¹Center For Clinical Studies, Houston, TX, USA
²Texas Tech School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
³Baylor College of Medicine, Houston, TX, USA
⁴Department of Dermatology, University of California San Diego, La Jolla, CA, USA
⁵Department of Dermatology, University of Texas Health Science Center, 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. Nawas, Tong and Peranteau have been sub-investigators on clinical trials sponsored by the same companies listed above. Hatch, Ramos, and Liu have no conflicts of interest to disclose.

ABSTRACT
Psoriasis is a chronic inflammatory skin disorder that affects 2% of the population. Evidence suggests that interleukin (IL)-23 plays a pivotal role in the pathogenesis of psoriasis. Guselkumab is a subcutaneously administered, humanized anti-IL23 monoclonal antibody indicated for the treatment of moderate-to-severe plaque psoriasis. Data from Phase I-III trials in this patient population reveal that guselkumab has proven to be superior to placebo or adalimumab based on achieving a Psoriasis Area and Severity Index (PASI) 90% reduction, or a static Physician Global Assessment (sPGA) score of 0 or 1 from baseline. This article reviews the current status of guselkumab as a therapy for moderate-to-severe plaque psoriasis.

Key Words:
biologics, cytokine, IL-23, interleukin-23 inhibitor, monoclonal antibody, psoriasis, Th17

Introduction

Psoriasis is the most common chronic autoimmune skin condition affecting about 2% of the population.¹ This disease has a significant impact on quality of life, mental health and work productivity, and it is linked to other comorbid conditions such as cardiovascular disease, metabolic syndrome, and arthritis.^2,3 Psoriasis is thought to arise from a combination of pathogenic factors including genetic susceptibility and environmental exacerbation, which results in activation of dendritic cells in the skin and differentiation of T cells.⁴ In turn, these T cells produce cytokines that induce keratinocyte hyperproliferation and result in characteristic raised, well-demarcated erythematous lesions of psoriasis.

Accumulating evidence suggests that the proinflammatory cytokine interleukin (IL)-23 and its resulting T helper 17 (Th17) pathway play a more important role in mediating psoriasis than IL-12.^5,6 IL-23 induces differentiation and maintenance of Th17 cells, which produce the effector cytokines IL-17, IL-22, and tumor necrosis factor-alpha (TNFα).^7,8 IL-23 is a heterodimer composed of two subunits, p40 and p19.⁸ While p40 is also present in IL-12, p19 is specific for IL-23.⁸ Levels of IL-23p19 and IL-12/23p40 messenger RNA (mRNA) are upregulated in psoriatic plaques and decrease with effective treatment.^7-11

This paper focuses on guselkumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits intracellular IL-23 and downstream signaling by targeting the p19 subunit.^12,13 Guselkumab decreases blood and skin lesion levels of effector IL-17A and decreases epidermal hyperplasia and inflammation by downregulating T cells and myeloid dendritic cells.¹² This evidence further establishes the IL-23/Th17 axis as the primary driver of psoriatic inflammation. Additionally, another goal for guselkumab is increased safety by maintaining the IL-12/Th1 axis, an important regulator of immune function, unlike the previous medications that targeted both IL-12 and IL-23. IL-12 is required for appropriate Th1 response and defense against intracellular pathogens due to its role in the production of interferon gamma (INFγ) by T- and natural killer (NK)-cells.¹⁴ Animal studies have demonstrated that anti-p40 antibodies enhance mycobacterial growth, but that p19-deficient mice are indistinguishable from wild type animals as long as IL-12 is functional.⁶ In contrast, patients deficient in the p40 subunit are more susceptible to low virulence nontuberculous Mycobacterium and Salmonella.⁶

Additional monoclonal antibodies targeting both IL-12/23 have been investigated for the treatment of psoriasis. Briakinumab, has been found to be associated with a significantly higher rate of major adverse cardiovascular events, infections, and nonmelanoma skin cancers as compared with placebo. Resultantly, this drug has been withdrawn from the market.¹⁵ Conversely, ustekinumab, has shown a safer profile with a similar rate of adverse events in comaparison to placebo.¹²

