Abstract
Background
DMB-3115 is a biosimilar to Stelara (hereinafter referred to as ustekinumab).
Objectives
To evaluate the clinical similarity of DMB-3115 with ustekinumab in patients with moderate-to-severe plaque psoriasis.
Methods
In this phase 3, randomized, double-blind, parallel-arm study, adults with moderate-to-severe plaque psoriasis were randomized to receive DMB-3115 or ustekinumab (weeks 0-28), followed by re-randomization to continue treatment or switch to DMB-3115 (weeks 28-52). The primary efficacy endpoints were percent change in Psoriasis Area and Severity Index score from baseline to week 8 and week 12. The safety endpoint was the incidence of adverse events.
Results
A total of 598 patients were randomized to receive DMB-3115 (n = 299) or ustekinumab (n = 299). The least squares mean percent changes in Psoriasis Area and Severity Index score from baseline to week 8 were 77.5% (DMB-3115) and 77.9% (ustekinumab), and from baseline to week 12 were 87.6% (DMB-3115) and 87.9% (ustekinumab). Rates of treatment-emergent adverse events were similar between treatments during period 1 (DMB-3115: 47.5%; ustekinumab: 49.8%) and period 2 (DMB-3115: 18.7%; ustekinumab: 21.2%; switched to DMB-3115: 18.3%).
Limitations
Data were only through week 52.
Conclusions
DMB-3115 showed a similar clinical efficacy and safety profile to ustekinumab in patients with moderate-to-severe plaque psoriasis.
Key words: biologics, biosimilar, psoriasis, randomized clinical trial, ustekinumab
Capsule Summary.
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•
Stelara (hereinafter referred to as ustekinumab) is a monoclonal antibody and interleukin-12 and interleukin-23 inhibitor that is indicated for the treatment of moderate-to-severe plaque psoriasis.
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DMB-3115, a biosimilar of ustekinumab, has similar clinical and safety profiles to ustekinumab for the treatment of moderate-to-severe plaque psoriasis.
Introduction
Psoriasis is an immune-mediated ski disease that affects 1% to 3% of people worldwide and has a considerable impact on a patient’s life.1,2 Ustekinumab is a monoclonal antibody that disrupts the proinflammatory pathway that contributes to several chronic diseases, including psoriasis.3 Stelara (hereinafter referred to as ustekinumab; Janssen Biotech, Inc.) received marketing authorization in the European Union4 and United States5 for the treatment of moderate-to-severe plaque psoriasis, active psoriatic arthritis, Crohn’s disease, and ulcerative colitis.
DMB-3115 (Imuldosa) is biosimilar to ustekinumab and received approval from the European Medicines Agency (EMA)3 and the US Food and Drug Administration (FDA)6 in 2024. Development of an ustekinumab biosimilar is expected to address unmet medical needs by improving access to well-established drugs while reducing health care costs and improving affordability.7 DMB-3115 and Stelara have an identical primary structure, and the active substance for both is ustekinumab.3 DMB-3115 has been extensively characterized and compared with ustekinumab, demonstrating similar safety, tolerability, and immunogenicity in healthy participants.7 The primary objective of the current study was to evaluate the clinical similarity and compare efficacy, safety, and immunogenicity of DMB-3115 with ustekinumab in patients with moderate-to-severe chronic plaque psoriasis.
Methods
Study design
This phase 3, randomized, double-blind, multicenter, parallel-arm, active-controlled study (Fig 1) was conducted at 84 sites in 9 countries: Bulgaria, Czech Republic, Estonia, Georgia, Hungary, Latvia, Poland, Ukraine, and US (ClinicalTrials.gov identifiers: NCT04785326, EudraCT Number: 2020-005108-21).
Fig 1.
Study design diagram. EMA, European Medicines Agency; PASI, Psoriasis Area and Severity Index; US FDA, United States Food and Drug Administration.
Patients
Eligible patients were adults (18-75 years) who had moderate-to-severe plaque psoriasis for ≥6 months prior to study treatment initiation. Moderate-to-severe plaque psoriasis was defined as a Psoriasis Area and Severity Index (PASI) score of ≥12, Physician’s Global Assessment (PGA) score of ≥3, and body surface area of ≥10% affected by plaque psoriasis. Patients were excluded if they had received any biological therapeutic agents for psoriasis within 90 days prior to screening, any monoclonal antibodies within 9 months prior to screening or with previous use of 2 or more biologics for treatment of psoriasis, or any biological therapeutic agents targeted at inhibiting interleukin (IL) cytokines IL-12, IL-23, IL-17, or integrin.
Interventions
Patients were randomized 1:1 to receive either DMB-3115 or ustekinumab. Randomization was stratified by body weight at baseline (≤100 kg or >100 kg), geographic region (European Union, US, or rest of world), and number of previous systemic therapies for psoriasis (<3 or ≥3). The study comprised 2 periods: patient randomization and treatment (period 1; weeks 0-28), and rerandomization following completion of period 1 (period 2; weeks 28-52). During period 1, patients received treatment at weeks 0, 4, and 16. Patients who did not achieve at least a 50% improvement from baseline in PASI score (PASI 50) response by week 12 were discontinued. Patients who achieved at least a 75% improvement from baseline in PASI score (PASI 75) response by week 28 were included in period 2. Patients who received DMB-3115 in period 1 were rerandomized to continue with DMB-3115, while patients who received ustekinumab were rerandomized (1:1) and restratified based on body weight at week 28 to continue ustekinumab or switch to DMB-3115. Doses at rerandomization were reassigned based on body weight at week 28 and administered every 12 weeks, up to week 40.
Outcome measures
The primary efficacy endpoints were the percent change in PASI score from baseline to week 8 in the per-protocol set (PPS; for EMA) and from baseline to week 12 in the intention-to-treat (ITT; for US FDA) set. The safety endpoint was the incidence of adverse events (AEs) and serious AEs, and all AEs were coded according to the Medical Dictionary for Regulatory Activities version 25.1.
Immunogenicity was assessed by the incidence of antidrug antibodies (ADA), binding and neutralizing. Serum pharmacokinetic (PK) parameters were estimated after the first dose (week 0) using the maximum observed serum concentration, time from dosing to maximum measured concentration, and area under the concentration-time curve from week 0 to week 4.
Subgroup analyses
The subgroup analyses of the primary efficacy endpoint were performed based on baseline body weight (≤100 kg or >100 kg), geographic region (European Union, US, or rest of world), and the number of previous systemic therapies for psoriasis (<3 or ≥3). Similar results were seen for all subgroups and treatment arms, and no statistically significant treatment difference was observed between the PPS and ITT set. There were no statistically significant treatment differences in the percent changes in the PASI scores from baseline to weeks 8 and 12 in PPS and ITT.
