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TREMFYA® (guselkumab)

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Retreatment of Plaque Psoriasis with TREMFYA After a Drug Free Interval

Last Updated: 01/04/2025

SUMMARY

A phase 3, multicenter, randomized, double-blind, placebo and active comparator-controlled study, VOYAGE 2, evaluated the safety and efficacy of TREMFYA compared to placebo and adalimumab in patients with moderate to severe plaque psoriasis (PsO). Other efficacy and safety assessments were conducted in patients with interrupted TREMFYA treatment.¹
A phase 3b, randomized, double-blind, parallel group, multicenter study (GUIDE) evaluated the safety and efficacy of TREMFYA in super responder (SR) and nonsuper responder (nSR) adult patients with moderate to severe plaque PsO. The study also assessed the effects of TREMFYA withdrawal in SRs and subsequent response upon retreatment in those who lost disease control.²^,³

CLINICAL DATA

VOYAGE 2

Reich et al (2017)¹ reported results from 992 patients with moderate to severe plaque PsO in a phase 3, multicenter, randomized, double-blind, placebo and active comparator-controlled study evaluating the efficacy and safety of TREMFYA compared to placebo and adalimumab. Other efficacy and safety assessments were conducted in patients with interrupted TREMFYA treatment, and patients who were adalimumab nonresponders who were switched to TREMFYA.

Study Design/Methods

Adult patients (≥18 years of age) with a diagnosis of plaque PsO for ≥6 months who were candidates for phototherapy or systemic therapy and had a baseline Investigator’s Global Assessment (IGA) score ≥3, a Psoriasis Area and Severity Index (PASI) score ≥12, and ≥10% of their body surface area (BSA) involved were eligible for enrollment.
Eligible patients were randomized in a 2:1:1 ratio (TREMFYA [n=496]: placebo [n=248]: adalimumab [n=248]) to 1 of 3 treatment arms as shown in Figure: VOYAGE 2 Study Design.

VOYAGE 2 Study Design⁴

Abbreviations: DBL, database lock; IGA, Investigator’s Global Assessment; nonres, nonresponders; PASI 90, ≥90% improvement in Psoriasis Area and Severity Index score from baseline; q2w, every 2 weeks; q8w, every 8 weeks; R, randomization; res, responders; SE, secondary endpoint.
^aTo maintain blinding, both guselkumab and adalimumab placebos were administered, as necessary.
^bAt week 28, guselkumab-treated patients achieving ≥PASI 90 from baseline were randomized in a 1:1 ratio to guselkumab or placebo.
^cUpon loss of ≥50% of week-28 PASI 90 response or if prerequisite loss of week-72 PASI 90 response was not observed, patients were initiated or retreated with guselkumab.
^dPatients with <PASI 90.
^ePatients with ≥PASI 90 from baseline at week 28.
^fGuselkumab was started at week 28 (5 weeks after the last dose of adalimumab).
^gProportions of patients achieving an IGA score of cleared/minimal disease (IGA 0/1) and PASI 90 at week 16 in the guselkumab group.
^hDue to inclusion of the randomized withdrawal and retreatment period (weeks 28-76), some patients initiated or were retreated with
guselkumab q8w beginning at week 76. Efficacy compared to baseline for guselkumab-treated patient was evaluated starting at week 100 to
allow time for adequate response.
ⁱThe last dose of guselkumab was administered at week 252; efficacy was evaluated through week 252.
^jSafety was evaluated through week 264.

Major secondary endpoints included the time to loss of PASI 90 response in the TREMFYA maintenance vs withdrawal groups.

Results

Patient Characteristics

Baseline demographics and disease characteristics were generally comparable among treatment groups.

Efficacy

Randomized Withdrawal and Retreatment Results from Week 28 to Week 48

During the randomized withdrawal and retreatment period (week 28-48), PASI 90 response was better maintained by the TREMFYA week-28 responders who continued TREMFYA vs those who were rerandomized to placebo.
Among patients withdrawn from TREMFYA at week 28, PASI 90 response rates began to diverge from the maintenance group at week 32.
The median time to loss of PASI 90 response in patients withdrawn from TREMFYA was 15.2 weeks (23 weeks after the last TREMFYA dose) for patients randomized to the withdrawal group.
Of the 375 patients randomized to TREMFYA at baseline who achieved PASI 90 response at week 28, 182 patients were rerandomized to placebo (TREMYFA withdrawal) and 193 patients continued TREMFYA treatment (TREMFYA maintenance).⁵
Through week 48, 88.6% (171/193) of patients in the TREMFYA maintenance group sustained a PASI 90 response vs 36.8% (67/182) of patients in the TREMFYA withdrawal group.¹
Through week 48, a small number of patients (n=16) were retreated with TREMFYA due to ≥50% loss of week-28 PASI 90 response.