Clinical Trials

Phase I

This first-in-human, randomized, double-blind, placebocontrolled Phase I study showed that a single dose of guselkumab results in a significant clinical response. In this trial, 24 patients with moderate-to-severe plaque psoriasis received a single dose of guselkumab consisting of either 10 mg, 30 mg, 100 mg or 300 mg or a placebo. At week 12, Psoriasis Area and Severity Index (PASI) 75 was achieved in 50%, 60%, 60% and 100% of patients, respectively, as compared with 0% in the placebo group. In addition, the trial reported a decrease in both psoriasis gene expression and serum IL-17A levels in the guselkumab-treated group. The overall incidence of adverse reactions was similar in the treatment (65%) and placebo arms (50%).¹⁶

Phase II – Efficacy

The efficacy of guselkumab was evaluated in a Phase II randomized, double-blind, placebo controlled, active-comparator trial (X-PLORE).¹⁷ In this trial, the efficacy of guselkumab was compared with adalimumab, a TNFα inhibitor used to treat plaque psoriasis. Two hundred and ninety-three patients were randomized to receive either gusekumab, adalimumab, or placebo. A total of 39 patients in the placebo group were crossed over to receive guselkumab at week 16. After 16 weeks of treatment, the percentage of patients achieving a physician’s global assessment(PGA, primary endpoint) of 0 or 1 was significantly higher in each guselkumab group than placebo (34% for 5 mg, 61% for 15 mg, 79% for 50 mg, 86% for 100 mg, 83% for 200 mg, and 7% for placebo). Likewise, the percentage of patients with at least a 75% improvement from baseline in PASI score was significantly higher in each guselkumab group.

The percentage of patients with a PGA score of 0 or 1 reached a maximum at week 20 in most guselkumab groups, which was maintained through week 40. In addition, the group that crossed over from placebo to guselkumab at week 16 achieved similar PGA scores as the group that received 100 mg guselkumab. Finally, at both weeks 16 and 40, the percentage of patients with a PGA score of 0 or 1 was higher in most guselkumab groups (50 mg, 100 mg, and 200 mg) compared to the adalimumab group.

Phase II – Safety

Up to week 16, the proportion of patients with adverse events was similar in the different treatment groups (52% for placebo, 50% for guselkumab, 56% for adalimumab), and there was no demonstrable relationship between the guselkumab dose and rate of adverse events through to termination of the study. However, through week 52, a higher proportion of patients in the adalimumab group (61%) experienced an adverse event compared with guselkumab groups (49%). Of note, two serious infections, one case of grade 3 cervical intraepithelial neoplasia, and three major adverse cardiovascular events, including one death from myocardial infarction, occurred in the guselkumab group.

Phase III

Preliminary results for the VOYAGE 1 and VOYAGE 2 trials have been published. In the VOYAGE 1 trial, patients were randomly assigned to three arms: guselkumab 100 mg at weeks 0 and 4, then every 8 weeks; placebo at weeks 0, 4 and 12 then guselkumab at week 16 and 20, then every 8 weeks; or adalimumab 80 mg at week 0, 40 mg week 1, then 40 mg every 2 weeks. At week 16, the patients exhibited improved responses to guselkumab as compared with placebo (PASI 90 response of 73.3% vs. 2.9%) and adalimumab at week 16 (73.3% vs. 49.7%). Furthermore, guselkumab comparisons to adalimumab were also significantly superior at weeks 24 and 48 (80.2% vs. 53%, and 76.3% vs. 47.9%, respectively). Adverse events were similar among all groups.

In the VOYAGE 2 trial, patients were randomized to identical comparison arms, however at week 28 PASI 90 responders were re-randomized to guselkumab or placebo with further crossover for those who lost response. The results showed that at week 16, 70.0% of patients receiving guselkumab had a PASI 90 as compared with 2.4% in placebo. When compared to adalimumab, guselkumab demonstrated 75% and 100% of PASI 90 improvement at 16 and 24 weeks, respectively. In addition, guselkumab showed improved outcomes in those who were adalimumab nonresponders.

Currently a Phase III, multicenter, randomized, double-blind study evaluating the efficacy and safety of guselkumab is ongoing.¹⁶ This study examines patients with moderate-to-severe plaque-type psoriasis who experienced an inadequate response to ustekinumab. Results from the study are planned for presentation at upcoming scientific meetings according to a Janssen press release. Other Phase III trials of guselkumab are also currently underway (Table 1).^17-19

Conclusion

Guselkumab is a monoclonal IL-23 antibody that treats psoriasis. Targeting IL-23 is believed to block a specific mediator of psoriatic inflammation. Data from a Phase II study shows that guselkumab is safe and efficacious. Preliminary results have demonstrated superiority of guselkumab over placebo and adalimumab. Guselkumab was superior to both placebo and adalimumab (p<0.001 for all comparisons of guselkumab with placebo and adalimumab). Further data from Phase III trials is expected to be available in the summer 2018.

