Yun Tong, MD1,2; Andrew J. Peranteau, MD1; Zeena Nawas, MD1,3; Stephen K. Tyring, MD, PhD1,3

1Center for Clinical Studies, Houston, TX, USA
2Department of Dermatology, University of California San Diego, La Jolla, CA, USA
3Department of Dermatology, The University of Texas Health Science Center at Houston, Houston, TX, USA

Conflicts of Interest:
Dr. Tyring has been an investigator for clinical trials sponsored by Abbvie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Contravir, Cutanea, Dermira, Galderma, Genocea, Innovaderm, Janssen, Eli Lilly and Company, Leo Pharma, Merck, MSD, Medimmune, Novan, Novartis, Pfizer, Promius, Regeneron, Tolmar, Vitae, Watson-Actavis, and Xoma. Drs. Tong, Peranteau, and Nawas have been sub-investigators on clinical trials sponsored by the same companies listed above.

ABSTRACT
Psoriasis is a chronic immune-mediated inflammatory disease with epidermal hyperplasia that affects 2-3% of the population. Interleukin (IL)-17 signaling has a central role in its pathogenesis. Brodalumab is a monoclonal antibody that neutralizes IL-17 receptor type A. Brodalumab is highly effective in the reversal of psoriatic phenotype and gene expression patterns.

Key Words:
IL-17, interleukin-17, interleukin-17A, monoclonal antibody, chronic plaque psoriasis

Introduction

An immune-mediated disease, psoriasis affects approximately 120 million people or 2% of the population.1,2 The most common form of the disease, psoriasis vulgaris, accounts for 80% of all cases.3 Psoriasis is increasingly recognized as more than a skin disease and may be associated with a constellation of comorbidities including psoriatic arthritis,4 stroke, heart failure, obesity, hypertension, and diabetes. Severe psoriasis is considered an independent risk factor for cardiovascular mortality5 and psychiatric disorders including depression, anxiety, and suicidal tendency from physical and mental distress.6 Even patients with limited psoriatic involvement often report a substantial negative impact on their daily quality of life (QoL).

For people with moderate-to-severe plaque psoriasis (17% of all psoriasis patients2), topical medications usually provide unsatisfactory results.3 Advances in the understanding of cytokines in psoriasis have led to the development of more efficacious therapeutic options including biological agents targeting tumor necrosis factor (TNF)-α, interleukin (IL)-23, and IL-17. Current pathogenic models indicate dysfunctional IL-17 signaling may play a pivotal inflammatory role in the pathophysiology of psoriasis.3,7

Rationale for IL-17 Inhibitors

The main physiological function of IL-17 is protection from extracellular bacteria and fungi by inducing the production of chemokines and cytokines such as TNF-α to recruit inflammatory cells to local sites of infection.8 Additionally, IL-17 has a role in vascular dysfunction and hypertension.5 In psoriasis, the IL-17 pathway is altered.7 Activities of IL-17 and TNF-α are additive and synergistic drivers of inflammation upregulation that lead to a self-sustaining keratinocyte hyperproliferation of psoriasis.3,9 Given the importance of IL-17 in inducing and mediating proinflammatory responses, it is also linked to other immune mediated diseases including rheumatoid arthritis, spondyloarthritis, uveitis, Crohn’s disease, multiple sclerosis, andasthma.10

T-helper (Th)-17 cells and IL-17 messenger RNA (mRNA) are increased in psoriasis plaques11 and synovial fluid of psoriatic arthritis patients.12 Many cells are rich sources of IL-17, including gamma/delta (γδ) T-cells, which appear to have a central role in the development of psoriasis, Tc17 (a subset of CD8+, T-cells that are critical in cellular immune response), mast cells, macrophages, natural killer (NK) cells, and neutrophils.3,7,8,11,13,14

Current US FDA-approved IL-17 inhibitors include secukinumab and ixekizumab, and brodalumab is still under regulatory review at the time of this writing. Secukinumab and ixekizumab are directed against IL-17, whereas brodalumab is a human G2 monoclonal antibody directed against the IL-17 receptor. Under clinical investigation, brodalumab appears to benefit patients with psoriatic disease, thus further supporting the view that IL-17 and the cells that produce it play a pivotal role in disease onset and perpetuation.14