Sample size
The sample size required for the primary endpoint was calculated based on the following assumptions: two-sided alpha of 0.05 (for EMA) or 0.10 (for US FDA), power of 90%, the difference between ustekinumab and DMB-3115 is 0, and the standard deviation (SD) is 0.3. One-to-one (1:1) randomization rate of period 1 was assumed. Equivalence margins of 15% and 10% were recommended by the EMA and US FDA, respectively. The SD assumption was derived from the observed SD of the mean improvement in PASI score in studies PHOENIX 18 and PHOENIX 2.9 Sample size was calculated using the 2 one-sided t-tests procedure as implemented in the R package power 2 one-sided t-tests. The overall sample size was based on the larger sample size calculated through EMA and US FDA’s recommendation.
For primary efficacy analysis, the US FDA sample size of 490 patients in total, or 245 patients per treatment arm at baseline, was selected to achieve 392 evaluable patients to have a 90% confidence interval (CI) for the difference in primary endpoint to fall entirely within the 10% equivalence margin with more than 90% power. A dropout rate of 20% was assumed for weeks 0-28, and 15% for weeks 28-52. Considering the 1:1 rerandomization rate for the ustekinumab arm in weeks 28-52 and the minimum requirement of safety analysis by EMA (N = 100), a total of 590 patients (a minimum of 400 completed patients) would be necessary; thus, 590 patients (295 patients per treatment arm) were planned to be enrolled.
Statistical analysis
ITT was used for demographic data and other baseline characteristics. Continuous variables were summarized by the number of observations, mean, SD, median, minimum, and maximum. Categorical variables were summarized by frequency counts and percentages for each category. The safety set comprised patients who received at least 1 dose. The PK set comprised patients who received at least 1 dose, had at least 1 measured concentration at a scheduled postdose PK time point, and had no major protocol deviations/events.
For the EMA, 95% CI was used for differences in means using estimates from an adjusted analysis of covariance model, whereas for the US FDA, 90% CI was used. Missing values for primary efficacy variables were imputed by a multiple imputation method.
Secondary efficacy endpoints were analyzed in the ITT. Logistic regression analysis was used for endpoints based on proportions of patients with PASI score responses and PGA scores. The percentage change from baseline in area under the effect curve for PASI score and change from baseline in Dermatology Life Quality Index were analyzed using analysis of covariance.
Noncompartmental PK parameter calculations were performed using Phoenix WinNonlin version 8.3 (Certara L.P.). All other analyses were performed using SAS software, version 9.4 (SAS Institute Inc).
Ethics
The trial was conducted in accordance with Good Clinical Practice, as defined by the International Council for Harmonisation and Declaration of Helsinki. Independent institutional review board approvals were obtained. All participants provided written informed consent.
Results
Patients
The study was conducted between April 28, 2021 and November 17, 2022. Of 831 patients screened, 598 were randomized to receive DMB-3115 (n = 299) or ustekinumab (n = 299) during weeks 0-28 (Fig 2).
Fig 2.
Disposition of patients with moderate-to-severe plaque psoriasis through the study (ITT). AE, Adverse event; ITT, intention-to-treat; PASI, Psoriasis Area and Severity Index.
The ITT and safety sets for weeks 0-28 included all 598 patients. The PPS to week 8 and to week 12 included 523 (87.5%) and 514 (86.0%) patients, respectively, who had completed the study up to that point and had no critical/major protocol deviations. The ITT set for weeks 28-52 comprised 531 patients who completed weeks 0-28 and were rerandomized. One patient did not receive treatment. The remaining 530 patients received study treatment and were included in the safety set. After weeks 0-28, 268 patients were rerandomized to continue with DMB-3115, and 132 ustekinumab-treated patients were rerandomized to continue with ustekinumab while 131 were rerandomized and switched to DMB-3115. A total of 512 (96.4%) patients completed the study; 15 (2.8%) patients prematurely discontinued study treatment during weeks 28-52 and an overall total of 4 (0.8%) patients withdrew after completion of both study treatment periods.
Patient demographic and baseline characteristics were well matched between treatment arms (Table I); most patients were male and white, and the mean (SD) body surface area affected by plaque psoriasis was 28.1% (14.5).
Table I.
Baseline patient demographics and characteristics (intention-to-treat)
| Characteristic | DMB-3115 (N = 299) |
Ustekinumab (N = 299) |
Total (N = 598) |
|---|---|---|---|
| Age (y) | |||
| Mean (SD) | 45.4 (13.03) | 45.7 (13.46) | 45.6 (13.23) |
| Median (min, max) | 45.0 (19.0, 73.0) | 46.0 (18.0, 75.0) | 45.0 (18.0, 75.0) |
| Sex, n (%) | |||
| Male | 202 (67.6) | 212 (70.9) | 414 (69.2) |
| Female | 97 (32.4) | 87 (29.1) | 184 (30.8) |
| Ethnicity, n (%) | |||
| Hispanic or Latino | 1 (0.3) | 5 (1.7) | 6 (1.0) |
| Non-Hispanic or Latino | 297 (99.3) | 294 (98.3) | 591 (98.8) |
| Not reported | 0 | 0 | 0 |
| Unknown | 1 (0.3) | 0 | 1 (0.2) |
| Race, n (%) | |||
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 3 (1.0) | 0 | 3 (0.5) |
| Black or African American | 1 (0.3) | 0 | 1 (0.2) |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| White | 295 (98.7) | 298 (99.7) | 593 (99.2) |
| Not reported | 0 | 1 (0.3) | 1 (0.2) |
| Unknown | 0 | 0 | 0 |
| Height, cm | |||
| Mean (SD) | 173.66 (9.603) | 173.77 (9.724) | 173.71 (9.656) |
| Median (min, max) | 174.00 (150.5, 202.0) | 174.00 (147.3, 227.1) | 174.00 (147.3, 227.1) |
| Weight, kg | |||
| Mean (SD) | 88.70 (20.131) | 88.72 (19.143) | 88.71 (19.627) |
| Median (min, max) | 88.10 (48.0, 139.0) | 88.00 (44.5, 139.5) | 88.00 (44.5, 139.5) |
| Body mass index, kg/m2 | |||
| Mean (SD) | 29.32 (6.025) | 29.34 (5.790) | 29.33 (5.904) |
| Median (min, max) | 28.70 (18.4, 52.5) | 28.70 (16.7, 47.5) | 28.70 (16.7, 52.5) |
| Percentage of BSA affected by plaque psoriasis, % | |||
| Mean (SD) | 27.60 (14.066) | 28.63 (14.944) | 28.11 (14.509) |
| Median (min, max) | 23.80 (10.0, 84.6) | 24.80 (10.0, 95.0) | 24.30 (10.0, 95.0) |
| Duration of plaque psoriasis, y | |||
| Mean (SD) | 18.3 (12.71) | 17.4 (11.84) | 17.9 (12.28) |
| Median (min, max) | 16.0 (1.0, 59.0) | 15.0 (1.0, 57.0) | 15.5 (1.0, 59.0) |
| Baseline body weight, n (%) | |||
| ≤100 kg | 217 (72.6) | 216 (72.2) | 433 (72.4) |
| >100 kg | 82 (27.4) | 83 (27.8) | 165 (27.6) |
| Geographic regions, n (%) | |||
| EU | 273 (91.3) | 270 (90.3) | 543 (90.8) |
| US | 10 (3.3) | 11 (3.7) | 21 (3.5) |
| ROW | 16 (5.4) | 18 (6.0) | 34 (5.7) |
| Number of previous systemic therapies for psoriasis, n (%) | |||
| <3 | 276 (92.3) | 277 (92.6) | 553 (92.5) |
| ≥3 | 23 (7.7) | 22 (7.4) | 45 (7.5) |
| PGA score | |||
| Mean (SD) | 3.194 (0.4045) | 3.204 (0.4119) | 3.199 (0.4079) |
| Median (min, max) | 3.000 (2.0, 4.0) | 3.000 (2.0, 4.0) | 3.000 (2.0, 4.0) |
| PGA score of 3 or more, n (%) | |||
| 3 (moderate) | 239 (79.9) | 236 (78.9) | 475 (79.4) |
| 4 (severe) | 59 (19.7) | 62 (20.7) | 121 (20.2) |
| PASI score | |||
| Mean (SD) | 21.16 (7.576) | 21.58 (8.631) | 21.37 (8.117) |
| Median (min, max) | 19.00 (12.0, 49.5) | 18.90 (6.6, 65.4) | 18.90 (6.6, 65.4) |
| DLQI score | |||
| n | 283 | 285 | 568 |
| Mean (SD) | 13.9 (7.07) | 14.3 (7.38) | 14.1 (7.22) |
| Median (min, max) | 14.0 (0.0, 30.0) | 14.0 (0.0, 30.0) | 14.0 (0.0, 30.0) |
BSA, Body surface area; DLQI, Dermatology Life Quality Index; EU, European Union; ITT, intention-to-treat; PASI, Psoriasis Area and Severity Index; PGA, Physician Global Assessment; ROW, rest of world; SD, standard deviation; US, United States.
