Guselkumab efficacy and safety in East Asian participants with moderately to severely active Crohn’s disease: subgroup analysis of the phase 3 GALAXI 2 and GALAXI 3 trials

1. Study Design and Participants

The global GALAXI 2 and 3 trials (NCT03466411) were conducted across 40 countries between January 8, 2020, and October 20, 2023. Details of the study design and participant eligibility criteria are reported elsewhere [12]. An overview of the study design is presented in Fig. 1. Eligible participants were adults (≥ 18 years of age) with moderately to severely active CD of at least 3 months’ duration (Crohn’s Disease Activity Index [CDAI] score of 220 to 450 and either mean daily stool frequency [SF] count > 3 or abdominal pain [AP] score > 1), a Simple Endoscopic Score for Crohn’s Disease (SES-CD) ≥ 6 (≥ 4 for isolated ileal disease) at screening, and inadequate response or intolerance to conventional or biologic therapy. Exclusion criteria included prior treatment with a biologic therapy targeting IL-12 or IL-23, except limited prior ustekinumab exposure at approved dosages and intervals with no evidence of inadequate response or intolerance.

Fig. 1.

Overview of GALAXI 2 and 3 trial design. ^aBiologic therapies: tumor necrosis factor antagonists or vedolizumab. To maintain treatment masking, all participants received active and/or placebo IV q4w through week 12 and active or placebo SC q4w through week 48. CDAI, Crohn’s Disease Activity Index; SF, stool frequency; AP, abdominal pain; SES-CD, Simple Endoscopic Score for Crohn’s Disease; 6-MP, 6-mercaptopurine; AZA, azathioprine; MTX, methotrexate; GUS, guselkumab; IV, intravenous; q4w, every 4 weeks; q8w, every 8 weeks; SC, subcutaneous; UST, ustekinumab.

The trials employed a treat-through design, whereby participants were randomized at week 0 and remained on the assigned treatment regimen through week 48. Participants were randomized in a 2:2:2:1 ratio to the following IV induction and SC maintenance regimens: guselkumab 200 mg IV every 4 weeks (q4w) at weeks 0, 4, and 8, followed by 100 mg SC every 8 weeks (q8w; guselkumab IV to 100 mg SC q8w); guselkumab 200 mg IV q4w at weeks 0, 4, and 8, followed by 200 mg SC q4w (guselkumab IV to 200 mg SC q4w); ustekinumab (approximately 6 mg/kg) IV at week 0 then 90 mg SC q8w; or placebo IV at weeks 0, 4, and 8. Placebo group participants not in clinical response (defined as ≥ 100-point decrease in CDAI score from baseline or achieving a CDAI score < 150) at week 12 received rescue treatment with ustekinumab (approximately 6 mg/kg IV at week 12 then 90 mg SC q8w).

The trial protocol was approved by an institutional review board or ethics committee at each participating site, including The First Affiliated Hospital, Sun Yat-sen University (IRB No. 2018-033-03). The trial was conducted in compliance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable local regulations [12]. All participants provided written informed consent prior to any study procedures.

The East Asian subpopulation included all participants from study sites located in China, Japan, South Korea, and the Taiwan region. Country-specific subgroup data for participants from Japan are included in Supplementary Table 1 and Supplementary Fig. 1.

2. Outcome Assessments and Endpoint Definitions

Efficacy assessments included symptom-based, endoscopic, and biomarker components. For evaluation of clinical response and remission, the CDAI components were assessed at each study visit (q4w), and a CDAI score was calculated if at least 4 of 8 components were available. Clinical response was defined as a ≥ 100-point reduction from baseline in CDAI score or a CDAI score < 150. Clinical remission was defined as a CDAI score < 150 (corticosteroid-free clinical remission: clinical remission with no receipt of corticosteroids for 90 days before the indicated timepoint). Remission based on the 2 patient-reported outcome (PRO) components of the CDAI (i.e., PRO-2 remission) was defined as AP mean daily score ≤ 1 and SF mean daily score ≤ 3 and no worsening of AP or SF from baseline. For evaluation of endoscopic endpoints, video endoscopic assessments of the terminal ileum and colon were done at screening and at weeks 12 and 48 and scored by blinded central readers using the SES-CD. Endoscopic response was defined as ≥ 50% improvement from baseline in SES-CD score or SES-CD score ≤ 2, while endoscopic remission was defined as SES-CD score ≤ 4, ≥ 2-point reduction from baseline, and no SES-CD subscore > 1 in any individual component.

