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Expert Review of Clinical Immunology

ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: http://www.tandfonline.com/loi/ierm20

Secukinumab (AIN457) for the treatment of psoriasis Anna López-Ferrer, Eva Vilarrasa & Lluís Puig To cite this article: Anna López-Ferrer, Eva Vilarrasa & Lluís Puig (2015): Secukinumab (AIN457) for the treatment of psoriasis, Expert Review of Clinical Immunology, DOI: 10.1586/1744666X.2015.1095092 To link to this article: http://dx.doi.org/10.1586/1744666X.2015.1095092

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Drug Profile

Secukinumab (AIN457) for the treatment of psoriasis Expert Rev. Clin. Immunol. Early online, 1–12 (2015)

Downloaded by [University of Otago] at 20:38 09 October 2015

Anna Lopez-Ferrer, Eva Vilarrasa and Lluı´s Puig* Department of Dermatology, Hospital de la Santa Creu i Sant Pau. Universitat Auto`noma de Barcelona, Campus de la UAB, Plaza Cı´vica, s/n, 08193 Bellaterra, Barcelona, Spain *Author for correspondence: Tel.: +34 9 35 53 70 07 Fax: +34 9 35 53 70 08 [email protected]

Psoriasis is a chronic inflammatory disease with a multifactorial origin that appears in patients with genetic predisposition and is induced by environmental factors, and characterized by alterations in the innate and adaptive immunity. IL-17A is one of the specific cytokines involved in the pathogenesis of psoriasis and its inhibition is highly effective in the treatment of patients with moderate and severe psoriasis. Secukinumab is a monoclonal antibody that specifically binds to IL-17A and inhibits the interaction to its receptor, and it has demonstrated its efficacy and safety in the treatment of psoriasis. Phase II and III clinical trials indicate that > 80% of the patients receiving secukinumab achieve Psoriasis Area Severity Index (PASI) 75 at week 12. In the Phase III efficacy of response and safety of two fixed secukinumab regimens in psoriasis trial, PASI 75 rates were 81.6% with 300 mg secukinumab, 71.6% with 150 mg secukinumab and 4.5% with placebo, and responses were maintained up to 52 weeks in the majority of patients. In the Phase III Full Year Investigative Examination Of Secukinumab versus Etanercept Using Two Dosing Regimens To Determine Efficacy in Psoriasis study, the efficacy of secukinumab was compared to etanercept. The results indicate that both doses of secukinumab (150 and 300 mg) showed superior efficacy compared with etanercept throughout the study; PASI 75 rates at week 12 were 77.1% with 300 mg secukinumab, 67% with 150 mg of secukinumab, 44% with etanercept and 4.9% with placebo. PASI 90 and PASI 100 were 54 and 24% with secukinumab 300 mg and 21 and 4% with etanercept at week 12. At week 52, PASI 90 continued to be higher in the secukinumab group (65%) compared with the etanercept group (33%). Regarding safety, the most common side effects were nasopharyngitis and headache. The rate of infections was higher with secukinumab than placebo. This was especially the case for Candida infections, which were more common in the secukinumab group (4.7% with secukinumab 300 mg and 2.3% with secukinumab 150 mg), but all cases were resolved with conventional treatment. Secukinumab is a well-tolerated treatment that has demonstrated efficacy in treating moderate-to-severe plaque psoriasis. Nevertheless, long-term studies are necessary to confirm Phase II and Phase III data. KEYWORDS: IL-17 inhibitors . psoriasis . secukinumab . treatment

Psoriasis is a chronic, immune-mediated inflammatory disease with multifactorial origin affecting 2–3% of general population worldwide [1,2]. The skin is the target of inflammation in psoriasis, but up to 30% of patients develop psoriatic arthritis and different comorbidities can be associated with psoriasis, may be related to systemic inflammation and require a multidisciplinary approach [3]. Recent advances in our understanding of the pathogenesis of psoriasis have provided new biologic therapies, which are very effective and have a favorable safety profile; conversely, the efficacy of therapeutic advances has provided confirmation and refinement of pathogenetic hypotheses. informahealthcare.com

10.1586/1744666X.2015.1095092

The Psoriasis Area Severity Index (PASI) is the most widely used method for objective measurement of psoriasis severity and extension [4], and it is considered the gold standard of psoriasis outcome instruments to be used in clinical trials. According to the EMA guideline [5], “the best evidence of efficacy is the percentage of patients who achieve the result of ‘clear or almost clear’ (PASI improvement greater than 90%) with respect to baseline, or PASI90 response. In studies enrolling severe patients, patients who achieve the result of ‘mild’ (PASI >75%) may also be considered as responders if defined prospectively”. Thus, even though PASI75 has been considered the primary end point in most clinical trials and a

2015 Informa UK Ltd

ISSN 1744-666X

1


Drug Profile

Lopez-Ferrer, Vilarrasa & Puig

benchmark of efficacy of new psoriasis treatments until now, PASI 90 responses define therapeutic success and are closer to the patients’ and physicians expectations. These levels of response used to be achieved and maintained in a minority of patients with previously available therapeutic agents, but have recently been shown to be attainable by a significant proportion of patients in clinical trials in both Phase II and Phase III studies with IL-17 inhibitors and other biologics under development. This suggests that PASI 90 response rates can be used for benchmarking of efficacy in clinical trials and may become a therapeutic goal in patients with moderate-severe psoriasis. According to a recently published meta-analysis [6], the probabilities to achieve a PASI 90 response compared with placebo (relative risk, RR) at weeks 24–28 are: secukinumab 40.15 (95% confidence interval [CI]: 20.97, 76.89), ustekinumab 31.63 (95% CI: 19.43, 51.51), infliximab 31.00 (95% CI: 13.45, 71.46), adalimumab 23.17 (95% CI: 12.51, 42.91) and etanercept 19.14 (95% CI: 11.59, 31.60). The indications of biologic treatments in patients with psoriasis differ in the European and US. guidelines [7–9]. According to the US FDA labels and American guidelines, biologics are approved for treatment of adult patients with moderate to severe psoriasis regardless of previous treatment, whereas according to the EMA approved Summaries of Product Characteristics all biologics are currently indicated in adult patients with moderate to severe psoriasis who failed to respond to traditional systemic treatments, including cyclosporine, methotrexate (MTX) or psoralen plus ultraviolet A (PUVA) photochemotherapy, or patients who have contraindications or are intolerant to systemics, except secukinumab – the most recently approved biological – which is “indicated for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy”. This might reflect a change in the overall perception of the safety profile of biologicals, in addition to the favorable evaluation of the secukinumab data set. Overview of the market