Efficacy
The least squares (LS) mean percent changes in PASI scores from baseline to week 8 in the PPS were 77.50% (DMB-3115) and 77.85% (ustekinumab). The 95% CI for LS mean difference of the primary efficacy endpoint at week 8 was entirely contained within the prespecified equivalence margin (−15%, 15%), therefore, both treatment arms were considered equivalent (LS mean difference [DMB-3115−ustekinumab]: −0.35; 95% CI: −3.60, 2.90; Table II). The LS mean percent changes in PASI scores from baseline to week 12 in the ITT were 87.59% (DMB-3115) and 87.89% (ustekinumab; Table II), and both treatments were considered equivalent (LS mean difference [DMB-3115−ustekinumab]: −0.30; 90% CI: −2.37, 1.76). The LS mean percent changes from baseline in PASI scores were similar at all timepoints between all treatment arms (Fig 3).
Table II.
Percent changes in Psoriasis Area and Severity Index scores from baseline to week 8 and week 12
| From baseline to week 8 (PPS for EMA) |
From baseline to week 12 (ITT for US FDA) |
|||
|---|---|---|---|---|
| DMB-3115 | Ustekinumab | DMB-3115 | Ustekinumab | |
| n | 256 | 267 | 299 | 299 |
| LS mean | 77.50 | 77.85 | 87.59 | 87.89 |
| SE of LS mean | 2.595 | 2.587 | 1.886 | 1.884 |
| 90% CI | - | - | 84.48, 90.69 | 84.79, 90.99 |
| 95% CI | 72.40, 82.60 | 72.77, 82.93 | - | - |
| LS mean difference (DMB-3115 – ustekinumab) | −0.35 | −0.30 | ||
| SE of LS mean difference | 1.655 | 1.255 | ||
| 90% CI for LS mean difference | - | −2.37, 1.76 | ||
| 95% CI for LS mean difference | −3.60, 2.90 | - | ||
CI, Confidence interval; EMA, European Medicines Agency; ITT, intention-to-treat; LS, least square; PASI, Psoriasis Area and Severity Index; PPS, per-protocol set; SE, standard error; US FDA, United States Food and Drug Administration.
Fig 3.
LS mean percent changes from baseline in PASI scores of patients with moderate-to-severe plaque psoriasis (ITT). ITT, Intention-to-treat; LS, least square; PASI, Psoriasis Area and Severity Index; SE, standard error.
During period 1, the proportions of patients with PASI 50 responses increased from baseline to weeks 8, 12, 16, and 28 in both treatment arms. Similar results were seen for patients with PASI 75, PASI 90, and PASI 100 responses. In period 2, the proportions of patients with PASI 50, PASI 75, PASI 90, and PASI 100 responses were similar between all 3 treatment arms at week 40 and week 52 (Table III, Table IV, Table V, Table VI).
Table III.
Secondary efficacy endpoints (Psoriasis Area and Severity Index 50/75/90/100, area under the effect curve, Physician Global Assessment, Dermatology Life Quality Index) at week 8 (intention-to-treat)
| Characteristic | DMB-3115 |
Ustekinumab |
|
|---|---|---|---|
| N = 299 | N = 299 | ||
| Patients with PASI-50 responses | n (%) | 255 (87.6) | 268 (90.8) |
| 95% CI | 84.846, 91.412 | 87.557, 94.138 | |
| Odds ratio (95% CI) | 0.73 (0.432, 1.223) | ||
| Patients with PASI-75 responses | n (%) | 155 (53.3) | 170 (57.6) |
| 95% CI | 47.532, 58.997 | 51.988, 63.266 | |
| Odds ratio (95% CI) | 0.84 (0.606, 1.168) | ||
| Patients with PASI-90 responses | n (%) | 69 (23.7) | 62 (21.0) |
| 95% CI | 18.825, 28.598 | 16.368, 25.666 | |
| Odds ratio (95% CI) | 1.18 (0.797, 1.745) | ||
| Patients with PASI-100 responses | n (%) | 20 (6.9) | 12 (4.1) |
| 95% CI | 3.966, 9.780 | 1.814, 6.322 | |
| Odds ratio (95% CI) | 1.72 (0.847, 3.500) | ||
| Percentage change from baseline in AUEC for PASI score | n | 291 | 295 |
| LS mean | 356.81 | 350.27 | |
| SE of LS mean | 15.193 | 15.114 | |
| 95% CI | 326.97, 386.65 | 320.59, 379.96 | |
| LS mean difference (DMB-3115 – ustekinumab) | 6.54 | ||
| SE of LS mean difference | 9.904 | ||
| 95% CI for LS mean difference | −12.92, 25.99 | ||
| Patients with PGA score of cleared or minimal | n (%) | 180 (61.2) | 186 (62.8) |
| 95% CI | 55.655, 66.794 | 57.333, 68.343 | |
| Odds ratio (95% CI) | 0.93 (0.665, 1.301) | ||
| Change from baseline in DLQI | n | 277 | 283 |
| LS mean | −9.21 | −9.28 | |
| SE of LS mean | 0.621 | 0.618 | |
| 95% CI | −10.43, −7.99 | −10.49, −8.07 | |
| LS mean difference (DMB-3115 – ustekinumab) | 0.07 | ||
| SE of LS mean difference | 0.375 | ||
| 95% CI for LS mean difference | −0.67, 0.81 | ||
Table IV.