Fatigue was assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a (SF-7a) at baseline and at weeks 8, 12, 24, and 48. Fatigue response was defined as a ≥ 7-point improvement from baseline in PROMIS Fatigue SF-7a score. For biomarker assessments, C-reactive protein (CRP) measurements were performed q4w through week 24 and q8w thereafter. Fecal calprotectin assessments were done at baseline and at weeks 4, 8, 12, 24, and 48.

The efficacy outcomes in GALAXI 2 and 3 were designed to assess short-term and long-term components. The composite co-primary endpoints compared guselkumab versus placebo based on (1) clinical response at week 12 and clinical remission at week 48 and (2) clinical response at week 12 and endoscopic response at week 48. Major secondary endpoints evaluating the short-term efficacy of guselkumab IV induction versus placebo (at week 12 unless otherwise noted) included clinical remission, endoscopic response, the composite of clinical remission and endoscopic response, fatigue response, and clinical response at week 4. Major secondary endpoints further assessing the short- and long-term efficacy of guselkumab (at week 12 and week 48) were (1) the composite of clinical response at week 12 and corticosteroid-free clinical remission at week 48 and (2) the composite of clinical response at week 12 and endoscopic remission at week 48. Finally, major secondary outcomes designed to evaluate the long-term efficacy of guselkumab SC maintenance versus ustekinumab at week 48 included clinical remission, endoscopic response, endoscopic remission, deep remission (clinical remission and endoscopic remission), and the composite of clinical remission and endoscopic response. PRO-2 remission was evaluated as an additional endpoint. Supplemental analyses were done in subpopulations based on CD medication history.

Safety was evaluated based on treatment-emergent adverse event (TEAE) reporting, infections, physical examinations, clinical laboratory tests, and vital signs. Levels of serum anti-drug antibodies were determined q4w through week 12 then q8w from week 24 using validated assays.

3. Statistical Analysis

Details of the primary analyses in the global GALAXI 2 and 3 populations are reported elsewhere [12]; we describe a subgroup analysis using pooled GALAXI 2 and 3 data for East Asian participants. The efficacy and safety analyses were based on the primary analysis set of randomized participants who received ≥ 1 (partial or complete) dose of study intervention and had a screening SES-CD score ≥ 6 (or ≥ 4 for isolated ileal disease). Data are summarized descriptively. Subgroup analyses were not preplanned with alpha control in the original study design. No statistical comparisons between treatment cohorts were made for these subgroup analyses. Pooled GALAXI 2 and 3 data were also included in the supplementary analyses of Japanese participants.

1. Participants: East Asian Subgroup

Of the 1,021 participants included in the pooled primary analysis set population of the global GALAXI 2 and 3 trials, 192 (98 GALAXI 2 and 94 GALAXI 3) were from sites located in East Asia and were included in the present subgroup analysis (118 China, 48 Japan, 23 South Korea, and 3 Taiwan region). Thirteen East Asian participants discontinued trial participation prior to week 48, most commonly due to participant withdrawal (Fig. 2).

Fig. 2.

Participant disposition in GALAXI 2 and 3 for the East Asian subpopulation. ^aParticipants who did not receive a maintenance dose and those who received placebo SC during the maintenance period; ^bParticipants who were not in clinical response to placebo induction dosing and crossed over to UST at W12 and continued to receive UST SC dosing in the maintenance period. GUS, guselkumab; IV, intravenous; SC, subcutaneous; q8w, every 8 weeks; q4w, every 4 weeks; UST, ustekinumab; W, week.

Baseline demographic and disease characteristics were generally similar across treatment groups of East Asian participants (Table 1). Overall, 18.8% (36/192) of East Asian participants were naive to biologic therapy, while 74.0% (142/192) had a history of intolerance or inadequate response to prior biologic therapy. As observed for the global population [12], the proportion of participants with ileal-only disease was higher in the guselkumab IV to 200 mg SC q4w group compared with other treatment groups.

Table 1.

Baseline Demographic and Disease Characteristics in GALAXI 2 and 3 (East Asian Subpopulation)

Relative to the global GALAXI 2 and 3 population, the East Asian subgroup included more men, fewer participants with SF count > 3, fewer participants with ileum-only disease, and more participants with ileocolonic disease (Supplementary Table 2). Mean age (33.5 years) and body weight (58.0 kg) were lower for the East Asian subgroup relative to the global population (36.5 years; 68.2 kg).

