Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1       Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, interleukin inhibitors, ATC code: L04AC16.

Mechanism of action

Guselkumab is a human IgG1λ monoclonal antibody (mAb) that binds selectively to the interleukin 23 (IL-23) protein with high specificity and affinity. IL-23 is a cytokine that is involved in inflammatory and immune responses. By blocking IL-23 from binding to its receptor, guselkumab inhibits IL-23- dependent cell signalling and release of proinflammatory cytokines.

Levels of IL-23 are elevated in the skin of patients with plaque psoriasis. In in vitro models, guselkumab was shown to inhibit the bioactivity of IL-23 by blocking its interaction with cell surface IL-23 receptor, disrupting IL-23-mediated signaling, activation and cytokine cascades. Guselkumab exerts clinical effects in plaque psoriasis and psoriatic arthritis through blockade of the IL-23 cytokine pathway.

Pharmacodynamic effects

In a Phase I study, treatment with guselkumab resulted in reduced expression of IL-23/Th17 pathway genes and psoriasis-associated gene expression profiles, as shown by analyses of mRNA obtained from lesional skin biopsies of patients with plaque psoriasis at Week 12 compared to baseline. In the same Phase I study, treatment with guselkumab resulted in improvement of histological measures of psoriasis at Week 12, including reductions in epidermal thickness and T-cell density. In addition, reduced serum IL-17A, IL-17F and IL-22 levels compared to placebo were observed in guselkumab treated patients in Phase II and Phase III plaque psoriasis studies. These results are consistent with the clinical benefit observed with guselkumab treatment in plaque psoriasis.

In psoriatic arthritis patients in Phase III studies, serum levels of acute phase proteins C-reactive protein, serum amyloid A, and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 were elevated at baseline. Guselkumab decreased the levels of these proteins within 4 weeks of initiation of treatment. Guselkumab further reduced the levels of these proteins by Week 24 compared to baseline and also to placebo.

Clinical efficacy and safety

Plaque psoriasis
The efficacy and safety of guselkumab was assessed in three randomised, double-blind, active controlled Phase III studies in adult patients with moderate to severe plaque psoriasis, who were candidates for phototherapy or systemic therapy.

VOYAGE 1 and VOYAGE 2
Two studies (VOYAGE 1 and VOYAGE 2) evaluated the efficacy and safety of guselkumab versus placebo and adalimumab in 1829 adult patients. Patients randomised to guselkumab (N=825) received 100 mg at Weeks 0 and 4, and every 8 weeks (q8w) thereafter through Week 48 (VOYAGE 1) and Week 20 (VOYAGE 2). Patients randomised to adalimumab (N=582) received 80 mg at Week 0 and 40 mg at Week 1, followed by 40 mg every other week (q2w) through Week 48 (VOYAGE 1) and Week 23 (VOYAGE 2). In both studies, patients randomised to placebo (N=422) received guselkumab 100 mg at Weeks 16, 20 and q8w thereafter. In VOYAGE 1, all patients, including those randomised to adalimumab at Week 0, started to receive open-label guselkumab q8w at Week 52. In VOYAGE 2, patients randomised to guselkumab at Week 0 who were Psoriasis Area and Severity Index (PASI) 90 responders at Week 28 were re- randomised to either continue treatment with guselkumab q8w (maintenance treatment) or receive placebo (withdrawal treatment). Withdrawal patients re-initiated guselkumab (dosed at time of retreatment, 4 weeks later and q8w thereafter) when they experienced at least a 50% loss of their Week 28 PASI improvement. Patients randomised to adalimumab at Week 0 who were PASI 90 non-responders received guselkumab at Weeks 28, 32 and q8w thereafter. In VOYAGE 2, all patients started to receive open-label guselkumab q8w at Week 76.

Baseline disease characteristics were consistent for the study populations in VOYAGE 1 and 2 with a median body surface area (BSA) of 22% and 24%, a median baseline PASI score of 19 for both studies, a median baseline dermatology quality of life index (DLQI) score of 14 and 14.5, a baseline investigator global assessment (IGA) score of severe for 25% and 23% of patients, and a history of psoriatic arthritis for 19% and 18% of patients, respectively.

Of all patients included in VOYAGE 1 and 2, 32% and 29% were naïve to both conventional systemic and biologic therapy, 54% and 57% had received prior phototherapy, and 62% and 64% had received prior conventional systemic therapy, respectively. In both studies, 21% had received prior biologic therapy, including 11% who had received at least one anti-tumour necrosis factor alpha (TNFα) agent, and approximately 10% who had received an anti-IL-12/IL-23 agent.
The efficacy of guselkumab was evaluated with respect to overall skin disease, regional disease (scalp, hand and foot and nails) and quality of life and patient reported outcomes. The co-primary endpoints in VOYAGE 1 and 2 were the proportion of patients who achieved an IGA score of cleared or minimal (IGA 0/1) and a PASI 90 response at Week 16 versus placebo (see Table 3).