The use of biologics in the treatment of patients with moderate and severe psoriasis has yielded significant PASI 75 response rates at the primary end point time in clinical trials, but the effectivity of biologics and the maintenance of this degree of response in real life may vary in different settings. Response to treatment decreases or is lost over the course of time in a significant proportion of patients, and this is especially important in the management of psoriasis as a chronic disease. Adalimumab, etanercept, infliximab, secukinumab and ustekinumab are the currently FDA and EMA approved biologics for the treatment of psoriasis. Market share depends on many factors, including convenience of administration, safety profile, pricing and local availability. The efficacy of systemic treatments can be compared indirectly with meta-analyses of randomized clinical trials or directly when head-to-head trials are available. In a recently published meta-analysis the efficacy was assessed as PASI75 response rates at the time of primary efficacy measurement (weeks 8–16) [10]. In placebo-controlled doi: 10.1586/1744666X.2015.1095092

trials, infliximab was the most efficacious (risk difference [RD] 76, 95% CI 73–79%), adalimumab (RD 61, 95% CI 56– 67%) and ustekinumab 45 mg (RD 63, 95% CI 59–66%) and 90 mg (RD 67, 95% CI 60–74%) each had similar efficacy. These biologics are more effective than etanercept and all conventional treatments. Head-to-head trials indicate the superiority of adalimumab and infliximab over MTX, the superiority of ustekinumab over etanercept, the non-significant superiority of cyclosporine over MTX and the dose-dependent efficacy of etanercept and ustekinumab. Fumaric acid is as efficacious as MTX. Safety of treatments could not be pooled due to a lack of standardization in reporting across trials. Another meta-analysis in which the SmPC-approved conditions of use and clinically relevant time points were taken into account [11] has shown that at the end of the induction Phase (week 24), ustekinumab 45 mg has the greatest probability of achieving PASI75 response (RD 75.5, 95% CI 71.5–79.4%), followed by ustekinumab 90 mg, infliximab, adalimumab and etanercept. At the time points recommended for primary failure assessment according to the approved SmPCs, ustekinumab 45 mg (at week 28) also has the greatest probability of achieving PASI 50 response (RD 80.7, 95% CI 77.2–84.2%), followed by ustekinumab 90 mg, infliximab, adalimumab and etanercept. The speed of action of biologics in psoriasis can be measured as the weighted mean time until 25% of patients achieve a PASI75 response; [12]; it is shortest for infliximab (3.5 weeks), followed by ustekinumab (4.6 for 90 mg, 5.1 for 45 mg, not weight-adapted), adalimumab (4.6 weeks) and etanercept (6.6 high dose, 9.5 low dose). Drug survival (time to drug discontinuation) has emerged as an important parameter reflecting the long-term therapeutic performance in a real-life setting. Drug survival reflects a drug’s effectiveness, safety and tolerability, but in psoriasis is mainly limited by a gradual loss of efficacy over time. In a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register) the overall survival rate in the first year was 77%, falling to 53% in the third year. When compared with adalimumab, patients on etanercept (HR 1.63; 95% CI 1.45–1.84) or infliximab (HR 1.56; 95% CI: 1.16–2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95%CI: 0.37–0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival [13]. At the present time, several new drugs are under different stages of development as anti-psoriatic agents. Targeting specific cytokines downstream the inflammatory and immune activation cascade can be expected to be more selective from both the efficacy and safety perspectives, by blocking mediators closer to the target cells and preserving the redundancy of the immune function. On the other hand, the effects of blocking cytokines might be different from those of blocking their receptors, if partial agonisms or disturbed regulation of the cytokine/ receptor homeostasis occur. Among the new biologics, IL-17A inhibitors (secukinumab and ixekizumab) and IL-17RA antagonist (brodalumab) can Expert Rev. Clin. Immunol.


