one page summary for clinical trial

wjb_4-1.pdf

Home >Science homework help >one page summary for clinical trial

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

n engl j med 373;2 nejm.org July 9, 2015136

From the Department of Dermatology, Feinberg School of Medicine, Northwest- ern University, Chicago (K.B.G.); the De- partment of Dermatology, University of Utah School of Medicine, Salt Lake City (K.C.D.); Innovaderm Research, Montreal (R.B.); the Department of Dermatology, Ludwig-Maximilians-Universität München, Munich ( J.C.P.), and the Dermatologi- kum Hamburg, Hamburg (K.R.) — both in Germany; and Janssen Research and Development, Spring House (Y.W., S.L., Y.-K.S., P.S., B.R.), and the Department of Dermatology, University of Pennsylva- nia, Philadelphia (B.R.) — both in Penn- sylvania. Address reprint requests to Dr. Reich at Dermatologikum Hamburg, Stephansplatz 5, Hamburg 20354, Ger- many, or at kreich@ dermatologikum . de.

BACKGROUND Little is known about the effect of specific anti–interleukin-23 therapy, as com- pared with established anti–tumor necrosis factor therapies, for the treatment of moderate-to-severe plaque psoriasis.

METHODS In a 52-week, phase 2, dose-ranging, randomized, double-blind, placebo-controlled, active-comparator trial, we compared guselkumab (CNTO 1959), an anti–interleu- kin-23 monoclonal antibody, with adalimumab in patients with moderate-to-severe plaque psoriasis. A total of 293 patients were randomly assigned to receive gusel- kumab (5 mg at weeks 0 and 4 and every 12 weeks thereafter, 15 mg every 8 weeks, 50 mg at weeks 0 and 4 and every 12 weeks thereafter, 100 mg every 8 weeks, or 200 mg at weeks 0 and 4 and every 12 weeks thereafter) through week 40, placebo, or adalimumab (standard dosage for psoriasis). At week 16, patients in the pla- cebo group crossed over to receive guselkumab at a dose of 100 mg every 8 weeks. The primary end point was the proportion of patients with a Physician’s Global Assessment (PGA) score of 0 (indicating cleared psoriasis) or 1 (indicating minimal psoriasis) at week 16.

RESULTS At week 16, the proportion of patients with a PGA score of 0 or 1 was signifi- cantly higher in each guselkumab group than in the placebo group: 34% in the 5-mg group, 61% in the 15-mg group, 79% in the 50-mg group, 86% in the 100-mg group, and 83% in the 200-mg group, as compared with 7% in the placebo group (P≤0.002 for all comparisons). Moreover, the proportion was significantly higher in the 50-mg, 100-mg, and 200-mg guselkumab groups than in the adalimumab group (58%) (P<0.05 for all comparisons). At week 16, the proportion of patients with at least a 75% improvement in Psoriasis Area and Severity Index scores was significantly higher in each guselkumab group than in the placebo group (P<0.001 for all comparisons). At week 40, the proportion of patients with a PGA score of 0 or 1 remained significantly higher in the 50-mg, 100-mg, and 200-mg guselku- mab groups than in the adalimumab group (71%, 77%, and 81%, respectively, vs. 49%) (P<0.05 for all comparisons). Between week 0 and week 16, infections were observed in 20% of the patients in the guselkumab groups, 12% in the adalim- umab group, and 14% in the placebo group.

CONCLUSIONS The results of this phase 2 trial suggest that guselkumab may be an effective therapy for plaque psoriasis and that control of psoriasis can be achieved with specific anti–interleukin-23 therapy. (Funded by Janssen Research and Develop- ment; X-PLORE ClinicalTrials.gov number, NCT01483599.)

A B S T R A C T

A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis

Kenneth B. Gordon, M.D., Kristina Callis Duffin, M.D., Robert Bissonnette, M.D., Jörg C. Prinz, M.D., Yasmine Wasfi, M.D., Ph.D., Shu Li, Ph.D., Yaung-Kaung Shen, Ph.D., Philippe Szapary, M.D., M.S.C.E.,

Bruce Randazzo, M.D., Ph.D., and Kristian Reich, M.D., Ph.D.

Original Article

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015 137

Guselk um a b vs. A da limum a b for Pl aque Psor i a sis

Psoriasis is a chronic skin disease that is characterized by the infiltration of inflammatory cells into the skin and ex- cessive keratinocyte proliferation, which result in raised, well-demarcated erythematous lesions1; the disease has a substantial effect on quality of life.2,3 The pathogenesis of psoriasis involves environmental factors and immune dysregula- tion in persons with a genetic predisposition.4 The proinflammatory interleukin-12–mediated type 1 helper T (Th1) cell and interleukin-23– mediated type 17 helper T (Th17) cell signaling pathways5,6 are up-regulated in psoriatic lesions; antibodies that inhibit both interleukin-12 and interleukin-237,8 and those that inhibit interleu- kin-179-13 inhibit the expression of molecular and clinical disease characteristics associated with psoriasis. Interleukin-12 induces the develop- ment of Th1 cells,14 whereas interleukin-23 is required for terminal differentiation of Th17 cells15 and maintenance of the Th17 phenotype.16 Th17 cells produce interleukin-17 and interleu- kin-22, both of which have proinf lammatory effects in skin that are relevant to the patho- genesis of psoriasis.17

