Tildrakizumab: the value of a personalized and flexible approach for treating moderate-to-severe plaque psoriasis in patients with high body weight or high disease burden

ABSTRACT

Introduction

The introduction of biologics for the treatment of plaque psoriasis is one of the major therapeutic advances of the last decades in dermatology. The efficacy of this class of drugs can be influenced by multiple factors including obesity, being overweight, prior treatment failures, and disease severity.

Areas covered

Most of the currently available approved biologics are limited by their lack of dosing flexibility for adapting the therapy to the complexity of real-world patients with psoriasis. Among the class of anti-interleukin-23, tildrakizumab allows a greater dosing flexibility, increasing clinical benefits of patients with high burden of the disease or body weight >90 kg.

Expert opinion

This meta-opinion discusses the clinical data that were foundational for tildrakizumab dosage flexibility, elaborates on the definition of high burden of disease specifically linked to tildrakizumab dosage, and profiles the ideal patient that could benefit from treatment with the higher approved tildrakizumab dosage of 200 mg.

KEYWORDS:

• Biologics
• body weight
• disease burden
• efficacy
• flexibility
• obesity
• psoriasis
• tildrakizumab

1. Introduction

Psoriasis is a chronic inflammatory skin disease, with a global prevalence rate of 2–3% of the world population [1,2]. The etiology of psoriasis is complex, and unfortunately, still not fully understood. Hyperactivation of the adaptive immune system along with the release of inflammatory cytokines, such as interleukin-12 (IL-12), IL-17, IL-22, IL-23, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-α, appear to be crucial in the pathogenesis of the disease [1]. A variety of different treatments are available for patients with psoriasis, including topical therapies, phototherapy, and injectable or oral systemic therapies [3].

This meta-opinion is focused on tildrakizumab because of its unique dose flexibility potentially providing greater clinical benefits for specific subgroups of patients with psoriasis (e.g. higher body weight and high disease burden) [4]. The aim of our article is to provide an overview of tildrakizumab data collected in multiple clinical trials as well as challenges experienced by clinicians. Moreover, we present a novel discussion on tildrakizumab dosage and profile the ideal patients that could benefit from treatment with tildrakizumab 200 mg.

1.1. Biologics: mechanisms of action and treatment flexibility

The introduction of biologics has been one of the major advances in the treatment of psoriasis in recent years [1]. Currently, four different classes of biologics are available, with different targets and mechanisms of action. These are the TNF-α inhibitors, anti-IL-12/23 agents, anti-IL-17, and anti-IL-23 agents [1].

Several studies have suggested an association between psoriasis and obesity (defined as body mass index [BMI] ≥30 kg/m²), increased abdominal and visceral fat, or being overweight [5,6]. It has been established that obesity or higher bodyweight has a negative impact on the clinical response to various biologics [6–9]. Several hypotheses have been postulated to explain reasons for this evidence, such as the effect of these conditions on pharmacokinetics (volume of distribution and clearance) and pharmacodynamics of biologics [6,7,10]. Additionally, obesity is known to be associated with altered inflammatory signaling, such as an increased pro-inflammatory cytokine released by macrophages and T helper 17 cells, and the production of pro-inflammatory adipokines (leptin and resistin) generated by adipocytes [5,10]. The released pro-inflammatory cytokines can interact with biologics and counteract the anti-inflammatory activity of these agents [10].

The decreased efficacy of biologics reported in obese patients with psoriasis may be linked to the limited number of drugs available that provide the flexibility to adjust the dose according to body weight. Among biologics allowing a certain dosage flexibility should be mentioned infliximab, certolizumab pegol, and adalimumab (TNF-α inhibitors), tildrakizumab (anti-IL-23), secukinumab and bimekizumab (anti-IL-17) [4,7,11–14]. According to clinical response, the maintenance dose of secukinumab 300 mg can be administered more frequently (every 2 weeks) to provide additional benefit in patients ≥90 kg, while the frequency of treatment with bimekizumab can be increased to improve the response in patients ≥120 kg who do not reach complete skin clearance after week 16 [12,14]. Ustekinumab, has two different fixed dosage depending on patient body weight: 45 mg in patients ≤100 kg and 90 mg in patients >100 kg [15].

