Study Overview
Hypothyroidism is a common endocrine disorder in which the thyroid gland does not produce enough hormone to meet the body’s needs. Standard treatment is daily oral levothyroxine sodium (LT4), a synthetic form of thyroid hormone that replaces what the body is missing. Although this therapy is highly effective, some people struggle with daily adherence, timing around food and other medications, or variable absorption in the gastrointestinal tract. These practical limitations have encouraged interest in alternative formulations.
This Phase 2 study evaluated XP-8121, a ready-to-use liquid levothyroxine sodium formulation designed for once-weekly subcutaneous (under-the-skin) administration. By bypassing the digestive system, this approach may offer a more convenient and potentially more reliable way to deliver thyroid hormone replacement.
The main goals of the study were to assess safety, tolerability, and the dose conversion factor needed when switching from daily oral levothyroxine to once-weekly XP-8121 subcutaneous therapy in adults with hypothyroidism.
Why This Matters
Daily levothyroxine is the standard of care worldwide, but real-world treatment can be challenging. Some patients must take the drug on an empty stomach and avoid certain foods, supplements, or medications that interfere with absorption, such as calcium or iron. Others may have digestive conditions that reduce absorption even when the medication is taken correctly. In addition, the need for lifelong daily dosing can affect convenience and adherence.
A long-acting or once-weekly formulation could reduce the burden of treatment, improve satisfaction, and help some patients maintain more stable thyroid hormone levels. XP-8121 is being developed with that goal in mind.
Study Design and Participants
This was a Phase 2, multicenter, nonrandomized, open-label, single-arm, self-controlled trial registered as NCT05823012. It enrolled 46 adults with hypothyroidism who had been taking a stable dose of oral levothyroxine for at least 3 months before screening. Participants also had documented normal thyroid-stimulating hormone (TSH) levels at least 3 months before screening and normal free thyroxine (fT4) at screening.
Because this was a self-controlled study, each participant served as their own reference point. Researchers compared thyroid hormone status before and after the switch to XP-8121 rather than comparing one group with another group receiving a different therapy.
The once-weekly XP-8121 dose was started at 50% of the target dose and then adjusted every 2 weeks for up to 8 weeks. Dose changes were guided by each participant’s response, especially trough fT4 levels, which represent hormone levels measured just before the next weekly dose. After dose titration, participants stayed on the selected dose for a 4-week maintenance period.
Main Findings
Of the 46 participants enrolled, 39 completed the study. Most participants were women, and most identified as White, reflecting the study population available during recruitment.
The central finding was that the final dose conversion factor from oral levothyroxine to XP-8121 subcutaneous therapy was approximately 4. In practical terms, this means that a once-weekly XP-8121 dose of roughly four times the total daily oral LT4 dose appeared to be the appropriate target when switching formulations. The study reported point estimates ranging from 4.02 to 4.24, with 90% confidence intervals supporting this conversion range.
Although participants were initially underdosed during titration, thyroid levels improved as dosing was adjusted. Among those who completed the study and were on a consistent dose for the final 6 weeks, TSH normalized in 79.5% and fT4 normalized in 100%.
These results suggest that once-weekly subcutaneous levothyroxine can restore biochemical thyroid control in many adults with hypothyroidism when the dose is properly individualized.
Safety and Tolerability
Safety was an important part of the study. Overall, 78 treatment-emergent adverse events were reported in 30 participants who received at least one dose of XP-8121. The most common adverse events were fatigue, reported in 21.7% of participants, and injection-site pain, reported in 10.9%.
Most adverse events were consistent with what might be expected during initiation of a new injectable therapy or during periods of thyroid hormone dose adjustment. The study conclusion was that once-weekly XP-8121 was generally well tolerated.
Because this was a relatively small Phase 2 study, it is not large enough to define rare risks or long-term safety. Larger and longer studies will be important to better understand how this therapy performs over time in broader patient populations.
Patient Experience and Preference
Beyond lab results, the study also looked at how participants felt about the treatment. A majority of those who completed the study reported greater satisfaction, convenience, and perceived effectiveness with once-weekly XP-8121 compared with daily oral levothyroxine. Many also expressed a preference for the weekly injectable option.
This is clinically meaningful because patient preference can influence adherence and long-term success. A treatment that is easier to fit into daily life may improve consistency and reduce the stress associated with managing chronic hypothyroidism.
Clinical Interpretation
The key practical takeaway from this study is that once-weekly subcutaneous levothyroxine may be a promising alternative for selected adults with hypothyroidism. The approximate 4:1 conversion factor from daily oral LT4 to weekly XP-8121 provides a useful starting point for dosing, though careful monitoring remains essential.
In clinical practice, thyroid hormone replacement must be individualized. Factors such as body weight, age, cardiac disease, concurrent medications, gastrointestinal absorption, and symptom response all matter. Even if a once-weekly injectable formulation becomes available more widely, clinicians would still need to monitor TSH and fT4 closely during the transition period.
This therapy may be especially appealing for patients who:
– Have difficulty taking a daily oral medication consistently
– Prefer fewer dosing events
– Have gastrointestinal issues that interfere with absorption
– Want a treatment option that bypasses the digestive tract
However, it is not yet clear whether this approach is best for all patients, including those with complex endocrine or cardiovascular conditions. Individuals with heart disease, older adults, and pregnant patients would likely require especially careful evaluation.
Limitations of the Study
As with any early-phase trial, there are important limitations. The study was open-label, meaning both participants and investigators knew what treatment was being given. There was no comparison group receiving standard oral therapy in parallel. The sample size was modest, and the follow-up period was relatively short.
In addition, the participant group was not very diverse, which may limit how broadly the findings can be applied. The study also focused on biochemical outcomes and short-term tolerability rather than long-term clinical outcomes such as symptom control, cardiovascular safety, or quality of life over many months or years.
These limitations do not reduce the value of the findings, but they do mean the results should be viewed as early evidence rather than definitive proof of superiority over oral therapy.
What Comes Next
Future studies will need to answer several important questions. Researchers should determine whether once-weekly subcutaneous levothyroxine maintains stable thyroid control over longer periods, whether it improves adherence in routine practice, and how it compares with standard oral levothyroxine in larger and more diverse groups.
It will also be important to understand patient selection: who benefits most from this approach, who should avoid it, and how best to transition safely from oral tablets to injectable therapy. Practical issues such as injection training, access, cost, and insurance coverage will also shape real-world use.
Conclusion
This Phase 2 study suggests that XP-8121, a once-weekly subcutaneous levothyroxine sodium formulation, is generally well tolerated and may offer a convenient alternative to daily oral therapy for adults with hypothyroidism. The findings support a dose conversion factor of about four times the daily oral LT4 dose when transitioning to XP-8121.
While more research is needed, this approach could represent an important step toward more flexible thyroid hormone replacement options, especially for patients who struggle with daily oral treatment or absorption issues.
