Key clinical-trial evidence for guselkumab

Author: Anoma Ranaweera B.V.Sc; PhD (Clinical Biochemistry, University of Liverpool, UK). DermNet NZ Editor in Chief: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, January 2018.


Introduction

In July 2017, the U.S. Food and Drug Administration (FDA) approved guselkumab (TREMFYA™; Janssen Biotech, PA, USA) for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Guselkumab is the first and only approved biologic therapy that selectively blocks only IL-23, a cytokine that plays a key role in plaque psoriasis.

Guselkumab received FDA approval based on results from a clinical development program that included more than 2,000 patients in the Phase 3 VOYAGE 1, VOYAGE 2 and NAVIGATE studies.

In September 2017, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending marketing authorisation in the European Union for the use of guselkumab in the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy.

Guselkumab is currently unavailable in NZ (January 2018).

Moderate to severe psoriasis suitable for guselkumab

VOYAGE 1 and 2 (guselkumab compared with placebo or adalimumab)

  • 1443 patients were randomised to either guselkumab (100 mg at weeks 0 and 4 and every 8 weeks thereafter), placebo or U.S. licensed adalimumab (80 mg at week 0 and 40 mg at week 1, followed by 40 mg every other week thereafter).
  • Patients had an Investigator’s Global Assessment (IGA) score of ≥ 3 (moderate) on a 5-point scale of overall disease severity, a Psoriasis Area and Severity Index (PASI) score ≥ 12, and a minimum affected body surface area (BSA) of 10%.
  • Patients with guttate, erythrodermic, or pustular psoriasis were excluded.
  • The two co-primary endpoints were the proportion of individuals who achieved an IGA score of 0 (cleared) or 1 (minimal); and the proportion of subjects who achieved at least a 90% reduction from baseline in the PASI composite score (PASI 90).
  • Both trials assessed the responses at week 16 compared to placebo for the two co-primary endpoints.
  • Efficacy results are summarised in Table 1.

Table 1. Efficacy results at week 16 in adults with plaque psoriasis compared with placebo

 

VOYAGE 1

VOYAGE 2

Primary Endpoint

No patients (%)

Guselkumab

(n = 329)

Placebo

(n = 174)

Guselkumab

(n = 496)

Placebo

(n = 248)

IGA response of 0/1

280 (85)

12 (7)

417 (84)

21 (8)

PASI 90 response

241 (73)

5 (3)

347 (70)

6 (2)

Comparison of guselkumab with adalimumab

  • Table 2 presents the results of an analysis of all the North American sites (U.S. and Canada) demonstrating superiority of guselkumab to adalimumab.

Table 2.  Efficacy results for guselkumab vs adalimumab in plaque psoriasis

 

VOYAGE 1

VOYAGE2

Endpoint

No. patients (%)

Guselkumab

(n = 115)

Adalimumab

(n =115)

Guselkumab

(n = 160)

Adalimumab

(n= 81)

IGA response of 0/1 (cleared or minimal)

Week 16

97 (84)

70 (61)

119 (74)

50 (62)

Week 24

97 (84)

62 (54)

119 (74)

46 (57)

Week 48

91 (79)

62 (54)

NA

NA

IgA response of 0 (cleared)

Week 24

61 (53)

27 (23)

76 (48)

23 (28)

Week 48

54 (47)

28 (24)

NA

NA

PASI 75 response

Week 16

105 (91)

80 (70)

132 (83)

51 (63)

PASI 90 response

Week 16

84 (73)

47 (44)

102 (64)

34 (42)

Week 24

92 (80)

51 (41)

113 (71)

41 (51)

Week 48

84 (73)

53 (46)

NA

NA

Maintenance of response

  • To evaluate maintenance and durability of response (VOYAGE 2), patients randomised to guselkumab at week 0 and who were PASI 90 responders at week 28 were re-randomised to guselkumab every 8 weeks or placebo.
  • At week 48, 89% of patients who continued treatment with guselkumab maintained PASI 90 compared to 37% who were re-randomised to placebo.

Patient-reported outcomes

  • Based on the Psoriasis Symptoms and Signs Diary (PSSD) at week 16, patients treated with guselkumab showed greater improvements in itch, pain, stinging, burning and skin tightness compared to placebo, in both VOYAGE 1 and 2  trials.
  • A greater proportion of patients treated with guselkumab compared with adalimumab achieved a PSSD symptom score of 0 (symptom-free) at week 24, in both trials.

 Adverse events with guselkumab (VOYAGE 1 and 2)

  • Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice.
  • Table 3 summarises commonly observed side effects in VOYAGE 1 and 2 trials.

Table 3. Adverse reactions occurring in ≥ 1% of patients through week 16 in Voyage 1 and Voyage 2   trials    

 

Guselkumab

 n = 283

No. (%)

 

Adalimumab

 n = 196

No. (%)

 

Placebo

n = 422

No. (%)

Upper respiratory infections

118 (14.3)

21 (10.7)

54 (12.8)

Headache

38 (4.6)

2 (1)

14 (3.3)

Injection site reactions

37 (4.5)

15 (7.7)

12 (2.8)

Arthralgia

22 (2.7)

4 (2)

9 (2.1)

Diarrhoea

13 (1.6)

3 (1.5)

4 (0.9)

Gastroenteritis

11 (1.3)

4 (2)

4 (0.9)

Tinea infections

9 (1.1)

0

0

Herpes simplex infections

9 (1.1)

0

2 (0.5)

Elevated liver enzymes

  • Elevated liver enzymes were reported more frequently in the guselkumab group (2.6%) than in the placebo group (1.9%).
  • Of the 21 patients who reported elevated liver enzymes in the guselkumab group, all events except one were mild to moderate in severity and none of the events led to discontinuation of the drug.

