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

Abstract

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.

Keywords

XP-8121 levothyroxine subcutaneous hypothyroidism TSH once-weekly

Introduction

Hypothyroidism, defined as a deficiency of circulating thyroxine (T4), is a chronic condition requiring lifelong thyroid hormone replacement therapy.^1–4 The current global standard of care is daily oral levothyroxine (LT4) sodium, a synthetic form of T4.⁴ While oral formulations have been used for decades with acceptable safety profiles,⁵ LT4 is a narrow therapeutic index drug, and small deviations in dosing can produce clinically meaningful consequences signaled by changes in serum thyrotropin (TSH) levels.⁶

Despite widespread use, up to 40% of patients treated with oral LT4 are either over- or undertreated, largely due to challenges such as drug–food and drug–drug interactions, adherence, gastrointestinal (GI) malabsorption, and other medical comorbidities.^1,7,8 Additional barriers include lack of all possible dosage strengths, requiring some patients to split or combine tablets, and general dissatisfaction among some individuals with daily oral therapy.⁹ Quantification of weekly missed doses with LT4 tablets is not provided in major guidelines or labeling; however, adherence signals from observational data are informative. In a large cross-sectional study of adults with hypothyroidism on LT4 (n = 856), 28% were nonadherent by medication possession ratio of <80%, corresponding to ≥73 days/year without LT4, an average of ∼1.4 tablets missed per week among nonadherent patients (73/52 ≈ 1.4).¹⁰ Self-report findings were concordant, with ∼25% acknowledging missed doses, most often due to forgetfulness. Survey data cited by the American Thyroid Association similarly suggest ∼22% nonadherence⁴ but do not specify a weekly average, and Food and Drug Administration (FDA) labeling emphasizes adherence and offers missed dose instructions without quantifying typical weekly omissions. Collectively, these data underscore the potential value of dosing strategies that reduce day-to-day adherence demands. These limitations highlight the need for alternative formulations that provide more predictable thyroid hormone exposure and improved patient experience, particularly for those with absorption challenges or difficulty maintaining target TSH levels.^11,12

XP-8121 (LT4 sodium for subcutaneous [SC] administration) is a ready-to-use liquid formulation designed for once-weekly SC injection. By bypassing the GI tract, XP-8121 may reduce variability in absorption and result in more predictable T4 pharmacokinetics (PK) and TSH pharmacodynamics. In a Phase 1 study of healthy volunteers (N = 60), SC administration of XP-8121 demonstrated slower absorption than oral LT4, and exposure was dose proportional across the studied dose range of 600–1500 μg. These data informed the population pharmacokinetic (PPK) model used to derive the starting dose conversion factor of 4 times daily oral LT4.¹³ These findings supported advancement to the present Phase 2 study, designed to confirm the oral-to-SC dose conversion factor, evaluate safety and tolerability, and explore patient-reported satisfaction with once-weekly therapy.

Materials and Methods

Study design

This was a Phase 2, multicenter, nonrandomized, open-label, single-arm, self-controlled study in adults with hypothyroidism (NCT05823012; Fig. 1). Screening occurred within 28 days prior to the planned start of the titration period. Participants were required to be on a consistent (no dose adjustments) oral LT4 dose (Synthroid^® or an FDA-approved generic equivalent) to have a normal TSH (reference: 0.47–4.68 μIU/mL) for at least 3 months prior to screening and normal free thyroxine (fT4) (reference: 0.78–1.42 ng/dL) at screening by the central laboratory. The study consisted of two treatment phases following screening: a titration period and a maintenance period. During titration, doses were adjusted using a prespecified scheme informed by trough fT4 as a rapid, objective marker of biochemical response. During maintenance, participants remained on the end-of-titration dose unless fT4 or TSH indicated over-replacement. A PK substudy was conducted to characterize T4 and triiodothyronine (T3) over one 168-hour sampling window and required participants to be on oral Synthroid prior to screening (Supplementary Data S1). SC injections were administered by healthcare staff using a vial and syringe.

FIG. 1.

XP-8121 phase 2 study design schema.

