Limitations of current monoclonal antibodies for plaque-type psoriasis and an outlook for the future

KEYWORDS:

• Moderate-severe psoriasis
• biologic agents
• efficacy
• safety
• immunogenicity
• pharmacogenomic

1. Introduction

Psoriasis is a chronic immune-mediated disease; although its pathogenesis is complex and still largely unknown, over the past several years, it has become clear that psoriasis goes beyond the skin. Improvements in our understanding of the pathogenesis have subsequently led to the development of novel drugs that act systemically on specific molecular components of the immune response [1]. Several cytokine pathways have been identified and investigated as targets for systemic therapies. Biologic agents have revolutionized the way to manage the psoriatic disease. They selectively inhibit cytokines associated with psoriatic plaque formation, such as tumor necrosis factor (TNF)-α, interleukin (IL)-12/23, and IL-17A. Current consensus is that mild psoriasis can be effectively treated with topical agents, whereas systemic or biologic therapies are indicated for moderate to severe disease [1]. However, psoriasis at any severity grade can negatively impact on patient’s quality of life, thereby challenging the tag of “mild” disease. For this reason, in addition to body surface area affected and Psoriasis Area and Severity Index (PASI), other factors must be considered to evaluate treatment strategies, such as Dermatology Life Quality Index score and the burdens associated with symptoms of pain and itching [1]. An earlier use of biologics, targeting the underlying inflammation, may slow disease progression and prevent associated comorbidities, such as atherosclerosis and metabolic syndrome [2]. Patients affected by debilitating disease can now enjoy clear or almost-clear skin in most cases with biologic therapies. All biologics yield greater efficacy rates (PASI-75 responses ranging from 40% to 90%) with fewer adverse events and better overall tolerability when compared with conventional systemic therapies [3]. From a patient perspective, biologics seems to be as “wonder drugs,” nevertheless, they are not lacking of risks and limitations.

2. Limitations of the current treatments and future perspective

The ideal therapy for the treatment of psoriasis should be effective and safe, keeping these features overtime. Moreover, it should have an easy route of administration and good tolerability. Does it exist?

