Efficacy and safety of subcutaneous guselkumab in East Asian participants with moderately to severely active Crohn’s disease: subgroup analysis of the phase 3 GRAVITI study
Article information
Abstract
Background/Aims
The GRAVITI (NCT05197049) study demonstrated efficacy and safety of guselkumab, a dual-acting interleukin-23p19 subunit inhibitor, as subcutaneous (SC) induction and maintenance therapy in participants with moderate to severely active Crohn’s disease (CD). We report post hoc subgroup analyses in East Asian participants.
Methods
Seventy-one East Asian participants were randomized 1:1:1 to guselkumab 400 mg SC every 4 weeks (q4w) (x3) followed by 100 mg SC every 8 weeks (q8w) starting at Week 16 (n = 23), guselkumab 400 mg SC q4w (x3) followed by 200 mg SC q4w starting at Week 12 (n = 20), or placebo (n = 28) in the phase 3 double-blind, placebo-controlled, treat-through GRAVITI study. From Week 16, placebo participants meeting rescue criteria were eligible for rescue treatment with guselkumab. Clinical remission at Week 12 and endoscopic response at Week 12 were co-primary endpoints, additional endpoints included Patient-Reported Outcome-2 remission (Week 12), clinical response (Week 12), clinical remission (Week 24 and Week 48), and endoscopic response (Week 48), and safety through Week 48.
Results
Greater proportions of East Asian participants receiving guselkumab 400 mg SC achieved clinical remission versus placebo (41.9% vs. 14.3%) and endoscopic response versus placebo (39.5% vs. 21.4%) at Week 12. At Week 48, greater proportions of participants in both guselkumab groups (100 mg SC q8w, 69.6%; 200 mg SC q4w, 60.0%) achieved clinical remission versus placebo (10.7%) and endoscopic response versus placebo (43.5%, 60.0%; vs. placebo 0.0%). The adverse event profile was generally consistent with the global population.
Conclusions
Efficacy and safety results of SC guselkumab in East Asian participants with moderately to severely active CD reflect findings from the global study.
INTRODUCTION
Crohn’s disease (CD) is a chronic inflammatory bowel disease that is characterized by inflammation of the intestine. Affecting any part of the gastrointestinal tract from mouth to anus, symptoms typically include abdominal pain, severe diarrhea, fatigue, weight loss, and malnutrition. CD incidence and prevalence has been increasing in non-Western countries, including Asian countries, due in part to an increasingly Westernized diet, elevated socioeconomic status, and hygiene improvements [1]. The estimated prevalence in Asia is up to 18.6 per 100,000 people [2-4]. Characteristics of CD in Asian populations are known to be different to Western counterparts in many ways [5]. The clinical course of CD in Asian patients has lower rates of disease behavior progression, major surgery, and hospitalization [6]. Further, Asian patients with CD have distinct phenotypic characteristics including a higher prevalence of perianal fistulas, and mutations in TNFSF15, which have much larger effects on CD risk compared to Western counterparts [7, 8].
Anti-tumor necrosis factor (TNF) therapies are commonly used to treat CD in Asian countries [9,10]; however, 10%–30% of patients fail to respond to initial treatment, and 23%–46% of patients lose response over time, highlighting the need for effective targeted therapies in this population [11].
Guselkumab is a selective, dual-acting interleukin (IL)-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64, a receptor on cells that produce IL-23 [12]. Guselkumab intravenous induction followed by subcutaneous (SC) maintenance demonstrated efficacy and safety in participants with moderate to severely active CD in the Phase 2 GALAXI-1 study [13,14] and these results were confirmed in the phase 3 GALAXI-2 and GALAXI-3 studies [15]. SC administration of biologics is generally preferred by patients and healthcare providers and has proven effective, safe, and well-tolerated [16-18]. The phase 3 double-blind treat-through GRAVITI study in participants with moderately to severely active CD demonstrated that SC guselkumab is effective, safe, and well-tolerated [19]. With guselkumab treatment, the co-primary endpoints of clinical remission and endoscopic response at Week 12 were met. Guselkumab recipients also achieved prespecified, multiplicity-controlled endpoints evaluating clinical, endoscopic, and patient-reported outcomes up to 48 weeks at higher rates compared with placebo recipients.