Guselkumab (CNTO 1959, Janssen Research and Development) is a fully human IgG1 lambda monoclonal antibody that inhibits interleukin-23– specific intracellular and downstream signaling. A phase 1 study showed that a single dose of guselkumab resulted in significant clinical re- sponses in patients with moderate-to-severe plaque psoriasis.18 This phase 2, dose-ranging, 52-week study included an active-comparator group that received adalimumab, an anti–tumor necrosis factor α (TNF-α) therapy that is widely used for the treatment of moderate-to-severe plaque psoriasis.

M e t h o d s

Patients

We conducted this multicenter, phase 2, random- ized, double-blind, placebo-controlled, active- comparator trial (X-PLORE) at 31 sites in North America and 12 sites in Europe from October 2011 through August 2013. Patients were 18 years of age or older and had had moderate-to-severe plaque psoriasis for 6 months or longer. Moder- ate-to-severe plaque psoriasis was defined as disease involvement of 10% or more of the total body-surface area at baseline, a score of 3 or

higher on the Physician’s Global Assessment (PGA; on which scores range from 0 to 5, with 0 indicating cleared psoriasis, 1 minimal psoriasis, 2 mild psoriasis, 3 moderate psoriasis, 4 marked psoriasis, and 5 severe psoriasis), and a score of 12 or higher on the Psoriasis Area and Severity Index (PASI; on which scores range from 0 to 72, with higher scores indicating more severe dis- ease). Patients could have received previous sys- temic treatment or phototherapy but were ex- cluded if they had been previously exposed to adalimumab or guselkumab.

Study Design

The study consisted of a screening phase (weeks −4 to 0), a treatment phase (weeks 0 to 40), and a follow-up phase through 1 year (weeks 40 to 52) (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). At baseline, 293 patients were ran- domly assigned to receive subcutaneously admin- istered placebo (42 patients), one of five gusel- kumab regimens (5 mg at weeks 0 and 4 and every 12 weeks thereafter [41 patients], 15 mg every 8 weeks [41 patients], 50 mg at weeks 0 and 4 and every 12 weeks thereafter [42 patients], 100 mg every 8 weeks [42 patients], or 200 mg at weeks 0 and 4 and every 12 weeks thereafter [42 patients]), or adalimumab (80 mg at week 0 and 40 mg at week 1 and every other week thereafter through week 39 [43 patients]). At week 16, patients in the placebo group crossed over to receive guselkumab at a dose of 100 mg every 8 weeks. Adalimumab was not adminis- tered in a blinded, placebo-controlled manner; however, to ensure objectivity, all efficacy assess- ments were performed by an evaluator at each study site who was unaware of the study-group assignments.

Study Oversight

This study was sponsored by Janssen Research and Development. Janssen supplied the study agents and collected and analyzed the data. All the authors had full access to the data and vouch for the completeness and accuracy of the data and analyses and the fidelity of this report to the study protocol (available at NEJM.org). All the authors collaborated on writing the manuscript, with the assistance of professional medical writ- ers employed by Janssen, and made the decision to submit the manuscript for publication.

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015138

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

Efficacy and Safety Analyses

Efficacy assessments were performed with the use of the PGA, the PASI, and the Dermatology Life Quality Index (DLQI; on which scores range from 0 to 30, with higher scores indicating a more negative effect on quality of life). Safety assessments included documentation of adverse events, injection-site and allergic reactions, and concomitant medications.

The primary end point was the proportion of patients with a PGA score of 0 or 1 at week 16 in each guselkumab group, as compared with the proportion in the placebo group. Major pre- specified secondary end points were the propor- tion of patients with at least a 75% improvement from baseline in the PASI score at week 16 and the change in the DLQI score from baseline to week 16. An additional prespecified secondary end point was the difference (with 95% confi- dence intervals) between the proportion of pa- tients with a PGA score of 0 or 1 at weeks 16 and 40 in each guselkumab group and the propor- tion in the adalimumab group.

Statistical Analysis

Multiplicity adjustment was performed only for the five pairwise comparisons of the primary end point between guselkumab, sequentially from the highest dose (200 mg) to the lowest dose (5 mg), and placebo (each at a two-sided alpha signifi- cance level of 0.05).19 If a given comparison in the test sequence was not significant, the re- maining subsequent comparisons were not con- sidered to be significant.

