Introduction

ABP 654 is a biosimilar to ustekinumab reference product that is supplied in a prefilled syringe (PFS). The ABP 654 autoinjector (AI) is in development as a single-use, disposable, handheld, latex-free, mechanical injection device that aims to offer additional convenience for patients and healthcare professionals.

Aims & Methods

This clinical study was designed to evaluate the comparability, based on exposure (maximum observed serum concentration [C_max] and area under the serum concentration-time curve from time 0 extrapolated to infinity [AUC_inf]), of ABP 654 after a single subcutaneous (SC) injection delivered by PFS or AI in healthy male and female adults. The study also assessed additional pharmacokinetics (PK) parameters, safety, tolerability, and immunogenicity.
A total of 156 subjects (78 subjects in the PFS group and 78 subjects in the AI group) were randomized in a 1:1 ratio to receive a single 90 mg SC injection of ABP 654 administered either via PFS or AI. Serum concentrations of ABP 654 were determined using a validated electrochemiluminescent assay. PK variables were calculated from the serum concentration data using noncompartmental methods and actual sampling times. Blood samples for antidrug antibody (ADA) assessments were collected at various times. Samples testing positive for binding ADAs were also tested for neutralizing ADAs. Adverse events (AEs) were graded by severity according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Results

Mean (± SD) serum ABP 654 concentration-time profiles show a high degree of similarity between the PFS and AI groups with overlapping profiles over the course of the study. PK comparability was established between the PFS and AI groups based on the 90% CIs of the geometric mean ratios (GMR) for the primary PK endpoints of AUC_inf and C_max being contained within the prespecified margin of 0.8 to 1.25. Exposure was comparable between the 2 groups. Peak concentrations were observed on average about 8 days following injection. After achieving peak ABP 654 concentrations, levels declined in a monophasic manner with a t_1/2 of about 23 days. The estimated t_1/2 was comparable for both groups. The mean percentage of AUC_inf due to extrapolation from the last quantifiable concentration observed to infinity (AUC%Extrap) was 5.13% and 4.53% for the PFS and AI groups, respectively, confirming the adequacy of the duration of PK sampling for the evaluation of AUC_inf. The frequency, type, and severity of AEs were comparable between the groups and consistent with the safety profile of ustekinumab. Through the end of the study, 10 (12.8%) subjects in the PFS group and 16 (20.5%) subjects in the AI group tested positive for the development of binding ADAs. This numerical difference is not considered clinically impactful, based on demonstrated PK comparability and similarity of safety profiles between treatment arms.

Table 1. Summary of ABP 654 PFS and ABP 654 AI PK Parameters

Conclusion

PK comparability was established between the PFS and AI groups. Both treatments were safe and well-tolerated. Overall, the results support conclusions of PK comparability and similar safety and immunogenicity profiles between ABP 654 administered via PFS and AI.

Disclosure

V. Chow, D. Mytych, J. Cao, C. Barragan, W. Radziszewski and J. Franklin are Amgen employees and shareholders. P. Winkle has no conflicts.

Introduction

Mirikizumab (miri), a humanized IgG4 monoclonal antibody that selectively binds to interleukin-23 subunit p19, is approved for the treatment of moderately to severely active ulcerative colitis and Crohn’s disease. In ulcerative colitis, maintenance treatment with 200 mg miri given as two 1-mL subcutaneous (SC) injections every 4 weeks was efficacious and safe in the phase 3 maintenance LUCENT-2 and long-term extension LUCENT-3 trials. As SC injections can be associated with pain/discomfort and thus poor patient experience, an investigational 2-mL single injection delivering the same miri dose has been developed.