Higher prevalence of infectious diseases (e.g., cytomegalovirus, hepatitis B virus, and tuberculosis) in Asian countries, coupled with racial differences in medication response and treatment-related adverse events (AEs), can impact CD treatment selection and success [20-23]. The GRAVITI clinical study included participants from East Asia (China, Japan, Korea, and Taiwan). Patients with active tuberculosis, active hepatitis B infection or clinically significant opportunistic infections were excluded from the study. We describe here a post hoc subgroup analysis of East Asian participants from the GRAVITI phase 3 treatthrough trial with moderately to severely active CD.
METHODS
1. Study Design and Treatment
Detailed eligibility criteria and study design descriptions have been published [19]. Briefly, GRAVITI was a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study with a treat-through design, which evaluated the efficacy and safety of 12 weeks of guselkumab SC induction therapy followed by SC maintenance therapy. The study consisted of up to 5 weeks of a screening phase, a 24-week main treatment phase, and a 72-week extension treatment phase, for a total of 96 weeks of treatment (Fig. 1). Global study data through Week 48 have been published [19].
Study design of the GRAVITI Phase 3 study. participants received matching placebo at each time point to maintain the blind. Only active treatment administrations are depicted in the figure. SC, subcutaneous; q4w, every 4 weeks; q8w, every 8 weeks; R, randomized; U, study unblinding; E, endoscopy; CDAI, Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease.
Randomization was stratified by baseline Crohn’s Disease Activity Index (CDAI; ≤300 or >300), Simple Endoscopic Score for Crohn’s Disease (SES-CD; ≤ 12 or >12), and inadequate response or intolerance to biologic therapy status (yes or no) at baseline (Week 0). Participants were allocated 1:1:1 in a treat-through design to guselkumab 400 mg SC every 4 weeks (q4w) ( ×3) followed by guselkumab 200 mg SC q4w starting at Week 12, guselkumab 400 mg SC q4w ( ×3) followed by guselkumab 100 mg SC every 8 weeks (q8w) starting at Week 16, or placebo. Participants in the placebo group had to meet at least 1 of the following rescue criteria to be eligible for rescue therapy: (1) at both Weeks 12 and 16: CDAI score >220 and <70-point reduction from baseline CDAI; or (2) at Week12: SES-CD score increase by ≥ 50% from baseline. Participants in the placebo group who met the criteria for rescue therapy received guselkumab 400 mg SC at Weeks 16, 20, and 24 followed by guselkumab 100 mg SC q8w. Participants randomized to guselkumab who met the rescue criteria received blinded sham rescue with a matching placebo SC injection and continued their assigned treatment regimen to maintain the blind.
All participants gave written informed consent. The study protocol was approved by investigational review boards or ethics committees at each site, including the Medical Ethics Committee of Sir Run Run Shaw Hospital (SRRSH), affiliated with Zhejiang University School of Medicine (IRB No. 20220301-5). The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Study data were available to all authors, and all authors approved of the final manuscript.
2. Participants
This post hoc subgroup analysis evaluated data from 71 East Asian participants enrolled at GRAVITI study sites located in China, Japan, Korea, and Taiwan. The global GRAVITI study enrolled 347 adults with moderately to severely active CD with a history of inadequate response or intolerance to biologic therapy (vedolizumab, infliximab, certolizumab pegol, adalimumab, or approved biosimilars for these agents), 6-mercaptopurine (6-MP), azathioprine (AZA), oral corticosteroids, or methotrexate. A complete list of inclusion and exclusion criteria has been published [19].