2. Current evidence

2.1. Tildrakizumab: unique flexibility at physician’s discretion among anti-IL-23 class

Tildrakizumab is a humanized monoclonal antibody (IgG1/k class), which binds to the IL-23 p19 subunit, thereby specifically inhibiting the interaction with the IL-23 receptor involved in the pathophysiology of psoriasis [4].

In contrast to other available biologics used in the treatment of moderate-to-severe plaque psoriasis, tildrakizumab dosing options allow greater flexibility. The recommended dose by subcutaneous injection is 100 mg at week 0 and 4, followed by subsequent injections every 12 weeks. In addition, at the discretion of the physician, in patients with a high disease burden or above 90 kg of body weight, a 200 mg dose of tildrakizumab may provide greater efficacy [4]. Additionally, it needs to be mentioned that the cost of pre-filled syringe containing 100 mg of tildrakizumab in 1 ml or 200 mg of tildrakizumab in 2 ml is identical [4].

These recommendations are based on pharmacokinetic modeling, showing a reduced exposure to tildrakizumab in patients with an increased body weight, and on the results of two phase III trials (reSURFACE 1 and 2), additionally supported by a real-world retrospective study [4,16].

2.2. reSURFACE 1 and 2 studies

The efficacy and safety of tildrakizumab in the treatment of plaque psoriasis were demonstrated in two phase III, double-blind, randomized, three-part studies, reSURFACE 1 and reSURFACE 2. These studies recruited adult patients with moderate-to-severe plaque psoriasis (involvement of body surface area ≥10% and a Psoriasis Area and Severity Index [PASI] ≥12). In reSURFACE 1, patients were randomized 2:2:1 to receive tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo, and in reSURFACE 2 patients were randomized 2:2:1:2 to receive tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg. Patients were randomized by region and stratified by bodyweight (≤90 kg or >90 kg), as well as by prior treatment with biologics [17].

In these studies, tildrakizumab 200 mg and 100 mg showed similar higher efficacy when compared with placebo and etanercept at week 28. Both dosages were well tolerated in the treatment of patients with plaque psoriasis [17]. Furthermore, tildrakizumab treatment with 200 mg or 100 mg maintained the long-term (5 years) control of psoriasis in tildrakizumab responders at week 28 and in etanercept partial-/non-responders, showing a reassuring safety profile [18].

Recently, a post hoc analysis of reSURFACE studies showed comparable long-term PASI and DLQI responses in younger and older patients (<65/≥65 years) with psoriasis independently from tildrakizumab dosage (100 mg and 200 mg) and without safety concerns related to the therapeutic regimens [19]. In another post hoc analysis (5-years data) of these studies, tildrakizumab demonstrated to maintain efficacy and showed a favorable safety profile in patients with psoriasis independently from the presence of concomitant metabolic syndrome [20].

A pooled post-hoc analysis performed on data collected from both reSURFACE 1 and 2, showed no correlation between body weight and changes in PASI or DLQI from baseline value [6]. These data suggest that at week 28, body weight has limited impact on the response to tildrakizumab in the overall population. In addition, the PASI or DLQI response rates were similar in patients with a body weight >90 kg treated with tildrakizumab 100 or 200 mg, with no significant differences reported at week 28, 52 or 244. However, when patients were stratified according to body weight, a trend showing a higher proportion of patients >90 kg responding to tildrakizumab 200 mg compared to tildrakizumab 100 mg was observed (considering both PASI < 3 and DLQI 0/1). When looking specifically at PASI < 3, this trend was particularly evident at week 52 but less noticeable at week 244. In general, no statistical differences were reported considering both timepoints and endpoints. Conversely, analyzing response to tildrakizumab in patients with a body weight ≥120 kg demonstrated a consistent trend of higher response rate in patients treated with tildrakizumab 200 mg, considering all the timepoints and endpoints, suggesting a clinical advantage for this subgroup of patients [6].