Secukinumab (AIN457) for the treatment of psoriasis

provide PASI 90 responses in the majority of patients with psoriasis [14]. Ixekizumab (LY2439821) is a humanized immunoglobulin G4 that selectively inhibits Il-17A. According to the results of a Phase II trial with 142 patients assigned to receive subcutaneous (s.c.) doses of 10, 25, 75, 150 mg or placebo, PASI 75 rates were 77, 83 and 82% with ixekizumab 25, 75 and 150 mg, respectively, versus 8% with placebo; the corresponding PASI 90 response rates were 50, 59 and 71 versus 0%. Regarding safety, higher rates of infection and infestation, infection-site reaction and headache occurred in the ixekizumab groups compared with placebo [15]. In two prospective, double-blind, multi-centre, Phase III studies (UNCOVER-2 and UNCOVER-3), patients were randomly assigned (1:2:2:2) to receive s.c. placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose in order to compare two different treatment regimens [16]. For UNCOVER-2 and UNCOVER-3, respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89.7%; [effect size 87.4% (97.5% CI 82.9–91.8) vs placebo; 48.1% (41.2–55.0) vs etanercept]) and 336 (87.3%; [80.0% (74.4–85.7) vs placebo; 33.9% (27.0–40.7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77.5%; [75.1% (69.5– 80.8) vs placebo; 35.9% (28.2–43.6) vs etanercept]) and 325 (84.2%; [76.9% (71.0–82.8) vs placebo; 30.8% (23.7– 37.9) vs etanercept]) patients; in the placebo group, by four (2.4%) and 14 (7.3%) patients and in the etanercept group by 149 (41.6%) and 204 (53.4%) patients (all p < 0.0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14/734 patients with ixekizumab every 2 weeks, 14/729 with ixekizumab every 4 weeks, 7/360 with placebo, and 14/739 with etanercept. Brodalumab (AMG-827) is a fully monoclonal antibody that targets the IL-17RA subunit. In a randomized Phase II trial, 198 subjects were allocated to receive brodalumab 70, 140 or 210 mg subcutaneously. PASI 75 and 90 rates at week 12 were 82 and 75% with brodalumab 210 mg versus 0% with placebo. The most common adverse events were upper respiratory tract infections, injection-site reactions and pain in extremities in the combined brodalumab group versus placebo group [17]. When the analysis was made taking into account the previous history of psoriatic arthritis or previous biologic use, the results were similar between subgroups of patients with or without a history of psoriatic arthritis and with or without a history of biologic use [18,19]. Tildrakizumab (MK-3222) is a humanized monoclonal antibody that targets the p19 subunit of the IL-23 molecule, and has demonstrated important clinical improvement in moderateto-severe psoriasis patients in a Phase I study [20]. In a randomized Phase IIb study [21], 355 subjects were treated with 5, 25, 100 and 200 mg of tildrakizumab subcutaneously. At week 16, PASI 75 responses were 33.3, 64.4, 66.3, 74.4 and 4.4% in the 5, 25, 100, 200 mg tildrakizumab and placebo groups, respectively. Tildrakizumab was generally safe and well tolerated. informahealthcare.com

Drug Profile

Guselkumab is a monoclonal antibody that also inhibits specifically IL-23 targeting the p19 subunit, and is being evaluated for the treatment of patients with psoriasis. Twenty-four patients were randomized to receive a single dose of placebo or 10, 30, 100 or 300 mg of s.c. guselkumab. At week 12, 50% (10 mg), 60% (30 and 100 mg) and 100% (300 mg) of guselkumab-treated patients, respectively, achieved a PASI 75 response compared with 0% of placebo-treated patients. The proportion of adverse events reported was comparable between the combined guselkumab (65.0%) and placebo (50.0%) groups through week 24 [22,23]. Small molecule inhibitors are being developed to treat patients with moderate and severe psoriasis with oral agents. Apremilast, a phosphodiesterase-4 inhibitor, modulates the production of intracellular inflammatory mediators through the regulation of cAMP production. In a Phase II study, 259 subjects were randomized to receive oral apremilast 20 mg once or twice daily (b.i.d.) or placebo. At week 12, a significantly greater proportion of patients receiving apremilast b.i.d. achieved PASI 75 versus placebo. In Phase III study (ESTEEM 1), 844 subjects were randomized to apremilast 30 mg b.i.d. versus placebo. The PASI 75 response rate at week 16 was 33.1 versus 5.3% in apremilast and placebo groups, respectively [24]. Tofacitinib is a JAK 1 and 3 inhibitor that blocks signaling of the cytokines that depend on these kinases. In a Phase IIb study, 197 subjects were randomized to receive oral tofacitinib 2, 5, 15 mg b.i.d. or placebo. At week 12, PASI 75 response rates were significantly higher for all tofacitinib groups versus placebo [25]. In a randomized Phase III study of tofacitinib 10 and 5 mg, the dose of 10 mg of tofacitinib met the primary end point of non-inferiority to high dose of etanercept [26,27]. Even though new drugs have demonstrated high efficacy and a favorable adverse event profile, these properties should be confirmed during long-term therapy and in clinical practice. Furthermore, additional head-to-head comparative trials are necessary to establish if there are any differences with respect to the existing systemic and biologic therapies. Introduction to the drug Mechanism of action of secukinumab & pharmacodynamics

Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the IL-17A cytokine and inhibits the interaction with its receptor. IL-17A is a pro-inflammatory cytokine that is usually involved in normal inflammatory and immune responses. Moreover, elevated levels of IL-17A are found in psoriatic plaques. Thus, in the presence of secukinumab, the inflammatory cascade that depends on IL-17A is inhibited. In the psoriatic plaques, secukinumab may reduce the presence of neutrophils in the epidermis and the levels of IL-17 are reduced. The levels of serum IL-17A (free and secukinumab-bound IL-17A) measured at week 4 and week 12 increase following secukinumab administration. These doi: 10.1586/1744666X.2015.1095092

Drug Profile


pharmacodynamic activities are based on small exploratory studies. The relationship between these pharmacodynamic activities and the mechanism(s) by which secukinumab exerts its clinical effects is unknown (Summary of product characteristics, Cosentyx [28]).