Overall skin disease
Treatment with guselkumab resulted in significant improvements in the measures of disease activity compared to placebo and adalimumab at Week 16 and compared to adalimumab at Weeks 24 and 48.
The key efficacy results for the primary and major secondary study endpoints are shown in Table 3 below.

Table 3:       Summary of clinical responses in VOYAGE 1 and VOYAGE 2 
Number of patients (%)
VOYAGE 1                                         VOYAGE 2
Placebo     guselkumab       adalimumab         Placebo      guselkumab       adalimumab (N=174)       (N=329)          (N=334)          (N=248)        (N=496)          (N=248) Week 16
PASI 75       10 (5.7)     300 (91.2)a    244 (73.1)b           20 (8.1)      428 (86.3)a      170 (68.5)b c
PASI 90        5 (2.9)     241 (73.3)     166 (49.7)b           6 (2.4)       347 (70.0)c      116 (46.8)b PASI 100       1 (0.6)     123 (37.4)a     57 (17.1)d           2 (0.8)       169 (34.1)a       51 (20.6)d IGA 0/1       12 (6.9)     280 (85.1)c    220 (65.9)b           21 (8.5)      417 (84.1)c      168 (67.7)b a
IGA 0          2 (1.1)     157 (47.7)      88 (26.3)d           2 (0.8)       215 (43.3)a       71 (28.6)d Week 24
PASI 75           -        300 (91.2)     241 (72.2)e               -          442 (89.1)      176 (71.0)e PASI 90           -        264 (80.2)     177 (53.0)b               -          373 (75.2)      136 (54.8)b PASI 100          -        146 (44.4)      83 (24.9)e               -          219 (44.2)       66 (26.6)e IGA 0/1           -        277 (84.2)     206 (61.7)b               -          414 (83.5)      161 (64.9)b IGA 0             -        173 (52.6)      98 (29.3)b               -          257 (51.8)       78 (31.5)b Week 48
PASI 75           -        289 (87.8)     209 (62.6)e               -               -                   - PASI 90           -        251 (76.3)     160 (47.9)b               -               -                   - PASI 100          -        156 (47.4)      78 (23.4)e               -               -                   - IGA 0/1           -        265 (80.5)     185 (55.4)b               -               -                   - IGA 0             -        166 (50.5)      86 (25.7)b               -               -                   - a p < 0.001 for comparison between guselkumab and placebo.
b p < 0.001 for comparison between guselkumab and adalimumab for major secondary endpoints.
c p < 0.001 for the comparisons between guselkumab and placebo for the co-primary endpoints.
d comparisons between guselkumab and adalimumab were not performed.
e p < 0.001 for comparison between guselkumab and adalimumab.

Response over time
Guselkumab demonstrated rapid onset of efficacy, with a significantly higher percent improvement in PASI as compared with placebo as early as Week 2 (p < 0.001). The percentage of patients achieving a PASI 90 response was numerically higher for guselkumab than adalimumab starting at Week 8 with the difference reaching a maximum around Week 20 (VOYAGE 1 and 2) and maintained through Week 48 (VOYAGE 1) (see Figure 1).



Figure 1:      Percent of subjects who achieved a PASI 90 response through week 48 by visit (subjects randomised at week 0) in VOYAGE 1



In VOYAGE 1, for patients receiving continuous guselkumab treatment, the PASI 90 response rate was maintained from Week 52 through Week 252. For patients randomised to adalimumab at Week 0 who crossed over to guselkumab at Week 52, the PASI 90 response rate increased from Week 52 through Week 76 and was then maintained through Week 252 (see Figure 2).

Figure 2: Percent of subjects who achieved a PASI 90 response by visit in the open-label phase in VOYAGE 1



The efficacy and safety of guselkumab was demonstrated regardless of age, gender, race, body weight, plaques location, PASI baseline severity, concurrent psoriatic arthritis, and previous treatment with a biologic therapy. Guselkumab was efficacious in conventional systemic-naive, biologic-naive, and biologic-exposed patients.

In VOYAGE 2, 88.6% of patients receiving guselkumab maintenance treatment at Week 48 were PASI 90 responders compared to 36.8% of patients who were withdrawn from treatment at Week 28 (p < 0.001). Loss of PASI 90 response was noted as early as 4 weeks after withdrawal of guselkumab treatment with a median time to loss of PASI 90 response of approximately 15 weeks.
Among patients who were withdrawn from treatment and subsequently re-initiated guselkumab, 80% regained a PASI 90 response when assessed 20 weeks after initiation of retreatment.
In VOYAGE 2, among 112 patients randomised to adalimumab who failed to achieve a PASI 90 response at Week 28, 66% and 76% achieved a PASI 90 response after 20 and 44 weeks of treatment with guselkumab, respectively. In addition, among 95 patients randomised to guselkumab who failed to achieve a PASI 90 response at Week 28, 36% and 41% achieved a PASI 90 response with an additional 20 and 44 weeks of continued treatment with guselkumab, respectively. No new safety findings were observed in patients who switched from adalimumab to guselkumab.