Several randomized-controlled trials have shown that available biologic agents are highly effective treatments for moderate-to-severe chronic plaque psoriasis. Recently, a meta-analysis reported that infliximab was the most effective among TNF-α inhibitors (in terms of mean PASI improvement) [4]. However, infliximab is the only to be administered by intravenous injection, and patients prefer more self-administered subcutaneous biologics than intravenous ones. Moreover, a substantial proportion of psoriatic patients do not or only partially respond to anti-TNF-α therapies (primary failure) or otherwise, after an initial response, subsequently experience a loss of responsiveness over time (secondary failure) [5]. The mechanisms underlying these events are not completely understood. One of the supposed reasons for secondary failure has been attributable to their immunogenicity, resulting in the development of antibodies targeting the therapeutic molecule (antidrug antibodies-aDAb) [6]. Nowadays, the world of biologics is not just anti-TNF-α with anti-IL-17 drugs showing an equal or greater chance of leading patients to PASI improvement when compared with other biologics or small molecule inhibitors [4,7]. All immunobiological agents can induce antibodies against themselves, but their clinical utility as well as their impact on clinical response course is a hot point still opened. In clinical practice, failure to one class of biologics does not predict that this patient will not respond to a different drug being in the same class. This heterogeneity is partially elucidated by genetic variants, a part from different pharmacokinetic and pharmacodynamic characteristics, which might act as predictors for treatment response. This is the research field of pharmacogenetics. HLA-C*06:02 represents the most promising in predicting ustekinumab response rates [8]. However, until now, pharmacogenetic research in psoriasis has mostly been based on small candidate gene groups, and wider spectrum of predictor markers are needed. Regarding anti IL-17 drugs, secukinumab showed a favorable profile of efficacy and safety [9]. Moreover, among the head-to-head trials, it was found to be significantly more effective than etanercept as well as ustekinumab after 12 weeks of treatment [10]. Similarly, ixekizumab has shown promising results on its efficacy in clinical trials [11], and a significant superiority has been reported respect to etanercept, adalimumab as well as ustekinumab [12–14]. Moreover, ixekizumab demonstrated persistent efficacy through 108 weeks [15]. The most recent approved biologic agent anti IL-23, guselkumab, represents a very promising therapy, providing an alternative mechanism of action with high efficacy and safety profiles, sustained total skin clearance, and rapid onset of effect [16]. In addition, it has already showed superior efficacy with respect to adalimumab and ustekinumab in phase II and III comparator trials, respectively [16]. However, additional studies are needed to completely assess these surprising data in efficacy and safety of anti-IL-17 and IL-23 drugs in real-life clinical settings. Moreover, although a recent in vitro study reported a significantly lower immunogenicity for secukinumab compared to ixekizumab and adalimumab [17], data on any potential immunogenicity of anti-IL-17 biologic agents should be deeply investigated. A concern on anti-IL-17 biologic agents regards their effects on cardiovascular risk, since data on IL-17 role in atherosclerosis are contradictory and necessitate to be largely studied. It has been reported that IL-17 could stabilize atheromatous plaques, indicating a protective role, but it could act synergistically with Th1 pathway playing a proatherogenic action [18]. An additional important aspect to take into account when treating the psoriatic disease with biological treatments includes “special populations,” such as pediatric and elderly ones; the spectrum of choices are limited since nowadays only etanercept, adalimumab and ustekinumab are approved for children. Moreover, due to the chronic nature of psoriasis, the population of elderly psoriatic patients is increasing. However, many of them are not adequately treated because management is complicated by comorbidities, polypharmacy, and progressive impairment of organ systems. For all these reasons, clinicians may hesitate to use systemic or biologic agents in these patients. Regarding safety, all available biologics are generally safe and well tolerated, but the risk of serious infections and malignancies has been reported [19]. A recent review study suggests that these events are rare and not statistically significant [19]. Biologic therapies are very expensive and their financial impact is relevant for many countries. In Italy, biologic drugs counts on the 13.7% of the national health service pharmaceutical expenditure [20], whereas in the United States, it has been estimated that their sales-based cost increased at an average of 20% per year [21]. In the decision process of the “ideal therapy,” the economic model plays another important role. Biosimilars could alleviate this high cost in the next few years, but the lack of clinical trials, especially comparative ones with originator drugs, limits their prescription. The pipeline for psoriasis contains several new drugs that are designed to inhibit different targets with unknown risks that will need to be explored. It contains a lot of small molecules that have the advantages to be used for those patients who do not meet the criteria for biological therapies and/or have a preference for oral drug. A small-molecule inhibitor of phosphodiesterase-4 is recently available [22]. Probably, these new agents will fill an unmet need in patients with moderate-to-severe psoriasis. Overall, these questions will be sufficiently answered only in the coming years programming longer follow-up times and large-scale safety registries.

3. Conclusions

This is an exciting era for the treatment of moderate-to-severe psoriasis. Deeper understanding of its pathogenesis has improved efficacy and safety of the novel immunotherapies. The rapid development of newer biologic and/or oral therapies for psoriasis will have to meet with very high expectations, without underestimating the cost-effectiveness ratio of such treatment.

4. Expert opinion

Psoriasis is a chronic, immune-mediated inflammatory disease for which treatment has rapidly evolved over the past few years due to the introduction of biological agents as well as small molecule inhibitor treatment. However, these therapies show significant variability in safety and particularly in efficacy. Finding the best biologic agent for all patients affected by moderate-to-severe psoriasis is a “mission impossible.” Each patient is an individual, the response to systemic agents is very heterogeneous, and personalized care for psoriatic patients represents a future goal. There is a great need of novel pharmacogenetic loci as well as a set of biomarkers in order to create predictor factors with adequate prognostic value to be applied in daily clinical practice. Moreover, these findings should be reproduced in larger cohort studies. Furthermore, pharmacogenetic studies investigating on IL-17 inhibitor response rates are lacking and necessitate to be performed. The use of pharmacogenetic approaches could optimize the treatment of psoriasis and minimize unnecessary costs, given that these ones have been increasing overtime. Cost considerations in the management of psoriasis have to be taken into account for the limited healthcare resources. Given the economic climate, it is recommended to consider cost-effectiveness ratio when a treatment for moderate or severe psoriasis is established. Biosimilars could alleviate this high cost in the next few years. Recently, several studies have demonstrated equivalent efficacy and comparable safety and immunogenicity with respect to their originator [23–25]. However, more robust data are required to address the lack of knowledge in this filed.

Declaration of interest

N. Balato has served as a speaker, consultant, advisory board member for, or has received research grants from: Abbott, Janssen-Cilag, Merck Serono, Schering-Plough, Wyeth. 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.

Additional information

Funding

This paper was not funded.