Pharmacokinetics & metabolism

Following a single s.c. dose of either 150 mg (one-half the recommended dose) or 300 mg in plaque psoriasis patients, secukinumab reached peak mean (±SD) serum concentrations (Cmax) of 13.7 ± 4.8 and 27.3 ± 9.5 mcg/ml, respectively, by approximately 6 days post-dose. Following multiple s.c. doses of secukinumab, the mean (±SD) serum trough concentrations of secukinumab ranged from 22.8 ± 10.2 mcg/ml (150 mg) to 45.4 ± 21.2 mcg/ml (300 mg) at week 12. At the 300 mg dose at week 4 and week 12, the mean trough concentrations resulted from the Sensoready pen were 23–30% higher than those from the lyophilized powder and 23–26% higher than those from the pre-filled syringe based on cross-study comparisons. Steady-state concentrations of secukinumab were achieved by week 24 following the every 4-week dosing regimens. The mean (±SD) steady-state trough concentrations ranged from 16.7 ± 8.2 mcg/ml (150 mg) to 34.4 ± 16.6 mcg/ml (300 mg). In healthy subjects and subjects with plaque psoriasis, secukinumab bioavailability ranged from 55 to 77% following s.c. dose of 150 mg (one-half the recommended dose) or 300 mg. The mean volume of distribution during the terminal phase (Vz) following a single intravenous administration ranged from 7.10 to 8.60 l in plaque psoriasis patients. Secukinumab concentrations in interstitial fluid in lesional and non-lesional skin of plaque psoriasis patients ranged from 27 to 40% of those in serum at 1 and 2 weeks after a single s.c. dose of secukinumab 300 mg. The elimination pathway of secukinumab has not been characterized. As a human IgG1k monoclonal antibody secukinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. The mean systemic clearance (CL) ranged from 0.14 to 0.22 l/day and the mean half-life ranged from 22 to 31 days in plaque psoriasis subjects following intravenous and s.c. administration across all psoriasis trials. Secukinumab exhibited dose-proportional pharmacokinetics in subjects with psoriasis over a dose range from 25 mg (approximately 0.083 times the recommended dose) to 300 mg following s.c. administrations. Secukinumab CL and volume of distribution increase as body weight increases. No formal trial of the effect of hepatic or renal impairment on the pharmacokinetics of secukinumab was conducted. Population pharmacokinetic analysis indicated that the CL of secukinumab was not significantly influenced by age in adult subjects with plaque psoriasis [28]. Subjects who are 65 years or older had apparent CL of secukinumab similar to subjects < 65 years old. doi: 10.1586/1744666X.2015.1095092

Clinical efficacy Phase I studies

The first results with secukinumab in patients with psoriasis came from a randomized Phase I proof-of-concept clinical trial that included 36 patients with chronic plaque-type psoriasis (TABLE 1). After a single administration of AIN457 (3 mg/kg), PASI was reduced relative to baseline by 58 and 4% in AIN457and placebo-treated patients, respectively. At week 12, mean reduction in PASI relative to baseline was 63% for AIN457 and 9% for placebo, respectively. All PASI response rates (PASI50, PASI75 and PASI90) were higher with AIN457 treatment than placebo. Skin samples from typical psoriasis plaques showed decreased production of inflammatory cytokines and chemokines, and a reduction in T-cell infiltration [29]. Phase II studies

In a randomized, double-blind, placebo-controlled Phase II dose-range study, secukinumab was tested in 125 patients diagnosed with psoriasis [30]. Patients were randomized to receive secukinumab (25, 75 or 150 mg) subcutaneously or placebo at weeks 0, 4 and 8, or a single dose of 25 mg secukinumab at week 0 followed by placebo. After 12 weeks, secukinumab at the two highest doses (75 and 150 mg) had significantly improved the PASI 75 score compared with placebo (57 and 82% of patients vs 9% for placebo). PASI 75 response rates for the two highest doses remained during the 24-week follow-up period. When body weight was analyzed, the results showed that patients weighing < 90 kg had better PASI 75 response rates than patients weighing > 90 kg (TABLE 1). In a separate Phase II, randomized, double-blind, placebocontrolled, regimen-finding study, secukinumab was tested in 404 patients with psoriasis [31]. The patients were randomized to receive placebo or 150 mg secukinumab in three different regimens: single (week 0; n = 66), early (weeks 0, 1, 2 and 4; n = 133) or monthly (weeks 0, 4 and 8; n = 138). After 12 weeks, PASI 75 responders from active treatment groups were re-randomized to either a fixed-interval regimen of 150 mg secukinumab at weeks 12 and 24 or a treatment-atstart-of-relapse regimen. The results after 12 weeks showed higher PASI 75 response rates with the early and monthly regimens than with placebo, and the best results were detected with the early regimen. Results in patients entering the maintenance period showed that the fixed-interval regimen was superior to the treatment-at-start-of-relapse regimen. However, both were very effective. The effect of body weight on treatment response rates showed slightly higher PASI 75 responses in patients weighing < 90 kg than in those weighing > 90 kg. Patients from that study who had involvement of hands, feet or nails were analyzed in a post-hoc study [32,33]; 131 patients because of involvement of hands and/or feet, and 304 because of psoriasis of the fingernails. There were clinically relevant improvements in hand and foot involvement after 12 weeks of treatment with secukinumab using the early regimen. The early and monthly regimens were associated with substantial reductions in affection of the fingernail. Expert Rev. Clin. Immunol.

[31]

ND 31.8

17.4

1.5

54.5

42.0

1.5

ND 3.0 10.6

1 150 mg (single) 4 150 mg (early) 3 150 mg (monthly) 5 placebo ND: Not determined; PASI: Psoriasis area severity index.

20 404

Drug Profile

Phase III studies

29

[30]

4 17 17 24 3 10 20 33 60 0 5 6 15 52 4.5 3 20 57 82 9.1 25 mg 25 mg 75 mg 150 mg placebo 1 3 3 3 3

Rich et al. (2013) Phase II

informahealthcare.com

21 125 Papp et al. (2013) Phase II

29

[29]

ND ND 10 45 18 36 Hueber et al. (2010) Phase I

ND

1 3 mg/kg iv 1 placebo

PASI 90 w12 (% patients) PASI75 w12 (% patients) Dosage Previous biologic therapy (% patients) Mean Baseline PASI Patients (n) Study(year) and phase

Table 1. Summary table of Phase I and II trial results.


PASI75 w24 (% patients)


Ref.