Regional disease
In VOYAGE 1 and 2, significant improvements were seen in scalp, hand and foot, and nail psoriasis (as measured by the Scalp-specific Investigator Global Assessment [ss-IGA], Physician’s Global Assessment of Hands and/or Feet [hf-PGA], Fingernail Physician’s Global Assessment [f-PGA] and Nail Psoriasis Severity Index [NAPSI], respectively) in guselkumab treated patients compared to placebo treated patients at Week 16 (p < 0.001, Table 4). Guselkumab demonstrated superiority compared to adalimumab for scalp and hand and foot psoriasis at Week 24 (VOYAGE 1 and 2) and Week 48 (VOYAGE 1) (p ≤ 0.001, except for hand and foot psoriasis at Week 24 [VOYAGE 2] and Week 48 [VOYAGE 1], p < 0.05).

Table 4:      Summary of Regional Disease Responses in VOYAGE 1 and VOYAGE 2 
VOYAGE 1                                         VOYAGE 2
Placebo      guselkumab       adalimumab        Placebo       guselkumab adalimumab ss-IGA (N)a             145            277              286             202             408        194 ss-IGA 0/1b, n (%)
Week 16               21 (14.5)     231 (83.4)c      201 (70.3)d     22 (10.9)     329 (80.6)c      130 (67.0)d hf-PGA (N)a          43          90                        95           63             114                  56 b hf-PGA 0/1 , n (%)
Week 16          6 (14.0)   66 (73.3)e              53 (55.8)d      9 (14.3)      88 (77.2)e        40 (71.4)d f-PGA (N)a           88         174                     173            123            246               124 f-PGA 0/1, n (%)
Week 16      14 (15.9)     68 (39.1)e              88 (50.9)d      18 (14.6)     128 (52.0)e      74 (59.7)d NAPSI (N)a          99          194                     191            140            280              140 Percent Improvement, mean (SD)

Week 16             -0.9 (57.9)   34.4 (42.4)e     38.0 (53.9)d     1.8 (53.8)   39.6 (45.6)e      46.9 (48.1)d a
Includes only subjects with ss-IGA, f-PGA, hf-PGA score ≥ 2 at baseline or baseline NAPSI score > 0.
b
Includes only subjects achieving ≥ 2-grade improvement from baseline in ss-IGA and/or hf-PGA.
c p < 0.001 for comparison between guselkumab and placebo for the major secondary endpoint.
d comparisons between guselkumab and adalimumab were not performed.
e p < 0.001 for comparison between guselkumab and placebo.

Health-related quality of life / Patient reported outcomes
Across VOYAGE 1 and 2 significantly greater improvements in health-related quality of life as measured by Dermatology Life Quality Index (DLQI) and in patient-reported psoriasis symptoms (itching, pain, burning, stinging and skin tightness) and signs (skin dryness, cracking, scaling, shedding or flaking, redness and bleeding) as measured by the Psoriasis Symptoms and Signs Diary (PSSD) were observed in guselkumab patients compared to placebo patients at Week 16 (Table 5). Signs of improvement on patient-reported outcomes were maintained through Week 24 (VOYAGE 1 and 2) and Week 48 (VOYAGE 1). In VOYAGE 1, for patients receiving continuous guselkumab treatment, these improvements were maintained in the open-label phase through Week 252 (Table 6).

Table 5: Summary of patient reported outcomes at week 16 in VOYAGE 1 and VOYAGE 2

VOYAGE 1                                   VOYAGE 2
Placebo     guselkumab adalimumab Placebo             guselkumab adalimumab DLQI, subjects
170          322         328              248              495          247 with baseline score
Change from baseline, mean (standard deviation)
Week 16                                                           -2.6 (6.9) -0.6 (6.4)   -11.2 (7.2)c -9.3 (7.8)b                      -11.3 (6.8)c -9.7 (6.8)b PSSD Symptom score, subjects with           129        248            273              198        410          200 baseline score > 0
Symptom score = 0, n (%)
Week 16
1 (0.8)    67 (27.0)a   45 (16.5)b         0         112 (27.3)a    30 (15.0)b 
PSSD Sign score,
subjects with baseline      129          248            274          198            411          201 score > 0
Sign score = 0, n (%)

Week 16
0    50 (20.2)a   32 (11.7)b         0          86 (20.9)a    21 (10.4)b a p < 0.001 for comparison between guselkumab and placebo.
b comparisons between guselkumab and adalimumab were not performed.
c p < 0.001 for comparison between guselkumab and placebo for major secondary endpoints.

