XP-8121 (levothyroxine sodium) maintain biochemical euthyroidism, and what is the target dose conversion factor from oral to subcutaneous administration? __SNAPSHOT__ {"studyDesign":"Phase 2, multicenter, nonrandomized, open-label, single-arm, self-controlled study (NCT05823012)","setting":"Multicenter; United States (institutional setting not further specified)","sampleSize":"n=46 enrolled; n=39 completed the study","population":"Adults with hypothyroidism on a consistent oral LT4 dose for ≥3 months prior to screening, with documented normal TSH ≥3 months prior to screening and normal free T4 (fT4) at screening. Mean baseline daily oral LT4 dose: 83.7 ± 31.14 mcg. The majority were female (80.4%) and identified as White (95.7%).","intervention":"XP-8121 (levothyroxine sodium for subcutaneous injection), a ready-to-use liquid formulation administered once weekly via subcutaneous injection. Dosing was initiated at 2× the participant's daily oral dose and titrated every 2 weeks (up to 8 weeks) toward a target of 4× the daily oral dose, guided by fT4 trough concentrations, followed by a 4-week maintenance period.","comparator":"Self-controlled (each participant's prior stable oral LT4 regimen served as the internal reference); no parallel control arm.","primaryOutcome":"Target dose conversion factor from daily oral LT4 to once-weekly XP-8121 SC, assessed as the geometric mean ratio of the weekly XP-8121 dose to the prior daily oral LT4 dose in the completer population; secondary outcomes included safety, tolerability, TSH normalization, and fT4 normalization.","followUp":"Up to 8 weeks titration + 4 weeks maintenance (approximately 12 weeks total active treatment); screening period duration not reported.","fundingSource":"Industry (Xeris Biopharma Holdings, Inc.); multiple authors are employees or paid consultants of the sponsor"}
Key findings
Of 46 enrolled participants, 39 completed the study. In the primary completer population (n=23, participants on an unchanged dose for ≥6 weeks through end of maintenance), the geometric mean dose conversion factor was 4.24 (90% CI: 4.06–4.42). Sensitivity analyses were consistent: when allowing dose changes during maintenance (n=27), the conversion factor was 4.02 (90% CI: 3.79–4.27); among participants maintaining both TSH and fT4 within range throughout maintenance while permitting dose modifications (n=25), it was 4.16 (90% CI: 3.98–4.35). Participants completing the maintenance period received a mean weekly XP-8121 dose of 324.4 ± 125.59 mcg. Among completers on a consistent dose at end of maintenance, TSH normalization was achieved in 79.5% and fT4 normalization in 100%. Notably, approximately 40% of participants considered stably euthyroid at screening were found to have TSH or fT4 outside normal range, underscoring challenges with oral LT4 maintenance (reported by sponsor; not a formal study endpoint). Treatment-emergent adverse events (TEAEs) occurred in 30 of 46 participants (65.2%); most were mild (87%) or moderate (13%) in severity. No deaths or serious adverse events (SAEs) were reported. The most frequent TEAEs (>2 participants) were fatigue (21.7%), injection site pain (10.9%), headache (8.7%), and urinary tract infection (6.5%). Across >450 injections, injection site discomfort was reported in 18% (mostly mild), erythema in 7%, and edema in 1% by Draize scale; no participant discontinued due to an injection site reaction. On the Treatment Satisfaction Questionnaire for Medication (TSQM-9), XP-8121 scored higher than oral LT4 in all three domains (effectiveness, convenience, global satisfaction); 72% of completers expressed a strong preference for the SC route. NNT/NNH calculations are not applicable given the single-arm design and absence of a parallel control group.
Practice implications
This Phase 2 single-arm study establishes that a once-weekly subcutaneous dose of XP-8121 approximating 4× the prior daily oral LT4 dose (geometric mean ~4.02–4.24×) can restore and maintain biochemical euthyroidism—fT4 normalization in 100% and TSH normalization in ~79.5% of completers on a stable dose—with an acceptable short-term safety and tolerability profile. The study did NOT establish superiority or non-inferiority versus oral LT4 in a head-to-head comparison; it was not designed or powered to do so. The incomplete TSH normalization rate (79.5%) at the end of maintenance, even after a structured titration period, suggests that some participants may require further dose adjustment beyond the 12-week study window, and that TSH normalization may lag behind fT4 normalization due to the kinetics of TSH suppression and recovery. Findings are most directly applicable to adults with stable, well-characterized primary hypothyroidism on a known oral LT4 dose; patients with malabsorption disorders, those on interfering medications, or those with secondary/central hypothyroidism were not specifically evaluated. The cohort was highly non-representative demographically (95.7% White, 80.4% female), limiting generalizability across diverse populations. Patient-reported preference for the SC route (72%) is notable but must be interpreted cautiously given the open-label design, sponsor affiliation, and absence of a validated preference comparison methodology. The study was designed explicitly to inform Phase 3 development and should be regarded as hypothesis-generating and dose-finding, not as definitive evidence of clinical equivalence or superiority. Practice should NOT change based on these results alone; confirmation in a Phase 3 randomized controlled trial is required. Only the abstract and press-release data were available for this review, which limits full assessment of analytical methods, baseline balance, and secondary endpoint reporting. __LIMITATIONS__ Single-arm, open-label, self-controlled design: no randomization, no blinded parallel control group; all participants and investigators knew the treatment, introducing performance and detection bias.,Small sample size (n=46 enrolled, n=39 completed; primary analysis n=23): substantially underpowered for definitive efficacy conclusions and subgroup analyses.,Short follow-up (~12 weeks total): insufficient to assess long-term cardiovascular effects, bone density implications, or durability of TSH normalization, all critical for a lifelong therapy.,Incomplete TSH normalization (79.5%) in completers on a stable dose raises concern about adequacy of the proposed conversion factor and the 12-week study duration to achieve full TSH equilibration.,Highly non-representative cohort (95.7% White, 80.4% female): results may not generalize to men, non-White patients, or populations with differing LT4 absorption profiles or comorbidities.,Surrogate endpoints only (fT4, TSH): no patient-important outcomes (e.g., symptom burden, quality of life with validated instruments, cardiovascular events) were the primary focus.,Strong industry involvement: multiple authors are sponsor employees, and the study was sponsor-funded, creating a high risk of publication and reporting bias.,Self-controlled design does not account for regression to the mean or temporal trends in TSH/fT4 independent of the intervention.,Dose titration protocol (initiation at 2× then escalation to 4× daily dose) may have introduced systematic underdosing during titration, potentially affecting steady-state assessments at the end of maintenance.,Only abstract-level and press-release data were available for full evaluation; complete methods, statistical analysis plan, and full adverse event tables were not independently verified. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ XP-8121, a once-weekly subcutaneous levothyroxine formulation, achieved fT4 normalization in all completers and TSH normalization in ~79.5% of completers using a dose conversion factor of approximately 4× the prior daily oral LT4 dose, with a favorable short-term safety profile and no serious adverse events in this small, open-label Phase 2 study. These are promising but preliminary Phase 2 dose-finding results that establish the groundwork for a Phase 3 pivotal trial; clinicians should not alter practice based on this evidence alone. The strong industry sponsorship, non-representative sample, single-arm design, and short follow-up preclude any conclusion about clinical equivalence or superiority to standard oral therapy.