Secondary efficacy endpoints (Psoriasis Area and Severity Index 50/75/90/100, area under the effect curve, Physician Global Assessment, Dermatology Life Quality Index) at week 12 (intention-to-treat)
| Characteristic | DMB-3115 |
Ustekinumab |
|
|---|---|---|---|
| N = 299 | N = 299 | ||
| Patients with PASI-50 responses | n (%) | 286 (98.6) | 288 (98.6) |
| 95% CI | 97.278, 99.963 | 97.297, 99.963 | |
| Odds ratio (95% CI) | 1.02 (0.314, 3.306) | ||
| Patients with PASI-75 responses | n (%) | 228 (78.6) | 239 (81.8) |
| 95% CI | 73.902, 83.339 | 77.428, 86.270 | |
| Odds ratio (95% CI) | 0.83 (0.551, 1.249) | ||
| Patients with PASI-90 responses | n (%) | 144 (49.7) | 144 (49.3) |
| 95% CI | 43.901, 55.410 | 43.581, 55.049 | |
| Odds ratio (95% CI) | 1.02 (0.738, 1.423) | ||
| Patients with PASI-100 responses | n (%) | 41 (14.1) | 37 (12.7) |
| 95% CI | 10.128, 18.148 | 8.856, 16.487 | |
| Odds ratio (95% CI) | 1.13 (0.703, 1.813) | ||
| Percentage change from baseline in AUEC for PASI score | n | 290 | 292 |
| LS mean | 686.93 | 684.68 | |
| SE of LS mean | 22.087 | 22.086 | |
| 95% CI | 643.55, 730.31 | 641.30, 728.06 | |
| LS mean difference (DMB-3115 – ustekinumab) | 2.24 | ||
| SE of LS mean difference | 14.326 | ||
| 95% CI for LS mean difference | −25.89, 30.38 | ||
| Patients with PGA score of cleared or minimal | n (%) | 245 (84.2) | 234 (80.1) |
| 95% CI | 80.001, 88.384 | 75.561, 84.713 | |
| Odds ratio (95% CI) | 1.34 (0.870, 2.054) | ||
| Change from baseline in DLQI | n | 277 | 280 |
| LS mean | −10.21 | −10.36 | |
| SE of LS mean | 0.626 | 0.619 | |
| 95% CI | −11.44, −8.98 | −11.58, −9.15 | |
| LS mean difference (DMB-3115 – ustekinumab) | 0.16 | ||
| SE of LS mean difference | 0.371 | ||
| 95% CI for LS mean difference | −0.57, 0.89 | ||
Table V.
Secondary efficacy endpoints (Psoriasis Area and Severity Index 50/75/90/100, area under the effect curve, Physician Global Assessment, Dermatology Life Quality Index) at week 28 (intention-to-treat)
| Characteristic | DMB-3115 |
Ustekinumab |
|
|---|---|---|---|
| N = 299 | N = 299 | ||
| Patients with PASI-50 responses | n (%) | 273 (99.3) | 268 (98.9) |
| 95% CI | 98.268, 100.000 | 97.647, 100.000 | |
| Odds ratio (95% CI) | 1.45 (0.352, 6.002) | ||
| Patients with PASI-75 responses | n (%) | 269 (97.8) | 266 (98.2) |
| 95% CI | 96.092, 99.545 | 96.553, 99.757 | |
| Odds ratio (95% CI) | 0.86 (0.286, 2.565) | ||
| Patients with PASI-90 responses | n (%) | 205 (74.5) | 212 (78.2) |
| 95% CI | 69.397, 79.694 | 73.315, 83.142 | |
| Odds ratio (95% CI) | 0.83 (0.559, 1.237) | ||
| Patients with PASI-100 responses | n (%) | 85 (30.9) | 84 (31.0) |
| 95% CI | 25.447, 36.371 | 25.490, 36.503 | |
| Odds ratio (95% CI) | 0.98 (0.682, 1.417) | ||
| Percentage change from baseline in AUEC for PASI score | n | 275 | 271 |
| LS mean | 2109.68 | 2114.45 | |
| SE of LS mean | 38.342 | 38.485 | |
| 95% CI | 2034.36, 2185.00 | 2038.85, 2190.04 | |
| LS mean difference (DMB-3115 – ustekinumab) | −4.77 | ||
| SE of LS mean difference | 24.900 | ||
| 95% CI for LS mean difference | −53.68, 44.15 | ||
| Patients with PGA score of cleared or minimal | n (%) | 259 (93.8) | 245 (90.4) |
| 95% CI | 91.004, 96.677 | 86.899, 93.912 | |
| Odds ratio (95% CI) | 1.67 (0.890, 3.144) | ||
| Change from baseline in DLQI | n | 258 | 256 |
| LS mean | −11.57 | −11.73 | |
| SE of LS mean | 0.522 | 0.522 | |
| 95% CI | −12.59, −10.54 | −12.75, −10.70 | |
| LS mean difference (DMB-3115 – ustekinumab) | 0.16 | ||
| SE of LS mean difference | 0.317 | ||
| 95% CI for LS mean difference | −0.46, 0.78 | ||
Table VI.