References

1. Koo J. Population-based epidemiologic study of psoriasis with emphasis on quality of life assessment. Dermatol Clin. 1996 Jul;14(3):485-96.
2. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014 Mar;70(3):512-6.
3. Villasenor-Park J, Wheeler D, Grandinetti L. Psoriasis: evolving treatment for a complex disease. Cleve Clin J Med. 2012 Jun;79(6):413-23.
4. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med. 2009 Jul 30;361(5):496-509.
5. Fitch E, Harper E, Skorcheva I, et al. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheumatol Rep. 2007 Dec;9(6):461-7.
6. Levin AA, Gottlieb AB. Specific targeting of interleukin-23p19 as effective treatment for psoriasis. J Am Acad Dermatol. 2014 Mar;70(3):555-61.
7. Toichi E, Torres G, McCormick TS, et al. An anti-IL-12p40 antibody downregulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol. 2006 Oct 01;177(7):4917-26.
8. Di Meglio P, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. F1000 Biol Rep. 2010 May 24;2.
9. D’Elios MM, Del Prete G, Amedei A. Targeting IL-23 in human diseases. Expert Opin Ther Targets. 2010 Jul;14(7):759-74.
10. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004 Jan 05;199(1):125-30.
11. Piskin G, Sylva-Steenland RM, Bos JD, et al. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol. 2006 Feb 01;176(3):1908-15.
12. Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial(PHOENIX 2). Lancet. 2008 May 17;371(9625):1675-84.
13. Kopp T, Riedl E, Bangert C, et al. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature. 2015 May 14;521(7551):222-6.
14. Gaspari AA, Tyring S. New and emerging biologic therapies for moderate-tosevere plaque psoriasis: mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors. Dermatol Ther. 2015 Jul-Aug;28(4):179-93.
15. Gordon KB, Langley RG, Gottlieb AB, et al. A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis. J Invest Dermatol. 2012 Feb;132(2):304-14.
16. Sofen H, Smith S, Matheson RT, et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-tosevere psoriasis. J Allergy Clin Immunol. 2014 Apr;133(4):1032-40.
17. Gordon KB, Duffin KC, Bissonnette R, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015 Jul 09;373(2):136-44.
18. Blauvelt A, Papp KA, Griffiths CE, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial. J Am Acad Dermatol. 2016 Dec 29. [Epub ahead of print] doi: 10.1016/j.jaad.2016.11.041.
19. Reich K, Armstrong AW, Foley P, et al. Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placeboand active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2016 Dec 29. [Epub ahead of print] doi: 10.1016/j.jaad.2016.11.042.

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 1^19,20 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.

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.

References

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19. Papp KA, Reid C, Foley P, et al. Anti-IL-17 receptor antibody AMG 827 leads to rapid clinical response in subjects with moderate to severe psoriasis: results from a phase I, randomized, placebo-controlled trial. J Invest Dermatol. 2012 Oct;132(10):2466-9.
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27. Papp K, Reich K, Leonardi C, et al. Efficacy and safety of brodalumab in patients with moderate to severe plaque psoriasis: Results of AMAGINE-1, a phase 3, randomized, double-blind, placebo-controlled study through week 12. J Am Acad Dermatol. 2015 May;72(5 Suppl 1):AB233.
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    follow-up. Br J Dermatol. 2013 Apr;168(4):844-54.
34. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis– results of two phase 3 trials. N Engl J Med. 2014 Jul 24;371(4):326-38.
35. Griffiths CE, 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 Aug 8;386(9993):541-51.
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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. Peranteau, Tong, and Nawas have been sub-investigators on clinical trials sponsored by the same companies listed above. Ashley Turkeltaub has no conflicts of interest to declare.

