TREMFYA Concentrate for solution for infusion Ref.[116446] Active ingredients: Guselkumab

Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors
ATC code: L04AC16

Mechanism of action

Guselkumab is a human IgG1λ monoclonal antibody (mAb) that binds selectively to the interleukin 23 (IL-23) protein with high specificity and affinity through the antigen binding site. IL-23 is a cytokine that is involved in inflammatory and immune responses. By blocking IL-23 from binding to its receptor, guselkumab inhibits IL-23-dependent cell signalling and release of proinflammatory cytokines.

Levels of IL-23 are elevated in the skin of patients with plaque psoriasis. In patients with ulcerative colitis or Crohn's disease, levels of IL-23 are elevated in the colon tissue. In in vitro models, guselkumab was shown to inhibit the bioactivity of IL-23 by blocking its interaction with cell surface IL-23 receptor, disrupting IL-23-mediated signalling, activation and cytokine cascades. Guselkumab exerts clinical effects in plaque psoriasis, psoriatic arthritis, ulcerative colitis, and Crohn's disease through blockade of the IL-23 cytokine pathway.

Myeloid cells expressing Fc-gamma receptor 1 (CD64) have been shown to be a predominant source of IL-23 in inflamed tissue in psoriasis, ulcerative colitis, and Crohn's disease. Guselkumab has demonstrated in vitro blocking of IL-23 and binding to CD64. These results indicate that guselkumab is able to neutralise IL-23 at the cellular source of inflammation.

Pharmacodynamic effects

In a Phase I study, treatment with guselkumab resulted in reduced expression of IL-23/Th17 pathway genes and psoriasis-associated gene expression profiles, as shown by analyses of mRNA obtained from lesional skin biopsies of patients with plaque psoriasis at Week 12 compared to baseline. In the same Phase I study, treatment with guselkumab resulted in improvement of histological measures of psoriasis at Week 12, including reductions in epidermal thickness and T-cell density. In addition, reduced serum IL-17A, IL-17F and IL-22 levels compared to placebo were observed in guselkumab treated patients in Phase II and Phase III plaque psoriasis studies. These results are consistent with the clinical benefit observed with guselkumab treatment in plaque psoriasis.

In psoriatic arthritis patients in Phase III studies, serum levels of acute phase proteins C-reactive protein, serum amyloid A, and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 were elevated at baseline. Guselkumab decreased the levels of these proteins within 4 weeks of initiation of treatment. Guselkumab further reduced the levels of these proteins by Week 24 compared to baseline and also to placebo.

In patients with ulcerative colitis or Crohn's disease, guselkumab treatment led to decreases in inflammatory markers including C-reactive protein (CRP) and faecal calprotectin through induction Week 12, which were sustained through one year of maintenance treatment. Serum protein levels of IL-17A, IL-22 and IFNγ were reduced as early as Week 4, and continued to decrease through induction Week 12. Guselkumab also reduced colon mucosal biopsy RNA levels of IL-17A, IL-22 and IFNγ at Week 12.

Clinical efficacy and safety

Ulcerative colitis

The efficacy and safety of guselkumab were evaluated in three Phase III multicentre, randomised, double-blind, placebo-controlled studies (QUASAR intravenous induction study, QUASAR maintenance study, and ASTRO subcutaneous induction study) in adult patients with moderately to severely active ulcerative colitis who had an inadequate response, loss of response, or intolerance to corticosteroids, conventional immunomodulators (AZA, 6-MP), biologic therapy (TNF blockers, vedolizumab), a Janus kinase (JAK) inhibitor, and/or sphingosine-1-phosphate receptor modulators (S1PRM) applicable only for ASTRO. In addition, efficacy and safety of guselkumab were evaluated in a randomised, double-blind, placebo-controlled, Phase IIb induction dose-finding study (QUASAR induction dose-ranging study) that enrolled a similar ulcerative colitis patient population as the Phase III induction study.