Secondary efficacy endpoints (Psoriasis Area and Severity Index 50/75/90/100, area under the effect curve, Physician Global Assessment, Dermatology Life Quality Index) at week 52 (intention-to-treat)
| Characteristic | DMB-3115 |
Ustekinumab |
Switched to DMB-3115 |
|
|---|---|---|---|---|
| N = 268 | N = 132 | N = 131 | ||
| Patients with PASI-50 responses | n (%) | 254 (99.2) | 128 (99.2) | 121 (99.2) |
| 95% CI | 98.140, 100.000 | 97.711, 100.000 | 97.580, 100.000 | |
| Odds ratio (95% CI) DMB-3115 vs ustekinumab |
1.15 (0.205, 6.406) | |||
| Odds ratio (95% CI) switched to DMB-3115 vs ustekinumab | 0.91 (0.131, 6.377) | |||
| Patients with PASI-75 responses | n (%) | 244 (95.3) | 124 (96.1) | 117 (95.9) |
| 95% CI | 92.723, 97.902 | 92.793, 99.455 | 92.384, 99.420 | |
| Odds ratio (95% CI) DMB-3115 vs ustekinumab |
0.92 (0.341, 2.503) | |||
| Odds ratio (95% CI) switched to DMB-3115 vs ustekinumab | 1.01 (0.310, 3.260) | |||
| Patients with PASI-90 responses | n (%) | 204 (79.7) | 103 (79.8) | 97 (79.5) |
| 95% CI | 74.759, 84.616 | 72.922, 86.768 | 72.346, 86.671 | |
| Odds ratio (95% CI) DMB-3115 vs ustekinumab |
1.05 (0.618, 1.786) | |||
| Odds ratio (95% CI) switched to DMB-3115 vs ustekinumab | 1.02 (0.551, 1.902) | |||
| Patients with PASI-100 responses | n (%) | 116 (45.3) | 55 (42.6) | 52 (42.6) |
| 95% CI | 39.215, 51.410 | 34.101, 51.170 | 33.848, 51.398 | |
| Odds ratio (95% CI) DMB-3115 vs ustekinumab |
1.11 (0.719, 1.704) | |||
| Odds ratio (95% CI) switched to DMB-3115 vs ustekinumab | 0.99 (0.597, 1.641) | |||
| Percentage change from baseline in AUEC for PASI score | n | 256 | 129 | 122 |
| LS mean | 4398.38 | 4388.05 | 4418.21 | |
| SE of LS mean | 52.700 | 58.873 | 58.729 | |
| 95% CI | 4294.84, 4501.92 | 4272.38, 4503.72 | 4302.82, 4533.59 | |
| LS mean difference (DMB-3115 – ustekinumab) | 10.33 | |||
| SE of LS mean difference | 41.337 | |||
| 95% CI for LS mean difference | −70.89, 91.55 | |||
| LS mean difference (switched to DMB-3115 – ustekinumab) | 30.16 | |||
| SE of LS mean difference | 48.357 | |||
| 95% CI for LS mean difference | −64.85, 125.16 | |||
| Patients with PGA score of cleared or minimal | n (%) | 228 (88.7) | 111 (86.0) | 106 (86.9) |
| 95% CI | 84.848, 92.584 | 80.067, 92.026 | 80.895, 92.875 | |
| Odds ratio (95% CI) DMB-3115 vs ustekinumab |
1.31 (0.701, 2.455) | |||
| Odds ratio (95% CI) switched to DMB-3115 vs ustekinumab | 1.09 (0.531, 2.232) | |||
| Change from baseline in DLQI | n | 235 | 119 | 116 |
| LS mean | −11.72 | −11.29 | −11.40 | |
| SE of LS mean | 0.550 | 0.606 | 0.598 | |
| 95% CI | −12.81, −10.64 | −12.48, −10.10 | −12.58, −10.23 | |
| LS mean difference (DMB-3115 – ustekinumab) | −0.43 | |||
| SE of LS mean difference | 0.406 | |||
| 95% CI for LS mean difference | −1.23, 0.37 | |||
| LS mean difference (switched to DMB-3115 – ustekinumab) | −0.11 | |||
| SE of LS mean difference | 0.470 | |||
| 95% CI for LS mean difference | −1.04, 0.81 | |||
AUEC, Area under the effect curve; CI, confidence interval; DLQI, Dermatology Life Quality Index; ITT, intention-to-treat; LS, least squares; n, number of observations; N, number of patients; PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment; SE, standard error.
The LS mean percent changes in area under the effect curve for PASI scores increased from baseline to weeks 8, 12, 16, and 28 in both treatment arms. The LS mean percent changes in area under the effect curve for PASI scores were similar between all 3 treatment arms during period 2 (Table III, Table IV, Table V, Table VI). The proportions of patients with PGA scores of clear or minimal psoriasis increased in both treatment arms from baseline to weeks 8, 12, 16, and 28. The proportions of patients with PGA scores of clear or minimal psoriasis at week 52 were similar across all 3 treatment arms (Table III, Table IV, Table V, Table VI). The LS mean reductions in Dermatology Life Quality Index scores from baseline to weeks 8, 12, 16, 28 were seen in both treatment arms during period 1 and the LS mean changes in Dermatology Life Quality Index scores from baseline to week 52 were similar between all 3 treatment arms during period 2 (Table III, Table IV, Table V, Table VI).
Safety
During period 1, 291 (48.7%) patients experienced a total of 550 treatment-emergent AEs (TEAEs): 142 (47.5%) patients and 270 TEAEs in the DMB-3115 arm, and 149 (49.8%) patients and 280 TEAEs in the ustekinumab arm (Table VII). A total of 27 (4.5%) patients experienced treatment-related TEAEs: 14 (4.7%) patients in the DMB-3115 arm and 13 (4.3%) patients in the ustekinumab arm. A numerically higher proportion of patients experienced TEAEs that led to study discontinuation in the ustekinumab arm (4.3%) compared with the DMB-3115 arm (2.7%). The incidence of grade 1 and grade 2 TEAEs was similar between the treatment arms (grade 1: DMB-3115: 78 [26.1%] patients; ustekinumab: 85 [28.4%] patients; grade 2: DMB-3115: 59 [19.7%] patients; ustekinumab: 62 [20.7%] patients). The proportions of patients experiencing serious TEAEs were similar between the DMB-3115 arm (1.7%) and the ustekinumab arm (1.0%).
Table VII.
Overview of adverse events (safety set)
| Adverse events, n (%) | Period 1 |
Period 2 |
|||||
|---|---|---|---|---|---|---|---|
| DMB-3115 (N = 299) |
Ustekinumab (N = 299) |
Total (N = 598) |
DMB-3115 (N = 267) |
Ustekinumab (N = 132) |
Switched to DMB-3115 (N = 131) |
Total (N = 530) |
|
| Overall TEAEs | 270 | 280 | 550 | 57 | 49 | 30 | 136 |
| Overall non-TEAEs | 10 | 31 | 41 | 0 | 0 | 0 | 0 |
| Patients with at least 1 TEAE | 142 (47.5) | 149 (49.8) | 291 (48.7) | 50 (18.7) | 28 (21.2) | 24 (18.3) | 102 (19.2) |
| TEAEs by intensity | |||||||
| Grade 1 | 78 (26.1) | 85 (28.4) | 163 (27.3) | 28 (10.5) | 15 (11.4) | 9 (6.9) | 52 (9.8) |
| Grade 2 | 59 (19.7) | 62 (20.7) | 121 (20.2) | 21 (7.9) | 11 (8.3) | 15 (11.5) | 47 (8.9) |
| Grade 3 | 2 (0.7) | 1 (0.3) | 3 (0.5) | 1 (0.4) | 2 (1.5) | 0 | 3 (0.6) |
| Grade 4 | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Grade 5 | 2 (0.7) | 1 (0.3) | 3 (0.5) | 0 | 0 | 0 | 0 |
| Severe TEAE (Grade 3-5) | 5 (1.7) | 2 (0.7) | 7 (1.2) | 1 (0.4) | 2 (1.5) | 0 | 3 (0.6) |
| Serious TEAE | 5 (1.7) | 3 (1.0) | 8 (1.3) | 0 | 2 (1.5) | 0 | 2 (0.4) |
| Related TEAE | 14 (4.7) | 13 (4.3) | 27 (4.5) | 1 (0.4) | 0 | 0 | 1 (0.2) |
| TEAE of special interest | 7 (2.3) | 6 (2.0) | 13 (2.2) | 0 | 0 | 0 | 0 |
| Related TEAE of special interest | 5 (1.7) | 5 (1.7) | 10 (1.7) | 0 | 0 | 0 | 0 |
| Treatment-related serious TEAE | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| TEAE with an outcome of death | 2 (0.7) | 1 (0.3) | 3 (0.5) | 0 | 0 | 0 | 0 |
| Patients discontinued due to TEAE | 8 (2.7) | 13 (4.3) | 21 (3.5) | 0 | 0 | 0 | 0 |
AE, Adverse event; TEAE, treatment-emergent AE.