ABSTRACT
Psoriasis is a multifactorial chronic skin disease that can have significant detrimental effects on patients’ physical, mental, and psychosocial wellbeing. Patients often suffer from a decreased quality of life along with numerous comorbidities. Recent advances in our understanding of the innate and adaptive immune systems have led to the identification of interleukin (IL)-17 as a key pro-inflammatory mediator in psoriasis. This knowledge has in turn led to the development of newer biologic agents that have been shown to be more effective than traditional therapies. In this article, we review phase 1-3 clinical trials of the anti-IL-17 monoclonal antibody, ixekizumab, for treatment of moderate-to-severe plaque psoriasis.

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

Introduction

Psoriasis is a chronic immune-mediated inflammatory skin
disease characterized by inflamed, thickened, scaly, and pruritic
plaques.¹ Although prevalence estimates vary by study, about
2-3% of the world’s population – approximately 125 million
people – are affected by psoriasis.^2-4 While topical therapies alone
are generally sufficient to control mild psoriasis, patients with
moderate-to-severe disease typically require systemic therapy.^5,6

Systemic treatments target specific immunological pathways
implicated in the pathogenesis of psoriasis.^5-7 This includes
biologics such as etanercept, adalimumab, and infliximab
– inhibitors of tumor necrosis factor alpha (TNFα).⁵ Use of
these biologics is often preferred due to non-compliance and
frustration caused by the lack of efficacy with traditional topical
therapies and phototherapy.⁸ Moreover, topical treatments and
phototherapy do not address the underlying joint disease seen
in psoriatic arthritis, which can affect up to 30% of patients with
psoriasis.⁹

Despite the advantages of TNFα treatment, some patients
experience insufficient response, loss of efficacy, or side
effects that preclude them from using these drugs long-term.
Additionally, newer trials with biologics targeting interleukin
(IL)-12/23 and IL-17 have shown increased efficacy in a greater
proportion of patients,⁵ prompting further investigations of these
therapeutic options.¹⁰

Rationale for IL-17 Inhibition in Psoriasis

Dysregulation of both the innate and adaptive immune systems
has long been implicated in psoriasis. Early studies indicated
that TNFα-producing T-helper (Th)1 cells drives much of
the inflammatory cycle, as evidenced by the favorable clinical
response to TNFα antagonists.¹ In recent years, however, novel
pathways have been discovered that implicate the p40 subunit of
IL-12 and IL-23 in the induction of autoimmunity. IL-23 has also
been found to be a key driver of Th17 cells, a T-cell subset distinct
from both Th1 and Th2 cells. This subgroup of CD4+ T cells
provides protection against extracellular bacterial and fungal
pathogens, and are now understood to play a central role in the
pathogenesis of psoriasis.^5,10

In the psoriatic pathway, activated dendritic cells act as antigen
presenting cells that produce an array of inflammatory cytokines,
including TNFα and IL-23. IL-23 drives activation of Th17
cells, which in turn produce IL-17, IL-6, TNF, and other proinflammatory
cytokines.¹¹ These cytokines induce changes in
keratinocytes and the skin vasculature through production of
IL-20 (a modulator of keratinocyte function) and nitric oxide (a
vasodilator).¹² Keratinocytes then respond to these inflammatory
signals by producing chemokines, cytokines, and antimicrobial
peptides (AMP), which enhance recruitment of neutrophils and
other inflammatory cells.^12,13

One of the cytokines produced by activated Th17 cells, IL-17A, is
particularly central to the pathophysiology of psoriasis. IL-17A
has several crucial functions including activation, recruitment,
and inhibition of apoptosis in neutrophils, enhancement
of angiogenesis, the propagation of other inflammatory
cytokines (TNFα, IL-1, IL-6), and the direct activation of
keratinocytes leading to increased production of chemokines.
These chemokines in turn cause macrophages, fibroblasts, and
endothelial cells to be recruited, amplifying the inflammatory
response in psoriatic lesions.^14-18

Therapeutic interventions that target IL-17 and, thus, this critical
pathway have become a promising new area of development
in the armamentarium of antipsoriatic agents. Currently, three
monoclonal antibodies targeting IL-17 exist for psoriasis:
brodalumab (an anti-IL-17-receptor) as well as the FDA-approved
drugs secukinumab and ixekizumab, which both selectively bind
and neutralize IL-17A. In this review we will focus on clinical trial
results from phase 1-3 studies of ixekizumab.