The primary end point and other key binary end points associated with PGA and PASI scores at week 16 were analyzed on an intention-to- treat basis. Patients in whom the study drug was discontinued because of unsatisfactory thera- peutic effect or an adverse event of worsened psoriasis or patients who used a therapy after baseline that was prohibited in the protocol be- cause it could improve psoriasis were considered in the analysis of binary end points (e.g., at least 75% improvement in PASI score) as not having had a response and were assigned a score of zero in the analysis of continuous end points (e.g., change in DLQI score) from that point onward. Patients with missing PGA or PASI scores at week 16 were categorized as not having had a response.

Efficacy was analyzed according to treatment

group. Analyses of the placebo group after week 16 included only patients who had crossed over to receive guselkumab. Data were compared with the use of the Cochran–Mantel–Haenszel chi- square test for binary variables and analysis of covariance with the van der Waerden normal scores for continuous variables. Differences in response rates between the guselkumab groups and adalimumab group and the corresponding 95% confidence intervals were calculated, with stratification according to baseline weight (≤90 kg vs. >90 kg), at weeks 16 and 40. Safety analyses included patients who underwent randomization and received at least one dose of a study drug. Adverse events were summarized in two time periods: week 0 to week 16 and week 16 to week 52. The visit at week 16 (for the adalimumab group) or the injection at week 16 (for the other treatment groups) marked the beginning of the second time period.

R e s u l t s

Patient Characteristics

Of the 394 patients who were screened, 293 were randomly assigned to receive guselkumab (208 patients), adalimumab (43 patients), or placebo (42 patients) (Fig. S1B in the Supplementary Ap- pendix). One patient in the 200-mg guselkumab group underwent randomization but was not treated and therefore was not included in the safety analysis. A total of 39 of 42 patients in the placebo group crossed over to receive guselku- mab at week 16, in accordance with the proto- col. The study agent was discontinued in 15% of the patients in the guselkumab groups and in 26% of the patients in the adalimumab group.

Although some variability was observed, base- line demographic and disease characteristics were generally similar among the treatment groups (Table 1, and Table S1 in the Supple- mentary Appendix). A total of 91% of the pa- tients were white and 71% were men; the me- dian age was 45 years, the mean baseline weight was 91.3 kg (weight ≤90 kg, 51%; weight >90 kg, 49%), the mean duration of psoriasis was approximately 19 years, and the median base- line PASI score was 18.2. In addition, 44% of the patients had a baseline PGA score of 4 or 5, and 70% had received previous treatment with conventional systemic therapies or biologic agents (Table 1).

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015 139

Guselk um a b vs. A da limum a b for Pl aque Psor i a sis

Efficacy Weeks 0 to 16

At week 16, the proportion of patients with a PGA score of 0 or 1 (primary end point) was significantly higher in each guselkumab group than in the placebo group: 34% in the 5-mg group, 61% in the 15-mg group, 79% in the 50-mg group, 86% in the 100-mg group, and 83% in the 200-mg group, as compared with 7% in the placebo group (P = 0.002 for the comparison of the 5-mg group; P<0.001 for all other compari- sons) (Table 2 and Fig. 1A). Among the gusel- kumab groups, a dose response was observed among the four lowest-dose groups, whereas results were similar in the 100-mg and 200-mg groups (Table 2).

In addition, the proportion of patients with at least a 75% improvement from baseline in the PASI score, at least a 90% improvement, and a 100% improvement was significantly higher in each guselkumab group than in the placebo group at week 16 (P<0.001) (Table 2 and Fig. 1B, and Fig. S2 in the Supplementary Appendix). Clinical responses of a PGA score of 0 or 1 and at least a 75% improvement in PASI score were observed as early as week 4 after the initiation of guselkumab (Fig. 1). The decrease in DLQI score (indicating improve- ment in quality of life) from baseline to week 16 was significantly greater in the guselkumab groups than in the placebo group (P≤0.008) (Table 2).

Characteristic Placebo Group

(N = 42) Guselkumab Groups

(N = 208) Adalimumab Group

(N = 43)

Median age — yr 46.5 44.0 50.0

Male sex — no. (%) 28 (67) 149 (72) 30 (70)

White race — no. (%)† 39 (93) 189 (91) 39 (91)

Weight — kg 93.6±22.62 90.7±22.34 91.6±19.88

Duration of psoriasis — yr 18.0±13.30 18.5±12.17 19.3±12.79

Involvement of body-surface area — % 27.5±19.26 24.6±14.48 26.8±16.80

PASI score‡ 21.8±9.98 20.9±8.05 20.2±7.58

PGA score — no. (%)§

3 22 (52) 116 (56) 24 (56)

4 19 (45) 81 (39) 14 (33)

5 1 (2) 11 (5) 4 (9)

Psoriatic arthritis — no. (%) 12 (29) 52 (25) 11 (26)

Scalp psoriasis — no. (%) 41 (98) 192 (92) 39 (91)

Previous treatment — no. (%)

Conventional systemic therapy¶ 21 (50) 109 (52) 17 (40)

Biologic agent‖ 15 (36) 85 (41) 26 (60)