Table 6:      Summary of patient reported outcomes in the open-label phase in VOYAGE 1  guselkumab                        adalimumab-guselkumab
Week 76      Week 156      Week 252       Week 76    Week 156 Week 252 DLQI score > 1 at                                       374                                    235 445          420                         264         255 baseline, n
Subjects with DLQI           337                         272           198                          174 308 (73.3%)                                190 (74.5%)
0/1                        (75.7%)                     (72.7%)       (75.0%)                      (74.0%) PSSD Symptom                                             297                                        200 Score, subjects with         347          327                          227             218 baseline score > 0
Symptom score = 0,           136                         126                                         96 130 (39.8%)                  99 (43.6%)     96 (44.0%) n (%)                      (39.2%)                     (42.4%)                                    (48.0%) PSSD Sign score,                                         297                                        201 subjects with                347          327                          228             219 baseline score > 0
Sign score = 0, n            102                          98                                         76 94 (28.7%)                   71 (31.1%)     69 (31.5%)
(%)                        (29.4%)                     (33.0%)                                    (37.8%) 
In VOYAGE 2, guselkumab patients had significantly greater improvement from baseline compared to placebo in health-related quality of life, anxiety and depression, and work limitation measures at Week 16, as measured by the 36-item Short Form (SF-36) health survey questionnaire, Hospital Anxiety and Depression Scale (HADS), and Work Limitations Questionnaire (WLQ), respectively.
The improvements in SF-36, HADS and WLQ were all maintained through Week 48 and in the open-label phase through Week 252 among patients randomised to maintenance therapy at Week 28.

NAVIGATE
The NAVIGATE study examined the efficacy of guselkumab in patients who had an inadequate response (ie, who had not achieved a ‘cleared’ or ‘minimal’ response defined as IGA ≥ 2) to ustekinumab at Week 16. All patients (N=871) received open-label ustekinumab (45 mg ≤100 kg and 90 mg >100 kg) at Weeks 0 and 4. At Week 16, 268 patients with an IGA ≥ 2 score were randomised to either continue ustekinumab treatment (N=133) q12w, or to initiate guselkumab treatment (N=135) at Weeks 16, 20, and q8w thereafter. Baseline characteristics for randomised patients were similar to those observed in VOYAGE 1 and 2.

After randomisation, the primary endpoint was the number of post-randomisation visits between Weeks 12 and 24 at which patients achieved an IGA score 0/1 and had ≥ 2 grade improvement.
Patients were examined at four week intervals for a total of four visits. Among patients who inadequately responded to ustekinumab at the time of randomisation, significantly greater improvement of efficacy was observed in patients who switched to guselkumab treatment compared to patients who continued ustekinumab treatment. Between 12 and 24 weeks after randomisation, guselkumab patients achieved an IGA score 0/1 with ≥ 2 grade improvement twice as often as ustekinumab patients (mean 1.5 vs 0.7 visits, respectively, p < 0.001). Additionally, at 12 weeks after randomisation a higher proportion of guselkumab patients compared to ustekinumab patients achieved an IGA score 0/1 and ≥ 2 grade improvement (31.1% vs. 14.3%, respectively; p = 0.001) and a PASI 90 response (48% vs
23%, respectively, p < 0.001). Differences in response rates between guselkumab and ustekinumab treated patients were noted as early as 4 weeks after randomisation (11.1% and 9.0%, respectively) and reached a maximum 24 weeks after randomisation (see Figure 3). No new safety findings were observed in patients who switched from ustekinumab to guselkumab.

Figure 3: Percent of subjects who achieved an IGA Score of cleared (0) or minimal (1) and at least a 2-grade improvement in IGA from week 0 through week 24 by visit after randomisation in NAVIGATE



ECLIPSE
Efficacy and safety of guselkumab were also investigated in a double-blind study compared to secukinumab. Patients were randomised to receive guselkumab (N=534; 100 mg at Week 0, 4 and q8w thereafter), or secukinumab (N=514; 300 mg at Week 0, 1, 2, 3, 4, and q4w thereafter). The last dose was at week 44 for both treatment groups.

Baseline disease characteristics were consistent with a population of moderate to severe plaque psoriasis with a median BSA of 20%, a median PASI score of 18, and an IGA score of severe for 24% of patients.

Guselkumab was superior to secukinumab as measured by the primary endpoint of PASI 90 response at Week 48 (84.5% versus 70.0%, p < 0.001). Comparative PASI response rates are presented in Table 7.