Disease activity was assessed by the modified Mayo score (mMS), a 3-component Mayo score (0-9) which consists of the sum of the following subscores (0 to 3 for each subscore): stool frequency (SFS), rectal bleeding (RBS), and findings on centrally reviewed endoscopy (ES). Moderately to severely active ulcerative colitis was defined as a mMS between 5 and 9, a RBS ≥1, and an ES of 2 (defined by marked erythema, absent vascular pattern, friability, and/or erosions) or an ES of 3 (defined by spontaneous bleeding and ulceration).

Induction study: QUASAR IS

In the induction study QUASAR IS, patients were randomised in a 3:2 ratio to receive either guselkumab 200 mg or placebo by intravenous infusion at Week 0, Week 4, and Week 8. A total of 701 patients were evaluated. At baseline the median mMS was 7, with 35.5% of patients having a baseline mMS of 5 to 6 and 64.5% having a mMS of 7 to 9, and 67.9% of patients with a baseline ES of 3. The median age was 39 years (ranging from 18 to 79 years); 43.1% were female; and 72.5% identified as White, 21.4% as Asian and 1% as Black.

Enrolled patients were permitted to use stable doses of oral aminosalicylates, MTX, 6-MP, AZA and/or oral corticosteroids. At baseline, 72.5% of patients were receiving aminosalicylates, 20.8% of patients were receiving immunomodulators (MTX, 6-MP, or AZA), and 43.1% of patients were receiving corticosteroids. Concomitant biologic therapies or JAK inhibitors were not permitted.

A total of 49.1% of patients had previously failed at least one biologic therapy, and/or JAK inhibitor. Of these patients, 87.5%, 54.1% and 18% had previously failed a TNF blocker, vedolizumab or a JAK inhibitor, respectively, and 47.4% had failed treatment with 2 or more of these therapies. A total of 48.4% of patients were biologic and JAK inhibitor naïve, and 2.6% had previously received but had not failed a biologic or JAK inhibitor.

The primary endpoint was clinical remission as defined by the mMS at Week 12. Secondary endpoints at Week 12 included symptomatic remission, endoscopic healing, clinical response, histologic endoscopic mucosal healing, fatigue response and IBDQ remission (Table 3).

Significantly greater proportions of patients were in clinical remission at Week 12 in the guselkumab treated group compared to the placebo group.

Table 3. Proportion of patients meeting efficacy endpoints at Week 12 in QUASAR IS:

^a Guselkumab 200 mg as an intravenous induction at Week 0, Week 4, and Week 8.
^b A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability.
^c p<0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method (adjusted for stratification factors: biologic and/or JAK-inhibitor failure status and concomitant use of corticosteroids at baseline).
^d An additional 7 patients in the placebo group and 11 patients in the guselkumab group were previously exposed to but did not fail a biologic or JAK inhibitor.
^e Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) and/or a Janus kinase (JAK) inhibitor for ulcerative colitis.
^f A stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0.
^g An endoscopy subscore of 0 or 1 with no friability.
^h Decrease from induction baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥ 1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.
ⁱ A combination of histologic healing [neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system] and endoscopic healing as defined above.
^j Fatigue was assessed using the PROMIS-Fatigue Short form 7a. Fatigue response was defined as a ≥7-point improvement from baseline which is considered clinically meaningful.
^k Total Inflammatory Bowel Disease Questionnaire score ≥170.

QUASAR IS and QUASAR induction dose-ranging study also enrolled 48 patients with a baseline mMS of 4, including an ES of 2 or 3 and a RBS ≥1. In patients with a baseline mMS of 4, guselkumab efficacy relative to placebo, as measured by clinical remission, clinical response, and endoscopic healing at Week 12, was consistent with the total moderately to severely active ulcerative colitis population.

Rectal bleeding and stool frequency subscores:

Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in patients treated with guselkumab and continued to decrease through Week 12.

Maintenance study: QUASAR MS

The QUASAR MS evaluated 568 patients who achieved clinical response at 12 weeks following the intravenous administration of guselkumab in either QUASAR IS or from the QUASAR induction dose-ranging study. In the QUASAR MS, these patients were randomised to receive a subcutaneous maintenance regimen of either guselkumab 100 mg every 8 weeks, guselkumab 200 mg every 4 weeks or placebo for 44 weeks.