Randomized Withdrawal and Retreatment Results from Week 28 to Week 48

Of the 182 patients in the TREMFYA withdrawal group, 173 patients were retreated.⁵
Through week 72, PASI 90 and IGA 0/1 responses were reported in 86.0% and 86.5% for patients in the TREMFYA maintenance group (n=193) vs 11.5% and 15.9% for patients in the TREMFYA withdrawal group (n=182), respectively (P<0.001).⁵

Randomized Withdrawal and Retreatment Results from Week 28 To Week 72 in Patients Retreated with TREMFYA through Week 52

Using treatment failure rules, this analysis only includes retreatment efficacy data collected through week 72 from the double-blind randomized withdrawal and retreatment period in patients who lost response and were retreated with TREMFYA through week 52 (n=53).⁵
- TFR defined patients who discontinued study agent due to lack of efficacy or an adverse event (AE) of worsening of psoriasis or who started protocol-prohibited medication/therapy during the study that could improve psoriasis as treatment failures from that point forward.¹^,⁵
- No imputation was performed for missing data after retreatment of TREMFYA commenced.⁵
In the TREMFYA withdrawal group, 51 patients were evaluated 20 weeks after retreatment and 80.4% (41/51) of patients achieved a PASI 90 response.⁵
Of the 29 patients in the placebo → TREMFYA withdrawal group who achieved PASI 90 response at week 28, 85.7% (24/29) attained a PASI 90 response after 20 weeks of retreatment with TREMFYA.⁵

Safety

Randomized Withdrawal and Retreatment Results from Week 28 to Week 48

No patients discontinued treatment because of an adverse event during this period.¹
One serious infection (appendicitis) was reported in the maintenance group.
No additional malignancies, nonmelanoma skin cancers (NMSCs), or major adverse cardiovascular event (MACE) were reported.
There were no adverse events reported among the 16 patients who were retreated.

Randomized Withdrawal and Retreatment Period from Week 28 to 76

Adverse Events from Week 28 to Week 76 in Patients Randomized at Week 28 During Withdrawal Including the Retreatment Period⁵

	TREMFYA Withdrawal^a (n=182)	TREMFYA Maintenance (n=193)
Average duration of follow-up, weeks	43.3	43.8
Average number of TREMFYA injections	1.7	5.9
≥1 AE, n (%)^b	107 (58.8%)	118 (61.1%)
Nasopharyngitis	33 (18.1%)	32 (16.6%)
Upper respiratory tract infection	17 (9.3%)	14 (7.3%)
Pharyngitis	3 (1.6%)	8 (4.1%)
Sinusitis	1 (0.5%)	7 (3.6%)
Bronchitis	0	6 (3.1%)
Discontinued due to ≥1 AE, n (%)	2 (1.1%)	1 (0.5%)
≥1 SAE, n (%)	10 (5.5%)	9 (4.7%)
Infections, n (%)	74 (40.7%)	79 (40.9%)
Serious infections	1 (0.5%)	4 (2.1%)
Malignancies (excluding NMSC), n (%)	0	0
NMSC, n (%)	0	2 (1.0%)
MACE, n (%)^c	2 (1.1%)	0
Deaths, n (%)	0	0
Abbreviations: AE, adverse event; MACE, major adverse cardiovascular event; NMSC, nonmelanoma skin cancer; SAE, serious adverse event. ^aIncludes patients who were randomized to placebo at week 28 and retreated with TREMFYA before week 72 upon more than 50% loss of week-28 response. ^bOccurring in ≥3% of patients. ^cIncludes sudden cardiac death, myocardial infarction, and stroke

After withdrawal from TREMFYA at week 28, 3 cases of psoriasis rebound (worsening of psoriasis by ≥25% from baseline) were reported more than 90 days after withdrawal. All three patients achieved PASI 90 responses after retreatment of TREMFYA.⁵
No serious injection site or anaphylactic reactions were reported from weeks 28 to 76.⁵