Table 7:       PASI response rates in ECLIPSE
Number of patients (%) guselkumab (N=534)             secukinumab (N=514)
Primary Endpoint
PASI 90 response at Week 48                     451 (84.5%) a                     360 (70.0%) Major Secondary Endpoints
PASI 75 response at both Week 12 and
452 (84.6%) b                     412 (80.2%)
Week 48 c
PASI 75 response at Week 12                     477 (89.3%)                       471 (91.6%) PASI 90 response at Week 12                     369 (69.1%) c                     391 (76.1%) PASI 100 response at Week 48                    311 (58.2%) c                     249 (48.4%) a p < 0.001 for superiority b p < 0.001 for non-inferiority, p=0.062 for superiority c formal statistical testing was not performed

Guselkumab and secukinumab PASI 90 response rates through Week 48 are presented in Figure 4.

Figure 4: Percent of subjects who achieved a PASI 90 response through week 48 by visit (Subjects randomised at Week 0) in ECLIPSE



Psoriatic arthritis (PsA)
Guselkumab has been shown to improve signs and symptoms, physical function and health-related quality of life, and reduce the rate of progression of peripheral joint damage in adult patients with active PsA.
DISCOVER 1 and DISCOVER 2
Two randomised, double-blind, placebo-controlled Phase III studies (DISCOVER 1 and DISCOVER 2) evaluated the efficacy and safety of guselkumab versus placebo in adult patients with active PsA (≥ 3 swollen and ≥ 3 tender joints, and a C-reactive protein (CRP) level of ≥ 0.3 mg/dL in DISCOVER 1, and ≥ 5 swollen and ≥ 5 tender joints, and a CRP level of ≥ 0.6 mg/dL in DISCOVER 2), despite conventional synthetic (cs)DMARD, apremilast, or nonsteroidal anti-inflammatory drug (NSAID) therapy. Patients in these studies had a diagnosis of PsA based on the Classification criteria for Psoriatic Arthritis [CASPAR]) for a median duration of 4 years. Patients with different subtypes of PsA were enrolled in both studies, including polyarticular arthritis with the absence of rheumatoid nodules (40%), spondylitis with peripheral arthritis (30%), asymmetric peripheral arthritis (23%), distal interphalangeal involvement (7%) and arthritis mutilans (1%). Over 65% and 42% of the patients had enthesitis and dactylitis at baseline, respectively, and over 75% of patients had ≥ 3% BSA psoriasis skin involvement.
DISCOVER 1 and DISCOVER 2 evaluated 381 and 739 patients, respectively, who received treatment with guselkumab 100 mg administered at Weeks 0 and 4 followed by every 8 weeks (q8w) or guselkumab 100 mg q4w, or placebo. At Week 24, placebo subjects in both studies crossed over to receive guselkumab 100 mg q4w. Approximately 58% of patients in both studies continued on stable doses of MTX (≤ 25 mg/week).

In both studies over 90% of patients had prior csDMARD use. In DISCOVER 1, 31% of patients had previously received anti-TNFα treatment. In DISCOVER 2, all patients were naive to biologic therapy.

Signs and symptoms
Treatment with guselkumab resulted in significant improvements in the measures of disease activity compared to placebo at Week 24. The primary endpoint in both studies was the percentage of patients who achieved American College of Rheumatology (ACR) 20 response at Week 24. The key efficacy results are shown in Table 8.

Table 8:       Clinical responses in DISCOVER 1 and DISCOVER 2

DISCOVER 1                                DISCOVER 2
Placebo      guselkumab    guselkumab       Placebo    guselkumab       guselkumab (N=126)        100 mg        100 mg         (N=246)      100 mg           100 mg q8w           q4w                         q8w              q4w
(N=127)       (N=128)                     (N=248)          (N=245)
ACR 20 response
Week 16                25.4%      52.0% b           60.2% b        33.7%        55.2% g          55.9% c Difference from                    26.7              34.8                        21.5             22.2 -     (15.3, 38.1)       (23.5, 46.0)
-        (13.1, 30.0)    (13.7, 30.7) placebo (95% CI)
Week 24                22.2%      52.0% a           59.4% a        32.9%        64.1% a          63.7% a Difference from                    29.8              37.1                        31.2             30.8 -     (18.6, 41.1)       (26.1, 48.2)
-        (22.9, 39.5)    (22.4, 39.1) placebo (95% CI)
ACR 50 response
Week 16                12.7%      22.8% d           26.6% c         9.3%        28.6% g          20.8% c Difference from                    10.2              13.9                        19.3             11.5 -      (1.0, 19.3)       (4.4, 23.4)
-        (12.6, 25.9)     (5.2, 17.7) placebo (95% CI)
Week 24                 8.7%      29.9% b           35.9% b        14.2%        31.5% g          33.1% c Difference from                    21.4              27.2                        17.2             18.8 -     (12.1, 30.7)       (17.6, 36.8)
-        (10.0, 24.4)    (11.5, 26.1) placebo (95% CI)
ACR 70 response
Week 24                 5.6%      11.8% d           20.3% b         4.1%        18.5% g          13.1% c Difference from                     6.4              14.8                        14.5              9.0 -     (-0.3, 13.1)       (6.9, 22.7)
-        (9.1, 19.9)      (4.1, 13.8) placebo (95% CI)
DAS 28 (CRP) LSMean changei from baseline
Week 24 c               -0.70      -1.43 b           -1.61 b        -0.97        -1.59 b          -1.62 b Difference from                    -0.73             -0.91                       -0.61            -0.65 -    (-0.98, -0.48)     (-1.16, -0.66)
-       (-0.80, -0.43)   (-0.83, -0.47) placebo (95% CI)
Minimal Disease Activity (MDA)
Week 24                11.1%      22.8% f           30.5% e         6.1%        25.0% e          18.8% e 
Table 8:       Clinical responses in DISCOVER 1 and DISCOVER 2

