SUMMARY

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• GRAVITI (NCT05197049) is a phase 3, treat-through clinical trial in adult patients with moderately to severely active Crohn’s disease (CD) that evaluates the efficacy and safety of subcutaneous (SC) induction with TREMFYA. Efficacy and safety results are summarized below.^1-10

CLINICAL DATA

Phase 3 Subcutaneous Induction Study in Crohn's Disease - GRAVITI

Hart et al (2025)² reported the efficacy and safety results of SC induction therapy with TREMFYA followed by SC maintenance therapy in adults with moderately to severely active CD through week 48.

Study Design/Methods

• GRAVITI is a phase 3, randomized, double-blind, placebo (PBO)-controlled, parallel-group, multicenter, treat-through study.
• Enrolled patients had a history of inadequate response or intolerance to oral corticosteroids (CSs), azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate (MTX), or biologics (BIO-IR; infliximab, adalimumab, certolizumab pegol, vedolizumab, or approved biosimilars for these therapies).
• A total of 347 patients were randomized 1:1:1 to:
  • TREMFYA 400 mg SC at weeks 0, 4, and 8 followed by 200 mg SC every 4 weeks (q4w; N=115)
  • TREMFYA 400 mg SC at weeks 0, 4, and 8 followed by 100 mg SC every 8 weeks (q8w; N=115)
  • PBO (N=117)
• Patients who met rescue criteria (Crohn’s Disease Activity Index [CDAI] >220 with <70-point reduction at both weeks 12 and 16, or ≥50% increase from baseline in the Simple Endoscopic Score for Crohn’s Disease [SES-CD] at week 12) received rescue treatment at week 16: PBO patients switched to TREMFYA 400 mg SC at weeks 16, 20, and 24 followed by 100 mg SC every 8 weeks, and TREMFYA patients stayed on TREMFYA per treat-through design (sham rescue).
• The coprimary endpoints were clinical remission at week 12 (CDAI <150) and endoscopic response at week 12 (≥50% improvement from baseline in the SES-CD).
• Other multiplicity-controlled endpoints were clinical remission at week 24, patient-reported outcome-2 (PRO-2) remission (an abdominal pain mean daily score ≤1 and stool frequency mean daily score ≤3 and no worsening of abdominal pain or stool frequency from baseline) at week 12, clinical response (CDAI ≥100-point reduction from baseline or clinical remission [CDAI <150]) at week 12, clinical remission at weeks 24 and 48, and endoscopic response at week 48. Endoscopic response, using an alternate definition (>50% improvement from baseline in SES-CD or SES-CD ≤2) was also assessed at weeks 12 and 48.
• Additional efficacy endpoints were endoscopic remission (SES-CD score ≤4 and ≥2-point reduction from baseline and no subscore >1 in any individual component) and deep remission (achieving both clinical and endoscopic remission) assessed at week 48.
• Inflammatory Bowel Disease Questionnaire (IBDQ) remission was defined as IBDQ score ≥170.
• All patients who met rescue criteria were considered not to have met efficacy endpoints after week 16.

Results

Patient Characteristics

• Baseline characteristics were similar across groups:
  • Mean age (standard deviation [SD]): 37.5 (12.89) years
  • Mean (SD) CD disease duration: 8 (8.053) years
  • Mean (SD) CDAI: 296.9 (52.68)
  • Mean (SD) SES-CD: 12.0 (6.94)
  • BIO-IR: 46.4% (n=161)
  • Bio naive: 46.4% (n=161)
  • Elevated CRP (>5 mg/L): 54.8% (n=190)
  • Elevated FCP (>250 µg/g): 71.7% (n=248)
• At week 16, 37.6% (n=44) of patients in the PBO group met rescue criteria and switched to TREMFYA. Additionally, 12.2% (n=14) of patients in each TREMFYA group (400 mg SC q4w→100 mg SC q8w and 400 mg SC q4w→200 mg SC q4w) met rescue criteria and received sham rescue with PBO.
• Prior to week 12, 4.3% (n=15) of patients discontinued the study drug (PBO SC: 10.3% [n=12/117]; TREMFYA 400 mg SC q4w: 1.3% [n=3/230]). The most common reason for discontinuation was patient withdrawal (2.0%).
• Through week 48, 15.3% (n=53) of patients discontinued the study drug (PBO SC: 26.5% (n=31/117); PBO→TREMFYA: 11.4% (n=5/44), TREMFYA q4w→q8w: 10.4% (n=12/115), TREMFYA q4w→q4w: 4.3% (n=5/115). The most common reason for discontinuation was patient withdrawal (4.0%, n=14), lack of efficacy (2.9%, n=10), worsening CD (2.6%, n=9).