3. Statistical Analysis
All analyses were subgroup analyses of East Asian participants. Data were summarized descriptively and considering that there was no pre-planned alpha control for the East Asian subgroup, no statistical comparisons were conducted between treatment cohorts for these subgroup analyses. China and Japan data were also analyzed separately and are presented in the supplement. Statistical methods for the efficacy and safety analyses have been published.
4. Outcome Assessment
Clinical outcomes of this subgroup analysis matched those of the global GRAVITI study and have been previously described [19]. Briefly, the co-primary endpoints were clinical remission (CDAI score <150) at Week 12 and endoscopic response at Week 12. Endoscopic response by an alternative definition was also evaluated at Week 12. Patient-Reported Outcome-2 (PRO-2) at Week 12, clinical response at Week 12, clinical remission at Weeks 24 and 48, and endoscopic response (also with an alternative definition) at Week 48 were additional endpoints. At Week 48, deep remission (achieving both clinical remission and endoscopic remission), endoscopic remission, and additional efficacy endpoints were assessed. Through Week 48, median change in fecal calprotectin and C-reactive protein (CRP) concentrations from baseline were assessed. Elevated CRP (>5 mg/L) and elevated fecal calprotectin ( >250 μg/g) were defined by a central laboratory. Inflammatory Bowel Disease Questionnaire (IBDQ) remission was defined as IBDQ score ≥170. The combined guselkumab 400 mg SC treatment group was compared to placebo for all endpoints assessed through Week 12; each guselkumab SC maintenance regimen was compared to placebo for assessments after Week 12. All participants who met rescue criteria were considered not to have met efficacy endpoints after Week 16.
5. Safety
Safety was assessed through Week 48 in East Asian participants. AEs, serious adverse events (SAEs), AEs leading to discontinuation of the study agent, AEs of interest, and infections were evaluated. Follow-up time-adjusted analyses (i.e., number of events per 100 participant-years; 100 PYs) for AEs, SAEs, AEs leading to discontinuation of study agent, and infections are also provided. Incidence of anti-drug antibodies was evaluated.
RESULTS
1. Participant Disposition and Baseline Characteristics
At baseline, 71 East Asian participants (51 China, 6 Japan, 11 Korea, and 3 Taiwan) were randomized 1:1:1 to guselkumab 400 mg SC q4w to 100 mg SC q8w (n=23); guselkumab 400 mg SC q4w to 200 mg SC q4w (n =20); or placebo SC q4w (n=28). Fifteen participants (53.6%) in the placebo group met the rescue criteria at Week 16 and switched to guselkumab; no participants in the guselkumab 400 mg SC q4w to 100 mg SC q8w group and 3 participants (15.0%) in the guselkumab 400 mg SC q4w to 200 mg SC q4w group also met rescue criteria (continuing their assigned treatment regimen and receiving sham rescue with placebo).
Among treatment groups, demographics and disease characteristics were generally comparable (Table 1). Overall, the mean (standard deviation [SD]) duration of CD was 6.0 (6.0) years, the mean (SD) age was 34.2 (12.6) years, and 66.2% of participants were men. Overall, the mean (SD) SES-CD score was 14.2 (8.7), and the mean (SD) CDAI score at baseline was 298.9 (49.7). Participants were receiving the following concomitant therapies at baseline: 6-MP/AZA (35.2%), oral aminosalicylates (32.4%), and oral corticosteroids (14.1%). Overall, 67.6% (n=48) of participants at baseline had an inadequate response or intolerance to prior biologic therapy, and most of these participants (62.0%; n=44) had an inadequate response or intolerance to ≥1 anti-TNF. At baseline, 28.2% (n=20) of participants were bio-naive. Less than 5% of participants were exposed to biologics but had no documented history of inadequate response or intolerance.
