14.1 Plaque Psoriasis
Three multicenter, randomized, double-blind, placebo-controlled trials, Trials 1, 2, and 3 (NCT 01474512, NCT 01597245, NCT 01646177), enrolled a total of 3866 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, a static Physician Global Assessment (sPGA) score of 3 in the overall assessment (plaque thickness/induration, erythema, and scaling) of psoriasis on a severity scale of 0 to 5, a Psoriasis Area and Severity Index (PASI) score 12, and who were candidates for phototherapy or systemic therapy.
In all three trials, subjects were randomized to either placebo or TALTZ (80 mg every 2 weeks [Q2W]) for 12 weeks, following a 160 mg starting dose. In the two active comparator trials (Trials 2 and 3), subjects were also randomized to receive U.S. approved etanercept 50 mg twice weekly for 12 weeks.
All three trials assessed the changes from baseline to Week 12 in the two co-primary endpoints: 1) PASI 75, the proportion of subjects who achieved at least a 75% reduction in the PASI composite score that takes into consideration both the percentage of body surface area affected and the nature and severity of psoriatic changes (induration, erythema and scaling) within the affected regions, and 2) sPGA of 0 (clear) or 1 (minimal), the proportion of subjects with an sPGA 0 or 1 and at least a 2-point improvement.
Other evaluated outcomes included the proportion of subjects with an sPGA score of 0 (clear), a reduction of at least 90% in PASI (PASI 90), a reduction of 100% in PASI (PASI 100), and an improvement of itch severity as measured by a reduction of at least 4 points on an 11-point itch Numeric Rating Scale.
Subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline sPGA score was severe or very severe in 51% of subjects in Trial 1, 50% in Trial 2, and 48% in Trial 3.
Of all subjects, 44% had received prior phototherapy, 49% had received prior conventional systemic therapy, and 26% had received prior biologic therapy for the treatment of psoriasis. Of the subjects who had received prior biologic therapy, 15% had received at least one anti-TNF alpha agent, and 9% had received an anti-IL 12/IL23. A total of 23% of study subjects had a history of psoriatic arthritis.
Clinical Response at Week 12
The results of Trials 1, 2, and 3 are presented in Table 2.
Table 2: Efficacy Results at Week 12 in Adults with Plaque Psoriasis in Trials 1, 2, and 3; NRIa |
|
|
| Trial 1 | Trial 2 | Trial 3 |
TALTZ 80 mgc
Q2W (N=433)
n (%) | Placebo
(N=431)
n (%) | TALTZ 80 mgc
Q2W (N=351)
n (%) | Placebo
(N=168)
n (%) | TALTZ 80 mgc
Q2W (N=385)
n (%) | Placebo
(N=193)
n (%) |
| sPGA of 0 (clear) or 1 (minimal)b | 354 (82) | 14 (3) | 292 (83) | 4 (2) | 310 (81) | 13 (7) |
| sPGA of 0 (clear) | 160 (37) | 0 | 147 (42) | 1 (1) | 155 (40) | 0 |
| PASI 75b | 386 (89) | 17 (4) | 315 (90) | 4 (2) | 336 (87) | 14 (7) |
| PASI 90 | 307 (71) | 2 (1) | 248 (71) | 1 (1) | 262 (68) | 6 (3) |
| PASI 100 | 153 (35) | 0 | 142 (40) | 1 (1) | 145 (38) | 0 |
Examination of age, gender, race, body weight, and previous treatment with a biologic did not identify differences in response to TALTZ among these subgroups at Week 12.
Subjects treated with TALTZ 80 mg Q2W experienced improvement in itch severity when compared to placebo at Week 12.
An integrated analysis of the U.S. sites in the two active comparator studies using U.S. approved etanercept, TALTZ demonstrated superiority to U.S. approved etanercept (50 mg twice weekly) on sPGA and PASI scores during the 12 week treatment period. The respective response rates for TALTZ 80 mg Q2W and U.S. approved etanercept 50 mg twice weekly were: sPGA of 0 or 1 (73% and 27%); PASI 75 (87% and 41%); sPGA of 0 (34% and 5%); PASI 90 (64% and 18%), and PASI 100 (34% and 4%).