Efficacy

• The coprimary endpoints and all multiplicity-controlled endpoints were met. TREMFYA 400 mg SC induction demonstrated superiority to PBO at week 12.
• Both TREMFYA SC maintenance dosage regimens were also superior to PBO at weeks 24 and 48.
• For the coprimary and other multiplicity-controlled endpoints at weeks 12, 24 and 48, see Table: Endpoints at Week 12, Clinical Remission at Week 24, and Summary of Clinical and Endoscopic Endpoints During Maintenance at Week 48.

• Median CRP and FCP levels decreased to within normal range with TREMFYA vs placebo through week 48.
  • At week 12 (TREMFYA vs placebo):
    • CRP ≤5 mg/L: 41.7% vs 15.7%
    • FCP ≤250 µg/g: 37.0% vs 8.1%
  • CRP and FCP levels remained consistent between weeks 12 and 48.
• IBDQ remission at week 48:
  • TREMFYA 400 mg SC q4w→100 mg SC q8w (N=115): 54.8%
  • TREMFYA 400 mg SC q4w→200 mg SC q4w (N=115): 48.7%
  • PBO group (N=117): 17.9%

Safety

• Key safety event rates per 100 patient years through week 48 were similar among treatment groups, see Table: Safety through Week 48.
• The most common adverse events reported in the TREMFYA groups were upper respiratory tract infections, abdominal pain, and COVID-19.
• No active tuberculosis, anaphylactic or serum sickness reactions were reported through week 48. One opportunistic infection was reported in a patient who received placebo (esophageal candidiasis) and one who received TREMFYA 400 mg SC q4w→200 mg SC q4w (fungal esophagitis).
• One malignancy (basal cell carcinoma) was reported in a patient who received TREMFYA 400 mg SC q4w→100 mg SC q8w through week 48.
• No major adverse cardiovascular events were reported through week 48.
• One venous thromboembolism adverse event occurred in the placebo group, and one case of portal vein thrombosis was reported in a patient with recurrent pancreatitis who received TREMFYA 400 mg SC q4w→200 mg SC q4w through week 48.
• Through week 48, the proportion of patients with adverse events of hepatic disorder was ≤5% and similar across treatment groups. No serious hepatic disorder adverse events were reported. Most were liver test abnormalities that resolved during treatment. No patients met the biochemical criteria of Hy’s law.
• Elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥5 times the upper limit of normal (ULN) were infrequent (placebo: 1 [0.9%], TREMFYA: 3 [1.3%]).
• Injection-site reactions were reported with 1.0% of TREMFYA injections and 0.3% of placebo injections through week 48. No serious or severe injection-site reactions occurred, and none led to discontinuation of study treatment.

• Antibodies to guselkumab through week 48 were detected in 24/274 (8.8%) patients (3 patients had neutralizing antibodies), with no impact on serum concentrations, efficacy, or injection-site reactions.

Subgroup Analyses

Corticosteroid Use and Corticosteroid Outcomes at Week 48

• Among all patients receiving oral CS at baseline, a greater proportion of patients receiving TREMFYA than that of patients receiving PBO was not receiving CS at week 48. For more details, see Table: Corticosteroid Use at Week 48: Primary Analysis Population.