East Asian Participants Baseline Demographics and Disease Characteristics
Elevated fecal calprotectin ( >250 μg/g) was reported in 62 (87.3%) participants (guselkumab combined, 83.7%; placebo, 92.9%). Elevated CRP ( >5 mg/L) was reported in 48 (67.6%) participants at baseline, with a higher proportion of participants from the placebo group (guselkumab combined, 55.8%; placebo, 85.7%).
Overall, 9 participants (12.7%) discontinued study agent before Week 48 (placebo SC, n=7; placebo to guselkumab rescue, n=1; guselkumab 400 mg SC q4w to 100 mg SC q8w, n=1) (Supplementary Fig. 1). In East Asian participants through Week 48, the most common reasons for discontinuation included lack of efficacy (n=2 [2.8%]; 1 placebo, 1 guselkumab); AE of worsening of CD (n=2 [2.8%]; 2 placebo); and withdrawal by participant (n=3 [4.2%]; 2 placebo, 1 guselkumab).
2. Efficacy
1) Week 12 Endpoints
The co-primary endpoints were met with guselkumab SC induction treatment in the East Asian population. Clinical remission at Week 12 was achieved in a greater proportion of participants in the combined guselkumab 400 mg SC q4w group (41.9%) versus placebo (14.3%) (Fig. 2). Endoscopic response at Week 12 was achieved in greater proportions of guselkumab-treated participants (39.5%) versus placebo (21.4%) (Fig. 2). PRO-2 remission and clinical response at Week 12 was achieved in greater proportions of participants in the combined guselkumab 400 mg SC q4w group versus placebo (46.5% vs. 17.9% and 65.1% vs. 21.4%, respectively) (Fig. 2, Supplementary Fig. 2). Similar results were observed in Chinese participants (Supplementary Table 1). Japanese participant numbers were too low to draw any conclusion.
Short-term efficacy endpoints in East Asian participants versus global study participants. Global GRAVITI study data were previously reported [19]. Clinical remission is defined as CDAI score <150. Endoscopic response is defined as ≥50% improvement from baseline in SES-CD score. PRO-2 remission is defined as abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3, and no worsening of abdominal pain or stool frequency from baseline. Clinical response is defined as ≥100-point reduction from baseline in CDAI score or CDAI score <150. Participants who had a CD-related surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID-19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. CDAI, Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease; PRO-2, Patient-Reported Outcome-2; CD, Crohn’s disease; COVID-19, coronavirus disease 2019; SC, subcutaneous; q4w, every 4 weeks.
2) Week 24 and Week 48 Endpoints
In the East Asian subgroup, clinical remission at Week 24 was achieved in greater proportions of participants in the guselkumab 400 mg SC q4w to 100 mg SC q8w group (69.6%) and the guselkumab 400 mg SC q4w to 200 mg SC q4w group (55.0%) compared with placebo (21.4%) (Fig. 3). Greater proportions of participants in the guselkumab 400 mg SC q4w to 100 mg SC q8w group (69.6%) and the guselkumab 400 mg SC q4w to 200 mg SC q4w group (60.0%) achieved clinical remission at Week 48 versus placebo (10.7%) (Fig. 3). Clinical remission through Week 48 is shown in Supplementary Fig. 3. Greater proportions of participants in the guselkumab 400 mg SC q4w to 100 mg SC q8w group (43.5%) and in the guselkumab 400 mg SC q4w to 200 mg SC q4w group (60.0%) achieved endoscopic response at Week 48 compared with placebo (0.0%) (Fig. 3). Greater proportions of guselkumab-treated participants achieved an alternative definition of endoscopic response (>50% improvement from baseline in SES-CD score or SES-CD score ≤2) at Week 48 compared with placebo (Fig. 3). In the East Asian population, clinical remission at Week 12, clinical response at Week 12 (Supplementary Fig. 2), PRO-2 remission at Week 12, endoscopic response at Week 12, clinical remission at Week 24, endoscopic response at Week 48, and clinical remission at Week 48 was achieved in greater proportions of bio-naive participants, those with an inadequate response or intolerance to biologics, and those with an inadequate response or intolerance to conventional CD therapies in the guselkumab groups versus placebo (Supplementary Fig. 3).