Several clinical psoriasis trials have confirmed that these three IL-17 inhibitors have significantly higher efficacy rates vs. placebo and TNF-α inhibitors, which are currently first-line therapy for psoriasis.1,3,7 More established monoclonal antibody biologics are directed against TNF-α, causing generalized immunosuppression.15 Additionally, some patients receiving anti-TNF therapy do not achieve adequate response or experience a secondary loss in efficacy due to formation of anti-TNF-α antibodies.16

The IL-17 family is composed of 6 different ligand homodimers, labeled A-F, and 5 receptors subtypes A-E.17 IL-17A is the most prevalent and prototypical isomer generally referred to as IL-17 when no distinction is made.16 Both secukinumab and ixekizumab are monoclonal antibodies that bind to and neutralize IL-17A. Additionally, IL-17A is the most potent, with 10-30 times greater effect than IL-17F.9 However, IL-17C, IL-17F, and IL-17A/F heterodimer are all capable of inducing the expression of psoriasis-related proinflammatory molecules in keratinocytes.18 IL-17C has been reported as the most abundant isoform in psoriatic lesions.7 All 3 cytokines require a heteromeric receptor for biological activity.10

IL-17 receptors are complexes composed of heteromeric subunits. Brodalumab targets IL-17 receptor A (IL-17RA) with high affinity and inhibits the activities of IL-17 ligands A, C, E (IL-25), F, and A/F heterodimer, all of which require subunit IL-17RA in their respective receptor complexes. IL-17A and IL-17F, which are homodimers, share a common IL-17RA/IL-17RC receptor complex.17 IL-17C mediates further signaling by docking to an IL-17RA/IL-17RE complex. IL-17E ligand interacts with an IL-17RA/IL-17RB complex. Perhaps broader coverage through blockade of a shared receptor may allow for better effect on controlling psoriasis but may lead to increased risk.10

Clinical Trials

Several clinical trials have been undertaken to evaluate the efficacy and safety of brodalumab. Fairly standard inclusionary and exclusionary items were used in the study to screen for adults with moderate-to-severe plaque psoriasis.

Phase 1 Trials

Significant improvements in the major clinical parameters were seen involving 25 patients who were followed for 85 days in a phase 119,20 clinical study assessing the safety and clinical response of brodalumab; 20 of the 25 subjects received a single dose of brodalumab and the remaining 5 received placebo. None of the 5 placebo patients achieved Psoriasis Area and Severity Index (PASI) 50. Significant PASI improvement occurred in the brodalumab higher dosing arms (350 mg SC and 700 mg IV). Six (of the 8) administered 350 mg achieved PASI 50, and 5 also achieved PASI 75. All 8 subjects in the 700 mg arm achieved PASI 50 by day 29, and all but 1 also achieved PASI 75 or greater (3 achieved PASI 90) at week 6 (Table 1). Decreases in IL-17 A, C, and F mRNA levels and improvements in histopathological parameters of epidermal thickness, Ki-67, keratin-16 gene expression, and infiltrating leukocyte subsets were observed.

Safety and adverse event profiles of brodalumab and placebo were similar. Two subjects (1 each from 350 mg and 700 mg arms) receiving brodalumab tested positive for non-neutralizing antibodies against brodalumab at week 12.

A Japanese phase 1 study21 evaluating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics in 8 healthy and 13 psoriatic patients, who received a single dose of brodalumab, added evidence that IL-17RA is a viable option against psoriasis. Three of the 6 patients who received a single dose of 140 mg SC achieved PASI 75 or greater. All 7 patients in the 350 mg SC arm achieved PASI 50, with 6 achieving PASI ≥75 (Table 1). In both healthy and psoriatic patients, brodalumab was well tolerated at the studied doses with respect to adverse events (AE), and safety profiles were similar to western trials. No anti-brodalumab antibodies were detected. Mean serum brodalumab concentration and PK parameters were comparable between psoriasis patients and healthy volunteers during the study. PK and occupancy data showed brodalumab is at maximum with a serum brodalumab concentration of approximately 1 ug/ml at 2 weeks after dosing 140 mg, implying 2-week interval SC dosing could maintain maximal IL-17RA occupancy.