Conventional systemic therapy or biologic agent¶‖

27 (64) 148 (71) 30 (70)

Topical agent 41 (98) 200 (96) 42 (98)

Phototherapy** 21 (50) 109 (52) 24 (56)

Psoralen plus ultraviolet A therapy 9 (21) 49 (24) 12 (28)

* Plus–minus values are means ±SD. † Race was self-reported. ‡ On the Psoriasis Area and Severity Index (PASI), scores range from 0 to 72, with higher scores indicating more severe disease. § On the Physician’s Global Assessment (PGA), scores range from 0 to 5, with 0 indicating cleared psoriasis, 1 minimal

psoriasis, 2 mild psoriasis, 3 moderate psoriasis, 4 marked psoriasis, and 5 severe psoriasis. ¶ Conventional systemic therapies included psoralen plus ultraviolet A therapy, methotrexate, acitretin, and cyclosporine. ‖ Biologic agents included ustekinumab, etanercept, infliximab, efalizumab, alefacept, and briakinumab. ** Phototherapy included ultraviolet B therapy and psoralen plus ultraviolet A therapy.

Table 1. Patient Characteristics.*

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015140

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

Weeks 16 to 40 The proportion of patients with a PGA score of 0 or 1 continued to increase over time, reaching the maximum response at week 20 in most guselkumab groups (Fig. 1A). Responses were generally maintained from week 24 to week 40, at which time 77% of patients in the 100-mg guselkumab group and 81% of patients in the 200-mg guselkumab group had a PGA score of 0 or 1. Between week 16 and week 40, a substan- tial proportion of patients in the guselkumab groups had a PGA score of 0 and a 100% im- provement from baseline in the PASI score (Fig. S2 in the Supplementary Appendix). After week 16, PGA scores among patients in the placebo group who had crossed over to receive gusel- kumab were similar to the scores among pa- tients in the 100-mg guselkumab group. Some variations in PGA scores were observed over time among guselkumab groups. A modest loss of ef- ficacy near the end of each dosing interval occurred more consistently among the patients who re- ceived guselkumab every 12 weeks than among those who received guselkumab every 8 weeks. The pattern of PASI scores was generally similar to that observed for PGA scores, with maximum responses achieved by approximately week 20 and maintained through week 40 (Fig. 1, and Fig. S2 in the Supplementary Appendix).

Comparison of Guselkumab with Adalimumab At week 16, the proportion of patients with a PGA score of 0 or 1 was higher in all gusel- kumab groups, except for the 5-mg group, than in the adalimumab group (Table 2 and Fig. 1A). The differences in proportions between the 50- mg, 100-mg, and 200-mg guselkumab groups and the adalimumab group were significant: 20 percentage points (95% confidence interval [CI], 2 to 39), 28 percentage points (95% CI, 10 to 46), and 25 percentage points (95% CI, 7 to 44), re- spectively. At week 40, the proportion of patients with a PGA score of 0 or 1 was significantly higher in the 50-mg, 100-mg, and 200-mg gusel- kumab groups than in the adalimumab group: 71%, 77%, and 81%, respectively, versus 49%. The differences in proportions between the 50-mg, 100-mg, and 200-mg guselkumab groups and the adalimumab group were 23 percentage points (95% CI, 2 to 44), 29 percentage points (95% CI, 9 to 49), and 33 percentage points (95% CI, 13 to 53), respectively. Moreover, P values for post hoc analyses of pairwise comparisons (performed with the use of the Cochran–Mantel–Haenszel chi-square test and stratified according to base- line weight [≤90 kg vs. >90 kg]) between the 50-mg, 100-mg, and 200-mg guselkumab groups and the adalimumab group were significant at week 16 (P = 0.05, P = 0.005, and P = 0.01, respec-

Outcome

Placebo Group

(N = 42)

5-mg Guselkumab

Group (N = 41)

15-mg Guselkumab

Group (N = 41)

50-mg Guselkumab

Group (N = 42)

100-mg Guselkumab

Group (N = 42)

200-mg Guselkumab

Group (N = 42)

Adalimumab Group

(N = 43)

PGA score of 0 or 1 — no. (%) 3 (7) 14 (34)† 25 (61)‡ 33 (79)‡ 36 (86)‡ 35 (83)‡ 25 (58)‡

PGA score of 0 — no. (%) 0 6 (15)§ 8 (20)† 11 (26)‡ 19 (45)‡ 15 (36)‡ 13 (30)‡

≥75% Improvement from base- line in PASI score — no. (%)

2 (5) 18 (44)‡ 31 (76) 34 (81)‡ 33 (79)‡ 34 (81)‡ 30 (70)‡

≥90% Improvement from base- line in PASI score — no. (%)

1 (2) 14 (34)‡ 14 (34)‡ 19 (45)‡ 26 (62)‡ 24 (57)‡ 19 (44)‡

100% Improvement from base- line in PASI score — no. (%)