DISCOVER 1                                        DISCOVER 2
Placebo        guselkumab      guselkumab         Placebo       guselkumab        guselkumab (N=126)          100 mg          100 mg           (N=246)         100 mg            100 mg q8w             q4w                              q8w               q4w (N=127)         (N=128)                          (N=248)           (N=245) Difference from                              11.9             19.3                            18.9              12.7 -               (2.9, 20.9)      (9.7, 28.9)
-          (12.8, 25.0)      (7.0, 18.4) placebo (95% CI)
Patients with ≥ 3% BSA and IGA ≥ 2 n=78                n=82               n=89          n=183           n=176             n=184 IGA response h
Week 24                 15.4%               57.3% b          75.3% b          19.1%           70.5% b          68.5% b Difference from                             42.0             60.0                             50.9               49.8 -              (28.9, 55.1)     (48.3, 71.8)
-          (42.2, 59.7)      (41.2, 58.4) placebo (95% CI)
PASI 90 response
Week 16                 10.3%               45.1% e          52.8% e           8.2%           55.1% e          53.8% e Difference from                             34.9             42.6                             46.6              45.6 -              (22.2, 47.6)     (30.5, 54.8)          -          (38.4, 54.8)      (37.6, 53.6) placebo (95% CI)
Week 24                 11.5%               50.0% e          62.9% e           9.8%           68.8% e          60.9% e Difference from                             38.6             51.7                             58.6              51.3 -              (25.8, 51.4)     (39.7, 63.7)          -                            (43.2, 59.3) placebo (95% CI)                                                                           (50.6, 66.6) a   p < 0.001 (primary endpoint) b   p < 0.001 (major secondary endpoint) c   p = 0.006 (major secondary endpoint) d   not statistically significant p=0.086 (major secondary endpoint) e nominal p < 0.001 f   nominal p = 0.012 g   not formally tested in the hierarchical testing procedure, nominal p < 0.001 (major secondary endpoint) h   defined as a IGA response of 0 (cleared) or 1 (minimal) and ≥ 2-grade reduction from baseline in the IGA psoriasis score i   LSmean change = least squares mean change

Clinical response was maintained up to Week 52 as assessed by ACR 20/50/70, DAS 28 (CRP), MDA, IGA and PASI 90 response rates in DISCOVER 1 and DISCOVER 2 (see Table 9).

Table 9:                     Clinical responses in DISCOVER 1 and DISCOVER 2 at week 52a 
DISCOVER 1                                     DISCOVER 2 guselkumab     guselkumab                      guselkumab     guselkumab 100 mg q8w     100 mg q4w                      100 mg q8w     100 mg q4w ACR 20
Nb                             112                124                                   234                     228 % Response                   67.9%              75.8%                                  79.1%                   75.9% ACR 50
Nb                             113                124                                   234                     228 % Response                   43.4%              55.6%                                  51.3%                   49.1% ACR 70
Nb                             114                124                                   234                     228 % Response                   28.9%              29.8%                                  29.5%                   28.1% DAS 28 (CRP) change from baseline
Nc                             112                123                                  234                       227 Mean (SD)                 -2.03 (1.250)      -1.99 (1.062)                        -2.08 (1.121)             -2.11 (1.128) MDA
Nb                             112                124                                   234                     228 % Response                   33.9%              40.3%                                  32.9%                   36.8% Patients with ≥ 3% BSA and IGA ≥ 2 at baseline
IGA Response
Nb                              75                 88                                   170                     173 % Response                   69.3%              83.0%                                  77.1%                   84.4% PASI 90
Nb                                           75                    88     170                173 % Response                                 66.7%                 76.1%   77.1%              81.5% a       There was no placebo arm beyond Week 24.
b       Evaluable subjects with an observed response status.
c       Subjects have an observed change from baseline.

Clinical response was maintained up to Week 100 as assessed by ACR 20/50/70, DAS 28 (CRP), MDA, IGA and PASI 90 response rates in DISCOVER 2 (see Table 10).

