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TREMFYA® (guselkumab)

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TREMFYA - Treatment of Crohn’s Disease with Subcutaneous Induction (GRAVITI Study)

Last Updated: 11/04/2024

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 induction with TREMFYA.

CLINICAL DATA

Phase 3 SUBCUTANEOUS INDUCTION STUDY IN CROHN'S DISEASE - GRAVITI¹

Panaccione et al (2023) reported the efficacy and safety results of subcutaneous induction therapy with TREMFYA in adults with moderately to severely active CD through week 48.

Study Design/Methods

GRAVITI is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter, treat-through study.
Enrolled patients had a history of inadequate response or intolerance to oral corticosteroids, azathioprine (AZA), mercaptopurine (6-MP), methotrexate (MTX), or biologics (BIO-IR).
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)
- Placebo (PBO; N=117)
Patients who met rescue criteria received rescue treatment at week 16: PBO patients switched to TREMFYA, and TREMFYA patients stayed on TREMFYA per treat-through design (sham rescue).
The co-primary endpoints were clinical remission at week 12 (Crohn’s Disease activity index [CDAI] <150) and endoscopic response at week 12 (≥50% improvement from baseline in SES-CD).
Other multiplicity-controlled endpoints were clinical remission at week 24, patient reported outcome-2 (PRO-2) remission at week 12, clinical response at week 12, clinical remission at week 48, and endoscopic response at week 48.
All endpoints assessed through week 12 compared the combined TREMFYA 400 mg SC treatment arm to placebo. Assessments after week 12 compared each TREMFYA SC maintenance regimen to placebo.
All patients who met rescue criteria were considered not to have met efficacy endpoints after week 16.
Safety was assessed through week 48.

Results

Patient Characteristics

Baseline characteristics were similar across groups:
- Mean age: 37.5 years
- Meaning CD disease duration: 8 years
- Mean CDAI: 296.9
- Mean SES-CD: 12.0
- BIO-IR: 46.4%

Efficacy

The co-primary and all multiplicity-controlled endpoints were met. TREMFYA 400 mg SC induction demonstrated superiority to placebo at week 12.
Both TREMFYA SC maintenance dosage regimens were also superior to placebo at weeks 24 and 48.
Additionally, in prespecified analyses of subpopulations defined by prior biologic history, greater proportions of TREMFYA-treated patients achieved the endpoints compared to those treated with placebo.
For the co-primary and other multiplicity controlled endpoints through week 48, see Table: Summary of Co-primary and Multiplicity-controlled Endpoints Through Week 48.

Table 1. Summary of Co-primary and Multiplicity-controlled Endpoints Through Week 48

Endpoints	TREMFYA Combined 400 mg SC q4w (N=230)	TREMFYA 400 mg SC q4w TREMFYA 100 mg SC q8w (N=115)	TREMFYA 400 mg SC q4w TREMFYA 200 mg SC q4w (N=115)	Placebo SC (N=117)
Clinical remission^a at week 12 (Co-primary endpoint)	56.1%	-	-	21.4%
Treatment difference vs placebo	34.9% P<0.001
Endoscopic response^b at week 12 (Co-primary endpoint)	41.3%	-	-	21.4%
Treatment difference vs placebo	19.9% P<0.001
PRO-2 remission^c at week 12	49.1%	-	-	17.1%
Treatment difference vs placebo	32.1% P<0.001
Clinical response^d at week 12	73.5%	-	-	33.3%
Treatment difference vs placebo	40.3% P<0.001
Clinical remission at week 24	-	60.9%	58.3%	21.4%
Treatment difference vs placebo		39.3% P<0.001	37% P<0.001
Clinical remission at week 48	-	60%	66.1%	17.1%
Treatment difference vs placebo		42.8% P<0.001	48.9% P<0.001
Endoscopic response at week 48	-	44.3%	51.3%	6.8%
Treatment difference vs placebo		37.5% P<0.001	44.6% P<0.001
Abbreviations: CD; Crohn’s disease; CDAI, Crohn’s Disease Activity Index; COVID-19 (coronavirus disease 2019); PRO-2, Patient-reported outcome; SC, subcutaneous; SES-CD, Simplified Endoscopic Activity Score for Crohn's Disease. ^aClinical remission: CDAI score <150 ^bEndoscopic response: ≥50% improvement from baseline in SES-CD score ^cPRO-2 remission: Abdominal pain average daily score ≤1 and stool frequency average daily score ≤3, and no worsening of abdominal pain or stool frequency from baseline ^dClinical response: ≥100-point reduction from baseline in CDAI score or CDAI score <150 Note: Participants who had a CD-related surgery (with the exception of minor procedures such as drainage of a superficial abscess or seton placement, etc.), a prohibited change in CD medication, discontinued study intervention for any reason (other than COVID-19 related reasons [excluding COVID-19 infection] or regional crisis), or met rescue criteria (only applicable after Week 16) were considered not to have met the endpoint at the designated timepoint. Participants who discontinued study intervention due to COVID-19 related reasons (excluding COVID-19 infection) or regional crisis had their observed data used, if available. After accounting for the aforementioned data handling rules, participants who were missing data pertaining to an endpoint at a designated timepoint were considered not to have achieved the endpoint. The adjusted treatment difference(s), and p-value(s) were based on the common risk difference by use of Mantel-Haenszel stratum weights and the Sato variance estimator. The stratification factors are baseline CDAI score (≤300 or >300), baseline SES-CD score (≤12 or >12), and BIO-failure status at baseline (yes or no).