Dosing and titration

The target dose was determined using PPK modeling on data from our Phase 1 study,¹³ which predicted that a weekly SC dose of XP-8121 at four times the daily oral Synthroid dose would provide a similar steady-state area under the curve (AUC_0–168hr). The initial starting dose of XP-8121 of 50% of the calculated 4× target was selected as a conservative approach to mitigate the risk of supratherapeutic exposure. Subsequently, XP-8121 was titrated at intervals no more frequently than every other week and in increments equal to 25% of the target dose, up to a maximum of 125% of the target or 1500 µg, whichever was lower. Weekly trough fT4 values and signs/symptoms of excess thyroid hormones were collected and used to guide dose adjustments at the subsequent weekly visit, with the goal of achieving biochemical euthyroidism with weekly XP-8121 dosing while minimizing risks of transient over- or under-replacement.

During the maintenance period, participants continued on their final titration dose, with a consistent dose defined as no dose adjustments over a 6-week period. If biochemical hyperthyroidism was present (elevated trough fT4 and/or low TSH), investigators could reduce the weekly dose by 1 level (25% of target) and continue that dose for the remainder of the study, as tolerated. Dose increases were not permitted during maintenance to preserve interpretability of the conversion factor and maintenance outcomes. Participants were permitted early termination at 14 (±2) days after their final dose of XP-8121 (if applicable).

Participants

Eligible participants were 18–65 years old with chronic hypothyroidism, maintained on a consistent oral LT4 dose for at least 3 months before screening. Eligibility required a TSH within the normal range at screening and documentation of a normal TSH at least 3 months prior. Key exclusion criteria included a LT4 dose exceeding 2 µg/kg/day, a total daily dose <50 µg or >375 µg, use of combination thyroid therapy (e.g., Synthroid^® plus liothyronine or Synthroid plus Armour^® Thyroid [LT4 tablets], United States Pharmacopeia), and use of any LT4 preparation other than those specified in the study. Full inclusion and exclusion criteria are provided in Supplementary Data S2. Participants provided written informed consent prior to study procedures.

Endpoints

Primary endpoints assessed (1) the oral-to-SC dose conversion factor and (2) safety and tolerability of once-weekly XP-8121 SC.

In addition to the primary endpoints, the study included several measures to further characterize the clinical and pharmacologic profile of XP-8121. These included safety and performance of starting with an initial dose at 50% of target based on prior oral LT4, the performance of the prespecified titration scheme in moving participants to biochemical euthyroidism, and the proportion of participants with TSH within the reference range after switching to XP-8121 SC. Total T4, fT4, and TSH were measured prior to the first XP-8121 SC dose and throughout titration and maintenance to evaluate trajectory and stability. A PK substudy of plasma thyroid hormone after multiple once-weekly injections was also planned to further characterize T4 and T3 levels after the last XP-8121 SC dose in the maintenance period.

Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory tests (chemistry, hematology, urinalysis), vital signs, electrocardiograms (ECGs), and physical examinations. Local tolerability was assessed using the Modified Draize Scale (erythema and edema)¹⁴ and an injection-site discomfort questionnaire administered weekly.

Participant-reported treatment satisfaction differences between oral LT4 and XP-8121 SC using the Treatment Satisfaction Questionnaire for Medication (TSQM-9).¹⁵ The TSQM-9 instrument, a validated nine-item questionnaire consisting of three domains (effectiveness, convenience, and global satisfaction), was administered under license. The Participant Preference Survey used in this study was not formally validated and represents an exploratory assessment.

Statistical analyses

The oral-to-SC dose conversion factor was assessed by comparing the ln-transformed final XP-8121 SC dose to the ln-transformed prior daily oral LT4 dose using a linear mixed-effects model with treatment as fixed effects and subject as a random effect. The conversion factor is presented as the ratio of geometric least squares means with 90% confidence intervals (CIs). The primary analysis of this endpoint was performed using the completer population, defined as all participants who completed the maintenance period and exhibited normalized TSH throughout the maintenance period while on a consistent dose for approximately 6 weeks. Sensitivity analyses examined the impact of allowing dose changes during maintenance and restricting it to participants who maintained both TSH and fT4 within range throughout maintenance.