Phase 1 and 2 Studies in Plaque Psoriasis

Forty patients diagnosed with psoriasis were studied in a
20-week-long, randomized, double-blind, placebo-controlled,
phase 1 trial. Patients were randomized to receive 5, 15, 50, or
150 mg of subcutaneous (SC) ixekizumab or placebo at weeks 0,
2, and 4. Punch biopsies were taken from the same lesional site at
weeks 0, 2, and 6. The study was designed to determine the effect
of IL-17 neutralization on the clinical features of psoriasis and
to identify roles of IL-17 in inflammatory pathways underlying
psoriasis.¹⁰

Significant dose-dependent reductions in keratinocyte
proliferation, hyperplasia, epidermal thickness, T-cell and
dendritic cell infiltration into the dermis and epidermis, and
keratinocyte expression of innate defense peptides were seen after
2 weeks compared with week 0. A biopsy done at week 6 showed
near normalization of skin in patients treated with the two
highest doses of ixekizumab (50 and 150 mg). Clinical efficacy
was measured with Psoriasis Area and Severity Index (PASI)
75 and PASI 90 (a ≥75% or ≥90% reduction in baseline PASI,
respectively) after 2, 6, and 20 weeks. The results were significant
at weeks 6 and 20 for subjects who received 15, 50, and 150 mg of
ixekizumab compared with placebo and relative to subjects who
received 5 mg of ixekizumab.¹⁰

In a randomized, double-blind, placebo-controlled, phase 2
trial, ixekizumab was evaluated in 142 patients with chronic,
moderate-to-severe plaque psoriasis. Patients were randomized
to receive placebo or 10, 25, 75, or 150 mg of SC ixekizumab at
weeks 0, 2, 4, 8, 12, and 16. At week 12, the proportion of patients
who achieved PASI 75 was significantly greater in the groups that
received ixekizumab (except for the low dose, 10 mg group) than
in the placebo group (77% in 25 mg group, 83% in 75 mg group,
and 82% in 150 mg group, as opposed to 8% of patients who
received placebo).¹⁹ For patients suffering from scalp psoriasis,
nail psoriasis, and psoriatic arthritis, significant improvements
were observed with the higher doses. Scalp psoriasis in particular
showed rapid clinical improvement, which was maintained
through 48 weeks of open label treatment.²⁰ Significant reductions
in the mean dermatology life quality index (DLQI) scores were
detected at 8 weeks and sustained through 16 weeks at the three
highest doses relative to placebo.¹⁹ In a post hoc analysis derived
from the same study, the early clinical improvements in disease
symptoms at weeks 4 and 6 were predictive of improvement in
PASI 75 at week 12 in more than 90% of the cases.²¹ An open-label
treatment study showed that clinical responses to ixekizumab
were maintained after 52 weeks.²²

Phase 3 Results

Ixekizumab was studied in the largest phase 3 program to date
in 3,866 patients with moderate-to-severe plaque psoriasis and
evaluated against placebo and etanercept. Study participants had
to meet inclusion criteria of ≥18 years of age, confirmed diagnosis
of psoriasis for more than 6 months before randomization, ≥10%
body-surface area involvement at screening and baseline visits,
at least a moderate clinical severity score based on the clinicianrated
static physician global assessment (sPGA), and have a score
of ≥12 on the PASI.²³ Baseline characteristics were similar across
all patients in the US phase 3 studies (Table 1).^24,25

In the three UNCOVER studies, patients were randomized to
either placebo or SC ixekizumab 80 mg every 2 or 4 weeks for a
12-week induction period, following a 160 mg loading dose. In the
two active comparator studies (UNCOVER-2 and UNCOVER-3),
additional cohorts were randomized to receive etanercept 50 mg
twice weekly for 12 weeks. In UNCOVER-1, treatment responders
either continued to receive placebo or ixekizumab 80 mg every
4 or 12 weeks for up to 60 weeks. In the UNCOVER-3 trial, patients
who completed the 12-week induction period were entered into a
long-term extension period at the discretion of the investigator
and patient. All of these patients received ixekizumab every 4
weeks. The patients who had received placebo during the 12-week
induction period received a 160 mg loading dose of ixekizumab
at week 12, followed by 80 mg every 4 weeks. The patients who
had received etanercept during the induction period underwent
a 4-week washout period before receiving 80 mg of ixekizumab
every 4 weeks starting at week 16.24 During UNCOVER-1 and
UNCOVER-2 trials, patients who received ixekizumab were
classified as having had a response or not having had a response at
week 12. Responders were those who had a 0 (clear) or 1 (almost
clear) on the sPGA and non-responders were defined as patients
with a sPGA score of >1. Responders then entered a randomized
withdrawal period (weeks 12-60) in which they were restratified
in a 1:1:1 ratio to receive SC placebo injections every 4 weeks,
80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every
12 weeks.²⁴

