FormalPara Key Summary Points

Why carry out this study?

The number of subcutaneous injections may affect treatment adherence and the overall patient experience.

Mirikizumab maintenance therapy for ulcerative colitis is administered with two 1-ml subcutaneous injections, but an investigational 2-ml single injection delivering the same mirikizumab dose has been developed.

This study assessed the pharmacokinetic and safety comparability between both administrations in healthy adults.

What was learned from the study?

Subcutaneous administration of citrate-free 200 mg mirikizumab via one 2-ml injection was bioequivalent to administration via two 1-ml injections.

Both administrations had similar safety profiles, and most reported treatment-emergent adverse events were mild.

Introduction

Mirikizumab is a monoclonal antibody directed against the p19 subunit of interleukin-23 approved for adults with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD) [1, 2]. In UC, maintenance treatment with mirikizumab administered as two 1-ml (total 200 mg) subcutaneous (SC) injections every 4 weeks was efficacious and safe in the phase 3 LUCENT-2 trial [3]. Furthermore, the long-term open-label study LUCENT-3 demonstrated the efficacy and safety of SC mirikizumab maintenance up to 152 weeks of treatment [4, 5].

SC injections are widely used to administer drugs owing to their favorable bioavailability [6]. However, SC administration of biologic therapies is linked to treatment-related anxiety and lower treatment adherence in patients with chronic conditions including inflammatory bowel disease [7]. Specifically, SC injections can be associated with injection site reactions (ISRs) and local pain and discomfort [6, 8]. For instance, in the LUCENT-2 and LUCENT-3 trials, 5.6–8.7% of participants experienced ISRs, and 2.9–4.4% reported injection site pain [3,4,5]. Both ISRs and pain can affect treatment adherence [9], although results from an integrated safety analysis of the LUCENT trials suggest that ISR frequency tends to decrease over time [10]. Patients’ perception of pain can further compromise adherence to therapies that may be self-administered [11, 12].

Pain associated with SC injections can be influenced by several factors, notably formulation excipients and pH [13] but also others such as injection site location, injection speed, and needle features [6, 8, 9]. Reducing the number of injections by increasing injection volume might reduce the burden on patients and improve treatment adherence in clinical practice; single 2-ml SC injections have become increasingly common for delivering antibody therapies [9]. However, changing injection volumes may affect pharmacokinetics (PK) and aspects related to local safety including ISRs [9].

This phase 1 study (NCT06475729) aimed to assess the PK bioequivalence (primary objective) and safety (secondary objective) of mirikizumab administered as an investigational one 2-ml SC injection compared with the commercially available administration (two 1-ml SC injections). Additionally, the study aimed to explore potential PK differences between injection site locations.

Methods

Study Design

NCT06475729 was a phase 1, open-label, two-arm, parallel-design, and single-dose study conducted in the USA. Healthy participants 18–65 years of age and with a body mass index of 18.0–34 kg/m2 were eligible. Exclusion criteria included (a) significant allergies to humanized monoclonal antibodies or mirikizumab, (b) prior or concomitant anti-interleukin-12 p40 or anti-interleukin-23 p19 antibody therapy, (c) current enrollment in an incompatible clinical study or prior study participation within the last 30 days or five half-lives, whichever is longer, increasing to 3 months or five half-lives for biologic agents, and (d) other relevant exclusions, such as pregnancy.

As a result of the impact of body weight on the PK of mirikizumab [14, 15], participants were stratified by weight category (< 75 kg, 75–85 kg, and > 85 kg, based on their weight on the day before the first study day) and randomized (1:1) to receive citrate-free 200 mg SC mirikizumab as either two 1-ml injections (each 100 mg) or one 2-ml (200 mg) injection, delivered via an autoinjector once on the first study day. Adjustment of dosage based on body weight was not performed [14, 15]. Participants in each arm were sub-randomized (1:1:1) by injection site location (arm, abdomen, or thigh). After receiving one full dose of mirikizumab, participants completed 4-h safety assessments. Subsequent blood sampling and safety assessments were conducted at predefined times up to 10 weeks post dose (see Fig. 1 for further detail).

Fig. 1
figure 1

Mirikizumab dosing and PK sampling. ED early discontinuation, P predose, PK pharmacokinetics

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The 1-ml autoinjector used the same design as Emgality (galcanezumab) prefilled pen [16], and the 2-ml autoinjector used the same design as Ebglyss (lebrikizumab) prefilled pen [17]. Both autoinjectors used in this study share the same design principles and common characteristics in needle gauge (27G) and needle insertion depth (approx. 5.5 mm). Injection rates were 27 ml/min for the 1-ml autoinjector and 36 ml/min for the 2-ml autoinjector.