Maintenance and Durability of Response
To evaluate the maintenance and durability of response, subjects originally randomized to TALTZ and who were responders at Week 12 (i.e., sPGA of 0 or 1) in Trial 1 and Trial 2 were re-randomized to an additional 48 weeks of either a maintenance dose of TALTZ 80 mg Q4W (every 4 weeks) or placebo. Non-responders (sPGA >1) at Week 12 and subjects who relapsed (sPGA 3) during the maintenance period were placed on TALTZ 80 mg Q4W.
For responders at Week 12, the percentage of subjects who maintained this response (sPGA 0 or 1) at Week 60 (48 weeks following re-randomization) in the integrated trials (Trial 1 and Trial 2) was higher for subjects treated with TALTZ 80 mg Q4W (75%) compared to those treated with placebo (7%).
For responders at Week 12 who were re-randomized to treatment withdrawal (i.e., placebo), the median time to relapse (sPGA 3) was 164 days in the integrated trials. Among these subjects, 66% regained a response of at least 0 or 1 on the sPGA within 12 weeks of restarting treatment with TALTZ 80 mg Q4W.
Psoriasis Involving the Genital Area
A randomized, double-blind, placebo-controlled trial (Trial 4) was conducted in 149 adult subjects with plaque psoriasis who had a minimum body surface area (BSA) involvement of 1%, a sPGA score of 3 (moderate psoriasis), a sPGA of Genitalia score of 3 (moderate psoriasis involving the genital area), who failed to respond to or were intolerant of at least one topical therapy used for treatment of psoriasis affecting the genital area, and who were candidates for phototherapy and/or systemic therapy.
Subjects had a median baseline PASI score of approximately 12. Baseline BSA involvement was at least 10% for approximately 60% of the enrolled subjects. Baseline sPGA of Genitalia score was severe or very severe in approximately 42% of the subjects; baseline sPGA score was severe or very severe in approximately 47% of the subjects.
Subjects randomized to TALTZ received an initial dose of 160 mg followed by 80 mg every 2 weeks for 12 weeks. The trial evaluated the primary endpoint of the proportion of subjects who achieved a 0 (clear) or 1 (minimal) response at Week 12 on sPGA of Genitalia. Other evaluated outcomes at Week 12 included the proportion of subjects who achieved a sPGA score of 0 (clear) or 1 (minimal), improvement of genital itch severity as measured by a reduction of at least 4 points in the 11-point Genital Psoriasis Symptoms Scale (GPSS) score Itch numeric rating scale (NRS), and the patient-perceived impact of psoriasis affecting the genital area on limiting frequency of sexual activity (intercourse or other activities) as measured by the Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) Item 2 (In the past week how often did your genital psoriasis limit the frequency of your sexual activity?). SFQ Item 2 score ranges from 0 to 4 (0=never, 1=rarely, 2=sometimes, 3=often, 4=always); where higher scores indicate greater limitations on the frequency of sexual activity in the past week.
The results of Trial 4 are presented in Table 3.
Table 3: Efficacy Results at Week 12 in Adults with Genital Psoriasis in Trial 4; NRIa |
|
| Endpoints | TALTZ 80 mg Q2Wb
n (%) | Placebo
n (%) |
| Number of subjects randomized | N=75 | N=74 |
| sPGA of Genitalia 0 (clear) or 1 (minimal) | 55 (73%) | 6 (8%) |
| sPGA 0 (clear) or 1 (minimal) | 55 (73%) | 2 (3%) |
| Number of subjects with baseline GPSSa Itch NRS Score 4 | N=56 | N=51 |
| GPSS Genital Itch ( 4 point improvement) | 31 (55%) | 3 (6%) |
| Number of subjects with baseline GenPs-SFQa Item 2 Score 2 | N=37 | N=42 |
| GenPs-SFQ Item 2 score 0 (never) or 1 (rarely) | 29 (78%) | 9 (21%) |
14.2 Psoriatic Arthritis
The safety and efficacy of TALTZ were assessed in 679 patients, in 2 randomized, double-blind, placebo-controlled studies (PsA1 and PsA2) in adult patients, age 18 years and older with active psoriatic arthritis (at least 3 swollen and at least 3 tender joints) despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid or disease modifying anti-rheumatic drug (DMARD) therapy. Patients in these studies had a diagnosis of PsA for at least 6 months across both studies. At baseline, 60% and 23% of the patients had enthesitis and dactylitis, respectively. In PsA2, all patients discontinued previous treatment with anti-TNF agents due to either inadequate response or intolerance. In addition, approximately 47% of patients from both studies had concomitant methotrexate (MTX) use.