0 4 (10)‡ 5 (12)‡ 8 (19)‡ 14 (33)‡ 12 (29)‡ 11 (26)‡

Change in DLQI score from baseline¶

−2.3±6.80 −6.2±5.24† −10.3±5.49‡ −11.1±7.38‡ −10.8±7.34‡ −11.4±6.83‡ −10.1±9.00‡

DLQI score of 0 or 1 — no./ total no. (%)¶‖

3/42 (7) 10/38 (26)§ 14/41 (34)† 17/40 (42)‡ 25/40 (62)‡ 26/37 (70)‡ 19/39 (49)‡

* Plus–minus values are means ±SD. The 5-mg, 50-mg, and 200-mg guselkumab groups received doses at weeks 0 and 4 and every 12 weeks thereafter, and the 15-mg and 100-mg guselkumab groups received doses every 8 weeks.

† P<0.01 for the comparison with placebo. ‡ P<0.001 for the comparison with placebo. § P<0.05 for the comparison with placebo. ¶ On the Dermatology Life Quality Index (DLQI), scores range from 0 to 30, with higher scores indicating a more negative effect on quality of life. ‖ Included are data from patients who underwent randomization and had a baseline DLQI score greater than 1.

Table 2. Efficacy Outcomes at Week 16.*

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015 141

Guselk um a b vs. A da limum a b for Pl aque Psor i a sis

tively) and at week 40 (P = 0.04, P = 0.01, and P = 0.003, respectively).

Safety Weeks 0 to 16

During the placebo-controlled period, the pro- portion of patients with one or more adverse events was similar among the treatment groups (52% in the placebo group, 50% in the guselku- mab groups, and 56% in the adalimumab group) (Table 3). Among the guselkumab groups, there was no evidence of a relationship between the dose and the rate of adverse events (Table S2 in the Supplementary Appendix). The rates of ad- verse events of infection were 14% in the placebo group, 20% in the guselkumab groups, and 12% in the adalimumab group.

The proportion of patients in whom the study agent was discontinued because of an adverse event, serious adverse event, or serious infection was low through week 16. All serious adverse events that occurred through week 16 were single events. A serious infection occurred in two pa- tients in the 50-mg guselkumab group (appendi- citis in one patient and lung abscess in one pa- tient). The proportion of adalimumab injections associated with an injection-site reaction was higher than the proportion of placebo or gusel- kumab injections associated with an injection- site reaction (6% vs. 1% and 1%, respectively).

Weeks 16 to 52 Between week 16 and week 52, the proportion of patients in whom the study agent was discontin- ued because of an adverse event was low and similar among the groups (Table 3, and Table S2 in the Supplementary Appendix). The proportion of patients with one or more adverse events through week 52 was somewhat higher in the adalimumab group than in the guselkumab groups (61% vs. 49%). Among the guselkumab groups, there was no evidence of a relationship between the dose and the rate of adverse events. As in the period between week 0 and week 16, the most commonly reported adverse event during the period between week 16 and week 52 was infec- tion, which was reported in approximately 30% of the patients. No additional serious infections were reported in patients in the guselkumab groups during this period, but a serious case of pneumo- nia was reported in a patient in the adalimumab group. No cases of tuberculosis or opportunistic infections were reported during the study.

One case of cancer (grade 3 cervical intraepi- thelial neoplasia) was reported during the study in a patient who was receiving guselkumab (Table S2 in the Supplementary Appendix). Between week 16 and week 52, major adverse cardiovascu- lar events were observed in three patients who were receiving guselkumab (one in the 5-mg group and two in the 100-mg group), including one death from a myocardial infarction (Table 3, and Table S2 in the Supplementary Appendix).

By week 52, antibodies to guselkumab had developed in 6% of the patients who had been

Figure 1. Efficacy Outcomes.

Panel A shows the proportion of patients with a score on the Physician’s Global Assessment (PGA) of 0 (indicating cleared psoriasis) or 1 (indicat- ing minimal psoriasis). Panel B shows the proportion of patients with at least a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) score. The 5-mg, 50-mg, and 200-mg guselkumab groups re- ceived doses at weeks 0 and 4 and every 12 weeks thereafter, and the 15- mg and 100-mg guselkumab groups received doses every 8 weeks. At week 16, patients in the placebo group crossed over to receive guselkumab at a dose of 100 mg every 8 weeks.

P at

ie n

ts w

it h

a P

G A

S co

re o

f 0

o r

1 (%

)

100

0 0 4 242016128 28 32 36 40

Week

P at

ie n

ts w

it h

≥ 75

% I

m p

ro ve

m en

t in

P A

S I

S co

re (

% )

100

0 0 4 242016128 28 32 36 40

Week

Placebo Placebo

crossover to 100-mg Guselkumab

50-mg Guselkumab

5-mg Guselkumab

Adalimumab

200-mg Guselkumab

15-mg Guselkumab

100-mg Guselkumab

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015142

T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e

treated with guselkumab (15 of 240 patients with serum samples that could be evaluated); the antibodies generally had low titers (≤1:320) and were non-neutralizing. No anaphylactic or serum sickness–like reactions associated with the administration of the study agent occurred through week 52.