• CS-free clinical remission at week 48³:
  • TREMFYA 100 mg SC q8w (N=115): 59.1% (adjusted treatment difference vs PBO Δ42.8% [31.6-53.9])
  • TREMFYA 200 mg SC q4w (N=115): 66.1% (adjusted treatment difference vs PBO Δ49.8% [38.9-60.7])
  • PBO group (N=117): 16.2%
• 90-day CS-free clinical remission at week 48^2,11:
  • TREMFYA 100 mg SC q8w (N=115): 58.3% (adjusted treatment difference vs PBO Δ41.9% [30.7-53.1])
  • TREMFYA 200 mg SC q4w (N=115): 65.2% (adjusted treatment difference vs PBO Δ49.0% [38.0-59.9])
  • PBO group (N=117): 16.2%

Efficacy by Baseline Disease Characteristics

• Predefined subgroup analyses were conducted based on the following⁴:
  • Disease duration: ≤5, >5 to ≤15, and >15 years
  • Disease location assessed by central reader: ileum, colon, and both
  • CDAI score: ≤300 and >300
  • CRP: ≤5 and >5 mg/L
  • Fecal calprotectin: ≤250 and >250 µg/g
  • SES-CD: ≤12 and >12
• Clinical remission and endoscopic response at week 12 were achieved by a greater proportion of patients treated with TREMFYA than that of patients treated with PBO across all subgroups. For more details, see Table: Clinical Remission at Week 12 by Baseline Disease Characteristics.

• For endoscopic response at week 12, see Table: Endoscopic Response at Week 12 by Baseline Disease Characteristics.

Efficacy by Baseline Disease Demographics

Study Design/Methods

• Predefined subgroup analyses were conducted based on the following⁵:
  • Gender: male and female
  • Race: White, non-White, Black or African American, Asian, other, and not reported/missing
  • Ethnicity: Hispanic or Latino, not Hispanic or Latino, and not reported/missing
  • Median age in years: ≤36, >36, <65, and ≥65
  • Weight in kg by quartile: <57.5, ≥57.5 to <68.5, ≥68.5 to <80.5, and ≥80.5
  • Disease duration: ≤5, >5 to ≤15, and >15 years
  • Concomitant CD-related medications: receiving or not receiving 5-aminosalicylic acid compounds, oral CSs, and AZA/6-MP/MTX as discrete categories

Results

• Clinical remission and endoscopic response at week 12 were achieved by a greater proportion of patients treated with TREMFYA than that of patients treated with PBO across all subgroups.⁵ For more details, see Table: Clinical Remission at Week 12 by Baseline Disease Characteristics.

• For endoscopic response at week 12, see Table: Endoscopic Response at Week 12 by Baseline Disease Characteristics.

Health-Related Quality of Life

Sands et al (2025)⁶ evaluated the HRQoL through week 48, as measured using the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 in the GRAVITI trial.

• PROMIS-29 consists of the following 7 domains as well as a pain intensity item: 5 symptom domains (anxiety, depression, fatigue, sleep disturbance, and pain interference) and 2 functional domains (physical function and social participation).
• Physical component summary (PCS) and mental component summary (MCS) scores were calculated on the basis of domain T-scores.
• Clinically meaningful improvement (CMI) was defined using predefined thresholds for each domain and for the PCS and MCS scores.
• Higher scores indicated better health outcomes for the functional domains and the PCS and MCS scores but worse symptoms for the symptom domains and pain intensity (rated on a 0-10 scale).