Both dosing regimens of ixekizumab resulted in significantly
greater levels of skin clearance vs. placebo and etanercept. At week
12 of the UNCOVER-1 trial, PASI 75 was achieved by 89.1 % and
82.6%% of patients and PASI 90 by 70.9% and 64.8% of patients
treated with ixekizumab either every 2 or 4 weeks, respectively.
PASI 90 was achieved in 71% and 68% of patients given ixekizumab
every 2 weeks in UNCOVER-2 and UNCOVER-3, respectively, and
60% and 65% in the ixekizumab 4 week dosing regimens vs. 0.6%
and 3% given placebo and 19% and 26% given etanercept. PASI
100 was achieved by 33-39% of patients treated with ixekizumab
across all three UNCOVER studies vs. 6% of patients treated
with etanercept (Figure 1). The patients given ixekizumab every
2 weeks achieved higher PASI 90 and PASI 100 rates in both trials
as compared to those dosing with ixekizumab every 4 weeks. In
both UNCOVER-2 and UNCOVER-3, patients achieved clearance
at a much quicker rate than with etanercept. For both studies and
dosing groups, a greater proportion of patients reached PASI 75
as early as week 1 compared with etanercept. By week 4 of both
studies, about 50% of patients given ixekizumab achieved PASI 75
vs. 8-12% of patients on etanercept.

Figure 1.
Proportion of patients achieving PASI-75, PASI-90,
PASI-100 from baseline through to week 12 in (A) UNCOVER-1,
(B) UNCOVER-2, and (C) UNCOVER-3

High response rates seen in the induction period of UNCOVER-3
generally persisted during the long-term extension period. By
week 60, over 70% of patients irrespective of ixekizumab every
2 or 4 weeks had achieved at least a PASI 90 and >50% had achieved
a PASI 100 response. In the UNCOVER-1 and UNCOVER-2 trials,
73.8% of patients that were randomly reassigned to ixekizumab
every 4 weeks maintained an sPGA score of 0 or 1 at week 60,
compared to 39.0% in the ixekizumab every 12 weeks group and
only 7.0% in the placebo group.²⁴

Additionally, according to subgroup analysis, PASI 75 response
rates in those given ixekizumab were comparable in biologic
naïve patients vs. those with previous biologic exposure. Patients
were also monitored with secondary endpoints of itch numeric
rating scale (NRS) as well as the DLQI. In both UNCOVER-2
and UNCOVER-3, patients receiving ixekizumab had greater
improvements in their DLQI scores (with results seen as early as
2 weeks) compared with placebo and etanercept. In both studies,
greater improvements in NRS scores were reported in ixekizumab
groups compared to placebo and etanercept.^23,26

Similarly impressive PASI results were also observed in a phase 3,
single-arm, open-label study in Japanese patients diagnosed
with plaque psoriasis (PP), erythrodermic psoriasis (EP), and
generalized pustular psoriasis (GPP). In this study, patients
received two 80 mg SC ixekizumab injections (160 mg dose)
followed by an 80 mg injection every 2 weeks through week 12
of the study (see Table 2 for pooled results of all phase 3 trials
in patients with PP). Thereafter, patients received an 80 mg
maintenance dose every 4 weeks for up to 52 weeks. In total 78
patients with PP, 8 with EP, and 5 with GPP were enrolled. At
week 12, 98.7% (77/78) of PP patients achieved PASI 75,
83.3% (65/78) achieved PASI 90, and 32.1% (25/78) achieved
PASI 100 with 46.2% (36/78) of patients eventually reaching
PASI 100 by week 24. Improvements similar to those in the
UNCOVER trials were also seen for the secondary endpoints of
Nail Psoriasis Severity Index (NAPSI), DLQI, and visual analogue
scale (VAS) scales. Of those with EP, 100% achieved PASI 75,
62.5% (5/8) achieved PASI 90, and 25% (2/8) achieved PASI 100
at week 12. At week 24, all patients continued to achieve PASI 75,
with 87.5% (7/8) achieving PASI 90, and 12.5% (1/8) achieving
PASI 100. In GPP patients, 80% (4/5) achieved PASI 75, 60% (3/5)
achieved PASI 90, and 20% (1/5) achieved PASI 100. Week 24
result were 80% (4/5), 40% (2/5), and 40% (2/5) achieving PASI
75, 90, and 100, respectively.²⁷