The primary endpoint was clinical remission as defined by mMS at Week 44. Secondary endpoints at Week 44 included but were not limited to symptomatic remission, endoscopic healing, corticosteroid-free clinical remission, histologic endoscopic mucosal healing, fatigue response and IBDQ remission (Table 4).

Significantly greater proportions of patients were in clinical remission at Week 44 in both guselkumab treated groups compared to the placebo.

Table 4. Proportion of patients meeting efficacy endpoints at Week 44 in QUASAR MS:

^a Guselkumab 100 mg as a subcutaneous injection every 8 weeks after the induction regimen.
^b Guselkumab 200 mg as a subcutaneous injection every 4 weeks after the induction regimen.
^c A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability.
^d Patients who achieved clinical response 12 weeks following the intravenous administration of guselkumab in either QUASAR induction study or QUASAR induction dose-ranging study.
^e p<0.001, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomisation stratification factors.
^f An additional 7 patients in the placebo group, 6 patients in the guselkumab 100 mg group, and 6 patients in the guselkumab 200 mg group were previously exposed to but did not fail a biologic or JAK inhibitor.
^g Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) and/or a Janus kinase [JAK] inhibitor for ulcerative colitis.
^h A stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0.
ⁱ Not requiring any treatment with corticosteroids for at least 8 weeks prior to Week 44 and also meeting the criteria for clinical remission at Week 44.
^j An endoscopy subscore of 0 or 1 with no friability.
^k A combination of histologic healing [neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system] and endoscopic healing as defined above.
^l Decrease from induction baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1.
^m p<0.01, adjusted treatment difference (95% CI) based on Cochran-Mantel-Haenszel method adjusted for randomisation stratification factors
ⁿ An endoscopy subscore of 0.
° Fatigue was assessed using the PROMIS-Fatigue Short form 7a. Fatigue response was defined as a ≥7-point improvement from induction baseline which is considered clinically meaningful.
^p Total Inflammatory Bowel Disease Questionnaire score ≥170.
^q Subjects who achieved clinical remission 12 weeks following intravenous administration of guselkumab in either QUASAR induction study or QUASAR induction dose-ranging study.
^r An additional 3 patients in the placebo group, 3 patients in the guselkumab 100 mg group, and 3 patients in the guselkumab 200 mg group were previously exposed to but did not fail a biologic or JAK inhibitor.

In QUASAR IS and QUASAR MS, the efficacy and safety of guselkumab was consistently demonstrated regardless of age, sex, race, body weight, and previous treatment with a biologic therapy or JAK inhibitor.

In QUASAR MS, patients with high inflammatory burden after completion of induction dosing derived additional benefit from guselkumab 200 mg subcutaneous q4w compared to 100 mg subcutaneous q8w dosing. Clinically meaningful numerical differences of >15% were observed between the two guselkumab dose groups among patients with a CRP level of >3 mg/L after completion of induction dosing for the following endpoints at Week 44: clinical remission (48% 200 mg q4w vs. 30% 100 mg q8w), maintenance of clinical remission (88% 200 mg q4w vs. 50% 100 mg q8w), corticosteroid-free clinical remission (46% 200 mg q4w vs. 30% 100 mg q8w), endoscopic healing (52% 200 mg q4w vs. 35% 100 mg q8w), and histologic-endoscopic mucosal healing (46% 200 mg q4w vs. 29% 100 mg q8w).

QUASAR MS enrolled 31 patients with an induction baseline mMS of 4, including an ES of 2 or 3 and a RBS ≥1 who achieved clinical response 12 weeks following the intravenous administration of guselkumab in QUASAR IS or QUASAR induction dose-ranging study. In these patients, guselkumab efficacy relative to placebo as measured by clinical remission, clinical response, and endoscopic healing at Week 44 was consistent with the total population.