Results

• Baseline mean PROMIS-29 domain scores were similar across the treatment groups in functional domain scores, symptom domain scores and pain intensity scores with all values indicating impaired HRQoL.
• At weeks 12 and 48, compared with patients receiving PBO, patients treated with TREMFYA showed a greater improvement in each domain T-score, the pain intensity numeric rating scale (NRS) score, and the PCS and MCS scores. For more details, see Table: Change from Baseline at Weeks 12 and 48 in PROMIS-29 Score.
• At weeks 12 and 48, greater percentage of patients treated with TREMFYA compared to PBO achieved CMI in each domain, the pain intensity NRS score, and the PCS and MCS scores, see Figure: CMI in Each PROMIS-29 Domain, Pain Intensity, PCS and MCS Scores at Weeks 12 and 48.

Additional Analyses Including Data from the GALAXI 2 and 3 Studies

Afzali et al (2025)⁷ evaluated the symptoms, health-related quality of life (HRQoL), and inflammatory markers of TREMFYA intravenous (IV) or SC induction in patients with CD through week 12 using data from the GALAXI and GRAVITI studies.

Study Design/Methods

• The analysis included patients from the GRAVITI (N=347), GALAXI 2 (N=508), and GALAXI 3 (N=513) through week 12.
• In the GRAVITI study, patients received induction therapy of TREMFYA 400 mg SC or PBO at weeks 0, 4, and 8.
• In the GALAXI 2 and 3 studies, patients received induction therapy of TREMFYA 200 mg IV or PBO at weeks 0, 4, and 8.
• In all 3 treat-through studies, patients in the TREMFYA groups received SC maintenance therapy following induction therapy.
• Improvements in symptoms (abdominal pain and stool frequency per CDAI components), HRQoL (IBDQ remission defined as IBDQ total score ≥170), and inflammatory markers (CRP and FCP) were evaluated through week 12.

Results

• For data on improvement in symptoms, HRQoL, and inflammatory markers across all 3 studies, see the Tables: Changes from Baseline in Daily Abdominal Pain/Stool Frequency and IBDQ Remission through Week 12 and CRP and FCP Levels through Week 12.

Richards et al (2025)⁸ conducted a post-hoc analysis to evaluate the endoscopic outcomes between TREMFYA and ustekinumab across ileal, ileocolonic, and colonic regions using data from the phase 3 GRAVITI and GALAXI 2 and 3 studies.

Study Design/Methods

• Endoscopic clustering was performed using baseline segmental SES-CD values across 5 intestinal regions: terminal ileum, right colon, transverse colon, left/sigmoid colon, and rectum from cohort 1 (n=1233; from the GALAXI 1, GALAXI 2, and GRAVITI studies) and cohort 2 (n=525; from the GALAXI 3 study).
• Patients from the GALAXI 2 and GALAXI 3 studies were pooled to assess the endoscopic outcomes at weeks 12 and 48 for the TREMFYA and ustekinumab groups.

Results

• Seven CD endoscopic subtypes such as ileum only, ileum dominant, right colon dominant, mid-colon, colonic, ileocolonic, and rectum dominant were identified.
• Patient clusters were used with baseline stricturing data (SES-CD narrowing >0) to consolidate groups with differential treatment effects.
• In total, TREMFYA showed higher endoscopic remission rates than ustekinumab at weeks 12 and 48, see Table: Endoscopic Remission Rates for TREMFYA vs Ustekinumab Across Ileal, Ileocolonic, and Colonic Regions.

• At week 12, patients in groups 2 and 3 with baseline stricturing who were TREMFYA endoscopic responders (and not ustekinumab responders) demonstrated a greater reduction in intestinal narrowing, leading to a 21% decrease in total SES-CD compared to a 5% reduction among TREMFYA non-responders.

Richards et al (2025)⁹ conducted an analysis to assess the comparison of pharmacodynamic and mechanistic response of TREMFYA SC vs TREMFYA IV induction using data from the GALAXI and GRAVITI studies.