A pooled analysis of the subgroups of patients recruited in the reSURFACE studies, and in the Phase II study P05495 confirmed that tildrakizumab efficacy was higher in patients with a lower body weight. However, the response observed in patients with a higher bodyweight was generally numerically higher in patients treated with tildrakizumab 200 mg compared to patients treated with the lower dose. These data suggest that tildrakizumab 200 mg could increase treatment response in patients with a higher body weight [21]. Moreover, the same study showed that when stratifying patients by PASI at baseline (PASI ≤ 20, PASI > 20), a higher proportion of patients with PASI > 20 responded to tildrakizumab 200 mg (59.4%) versus tildrakizumab 100 mg (48.6%), suggesting that patients with more severe disease have potentially a greater response to tildrakizumab 200 mg [21].

2.3. Tildrakizumab 200 mg/2 ml: a new formulation

With the aim of increasing convenience and comfort of treatment for the patients, and consequently enhance therapeutic compliance, a tildrakizumab 200 mg/2 ml prefilled syringe was developed. The safety and tolerability of this new preparation were evaluated in a phase I clinical study comparing a single subcutaneous injection of tildrakizumab 200 mg/2 ml with two 100 mg/1 ml tildrakizumab injections in healthy individuals [22]. The study demonstrated that tildrakizumab 200 mg as a single 2 ml injection is safe and generally well tolerated. The new 200 mg/2 ml preparation was also the preferred administration method for healthy subjects compared to two single injections [22].

3. Expert opinion

3.1. Patient profile suitable for tildrakizumab 200 mg: an evidence-based discussion

The efficacy of biologics in the treatment of psoriasis can be impacted by several factors (such as obesity, higher body weight or disease severity) which can lead to a lack or a loss of response [7–9]. Initially, in clinical practice tildrakizumab 100 mg was selected for patients usually showing a relatively short history of psoriasis, a moderate severity of the disease (PASI score ~ 10), and a lack of prior systemic treatment with biologics [23]. Subsequently, several clinical studies provided evidence supporting the effective use of tildrakizumab 100 mg also in patients with other characteristics, such as comorbidities (cardio‐metabolic comorbidities including cardiovascular diseases, arterial hypertension, type 2 diabetes mellitus and hyperlipidemia or psoriatic arthritis) [20,24], involvement of difficult-to-treat areas [24,25], or patient previously exposed to biologic agents [26]. Considering SmPC recommendations for the selection of the higher tildrakizumab dosage, based on our clinical experience with tildrakizumab 100 mg and the results of clinical and real-world studies, we hypothesize that tildrakizumab 200 mg might provide additional clinical benefits in patients with bodyweight >90 kg, a higher PASI score (PASI > 20), psoriasis located in difficult-to-treat areas, and/or prior therapy with at least one biologic failed or resulted in a partial response. Overall, these considerations suggest that tildrakizumab 200 mg might provide a new opportunity for treating higher bodyweight psoriatic patients with more severe inflammatory conditions and/or comorbidities (such as psoriatic arthritis, or cardio‐metabolic comorbidities) (Figure 1). This hypothesis is supported by the results of the two pooled analyses previously described in paragraph 2.2 [6,21]. Importantly, the favorable trend in terms of PASI and DLQI parameters particularly marked at week 52 and identified in the group of subjects treated with tildrakizumab 200 mg was exclusively observed in patients ≥90 kg or ≥120 kg, suggesting that the most appropriate dosage for patients <90 kg is 100 mg [6].

Figure 1. Scheme summarizing the characteristics of patients potentially eligible to tildrakizumab 200 mg. DTT: difficult-to-treat; prior therapy failure: prior therapy with at least one biologic failed or resulted in a partial response; comorbidities: cardio‐metabolic comorbidities (including cardiovascular diseases, arterial hypertension, type 2 diabetes mellitus, hyperlipidemia and metabolic syndrome) or psoriatic arthritis.

Dose adjustments to obtain better control of plaque psoriasis is common in clinical practice [27]. Consequently, in our opinion, in patients showing a partial or temporary response to tildrakizumab 100 mg, administering tildrakizumab 200 mg could represent a new suitable therapeutic option to potentially enhance drug efficacy. In this case, a subsequent reevaluation of patients after 12 weeks might be useful to confirm efficacy of the new dosage regimen. The dose adjustment analysis performed in the reSURFACE studies supports this hypothesis. In responders to tildrakizumab 200 mg at week 28, the switch to tildrakizumab 100 mg only minimally impacted efficacy, suggesting that in these patients the exposure to a higher dosage of tildrakizumab (200 mg) may be not required and a de-escalation to 100 mg dosage may be appropriate to maintain psoriasis control. In contrast, increasing tildrakizumab dosage (to 200 mg) in partial responders receiving tildrakizumab 100 mg, resulted in continued improvement of outcome parameters, although no statistical difference was observed compared with patients continuing on the 100 mg tildrakizumab dose [27].