Study Phase Dosing Arm Dosing PASI 50 PASI 75 PASI 90 PASI 100 SPGA 0 or 1 SPGA 0
Phase 1 Studies Papp, et al.19,20

  • Assessment at Day 43 (6 weeks)
  • 25 patients
Placebo (n=5) Single dose 0%
140 mg SC (n=4) 50% (2)
350 mg SC (n=8) 75% (6) 62.5% (5) 25% (2)
700 mg IV (n=8) 100% (8) 88% (7) 38% (2)
Osamu, et al.21

  • Assessment up to Day 64 (9 weeks)
  • 13 patients
140 mg SC (n=6) Single dose 50% (3) 50% (3)
350 mg SC (n=7) 100% (7) 85.7% (6) 28.6% (2)
Phase 2 Studies Papp, et al.22

  • Assessment at Week 12
  • 198 patients
Placebo (n=38) Weeks 0, 1, 2, 4, 6, 8, 10 15.8% (6) 0% 0% 0%
70 mg (n=39) Weeks 0, 1, 2, 4, 6, 8, 10 51.3% (20) 33.3% (13) 17.9% (7) 10.3% (4)
140 mg (n=39) Weeks 0, 1, 2, 4, 6, 8, 10 89.7% (35) 76.9% (30) 71.8% (28) 38.5% (18)
210 mg (n=40) Weeks 0, 1, 2, 4, 6, 8, 10 90% (36) 82.5% (30) 62.5% (25) 80% (32)
280 mg (n=42) Weeks 0, 4, 8 81% (34) 66.7% (28) 57.1% (24) 28.6% (12)
Nakagawa, et al.25

  • Assessment up to Day 64 (9 weeks)
  • 151 patients
Placebo (n=38) Weeks 0, 1, 2, 4, 6, 8, 10 7.9% (3) 2.6% (1) 5.3% (2)
70 mg (n=39) Weeks 0, 1, 2, 4, 6, 8, 10 25.6% (10) 15.4% (6) 2.6% (1) 25.6% (10)
140 mg (n=37) Weeks 0, 1, 2, 4, 6, 8, 10 78.4% (29) 64.9% (24) 35.1% (13) 78.4% (29)
210 mg (n=37) Weeks 0, 1, 2, 4, 6, 8, 10 94.6% (35) 91.9% (34) 59.5% (22) 94.6% (35)
Phase 2 Studies AMAGINE-126,27,29

  • Assessment at Week 12
  • 661 patients
Placebo (n=220) Weeks 0, 1, 2, 4, 6, 8, 10 2.7% (6) 0.9% (2) 0.5% (1) 1.4% (3) 0.5% (1)
140 mg (n=219) Weeks 0, 1, 2, 4, 6, 8, 10 60.3% (132) 42.5% (93) 23.3% (51) 53.9% (118) 23.3% (51)
210 mg (n=222) Weeks 0, 1, 2, 4, 6, 8, 10 83.3% (185) 70.3% (156) 41.9% (93) 75.7% (168) 41.9% (93)
AMAGINE-228

  • Assessment at Week 12
  • 1831 patients
Placebo (n=309) Weeks 0, 1, 2, 4, 6, 8, 10 8.1% (25) 3% 0.6% (2) 3.9% (12) 0.6% (2)
140 mg (n=610) Weeks 0, 1, 2, 4, 6, 8, 10 66.6% (406) 49% 25.7% (157) 58% (354) 25.7% (157)
210 mg (n=612) Weeks 0, 1, 2, 4, 6, 8, 10 86.3% (612) 70% 44.4% (272) 78.6% (481) 44.8% (274)
Ustekinumab (n=300) Weeks 0, 4, 8 70% (210) 3% 21.7% (65) 61% (183) 21.7% (65)
AMAGINE-328

  • Assessment at Week 12
  • 1881 patients
Placebo (n=315) Weeks 0, 1, 2, 4, 6, 8, 10 6% (19) 2% 0.3% (1) 4.1% (13) 0.3% (1)
140 mg (n=629) Weeks 0, 1, 2, 4, 6, 8, 10 69.2% (435) 52% 27% (170) 59.9% (377) 27% (170)
210 mg (n=624) Weeks 0, 1, 2, 4, 6, 8, 10 85.1% (531) 69% 36.7% (229) 79.6% (497) 36.7% (229)
Ustekinumab (n=313) Weeks 0, 4, 8 69.3% (217) 48% 18.5% (58) 57.2% (179) 18.5% (58)
Table 1: Summary of clinical investigations on brodalumab