During period 2, 102 (19.2%) patients experienced 136 TEAEs: DMB-3115, 50 (18.7%) patients and 57 TEAEs; ustekinumab, 28 (21.2%) patients and 49 TEAEs; switched to DMB-3115, 24 (18.3%) patients and 30 TEAEs (Table VII). One (0.4%) patient experienced a treatment-related TEAE in the DMB-3115 arm; no treatment-related TEAEs were reported in the ustekinumab arm or the switched to DMB-3115 arm. No TEAEs led to study discontinuation during period 2. The majority of the TEAEs during period 2 were grade 1 (9.8% of patients) or grade 2 (8.9% of patients). Two (1.5%) patients in the ustekinumab arm had serious TEAEs. No patients in either of the other 2 treatment arms experienced serious TEAEs (Table VIII, Table IX, Table X, Table XI).
Table VIII.
Treatment-emergent serious adverse events by system organ class and preferred term (safety set)
| System organ class Preferred term, n (%) |
Period 1 |
Period 2 |
|||||
|---|---|---|---|---|---|---|---|
| DMB-3115 (N = 299) |
Ustekinumab (N = 299) |
Total (N = 598) |
DMB-3115 (N = 267) |
Ustekinumab (N = 132) |
Switched to DMB-3115 (N = 131) |
Total (N = 530) |
|
| Number of patients with any TEAEs | 5 (1.7) | 3 (1.0) | 8 (1.3) | 0 | 2 (1.5) | 0 | 2 (0.4) |
| Cardiac disorders | 2 (0.7) | 0 | 2 (0.3) | 0 | 0 | 0 | 0 |
| Acute myocardial infarction | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Atrial fibrillation | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| General disorders and administration site conditions | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Sudden cardiac death | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Infections and infestations | 1 (0.3) | 2 (0.7) | 3 (0.5) | 0 | 0 | 0 | 0 |
| COVID-19 | 1 (0.3) | 1 (0.3) | 2 (0.3) | 0 | 0 | 0 | 0 |
| COVID-19 pneumonia | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| Injury, poisoning, and procedural complications | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Humerus fracture | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Musculoskeletal and connective tissue disorders | 0 | 0 | 0 | 0 | 1 (0.8) | 0 | 1 (0.2) |
| Back pain | 0 | 0 | 0 | 0 | 1 (0.8) | 0 | 1 (0.2) |
| Intervertebral disc disorder | 0 | 0 | 0 | 0 | 1 (0.8) | 0 | 1 (0.2) |
| Neoplasms benign, malignant and unspecified (incl. cysts and polyps) | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Gastric cancer | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Nervous system disorders | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| VIth nerve paralysis | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| Vascular disorders | 0 | 0 | 0 | 0 | 1 (0.8) | 0 | 1 (0.2) |
| Hypertension | 0 | 0 | 0 | 0 | 1 (0.8) | 0 | 1 (0.2) |
n, Number of observations; N, number of patients; TEAE, treatment-emergent adverse event.
Table IX.
Treatment-emergent adverse events leading to permanent discontinuation of study intervention by system organ class and preferred term (Safety set)
| System organ class Preferred term, n (%) |
Period 1 |
Period 2 |
|||||
|---|---|---|---|---|---|---|---|
| DMB-3115 (N = 299) |
Ustekinumab (N = 299) |
Total (N = 598) |
DMB-3115 (N = 267) |
Ustekinumab (N = 132) |
Switched to DMB-3115 (N = 131) |
Total (N = 530) |
|
| Number of patients with any TEAEs | 13 (4.3) | 19 (6.4) | 32 (5.4) | 0 | 0 | 0 | 0 |
| Infections and infestations | 12 (4.0) | 17 (5.7) | 29 (4.8) | 0 | 0 | 0 | 0 |
| COVID-19 | 12 (4.0) | 16 (5.4) | 28 (4.7) | 0 | 0 | 0 | 0 |
| Asymptomatic COVID-19 | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| COVID-19 pneumonia | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| Skin and subcutaneous tissue disorders | 1 (0.3) | 2 (0.7) | 3 (0.5) | 0 | 0 | 0 | 0 |
| Dermatitis exfoliative generalized | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| Guttate psoriasis | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| Psoriasis | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
n, Number of observations; N, number of patients; TEAE, treatment-emergent adverse events.
Table X.
Treatment-emergent adverse events leading to death by system organ class and preferred term (safety set)
| System organ class Preferred term, n (%) |
Period 1 |
Period 2 |
|||||
|---|---|---|---|---|---|---|---|
| DMB-3115 (N = 299) |
Ustekinumab (N = 299) |
Total (N = 598) |
DMB-3115 (N = 267) |
Ustekinumab (N = 132) |
Switched to DMB-3115 (N = 131) |
Total (N = 530) |
|
| Number of patients with any TEAEs | 2 (0.7) | 1 (0.3) | 3 (0.5) | 0 | 0 | 0 | 0 |
| General disorders and administration site conditions | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Sudden cardiac death | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Infections and infestations | 1 (0.3) | 1 (0.3) | 2 (0.3) | 0 | 0 | 0 | 0 |
| COVID-19 | 1 (0.3) | 1 (0.3) | 2 (0.3) | 0 | 0 | 0 | 0 |
n, Number of observations; N, number of patients; TEAE, treatment-emergent adverse event.
Table XI.
Treatment-emergent adverse events of special interest by adverse events of special interest category (safety set)
| AESI category, n (%) | Period 1 |
Period 2 |
|||||
|---|---|---|---|---|---|---|---|
| DMB-3115 (N = 299) |
Ustekinumab (N = 299) |
Total (N = 598) |
DMB-3115 (N = 267) |
Ustekinumab (N = 132) |
Switched to DMB-3115 (N = 131) |
Total (N = 530) |
|
| Confirmed myocardial infarction | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Congestive heart failure | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Hypersensitivity reactions | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Injection site reactions | 3 (1.0) | 5 (1.7) | 8 (1.3) | 0 | 0 | 0 | 0 |
| Malignancies | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
| Neurologic or demyelinating events | 0 | 1 (0.3) | 1 (0.2) | 0 | 0 | 0 | 0 |
| Opportunistic infections | 1 (0.3) | 0 | 1 (0.2) | 0 | 0 | 0 | 0 |
AESI, Adverse events of special interest; n, number of observations; N, number of patients.