Symptomatic remission over time:

In QUASAR MS symptomatic remission defined as stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0 was sustained through Week 44 in both guselkumab treatment groups, while a decline was observed in the placebo group (Figure 1):

Figure 1. Proportion of patients in symptomatic remission through Week 44 in QUASAR MS:

Week 24 responders to guselkumab extended treatment:

Guselkumab treated patients who were not in clinical response at induction Week 12, received guselkumab 200 mg subcutaneous at Weeks 12, 16 and 20. In QUASAR IS, 66/120 (55%) guselkumab treated patients who were not in clinical response at induction Week 12 achieved clinical response at Week 24. Week 24 responders to guselkumab entered QUASAR MS and received guselkumab 200 mg subcutaneous every 4 weeks. At Week 44 of QUASAR MS, 83/123 (67%) of these patients maintained clinical response and 37/123 (30%) achieved clinical remission.

Recapture of efficacy after loss of response to guselkumab:

Nineteen patients receiving guselkumab 100 mg subcutaneous q8w who experienced a first loss of response (10%) between Week 8 and 32 of QUASAR MS received blinded guselkumab dosing with 200 mg guselkumab subcutaneous q4w and 11 of these patients (58%) achieved symptomatic response and 5 patients (26%) achieved symptomatic remission after 12 weeks.

Histologic and endoscopic assessment:

Histologic remission was defined as a Geboes histologic score ≤2 B.0 (absence of neutrophils from the mucosa [both lamina propria and epithelium], no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system). In QUASAR IS, histologic remission at Week 12 was achieved in 40% of patients treated with guselkumab and 19% of patients in the placebo group. In QUASAR MS, histologic remission at Week 44 was achieved in 59% and 61% of patients treated with guselkumab 100 mg subcutaneous q8w and guselkumab 200 mg subcutaneous q4w and 27% of patients in the placebo group.

Normalisation of the endoscopic appearance of the mucosa was defined as ES of 0. In QUASAR IS, endoscopic normalisation at Week 12 was achieved in 15% of patients treated with guselkumab and 5% of patients in the placebo group.

Composite histologic-endoscopic mucosal outcomes:

Combined symptomatic remission, endoscopic normalisation, histologic remission, and faecal calprotectin ≤250 mg/kg at Week 44 was achieved by a greater proportion of patients treated with guselkumab 100 mg subcutaneous q8w or 200 mg subcutaneous q4w compared to placebo (22% and 28% vs 9%, respectively).

Health-related quality of life:

At Week 12 of QUASAR IS, patients receiving guselkumab showed greater and clinically meaningful improvements from baseline when compared with placebo in inflammatory bowel disease (IBD)-specific quality of life assessed by IBDQ total score, and all IBDQ domain scores (bowel symptoms including abdominal pain and bowel urgency, systemic function, emotional function, and social function). These improvements were maintained in guselkumab treated patients in QUASAR MS through Week 44.

Ulcerative colitis related hospitalisations:

Through Week 12 of QUASAR IS, lower proportions of patients in the guselkumab group compared with the placebo group had ulcerative colitis-related hospitalisations (1.9%, 8/421 vs. 5.4%, 15/280).

ASTRO:

In ASTRO, patients were randomised in a 1:1:1 ratio to receive guselkumab 400 mg subcutaneous induction at Weeks 0, 4 and 8 followed by guselkumab 100 mg subcutaneous maintenance every 8 weeks; or guselkumab 400 mg subcutaneous induction at Weeks 0, 4 and 8, followed by guselkumab 200 mg subcutaneous maintenance every 4 weeks; or placebo.

A total of 418 patients were evaluated. The median age of patients was 40 years (ranging from 18 to 80 years); 38.8% were female; and 64.6% identified as White, 28.9% as Asian, and 3.1% as Black.

Enrolled patients were permitted to use stable doses of oral aminosalicylates, immunomodulators (AZA, 6-MP, MTX), and/or oral corticosteroids (up to 20 mg/day prednisone or equivalent). At baseline, 77.3% of patients were receiving aminosalicylates, 20.1% of patients were receiving immunomodulators, and 32.8% of patients were receiving corticosteroids. Concomitant biologic therapies, JAK inhibitors, or S1PRMs were not permitted. A total of 40.2% of patients had previously failed treatment with at least one biologic therapy, JAK inhibitor, and/or S1PRM, 58.1% were biologic, JAK inhibitor, and S1PRM naïve, and 1.7% had previously received but had not failed a biologic, JAK inhibitor, or S1PRM.