Secukinumab has demonstrated efficacy in treating moderateto-severe plaque in several Phase III studies (TABLE 2). Efficacy of Response And Safety of two fixed secUkinumab REgimens in psoriasis (ERASURE) [34] was a Phase III, doubleblind, 52-week, randomized controlled trial that included 738 adult patients with moderate-to-severe plaque psoriasis [35]. The study was designed to evaluate efficacy after 12 weeks of treatment, and to assess long-term efficacy, tolerability and safety up to 1 year. Patients were randomly assigned to placebo or to s.c. secukinumab at a dose of 300 or 150 mg (administered once weekly at baseline and at weeks 1, 2, 3 and 4, and then every 4 weeks). Co-primary end points were ‡75% improvement in PASI 75 and a score of 0 (clear) or 1 (almost clear) on a 5-point 2011 modified investigator’s global assessment (IGA mod 2011 0/1) at week 12. At week 12, the proportion of patients who achieved PASI 75 rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab and 4.5% with placebo. The proportion of patients with a response of 0 or 1 on the IGA mod 2011 were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab and 2.4% with placebo. At week 16, 69.8 and 41.6% of patients in the 300 mg secukinumab achieved PASI 90 and PASI 100 responses, respectively. The rates of infection were higher with secukinumab than with placebo. Antidrug antibodies developed transiently in one patient in the 150 mg secukinumab cohort. The efficacy and safety of secukinumab have also been assessed in 87 Japanese patients with moderate-to-severe plaque psoriasis in a subanalysis from the Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis study at week 52 [36]. The results at week 12 showed that the percentage of PASI 75 responders was superior with secukinumab (300 and 150 mg) than placebo, with 82.8, 86.2 and 6.9% of patients reaching the PASI 75, respectively. PASI 90 results were also superior with secukinumab versus placebo at week 12 (62.1% with secukinumab 300 mg; 55.2% with secukinumab 150 mg; 0.0% placebo). Responses were maintained up to week 52 in the majority of patients. During the 12-week induction period, there were 48.3% adverse event incidences with secukinumab 300 mg, 55.2% with 150 mg and 41.4% with placebo [36]. The Phase III Full year Investigative eXamination of secukinumab vs. eTanercept Using 2 dosing Regimens to determine Efficacy in psoriasis (FIXTURE) [37] study compared the effects of subcutaneously administered secukinumab with those of placebo and etanercept at 12 weeks of treatment in 1306 patients with moderate-to-severe chronic plaque-type psoriasis [35]. Safety, tolerability and long-term efficacy were also evaluated for up to 1 year. The study had four arms: i) placebo etanercept and placebo secukinumab; ii) 50 mg etanercept and placebo secukinumab; iii) 150 mg secukinumab and placebo etanercept and iv) 300 mg secukinumab and placebo etanercept. Secukinumab was administered once weekly for 5 weeks, then every 4 weeks. Etanercept was administered at a dose of doi: 10.1586/1744666X.2015.1095092

Drug Profile


Table 2. Summary table of main Phase III trial results. Study

Patients (n)

Mean Baseline PASI

Previous biologic therapy (% patients)

Dosage


PASI 90 w12 (% patients)

PASI 75 w52 (% patients)

JUNCTURE

60 61 61

19 22 19

15 15 13

300 mg 6 150 mg 6 placebo

86.7 71.7 3.3

55 40 0

ND

59 59 59

21 21 21

39 47.5 44.1


75.9 69.5 0

60.3 45.8 0

ND

327 327 326

24 24 24

11.6 13.8 10.7


77.1 67 4.9

54.2 41.9 1.5

78 65 ND

245 245 248

22 22 21

28.6 29.8 29.4


81.6 71.6 4.5

59.2 39.1 1.2

75 60 ND

29 29 29

26 28 21

20.7 17.2 20.7


82.8 86.2 6.9

62.1 55.2 0

86.2 75.9 0

[41]

FEATURE [39]

FIXTURE [35]


ERASURE [35]

OHTSUKI [36]

ERASURE: Efficacy of Response and safety of two fixed secukinumab regimens in psoriasis; FIXTURE: Full year investigative examination of secukinumab versus etanercept using two dosing regimens to determine efficacy in psoriasis; ND: Not determined; PASI: Psoriasis area severity index.

50 mg twice weekly for 12 weeks, then once weekly. Coprimary end points at week 12 were PASI 75 and IGA mod 2011 0/1. Both doses of secukinumab showed superior efficacy compared with etanercept throughout the study. PASI 75 rates at week 12 in the Full Year Investigative Examination of Secukinumab versus Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis study were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept and 4.9% with placebo (p < 0.001 for each secukinumab dose vs comparators). And IGA mod 2011 0/1 rates were 62.5, 51.1, 27.2 and 2.8% with 300 mg of secukinumab, 150 mg of secukinumab, etanercept and placebo, respectively (p < 0.001 for each secukinumab dose vs comparators). In this study, PASI 90 and PASI 100 were also assessed at week 12, 16 and 52. Results were as follows: at week 12, PASI 90 was achieved in 54% of patients receiving 300 mg secukinumab and 21% of patients with etanercept; while PASI 100 was achieved in 24 and 4% of 300 mg secukinumab and etanercept patients, respectively. By week 16, 72% of patients receiving 300 mg secukinumab achieved PASI 90, at week 52, 65 and 33% of patients treated with 300 mg secukinumab and etanercept, respectively, had a PASI 90. The speed of onset of action was assessed by the median time to PASI50 response, which was 3.0 weeks (95% CI 2.8–3.2) for secukinumab at the dose of 300 mg versus 7.0 (95% CI 6.3–7.7) for etanercept 50 mg twice a week. The most common adverse events throughout the 52-week study were nasopharyngitis and headache (12– 36 patients per 100 patient years in all groups). Serious AEs were experienced by 6, 5 and 6% of patients who received 300 mg secukinumab, 150 mg secukinumab and etanercept, respectively [35]. The rates of infection were higher with doi: 10.1586/1744666X.2015.1095092