Immunogenicity and PK
The proportions of patients with confirmatory positive ADA increased from week 0/day 1 to week 2 followed by a gradual decline that was maintained to week 52 across all the treatment arms. The proportion of patients with ADA confirmed positivity was numerically higher in the switched to DMB-3115 arm compared with DMB-3115 and ustekinumab arms at week 0/day 1, week 0/day 2, and weeks 2, 4, 8, 12, 16, and 28, whereas it was numerically higher in ustekinumab arm compared with the DMB-3115 and the switched to DMB-3115 arms at week 40 and week 52 (Table XII). The proportions of patients with neutralizing positive ADAs increased from week 0/day 1 to week 0/day 2, and then fluctuated until week 52 across all the treatment arms. At week 52, the proportion of patients with neutralizing positive ADAs was similar between the DMB-3115 and ustekinumab arms but was numerically higher in the switched to DMB-3115 arm (Table XIII).
Table XII.
Summary of positive confirmatory antidrug antibody results by treatment at each measurement time (safety set)
| Number (%) of patients with a positive result | DMB-3115 (N = 299) |
Ustekinumab (N = 168) |
Switched to DMB-3115 (N = 131) |
Total (N = 598) |
|---|---|---|---|---|
| Wk 0/d 1 | 19 (6.4) | 8 (4.8) | 11 (8.4) | 38 (6.4) |
| Wk 0/d 2 | 14 (4.7) | 6 (3.6) | 8 (6.1) | 28 (4.7) |
| Wk 2 | 67 (22.6) | 87 (52.7) | 85 (64.9) | 239 (40.3) |
| Wk 4 | 61 (20.5) | 59 (35.5) | 57 (43.5) | 177 (29.7) |
| Wk 8 | 38 (12.9) | 42 (25.3) | 45 (34.6) | 125 (21.2) |
| Wk 12 | 35 (11.9) | 38 (23.3) | 40 (30.8) | 113 (19.3) |
| Wk 16 | 45 (15.7) | 44 (28.2) | 40 (30.5) | 129 (22.5) |
| Wk 28 | 36 (13.0) | 31 (21.8) | 34 (26.0) | 101 (18.4) |
| Wk 40 | 30 (11.6) | 29 (22.1) | 25 (20.0) | 84 (16.3) |
| Wk 52 | 23 (8.9) | 28 (21.5) | 23 (18.7) | 74 (14.5) |
Note: Percentages were calculated based on the denominator excluding missing values.
Table XIII.
Summary of positive neutralizing antidrug antibody results by treatment at each measurement time (safety set)
| Number (%) of patients with positive result | DMB-3115 (N = 299) |
EU-STELARA (N = 168) |
Switched to DMB-3115 (N = 131) |
Total (N = 598) |
|---|---|---|---|---|
| Wk 0/d 1 | 11/19 (57.9) | 4/8 (50.0) | 4/11 (36.4) | 19/38 (50.0) |
| Wk 0/d 2 | 9/14 (64.3) | 5/6 (83.3) | 6/8 (75.0) | 20/28 (71.4) |
| Wk 2 | 45/67 (67.2) | 53/87 (60.9) | 51/85 (60.0) | 149/239 (62.3) |
| Wk 4 | 39/61 (63.9) | 36/59 (61.0) | 31/57 (54.4) | 106/177 (59.9) |
| Wk 8 | 20/38 (52.6) | 27/42 (64.3) | 31/45 (68.9) | 78/125 (62.4) |
| Wk 12 | 16/35 (45.7) | 22/38 (57.9) | 16/40 (40.0) | 54/113 (47.8) |
| Wk 16 | 24/45 (53.3) | 31/44 (70.5) | 18/40 (45.0) | 73/129 (56.6) |
| Wk 28 | 24/36 (66.7) | 18/31 (58.1) | 18/35 (51.4) | 60/102 (58.8) |
| Wk 40 | 15/30 (50.0) | 16/30 (53.3) | 14/25 (56.0) | 45/85 (52.9) |
| Wk 52 | 10/23 (43.5) | 13/30 (43.3) | 11/23 (47.8) | 34/76 (44.7) |
Note: Percentages were calculated based on the number of patients available at each specified visit.
The median time to reach maximum plasma concentration was similar for DMB-3115 and ustekinumab treatments (167 hours). The geometric mean serum maximum plasma concentration was 2585 ng/mL for DMB-3115 versus 2653 ng/mL for ustekinumab. Area under the concentration-time curve from week 0 to week 4 was 1 202 000 h × ng/mL for DMB-3115 versus 1 183 000 h × ng/mL for ustekinumab (Table XIV). The mean serum concentration-time profiles for DMB-3115 and ustekinumab were similar between both treatments, indicating no clinically significant difference in PK exposure between treatments (Fig 4). PK results as a function of immunogenic status are shown in Figs 5 and 6. The median time to reach maximum plasma concentration and geometric mean serum maximum plasma concentration and area under the concentration-time curve from week 0 to week 4 were similar between treatments within each body-weight category (Figs 7 and 8, Table XV).
Table XIV.
Summary of serum ustekinumab pharmacokinetic parameters for first dose (week 0) by treatment (pharmacokinetic set)
| DMB-3115 (N = 295) |
Ustekinumab (N = 298) |
|||
|---|---|---|---|---|
| n | Geo mean (Geo CV%) | n | Geo mean (Geo CV%) | |
| Cmax, ng/mL | 289 | 2585 (57.7) | 292 | 2653 (60.1) |
| tmax, h∗ | 289 | 166.85 (17.50, 668.23) | 292 | 167.00 (21.58, 670.07) |
| AUCw0–w4, h × ng/mL | 283 | 1 202 000 (46.7) | 280 | 1 183 000 (51.1) |
AUCw0–w4, Area under the concentration-time curve from week 0 to week 4; Cmax, maximum plasma concentration; Geo CV%, geometric coefficient of variation (in percent); Geo mean, geometric mean; h, hours; n, number of observations; N, number of patients; tmax, time to reach maximum plasma concentration.
Median (minimum, maximum)
Fig 4.
Mean (SD) ustekinumab serum concentration-time profiles for each treatment from week 0 to week 52 on linear scale (concentrations after week 28 switch included) (PK set). PK, Pharmacokinetic; SD, standard deviation.
Fig 5.
Mean (SD) ustekinumab serum concentration-time profiles by overall binding antibody status for each treatment from week 0 to week 52 on linear scale (PK set). ADA, Antidrug antibody; PK, pharmacokinetic; SD, standard deviation.
Fig 6.