In ASTRO, the primary endpoint was clinical remission at Week 12 as defined by the mMS. Secondary endpoints at Week 12 included symptomatic remission, endoscopic healing, clinical response and histologic-endoscopic mucosal healing (see Table 5). Secondary endpoints at Week 24 included clinical remission and endoscopic healing (see Table 6).

Table 5. Proportion of patients meeting efficacy endpoints at Week 12 in ASTRO:

^a Guselkumab 400 mg subcutaneous induction at Week 0, Week 4, and Week 8
^b The adjusted treatment difference and the CIs were based on the common risk difference by use of Mantel-Haenszel stratum weights and Sato variance estimator. The stratification variables used were prior biologic, JAK inhibitor, and/or S1PRM failure status (Yes or No), and Mayo endoscopy subscore at baseline (moderate [2] or severe [3]).
^c A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0 or 1 with no friability
^d A stool frequency subscore of 0 or 1 and not increased from induction baseline, and a rectal bleeding subscore of 0
^e p<0.001
^f An additional 4 patients in the placebo group and 3 patients in the guselkumab group were previously exposed to but did not fail a biologic, JAK inhibitor or S1PRM
^g Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab), JAK inhibitor, and/or S1PRM for ulcerative colitis
^h An endoscopy subscore of 0, or 1 with no friability
ⁱ Decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1
^j An endoscopy subscore of 0, or 1 with no friability and Geboes score ≤3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue)

Table 6. Proportion of patients meeting efficacy endpoints at Week 24 in ASTRO:

^a Guselkumab 400 mg SC induction at Weeks 0, 4 and 8 followed by guselkumab 100 mg SC maintenance every 8 weeks
^b Guselkumab 400 mg SC induction at Weeks 0, 4 and 8, followed by guselkumab 200 mg SC maintenance every 4 weeks
^c The adjusted treatment difference and the CIs were based on the common risk difference by use of Mantel-Haenszel stratum weights and Sato variance estimator. The stratification variables used were prior biologic, JAK inhibitor, and/or S1PRM failure status (Yes or No), and Mayo endoscopy subscore at baseline (moderate [2] or severe [3]).
^d A stool frequency subscore of 0 or 1 and not increased from baseline, a rectal bleeding subscore of 0, and an endoscopy subscore of 0, or 1 with no friability
^e p<0.001
^f An additional 4 patients in the placebo group, 1 patient in the guselkumab 100 mg group, and 2 patients in the guselkumab 200 mg group were previously exposed to but did not fail a biologic, JAK inhibitor or S1PRM
^g Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab), JAK inhibitor, and/or S1PRM for ulcerative colitis
^h An endoscopy subscore of 0, or 1 with no friability

Symptomatic remission over time:

In ASTRO, symptomatic remission defined as stool frequency subscore of 0 or 1 and not increased from baseline, and a rectal bleeding subscore of 0 observed through Week 12, a greater proportion of patients in the guselkumab treatment groups achieved symptomatic remission compared with the placebo group (Figure 2):

Figure 2. Proportion of patients in symptomatic remission through Week 12 in ASTRO:

Rectal bleeding and stool frequency subscores

Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 in patients treated with guselkumab compared to placebo.

Histologic and endoscopic assessment

Histologic remission at Week 12 was achieved in 44% of patients treated with guselkumab 400 mg subcutaneous induction compared to 20% of patients on placebo.

Endoscopic normalisation at Week 24 was achieved in 21% and 26% of patients treated with guselkumab 400 mg subcutaneous induction, followed by guselkumab 100 mg administered by subcutaneous injection at Week 16, and every 8 weeks thereafter, or guselkumab 200 mg administered by subcutaneous injection at Week 12, and every 4 weeks thereafter, respectively, compared to 4% of patients on placebo.