secukinumab than with placebo in both studies and were similar to those with etanercept. The First study of sEcukinumAb in pre-filled syringes in subjecTs with chronic plaqUe-type psoriasis REsponse (FEATURE) trial [38] was designed to assess efficacy, safety and usability of secukinumab administration via pre-filled syringes in self-administered s.c. injection [39]. Adult subjects with moderate to severe psoriasis were randomized 1:1:1 to secukinumab 300 or 150 mg or matching placebo. Every treatment was delivered using a pre-filled syringe once weekly to week 4, and again at week 8. Co-primary end points at week 12 were secukinumab superiority over placebo for PASI 75 and IGA mod 2011 0/1 response rates. Secondary end points included prefilled syringes usability, which was determined by observer rating of successful, hazard-free self-injection and subject rating of acceptability by the Self-Injection Assessment Questionnaire. At week 12, PASI 75 rates were: 75.9, 69.5 and 0% for secukinumab 300, 150 mg and placebo; and IGA mod 2011 0/1 results at week 12 were: 69.0, 52.5 and 0%, respectively (p < 0.0001, for all comparisons vs placebo). Pre-filled syringe usability was high: 100% of subjects successfully self-administered treatment at week 1, and subjects reported high Self-Injection Assessment Questionnaire. No new or unexpected adverse events were observed. Judging the efficacy of secUkinumab in patients with psoriasis using autoiNjector: a Clinical Trial evalUating treatment REsults (JUNCTURE) [40] was a Phase III randomized controlled trial designed to determine efficacy, safety and usability of secukinumab administered via autoinjector/pen in patients with moderate-to-severe psoriasis [41]. Subjects were randomized to secukinumab 300, 150 mg or placebo self-injection once weekly to week 4, then every 4 weeks. Co-primary end points Expert Rev. Clin. Immunol.



at week 12 were PASI 75 and IGA mod 2011 0/1. Secondary end points included autoinjector usability (successful and hazard-free self-injection) and subject-reported acceptability on Self-Injection Assessment Questionnaire. At week 12, PASI 75 and IGA mod 2011 0/1 responses were superior with secukinumab 300 mg (86.7 and 73.3%, respectively) and 150 mg (71.7 and 53.3%, respectively) versus placebo (3.3 and 0%, respectively) (p < 0.0001 for all). All subjects successfully selfadministered treatment at week 1, without critical use-related hazards. Subject acceptability of autoinjector was high throughout 12 weeks. Adverse events were higher with secukinumab (300 mg, 70.0%; 150 mg, 63.9%) versus placebo (54.1%), with differences largely driven by mild/moderate nasopharyngitis [41]. The randomized, double-blind, Phase III SCULPTURE study [42] was designed to compare a fixed maintenance schedule of once-monthly dosing of secukinumab with dosing as needed to treat relapse [43]. A total of 966 patients with moderate-to-severe chronic plaque psoriasis received induction therapy of 5 once-weekly s.c. injections of either 150 or 300 mg secukinumab. At week 12, patients who achieved PASI 75 response were re-randomized to the same dose once monthly or as needed for relapse. To maintain blinding, patients in the ‘as needed’ cohorts received a placebo if there was no relapse. PASI 75 rates at week 52 were achieved by 78, 68, 62 and 52% of patients who received 300 mg once monthly, 300 mg as needed, 150 mg once monthly and 150 mg as needed, respectively. PASI 90 results at week 52 were achieved by 60 and 46% of patients who received 300 and 150 mg once monthly, respectively. Substantially lower PASI 90 rates were observed for those who received either dose of secukinumab on an as needed basis. Antidrug antibodies that did not affect clinical efficacy or safety were observed in three patients on monthly doses and two patients on ‘as needed’ therapy [43]. The Phase III STATURE trial [44] was designed to assess the potential to improve response to secukinumab in partial responders [45]. In this randomized, double-blind, controlled trial, 43 subjects with moderate to severe psoriasis who had been included in the SCULPTURE study and at week 12 had partial response (PASI improvement ‡50% but 3990 adult patients. Extension studies are ongoing to obtain longer term safety and efficacy data.


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Secukinumab has shown superior efficacy to etanercept (Full Year Investigative Examination of Secukinumab versus Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis study) and ustekinumab (CLEAR study) with similar safety in two randomized controlled trials.

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The most common adverse events reported in the clinical trials were worsening of disease, nasopharyngitis, upper-respiratory-tract infection, arthralgia, injection-site erythema, pain in the extremities, nausea, headache and pruritus.

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The safety profile of secukinumab was comparable with those of etanercept and ustekinumab.

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Secukinumab has been approved by the EMA and the FDA for the treatment of moderate-to-severe psoriasis since January 2015.

Papers of special note have been highlighted as: . of interest .. of considerable interest 1.

Gudjonsson JE, Elder JT. Psoriasis: epidemiology. ClinDermatol 2007;25(6): 535-46

2.

Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med 2009;361(5):496-509

3.

Boehncke W-H, Scho¨n MP. Psoriasis. Lancet 2015. [Epub ahead of print]

4.

Fredriksson T, Pettersson U. Severe psoriasis-oral therapy with a new retinoid. Dermatologica 1978;157(4):238-44

5.

Guideline on clinical investigation of medicinal products indicated for the treatment of psoriasis. committee for medicinal products for human use (CHMP). Available from: www.ema.europa. eu/ema/pages/includes/document/ open_document.jsp? webContentId=WC500003329 [Last accessed 28 August 2015]

6.

7.

8.

Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am AcadDermatol 2011; 65(1):137-74

9.