Table 10:        Clinical responses in DISCOVER 2 at week 100a
 guselkumab             guselkumab
100 mg q8w             100 mg q4w
ACR 20
Nb                                           223                                 219 % Response                                  82.1%                               84.9% ACR 50
Nb                                           224                                 220 % Response                                  60.7%                               62.3% ACR 70
Nb                                           224                                 220 % Response                                  39.3%                               38.6% DAS 28 (CRP) change from baseline
Nc                                           223                                  219 Mean (SD)                               -2.37 (1.215)                        -2.36 (1.120) MDA
Nb                                           224                                 220 % Response                                  44.6%                               42.7% Patients with ≥ 3% BSA and IGA ≥ 2 at baseline
IGA Response
Nb                                           165                                 170 % Response                                  76.4%                               82.4% PASI 90
Nb                                           164                                 170 % Response                                  75.0%                               80.0% a    There was no placebo arm beyond Week 24.
b    Evaluable subjects with an observed response status.
c    Subjects have an observed change from baseline.

Response over time
In DISCOVER 2, a greater ACR 20 response was observed in both guselkumab groups compared to placebo as early as Week 4 and the treatment difference continued to increase over time through Week 24 (Figure 5).



Figure 5:         ACR 20 response by visit through week 24 in DISCOVER 2 


In DISCOVER 2, for subjects receiving continuous guselkumab treatment at week 24, ACR 20 response was maintained from Week 24 to Week 52 (see Figure 6). For subjects receiving continuous guselkumab treatment at week 52, ACR 20 response was maintained from Week 52 to Week 100 (see Figure 7).

Figure 6:     ACR 20 response by visit from week 24        Figure 7:   ACR 20 response by visit from week 52 through week 52 in DISCOVER 2                            through week 100 in DISCOVER 2 


Responses observed in the guselkumab groups were similar regardless of concomitant csDMARD use, including MTX (DISCOVER 1 and 2). Additionally, examination of age, gender, race, body weight, and previous csDMARD use (DISCOVER 1 and 2) and previous anti-TNFα use (DISCOVER 1), did not identify differences in response to guselkumab among these subgroups.

In DISCOVER 1 and 2, improvements were shown in all components of the ACR scores including patient assessment of pain. At Week 24 in both studies, the proportion of patients achieving a modified PsA response criteria (PsARC) response was greater in the guselkumab groups compared to placebo.
PsARC responses were maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2.

Dactylitis and enthesitis were assessed based on pooled data from DISCOVER 1 and 2. At Week 24, among patients with dactylitis at baseline, the proportion of subjects with dactylitis resolution was greater in the guselkumab q8w group (59.4%, nominal p < 0.001) and q4w group (63.5%, p = 0.006) compared to placebo (42.2%). At Week 24, among patients with enthesitis at baseline, the proportion of subjects with enthesitis resolution was greater in the guselkumab q8w group (49.6%, nominal p < 0.001) and q4w group (44.9%, p = 0.006) compared to placebo (29.4%). At Week 52, the proportions of subjects with dactylitis resolution (81.2% in q8w group and 80.4% in q4w group) and enthesitis resolution (62.7% in q8w group and 60.9% in q4w group) were maintained. In DISCOVER 2, among subjects with dactylitis and enthesitis at baseline, the proportion of patients with dactylitis resolution (91.1% in q8w group and 82.9% in q4w group) and enthesitis resolution (77.5% in q8w group and 67.7% in q4w group) were maintained at Week 100.

In DISCOVER 1 and 2, patients treated with guselkumab who had spondylitis with peripheral arthritis as their primary presentation, demonstrated greater improvement from baseline in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) compared to placebo at Week 24. Improvement in BASDAI was maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2.

Radiographic response
In DISCOVER 2, inhibition of structural damage progression was measured radiographically and expressed as the mean change from baseline in the total modified van der Heijde-Sharp (vdH-S) score.
At Week 24, the guselkumab q4w group demonstrated statistically significantly less radiographic progression and the guselkumab q8w group showed numerically less progression than placebo (Table 11). The observed benefit with the guselkumab q4w dosing regimen on inhibition of radiographic progression (ie, smaller mean change from baseline in total modified vdH-S score in the q4w group versus placebo) was most pronounced in subjects with both a high C-reactive protein value and high number of joints with erosions at baseline.

Table 11:          Change from baseline in total modified vdH-S score at week 24 in DISCOVER 2 
N        LSMean changec (95% CId) from baseline in modified vdH-S score at Week 24
Placebo                         246                              0.95 (0.61, 1.29) guselkumab 100 mg q8w           248                             0.52 a (0.18, 0.86) guselkumab 100 mg q4w           245                             0.29 b (-0.05, 0.63) a   not statistically significant p = 0.068 (major secondary endpoint) b   p = 0.006 (major secondary endpoint) c   LSmean change = least squares mean change d   CI = confidence interval

At Week 52 and Week 100, the mean change from baseline in total modified vdH-S was similar in the guselkumab q8w and q4w groups (Table 12).