Aims & Methods

This phase 1 study (NCT06475729) aimed to assess the pharmacokinetic (PK) bioequivalence and safety of miri solution administered as one 2-ml injection compared with the commercially available two 1-ml injections. Healthy participants were stratified into weight categories (<75 kg, 75–85 kg, and >85 kg) and randomized (1:1) to receive one dose of 200 mg of SC citrate-free miri as either one (200 mg/2 mL) or two injections (each of 100 mg/1 mL) delivered by an autoinjector. Participants were sub-randomized (1:1:1) by injection site (arm, thigh, and abdomen). Blood samples were collected at pre-defined intervals up to 10 weeks post-dosing. The primary endpoint was PK, assessed by the maximum observed concentration (C_max), area under the concentration–time curve (AUC) from time zero to infinity (AUC_0–∞), and AUC from time zero to the last timepoint with measurable concentration (AUC_0–t). PK parameters were estimated using non-compartmental analysis. The secondary endpoint was safety, assessed by the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) among participants exposed to miri. Evaluating the impact of injection site location on PK was an exploratory endpoint.

Results

A total of 244 participants (mean age: 42.4 years; 55.3% female) received one 200 mg/2 ml injection and 240 (mean age: 42.7 years; 53.3% male) received two 100 mg/1 ml injections. Baseline characteristics were similar in both groups. The three primary PK parameters all fell within the bioequivalence range (geometric least-squares mean [GM] ratio: 0.800–1.250; see table). Results were generally consistent across injection site locations with no significant differences between them. TEAEs were reported in 48 participants with one injection (19.7%) and 55 with two injections (22.9%). Most TEAEs were mild (62/74 events with one injection [83.8%] vs 85/100 with two injections [85.0%]). Injection-site reactions occurred in 5/244 [2.0%] of participants with one injection and 4/240 [1.7%] with two injections. No SAEs were reported in either group.

Conclusion

Miri 200 mg administered as one 2-ml SC injection was bioequivalent to two 1-ml injections, and most TEAEs were mild. In clinical practice, reducing the number of injections may improve patient experience and treatment adherence.

Disclosure

YO, CDP, AUK, KT, PP, XZ: Employees and shareholders of Eli Lilly and Company.
EVL Jr: Consulted for Abivax, AbbVie, Astellas, Avalo, Biocon, Bristol-Myers Squibb, Celltrion, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Janssen, Merck, Morphic, Ono Pharma, Takeda, and TR1X Bio; received research support from AbbVie, Genentech, Gilead, Janssen, Merck, and Takeda; shareholder of Exact Sciences and Moderna.
GDH: Adviser and/or speaker for Abbvie, Alimentiv, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx.
SBH: Received advisory board and/or consulting fees from Abbvie, Takeda, Janssen, Celltrion, Pfizer, GSK, Ferring, Novartis, Roche, Gilead, NeoPharm, Predicta Med, Galmed, Medial Earlysign, and Eli Lilly; stocks/options in Galmed, Evinature, PredictaMed and Alma Therapeutics; and research support from Abbvie, Takeda, Janssen, Celltrion, Pfizer, Medtronic & Galmed.

Introduction

Ustekinumab is a recombinant human monoclonal IgG1 antibody targeting the interleukins IL-12 and IL-23. Ustekinumab is approved for treatment of moderately to severely active inflammatory bowel disorders, i.e. Crohn’s disease and ulcerative colitis, besides its approved use in moderate-to-severe plaque psoriasis and active psoriatic arthritis. The presented study provides the basis for the marketing authorisation of the proposed ustekinumab biosimilar FYB202, together with an extensive analytical characterisation and the results of an efficacy and safety trial in patients with moderate-to-severe plaque psoriasis.