2. Short-Term and Long-Term Guselkumab Efficacy in East Asian Participants

Consistent with findings in the global trials [12], numerically greater proportions of East Asian participants in both guselkumab cohorts achieved composite efficacy endpoints with both a short-term (week 12) and long-term (week 48) component relative to placebo participants (Fig. 3). In the East Asian subpopulation, 35/63 (55.6%) guselkumab IV to 100 mg SC q8w participants and 26/51 (51.0%) guselkumab IV to 200 mg SC q4w participants achieved the co-primary endpoint of clinical response at week 12 and clinical remission at week 48 compared with 1/32 (3.1%) placebo participants (Fig. 3A). These rates were similar to those observed in the global GALAXI 2 and 3 population (guselkumab IV to 100 mg SC q8w: 47.9%; guselkumab IV to 200 mg SC q4w: 51.4%; placebo: 12.2%) [12]. For the composite co-primary endpoint of clinical response at week 12 and endoscopic response at week 48, the response rate was 28/63 (44.4%) among East Asian guselkumab IV to 100 mg SC q8w participants and 20/51 (39.2%) among guselkumab IV to 200 mg SC q4w participants compared with 0/32 placebo participants (Fig. 3B). Responses in the East Asian subgroup were broadly consistent with those observed for the global population (guselkumab IV to 100 mg SC q8w: 36.4%; guselkumab IV to 200 mg SC q4w: 37.2%; placebo: 5.4%) [12]. Numerically higher proportions of East Asian participants receiving guselkumab also achieved the composite major secondary outcomes evaluating short- and long-term efficacy relative to placebo based on clinical response at week 12 and 90-day corticosteroid-free clinical remission at week 48 (Fig. 3C) and clinical response at week 12 and endoscopic remission at week 48 (Fig. 3D). Relative to global participants, placebo response rates tended to be numerically lower and guselkumab response rates higher among East Asian participants across these efficacy endpoints.

Fig. 3.

Proportions of participants achieving the composite primary (A, B) and major secondary (C, D) endpoints assessing short-term (W12) and long-term (W48) efficacy of guselkumab in the GALAXI 2 and 3 trials (East Asian subpopulation and global population).^a Handling of missing data: participants who had a CD-related surgery; had a prohibited change in concomitant CD medication (including placebo participants in clinical response who crossover to ustekinumab at W12); discontinued study agent due to lack of efficacy, an AE of worsening CD, or W20/24 nonresponder; or discontinued study agent for any other reason other than COVID-19-related reasons or regional crisis prior to the analysis timepoint were considered not to have met the endpoint criteria. 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 and nonresponder status at W12 and W48. After accounting for the above, participants who were missing CDAI score at W12 or CDAI or SES-CD score at W48 were considered not to have achieved the relevant endpoint. ^aData for global participants have been reported previously [12]; ^bClinical response is defined as ≥100-point reduction from baseline in CDAI score or CDAI score <150; ^cClinical remission is defined as CDAI score <150; ^dEndoscopic response is defined as ≥50% improvement from baseline in SES-CD score or SES-CD score ≤2; ^eCorticosteroid-free clinical remission is defined as clinical remission with no receipt of corticosteroids for 90 days before indicated timepoint; ^fEndoscopic remission (global definition) 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. W, week; GUS, guselkumab; IV, intravenous; SC, subcutaneous; q8w, every 8 weeks; q4w, every 4 weeks; CD, Crohn’s disease; AE, adverse event; COVID-19, coronavirus disease 2019; CDAI, Crohn’s Disease Activity Index; SES-CD, Simple Endoscopic Score for Crohn’s Disease.

Rates of attaining secondary endpoints designed to evaluate the short-term efficacy of guselkumab IV induction are summarized in Table 2. East Asian participants receiving guselkumab 200 mg IV achieved numerically higher rates of clinical remission, fatigue response, endoscopic response, and the composite of clinical remission and endoscopic response at week 12 compared with placebo participants. Placebo rates were generally lower for East Asians compared with the global population. In the guselkumab group, rates of attaining week 12 efficacy endpoints were similar between the East Asian subgroup and the global population.

Table 2.