Long-term efficacy endpoints in East Asian participants versus global study participants. (A) Clinical remission at Weeks 24 and 48. (B) Endoscopic and deep remission outcomes at Week 48. Global GRAVITI study data were previously reported.19 All participants in all treatment groups who met the rescue criteria were considered not to have met efficacy endpoints after Week 16. Clinical remission is defined as CDAI score <150. Endoscopic response is defined as ≥50% improvement from baseline in SES-CD score. Endoscopic response (alternative definition) is defined as >50% improvement from baseline in SES-CD score or SES-CD score ≤2. Endoscopic remission is defined as SES-CD score ≤4 and at least a 2-point reduction from baseline and no subscore greater than 1 in any individual component. Deep remission is defined as achieving both clinical remission and endoscopic remission. Participants who had a CD-related surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID-19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID- 19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. CDAI, Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease; CD, Crohn’s disease; COVID-19, coronavirus disease 2019; SC, subcutaneous; q4w, every 4 weeks; q8w, every 8 weeks.
3) Additional Clinical and Endoscopic Endpoints
Through Week 48, clinical response or PRO-2 remission was achieved in greater proportions of participants in each guselkumab treatment group compared with placebo (Supplementary Figs. 4 and 5). Greater proportions of guselkumab-treated participants achieved clinical response as early as Week 4 (the first assessment and after only one SC guselkumab dose). Greater proportions of guselkumab-treated participants achieved endoscopic remission at Week 12 and Week 48 compared with placebo (Fig. 3, Supplementary Table 2). Greater proportions of participants in the guselkumab 400 mg SC q4w to 100 mg SC q8w group (21.7%) and in the guselkumab 400 mg SC q4w to 200 mg SC q4w group (35.0%) achieved endoscopic remission at Week 48 compared with placebo (0.0%) (Fig. 3). The composite endpoints of clinical remission and endoscopic response, and deep remission (both clinical remission and endoscopic remission) compared with placebo were achieved in greater proportions of guselkumab-treated participants (Fig. 3, Supplementary Table 2). By achieving IBDQ remission, health-related quality of life outcomes were improved in greater proportions of guselkumab-treated participants versus placebo through Week 48 (Supplementary Fig. 6).
3. Biomarkers
Compared with placebo, median CRP concentrations decreased through Week 48 with guselkumab treatment. A greater proportion of participants receiving guselkumab (400 mg SC q4w to 100 mg SC q8w group, 46.2%; 400 mg SC q4w to 200 mg SC q4w, 54.5%) achieved CRP levels that were within the normal range ( ≤5 mg/L) at Week 48 versus placebo (0.0%) among East Asian participants with an elevated CRP ( >5 mg/L) at baseline (Fig. 4A). Compared with placebo through Week 48, median fecal calprotectin concentrations decreased with guselkumab treatment. A greater proportion of guselkumab-treated East Asian participants (400 mg SC q4w to 100 mg SC q8w group, 40.0%; 400 mg SC q4w to 200 mg SC q4w, 31.3%) achieved levels that were below ≤ 250 μg/g at Week 48 versus placebo (0.0%) among those with fecal calprotectin levels >250 μg/g at baseline (Fig. 4B).
Biomarker levels through Week 48. (A) CRP. (B) Fecal calprotectin. All participants in all treatment groups who met the rescue criteria were considered not to have met efficacy endpoints after Week 16. Participants who had a CD-related surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID-19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. CRP, C-reactive protein; CD, Crohn’s disease; COVID-19, coronavirus disease 2019; SC, subcutaneous; q4w, every 4 weeks; q8w, every 8 weeks.