Phase 2 Trials

A phase 2, randomized, double-blind, placebo-controlled, dose-ranging study assessing short-term efficacy and safety of brodalumab was significant for PASI reductions at week 12 (primary endpoint).22 Secondary endpoints of PASI 75, 90, and static physician global assessment (sPGA) at week 12 were also met. Statistically significant PASI improvement was seen as early as week 2. Dose response effect was seen in the study involving 198 patients who received either placebo, brodalumab at 70 mg, 140 mg, or 210 mg at weeks 0, 1, 2, and then every 2 weeks or monthly dosing of brodalumab 280 mg at weeks 0, 4, and 8; 188 patients completed through week 16. Primary endpoint was PASI improvement at week 12; 16% of patients in the placebo arm achieved significant (p<0.001) PASI improvement, whereas mean PASI improvements at week 12 for each brodalumab arm were as follows: bimonthly 70 mg (45%), 140 mg (85.9%), 210 mg (86.3%), and monthly 280 mg (76%). Seventy-two percent and 75% of the 140 mg and 210 mg recipients achieved PASI 75 or greater with 38% of the 140 mg arm and 62% of the 210 mg arm achieving PASI 100 (Table 1). At week 12, significant decreases of body surface area (BSA), sPGA, and Dermatology Quality of Life Index (DLQI) were also seen.

More AEs were reported in patients receiving brodalumab than placebo. Nasopharyngitis, upper respiratory infection, and arthralgia were the most common. Four serious adverse events (SAE) were reported during the trial including 2 cases of grade 3 asymptomatic neutropenia that normalized after withdrawal of brodalumab. Non-neutralizing antibodies were identified in all brodalumab arms (5-9.8%), which is similar to phase 1 observations.

A subanalysis of the data demonstrated patients with moderateto- severe plaque psoriasis received similar levels of benefit whether they had a history of prior biologic use or psoriatic arthritis.23

Of the original 198 patients, 181 (33 placebo and 148 brodalumab) enrolled in a 5-year (264 weeks) open-label extension (OLE) study and were initially administered brodalumab 210 mg every 2 weeks.24 At week 52, a protocol modification switched patients 100 kg were maintained at 210 mg every 2 weeks. During the OLE, 72% of patients maintained a sPGA of 0 or 1 (clear or almost clear) in comparison to 90% at week 12. Interim analysis at week 120 showed sustained clinical response and acceptable safety profiles through week 120. Non-neutralizing anti-brodalumab antibodies were discovered in 19 patients (11%) during the OLE, but only 2 of the 19 continued to show antibodies at final specimen collection. At interim analysis, 95% of patients reported an AE at some point during weeks 0-120 with nasopharyngitis being the most commonly reported AE at 26.5%. Fifteen SAEs were reported and 5 patients reported depression during the OLE.

A Japanese phase 2 study25 was conducted with dosing regimens of 70 mg, 140 mg, 210 mg, or placebo SC at weeks 0, 1, 2, 4, 6, 8, and 10. Efficacy was similar to the western phase 2 study22 (Table 1). At week 12, the primary endpoint of mean percentage improvements in the PASI scores were 37.7%, 82.2%, 96.8%, and 9.4% in the 70 mg, 140 mg, 210 mg, and placebo groups, respectively (p<0.001). Similarly, more patients in the brodalumab arms achieved sPGA of 0 or 1 than in the placebo group at week 12. PASI 90 response rates in the 140 mg and 210 mg brodalumab groups were 64.9% and 91.9%, respectively.

Phase 3 Trials

Three phase 3 trials were conducted: AMAGINE-1 evaluated the efficacy, safety, and withdrawal and retreatment effect of brodalumab compared with placebo. AMAGINE-2 and AMAGINE-3, 12-week induction trials followed by rerandomization at week 12, evaluated the efficacy and safety of induction and maintenance of brodalumab compared with both ustekinumab and placebo.

AMAGINE-1

AMAGINE-1 was a phase 3, randomized, double-blind, placebo-controlled trial composed of a 12-week induction phase followed by a withdrawal/retreatment phase from weeks 12 through 52.26,27 Using a 1:1:1 randomization, 661 patients were randomized to biweekly injections of 210 mg (n=222), 140 mg (n=219), and placebo (n=220) for 12 weeks. Re-randomization occurred at week 12 for patients with sPGA of 0/1 in the 210 mg and 140 mg arms to either continue their current dose or switch to placebo. Those re-randomized to placebo and subsequently lost disease control were restarted on their original dose. Subjects originally in the placebo arm and any patient with sPGA greater than 2 received brodalumab 210 mg every 2 weeks at week 12.