PsA1 Study (NCT 01695239) evaluated 417 biologic-naive patients, who were treated with either TALTZ 160 mg at Week 0 followed by 80 mg every 2 weeks (Q2W) or 4 weeks (Q4W), adalimumab 40 mg every 2 weeks, or placebo. PsA2 Study (NCT 02349295) evaluated 363 anti-TNF experienced patients, who were treated with TALTZ 160 mg at Week 0 followed by 80 mg every 2 or 4 weeks, or placebo. Patients receiving placebo were re-randomized to receive TALTZ (80 mg every 2 or 4 weeks) at Week 16 or Week 24 based on responder status. The primary endpoint was the percentage of patients achieving an ACR20 response at Week 24.
Clinical Response
In both studies, patients treated with TALTZ 80 mg Q4W demonstrated a greater clinical response including ACR20, ACR50, and ACR70 compared to placebo at Week 24 (Table 4). In PsA2, responses were seen regardless of prior anti-TNF exposure.
Table 4: Responsesa at Week 12 and 24; NRIb |
|
|
| PsA1 anti-TNF naive | PsA2 anti-TNF experienced |
TALTZ
80 mgc
Q4W
(N=107) | Placebo (N=106) | Difference from placebo (95% CI) | TALTZ
80 mgc
Q4W
(N=122) | Placebo (N=118) | Difference from placebo (95% CI) |
| ACR20 response |
| Week 12 (%) | 57 | 31 | 26 (13, 39) | 50 | 22 | 28 (16, 40) |
| Week 24 (%) | 58 | 30 | 28 (15, 41) | 53 | 20 | 34 (22, 45) |
| ACR50 response |
| Week 12 (%) | 34 | 5 | 29 (19, 39) | 31 | 3 | 28 (19, 37) |
| Week 24 (%) | 40 | 15 | 25 (14, 37) | 35 | 5 | 30 (21, 40) |
| ACR70 response |
| Week 12 (%) | 15 | 0 | 15 (8, 22) | 15 | 2 | 13 (6, 20) |
| Week 24 (%) | 23 | 6 | 18 (9, 27) | 22 | 0 | 22 (15, 30) |
The percentage of patients achieving ACR20 response by visit is shown in Figure 1.
Figure 1: Percent of Patients Achieving ACR20 Responsea in PsA1 Through Week 24
a Patients who met escape criteria (less than 20% improvement in tender and swollen joint counts) at Week 16 or had missing data at Week 24 were considered non-responders at Week 24.
The improvements in the components of the ACR response criteria are shown in Table 5.