Safety through Week 48

  • The frequency of adverse reactions was similar to the safety profile observed during the first 16 weeks of treatment. 

NAVIGATE trial (guselkumab compared with ustekinumab)

  • In this phase III, randomised, double-blind study, 871 patients received open-label ustekinumab (45 mg or 90 mg) at weeks 0 and 4.
  • At week 16, 268 patients with an inadequate response to ustekinumab [Investigator's Global Assessment (IGA) ≥ 2] were randomised (double-blind) to guselkumab 100 mg or to continue ustekinumab.
  • 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open-label ustekinumab.
  • The primary end point was the number of visits at which randomised patients achieved IGA 0/1 and at least a two-grade improvement from week 28 to week 40.
  • Improvement ≥  90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed.
  • The mean number of visits at which patients achieved IGA 0/1 and at least a two-grade improvement (week 28-40) was significantly greater in the guselkumab group vs the randomised ustekinumab group (1·5 vs. 0·7; P < 0·001).
  • Greater proportions of patients in the guselkumab compared with the ustekinumab group achieved IGA 0/1 and at least a two-grade improvement at week 28 and week 52.
  • Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52.
  • After week 16, 64·4% of patients in the guselkumab group and 55·6% in the ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type.
  • Overall, 6·7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4·5% (n = 6) for the ustekinumab group.
  • Tables 4 and 5 are a summary of the key results and adverse events from the NAVIGATE trial.

Table 4. Efficacy results of guselkumab vs ustekinumab (NAVIGATE trial)

Efficacy parameter

Guselkumab

 (n = 135)

Ustekinumab

(n = 133)

P value

Mean number of visits at which patients achieved IGA 0/1 and at least a two-grade improvement (relative to week 16) from week 28 through week 40

1.5

0.7

≤ 0·001

Mean number of visits at which patients achieved IGA 0 from week 28 through week 40

0.9

0.4

≤ 0·001

Mean number of visits at which patients achieved PASI 90 from week 28 through week 40

2.2

1.1

≤ 0·001

No. patients with IGA 0/1 and ≥ 2-grade improvement (relative to week 16) at week 28

42

19

≤ 0·001

No. patients with PASI 90 response at week 28

65

30

≤ 0·001

No. patients with DLQI > 1 at week 16,

103

105

P = 0.002

No. patients with DLQI 0/1 at week 52

40

20

 

No. patients with PSSD symptom score > 0 at week 16

123

126

 

No. patients with a PSSD symptom score of 0 at week 52

25

12

P <0.05

Table 5. Adverse events (NAVIGATE trial weeks 1-60) in patients randomised to guselkumab or ustekinumab

Adverse event (% patients)

Guselkumab  (n = 135)

Ustekinumab (n = 133)

Infections

57 (41.5%)

47 (35.3%)

Nasopharyngitis

23 (17%)

23 (17.3%)

Respiratory tract infections

15 (11.1%)

11 (8.3%)

Injection site reaction

7 (1.1 %)

0

Cardiovascular event

2 (1.5 %)

1 (0.8%)

Malignancies

2 (1.5%)

0

Guselkumab — future potential

  • Guselkumab has generated encouraging data for efficacy and safety in the treatment of moderate-to-severe chronic plaque psoriasis.
  • Results from phase III clinical trials suggest that guselkumab is superior to placebo at week 16 and is better able to clear or almost clear psoriasis plaques compared with adalimumab.
  • The effects were maintained through week 48.
  • Phase III studies of guselkumab report some of the highest PASI-90 rates (at week 16, 73.3% in VOYAGE 1 and 70.0% in VOYAGE 2) to date.
  • The potential of guselkumab to achieve PASI 90 in 70% or more of patients suggests that guselkumab may have a significant positive impact on patient quality of life.
  • Results of the NAVIGATE trial established that guselkumab, had substantial efficacy in adults with moderate-to-severe psoriasis and was more effective than ustekinumab in patients with an inadquate response to ustekinumab.
  • Potential reasons for the superior efficacy of guselkumab compared with ustekinumab include the central role of IL-23 in the pathogenesis of psoriasis, a more potent blockade of IL-23 with guselkumab, more frequent and higher dosing with guselkumab and/or enhanced Th17 responses in the setting of the inhibition of IL-12.
  • The favorable adverse event profile of guselkumab observed in Phase III studies suggest that IL-23 may be a more psoriasis-specific cytokine compared to other cytokines such as TNF-α and IL-17.
  • Overall, targeting IL-23, a key cytokine driving various other effector cytokines, may be responsible for the high efficacy and durable responses up to week 48. 
  • Further long-term studies are needed to understand the long-term efficacy and safety of guselkumab. 

 

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