Summary of Short-Term Efficacy Endpoints Evaluating GUS 200 mg IV Induction at Week 12 in GALAXI 2 and 3 (East Asian Subpopulation and Global Population)^a

CDAI scores generally decreased (indicating improvement) over time from week 4 through week 48 in East Asian guselkumab participants (Fig. 4A). Clinical and PRO-2 remission rates likewise increased throughout the trial period in guselkumab participants from approximately 10% to 30% at week 4 to > 60% by week 48 (Fig. 4B and C).

Fig. 4.

Plots of change from baseline in CDAI scores (A), clinical remission rates (B) and PRO-2 remission rates (C) through W48 in GALAXI 2 and 3 (East Asian subpopulation). Handling of missing data: Participants who had a CD-related surgery, a prohibited change in concomitant CD medication, or discontinued study agent due to lack of efficacy, an AE of worsening CD, or W20/24 nonresponder or discontinued study agent for any other reason other than COVID-19-related reasons or regional crisis prior to the analysis timepoint were considered not to have met the endpoint criteria. 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 and nonresponder status from that timepoint onwards. After accounting for the above, participants who were missing relevant scores at the designated analysis time-point were considered not to have achieved the endpoint at that timepoint. Clinical remission is defined as CDAI score <150. PRO-2 remission is defined as AP mean daily score at or below 1 and SF mean daily score at or below 3, and no worsening of AP or SF from baseline. CDAI, Crohn’s Disease Activity Index; GUS, guselkumab; IV, intravenous; SC, subcutaneous; q8w, every 8 weeks; q4w, every 4 weeks; PRO-2, patient-reported outcome-2; W, week; CD, Crohn’s disease; AE, adverse event; COVID-19, coronavirus disease 2019; AP, abdominal pain; SF, stool frequency.

Rates of attaining secondary endpoints evaluating the long-term efficacy of guselkumab SC maintenance treatment relative to the active comparator ustekinumab at week 48 are summarized in Fig. 5. Numerically higher proportions of East Asian guselkumab versus ustekinumab participants achieved endoscopic response, endoscopic remission, the composite of clinical remission and endoscopic response, and deep remission (composite of clinical remission and endoscopic remission) at week 48. Response rates among East Asian participants were similar to the corresponding rates in the global GALAXI 2 and 3 population [12].

Fig. 5.

Summary of proportions of participants achieving endoscopic response (A), endoscopic remission (B), the composite of clinical remission and endoscopic response (C), and deep remission (D) at W48 in GALAXI 2 and 3 (East Asian subpopulation and global population). Data for global participants have been reported previously [12]. Handling of missing data: Participants who had a CD-related surgery, a prohibited change in concomitant CD medication, or discontinued study agent due to lack of efficacy, an AE of worsening CD, or W20/24 nonresponder or discontinued study agent for any other reason other than COVID-19-related reasons or regional crisis prior to the analysis timepoint were considered not to have met the endpoint criteria. 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. After accounting for the above, participants who were missing endpoint data at the indicated timepoint were considered not to have achieved the relevant endpoint. ^aEndoscopic response is defined as ≥50% improvement from baseline in SES-CD score or SES-CD score ≤2; ^bEndoscopic remission (global definition) 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; ^cClinical remission is defined as CDAI score <150; ^dDeep remission is defined as the composite of clinical remission and endoscopic remission. W, week; GUS, guselkumab; IV, intravenous; SC, subcutaneous; q8w, every 8 weeks; q4w, every 4 weeks; AE, adverse event; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; COVID-19, coronavirus disease 2019; SES-CD, Simple Endoscopic Score for Crohn’s Disease.

The effects of guselkumab relative to ustekinumab on biomarkers of disease activity (CRP and fecal calprotectin concentrations) in East Asian participants are presented in Supplementary Figs. 2 and 3. Among participants with elevated CRP (> 3 mg/L) concentrations at baseline, approximately 55% of guselkumab-treated participants had normal CRP levels (i.e., ≤ 3 mg/L) at week 48. Among those with elevated fecal calprotectin levels (> 250 µg/g) at baseline, approximately 41% of guselkumab-treated participants achieved normal levels (i.e., ≤ 250 µg/g) by week 48.

Efficacy of guselkumab in East Asian participants was generally consistent across subgroups with a history of inadequate response or intolerance to biologic therapies, inadequate response to prior conventional therapy, and those without prior exposure to biologic therapies; however, participant numbers in these subgroups were small (Supplementary Tables 3-5).