Co-primary endpoints of PASI 75 and sPGA 0/1 at week 12 were statistically significant for either dosage groups compared with placebo. At week 12, PASI 75 for placebo, brodalumab 140 mg, and brodalumab 210 mg were 2.7%, 60.3%, and 83.3%, respectively (Table 1), indicating a majority of brodalumab patients achieved 75% improvement of their psoriasis while only 2.7% of patients on placebo did so. Similarly, only 1.4% of patients on placebo compared to 53.9% on brodalumab 140 mg and 75.7% on brodalumab 210 mg had a treatment response of sPGA 0/1. Following withdrawal, most subjects were able to recover treatment sPGA response with retreatment.

No meaningful or dose effect on AE rates were observed through 52 weeks. Most reported AEs included nasopharyngitis, upper respiratory tract infection, and headache. Three SAEs were reported: cellulitis (n=2) and diverticulitis (n=1). Hospital Anxiety and Depression Scale was analyzed at week 12. Statistically significant decreases (p<0.001) in mean depression were observed for 210 mg (5.5% to 3.4%) and 140 mg (5.2% to 3.5%) doses at week 12. The placebo arm was unchanged (5.3% at baseline and 5.5% at week 12).

AMAGINE-2 and AMAGINE-3

Most recently, AMAGINE-2 and AMAGINE-3, two large, parallelgroup, double-blind, placebo-controlled, active comparatorcontrolled, multinational phase 3 trials were conducted involving a 12-week induction phase and 40-week maintenance phase.28 During the 12-week induction phase, patients were randomized utilizing a 2:2:1:1 ratio to receive brodalumab 210 mg or 140 mg every 2 weeks, ustekinumab (45 mg for subjects <100 kg in weight and 90 mg for subjects >100 kg) every 4 weeks, or placebo.

All primary endpoints for all brodalumab doses against placebo and ustekinumab were met. Multiple endpoints were evaluated including primary endpoints of PASI 75 and sPGA 0/1 at week 12 of brodalumab compared to placebo. Another primary endpoint compared brodalumab to ustekinumab for PASI 100. Brodalumab 210 mg was superior (p<0.001) to ustekinumab at week 12 (AMAGINE-2: 44% vs 22%; AMAGINE-3 37% vs 19%). Brodalumab 210 mg was superior for maintenance of clinical responses.

Regarding secondary endpoints, both doses of brodalumab were superior to placebo at all secondary endpoints including PASI 100 and sPGA 0. While brodalumab 210 mg was superior to ustekinumab in both studies for PASI 100; brodalumab 140 mg was superior to ustekinumab in the AMAGINE-3 study (p<0.007) but not in the AMAGINE-2 trial (p=0.08); however, the nominal p-value was significant (p<0.001). The median time to PASI 75 of brodalumab 210 mg was 4 weeks vs. approximately 2 months for ustekinumab.

At week 12, patients on brodalumab were re-randomized to receive brodalumab 210 mg every 2 weeks, 140 mg every 2 weeks, 140 mg every 4 weeks, or 140 mg every 8 weeks. Placebo patients were switched to brodalumab 210 mg every 2 weeks. Patients on ustekinumab continued to receive ustekinumab; 55 (18%) and 69 (22%) subjects assigned to ustekinumab received rescue therapy with brodalumab at week 16. Patients on 210 mg or 140 mg of brodalumab every 2 weeks maintained or achieved a sPGA 0/1 at a higher rate than 140 mg every 4 weeks or 8 weeks (p<0.001). The majority of placebo patients who switched to brodalumab achieved PASI 100 at week 52; 40% of patients on ustekinumab who received brodalumab rescue therapy were able to achieve PASI 100.

Anti-brodalumab antibodies that were non-neutralizing and did not cause a loss in efficacy or AE, were detected in 1.8% and 2.3% in patients in AMAGINE-2 and AMAGINE-3, respectively. Four patients had antibodies detected at baseline. Six patients were positive for non-neutralizing anti-brodalumab antibodies after initiating ustekinumab.

Higher percentages of patients on brodalumab or ustekinumab reported an AE during the first 12 weeks than placebo patients. Most common AEs were nasopharyngitis, upper respiratory tract infection, headache, and arthralgia. Non-serious and reversible neutropenia events were more frequent among brodalumab and ustekinumab. No clinically apparent differences were noticed among all study groups throughout the study. One patient (placebo followed by 210 mg of brodalumab) in AMAGINE-2 committed suicide 27 days after the last dose. An additional patient from AMAGINE-2 in the OLE receiving 210 mg of brodalumab every 2 weeks committed suicide 19 days after the last dose.