D i s c u s s i o n

This study provides several insights into the pathogenesis of and therapeutic options for pso- riasis. Benefits observed with the use of TNF antagonists in the treatment of psoriasis have shown that proinflammatory cytokines are ef- fective targets for psoriasis therapy. A better understanding of the pathogenesis of psoriasis now allows selective cytokine targeting that is specific to psoriasis, an approach that may trans- late into effective treatments for psoriasis that

have less effect on normal immune function than do current treatments.

One example of a drug that selectively targets cytokines is ustekinumab, a monoclonal anti- body that modulates proinflammatory Th1 and Th17 pathways through the inhibition of both interleukin-12 and interleukin-23; it has proved to be a safe and effective treatment for both psoriasis and psoriatic arthritis.7,8,20-25 Interleu- kin-23 is a heterodimeric cytokine that is com- posed of p19 and p40 subunits. Interleukin-12 is also a heterodimeric cytokine that is composed of the same p40 subunit as interleukin-23 and a unique p35 subunit. In contrast to ustekinumab, which targets p40 and therefore antagonizes the activity of both interleukin-12 and interleukin-23, guselkumab antagonizes the activity of only inter- leukin-23, through its p19 subunit. Thus, results from the clinical trials of guselkumab provide further insight into the relative importance of

Outcome Placebo Group

(N = 42) Guselkumab Groups

(N = 207) Adalimumab Group

(N = 43)

number (percent)

Weeks 0–16*

Patients in whom study agent was discontinued because of ≥1 adverse events

3 (7) 5 (2) 3 (7)

Patients with ≥1 adverse events 22 (52) 103 (50) 24 (56)

Patients with ≥1 serious adverse events 1 (2) 3 (1) 1 (2)

Patients with ≥1 infections 6 (14) 41 (20) 5 (12)

Patients with ≥1 serious infections 0 2 (1) 0

Patients with ≥1 infections requiring treatment 3 (7) 14 (7) 2 (5)

Guselkumab Groups (N = 235)

Adalimumab Group (N = 38)

Weeks 16–52†

Patients in whom study agent was discontinued because of ≥1 adverse events

3 (1) 1 (3)

Patients with ≥1 adverse events 115 (49) 23 (61)

Patients with ≥1 serious adverse events 4 (2) 1 (3)

Patients with ≥1 infections 70 (30) 14 (37)

Patients with ≥1 serious infections 0 1 (3)

Patients with ≥1 infections requiring treatment 21 (9) 6 (16)

Patients with ≥1 cancers 1 (<1) 0

Patients with ≥1 major adverse cardiovascular events‡ 3 (1) 0

* Data for weeks 0 to 16 included patients who received at least one dose of a study drug. One patient in the 200-mg guselkumab group underwent randomization but was not treated and therefore was not included in the safety analysis.

† Data for weeks 16 to 52 included patients who received at least one dose of a study drug at or after week 16. Data for the guselkumab groups included patients who were originally assigned to receive guselkumab, as well as patients originally assigned to the placebo group who crossed over at week 16, per protocol, to receive guselkumab at a dose of 100 mg every 8 weeks. Eleven patients in the guselkumab groups and five patients in the adalimumab group did not receive the study agent at or after week 16; therefore, these patients were not included in the safety analyses from weeks 16 to 52.

‡ Major adverse cardiovascular events were defined as myocardial infarction, stroke, or cardiovascular death.

Table 3. Safety Outcomes from Weeks 0 to 16 and Weeks 16 to 52.

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015 143

Guselk um a b vs. A da limum a b for Pl aque Psor i a sis

the Th17 pathway, as compared with the Th1 pathway, in the pathogenesis of psoriasis.

Recently reported results from a small (24 par- ticipants) proof-of-concept study showed that selective antagonism of interleukin-23 with gusel- kumab resulted in clinical improvement of pso- riasis, characterized by reductions in epidermal thickness, T-cell and dendritic-cell infiltration, expression of genes associated with psoriasis, and serum interleukin-17A levels.18 The results of this study validate the use of interleukin-23 as a therapeutic target by showing that therapy in- volving selective antagonism of this single cyto- kine in patients with moderate-to-severe psoria- sis is highly efficacious, as compared with adalimumab therapy. In addition, these data suggest that activation of the proinflammatory Th1 pathway by interleukin-12 may not be as critical to psoriasis immunopathogenesis as had been previously thought.26 Interleukin-23 has an essential role in the terminal differentiation of Th17 cells15 and maintenance of the Th17 phe- notype.16 Th17 cells are believed to be a chief source of interleukin-17A in vivo, but a critical role of interleukin-23 in the regulation of inter- leukin-17A production by neutrophils has also been recently shown.27 Because neutrophils are found at higher densities in psoriatic lesional skin than are Th17 cells and because the release of interleukin-17A by neutrophils in human psori- atic lesions has been described in the literature,28 one can hypothesize that the effects of interleu- kin-23 inhibition by guselkumab that were shown in this clinical trial could involve modulation of neutrophils in addition to Th17 cells.