Through Week 100

No safety signals were observed upon retreatment.⁵
No tuberculosis, opportunistic infections, or serious hypersensitivity reactions were reported.⁶
Through week 100, 10.9% of patients in the TREMFYA withdrawal group and 6.7% in the TREMFYA maintenance group developed antibodies to TREMFYA.⁵

GUIDE

Eyerich et al (2021)² reported results from the GUIDE study, a phase 3b, randomized, double-blind, parallel group, multicenter study that evaluated the safety and efficacy of TREMFYA in adult patients with moderate to severe plaque PsO. Asadullah et al (2024)³ evaluated the effects of TREMFYA withdrawal in SRs and subsequent response upon retreatment where disease control (PASI <3) was not maintained through week 116.

Study Design/Methods

The study consisted of screening, part 1 (weeks 0-28), part 2 (weeks 28-68), and part 3 (long-term extension, weeks 68-220).²^,⁷^-¹⁰
Patients who did not achieve the criteria of SRs (ie, nSRs) remained in the study with TREMFYA 100 mg every 8 weeks (q8w) through week 68.²
- SRs were defined as patients who experienced complete skin clearance (absolute PASI=0) at weeks 20 and 28 with TREMFYA 100 mg q8w.²
- nSRs were defined as patients who had PASI >0 at weeks 20 or 28.²
The study design is presented in the Figure: GUIDE Study Design.

GUIDE Study Design²^,⁷^,¹¹

A screenshot of a computer screen

Description automatically generated

Abbreviations: anti-TNF α, anti-tumor necrosis factor α; BCG, Bacille Calmette-Guerin; BSA, body surface area; DLQI, Dermatology Life Quality Index; GUS, guselkumab; HBV, hepatitis B virus; HCV, hepatitis C virus; IL, interleukin; nSRs, nonsuper responders; PASI, Psoriasis Area and Severity Index; PsO, psoriasis; q8w, every 8 weeks; q16w, every 16 weeks; R, randomized; SRs, super responders; TB, tuberculosis; W, week.
^aMethotrexate, azathioprine, cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, tacrolimus.
^bUnless 2 negative HCV RNA test results 6 months apart after completing antiviral treatment and prior to baseline and have a third negative HCV RNA test result at baseline.
^cRituximab, alemtuzumab, abatacept, or visilizumab

Results

Patient Characteristics

A total of 880 patients received TREMFYA in part 1 of the study, which comprised of 357 (40.6%) patients with short disease duration (SDD; ≤2 years from symptom onset) and 523 (59.4%) patients with long disease duration (LDD; >2 years from symptom onset).³^,⁸^-¹⁰^,¹²
Overall, 303 (34.4%) patients were SRs and 577 (65.6%) were nSRs. A higher proportion of patients with SDD vs LDD were SRs (43.7% [n=156/357] vs 28.1% [n=127/523], P<0.001).⁷^,⁹^,¹⁰^,¹²
A total of 822 patients received TREMFYA in part 2 of the study, which included 297 (36.1%) SR patients and 525 (63.9%) nSR patients.⁷
A total of 273 SRs withdrew TREMFYA in part 3 of the study, which included 136 (49.8%) and 137 (50.2%) patients who received TREMFYA 100 mg q8w and every 16 weeks (q16w), respectively.³
Of the 273 SRs, 186 were retreated with TREMFYA (median treatment duration, 259 days), 74 remained treatment free through week 116, and 13 discontinued or were lost to follow-up.³

Efficacy

TREMFYA Withdrawal and Retreatment Results from Week 68 to Week 116

SRs who regained disease control (PASI <3/≤1/0) upon retreatment initiation is given in Table: Proportion of SRs Achieving Absolute PASI Response After Retreatment with TREMFYA in Overall Retreated Patients and Those with Prior Dosing in Part 2 (NRI).
Following retreatment, 97.8% of patients during the withdrawal phase regained disease control within 24 weeks of initiating retreatment.³

Proportion of SRs Achieving Absolute PASI Response After Retreatment with TREMFYA in Overall Retreated Patients and Those with Prior Dosing in Part 2 (NRI)³

	Retreatment at Week 8	Retreatment at Week 16	Retreatment at Week 24
Overall retreated patients	n=186
Absolute PASI <3, %	75.8	87.1	92.5
Absolute PASI ≤1, %	41.4	66.1	78.5
Absolute PASI=0, %	21.0	46.2	58.1
Patients with prior q8w dosing in Part 2	n=87
Absolute PASI <3, %	78.2	86.2	95.4
Absolute PASI ≤1, %	43.7	66.7	80.5
Absolute PASI=0, %	19.5	47.1	57.5
Retreatment phase in part 3 does not include an induction scheme, ie, the retreatment dosing interval was q8w. Abbreviations: NRI, nonresponder imputation; PASI, Psoriasis Area and Severity Index; q8w, every 8 weeks; SR, super responder.