In addition, descriptive statistics are reported for safety, tolerability, study drug exposure/compliance, height/weight/BMI, fT4/TSH, and participant-reported outcomes. No formal hypothesis testing was prespecified for efficacy endpoints; p-values for TSQM-9 comparisons are presented as descriptive.

Statistical analyses were performed using SAS version 9.4 or higher.

Institutional Review Board information

The Institutional Review Board (IRB) (ADVARRA; initial approval date: 24 March 2023) was a properly constituted board/committee operating in accordance with 21 Code of Federal Regulations (CFR) Part 56 “Institutional Review Boards.” This trial was designed and monitored in accordance with contract research organization and sponsor procedures, which comply with the ethical principles of good clinical practices (GCPs) as required by the major regulatory authorities. The study was conducted in full conformance with the protocol; current FDA regulations, including the Federal Food, Drug, and Cosmetic Act and applicable CFR (Title 21); International Council for Harmonisation guidelines; GCP guidelines; good laboratory practices guidelines; local ethical and regulatory requirements; and IRB requirements relative to clinical studies. All study participants signed a written informed consent form and were fully informed about the nature, objectives, and possible risks of participating in the study.

Results

Participant disposition and baseline characteristics

Forty-six participants enrolled; 39 completed the study (Fig. 2). Seven participants discontinued: inability to achieve a tolerable replacement dosage (n = 4; 8.7%), adverse events (n = 2; 4.3%), and inability to achieve an adequate replacement dosage (n = 1; 2.2%). Median (range) age at consent was 54.5 (33–65) years (Table 1). A majority of the participants were female (37/46; 80.4%) and White (44/46; 95.7%). At titration baseline (postscreening, predose), 40/46 (87.0%) had TSH within range and 41/46 (89.1%) had fT4 within range; mean (standard deviation [SD]) TSH was 1.96 (1.08) mIU/L and mean (SD) fT4 was 14.60 (2.71) pmol/L (Table 2). Eligibility was not restricted by hypothyroidism etiology; however, all enrolled participants were classified as having primary hypothyroidism.

FIG. 2.

Participant flow.

Table 1.

Demographics and Baseline Characteristics (Safety Population)

Disposition parameter	All participants (N = 46)
Sex, n (%)
Age at informed consent, median years (min, max)	54.5 (33, 65)
Male	9 (19.6)
Female	37 (80.4)
Race, n (%)
White	44 (95.7)
Asian	1 (2.2)
Multiple	1 (2.2)
Ethnicity, n (%)
Hispanic or Latino	29 (63.0)
Not Hispanic or Latino	17 (37.0)
Baseline body mass index, median kg/m² (min, max)	29.50 (23.1, 39.9)
Hypothyroidism history type, n (%)
Primary	46 (100.0)
Prior daily oral levothyroxine brand, n (%)
Synthroid^®	9 (19.6)
Other brand or generic	37 (80.4)
Prior daily oral levothyroxine dose (μg), n (%)
50	14 (30.4)
75	12 (26.1)
88	3 (6.5)
100	8 (17.4)
112	3 (6.5)
125	3 (6.5)
150	2 (4.3)
175	1 (2.2)

Table 2.

Summary of Thyrotropin and Free Thyroxine Blood Concentrations Over Time and Changes from Baseline—Maintenance Period (Safety Population)

Parameter	Titration baseline^a	Maintenance baseline	Maintenance Day 29
Parameter	Titration baseline^a	Maintenance baseline	Maintenance Day 29	Change from titration baseline	Change from maintenance baseline
n	46	42	39	39	39
Free T4 (pmol/L)
Mean (SD)	14.60 (2.71)	14.50 (2.41)	14.14 (1.80)	−0.12 (2.57)	−0.06 (2.00)
Median (min, max)	14.75 (7.3, 23.3)	14.70 (10.4, 20.6)	14.20 (10.4, 18.0)	−0.20 (−5.6, 7.2)	0.10 (−5.5, 4.5)
TSH (mIU/L)
Mean (SD)	1.96 (1.08)	2.97 (2.18)	2.49 (1.51)	0.43 (1.48)	−0.52 (2.13)
Median (min, max)	1.82 (0.15, 4.98)	2.60 (0.43, 13.00)	2.34 (0.11, 5.72)	0.17 (−1.78, 4.73)	−0.20 (−7.28, 5.02)