This phase 2 study evaluated the use of gusel- kumab at a broad range of doses and two differ- ent dosing intervals for up to 40 weeks of con- tinuous treatment. The onset of guselkumab activity was rapid; efficacy was evident at the earli- est assessment (week 4). Several of the guselku- mab regimens were associated with considerably better response rates than those associated with adalimumab, a biologic agent that is commonly used to treat psoriasis. The efficacy of guselku- mab continued to increase beyond week 16 (pri- mary end-point assessment) and was maintained through week 40. Moreover, the majority of pa- tients in the 100-mg guselkumab group had completely cleared psoriasis, as indicated by a PGA score of 0 (in 62% of patients) and a 100% improvement from baseline in PASI score (in 54% of patients) after 40 weeks of continuous

treatment. Total clearance of psoriasis is corre- lated with improvements in patient-reported health-related quality of life.29

At week 16, which was the end of the placebo- controlled period, the rates of adverse events, seri- ous adverse events, and infections were similar among the placebo, guselkumab, and adalimu- mab groups. Between week 0 and week 16, infec- tions were reported in 14% of the patients in the placebo group, in 20% of those in the guselku- mab groups, and in 12% of those in the adalimu- mab group; between week 16 and week 52, infec- tions were reported in 30% of the patients in the guselkumab groups and in 37% of those in the adalimumab group. Between week 16 and week 52, major adverse cardiovascular events were re- ported in three patients receiving treatment with guselkumab.

The inclusion of groups receiving various regimens of guselkumab, the inclusion of an active-comparator group, and the 40-week dura- tion of continuous treatment provide substantial information about the emerging benefit–risk pro- file of guselkumab. However, this study has some limitations that are typical of phase 2, dose- ranging studies. The relatively small overall sam- ple size and the multiple treatment groups re- sulted in some imbalances among groups with respect to certain baseline patient characteristics (e.g., previous treatments for psoriasis) (Table 1, and Table S1 in the Supplementary Appendix); these imbalances may have inf luenced the re- sults. Furthermore, some elements of the study design limited the ability to assess uncommon adverse events or adverse events that might have developed during long-term treatment: there was a relatively small amount of total exposure to guselkumab, and there were more patients re- ceiving guselkumab than other treatments (i.e., the study included seven groups with an equal number of patients in each group, yielding a 5:2 ratio of guselkumab to adalimumab or placebo during the placebo-controlled period and a 6:1 ratio of guselkumab to adalimumab after the placebo-controlled period). It is also difficult to interpret the significance of the rates of rare adverse events, such as the three reported major adverse cardiovascular events. Another potential issue was the use of a blinded efficacy evaluator at each site instead of the administration of adalimumab in a blinded manner. However, the efficacy outcomes for adalimumab in this phase 2 trial were similar to those reported in a large

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.

n engl j med 373;2 nejm.org July 9, 2015144

Guselk um a b vs. A da limum a b for Pl aque Psor i a sis

pivotal, placebo-controlled, phase 3 study of adali- mumab.30

In the current era, in which treatment op- tions for psoriasis are expanding, head-to-head comparisons of new therapies with established products are important for allowing evidence- based treatment decisions. Guselkumab has more robust efficacy than does adalimumab and has a mechanism of action that is more specifi- cally targeted to psoriasis than does ustekinu- mab. Larger and longer-term phase 3 trials

(ClinicalTrials.gov numbers, NCT02207231, NCT02207244, and NCT02203032) are under way to examine the safety and comparative efficacy of guselkumab for the treatment of moderate- to-severe psoriasis.

Supported by Janssen Research and Development. Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org. We thank Kristin Ruley Sharples, Ph.D., and Cynthia Arnold,

B.S., of Janssen Scientific Affairs and Michelle Perate, M.S., a paid consultant for Janssen Scientific Affairs, for their writing and editorial support in the preparation of an earlier version of the manuscript.