Psoriasis can be located in difficult-to-treat areas, such as the scalp, face, genitals, nails, palms of hands or feet, or the anterior face of tibia, consequently affecting patient quality of life [25,28]. Although limited data about the effect of biologics in these patients are available, recent studies based on real-world evidence demonstrated the efficacy of tildrakizumab 100 mg in treating psoriasis localized in these areas [24,25]. The results of the study reported by Galluzzo and coworkers showed that tildrakizumab 100 mg reduced the mean score of the static Physician’s Global Assessment of Genitalia (3.3 to 0.2), Psoriasis Scalp Severity Index (36.2 to 2.7), Nail Psoriasis Severity Index (48.4 to 15.7), and PASI (5.3 to 0) at week 28 [25]. These data have been supported by the results of the retrospective study performed by Narcisi and coworkers, confirming that tildrakizumab is an effective option to treat patients with psoriasis located in difficult-to-treat areas [24]. Considering this therapeutic landscape, the possibility to test in further studies tildrakizumab 200 mg to compare the efficacy of the two dosages in these patients could generate useful evidence for improving clinical benefits of this challenging patient population.

Finally, the selection of the most effective therapy for patients that have failed prior treatments with biologics, is a crucial aspect to consider in order to achieve clinical remission. Despite the fact that a higher efficacy of tildrakizumab in patients not previously treated with biologics has been reported, the reSURFACE studies highlighted that in 8 out 10 partial/not-responders to etanercept, treatment with tildrakizumab 200 mg resulted in PASI75 [29,30]. These data suggest that the respective patient population could also be a suitable target for the 200 mg dose of tildrakizumab.

Biologic-based treatment of psoriatic patients showed positive efficacy results and an overall favorable safety profile; however, these agents as well as other class of drugs have been associated with adverse effects that can be related to different factors, such as their mechanism of action or dosing. Considering their immunomodulatory activity, different class of biologics have been linked to an increased rate of infections. Inhibitors of TNF have shown an increased rate of upper respiratory tract infections, rhinitis, sinusitis, and pharyngitis, as well as cases of tuberculosis. Additionally, long-term safety studies testing anti-IL-12/23 reported that the most common adverse events (AEs) were upper respiratory tract infections, headache, nasopharyngitis, and arthralgia, while patients treated with anti-IL-17 showed an increased risk of developing Candida infections or exacerbation (or induction) of inflammatory bowel disease [31]. As regard anti-IL-23 p19 agents, nasopharyngitis, upper respiratory tract infections and headache were the most common associated AEs [32]. Nevertheless, the meta-analysis of clinical trial data performed by Shear and coworkers concluded that biologics anti-IL-23 were associated with the lowest rates of safety events in comparison to other FDA- or EMA-approved therapies for treating moderate-to-severe psoriasis [31]. In particular, the five-year safety data of tildrakizumab based on the reSURFACE studies showed a favorable safety profile, including low rates of events, such as infections, malignancies, and major adverse cardiovascular events, comparable to events showed in the Psoriasis Longitudinal Assessment and Registry [33]. Importantly, the pooled analyses from the reSURFACE pivotal studies over 5 years showed an equal rate of adverse events using both tildrakizumab dosages as well as for patients stratified by body weights, suggesting that tildrakizumab 200 mg potential benefits have not additional safety concerns [6,33]. Considering more fragile patient populations, the post hoc analysis of reSURFACE 1/2 performed to evaluate the efficacy and safety of tildrakizumab among younger and older adults with psoriasis (<65/≥ 65 years) showed that although comorbidities and comedications were more common in older patients, tildrakizumab showed a similar safety profile in the analyzed age groups independently from the administered dosage [19]. Additionally, safety data of tildrakizumab in patients with psoriasis and concomitant metabolic syndrome showed a similar safety profile in the group with and without the comorbidity. Overall exposure‐adjusted incidence rates of treatment‐emergent adverse events were similar for both groups receiving tildrakizumab 100 mg or 200 mg [20]. Nevertheless, considering that psoriasis is a chronic inflammatory disease and patients with moderate-to-severe plaque psoriasis can be exposed to treatment even for decades, longer treatment data are required to confirm the safety profile of tildrakizumab in this perspective [30] and the exposure to the higher dose of 200 mg should be limited to patients for which clinicians envisage the opportunity to reach improved clinical benefits compared to 100 mg dose administration. The major limitation of this study concerns the limited data currently available directly comparing the efficacy of different tildrakizumab dosages (100 and 200 mg) in the highlighted patient subpopulations. Consequently, real-world data are highly awaited to confirm the most appropriate dosage of tildrakizumab for treating these patients.