Abdominal pain and bowel urgency

A greater proportion of patients treated with guselkumab 400 mg subcutaneous induction compared to placebo had no abdominal pain (56% vs 31%), and no bowel urgency (49% vs 24%) at Week 12.

Health-related quality of life

Disease-specific health-related quality of life was assessed with the IBDQ. A greater proportion of patients in the combined 400 mg SC guselkumab group (61%) achieved IBDQ remission at Week 12 compared with the placebo group (34%).

Crohn's disease

The efficacy and safety of guselkumab were evaluated in three Phase III clinical studies in adult patients with moderately to severely active Crohn's disease who had an inadequate response, loss of response or intolerance to either oral corticosteroids, conventional immunomodulators (AZA, 6-MP, MTX) and/or biologic therapy (TNF blocker or vedolizumab): two identically designed 48-Week multicentre, randomised, double-blind, placebo- and active-controlled (ustekinumab), parallel group studies (GALAXI 2 and GALAXI 3) and one 24-Week multicentre, randomised, double-blind, placebo-controlled, parallel group study (GRAVITI). All three studies had a treat-through study design: patients randomised to guselkumab (or ustekinumab for GALAXI 2 and GALAXI 3) maintained that treatment assignment for the duration of the study.

GALAXI 2 and GALAXI 3

In the Phase III studies GALAXI 2 and GALAXI 3, moderately to severely active Crohn's disease was defined as a Crohn's Disease Activity Index [CDAI] score of ≥220 and ≤450 and a Simple Endoscopic Score for CD (SES-CD) of ≥6 (or ≥4 for patients with isolated ileal disease). Additional criteria for GALAXI ⅔ included a mean daily stool frequency (SF) >3 or mean daily abdominal pain score (AP) >1.

In GALAXI 2 and GALAXI 3 studies, patients were randomised in a 2:2:2:1 ratio to receive guselkumab 200 mg intravenous induction at Weeks 0, 4 and 8 followed by guselkumab 200 mg subcutaneous q4w maintenance; or guselkumab 200 mg intravenous induction at Weeks 0, 4 and 8, followed by guselkumab 100 mg subcutaneous q8w maintenance; or ustekinumab approximately 6 mg/kg intravenous induction at Week 0 followed by ustekinumab 90 mg subcutaneous q8w maintenance; or placebo. Placebo non-responders received ustekinumab starting at Week 12.

A total of 1021 patients were evaluated in GALAXI 2 (n=508) and GALAXI 3 (n=513). The median age was 34 years (ranging from 18 to 83 years), 57.6% were male; and 74.3% identified as White, 21.3% as Asian and 1.5% as Black.

In GALAXI 2, 52.8% of patients had previously failed treatment with at least one biologic therapy (50.6% were intolerant or failed at least 1 prior anti-TNFα therapy, 7.5% were intolerant or failed prior vedolizumab therapy), 41.9% were biologic naïve, and 5.3% had previously received but had not failed a biologic. At baseline, 37.4% of the patients were receiving oral corticosteroids and 29.9% of the patients were receiving conventional immunomodulators.

In GALAXI 3, 51.9% of patients had previously failed treatment with at least one biologic therapy (50.3% were intolerant or failed at least 1 prior anti-TNFα therapy, 9.6% were intolerant or failed prior vedolizumab therapy), 41.5% were biologic naïve, and 6.6% had previously received but had not failed a biologic. At baseline, 36.1% of the patients were receiving oral corticosteroids and 30.2% of the patients were receiving conventional immunomodulators.

The results of the co-primary and major secondary endpoints compared to placebo in GALAXI 2 and GALAXI 3 are presented in Tables 7 (Week 12) and 18 (Week 48). The results of the major secondary endpoints at Week 48 compared to ustekinumab are presented in Tables 9 and 10.