Safety and Tolerability Profile

In the phase 2 study, adverse events (AEs) were similar for the
combined ixekizumab and placebo groups. The most common
adverse events were nasopharyngitis, upper respiratory infection,
injection site reaction and headache.¹⁹ A total of 4 patients
discontinued the study due to the hypertriglyceridemia (1 placebo
patient), peripheral edema (1 patient in the 10 mg ixekizumab
group), hypersensitivity (1 patient in the 10 mg ixekizumab
group), and urticaria (1 patient receiving 25 mg of ixekizumab).
There were 2 cases of grade 2 neutropenia (i.e., 1000 to <1500
cells per cubic millimeter) in the 75 mg and 150 mg dosing groups
with no reported symptoms. In 1 patient in the ixekizumab
150 mg group with a history of treated basal cell carcinoma, 2 new
basal cell carcinomas were detected during the study. No other
cancers were reported.¹⁹ Two patients who received ixekizumab
had elevation of creatine kinase and aspartate aminotransferase
levels. No serious adverse events or death were reported in phase
2 trials.¹⁰

In all phase 3 studies (UNCOVER-1, UNCOVER-2 and
UNCOVER-3), the percentage of patients with AEs was higher
in the ixekizumab groups compared to those in placebo groups.
The most common AEs were the same as those in the phase 2
studies (Table 3). As well, infections did occur more frequently
in patients on ixekizumab compared with etanercept. During the
induction period, 16 cases of likely Candida spp. infections were
reported in patients receiving ixekizumab every 2 weeks (1.6%),
7 of those receiving ixekizumab every 4 weeks (0.6%), and 4 on
placebo (0.5%). The exposure-adjusted incidence rates of at least
1 serious AE and of discontinuation of study due to AEs were
similar in patients receiving either ixekizumab or placebo.²⁴ No
deaths were reported in any of the studies during the induction
period but 3 people who had received ixekizumab at some point
during the trial did die between weeks 12 and 60. Two of the
deaths were related to vascular causes (1 myocardial infarction
and 1 ischemic stroke) while the third died of unknown causes.
Among patients who received ixekizumab at some point during
the 60-week combined treatment period, 7 developed ulcerative
colitis and 4 developed Crohn’s disease compared with no cases of
Crohn’s or ulcerative colitis in those who received only placebo. At
12 weeks, 3.2% of placebo patients were found to be neutropenic
while 8.5% and 9.3% were found to be neutropenic in the 4-week
and 2-week ixekizumab dosing groups, respectively.²⁴ No other
clinically significant changes in lab values, vital signs, or ECGs
were noted in the ixekizumab groups compared with placebo.
Five cases of treatment emergent depression were noted in the
ixekizumab groups, and 2 suicide attempts were reported in
patients in the ixekizumab group. One patient had a previously
undisclosed suicide attempt and both had psychosocial triggers
preceding the attempt, which was not felt to be related to the
study drug.²⁸

Discussion

The results from phase 1-3 trials with ixekizumab unquestionably
demonstrate incredible promise in the treatment of moderateto-
severe plaque psoriasis. With several IL-17 blocking drugs
currently on the market or in late stage clinical trials (i.e.,
ixekizumab, brodalumab, and secukinumab), data from these
investigations adds to the mounting body of evidence implicating
IL-17A as a cytokine integral to the pathogenesis of psoriasis.²⁹
Several authors have noted that in previous clinical trials of
biologics, PASI 75 was often used as a benchmark to measure
clinical success, however, because of the exceptional efficacy of
the IL-17A inhibitors in the treatment of psoriasis, PASI 90 may
now become the new standard for primary endpoints in clinical
investigations.³⁰ In addition to high response rates in the 2-week
dosing group (68-71% of patients achieving PASI 90), roughly
40% of patients in those same dosing groups experienced
complete remission of their psoriasis (i.e., PASI 100) by week 12,
with 55% achieving a PASI 100 by week 60 after every 2-week
induction dosing followed by 4-week maintenance dosing
through week 60. Among patients in the 2-week and 4-week
dosing groups who had a sPGA score of 0 or 1 at week 12 and were
randomly reassigned to ixekizumab every 4 weeks through week
60, 78.3% and 68.7%, respectively, maintained an sPGA score of
0 or 1, indicating the high initial response to ixekizumab persists
with 4-week maintenance dosing.²⁴ Secondary endpoints such
as health related quality of life and itch scores were similarly
impressive. The overall safety profile of ixekizumab in phase 2
and 3 studies has also been comparable with etanercept, although
slightly higher in ixekizumab groups compared with etanercept
or placebo.²³