References 1. Zhao Y, Fishelevich R, Petrali JP, et al. Activation of keratinocyte protein kinase C zeta in psoriasis plaques. J Invest Derma- tol 2008; 128: 2190-7. 2. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007; 370: 263-71. 3. Rapp SR, Feldman SR, Exum ML, Fleischer AB Jr, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol 1999; 41: 401-7. 4. Lara-Corrales I, Xi N, Pope E. Child- hood psoriasis treatment: evidence pub- lished over the last 5 years. Rev Recent Clin Trials 2011; 6: 36-43. 5. Yawalkar N, Tscharner GG, Hunger RE, Hassan AS. Increased expression of IL-12p70 and IL-23 by multiple dendritic cell and macrophage subsets in plaque psoriasis. J Dermatol Sci 2009; 54: 99-105. 6. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007; 445: 866-73. 7. Leonardi CL, Kimball AB, Papp KA, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76- week results from a randomised, double- blind, placebo-controlled trial (PHOENIX 1). Lancet 2008; 371: 1665-74. 8. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal anti- body, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675-84. 9. Papp KA, Langley RG, Sigurgeirsson B, et al. Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-rang- ing study. Br J Dermatol 2013; 168: 412-21. 10. Krueger JG, Fretzin S, Suárez-Fariñas M, et al. IL-17A is essential for cell activa- tion and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Im- munol 2012; 130: 145-54. 11. Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti–interleukin-17–recep- tor antibody for psoriasis. N Engl J Med 2012; 366: 1181-9.

12. Leonardi C, Matheson R, Zachariae C, et al. Anti–interleukin-17 monoclonal anti- body ixekizumab in chronic plaque pso- riasis. N Engl J Med 2012; 366: 1190-9. 13. Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psori- asis: a randomized, double-blind, placebo- controlled, phase II regimen-finding study. Br J Dermatol 2013; 168: 402-11. 14. Manetti R, Parronchi P, Giudizi MG, et al. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-produc- ing Th cells. J Exp Med 1993; 177: 1199-204. 15. McGeachy MJ, Chen Y, Tato CM, et al. The interleukin 23 receptor is essential for the terminal differentiation of inter- leukin 17-producing effector T helper cells in vivo. Nat Immunol 2009; 10: 314-24. 16. Stritesky GL, Yeh N, Kaplan MH. IL-23 promotes maintenance but not commit- ment to the Th17 lineage. J Immunol 2008; 181: 5948-55. 17. Elloso MM, Gomez-Angelats M, Fourie AM. Targeting the Th17 pathway in pso- riasis. J Leukoc Biol 2012; 92: 1187-97. 18. Sofen H, Smith S, Matheson RT, et al. Guselkumab (an IL-23-specific mAb) dem- onstrates clinical and molecular response in patients with moderate-to-severe pso- riasis. J Allergy Clin Immunol 2014; 133: 1032-40. 19. Maurer W, Hothorn L, Lehmacher W. Multiple comparisons in drug clinical tri- als and preclinical assays: a-priori ordered hypotheses. In: Vollmar J, ed. Biometrie in der chemisch-pharmazeutischen Indus- trie. Stuttgart, Germany: Fischer Verlag, 1995: 3-18. 20. Griffiths CE, Strober BE, van de Kerk- hof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010; 362: 118-28. 21. McInnes IB, Kavanaugh A, Gottlieb AB, et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 2013; 382: 780-9. 22. Ritchlin C, Rahman P, Kavanaugh A, et al. Efficacy and safety of the anti-IL-12/23

p40 monoclonal antibody, ustekinu mab, in patients with active psoriatic arthritis de- spite conventional non-biological and bio- logical anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-con- trolled, randomised PSUMMIT 2 trial. Ann Rheum Dis 2014; 73: 990-9. 23. Papp KA, Griffiths CE, Gordon K, et al. Long-term safety of ustekinumab in pa- tients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol 2013; 168: 844-54. 24. Kimball AB, Papp KA, Wasfi Y, et al. Long-term efficacy of ustekinumab in pa- tients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol 2013; 27: 1535-45. 25. Langley RG, Lebwohl M, Krueger GG, et al. Long-term efficacy and safety of ustekinumab, with and without dosing adjustment, in patients with moderate- to-severe psoriasis: results from the PHOENIX 2 study through 5 years of fol- low-up. Br J Dermatol 2015; 172: 1371-83. 26. Benson JM, Peritt D, Scallon BJ, et al. Discovery and mechanism of ustekinumab: a human monoclonal antibody targeting interleukin-12 and interleukin-23 for treat- ment of immune-mediated disorders. MAbs 2011; 3: 535-45. 27. Taylor PR, Roy S, Leal SM Jr, et al. Acti- vation of neutrophils by autocrine IL-17A- IL-17RC interactions during fungal infec- tion is regulated by IL-6, IL-23, RORγt and dectin-2. Nat Immunol 2014; 15: 143-51. 28. Lin AM, Rubin CJ, Khandpur R, et al. Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol 2011; 187: 490-500. 29. Viswanathan HN, Chau D, Milmont CE, et al. Total skin clearance results in improvements in health-related quality of life and reduced symptom severity among patients with moderate to severe psoria- sis. J Dermatolog Treat 2014: 1-5. 30. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to se- vere psoriasis: a randomized, controlled phase III trial. J Am Acad Dermatol 2008; 58: 106-15. Copyright © 2015 Massachusetts Medical Society.

The New England Journal of Medicine Downloaded from nejm.org on June 20, 2016. For personal use only. No other uses without permission.