Table 7. Proportion of patients meeting co-primary and major secondary efficacy endpoints with guselkumab versus placebo at Week 12 in GALAXI 2 and GALAXI 3:

^a Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 – Two guselkumab treatment groups were combined for this column as patients received the same intravenous induction dose regimen prior to Week 12.
^b Clinical remission is defined as CDAI score <150.
^c An additional 9 patients in the placebo group and 38 patients in the guselkumab 200 mg intravenous group were previously exposed to but did not fail a biological therapy.
^d Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers or vedolizumab) for Crohn's disease.
^e Endoscopic response is defined as ≥50% improvement from baseline in SES-CD score or SES-CD Score ≤2.
^f 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.
^g Fatigue response is defined as improvement of ≥7 points in PROMIS Fatigue Short Form 7a.
^h Endoscopic remission is defined as SES-CD Score ≤2.
ⁱ p<0.001
^j p<0.05

Table 8. Proportion of patients meeting major secondary efficacy endpoints with guselkumab versus placebo at Week 48 in GALAXI 2 and GALAXI 3:

Table 10. Proportion of patients meeting major secondary efficacy endpoints with guselkumab versus ustekinumab at Week 48 in GALAXI 2 and GALAXI 3:

^a Ustekinumab 6 mg/kg intravenous induction at Week 0 followed by ustekinumab 90 mg subcutaneous q8w thereafter for up to 48 weeks.
^b Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 100 mg subcutaneous q8w thereafter for up to 48 weeks.
^c Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 200 mg subcutaneous q4w thereafter for up to 48 weeks.
^d A combination of clinical remission and endoscopic response as defined below.
^e Endoscopic response is defined as ≥50% improvement from baseline in SES-CD score or SES-CD Score ≤2.
^f Endoscopic remission is defined as SES-CD Score ≤2.
^g Clinical remission is defined as CDAI score <150.
^h Corticosteroid-free clinical remission is defined as CDAI score <150 at Week 48 and not receiving corticosteroids at Week 48.
ⁱ Durable clinical remission is defined as CDAI <150 for ≥80% of all visits between Week 12 and Week 48 (at least 8 of 10 visits), which must include Week 48.
^j 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.
^k p<0.05
^l Responses at Week 48 were evaluated irrespective of clinical response at Week 12

Table 10. Proportion of patients meeting efficacy endpoints with guselkumab versus ustekinumab at Week 48 in pooled GALAXI 2 and GALAXI 3:

^a Ustekinumab 6 mg/kg intravenous induction at Week 0 followed by ustekinumab 90 mg subcutaneous q8w thereafter for up to 48 weeks.
^b Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 100 mg subcutaneous q8w thereafter for up to 48 weeks.
^c Guselkumab 200 mg intravenous induction at Week 0, Week 4 and Week 8 followed by guselkumab 200 mg subcutaneous q4w thereafter for up to 48 weeks.
^d A combination of clinical remission and endoscopic response as defined below.
^e An additional 14 patients in the ustekinumab group, 21 patients in the guselkumab 200 mg subcutaneous q4w group, and 17 patients in the guselkumab 100 mg subcutaneous q8w group were previously exposed to but did not fail a biological therapy.
^f Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) for Crohn's disease.
^g Endoscopic response is defined as ≥50% improvement from baseline in SES-CD score or SES-CD Score ≤2.
^h Endoscopic remission is defined as SES-CD Score ≤2.
ⁱ Clinical remission is defined as CDAI score <150.

In GALAXI 2 and GALAXI 3, the efficacy and safety of guselkumab was consistently demonstrated regardless of age, sex, race and body weight.

In the pooled GALAXI Phase III studies subpopulation analysis, patients with high inflammatory burden after completion of induction dosing derived additional benefit from guselkumab 200 mg subcutaneous q4w compared to the 100 mg subcutaneous q8w maintenance dose regimens. A clinically meaningful difference was observed between the two guselkumab dose groups among patients with a CRP level of >5 mg/L after completion of induction, for the endpoints of clinical remission at Week 48 (100 mg subcutaneous q8w: 54.1% vs 200 mg subcutaneous q4w: 71.0%); endoscopic response at Week 48 (100 mg subcutaneous q8w: 36.5% vs 200 mg subcutaneous q4w: 50.5%); and PRO-2 remission at Week 48 (100 mg subcutaneous q8w: 51.8% vs 200 mg subcutaneous q4w: 61.7%).