Additionally, it is important to note that previous biologic
exposure did not seem to affect the efficacy of ixekizumab. This
is in contrast to patients treated with etancercept, where prior
biologic exposure resulted in lower response rates compared to
biologic naïve patients. These results have been demonstrated
in previous studies as well.²³ Treatment emergent anti-drug
antibodies (TE-ADA) was also assessed during the study, as
higher levels can result in reduced biologic efficacy over time.
However, the vast majority of patients in both the 2-week and
4-week ixekizumab dosing groups showed no or low levels of
TE-ADA.³¹

As Th17 cells contribute to the pathogenesis of several
inflammatory diseases, it is important to continue to monitor
these diseases in long-term studies. One of the main functions
of Th17 cells and IL-17 is in the adaptive immune response
against bacterial and fungal infections. IL-17A is needed for
mucocutaneous immunity against Candida albicans (C. albicans),
and it has been shown in humans that genetic deficiency in
IL-17RA is associated with recurrent or persistent mucocutaneous
infections caused by C. albicans as well as infections with
Staphylococcus aureus. IL-17A deficiency is also associated with
chronic mucocutaneous candidiasis. Although more cases of
candida infections were seen in ixekizumab groups as opposed to
etanerecpt or placebo, overall the infections were non-invasive in
nature, infrequent, and treatable.^{23, 28}

In total, 11 patients developed inflammatory bowel disease during
the phase 3 trials with 4 of those patients having a prior history
of the disease.²⁴ Moreover, another IL-17 inhibitor, secukinumab,
was not only shown to be ineffective in treating Crohn’s disease,
but rather exacerbated the condition in a previous trial, although
this study is limited by a small sample size.³² In combination,
these results indicate that patients taking drugs that block IL-17A
should be monitored for such potential AEs and further research
is needed to understand the gastrointestinal effects of IL-17
inhibition.²⁸

Although studies have demonstrated that low levels of IL-17 have
been associated with repeat myocardial infarctions and may
negatively impact atherosclerotic plaque stability, the interactions
are complex and merit further investigation. Although 3 patients
died in the 60 week phase 3 studies (2 from vascular causes and
1 from unknown cause), the exposure-adjusted incidence rates of
major adverse cardiovascular and cerebrovascular events (MACE)
in the induction period were similar in the placebo group and the
4-week dosing group (0.6 and 0.8 incidence rate per 100 patient
years, respectively). No patients in the 2-week dosing group
experienced a MACE.²⁴

A side effect of particular importance is depression and suicidal
behavior. In May 2015, the pharmaceutical companies developing
brodalumab, a human anti-IL-17RA monoclonal antibody,
abruptly halted phase 3 clinical trials based on suicidal ideation
and behavior observed in the brodalumab groups.³³ A pivotal
question then becomes whether suicide risk might be a class
effect of IL-17 related products. Key differences do exist however,
most notably that brodalumab blocked the receptor and not
the inflammatory cytokine. Secukinumab, the IL-17A blocking
drug recently approved by the FDA, has not demonstrated a link
to increased suicide risk.³⁴ Additionally, some have questioned
whether the studies were even powered sufficiently to detect this
effect in a population that has higher baseline depression rates.^32,34
Another possible confounder is that suicide rates have accelerated
dramatically in the US since 2008, particularly in white men, who
are overrepresented in clinical studies on psoriasis, including
the brodalumab trials.³⁴ Finally, recently published details from
the brodalumab trials noted that the investigators felt there was
no reasonable possibility that the suicides were related to the
investigational product.³⁵

Overall, ixekizumab demonstrates high levels of skin clearance as
evidenced by the sum of available clinical data. Long-term data
on safety and efficacy beyond 60 weeks of treatment remains
to be seen, therefore, ongoing trials will shed more light on how
ixekizumab will be incorporated into the treatment paradigm for
psoriasis.

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