4. Conclusions

Clinical management of specific populations of patient with plaque psoriasis, such as obese patients [7], patients with a high burden of disease, patients who failed prior therapies with one or more biologics [34], or patients with a localization of psoriasis in difficult-to-treat areas [25], can be substantially complex.

Based on our analysis, treatment with tildrakizumab 200 mg, associated with enhanced treatment efficacy as well as faster onset of clinical response, could benefit these challenging patient populations. We highlight that tildrakizumab has a higher dose flexibility compared to other biologics, allowing physicians the unique opportunity of selecting the dosage based on clinical experience and their discretion. However, at present, there is limited clinical information about the efficacy of tildrakizumab 200 mg in these patients, and further studies are needed to confirm the clinical benefits of this treatment.

Article highlights

• The efficacy of biologics for the treatment of plaque psoriasis can be influenced by multiple factors including being obese or overweight and disease severity.

• Tildrakizumab allows flexibility at physician’s discretion introducing an additional dosage of 200 mg that may increase clinical benefits of patients with high burden of the disease or body weight >90 kg.

• Challenging populations with psoriasis such as obese patients, patients with a high burden of disease, patients who failed prior therapies with one or more biologics, or patients with a localization of psoriasis in difficult-to-treat areas could potentially benefit from tildrakizumab 200 mg therapy.

• Safety data based on reSURFACE pivotal studies showed a favorable safety profile over 5 years using both tildrakizumab dosages (100 and 200 mg).

Declaration of interest

P Gisondi served as advisory board member and consultant for Amgen, Abbvie, Almirall, Bristol Mayer Squibb, Eli Lilly, Novartis, Jannsen, Pierre Fabre, Sanofi, UCB. P Dapavo served as advisory board member for Eli Lilly, Novartis, Amgen, Abbvie, Leopharma, Bristol, UCB, Janssen, and Almirall. M Burlando served as advisory board member and consultant for Almirall, Janssen, Amgen, Abbvie, Eli Lilly, Novartis, UCB; she has received speaker’s honoraria or has participated in clinical trials for Almirall, Janssen, Amgen, Abbvie, Eli Lilly, Novartis, UCB. C Guarneri served as advisory board member and consultant for Almirall, Abbvie, Amgen, Boheringer-Ingheleim, Ely-Lilly, Janssen, Leopharma, Merck, Novartis, Pfizer, Sanofi and UCB Pharma; he has received speaker’s honoraria or has participated in clinical trials for the same companies. M Megna served as advisory board member and consultant and/or has received speaker’s honoraria or has participated in clinical trials for Eli Lilly, Novartis, Almirall, Leo Pharma, UCB, Janssen, Abbvie, Amgen. Alessandra Narcisi served on advisory boards, received honoraria for lectures and research grants from Almirall, Abbvie, Leo Pharma, Celgene, Eli Lilly, Janssen, Novartis, Sanofi-Genzyme, Amgen and Boehringer Ingelheim. M Talamonti served as advisory board member and consultant for AbbVie, Almirall, Eli Lilly and Company, Janssen, Leo, Novartis, and has received speaker’s honoraria or has participated in clinical trials for AbbVie, Almirall, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Leo, Novartis, Sanofi Genzyme, Sun Pharma, and UCB Pharma. 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.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from Expert Opinion on Biological Therapy for their review work, but have no other relevant financial relationships to disclose.

Additional information

Funding

This paper was funded by Almirall S.p.A., Italy. This funder sponsored the editorial assistance for the writing only, and had no role in content of the manuscript.