^aBaseline is the last nonmissing assessment prior to the protocol-defined study treatment within each period.

max, maximum; min, minimum; SD, standard deviation; T4, thyroxine; TSH, thyrotropin.

Dose-conversion and efficacy

In the primary analysis for determining the oral-to-SC dose conversion factor in the completer population (n = 23), the geometric mean ratio of weekly XP-8121 SC dose to prior daily oral LT4 dose was 4.24 (90% CI, 4.06–4.42) (Table 3). Sensitivity analyses were consistent when allowing dose changes during maintenance (n = 27) (4.02 [90% CI, 3.79–4.27]) and among participants who maintained both TSH and fT4 within range throughout maintenance while allowing dose modifications (n = 25) (4.16 [90% CI, 3.98–4.35]). These estimates support a practical conversion close to four times the daily oral LT4 dose when transitioning to once-weekly XP-8121 SC therapy.

Table 3.

Summary of Levothyroxine Doses and Dose Conversion Factor (Completer Population)

Parameters	All participants (N = 23)
Final XP-8121 dose, which maintains normalized TSH throughout the maintenance period in the original scale (μg)
Mean (SD)	282.6 (98.41)
Median (min, max)	200.0 (200, 500)
Daily oral levothyroxine dose prior to study (μg)
Mean (SD)	65.3 (17.72)
Median (min, max)	50.0 (50, 100)
Dose conversion factor^a
Mean (SD)	4.27 (0.56)
Median (min, max)	4.00 (4.0, 5.7)
Analysis of dose conversion factor^b
Geometric LSM for weekly XP-8121 (μg)	267.60
Geometric LSM for daily oral levothyroxine (μg)	63.11
Geometric mean ration (final dose conversion factor)	4.24
90% CI	[4.06–4.42]

The dose conversion factor was assessed using the completer population and by comparing the final XP-8121 SC dose (in μg) that maintains normalized TSH throughout the maintenance period to the daily oral LT4 dose (in μg) that each participant was taking before the study.

The dose conversion factor was assessed by comparing the natural log-transformed final XP-8121 SC dose (in μg) that maintains normalized TSH throughout the maintenance period to the natural log-transformed daily oral LT4 dose (in μg) the participant was taking before the study, using a linear mixed-effects model with treatment as the fixed effect and subject as the random effect. Geometric LSMs are calculated by exponentiating the LSM from the ANOVA. The geometric mean ratio (i.e., final dose conversion factor) and the corresponding 90% CI were found by exponentiating the differences of log-transformed LSM and 90% CI of the difference.

ANOVA, analysis of variance; CI, confidence interval; LSM, least squares mean; LT4, levothyroxine; SC, subcutaneous.

The conservative starting dose (50% of target) led to a predictable pattern: mean TSH rose and mean fT4 fell after the first XP-8121 SC dose, followed by normalization toward baseline as doses were increased during titration (Figs. 3 and 4). At the final study assessment (maintenance period Day 29), 31 participants achieved TSH values within the normal reference range. This represents 79.5% of those who completed the maintenance period (n = 39), and 67.4% of the total treated population (n = 46). All participants who completed the maintenance period had free T4 values within the reference range.

FIG. 3.

Observed mean (±SE) TSH concentration over time (safety population).

FIG. 4.

Observed mean (±SE) for free T4 concentration over time (safety population).

These findings indicate that biochemical control was achieved in a proportion of participants following titration from a conservative starting dose.