Aims & Methods

The primary objective of the three-arm trial RUSTIC was A) to prove pharmacokinetic (PK) similarity in terms of AUC_0-inf and C_max of the proposed ustekinumab biosimilar FYB202 to both EU-approved (EU-Ref) and US-licensed ustekinumab (US-Ref) and B) to prove PK similarity of both reference drugs. PK similarity was concluded if the 90% confidence interval (CI) of the geometric mean ratios was contained within the acceptance interval of 80.00–125.00% (analysis of covariance [ANCOVA] with body weight as covariate). Treatments included a single 45-mg subcutaneous injection. The multi-centric clinical trial was conducted at four German trial sites. Safety analyses comprised immunogenicity (anti-drug antibodies [ADAs] and neutralising antibodies [NAbs]), adverse events (AEs), vital signs, body temperature, 12-lead electrocardiograms, and local tolerability (subject- and investigator-assessed). Healthy male and female subjects (18–55 years, body weight 60–90 kg, body-mass index 20.5–30.0 kg/m²) were included in the trial and observed for up to 112 days after dosing.

Results

Overall, 491 subjects were randomised (FYB202: n=164, EU-Ref: n=163, US-Ref: n=164); 486 subjects completed the trial, and 478 subjects were included in the PK analysis set. PK similarity was demonstrated for all three comparisons: all 90% CIs of the respective geometric mean ratios for AUC_0-inf and C_max were contained within the acceptance interval of 80.00–125.00% (Table 1). After administration of FYB202, fewer subjects had at least one positive ADA result at trial end compared to the reference groups (FYB202: 20%, EU-Ref: 42%, US-Ref: 51%). ADA titre levels were similar between all three groups. The percentage of subjects with at least one positive NAb-reactive result at trial end was slightly lower in the FYB202 group compared to the reference groups (FYB202: 11%, EU-Ref: 15%, US-Ref: 18%). More than half of the subjects had at least one treatment-related AE (FYB202: 53%, EU-Ref: 55%, US-Ref: 57%); no treatment-related serious AEs occurred. Local tolerability at the injection site was comparable in all treatment groups.

Table 1: Point estimates and 90% confidence intervals [%] for the primary pharmacokinetic parameters of ustekinumab (PK analysis set; N=478)

Conclusion

The RUSTIC trial demonstrated bioequivalent PK characteristics between FYB202 and both EU-approved and US-licensed ustekinumab and for the two reference drugs. No clinically meaningful differences with respect to the overall safety, immunogenicity and local tolerability were observed.

Disclosure

The trial is registered in the EU Clinical Trials Register (EudraCT no. 2022-000832-43).

The clinical trial was financed by Formycon AG, Martinsried, Germany and conducted by SocraTec R&D GmbH, Oberursel/Erfurt, Germany (data management: SocraMetrics GmbH, Erfurt, Germany). During conduct of the trial and preparation of the abstract, S.B. and K.N. were employees of Formycon AG. J.K. and M.A. were employees of SocraTec R&D GmbH. R-S.W. was an employee of SocraMetrics GmbH. B.S. was cofounder and managing director of SocraTec R&D GmbH and SocraMetrics GmbH.

Introduction

Cobitolimod (MW 5925.18 Da) is a DNA-based oligonucleotide functioning as an immunomodulatory Toll-like receptor 9 agonist. Cobitolimod is in phase III clinical development as a new therapy for moderate to severe left-sided ulcerative colitis (UC). This phase Ib study aimed to evaluate the pharmacokinetics (PK), safety and tolerability of rectally administered cobitolimod in patients with moderate to severe UC.

Aims & Methods

The phase Ib open-label study was conducted at a single center in Sweden (NCT05404074). The patients had moderate to severe UC defined by a 3-component Mayo score of 5 to 9, with an Investigator read endoscopic subscore ≥2, and with stool frequency and rectal bleeding subscores each ≥1. Patients received one cobitolimod enema (500 mg/50 ml) at week 0, and blood samples for PK analysis were collected pre-dose, 15 min, 30 min, 1h, 2h, 4h, 8h, 12h and 24h after dosing. Patients received a second cobitolimod enema (500 mg/50 ml) at week 3, and at week 6 the degree of clinical remission was evaluated. Clinical remission was defined by the 3-component Mayo score with a rectal bleeding subscore = 0, a stool frequency subscore ≤1 (≥1 point decrease from baseline), and an Investigator read endoscopic subscore ≤1. Patients in clinical remission at week 6 received a third cobitolimod enema (500 mg/50 ml), and blood samples were collected for a second PK analysis as described above. The primary endpoint was PK parameters: maximum plasma concentration (C_max), time to C_max (T_max), area under the curve from 0 to timepoint t (AUC_t) and half-life (T_1/2). Secondary endpoints included safety and tolerability.