4. Safety
The mean duration of follow-up in the East Asian population was 25.6 weeks for the placebo group, 47.5 weeks for the guselkumab 400 mg SC q4w to 100 mg SC q8w group, and 48.4 weeks for the guselkumab 400 mg SC q4w to 200 mg SC q4w group (Table 2). Due to the number of participants who met rescue criteria and crossed over to guselkumab, there was a shorter duration of follow-up for the placebo group.
Key Safety Events through Week 48: East Asian Study Participants (Safety Analysis Set)
AEs were reported through Week 48 in 19/28 (392.5 events per 100 PYs of follow-up) participants in the placebo group, 19/23 (248.3 per 100 PYs) in the guselkumab 400 mg SC q4w to 100 mg SC q8w group, and 18/20 (447.0 per 100 PYs) in the guselkumab 400 mg SC q4w to 200 mg SC q4w group. Upper respiratory tract infection, abdominal pain, and COVID-19 were the most reported AEs through Week 48 in East Asian participants in the guselkumab groups (Table 2).
The proportion of guselkumab-treated East Asian participants reporting ≥1 SAE or AE leading to discontinuation of study agent was not greater than placebo through Week 48. In 2/28 (14.5 per 100 PYs) placebo participants, 1/23 (4.8 per 100 PYs) guselkumab 400 mg SC q4w to 100 mg SC q8w participant, and 1/20 (5.4 per 100 PYs) guselkumab 400 mg SC q4w to 200 mg SC q4w participant, SAEs were reported. The proportion of East Asian participants with AEs leading to discontinuation of study agent through Week 48 was 2/28 (14.5 per 100 PYs) for the placebo group and none for the guselkumab groups. CD and nodule formation at the administration site were the causes of discontinuation for these placebo participants. Serious infection rates were low (3.4%) and there were no AEs of interest in guselkumab-treated participants (Table 2). Safety in Chinese and Japanese participants are presented in Supplementary Tables 3 and 4.
5. Immunogenicity
Through Week 48, antibodies to guselkumab were detected in 7 out of 57 (12.3%) guselkumab-treated East Asian participants who had 1 or more samples after the first guselkumab administration. Only 3 out of 57 (5.3%) were positive for neutralizing antibodies. No effects of antibodies to guselkumab were observed on injection-site reactions, efficacy, or serum guselkumab concentrations.
DISCUSSION
The baseline characteristics, efficacy, and safety of guselkumab induction and maintenance therapy in the subgroup of East Asian participants with moderately to severely active CD was broadly consistent with observations in the global study population (Figs. 2 and 3). The clinical course of CD in Asian patients has been shown to be a milder disease course [6]; however, baseline characteristics and baseline disease severity scores of East Asian and global study participants were similar, with a few exceptions. In the global study, 46.4% of participants were biologic naive compared to 28.2% of East Asian participants; 46.4% of the global study population had an inadequate response or intolerance to biologics compared to 67.6% of East Asian participants. At baseline, elevated CRP ( >5 mg/L) was reported in 48 (67.6%) East Asian participants and elevated fecal calprotectin ( >250 μg/g) was reported in 62 (87.3%) East Asian participants; numerically greater than the global study population (CRP, 54.8%; fecal calprotectin, 71.7%) [19]. The duration of CD at baseline was numerically higher in the guselkumab 400 mg SC q4w to 100 mg SC q8w group (8.92 years) than in the 400 mg SC q4w to 200 mg SC q4w group (4.18 years) (Table 1).
Guselkumab-treated participants achieved higher rates of co-primary endpoints and secondary outcomes compared to placebo. The co-primary endpoint of clinical remission at Week 12 was achieved by 41.9% of guselkumab-treated East Asian participants versus 56.1% of global study participants (Fig. 2). Over time, higher proportions of East Asian participants in both guselkumab groups achieved clinical remission (69.6% at Week 24 and at Week 48 in the 400 mg SC q4w to 100 mg SC q8w group; 55% at Week 24 and 60% at Week 48 in the 400 mg SC q4w to 200 mg SC q4w group) compared to placebo. Endoscopic response at Week 12 was achieved by similar proportions of participants in the East Asian subgroup (39.5%) versus the global study (41.3%), which suggests that mucosal healing rates were similar despite a numerically lower proportion of East Asian participants having clinical symptom relief at Week 12. Similar to the overall study, guselkumab showed efficacy in both bio-naive participants and those with intolerance or inadequate response to biologics.