SRs who regained disease control among subgroups categorized by TREMFYA dosing interval in study part 2 (q8w/q16w) or by baseline body weight (<90 kg/>90 kg) are shown in Table: Proportion of SRs Achieving Absolute PASI Response at Retreatment Week 24 with TREMFYA per Previous Dosing Interval and Baseline Body Weight (NRI).

Proportion of SRs Achieving Absolute PASI Response at Retreatment Week 24 with TREMFYA per Previous Dosing Interval and Baseline Body Weight (NRI)³

	By Prior Dosing Interval		By Body Weight
	Part 2: TREMFYA 100 mg q8w (n=87)	Part 2: TREMFYA 100 mg q16w (n=99)	≤90 Kg (n=132)	>90 Kg (n=54)
Absolute PASI <3, %	95.4	89.9	92.4	92.6
P-Value	0.144^a		0.968^a
Absolute PASI=0, %	57.5	58.6	59.1	55.6
P-Value	0.878^a		0.659^a
Patients with PASI >5 during withdrawal phase were retreated with TREMFYA at retreatment weeks 0, 8, and 16. Abbreviations: NRI, nonresponder imputation; PASI, Psoriasis Area and Severity Index; q8w, every 8 weeks; q16w, every 16 weeks; SR, super responder. ^aThese endpoints were not controlled for multiple comparisons. Therefore, the P-value is nominal.

At retreatment week 0, mean PASI was 7.3 and DLQI score was 11.2. Both mean PASI and DLQI decreased over time with TREMFYA retreatment as shown in Table: Mean PASI and DLQI After TREMFYA Retreatment through Week 116.
At retreatment week 0 (n=178), Psoriasis Symptoms and Signs Diary (PSSD) item scores were 6.0, 4.7, 3.8 and 4.1 for Question 1 (Q1; itch), Q9 (burning), Q10 (stinging), and Q11 (pain from lesions).³
At retreatment week 24, the mean PSSD Q1, Q9, Q10, and Q11 scores were 1.0 (n=174), 0.4 (n=175), 0.3 (n=175), and 0.3 (n=175), respectively.³

Mean PASI and DLQI through Week 116 After TREMFYA Retreatment through Week 116³

	Retreatment at Week 8	Retreatment at Week 16	Retreatment at Week 24
	n=184	n=172	n=180
Mean PASI	1.8	0.8	0.5
	n=3	n=171	n=180
Mean overall DLQI	3.0	1.5	1.4
	-	n=171	n=180
Mean DLQI Q1 (itchy, sore, painful, or stinging skin)	-	0.5	0.4
Data prior to week 68 were not considered. Patients with PASI >5 during withdrawal phase were retreated with TREMFYA at retreatment weeks 0, 8, and 16. Abbreviations: DLQI, Dermatology Life Quality Index; OC, observed cases; PASI, Psoriasis Area and Severity Index; PSSD, Psoriasis Symptoms and Signs Diary; Q, Question.

Overall, 221 (81.0%) patients withdrawn from treatment achieved PASI=0 at week 68.³
Among the 74 patients who remained treatment-free through week 116, 67 (91.0%) had PASI=0 at week 68.³^,¹³
Mean PASI and PASI=0 responses after retreatment at week 68 are shown in the Table: PASI Response Over Time After Retreatment with TREMFYA in Patients with PASI=0 vs PASI >0 at Week 68.