Ethical Approval

The study was conducted in accordance with principles derived from the Declaration of Helsinki, the Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Council on Harmonisation guidelines and with applicable laws and regulations. The study protocol and the consent forms used were approved by the Salus Institutional Review Board, which covered the ethical approval from each site related to this study (I6T-MC-AMCB). Participants provided written informed consent before they entered the study. The informed consent forms outlined why the research was being done and what it would involve, and it noted that study data that did not directly identify participants could be published.

Pharmacokinetics

The PK analysis set comprised all participants who received a full dose of mirikizumab and had evaluable PK data. Mirikizumab serum concentrations were assessed with a validated enzyme-linked immunosorbent assay using samples collected during the study (Fig. 1). The assay range defining the quantifiable concentrations was 100–10,000 ng/ml.

The primary PK parameters were maximum observed concentration (Cmax), area under the concentration versus time curve from time zero to infinity (AUC0–∞), and area under the concentration versus time curve from zero to the last timepoint with a measurable concentration (AUC0–t). Calculating AUC0–∞ and AUC0–t required three consecutive concentrations above the lower limit of quantification, with at least one concentration following Cmax. The study was not powered for direct comparisons by injection site location, so assessment of the different injection site locations was only intended to explore potential differences.

The secondary PK parameter was the time of maximum observed concentration (tmax). The tmax of mirikizumab was compared between the two administrations by Wilcoxon rank-sum test. If Cmax occurred at more than one time point, tmax was assigned to the first occurrence of Cmax. The half-life associated with the terminal rate constant in a noncompartmental analysis was estimated.

PK parameters were determined from serum concentrations with noncompartmental analysis using Phoenix WinNonlin Version 8.3.5 (Certara, Radnor, PA, USA).

Safety

The safety analysis set comprised all participants who received mirikizumab. Safety assessments included laboratory parameters, vital signs, adverse events (AEs), physical examination, electrocardiogram, and hepatic monitoring. AEs were recorded up to day 71 or early discontinuation (if applicable).

Key safety endpoints were treatment-related adverse events (TEAEs) and serious adverse events (SAEs). TEAEs were defined as adverse events that either occurred post dose or started prior to dosing but for which severity worsened post dose. TEAEs were summarized on the basis of their relationship with mirikizumab, by preferred term using Medical Dictionary for Regulatory Activities (MedDRA) Version 27.1, and by severity. For events that changed in severity, the worst severity was recorded. SAEs were defined as any untoward medical occurrences that, at any dose, met one or more of the following criteria: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or resulted in medical or surgical intervention to prevent life-threatening illness or injury or permanent impairment to a body structure or a body function; other events not included in the above list were reported as SAEs based on medical/scientific judgement. Additionally, spontaneously reported ISRs were recorded. When injection site pain was reported, its intensity was quantified using the 100-mm validated pain visual analog score (VAS), where participants visually rate their pain on a 100-mm line anchored by verbal descriptors (“no pain” and “worst imaginable pain”) [18]. Categories were defined as mild (VAS 0–30 mm), moderate (VAS > 30–70 mm), or severe (VAS 70–100 mm). ISR assessments were conducted at the next planned visit following event reporting.

Statistical Analysis

For continuous data, summary statistics included mean and standard deviation (SD). For categorical data, frequency counts were presented. SAS® Version 9.4 (SAS Institute Inc., Cary, NC, US) was used for statistical analyses.

Cmax, AUC0–∞, and AUC0–t were log-transformed and analyzed using a linear fixed effects model. The model included administration (two 1-ml or one 2-ml injections), injection site location, and weight category stratification as fixed effects. Least-squares mean (LSM) differences between administrations across all locations were back-transformed to calculate the ratios of geometric LSMs and the corresponding 90% confidence intervals (CIs). Bioequivalence was defined by the 90% CI of the ratio of geometric LSMs being entirely contained within the interval 0.800–1.250 (range recommended in FDA guidance [19]).

Results

Participants

A total of 484 participants received a complete dose of mirikizumab (N = 240 received two 1-ml injections and N = 244 received one 2-ml injection) (Fig. S1). Mean participant age was 42.5 (SD 12.1) years. Around half (51.0%) of the participants were female and most (72.5%) were White. Demographics were similar between both study groups. Approximately one-third of participants were administered mirikizumab in each of the possible injection site locations (Table 1).