3. Safety in East Asian Participants

Table 3 summarizes TEAEs reported in East Asian and global GALAXI 2 and 3 trial participants. In the East Asian subpopulation, TEAEs were reported in 55/63 (87.3%) participants in the guselkumab IV to 100 mg SC q8w group, 46/51 (90.2%) in the guselkumab IV to 200 mg SC q4w group, 23/32 (71.9%) in the placebo group (excluding events after ustekinumab crossover), and 41/46 (89.1%) in the ustekinumab group through week 48 (Table 3). The rates of TEAEs in East Asian participants were numerically higher than in the global population in all treatment groups, including the placebo group (guselkumab IV to 100 mg SC q8w: 219/286 [76.6%]; guselkumab IV to 200 mg SC q4w: 230/296 [77.7%]; placebo: 79/148 [53.4%]; ustekinumab: 229/291 [78.7%]).

Table 3.

Summary of TEAEs through Week 48 in GALAXI 2 and 3 (East Asian Subpopulation and Global Population)^a

The most common TEAEs reported in East Asian guselkumab participants were coronavirus disease 2019, upper respiratory tract infections, and arthralgia (Supplementary Table 6). Placebo participants experienced higher rates of TEAEs of CD worsening (3/32 [9.4%], excluding events after crossover to ustekinumab) relative to guselkumab and ustekinumab group participants (guselkumab IV to 100 mg SC q8w: 0/63; guselkumab IV to 200 mg SC q4w: 3/51 [5.9%]; ustekinumab: 2/46 [4.3%]). Frequencies and types of common TEAEs were generally consistent between East Asian and global trial participants, with some exceptions (e.g., upper respiratory tract infections and pyrexia were more common among East Asians).

Serious TEAEs were reported in 11 East Asian participants with guselkumab (guselkumab IV to 100 mg SC q8w: 7 [11.1%]; guselkumab IV to 200 mg SC q4w: 4 [7.8%]), 5 (15.6%) placebo participants, and 6 (13.0%) ustekinumab participants (Table 3, Supplementary Table 7). Rates of serious TEAEs were similar in East Asian and global participants (Table 3). Most of the serious events reported in the East Asian subpopulation fell under the Medical Dictionary for Regulatory Activities system organ class of gastrointestinal disorders (guselkumab: 9 [7.9%]; placebo: 4 [12.5%]; ustekinumab: 4 [8.7%]) (Supplementary Table 7). Two guselkumab participants (guselkumab IV to 100 mg SC q8w: 1 [1.6%]; guselkumab IV to 200 mg SC q4w: 1 [2.0%]) experienced serious TEAEs of intestinal obstruction; no other serious TEAEs were reported in more than 1 guselkumab participant. Serious TEAEs of worsening CD were more frequent among placebo participants (2 [6.3%]) relative to guselkumab participants (1 [0.9%]).

Nine East Asian participants in the guselkumab groups (guselkumab IV to 100 mg SC q8w: 3 [4.8%]; guselkumab IV to 200 mg SC q4w: 6 [11.8%]), 3 (9.4%) placebo participants, and 2 (4.3%) ustekinumab participants discontinued study agent due to TEAEs (Table 3). Rates of TEAEs leading to discontinuation of study agent were similar to those reported in the global population (Table 3). Details of individual TEAEs leading to discontinuation of study agent in East Asian participants are summarized in Supplementary Table 7. Discontinuation due to TEAEs of worsening CD was more common in placebo participants (2 [6.3%]) relative to guselkumab participants (1 [0.9%]). No deaths were reported among East Asian participants.

Infections were reported in 36/63 (57.1%) participants in the guselkumab IV to 100 mg SC q8w group, 28/51 (54.9%) in the guselkumab IV to 200 mg SC q4w group, 8/32 (25.0%) in the placebo group (excluding events after ustekinumab crossover), and 24/46 (52.2%) in the ustekinumab group (Table 3). Rates of infection were generally similar to observations in the global population. Among East Asian participants, no serious infections or cases of tuberculosis were reported in guselkumab group participants.

Among East Asian participants with samples suitable for immunogenicity assessments, 1/63 (1.6%) guselkumab IV to 100 mg SC q8w and 8/50 (16.0%) guselkumab IV to 200 mg SC q4w participants had antibodies to guselkumab through week 48. Neutralizing antibodies were detected in 1 participant (in the guselkumab IV to 100 mg SC q8w group). Due to the low number of participants testing positive for antibodies to guselkumab, the relationship between anti-drug antibodies and efficacy or safety could not be assessed.

Safety data for the subgroup of participants from Japan are summarized in Supplementary Table 1.