Safety

Key safety event rates per 100 patient years through week 48 were similar among treatment groups, see Table: Safety through Week 48.

Table 2. Safety Through Week 48

	Placebo SC^a	TREMFYA 400 mg SC q4w TREMFYA 100 mg SC q8w	TREMFYA 400 mg SC q4w TREMFYA 200 mg SC q4w	All TREMFYA^b
Safety analysis set, N	117	115	115	274
Average duration of follow-up, weeks	30.0	47.0	48.0	44.8
Average exposure, number of administrations	7.1	6.8	11.8	8.5
Total PYs of follow-up, years	67.3	103.5	105.7	235.0
Deaths,^c n (%)	0	1 (0.9%)	0	1 (0.4%)
Participants with 1 or more:
AEs, n (%)	77 (65.8%)	95 (82.6%)	92 (80.0%)	220 (80.3%)
Events per 100 PYs follow-up	413.0	307.2	327.2	312.8
SAEs, n (%)	16 (13.7%)	15 (13.0%)	9 (7.8%)	25 (9.1%)
Events per 100 PYs follow-up	37.1	15.5	13.2	13.2
AEs leading to DC of study agent, n (%)	10 (8.5%)	4 (3.5%)	3 (2.6%)	8 (2.9%)
Events per 100 PYs follow-up	14.9	6.8	2.8	4.7
Serious infections,^d n (%)	0	2 (1.7%)	1 (0.9%)	4 (1.5%)
Adverse events of special interest, n (%)
Active tuberculosis	0	0	0	0
Malignancies^e	0	1 (0.9%)	0	1 (0.4%)
Abbreviations: AE, adverse event; DC, discontinuation; MedDRA, Medical Dictionary for Regulatory Activities; PY, participant-years; SAE, serious adverse event; SC, subcutaneous.^a Includes all placebo participants excluding data after a participant is rescued with TREMFYA. ^b Includes all participants initially randomized to TREMFYA at Week 0, and placebo participants who were rescued with TREMFYA; only data after a participant crossed over to TREMFYA is included. ^c Fatal gunshot wound (non-suicidal). ^d Infections were defined as any adverse event which was coded to the MedDRA system organ class 'Infections and infestations'. ^e Basal cell carcinoma of skin; participant continued in the study. Note: Participants are counted only once for any given event under specific column, regardless of the number of times they actually experienced the event.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 16 October 2024.

References

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Panaccione R, Hart A, Steinwurz F, et al. Efficacy and safety of subcutaneous guselkumab induction therapy in patients with moderately to severely active Crohn’s disease: results through week 48 from the phase 3 GRAVITI study. Abstract presented at: American College of Gastroenterology; October 27-30, 2024; Philadelphia, PA.