Table 5: Efficacy results in ACR Components at Week 12 and 16 |
|
| PsA1 | PsA2 |
TALTZ 80 mga
Q4W (N=107) | Placebo
(N=106) | TALTZ 80 mga
Q4W (N=122) | Placebo
(N=118) |
| No. of Swollen Joints | | | | |
| Baseline | 11.4 | 10.6 | 13.1 | 10.3 |
| Mean Change at Week 12 | -6.2 | -3.2 | -5.8 | -2.6 |
| Mean Change at Week 16 | -6.2 | -3.0 | -7.4 | -2.6 |
| No. of Tender Joints | | | | |
| Baseline | 20.5 | 19.2 | 22.0 | 23.0 |
| Mean Change at Week 12 | -10.3 | -3.5 | -9.4 | -5.4 |
| Mean Change at Week 16 | -9.7 | -4.0 | -10.1 | -3.0 |
| Patient's Assessment of Pain | | | | |
| Baseline | 60.1 | 58.5 | 63.9 | 63.9 |
| Mean Change at Week 12 | -26.6 | -9.1 | -29.8 | -11.9 |
| Mean Change at Week 16 | -26.1 | -10.6 | -30.1 | -12.3 |
| Patient Global Assessment | | | | |
| Baseline | 62.7 | 61.1 | 66.4 | 64.1 |
| Mean Change at Week 12 | -29.7 | -11.1 | -34.5 | -10.7 |
| Mean Change at Week 16 | -30.4 | -13.2 | -35.3 | -15.7 |
| Physician Global Assessment | | | | |
| Baseline | 57.6 | 55.9 | 60.3 | 58.9 |
| Mean Change at Week 12 | -34.0 | -16.6 | -34.4 | -15.9 |
| Mean Change at Week 16 | -35.5 | -16.5 | -32.9 | -9.7 |
| Disability Index (HAQ-DI)b | | | | |
| Baseline | 1.2 | 1.2 | 1.2 | 1.2 |
| Mean Change at Week 12 | -0.4 | -0.1 | -0.4 | -0.1 |
| Mean Change at Week 16 | -0.4 | -0.1 | -0.5 | -0.1 |
| CRP (mg/L) | | | | |
| Baseline | 12.8 | 15.1 | 17.0 | 12.1 |
| Mean Change at Week 12 | -8.8 | -3.2 | -11.4 | -4.3 |
| Mean Change at Week 16 | -9.3 | -3.2 | -11.2 | -5.9 |
Treatment with TALTZ resulted in improvement in dactylitis and enthesitis in patients with pre-existing dactylitis or enthesitis.
Treatment with TALTZ 80 mg Q4W resulted in an improvement in psoriatic skin lesions in patients with PsA.
Radiographic Response
Radiographic changes were assessed in PsA1. Inhibition of progression of structural damage was assessed radiographically and expressed as the change in modified total Sharp score (mTSS) at Week 16, compared to baseline. The total Sharp score was modified for psoriatic arthritis by addition of hand distal interphalangeal (DIP) joints.
TALTZ 80 mg Q4W inhibited the progression of structural joint damage (mTSS) compared to placebo at Week 16. The adjusted mean change from baseline in the mTSS was 0.13 for TALTZ 80 mg Q4W and 0.36 for placebo (difference in means TALTZ minus placebo: -0.23, 95% CI: (-0.42, -0.04)).
Physical Function
TALTZ treated patients showed improvement in physical function compared to patients treated with placebo as assessed by the Health Assessment Questionnaire-Disability Index (HAQ-DI) at Week 12 and 24. In both studies, the proportion of HAQ-DI responders ( 0.35 improvement in HAQ-DI score) was greater in the TALTZ 80 mg Q4W groups compared to placebo at week 12 and 24.
Other Health-Related Outcomes
General health status was assessed by the Short Form health survey (SF-36). At Week 12 in PsA1 and PsA2, patients treated with TALTZ showed greater improvement from baseline in the SF-36 physical component summary (PCS) score compared to patients treated with placebo but this improvement was not consistent in both studies for the SF-36 mental component summary (MCS) score. At Week 12, there was consistent evidence of effect in the physical-functioning, role-physical, bodily-pain, and general health domains but not in the social-functioning, role-emotional, vitality, and mental health domains.
14.3 Ankylosing Spondylitis
The safety and efficacy of TALTZ were assessed in 567 patients, in 2 randomized, double-blind, placebo-controlled studies (AS1 and AS2) in adult patients, age 18 years and older with active ankylosing spondylitis. Patients had active disease as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 4 despite non-steroidal anti-inflammatory drug (NSAID), corticosteroid, or disease modifying anti-rheumatic drug (DMARD) therapy. At baseline, patients had symptoms of AS for an average of 17 years across both studies. At baseline, approximately 32% of the patients were on a concomitant cDMARD. In AS2, all patients discontinued previous treatment with 1 or 2 TNF inhibitors due to either inadequate response or intolerance.