Giannetti A. Commentary on the European S3-guidelines on the systemic treatment of psoriasis. J EurAcadDermatolVenereol 2010; 24(3):368; author reply 368–9

10.

Schmitt J, Rosumeck S, Thomaschewski G, et al. Efficacy and safety of systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials. Br J Dermatol 2014;170(2):274-303

11.

Puig L, Lopez A, Vilarrasa E, Garcıá I. Efficacy of biologics in the treatment of moderate-to-severe plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials with different time points. J Eur Acad Dermatol Venereol 2014;28(12):1633-53

Nast A, Jacobs A, Rosumeck S, Werner RN. Efficacy and safety of systemic long-term treatments for moderate-to-severe psoriasis: A systematic review and meta-analysis. J Invest Dermatol 2015; Epub ahead of print

12.

Pathirana D, Ormerod AD, Saiag P, et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris.

13.

doi: 10.1586/1744666X.2015.1095092

therapies for the treatment of psoriasis: a prospective observational cohort study from the british association of dermatologists biologic interventions register (BADBIR). J Invest Dermatol 2015

J EurAcadDermatolVenereol 2009; 23(Suppl 2):1-70

References

Nast A, Sporbeck B, Rosumeck S, et al. Which antipsoriatic drug has the fastest onset of action? Systematic review on the rapidity of the onset of action. J Invest Dermatol 2013;133(8):1963-70 Warren RB, Smith CH, Yiu ZZ, et al. Differential drug survival of biologic

14.

Chen Y, Qian T, Zhang D, et al. Clinical efficacy and safety of anti-IL-17 agents for the treatment of patients with psoriasis. Immunotherapy 2015;1-15

15.

Leonardi C, Matheson R, Zachariae C, et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N Engl J Med 2012;366(13): 1190-9

16.

Griffiths CEM, Reich K, Lebwohl M, et al. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet 2015;386(9993):541-51

17.

Papp KA, Leonardi C, Menter A, et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl J Med 2012; 366(13):1181-9

18.

Gooderham M, Posso-De Los Rios CJ, Rubio-Gomez GA, Papp K. Interleukin-17 (IL-17) inhibitors in the treatment of plaque psoriasis: a review. Skin Therapy Lett 2015; 20(1):1-5

19.

Papp K, Menter A, Strober B, et al. Efficacy and safety of brodalumab in subpopulations of patients with difficult-to-treat moderate-

Expert Rev. Clin. Immunol.


to-severe plaque psoriasis. J Am Acad Dermatol 2015;72(3):436-9.e1 20.

Kopp T, Riedl E, Bangert C, et al. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature 2015; 521(7551):222-6

21.

Papp K, Thaçi D, Reich K, et al. Tildrakizumab (MK-3222), an AntiIL-23p19 Monoclonal Antibody, Improves Psoriasis in a Phase 2b Randomized Placebo- Controlled Trial. Br J Dermatol 2015; Epub ahead of print

31.

Sofen H, Smith S, Matheson RT, et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis. J Allergy ClinImmunol 2014;133(4): 1032-40

32.

22.


30.

23.

24.

25.

26.

Gordon KB, Duffin KC, Bissonnette R, et al. A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis. N Engl J Med 2015;373(2):136-44 Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am AcadDermatol 2015;73(1):37-49 Papp KA, Menter A, Strober B, et al. Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study. Br J Dermatol 2012;167(3):668-77 Bachelez H, van de Kerkhof PCM, Strohal R, et al. Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. Lancet 2015;386(9993):552-61

27.

Papp KA, Menter MA, Abe M, et al. Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two, randomised, placebo-controlled, Phase 3 trials. Br J Dermatol 2015; Epub ahead of print

28.

Cosentyx summary of product characteristics. Available from: http://ec. europa.eu/health/documents/communityregister/2015/20150115130444/ anx_130444_en.pdf [Last accessed 24 July 2015]

29.

Hueber W, Patel DD, Dryja T, et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. SciTransl Med 2010; 2(52):52ra72

informahealthcare.com

33.

34.

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-ranging study. Br J Dermatol 2013;168(2):412-21 Rich P, Sigurgeirsson B, Thaci D, et al. Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study. Br J Dermatol 2013;168(2):402-11 Sigurgeirsson B, Kircik L, Nemoto O, et al. Secukinumab improves the signs and symptoms of moderate-to-severe plaque psoriasis in subjects with involvement of hands and/or feet: subanalysis of a randomized, double-blind, placebo-controlled, phase 2 dose-ranging study. J EurAcadDermatolVenereol 2014; 28(8):1127-9 Paul C, Reich K, Gottlieb AB, et al. Secukinumab improves hand, foot and nail lesions in moderate-to-severe plaque psoriasis: subanalysis of a randomized, double-blind, placebo-controlled, regimen-finding phase 2 trial. J EurAcadDermatolVenereol 2014;28(12): 1670-5 Efficacy and safety of subcutaneous secukinumab for moderate to severe chronic plaque-type psoriasis for up to 1 year (ERASURE). Available from: https:// clinicaltrials.gov/ct2/show/NCT01365455

35.

Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis–results of two phase 3 trials. N Engl J Med 2014; 371(4):326-38

..

Describes the results of the Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis and Full Year Investigative Examination of Secukinumab versus Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis Phase III randomized clinical trials of secukinumab versus etanercept and versus etanercept and placebo, respectively.

36.

37.

Ohtsuki M, Morita A, Abe M, et al. Secukinumab efficacy and safety in Japanese patients with moderate-to-severe plaque psoriasis: subanalysis from ERASURE, a randomized, placebo-controlled, phase 3 study. J Dermatol 2014;41(12): 1039-46 Safety and efficacy of secukinumab compared to etanercept in subjects with moderate to severe, chronic plaque-type psoriasis (FIXTURE). Available from:

Drug Profile

https://clinicaltrials.gov/ct2/show/ NCT01358578 38.