Discussion

IL-17 cytokine pathway plays an important role in psoriasis. Clinical trials validate the role of brodalumab for treating moderate-to-severe plaque psoriasis. By targeting IL-17RA, brodalumab has proven to be exceptionally efficacious with improvement of PASI 75 in over 80%, and approximately 70% of those patients achieved PASI 90 on brodalumab 210 mg by week 12 in 3 large phase 3 clinical trials. Patients with psoriasis experience impairment of their QoL. A PASI 90 response is necessary to achieve a DLQI of 0 or 1. Indeed, the new class of IL-17 antagonists has eminently shifted the expectation of treatment response, such that PASI 90 may be regarded as the new standard.30 Based on efficacy alone, brodalumab and other IL-17 class biologics could become first-line therapy for moderate-tosevere plaque psoriasis. Safety considerations of depression and suicidality, however, could hamper the use of brodalumab in favor of the other IL-17 biologics secukinumab and ixekizumab.

Il-17 blockade compared to TNF-α or Il-12/23 may be associated with lower potential for broad immune system adverse effects.9 Il-17RA deficient patients, however, have higher associated recurrent mucocutaneous infections caused by Candida albicans. Two studies reported increased rates of candida infections with brodalumab vs. ustekinumab (5.2 and 5.7 per 100 patientyears vs. 4.1 and 1.6 per 100 patient-years, AMAGINE-2 and AMAGINE-3, respectively). Meta-analysis of several phase 2 trials for IL-17 agents, brodalumab, ixekizumab, and secukinumab, demonstrated no significant difference between biotherapy groups and placebo for adverse events including infections, upper respiratory tract infections, and headaches, excluding nasopharyngitis.2 Overall, IL-17 agents appear tolerable and are promising therapies with possibly less side effects than current biologics.

While the majority of clinical data points to brodalumab’s improvement of depression and QoL, OLE studies of AMAGINE-1, AMAGINE-2, and AMAGINE-3 were terminated in May 2015. Amgen, one of the co-developers with AstraZeneca, withdrew due to fears of gray box labeling requirements that would preclude universal first-line adoption in an increasingly competitive market for psoriasis, which already includes the anti-IL-17 antibodies secukinumab and ixekizumab without restrictive labeling. Valeant Pharmaceuticals, in September 2015, entered into an agreement with AstraZeneca to develop and commercialize brodalumab.31 Four instances of suicidal ideation among 3180 pooled patients on brodalumab (0.13%) were reported against 1 report out of 613 patients (0.16%) on ustekinumab.32 Lebwohl28 reported 2 suicides were completed in the 210 mg treatment arm of AMAGINE-2, with 1 during the study and 1 in the OLE compared to none in patients on ustekinumab or placebo. During its own long-term treatment trials, however, 2 suicides (0.06%) in 3117 subjects on ustekinumab were reported.33 Comparatively, no suicides were reported during the treatment periods of secukinumab phase 3 trials.34 Ixekizumab phase 3 trials UNCOVER-2 and UNCOVER-3 reported no deaths with 2 (0.14%) out of 1469 subjects on ixekizumab attempting suicide.35 No subjects on placebo (n=361) or etanercept comparator (n=740) attempted suicide.

Theoretically, brodalumab does not cross the intact blood-brain barrier due to its inherent size. The anti-TNF pathway has been associated with central demyelination,11 of which IL-17 may be significantly involved. Indirect action by brodalumab on the brain may be possible as there is evidence of peripheral cytokine modulation. Alternatively, Danesh and Kimball36 suggest the suicides may be considered within the context of broader suicide trends and attributable to the economic recession. They argue that participants were predominantly middle-aged white males who represent the demographic most at risk for suicide, which as a group has climbed from 20.7 suicides in 2007 to 23.4 per 100,000 in 2013. Before the recession from 1999-2007, suicide mortality increased 0.12 per 100,000 per year whereas an additional 0.51 deaths per 100,000 per year were experienced between 2008-2010 (translating to an additional 1580 suicides annually).36,37 With the lack of a comparator or placebo during OLE, and more details out of public domain, it remains to be seen what effect IL-17RA inhibition has on suicidality. The key difference in brodalumab’s IL-17 inhibition is the receptor target as compared to the IL-17A ligand for secukinumab and ixekizumab. Perhaps this difference has unknown effects on suicidal behavior. Given the substantial improvement in QoL and depression for the majority of subjects in all brodalumab trials, more investigations are warranted.

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