Table 1 Baseline demographics
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Pharmacokinetics

The mean serum concentration versus time profiles of mirikizumab were similar between two 1-ml and one 2-ml injections (Fig. 2). The calculated Cmax, AUC0–∞, and AUC0–t were similar with two 1-ml and one 2-ml injections (Table 2). The geometric LSM ratios (90% CI) were within the prespecified equivalence limits of 0.800 and 1.250, demonstrating bioequivalence between administrations (Cmax 1.039 [0.9853, 1.0956] µg/ml; AUC0–∞ 1.011 [0.9564, 1.0685] µg·day/ml; AUC0–t 1.011 [0.9568, 1.0678] µg·day/ml).

Fig. 2
figure 2

Mean serum concentration profiles of mirikizumab. aBoth groups received citrate-free 200 mg SC mirikizumab. Data shown as mean with two-sided SD in linear scale (a) and semi-logarithmic scale (b). SC subcutaneous, SD standard deviation

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Table 2 Summary of the pharmacokinetic parameters of mirikizumab
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The difference in tmax between administrations was not statistically significant (p = 0.1532; Table 3). Serum concentrations of mirikizumab declined after tmax, with a geometric mean half-life of 10.5 days for the two 1-ml injection group and 10.2 days for the one 2-ml injection group.

Table 3 Summary of the tmax of mirikizumab
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The geometric LSMs for Cmax, AUC0–∞, AUC0–t, and tmax were similar between the two 1-ml and one 2-ml injection groups when each injection site location was analyzed separately (Tables S1–S2). For all injection site locations, the 90% CIs of the ratios of geometric LSM were contained within the equivalence limits. Analysis of the four parameters by injection site location showed comparable values between the two 1-ml and one 2-ml injection groups (Figs. S2–S5).

Safety

The proportion of participants with TEAEs was similar between the two 1-ml and one 2-ml injection groups. A total of 55 participants receiving two 1-ml (22.9%) and 48 receiving a one 2-ml injection (19.7%) reported TEAEs. TEAEs that were considered related to mirikizumab were experienced by 15 participants receiving two 1-ml (6.2%) and 22 receiving one 2-ml injection (9.0%). The most frequent treatment-related TEAEs were headache and ISR, each reported in nine participants (1.9%). Most TEAEs were mild in severity across both administrations. However, three events (3/100 TEAEs [3.0%]) reported in the two 1-ml group were considered severe: hyperkalemia (n = 2) and alanine aminotransferase increased (n = 1). The two events of severe hyperkalemia were reported in the same participant; in the first event, potassium levels increased by 1.3 times the upper limit of normal on day 29 post-dose and resolved after 22 days, and in the second event, potassium levels increased by 1.2 times the upper limit of normal on day 70 post-dose and resolved after 14 days. The severe event of alanine aminotransferase increased was reported in a participant on day 15 and resolved after approximately 40 days and 22 h. No TEAEs were reported as related to the study device, no participants discontinued the study because of AEs after receiving mirikizumab, and no deaths or other SAEs occurred during the study (Table 4). TEAEs reported in ≥ 3 participants are listed in Table S3.

Table 4 Summary of TEAEs (safety analysis set)
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The proportion of participants with ISRs observed after mirikizumab administration was similar between administrations: four participants (1.7%) with two 1-ml injections and five participants (2.0%) with one 2-ml injection (Table 5). With two 1-ml injections, ISRs were reported by two participants each at the thigh and abdomen; no ISRs were reported at the arm injection site. With one 2-ml injection, ISRs were reported by two participants each at the arm and thigh and by one participant at the abdomen injection site.

Table 5 Summary of ISRs (safety analysis set)
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Almost half (45.5% [5/11]) of ISRs were reported within the first 24 h of mirikizumab administration, with another 45.5% reported between 24 h and 4 days after administration and 9.1% (one ISR) after > 4 days. With two 1-ml injections, two ISRs (33.3%) were reported within 1 h, and the remaining four (66.7%) were reported between 24 h and 4 days. With one 2-ml injection, two ISRs (40.0%) were reported between 1 and 6 h, with the remaining three (60.0%) reported after 6 h (Table 5).

The most frequently reported ISR with two 1-ml injections was erythema (3/6 [50.0%] ISRs). With one 2-ml injection, it was edema (2/5 [40.0%] ISRs). Overall, only edema ISRs (2/11 [18.2%]) were categorized as severe (> 5 mm); the two events that occurred were both reported by participants in the one 2-ml injection group who received an injection in the thigh (Table S4).