PASI Response Over Time After Retreatment with TREMFYA in Patients with PASI=0 vs PASI >0 at Week 68³

	Retreatment Week 8	Retreatment Week 16	Retreatment Week 24
Mean PASI (OC)
	n=42	n=36	n=41
Mean PASI >0	2.4	1.4	1.1
	n=141	n=135	n=138
Mean PASI=0	1.6	0.6	0.3
PASI=0 After Initiating Retreatment (NRI), %
	n=42	n=42	n=42
PASI >0	9.5	21.4	31.0^a
	n=143	n=143	n=143
PASI=0	24.5	53.8	66.4^a
Patients with PASI >5 during withdrawal phase were retreated with TREMFYA at retreatment weeks 0, 8, and 16. Abbreviations: NRI, nonresponder imputation; OC, observed cases; PASI, Psoriasis Area and Severity Index. ^aNominal P-value <0.001 for PASI >0 vs PASI=0 groups at week 24. The endpoints were not controlled for multiple comparisons. Therefore, the P-value is nominal, and statistical significance has not been established.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 10 March 2024.

References

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1	Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76(3):418-431.
2	Eyerich K, Weisenseel P, Pinter A, et al. IL-23 blockade with guselkumab potentially modifies psoriasis pathogenesis: rationale and study protocol of a phase 3b, randomised, double-blind, multicentre study in participants with moderate-to-severe plaque-type psoriasis (GUIDE). BMJ Open. 2021;11(9):e049822.
3	Asadullah K, Schäkel K, Pinter A, et al. GUIDE trial (part 3): following guselkumab withdrawal and a long treatment-free period, disease control is rapidly regained upon re-treatment in psoriasis super responders. Oral Presentation presented at: American Academy of Dermatology Annual Meeting; March 8-12, 2024; San Diego, CA.
4	Reich K, Armstrong AW, Langley RG, et al. Maintenance of response through up to 5-years of continuous guselkumab treatment of psoriasis in the VOYAGE 2 phase 3 trial. Poster presented at: American Academy of Dermatology; April 23-25, 2021; E-Congress.
5	Gordon KB, Armstrong AW, Foley P, et al. Guselkumab efficacy after withdrawal is associated with suppression of serum IL-23-regulated IL-17 and IL-22 in psoriasis: VOYAGE 2 study. J Invest Dermatol. 2019;139(12):2437-2446.
6	Gordon KB, Armstrong AW, Foley P, et al. Long-term efficacy of guselkumab treatment after drug withdrawal and retreatment in patients with moderate to severe plaque psoriasis: results from VOYAGE 2. Oral Presentation presented at: 76th Annual Meeting of the American Academy of Dermatology; February 15-20, 2018; San Diego, CA.
7	Schäkel K, Asadullah K, Pinter A, et al. 16-week treatment interval of guselkumab is non-inferior to 8-week dosing for maintaining psoriasis control in super responders: GUIDE study primary result. Poster presented at: EADV congress; September 7-10, 2022; Milan, Italy.
8	Schäkel K, Asadullah K, Pinter A, et al. Prolonged q16w treatment interval of guselkumab is non-inferior to q8w dosing for maintaining disease control in super responders: primary results from GUIDE at Week 68 in patients with psoriasis. Poster presented at: ESDR congress; September 28-October 1, 2022; Amsterdam, the Netherlands.
9	Schäkel K, Reich K, Asadullah K, et al. Prognostic factors for early PASI 100 response in psoriasis patients treated with guselkumab: results from the GUIDE study. Poster presented at: AAD annual meeting; March 25-29, 2022; Boston, MA.
10	Schäkel K, Reich K, Asadullah K, et al. Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance ('clinical super response’): week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study. J Eur Acad Dermatol Venereol. 2023;37(10):2016-2027.
11	Janssen-Cilag G.m.b.H. A study to evaluate further therapeutic strategies with guselkumab in participants with moderate-to-severe plaque-type psoriasis (GUIDE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2023 April 24]. Available from: https://clinicaltrials.gov/study/NCT03818035 NLM Identifier: NCT03818035.
12	Schäkel K, Reich K, Asadullah K, et al. Early disease intervention in psoriasis leads to a faster and higher rate of complete skin clearance: week 28 results from the GUIDE study [abstract]. Exp Dermatol. 2021;30(Suppl 2):34. Abstract 73.
13	Schäkel K, Asadullah K, Pinter A, et al. Treatment-free period of more than 1 year in guselkumab super responders with short disease duration of psoriasis: withdrawal data from the GUIDE trial. Oral Presentation presented at: European Academy of Dermatology and Venereology 2023; October 11-14, 2023; Berlin, Germany.