The safety results of the East Asian subgroup were consistent with other indications and the GRAVITI global study [13-15,19,24-27]. Through Week 48, safety event rates per 100 PYs were similar between the guselkumab (400 mg SC q4w to 100 mg SC q8w and 400 mg SC q4w to 200 mg SC q4w: 248.3 and 447.0, respectively) and placebo groups (392.5).
Immunogenicity rates were low among guselkumab-treated East Asian participants (7/57; 12.3%) through Week 48, with SC induction and SC maintenance. Three East Asian participants with antibodies tested positive for neutralizing antibodies, and no impact on efficacy or safety was observed.
A limitation was that the subgroup analysis was not powered to detect treatment differences in East Asian participants. No statistical comparisons were made between treatment cohorts for this subgroup analysis. Despite the constraints posed by the limited number of East Asian participants, a substantial improvement was observed.
Overall, the results support the efficacy and safety of guselkumab SC induction and SC maintenance regimens in East Asian participants with moderately to severely active CD and are consistent with the global population.
Notes
Funding Source
This study was supported by Johnson & Johnson, and employees of Johnson & Johnson had a role in study design, analysis, interpretation and publication.
Conflict of Interest
Liu W, Guo H, Kim TO, and Takeuchi K serve as clinical investigators for Johnson & Johnson. Hisamatsu T receives grant support from AbbVie, Daiichi-Sankyo, EA Pharma Co., Ltd., JIMRO, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co., Ltd.; receives consulting fees from EA Pharma Co., Ltd., Johnson & Johnson, Gilead Sciences, Eli Lilly, and Bristol Myers Squibb; and receives lecture fees from AbbVie, EA Pharma Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Kissei Pharmaceutical Co., Ltd. Fable J, Olurinde M, Wahking B, Herr K, and Zhuo J are employees of Johnson & Johnson. Cao Q serves as a steering committee adviser for Bristol Myers Squibb Company and Johnson & Johnson and receives research grants from Johnson & Johnson and Takeda.
Data Availability Statement
The data sharing policy of Johnson & Johnson is available at https://innovativemedicine.jnj.com/our-innovation/clinicaltrials/transparency. As noted on this site, requests for access to the trial data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
Author Contributions
Conceptualization: Olurinde M, Herr K, Wahking B. Data curation: Zhuo J. Formal analysis: Zhuo J. Investigation: Liu W, Guo H, Kim TO, Takeuchi K, Hisamatsu T, Fable J, Olurinde M. Methodology: Olurinde M. Writing–original draft: Fable J, Olurinde M, Wahking B, Herr K, and Zhuo J. Writing–review & editing: all authors. Approval of final manuscript: all authors.
Additional Contributions
Medical writing support was provided by Jackie L. Johnson, PhD, of Certara under the direction of the authors in accordance with Good Publication Practice guidelines (Ann Inter Med. 2015;163:461-464) and was funded by Johnson & Johnson.
Supplementary Material
Supplementary materials are available at the Intestinal Research website (https://www.irjournal.org).
Supplementary Table 1.
Summary of Co-Primary and Secondary Efficacy Outcomes through Week 48 in Chinese and Japanese Participants
Supplementary Table 2.
Endoscopic Outcomes at Week 12 and Week 48
Supplementary Table 3.
Key Safety Events through Week 48 in Chinese Participants: Safety Analysis Set
Supplementary Table 4.
Key Safety Events through Week 48 in Japanese Participants: Safety Analysis Set
Supplementary Fig. 1.