Results

Eight patients with active disease were enrolled in the study and included in the safety analysis set. One patient was excluded from the pharmacokinetic analysis set (PKAS) due to an immediate bowel movement following administration. Of the 7 patients included in the PKAS, 4 patients achieved clinical remission at week 6. Rectal administration of 500 mg cobitolimod at week 0 resulted in median C_max of 21.7 ng/ml, median T_max of 1h, median T_last of 4h, and median AUC_0-last of 71.7 h*ng/ml (n=7). For the 4 patients in remission at week 6, corresponding numbers were: median C_max of 15.5 ng/ml, median T_max of 0.5h, median T_last of 4h and median AUC_0-last of 27.6 h*ng/ml. T_1/2 was <2.5h both at week 0 and week 6.
In total, 24 adverse events occurred in the study, out of which the majority was mild and judged as unlikely related to study drug. No serious adverse events were reported.

Table 1. PK parameters per patient

Conclusion

The study demonstrates that rectally administered cobitolimod results in a low systemic exposure of short duration both in patients with active disease and in clinical remission. Cobitolimod was safe and well tolerated at a dose of 500 mg.

Disclosure

Thomas Knittel is a consultant for and a shareholder in InDex Pharmaceuticals, Sweden. Pernilla Sandwall is a former employee and a shareholder in InDex Pharmaceuticals, Sweden. Christine Dieterich Johansson is employed by InDex Pharmaceuticals, Sweden. Arezou Zargari is employed by and a shareholder in InDex Pharmaceuticals, Sweden. Johan Bring is a consultant for InDex Pharmaceuticals, Sweden. Per Hellström receives consultancy fees from: Clinical trial consultants, Sweden; ROSE pharma, USA; Pharmanovia, Denmark; Swedish Agricultural University, Uppsala; Pharmacosmos, Denmark; Stockholm Diabetes Association, Sweden; Celltrion, Finland; Mag-tarmförbundet, Sweden; Karolinska Institutet, Sweden; Bristol-Myers Squibb, Sweden; ClinSmart, Sweden; InDex Pharmaceuticals, Sweden; Takeda pharmaceutical company; Mediahuset, Sweden; Bonnier Healthcare Sweden; Folkuniversitetet, Stockholm, Sweden; Biogaia, Stockholm, Sweden; Norgine, Denmark; Nanologica AB, Södertälje, Sweden.

Introduction

Risankizumab (RZB) is a high-affinity humanised immunoglobulin (Ig) G1 monoclonal antibody that selectively binds to the p19 subunit of the interleukin-23 (IL-23) cytokine and inhibits its interaction with the IL-23 receptor.^1,2 Long-term RZB therapy for 3 years of maintenance showed durable efficacy and a well-tolerated safety profile in patients with ulcerative colitis (UC) in the COMMAND open-label extension (OLE) study.^1,3 This post hoc analysis evaluated the long-term efficacy of RZB in improving patient-reported outcomes through week (wk) 96 of the ongoing COMMAND OLE study.