Mean (SD) ustekinumab serum concentration-time profiles by overall neutralizing antibody status for each treatment from week 0 to week 52 on linear scale (PK set). NAb, Neutralizing antibody; PK, pharmacokinetic; SD, standard deviation.
Fig 7.
Mean ustekinumab serum concentration-time profiles by body-weight category for each treatment from week 0 to week 4 on (A) linear (SD) and (B) semilogarithmic scale (PK set). PK, Pharmacokinetic; SD, standard deviation.
Fig 8.
Mean (SD) ustekinumab serum concentration-time profiles by body-weight category for each treatment from week 0 to week 28 on linear scale (PK set). PK, Pharmacokinetic; SD, standard deviation.
Table XV.
Summary of serum ustekinumab pharmacokinetic parameters for first dose (week 0) by body-weight category and treatment (pharmacokinetic set)
| Body weight/dose | DMB-3115 |
Ustekinumab |
||
|---|---|---|---|---|
| n | Geo mean (Geo CV%) | n | Geo mean (Geo CV%) | |
| ≤100 kg/45 mg | N = 214 | N = 215 | ||
| Cmax, ng/mL | 211 | 2348 (51.3) | 209 | 2314 (49.8) |
| tmax, h∗ | 211 | 166.55 (17.50, 668.23) | 209 | 167.17 (21.58, 670.07) |
| AUCw0–w4, h × ng/mL | 208 | 1 117 000 (44.0) | 201 | 1 073 000 (45.6) |
| >100 kg/90 mg | N = 81 | N = 83 | ||
| Cmax, ng/mL | 78 | 3352 (64.1) | 83 | 3740 (66.4) |
| tmax, h∗ | 78 | 167.13 (20.28, 403.53) | 83 | 166.75 (22.33, 337.53) |
| AUCw0–w4, h × ng/mL | 75 | 1 471 000 (47.3) | 79 | 1 514 000 (54.6) |
AUCw0–w4, Area under the concentration-time curve from week 0 to week 4; Cmax, maximum plasma concentration; Geo CV%, geometric coefficient of variation (in percent); Geo mean, geometric mean; h, hours; n, number of observations; N, number of patients; PK, pharmacokinetic; tmax, time to reach maximum plasma concentration.
Median (minimum, maximum).
Discussion
In this study, the DMB-3115 and ustekinumab arms were well matched regarding demographic and baseline characteristics, and most patients completed the study. The LS mean percent changes in PASI scores from baseline to week 8 and to week 12 were considered equivalent in both treatment arms and the primary efficacy endpoints were entirely contained within the prespecified equivalence margin, demonstrating therapeutic equivalence of DMB-3115 and ustekinumab. Analyses in period 1 showed an increase in the percentages of patients with PASI 50, PASI 75, PASI 90, and PASI 100 responses from baseline to weeks 8, 12, 16, and 28 in both treatment arms. During period 2, the percentages of patients with PASI 50, PASI 75, PASI 90, and PASI 100 responses were similar among all treatment arms at week 52 for both 8- and 12-week analysis sets (ITT).
EMA guidance recommends a 1-year intermittent or prolonged use efficacy study for the evaluation of psoriasis treatments.10 This phase 3 study assessed the efficacy of DMB-3115 for up to 52 weeks. Throughout the study, DMB-3115 demonstrated a similar clinical response to ustekinumab. Other clinical studies have shown that ustekinumab efficacy is maintained for up to 5 years of treatment for Crohn's disease11 and psoriasis,12 and up to 3 years of treatment for ulcerative colitis.13 The efficacy of DMB-3115 treatment for over 52 weeks has not been evaluated in a clinical setting; however, it is reasonable to assume that DMB-3115 will perform equivalently to ustekinumab.
Efficacy was evaluated in patients with plaque psoriasis; however, based on available evidence and in accordance with FDA14 and EMA15 guidance, we can extrapolate the efficacy and safety analyses to other indications for which ustekinumab is approved (active psoriatic arthritis, pediatric plaque psoriasis, ulcerative colitis, and Crohn’s disease).
The safety profiles of DMB-3115 and ustekinumab were similar. Furthermore, safety patterns before and after switching from ustekinumab to DMB-3115 were similar, and no new safety signals were identified. For immunogenicity outcomes, the proportion of patients with ADAs and neutralizing ADAs reached a maximum at 2 weeks after starting treatment. In general, the proportion of patients with ADAs was numerically higher in the ustekinumab arm compared with the DMB-3115 arm for weeks 0-28 and was similar between ustekinumab and switched to DMB-3115 arms, but was higher than the DMB-3115 arm for weeks 28-52. The incidence of neutralizing positive ADA patients was similar between all 3 treatment arms for weeks 28-52. The PK of DMB-3115 was similar to that of ustekinumab regardless of body weight or antibody status.
Conclusions
This study demonstrated equivalent efficacy between DMB-3115 and ustekinumab, as shown by the similar LS mean percent changes in PASI score from baseline. Both treatments provided improved efficacy in patients with moderate-to-severe plaque psoriasis with no clinically meaningful differences in efficacy and safety.
Data availability
All data generated or analyzed during this study, which support the findings of this study, are included within this article. Researchers interested in further analyses not present in the manuscript may contact the corresponding author.
Conflicts of interest
Dr Tichý has served as a consultant, speaker, or investigator for AbbVie, Almirall, BMS, Eli Lilly, Janssen, Leo Pharma, Novartis, Sanofi, and UCB. Dr Draelos received funding from Dong-A ST Co Ltd for this study. Dr Cetkovska has served as a consultant, speaker, or investigator for AbbVie, Almirall, Amgen, Eli Lilly, Janssen, Leo Pharma, Novartis, Pfizer, Sanofi, and UCB. Dr Rich has served as an investigator for AbbVie, Aflasigma, Allakos, Amgen, Arcutis, Aslan, Bristol Myers Squibb, Dermavant, Dermbiont, Dermira, Eli Lilly, Galderma, Hallux, Incyte, Janssen, Leo, Moberg, Pfizer, Sun, Technoderma, Teva, UCB, and Veradermics, and on advisory boards for Alumis, Oruka, and Veradermics. Drs Vekovska, Imko-Walczuk, and Weglowska have no conflicts of interest to declare.
Acknowledgments
Medical writing and editorial assistance were provided by Melanie Francis via IQVIA, and Chrysi Petraki, Nathaniel Grubbs, and Florencia Dobler of IQVIA, funded by Dong-A ST Co, Ltd and Meiji Seika Pharma Co, Ltd.
Footnotes
Funding sources: This study was funded by Dong-A ST Co Ltd and Meiji Seika Pharma Co Ltd.
Patient consent: The authors obtained written consent from patients for their photographs and medical information to be published in print and online and with the understanding that this information may be publicly available. Patient consent forms were not provided to the journal but are retained by the authors.
IRB approval status: Independent institutional review board approvals were obtained.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study, which support the findings of this study, are included within this article. Researchers interested in further analyses not present in the manuscript may contact the corresponding author.