East Asian participant disposition through Week 48. aRescue treatment: guselkumab 400 mg SC at Weeks 16, 20, and 24, followed by 100 mg SC q8w; bIncludes participants who discontinued study agent administration prior to Week 12; cIncludes participants who terminated the study prior to Week 12. SC, subcutaneous; q4w, every 4 weeks; q8w, every 8 weeks.
Supplementary Fig. 2.
(A) Co-primary endpoints and (B) additional Week 12 endpoints for the overall population and the subpopulations of bio-naive, inadequate response or intolerance to biologics, and inadequate response or intolerance to conventional CD therapies. Clinical remission is defined as CDAI score <150. Endoscopic response is defined as ≥50% improvement from baseline in SES-CD score. PRO-2 remission is defined as abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3, and no worsening of abdominal pain or stool frequency from baseline. Clinical response is defined as ≥100-point reduction from baseline in CDAI score or CDAI score <150. Participants who had a CD-related surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID-19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. CD, Crohn’s disease; SC, subcutaneous; q4w, every 4 weeks; CDAI, Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease; PRO-2, Patient-Reported Outcome-2; COVID-19, coronavirus disease 2019.
Supplementary Fig. 3.
Clinical and endoscopic endpoints during maintenance. All participants in all treatment groups who met the rescue criteria were considered not to have met efficacy endpoints after Week 16. Clinical remission is defined as CDAI score <150. Endoscopic response is defined as ≥50% improvement from baseline in SES-CD score. Participants who had a CD-related surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID- 19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. CD, Crohn’s disease; SC, subcutaneous; q4w, every 4 weeks; q8w, every 8 weeks; CDAI, Crohn’s Disease Activity Index; COVID-19, coronavirus disease 2019; SES-CD, Simple Endoscopic Score for Crohn’s Disease.
Supplementary Fig. 4.
PRO-2 remission through Week 48. PRO-2 remission is defined as AP mean daily score ≤1 and SF mean daily score ≤3, and no worsening of AP or SF from baseline. All participants in all treatment groups who met the rescue criteria were considered not to have met efficacy endpoints after Week 16. Participants who had a CD-related surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID-19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. PRO-2, Patient-Reported Outcome- 2; SC, subcutaneous; q4w, every 4 weeks; q8w, every 8 weeks; AP, abdominal pain; SF, stool frequency; CD, Crohn’s disease; COVID- 19, coronavirus disease 2019.
Supplementary Fig. 5.
Clinical response through Week 48. All participants in all treatment groups who met the rescue criteria were considered not to have met efficacy endpoints after week 16. Clinical response is defined as ≥100-point reduction from baseline in CDAI score or CDAI score <150. Participants who had a CD-related surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID-19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. SC, subcutaneous; q4w, every 4 weeks; q8w, every 8 weeks; CDAI, Crohn’s Disease Activity Index; CD, Crohn’s disease; COVID-19, coronavirus disease 2019.
Supplementary Fig. 6.
IBDQ remission through Week 48. IBDQ remission was defined as IBDQ score ≥170. All participants in all treatment groups who met the rescue criteria were considered not to have met efficacy endpoints after Week 16. Participants who had a CDrelated surgery, a prohibited change in concomitant CD medications, discontinued study agent due to lack of efficacy or an adverse event of worsening CD, or discontinued study agent due to COVID-19 infection or for reasons other than lack of efficacy or an adverse event of worsening CD, COVID-19-related reasons, or regional crisis before the designated analysis timepoint were considered not to have achieved the binary endpoint from that timepoint onwards. Participants who had discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available, to determine responder status from that timepoint onwards. IBDQ, Inflammatory Bowel Disease Questionnaire; q4w, every 4 weeks; q8w, every 8 weeks; SC, subcutaneous; CD, Crohn’s disease; COVID-19, coronavirus disease 2019.