Interleukin 17-A inhibition in the treatment of psoriasis

Abstract

Interleukin (IL) 17-A appears to be integral to the pathogenesis of chronic plaque psoriasis. Recent clinical trials have shown that blockade of this cytokine with the biologic therapies—secukinumab, ixekizumab and brodalumab—have led to unprecedented treatment efficacy for psoriasis. In addition, their dual efficacy towards psoriatic arthritis increases their potential clinical utility and they promise to be an important treatment option for patients who have tumour necrosis factor inhibitor resistant disease. Here, we present the evidence for the high treatment efficacy of the IL-17A inhibitors but also discuss some potential questions and areas of research needed, including the lack of evidence behind the drug survival, immunogenicity and safety profile.

Keywords:

• psoriasis
• brodalumab
• ixekizumab
• secukinumab
• interleukin-17

With the introduction of biological therapies over the past 10 years, treatment for psoriasis, a chronic, life-ruining, inflammatory cutaneous condition affecting 2% of the population, has been radically transformed. The commonly prescribed biological agents for psoriasis, including the TNFIs – etanercept, infliximab and adalimumab; and an IL 12/23 inhibitor ustekinumab – are highly effective for the majority of patients with severe psoriasis. Recently, an IL-17A inhibitor secukinumab has been licensed for the treatment of severe psoriasis in the US and in Europe, while the results of a large Phase III clinical trial have been published on the efficacy of ixekizumab, another IL-17A inhibitor.[1] The results of one Phase II [2] and two Phase III clinical trials have also been published of brodalumab, an IL-17 receptor A inhibitor.[3] How are these agents different from the existing biological treatments and why are they needed?

Psoriasis is considered a prototypical IL-17-mediated disease. The number of Th-17 cells, which produce IL-17A, are increased in the skin of patients with psoriasis.[4] Targeting IL-23, an upstream cytokine directing differentiation of T cells into Th-17 cells, has reaped rich reward. Ustekinumab, an inhibitor of the p40 subunit common to IL-12 and IL-23, has been shown to be effective in both clinical trials [5] and the real-world clinic.[6] Recent large Phase III trials involving secukinumab, ixekizumab and brodalumab have shown that an IL-17-targeted approach can produce even better treatment efficacy, probably because mast cells, macrophages and neutrophils are also sources of IL-17A in the skin.

FIXTURE, a Phase III randomized, double-blinded, placebo-controlled trial, found that secukinumab had a significantly higher Psoriasis Area nd Severity Index (PASI) 75 (or 75% reduction in the PASI score) at 77.1% compared with etanercept (44%) at week 12.[7] More impressively, 54.2% of patients on secukinumab achieved the secondary end point of PASI 90 (or 90% reduction in the PASI score) at week 12, which again was significantly better than etanercept. Similarly, two Phase III randomized controlled trials (RCTs), UNCOVER-2 and UNCOVER-3, found that treatment with ixekizumab (dosed every 2 weeks) achieved a PASI 75 of 89.7% (UNCOVER-2) and 84.2% (UNCOVER-3) at week 12 compared with etanercept, which achieved a PASI 75 of 41.6% (UNCOVER-2) and 53.4% (UNCOVER-3).[1] PASI 90 data were similarly impressive for ixekizumab, achieving percentages of up to 59.7% (UNCOVER-2) and 65.3% (UNCOVER-3) that were significantly better than etanercept at week 12. AMAGINE-1, a large Phase III RCT, also found that brodalumab achieved a PASI 75 of up to 83.3% at week 12 and a PASI 90 of 70.3% at the same time point.[8]

The efficacy of the IL-17A inhibitors has elevated the standard of care for patients with severe psoriasis to the extent that PASI 90, instead of PASI 75, should now be considered as the criterion for assessment of treatment response.[9] This is exemplified by the recent CLEAR trial, a RCT involving a head-to-head comparison between secukinumab and ustekinumab,[10] which used a primary end point of the PASI 90 at week 16. The results showed that secukinumab achieved a PASI 90 of 79%, a significantly higher result than ustekinumab (57.6%). The AMAGINE-2 and AMAGINE-3 studies, which are similar Phase III RCTs comparing brodalumab to ustekinumab, used an even more stringent primary end point of PASI 100 and found that brodalumab achieved a PASI 100 of 44 and 37% in the respective studies at week 12, which was significantly better than ustekinumab (22% in AMAGINE-2 and 19% in AMAGINE-3).[3]