PK substudy

Twelve participants were planned for the PK substudy; however, only two participants enrolled and completed the full sampling period. Enrollment in the PK substudy was lower than estimated and was likely due to additional requirements including the following: (1) on a consistent dose of Synthroid for at least 3 months prior to screening; (2) maintain normal trough fT4 and total T4 levels on XP-8121 prior to starting the PK substudy; and (3) be housed in the CRU for 9 days and 8 nights to undergo PK sample collections. PK results from these two participants provide interesting insight into the plasma T4 and T3 levels measured over 7 days after administration of XP-8121 SC at steady state. Detailed profiles are reported in Supplementary Data S1. The plasma concentration over time curve was flat for both participants, with no clear Tmax, and the coefficient of variation for T4 and T3 concentrations was consistently lower than 8.5% in each participant, indicating stability.

Safety and tolerability

Overall, 78 TEAEs were reported in 30/46 participants (65.2%). Most events were mild (68/78) in severity, and 10 events were moderate. Study-drug-related TEAEs occurred in 17/46 participants (37.0%). One participant (2.2%) discontinued due to moderate fatigue; the event was unrelated to study drug and resolved before the last visit. Common study-drug-related TEAEs (≥2 participants) included injection-site pain, fatigue, and headache (Table 4). There were no deaths, no serious adverse events, and no severe TEAEs.

Table 4.

Overall Summary of Adverse Events and Treatment-Emergent Adverse Events Considered Related to Study Drug (Safety Population)

	Titration period (N = 46)	Maintenance period (N = 42)	Overall (N = 46)
n (%) [no. of events]
Any adverse events	27 (58.7) [63]	10 (23.8) [15]	30 (65.2) [78]
Any TEAEs	27 (58.7) [63]	10 (23.8) [15]	30 (65.2) [78]
Any drug-related TEAEs	16 (34.8) [19]	3 (7.1) [4]	17 (37.0) [23]
Any TEAEs leading to premature discontinuation of study drug^a	1 (2.2) [1]	0	1 (2.2) [1]
System organ class preferred term, n (%) [no. of events]
Gastrointestinal disorders	1 (2.2) [1]	0	1 (2.2) [1]
Frequent bowel movements	1 (2.2) [1]	0	1 (2.2) [1]
General disorders and administration site conditions	10 (21.7) [12]	2 (4.8) [2]	11 (23.9) [14]
Injection site pain	3 (6.5) [4]	2 (4.8) [2]	5 (10.9) [6]
Fatigue	2 (4.3) [2]	0	2 (4.3) [2]
Feeling jittery	1 (2.2) [1]	0	1 (2.2) [1]
Injection site bruising	1 (2.2) [1]	0	1 (2.2) [1]
Injection site hemorrhage	1 (2.2) [1]	0	1 (2.2) [1]
Injection site edema	1 (2.2) [1]	0	1 (2.2) [1]
Injection site paresthesia	1 (2.2) [1]	0	1 (2.2) [1]
Temperature intolerance	1 (2.2) [1]	0	1 (2.2) [1]
Metabolism and nutrition disorders	0	1 (2.4) [1]	1 (2.2) [1]
Increased appetite	0	1 (2.4) [1]	1 (2.2) [1]
Nervous system disorders	2 (4.3) [2]	0	2 (4.3) [2]
Headache	2 (4.3) [2]	0	2 (4.3) [2]
Psychiatric disorders	1 (2.2) [1]	1 (2.4) [1]	2 (4.3) [2]
Anxiety	0	1 (2.4) [1]	1 (2.2) [1]
Nervousness	1 (2.2) [1]	0	1 (2.2) [1]
Skin and subcutaneous tissue disorders	3 (6.5) [3]	0	3 (6.5) [3]
Alopecia	1 (2.2) [1]	0	1 (2.2) [1]
Ecchymosis	1 (2.2) [1]	0	1 (2.2) [1]
Pruritus	1 (2.2) [1]	0	1 (2.2) [1]

Participants are counted once within each category within each column for n, but can be counted multiple times for events. Treatment-related are those TEAEs with a possible, probable, definitely, or missing relationship to study medication. If a participant had more than one occurrence of the same event, the highest relationship is summarized for n, but all relationships are summarized for events.