One participant in each treatment group reported pain after mirikizumab administration. One participant who received two 1-ml injections in the thigh recorded a mean VAS pain score of 5.0 and a score category of mild pain, and one participant who received one 2-ml injection in the abdomen recorded a mean VAS pain score of 63.0 and a score category of moderate pain (Table S5).

Discussion

Mirikizumab has demonstrated efficacy and safety in UC [3,4,5, 10] and CD [20]. Mirikizumab maintenance therapy is currently approved for SC administration via either two consecutive 100 mg/ml injections (UC) or two consecutive injections of 100 mg/ml and 200 mg/2 ml in any order (CD) [1]. Although reducing the number of required injections by increasing injection volume might be beneficial for treatment adherence, injection volume may affect PK and safety (including ISRs) [9]. Therefore, this study assessed these aspects for an investigational one 2-ml single injection of mirikizumab compared with the standard two 1-ml injections.

This study demonstrates bioequivalence between the two 1-ml and one 2-ml SC injections of mirikizumab. The 90% CIs for all comparisons were fully within the range of 0.800–1.250. Results of the exploratory analyses by injection site location also showed that comparisons between two 1-ml and one 2-ml SC injections were within the bioequivalence limits for each injection site location. Similar results have been observed in PK studies of other monoclonal antibody therapies, such as risankizumab, lebrikizumab, and secukinumab, which have demonstrated bioequivalence between one and two injections as well as between administration devices (prefilled syringes and autoinjectors) [21,22,23].

Fewer than 25% of participants had TEAEs, and most reported TEAEs were mild in severity. The frequencies of TEAEs were similar between the two 1-ml and one 2-ml mirikizumab injections. The two most common TEAEs were headache and ISRs, which were also among the most frequent AEs in previous LUCENT studies of UC [3,4,5, 10]. Local tissue effects may be exacerbated with larger-volume injections [24]. However, the rates of reported ISR were low (approximately 2% of participants) and were similar between the two 1-ml and one 2-ml mirikizumab injections. ISRs included pain in one participant receiving two 1-ml injections and another receiving one 2-ml mirikizumab injection. These patients reported mild to moderate pain, and there were no reports of severe pain with either administration.

Overall, this study adds to the existing evidence suggesting that an SC injection can deliver volumes larger than 1 ml without safety/tolerability concerns [6]. ISRs, including local pain/discomfort associated with SC injections, can affect treatment adherence [6, 8, 9]. However, our findings suggest that the frequency of ISRs does not increase when using a one 2-ml injection, so treatment adherence is unlikely to be affected.

This study used the same formulation (citrate-free mirikizumab) and administration device (autoinjectors of same design principles) for both administrations, which enables a clear comparison of volume/injection number effect. Further, a study population comprising healthy participants may reduce potential confounding factors, such as concomitant medications or disease-related pain. In addition, injections were administered by trained personnel, further avoiding potential confounding. The study followed a parallel-group design to account for the typically long half-lives of monoclonal antibodies and to avoid the potential immunogenicity that a crossover design may trigger. Serum samples were collected for over 10 weeks (71 days) after mirikizumab administration, which also accounts for the drug’s estimated half-life of approximately 10 days [14]. Finally, participants were stratified by body weight to account for the fact that weight is known to affect the PK of mirikizumab [14].

However, some study limitations exist. The use of healthy participants and healthcare professional administration might reflect real-world administration conditions less accurately than the use of patients and self-injection. For instance, safety findings with a single-dose administration (via either one or two injections) may differ from those with real-world administration, in which patients receive mirikizumab maintenance therapy every 4 weeks [1]. Further, results might not be generalizable to other populations. Mean VAS pain scores were not compared between administrations to assess the frequency of injection site pain, as this event was only reported by one participant in each treatment group. Finally, direct measurements of clinical efficacy could not be collected in this study of healthy participants; however, the equivalent PK demonstrated in this study suggests that both administrations are likely to have equivalent efficacy.

Conclusion

Administration of citrate-free 200 mg SC mirikizumab via one 2-ml injection was bioequivalent to administration via two 1-ml injections. No notable differences in safety profile were found between the two administrations, and most reported TEAEs were mild. These results encourage further clinical development of the SC single injection of citrate-free mirikizumab. In clinical practice, reducing the number of injections may prevent the risk of incomplete/partial dosing and thus improve treatment adherence.