However, treatment efficacy within a clinical trial is not the only facet of a drug that is important. It is estimated that approximately 30% of patients treated with systemic therapies for psoriasis in a real-world clinical setting would not be eligible for clinical trials because of stringent eligibility criteria.[11] It is, therefore, important to consider the real-world utility of IL-17 inhibitors by the use of observational studies. While there is emerging evidence regarding the drug survival of the biological therapies that are currently widely in use, with around 50% of first-course biological therapy failing in patients with psoriasis after 3 years,[6] little is known about the drug survival of IL-17 inhibitors. The fact that ixekizumab (2 or 4 weekly injections), brodalumab (2 weekly injections) and secukinumab (4 weekly injections) have relatively frequent dosing regimens compared with ustekinumab (12 weekly injections) may potentially discourage patient adherence.

It is recognized that the immunogenicity of biological therapies is an important contributor to primary or secondary ineffectiveness. Through work on adalimumab, a humanized monoclonal antibody to TNF, the development of antidrug antibodies (ADAs) has been shown to be associated with a lower likelihood of clinical remission or adequate response in both patients with rheumatoid arthritis [12] and psoriasis.[13] Little is known about the immunogenicity of secukinumab, ixekizumab or brodalumab, which are humanized monoclonal antibodies – anti-secukinumab antibodies were detected in only 0.4 and 0.3% of all patients in the FIXTURE and ERASURE trials up to week 60, respectively, with no statistical association with loss of efficacy. Anti-brodalumab antibodies, described as being non-neutralizing, were detected at week 52 in 1.8 and 2.3% of patients treated with brodalumab in the AMAGINE-2 and AMAGINE-3 studies, respectively, again with no statistical association with a loss of efficacy. However, as anti-secukinumab antibodies were measured by an ELISA-based method, this may underestimate the true prevalence of ADAs,[14] while it is unclear from the published protocol regarding the specific methodology used to measure ADAs in the AMAGINE-2 and AMAGINE-3 studies. No equivalent data have been reported on the immunogenicity of ixekizumab in any of the clinical trials involving patients with psoriasis. Further work with drug survival and measurement of drug trough levels in conjunction with ADAs and accompanying drug response data will help elucidate the true impact of any underlying immunogenicity of IL-17A inhibitors.

Determining the safety profile of any drug is a matter of paramount importance. As IL-17 is important in immunological protection against infections, especially against candida, is there any evidence of increased infections in patients treated with IL-17A inhibitors? Neutropenia has been noted as an AE in trials involving secukinumab,[7] ixekizumab [1] and brodalumab,[3,8] which may predispose the patient to infections. In the ERASURE trial, there were higher proportions of patients with infections in the secukinumab group compared with placebo, but the exposure-adjusted incidence rate of serious infections was similar in the secukinumab groups to placebo at 52 weeks. The FIXTURE trial showed that the proportion of patients with infections was similar in the secukinumab groups compared with etanercept, but there were more candida infections in the secukinumab groups. Notably, there were no cases of invasive candidiasis. The CLEAR trial, which has only reported the 16-week data so far, found similar proportion of patients with infections in the secukinumab group (29.3%) versus the ustekinumab group (25.3%), while the number of serious adverse events was the same in the two groups.

Regarding ixekizumab, the proportion of serious adverse events was also the same (2%) in the ixekizumab, etanercept and placebo groups in the pooled analysis for the first 12-weeks treatment in the UNCOVER-2 and UNCOVER-3 trials. However, infections occurred more frequently in patients on ixekizumab compared with etanercept, with 16 patients reporting candida infections in the combined ixekizumab groups compared with 5 and 2 patients in the etanercept and placebo groups, respectively. Reassuringly, there were again no cases of invasive candidiasis in the first 12 weeks of treatment and no subject was withdrawn from the trial because of candidiasis. Similarly, both AMAGINE-2 and AMAGINE-3 have reported a higher overall exposure-adjusted event rate of 5.2 and 5.7 per 100 patient-years of candida infections in the brodalumab groups in the respective trials compared with ustekinumab (AMAGINE-2, 4.1; AMAGINE-3, 1.6 per 100 patient-years). Despite the fact that the overall patient-years in the ustekinumab group was lower in both studies, it should be noted that serious infectious episodes including appendicitis, pneumonia, sepsis and urinary tract infection were only found in the brodalumab treatment groups.