In addition to the one participant with a TEAE leading to premature discontinuation of the study drug, one participant withdrew from the study before the final dose administration due to a fear of recurrent injection site pain. The reason for study discontinuation was documented as an AE; however, no individual AE was noted at the time of study discontinuation.

AE, adverse event; TEAE, treatment-emergent adverse event.

No clinically significant abnormalities or trends were observed in vital signs, ECGs, or physical examinations. Laboratory evaluations (chemistry, hematology, urinalysis) showed no consistent, clinically meaningful changes over time beyond isolated out-of-range values. On weekly Modified Draize assessments, no moderate or severe erythema or edema was observed. Injection site discomfort was reported by 15.4–46.2% of participants across titration and maintenance. The majority of the reported injection site discomfort was mild. (Table 5).

Table 5.

Subcutaneous Injection Assessments of XP-8121 SC Tolerability

Category	Score	Count
Intensity of injection site discomfort
None	0	364
Mild	1–3	57
Moderate	4–6	17
Severe	7–10	8
Total		446
Modified Draize Scale—erythema
None	0	421
Very Slight	1	29
Slight	2	1
Moderate	3	0
Severe	4	0
Total		451
Modified Draize Scale—edema
None	0	445
Very Slight	1	4
Slight	2	2
Moderate	3	0
Severe	4	0
Total		451

TSQM-9 scores

Treatment satisfaction favored once-weekly XP-8121 SC over daily oral LT4 across all assessed domains. At Maintenance Day 22 after the last XP-8121 dose, among 39 participants with data for both treatments, mean [SD] TSQM-9 scores were higher for XP-8121 SC versus oral LT4 for Convenience (80.34 [17.52] vs. 68.38 [20.32]; p = 0.0026), Overall Satisfaction (84.07 [19.56] vs. 65.93 [17.76]; p < 0.0001), and Effectiveness (83.33 [25.07] vs. 69.94 [16.65]; p = 0.0037).

Participant preference surveys

A majority of the participants (33/46; 71.7%) preferred a once-weekly injection to daily oral LT4 (Table 6). The most frequently reported reasons among those preferring injection were convenience, reduced dosing frequency, and ease of administration. Eight participants (17.4%) preferred oral LT4, most often citing convenience and ease of administration.

Table 6.

Summary of Participant Preference Survey (Safety Population)

Parameter, n (%)	All participants (N = 46)
If you had the choice between these two medications for thyroid replacement therapy, which one would you choose?
Once-daily oral pill	8 (17.4)
Once-weekly injection	33 (71.7)
No preference	5 (10.9)
If you prefer one of the administration methods, how strong is the preference?^a
Once-daily oral pill
Very strong	5 (62.5)
Fairly strong	2 (25.0)
Slightly strong	1 (12.5)
Not very strong	0
Once-weekly injection
Very strong	18 (54.5)
Fairly strong	9 (27.3)
Slightly strong	3 (9.1)
Not very strong	3 (9.1)
If you prefer one of the administration methods, what are the main reason(s) for your preference?^a,b
Once-daily oral pill
Convenience	4 (50.0)
Ease of administration	3 (37.5)
Frequency of administration	0
My level of compliance with therapy	1 (12.5)
Confidence in my therapy	2 (25.0)
Other	2 (25.0)
Once-weekly injection
Convenience	20 (60.6)
Ease of administration	15 (45.5)
Frequency of administration	18 (54.5)
My level of compliance with therapy	9 (27.3)
Confidence in my therapy	12 (36.4)
Other	0

Percentages are based on the number of participants in the safety population who chose the indicated preferred method.

Participants may have chosen >1 response.

Additional systematic quality-of-life measures were not collected, limiting assessment of patient-reported outcomes beyond treatment satisfaction and symptom reporting.