AS1 Study (NCT 02696785) evaluated 341 biologic-naive patients, who were treated with either TALTZ 80 mg or 160 mg at Week 0 followed by 80 mg every 2 weeks (Q2W) or 4 weeks (Q4W), adalimumab 40 mg every 2 weeks, or with placebo. Patients receiving placebo were re-randomized at Week 16 to receive TALTZ (160 mg starting dose, followed by 80 mg Q2W or Q4W). Patients receiving adalimumab were re-randomized at Week 16 to receive TALTZ (80 mg Q2W or Q4W). AS2 Study (NCT 02696798) evaluated 316 TNF-inhibitor experienced patients (90% were inadequate responders and 10% were intolerant to TNF inhibitors). All patients were treated with TALTZ 80 or 160 mg at Week 0 followed by 80 mg Q2W or Q4W, or with placebo. Patients receiving placebo were re-randomized at Week 16 to receive TALTZ (160 mg initial dose, followed by 80 mg Q2W or Q4W). The primary endpoint in both studies was the percentage of patients achieving an Assessment of Spondyloarthritis International Society 40 (ASAS40) response at Week 16.
Clinical Response
In both studies, patients treated with TALTZ 80 mg Q4W demonstrated greater improvements in ASAS40 and ASAS20 responses compared to placebo at Week 16 (Table 6). Responses were seen regardless of concomitant therapies. In AS2, responses were seen regardless of prior TNF-inhibitor exposure.
Table 6: ASAS20 and ASAS40 Responses at Week 16, NRIa,b |
|
|
|
|
| AS1 biologic-naive | AS2 TNF-inhibitor experienced |
TALTZ
80 mg
Q4Wc
(N=81) | Placebo (N=87) | Difference from placebo (95% CI) | TALTZ
80 mg
Q4Wc
(N=114) | Placebo (N=104) | Difference from placebo (95% CI) |
| ASAS20 responsed, % | 64 | 40 | 24 (9, 39) | 48 | 30 | 18 (6, 31) |
| ASAS40 responsed,e, % | 48 | 18 | 30 (16, 43) | 25 | 13 | 13 (3, 23) |
The percent of patients achieving ASAS40 response by visit in AS1 is shown in Figure 2.
Figure 2: ASAS40 Response through Week 16, NRIa
a Patients with missing data were counted as non-responders.
The improvement in the main components of the ASAS40 response criteria and other measures of disease activity are shown in Table 7.
Table 7: ASAS Components and Other Measures of Disease Activity at Week 16a,b |
|
|
|
| AS1 biologic-naive | AS2 TNF-inhibitor experienced |
TALTZ 80 mg
Q4Wc (N=81) | Placebo
(N=87) | TALTZ 80 mg
Q4Wc (N=114) | Placebo
(N=104) |
| ASAS Components |
| Patient Global Assessment (0-10) |
| Baseline | 6.9 | 7.1 | 8.0 | 7.8 |
| Mean Change from Baseline | -2.5 | -1.4 | -2.4 | -0.7 |
| Total Spinal Pain (0-10) |
| Baseline | 7.2 | 7.4 | 7.9 | 7.8 |
| Mean Change from Baseline | -3.2 | -1.7 | -2.4 | -1.0 |
| BASFI (0-10) |
| Baseline | 6.1 | 6.4 | 7.4 | 7.0 |
| Mean Change from Baseline | -2.4 | -1.2 | -1.7 | -0.6 |
| Inflammation (0-10)d |
| Baseline | 6.5 | 6.8 | 7.2 | 7.2 |
| Mean Change from Baseline | -3.2 | -1.3 | -2.4 | -0.7 |
| Other Measures of Disease Activity |
| BASDAI Score |
| Baseline | 6.8 | 6.8 | 7.5 | 7.3 |
| Mean Change from Baseline | -2.9 | -1.4 | -2.2 | -0.9 |
| BASMI |
| Baseline | 3.9 | 4.5 | 4.7 | 4.9 |
| Mean Change from Baseline | -0.5 | -0.1 | -0.3 | -0.0 |
| hsCRP (mg/L) |
| Baseline | 12.2 | 16.0 | 20.2 | 16.0 |
| Mean Change from Baseline | -5.2 | 1.4 | -11.1 | 9.7 |
Health-Related Outcomes
General health status and quality of life was assessed by the Short Form health survey (SF-36). At Week 16, in AS1 and AS2, compared to placebo, patients treated with TALTZ showed greater improvement from baseline in the SF-36 physical component summary (PCS) score and the physical functioning, role physical, bodily pain, vitality, and general health domains, with no consistent improvements in the mental component summary (MCS), social functioning, role emotional, and mental health domains.