Aims & Methods

COMMAND OLE is a 220-wk study enrolling patients who completed 52-wks maintenance dosing or enrolled directly as responders to induction.^1,3 This analysis included patients who completed 52 wks maintenance and an additional 96 wks of RZB treatment in the OLE. All patients received subcutaneous (SC) RZB180 Q8w starting at OLE wk 0, except patients who had prior rescue therapy (single RZB 1200 mg intravenous dose, then SC RZB360 Q8w) who continued RZB360 in the OLE. The OLE study was not designed to compare RZB180 and RZB360 groups. The data cut-off date for this interim analysis was 30 June 2024. Efficacy outcomes included the percentage of patients who achieved the absence of abdominal pain, bowel urgency, faecal incontinence, nocturnal bowel movements, tenesmus, sleep disruption due to UC symptoms; Inflammatory Bowel Disease Questionnaire (IBDQ) response; a meaningful within-person change (MWPC) in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, Short-Form Health Survey-36 version 2 Mental Component Score (SF-36v2 MCS), and SF-36v2 Physical Component Score (PCS). Results were reported using as-observed (AO; Table) and nonresponder imputation (NRI) methods (Table). Safety was reported previously.³

Results

Of the 1003 patients (RZB180 = 701; RZB360 = 302) who entered the OLE, 398 (39.7%) patients (RZB180 = 262; RZB360 = 136) completed wk 96 at data cut-off date. In the AO analysis, RZB180- or RZB360-treated patients showed sustained improvements from OLE wks 0 to 96 in the absence of abdominal pain, bowel urgency, nocturnal bowel movements, tenesmus, faecal incontinence, sleep disruption due to UC symptoms, IBDQ response, MWPC in FACIT-Fatigue, SF-36 PCSv2, and SF-36v2 MCS (Table). Using the more conservative NRI analysis, similar results were observed for most endpoints through OLE wk 96 (Table). Despite RZB360-treated patients were more likely to have numerically higher clinical and endoscopic activity at OLE wk 0 compared with RZB180-treated patients (Adapted Mayo Score [AMS], mean [standard deviation], RZB180, 2.0 [1.4]; RZB360, 3.5 [2.0]; endoscopic subscore: RZB180, 1.1 [1.0]; RZB360, 1.9 [1.0]; clinical remission per AMS, RZB180, 54.8%; RZB360, 24.8%), at OLE wk 96, both RZB dosing regimens exhibited consistent and similar sustained improvements throughout all investigated patient-reported outcomes.

Conclusion

RZB-treated patients who completed OLE wk 96 (3 years of total maintenance therapy) experienced sustained improvement in quality of life and patient-reported outcomes.

References

1. Louis E, et al. JAMA. 2024; 332:881-97.
2. Singh S, et al. mAbs. 2015;7:778-91.
3. Atreya R, et al. J Crohn’s Colitis. 2025;19(S1):i108-i110 [Abstract].

Disclosure

Funding: AbbVie funded this study (COMMAND; NCT03398135) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Acknowledgments: AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Paulette A. Krishack, PhD, of AbbVie, provided medical writing support; S. Michael Austin, of AbbVie, provided editorial support.
Disclosures: Luc Biedermann has received lecture and consulting fees from Takeda, Sanofi, AbbVie, Falk, Bristol Myer Squibb, and Pfizer and is on advisory boards for AbbVie, Amgen, Bristol Myers Squibb, Falk, Janssen, Pfizer, Takeda, and Sanofi.
Julian Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman, and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.
Silvio Danese has received consultancy fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Enthera, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, Lilly, Merck Sharp and Dohme, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB and Vifor.
Satoshi Tanida received speaker fees from JIMRO, Mitsubishi Tanabe Pharma, AbbVie, Janssen, Kissei, writing fees from Pfizer, and research funding from AbbVie.
Parambir S. Dulai received research support and/or consulting for AbbVie, Abivax, Adiso, Alimentiv, Bristol Meyer Squibb, Celltrion, Genentech/Roche, Geneoscopy, Janssen, Pfizer, Takeda.
Nidhi Shukla, Jasmina Kalabic, Pierre Morisset, Cecile Holweg, and Dolly Sharma, are employees of AbbVie and may own stock options.
Joana Torres has received grant funding/speaker fees from and/or has participated in advisory boards for AbbVie, Galapagos, Janssen, and Pfizer.