Clinical remission over time:

CDAI scores were recorded at each patient visit. The proportion of patients in clinical remission through Week 48 is presented in Figure 3.

Figure 3. Proportion of patients in clinical remission through Week 48 in pooled GALAXI 2 and GALAXI 3:

Health-related quality of life:

Greater improvements from baseline were seen at Week 12 in guselkumab treatment groups when compared with placebo for inflammatory bowel disease (IBD)-specific quality of life assessed by IBDQ total score. The improvements were maintained through Week 48 in both studies.

GRAVITI

In the Phase III GRAVITI study, moderately to severely active Crohn's disease was defined as a CDAI score of ≥220 and ≤450 and a CD (SES-CD) of ≥6 (or ≥4 for patients with isolated ileal disease) and a mean daily SF ≥4 or mean daily AP score ≥2.

In GRAVITI, patients were randomised in a 1:1:1 ratio to receive guselkumab 400 mg subcutaneous induction at Weeks 0, 4 and 8 followed by guselkumab 100 mg q8w subcutaneous maintenance; or guselkumab 400 mg subcutaneous induction at Weeks 0, 4 and 8, followed by guselkumab 200 mg q4w subcutaneous maintenance; or placebo. All patients in the placebo group who met rescue criteria received the induction dosing with guselkumab 400 mg subcutaneous at Weeks 16, 20, and 24 followed by guselkumab 100 mg subcutaneous q8w.

A total of 347 patients were evaluated. The median age of patients was 36 years (ranging from 18 to 83 years), 58.5% were male, and 66% identified as White, 21.9% as Asian and 2.6% as Black.

In GRAVITI, 46.4% of patients had previously failed treatment with at least one biologic therapy, 46.4% were biologic naïve, and 7.2% had previously received but had not failed a biologic. At baseline, 29.7% of the patients were receiving oral corticosteroids and 28.5% of the patients were receiving conventional immunomodulators.

The results of the co-primary and major secondary efficacy endpoints compared to placebo at Week 12 are presented in Table 11.

Table 11. Proportion of patients meeting co-primary and major secondary efficacy endpoints with guselkumab versus placebo at Week 12 in GRAVITI:

^a Guselkumab 400 mg subcutaneous at Week 0, Week 4 and Week 8
^b Clinical remission: CDAI score <150
^c p<0.001
^d An additional 8 patients in the placebo group and 17 patients in the guselkumab 400 mg subcutaneous group, were previously exposed to but did not fail a biological therapy.
^e Includes inadequate response, loss of response, or intolerance to biologic therapy (TNF blockers, vedolizumab) for Crohn's disease.
^f Endoscopic response: ≥50% improvement from baseline in SES-CD score.
^g Clinical response: ≥100-point reduction from baseline in CDAI score or CDAI score <150.
^h PRO-2 remission: 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.

Clinical remission at Week 24 was achieved by a significantly greater proportion of patients treated with guselkumab 400 mg subcutaneous induction followed by guselkumab 100 mg subcutaneous q8w or 200 mg subcutaneous q4w compared to placebo (60.9% and 58.3% vs 21.4% respectively, both p-values <0.001). Clinical remission at Week 48 was achieved by 60% and 66.1% of patients treated with guselkumab 400 mg subcutaneous induction followed by guselkumab 100 mg subcutaneous q8w or 200 mg subcutaneous q4w, respectively (both p-values <0.001 compared to placebo).

Endoscopic response at Week 48 was achieved by 44.3% and 51.3% of patients treated with guselkumab 400 mg subcutaneous induction followed by guselkumab 100 mg subcutaneous q8w or 200 mg subcutaneous q4w, respectively (both p-values <0.001 compared to placebo).

Health-related quality of life:

In GRAVITI, clinically meaningful improvements were observed in IBD-specific quality of life as assessed with IBDQ total score at Week 12 and Week 24 compared to placebo.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with guselkumab in one or more subsets of the paediatric population in ulcerative colitis and Crohn's disease (see section 4.2 for information on paediatric use).