Table 12:  Change from baseline in total modified vdH-S score at week 52 and week 100 in DISCOVER 2

Na            Mean change (SDb) from baseline in total modified vdH-S score
Week 52 guselkumab 100 mg q8w                      235                             0.97 (3.623) guselkumab 100 mg q4w                      229                             1.07 (3.843) Week 100 guselkumab 100 mg q8w                      216                             1.50 (4.393) guselkumab 100 mg q4w                      211                             1.68 (7.018) a  Evaluable subjects have observed change for the specified time period b  SD = standard deviation
Note: no placebo group beyond Week 24

Physical function and health-related quality of life
In DISCOVER 1 and 2, guselkumab treated patients showed significant improvement (p < 0.001) in physical function compared to placebo as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 24. Improvements in HAQ-DI were maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2.

A significantly greater improvement from baseline in the SF-36 Physical Component Summary (PCS) score was observed in guselkumab treated patients compared to placebo at Week 24 in DISCOVER 1 (p < 0.001 for both dose groups) and DISCOVER 2 (p = 0.006 for q4w group). At Week 24, a greater increase from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score was observed in guselkumab treated patients compared to placebo in both studies. In DISCOVER 2, greater improvements in health-related quality of life as measured by the Dermatology Life Quality Index (DLQI) were observed in guselkumab treated patients compared to placebo at Week 24.
Improvements in SF-36 PCS, FACIT-F and DLQI scores were maintained from Week 24 to Week 52 in DISCOVER 1 and Week 100 in DISCOVER 2.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
Following a single 100 mg subcutaneous injection in healthy subjects, guselkumab reached a mean (± SD) maximum serum concentration (Cmax) of 8.09 ± 3.68 mcg/mL by approximately 5.5 days post dose.

Steady-state serum guselkumab concentrations were achieved by Week 20 following subcutaneous administrations of 100 mg guselkumab at Weeks 0 and 4, and every 8 weeks thereafter. The mean (± SD) steady-state trough serum guselkumab concentrations in two Phase III studies in patients with plaque psoriasis were 1.15 ± 0.73 mcg/mL and 1.23 ± 0.84 mcg/mL.
The pharmacokinetics of guselkumab in subjects with psoriatic arthritis was similar to that in subjects with psoriasis. Following subcutaneous administration of 100 mg of guselkumab at Weeks 0, 4, and every 8 weeks thereafter, mean steady-state trough serum guselkumab concentration was also approximately 1.2 mcg/mL. Following subcutaneous administration of 100 mg of guselkumab every 4 weeks, mean steady-state trough serum guselkumab concentration was approximately 3.8 mcg/mL.

The absolute bioavailability of guselkumab following a single 100 mg subcutaneous injection was estimated to be approximately 49% in healthy subjects.

Distribution

Mean volume of distribution during the terminal phase (Vz) following a single intravenous administration to healthy subjects ranged from approximately 7 to 10 L across studies.

Biotransformation

The exact pathway through which guselkumab is metabolised has not been characterised. As a human IgG mAb, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Elimination

Mean systemic clearance (CL) following a single intravenous administration to healthy subjects ranged from 0.288 to 0.479 L/day across studies. Mean half-life (T1/2) of guselkumab was approximately 17 days in healthy subjects and approximately 15 to 18 days in patients with plaque psoriasis across studies.

Population pharmacokinetic analyses indicated that concomitant use of NSAIDs, oral corticosteroids and csDMARDs such as methotrexate, did not affect the clearance of guselkumab.

Linearity/non-linearity

The systemic exposure of guselkumab (Cmax and AUC) increased in an approximately dose-proportional manner following a single subcutaneous injection at doses ranging from 10 mg to 300 mg in healthy subjects or patients with plaque psoriasis.

Elderly patients

No specific studies have been conducted in elderly patients. Of the 1384 plaque psoriasis patients exposed to guselkumab in Phase III clinical studies and included in the population pharmacokinetic analysis, 70 patients were 65 years of age or older, including 4 patients who were 75 years of age or older. Of the 746 psoriatic arthritis patients exposed to guselkumab in Phase III clinical studies, a total of 38 patients were 65 years of age or older, and no patients were 75 years of age or older.

Population pharmacokinetic analyses in plaque psoriasis and psoriatic arthritis patients indicated no apparent changes in CL/F estimate in patients≥ 65 years of age compared to patients < 65 years of age, suggesting no dose adjustment is needed for elderly patients.

Patients with renal or hepatic impairment

No specific study has been conducted to determine the effect of renal or hepatic impairment on the pharmacokinetics of guselkumab. Renal elimination of intact guselkumab, an IgG mAb, is expected to be low and of minor importance; similarly, hepatic impairment is not expected to influence clearance of guselkumab as IgG mAbs are mainly eliminated via intracellular catabolism.