Discussion

This Phase 2 study builds upon prior Phase 1 investigations and confirms that XP-8121 SC weekly provides an oral-to-SC dose conversion of approximately four times the daily oral LT4 dose. Once-weekly administration was safe and well tolerated, with TEAEs primarily mild or moderate and no severe events attributed to the study drug. Importantly, the majority of participants who completed the study achieved and maintained biochemical control, while 67% of the overall study population had TSH within the normal range at study end. The completer population was defined for the purpose of estimating dose conversion and is not intended to represent outcomes in the overall study population. In addition, participant-reported outcomes demonstrated significantly greater satisfaction, convenience, and perceived effectiveness with XP-8121 SC compared with daily oral LT4.

The conservative dosing approach, beginning at 50% of the predicted weekly target and titrated biweekly, ensured participant safety but introduced transient under-replacement during early titration. Extrapolating from the safety profile observed at target doses, initiating therapy at 100% of the weekly target dose may mitigate early hypothyroidism without compromising safety.

Findings from this trial reinforce the potential of XP-8121 to address limitations of oral LT4 therapy. Daily oral dosing remains vulnerable to variability from food effects, drug interactions, tablet manipulation, and GI absorption.^7,16 In contrast, weekly SC delivery bypasses the GI tract, offering consistent PK and the possibility of improved hormone replacement, particularly in patients with malabsorption, adherence challenges, or dissatisfaction with daily therapy.⁹

Limitations of this study include its open-label design, relatively short follow-up, conservative starting dose, and exclusion of individuals with baseline out-of-range TSH. The study population was predominantly White and restricted to adults aged 18–65 years per inclusion criteria, and information on hypothyroidism classification (e.g., overt vs. subclinical) at the time of diagnosis was not collected. Interpretation of dose conversion is further limited by the population used for estimation. Participants who did not meet criteria for the completer population, as well as those included in sensitivity analyses, were excluded for the primary dose conversion calculation. As with many interventional studies, selection bias may be present, as individuals with greater interest in alternative treatment approaches may have been more likely to enroll. Furthermore, treatment satisfaction was assessed among participants who completed the study, which may introduce selection bias. Patients who discontinued treatment were not included in these analyses, and their experiences may differ from those who completed the study. Therefore, preference-related findings should be interpreted with caution. These factors may limit generalizability and obscure real-world treatment patterns. Nevertheless, these findings are consistent with Phase 1 data and support continued clinical development.

Future work should include randomized, controlled trials to evaluate XP-8121 SC against oral LT4 over longer durations, confirm durability of biochemical control, and further assess participant-reported outcomes and quality-of-life measures. Studies in specific populations, such as individuals with GI malabsorption, medication regimens with known drug–LT4 interaction, or unstable TSH levels for unknown reasons, will be particularly valuable. Additional efforts to refine titration regimens and validate conversion ratios in more diverse and clinically representative populations will inform practical implementation.

In conclusion, XP-8121 SC represents a novel, once-weekly LT4 formulation that bypasses GI absorption, offers predictable exposure, and demonstrates a favorable safety and satisfaction profile. With no approved injectable LT4 alternatives currently available, XP-8121 SC has the potential to fill a meaningful unmet need in the management of hypothyroidism.

Authors’ Contributions

V.C. contributed to study design, data analysis, and article writing and review. R.H. contributed to study design, data analysis, and article writing and review. D.R. contributed to study design, data analysis, and article writing and review. R.F. contributed to study design, data analysis, and review and revision of the article. F.B. performed the research and contributed to data analysis and article writing and review. M.D.E. contributed to data analysis and review and revision of the article. A.C.B. contributed to data analysis and review and revision of the article.

Footnotes

Acknowledgments

The authors would like to thank Natasha Wadlington, PhD, and Heather Fitzgerald, PharmD, at SB Pharma Solutions, LLC, for editorial assistance.

Funding Information

This study was sponsored by Xeris Pharmaceuticals, Inc., Chicago, IL, USA.

Author Disclosure Statement

V.C., R.H., D.R., and R.F. are employees of the study sponsor. F.B. has received research support from Xeris Pharmaceuticals and served as the principal investigator for the study. M.D.E. and A.C.B. are consultants to Xeris Pharmaceuticals but did not receive honoraria for the work presented here or for preparing this article. A.C.B. is a consultant for AbbVie, Acella, Synthonics.

Supplemental Material

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