Another important comorbidity of psoriasis is inflammatory bowel disease – indeed, the prevalence of psoriasis in Crohn’s disease is as high as 10%. A Phase II clinical trial showed that secukinumab was not only ineffective for Crohn’s disease, but four patients suffered from a worsening of disease.[15] In the FIXTURE/ERASURE trials, one patient presented with a new diagnosis of Crohn’s disease. In the UNCOVER-2 and UNCOVER-3 trials, one patient with ulcerative colitis experienced an exacerbation on ixekizumab, while another patient developed newly diagnosed Crohn’s disease while on the drug and discontinued the study. Similarly, one case of treatment-emergent Crohn’s disease has been reported in the AMAGINE-2 study.

The recent withdrawal of Amgen from the development program of brodalumab due to concerns over suicide risk highlights another important area for monitoring.[16] It should be noted that the brodalumab development program continues with new partners. Three suicide attempts were reported from one individual in the highest dose treatment arm within AMAGINE-2.[3] The same study reported two incidences of reported suicidal ideation, with one patient completing suicide during the study and one patient completing suicide after week 52 in the open-label extension. There were two suicide attempts in the ixekizumab groups in UNCOVER-2 and UNCOVER-3, which were not thought to be related to the study drug, while there were no suicide attempts listed in the FIXTURE, ERASURE or CLEAR trials with patients on secukinumab. Although the mechanism of action of IL-17A inhibitors is different to the IL-17 RA inhibitor, careful monitoring will be needed to ascertain the true risk of treatment-emergent depression and suicidal ideation. Theoretically, monoclonal antibodies do not cross the blood–brain barrier due to their large size, but there has been a suggested association of TNFIs with central demyelination,[17] while an early licensed biological psoriasis efalizumab (anti-LFA-1) was withdrawn because of an association with progressive multifocal leukoencephalopathy, so there is evidence that the peripheral cytokine modulation can affect the brain indirectly. In contrast, there is evidence from clinical trials that TNFIs and ustekinumab have a beneficial effect on depression.[18] It remains to be seen what effect IL-17A inhibitors will have on suicidal risk, which, given its rare occurrence, might be best assessed using prospective registry data.

An important factor to consider for any biological therapy for psoriasis is its efficacy for psoriatic arthritis (PsA). The recently published results from FUTURE 2, a double-blind Phase III RCT, found that secukinumab achieved a 54% ACR20 (or 20% improvement in the American College of Rheumatology response criteria) at week 24, which was significantly better than placebo.[19] The results for SPIRIT-P1, a Phase III RCT comparing ixekizumab against adalimumab and placebo for the treatment of PsA (ClinicalTrials.gov identifier NCT01695239) and AMVISION-1/AMVISION-2, two Phase III RCTs investigating brodalumab for PsA (ClinicalTrials.gov identifier NCT02029495/NCT02024646) are currently awaited. There is currently a small but significant group of patients with resistant or refractory severe psoriasis to both the TNFIs and ustekinumab. In addition, there are patients who have both psoriasis and PsA and have skin-responsive but joint-resistant psoriatic disease, or vice versa. These patients are significantly burdened by their condition, and current management options of combination therapy with conventional systemic medications are limited due to poor efficacy and/or high treatment toxicity.

With the emerging evidence of the efficacy of the IL-17A inhibitors for both psoriasis and PsA, their addition to the armamentarium is welcomed by both dermatologists and by patients. Further evidence over the safety and persistence of these highly effective biologics is needed to fully ascertain their role in the treatment ladder for severe psoriasis.

Christopher EM Griffiths

Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

Author for correspondence:Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UKTel.:0161 206 4392Fax: [phone] [email protected]

Zenas ZN Yiu

Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK

Author for correspondence:Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UKTel.:0161 206 4392Fax: [phone] [email protected]

Financial & competing interests disclosure

CEM Griffiths has received honoraria and/or research grants from Abbvie, Actelion, Amgen, Celgene, Lilly, GSK-Stiefel, Janssen, MSD, Novartis, Pfizer and Sandoz. CEM Griffiths is a National Institute for Health Research Senior Investigator. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed

ORCID

Zenas ZN Yiu http://orcid.org/0000-0002-1831-074X

Additional information

Notes on contributors

Zenas ZN Yiu

Christopher EM Griffiths