Study Design/Methods

• Using a 92-analyte inflammatory protein panel, serum proteins were analyzed at weeks 0 and 12 in patients randomized to receive TREMFYA 400 mg SC q4w or PBO in the GRAVITI trial (n=290) and a subset of patients randomized to TREMFYA 200 mg IV q4w or PBO in the GALAXI trials (n=292).
• In the GRAVITI trial, transcriptional profiling from each of the 5 anatomic segments was performed at weeks 0 and 12 in 277 patients using ribonucleic acid (RNA) sequencing.
• Segmental molecular inflammation was assessed using the tissue inflammation score (bMIS), which is correlated with segmental histology scores (ie, Global Histologic Disease Activity Score [GHAS]), endoscopic scores, and subscores defined by SES-CD.
• Treatment effect was analyzed using molecularly inflamed samples (bMIS >0) from segments with SES-CD >0 at baseline, and transcriptional gene modules were assessed for differential expression.

Results

• Serum protein changes at week 12 with TREMFYA 400 mg SC q4w induction were highly correlated with those seen with TREMFYA 200 mg IV q4w induction (R=0.96; P<0.05). Similar reductions were observed with interferon gamma, interleukin (IL)-17A, CRP, and FCP (P<0.05).
• For tissue, segmental molecular inflammation assessed by bMIS was correlated with segmental histological and endoscopic subscores.
• At week 12, TREMFYA SC induction reduced key cellular and inflammatory transcriptional modules across all anatomic segments, including plasma cell, inflammatory epithelial, neutrophil, and IL-23/T helper 17 biology.
• Reduction in molecular inflammation across the 5 anatomic segments corresponded to segmental endoscopic improvement observed in isolated ileal, ileocolonic, and colonic patient subgroups.
• For anti-inflammatory effect of TREMFYA IV and SC induction at week 12, see Figure: TREMFYA IV and SC Induction Show Similar Anti-inflammatory Effects in Serum at Week 12.

Pooled Analyses

Danese et al (2025)¹⁰ conducted an analysis using data from phase 2/3 CD studies to assess safety event rates (proportion of patients with ≥1 event) during the induction period (weeks 0-12) for IV induction (TREMFYA 200 mg IV q4w in GALAXI 1, 2, and 3) and SC induction (TREMFYA 400 mg SC q4w in GRAVITI).

Study Design/Methods

• Safety events were defined as the proportion of patients with ≥1 AE during the induction period (weeks 0-12).

Results

• Serious infections were reported in 1 patient each in the TREMFYA IV and SC groups but did not result in treatment discontinuation. No serious infections were reported in patients receiving PBO in either group.
• During the induction period in GRAVITI, 6 (0.4%) of 1376 TREMFYA SC injections were associated with injection-site reactions (ISRs), including pruritus, erythema, and swelling. ISRs beyond the induction period with TREMFYA SC remained low (≤1%) and were comparable regardless of induction administration route.
• During the induction period, no cases of active tuberculosis, anaphylaxis, serum sickness reactions, major adverse cardiovascular events, or venous thromboembolism were reported.
• One opportunistic infection (esophageal candidiasis) was reported in patients receiving PBO in both the IV and SC induction groups, whereas 2 opportunistic infections (cytomegalovirus infection and esophageal candidiasis) were reported in the TREMFYA IV induction group and none in the TREMFYA SC induction group.
• One malignancy (basal cell carcinoma), which did not result in discontinuation, was reported in a patient in the TREMFYA 400 mg SC group.
• During the induction period, 1 death (attributed to a nonsuicidal [not self-inflicted] gunshot wound) was reported in a patient treated with TREMFYA SC.
• During the induction period, clinically significant hepatic disorders were reported in 2 patients in the TREMFYA 200 mg IV group (1 serious AE and 1 AE leading to discontinuation) and 1 patient in the TREMFYA 400 mg SC group (1 AE leading to discontinuation).
• All cases of hepatic disorders were confounded by additional diagnoses or concomitant medications.
• For details on safety events, see Table: Patients with ≥1 Safety Events During the Induction Period (Weeks 0-12).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 21 April 2025.