First study of secukinumab in pre-filled syringes in subjects with chronic plaque-type psoriasis: response at 12 weeks (FEATURE). Available from: https://clinicaltrials.gov/ct2/ show/NCT01555125

39.

Blauvelt A, Prinz JC, Gottlieb AB, et al. Secukinumab administration by pre-filled syringe: efficacy, safety and usability results from a randomized controlled trial in psoriasis (FEATURE). Br J Dermatol 2015; 172(2):484-93

40.

Judging the efficacy of secukinumab in patients with psoriasis using autoinjector: a clinical trial evaluating treatment results (JUNCTURE). Available from: https:// clinicaltrials.gov/ct2/show/NCT01636687

41.

Paul C, Lacour J-P, Tedremets L, et al. Efficacy, safety and usability of secukinumab administration by autoinjector/pen in psoriasis: a randomized, controlled trial (JUNCTURE). J Eur Acad Dermatol Venereol 2014;29(6):1082-90

42.

Efficacy and safety of subcutaneous secukinumab (AIN457) for moderate to severe chronic plaque-type psoriasis assessing different doses and dose regimens (SCULPTURE). Available from: https:// clinicaltrials.gov/ct2/show/NCT01406938

43.

Mrowietz U, Leonardi CL, Girolomoni G, et al. Secukinumab retreatment-as-needed versus fixed-interval maintenance regimen for moderate to severe plaque psoriasis: A randomized, double-blind, noninferiority trial (SCULPTURE). J Am AcadDermatol 2015;73(1):27-36.e1

..

This randomized clinical trial demonstrates that fixed-interval maintenance regime of secukinumab provides better efficacy results than retreatment as needed.

44.

Efficacy and safety of intravenous and subcutaneous secukinumab in moderate to severe chronic plaque-type psoriasis (STATURE). Available from: https:// clinicaltrials.gov/ct2/show/NCT01412944

45.

Thaçi D, Humeniuk J, Frambach Y, et al. Secukinumab in psoriasis: Randomized, controlled phase 3 trial results assessing the potential to improve treatment response in partial responders (STATURE). Br J Dermatol 2015; Epub ahead of print

46.

Efficacy of secukinumab compared to ustekinumab in patients with plaque-type psoriasis. Available from: https:// clinicaltrials.gov/ct2/show/NCT02074982

47.

Thaçi D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in

doi: 10.1586/1744666X.2015.1095092

Drug Profile


clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am AcadDermatol 2015;73(3):400-9 ..

48.


49.

50.

51.

Demonstrates superior efficacy of secukinumab over ustekinumab at week 16 in psoriasis. Plaque psoriasis eficacy and safety with secukinumab (OPTIMISE). ClinicalTrials. gov. Availablefrom https://clinicaltrials.gov/ ct2/show/NCT02409667? term=secukinumab+optimise&rank=1 [Last accessed 24 July 2015] Griffiths C, Reich K, Leonardi CL, et al. Secukinumab demonstrates an acceptable safety profile in moderate to severe plaque psoriasis : Pooled analysis of 10 phase 2/ 3 studies. P051, 4th World Psoriasis and Psoriatic Arthritis Conference; 8 – 11 July 2015; Stockholm, Sweden Puel A, Cypowyj S, Bustamante J, et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 2011; 332(6025):65-8 McInnes IB, Sieper J, Braun J, et al. Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II

doi: 10.1586/1744666X.2015.1095092

proof-of-concept trial. Ann Rheum Dis 2014;73(2):349-56

58.

Reich K, Papp KA, Matheson RT, et al. Evidence that aneutrophil-keratinocyte crosstalk is an early target of IL-17A inhibition inpsoriasis. Exp Dermatol 2015;24(7):529-35

.

Interesting review on the dynamics and mechanism of action of secukinumab in psoriasis.

..

Demonstrates the efficacy of secukinumab versus placebo at 24 weeks in psoriatic arthritis.

52.

Duarte JH. Therapy: Secukinumab improves symptoms of psoriatic arthritis. Nat Rev Rheumatol 2015;11(9):503

53.

Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn’s disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 2012;61(12):1693-700

59.

Johnston A, Guzman AM, Swindell WR, et al. Early tissue responses in psoriasis to the antitumour necrosis factor-a biologicetanercept suggest reduced interleukin-17 receptor expression and signalling. Br J Dermatol 2014;171(1): 97-107

54.

Dige A, Støy S, Rasmussen TK, et al. Increased levels of circulating Th17 cells in quiescent versus active Crohn’s disease. J Crohns Colitis 2013;7(3):248-55

60.

55.

Colombel JF, Sendid B, Jouault T, Poulain D. Secukinumab failure in Crohn’s disease: the yeast connection? Gut 2013; 62(5):800-1

Xiong HZ, Gu JY, He ZG, et al. Efficacy and safetyof secukinumab in the treatment of moderate to severe plaque psoriasis: ameta-analysis of randomized controlled trials. Int J ClinExp Med 2015;8(3): 3156-72

61.

McInnes IB, Mease PJ, Kirkham B, et al. FUTURE 2 Study Group. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2015; Epub ahead of print

62.

Blauvelt A, Lebwohl MG, Bissonnette R. IL-23/IL-17A Dysfunction PhenotypesInform Possible Clinical Effects from Anti-IL-17A Therapies. J Invest Dermatol 2015;135(8):1946-53

56.

Van den Berg WB, McInnes IB. Th17 cells and IL-17 a–focus on immunopathogenesis and immunotherapeutics. Semin Arthritis Rheum 2013;43(2):158-70

57.

Teng MW, Bowman EP, McElwee JJ, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies forimmune-mediated inflammatory diseases. Nat Med 2015; 21(7):719-29

.

Excellent review.

Expert Rev. Clin. Immunol.

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