Brodalumab Is Effective for Psoriasis Patients with Difficult-To-Treat Body Regions: Results from an Observational Clinical Study

Plaque psoriasis is the most common form of psoriasis and affects up to 2% of the adult population [1]; this condition is characterized by relapsing exacerbations and remissions of thickened, erythematous, scaly skin lesions due to hyperproliferation of keratinocytes. In addition to stigmatization due to unsightly lesions, patients with plaque psoriasis also suffer from pain, pruritus, and other comorbidities that involve multiple domains, including psychological, metabolic, arthritic, and cardiovascular [1, 2], resulting in significant impairment in quality of life (QoL) and work productivity [3].

The interleukin (IL)-23-dependent IL-17 signaling pathway plays a key role in the pathogenesis of psoriasis [4]. During the initial disease outbreak, different immune cells are activated to produce proinflammatory cytokines, mainly interferon-α and tumor necrosis factor (TNF). These proinflammatory cytokines stimulate the development of T-helper (Th) 17 cells, which produce different subtypes of IL-17 and are a key driver of psoriatic inflammation [5‒7]. Enhanced levels of IL-17A/F are found in skin lesions as well as in the peripheral blood of patients with psoriasis. Different IL-17-driven molecular processes are responsible for plaque development and for persistence and worsening of psoriatic inflammation [5, 6].

Curative treatment options for plaque psoriasis are not currently available. The aim of therapeutic interventions is to alleviate and heal acute symptoms, shorten phases of acute inflammation, and avoid new disease episodes. Psoriasis severity is usually the main factor influencing the choice of therapy. Topical therapies and phototherapy may be used to reduce acute inflammatory lesions in mild to moderate forms [8], but systemic therapy is usually required for moderate-to-severe psoriasis. Systemic biologic agents for psoriasis include inhibitors of TNF (infliximab, adalimumab, eternacept and certolizumab), IL-12/IL-23 (ustekinumab), IL-17A/(F) and its receptor (secukinumab, brodalumab, bimekizumab, ixekizumab), and IL-23 (risankizumab, guselkumab, tildrakizumab) [9].

Brodalumab is a recombinant, human, monoclonal antibody that binds with high affinity to the IL-17 receptor A, thereby inhibiting the proinflammatory signaling of IL-17A, −17F, −17A/F, −17C, and −17E [7, 10]. A unique feature of this antibody is the ability to block signal transmission via receptor inhibition, resulting in down-modulation of the entire receptor-controlled pathway rather than inhibition of a single cytokine as for other IL-17 inhibitors [7, 11]. Brodalumab was approved by the European Medicines Agency for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients in September 2017. In two phase 3 clinical trials, brodalumab at a dose of 210 mg every 2 weeks resulted in high rates of skin clearance, with 85%–86% of patients achieving a 75% improvement in Psoriasis Area and Severity Index (PASI) scores and 37%–44% achieving a 100% improvement in PASI at week 12 [12]. Efficacy was maintained through 120 weeks of treatment in patients remaining on therapy [13]. Brodalumab had a favorable safety profile and was well tolerated [13].

Although overall skin involvement is the most noticeable symptom of psoriasis, the management of this condition is complicated by the occurrence of lesions on parts of the body that do not respond well to common therapies. These regions, including the scalp, nails, palms, soles, and genitals have been characterized as “difficult-to-treat” or “impactful” areas. In particular, scalp and nail involvement are observed in up to 80% of patients and are associated with more extensive disease and worse health-related QoL [14‒16]. The skin structure in difficult-to-treat areas differs from the structure on other body parts; as a result, impaired absorption can reduce the effectiveness of topical options [17‒19]. Psoriatic lesions in difficult-to-treat areas thus represent a challenge for physicians as well as patients.

Systemic biologic therapies have been shown to be effective for the treatment of difficult-to-treat areas in patients with psoriasis [20], and there is growing evidence that brodalumab has beneficial effects for this patient population [14, 21, 22]. However, there are limited data on treatment outcomes with brodalumab in difficult-to-treat areas during routine clinical care. This explorative observational study was designed to evaluate brodalumab under real-world conditions, particularly with respect to its effect on scalp and nail psoriasis.

This was a non-interventional, observational, prospective, one-arm, multicenter study including adult patients (≥18 years) with moderate-to-severe plaque psoriasis and nail and scalp involvement, as determined by a score greater than 0 on Psoriasis Scalp Severity Index (PSSI) and Nail Psoriasis Severity Index (NAPSI) assessments, who received brodalumab treatment in clinical routine care (the ODIN study). The study recruitment period was from December 8, 2018 to May 18, 2021.

The decision to initiate treatment with brodalumab was made by the physician and patient during routine clinical care. The dose and schedule of brodalumab administration were determined by the treating physician. Concomitant topical and systemic therapies were allowed. Patients were observed over a period of 60 weeks at 9 visits (online suppl. Fig. S1; for all online suppl. material, see https://doi.org/10.1159/000542348). Disease activity and adverse events were assessed at every visit, starting at baseline (visit 1/week 0) prior to brodalumab initiation. Outcomes were documented at 2, 4, 8, 12, 24, 36, 48, and 60 weeks after brodalumab initiation. Visit 9/week 60 was defined as the end-of-study visit.

The study protocol was reviewed and approved by Ethics Committees at each of the participating sites, including the leading Ethics Committee, University Hospital Frankfurt (received on November 11, 2018; No. 56/18). The full list of participating site supervisors and Ethics Committees can be found in online supplementary Table S1. All patients provided written informed consent for study participation.

The co-primary endpoints were (1) the proportion of patients achieving a 75% improvement in PSSI (PSSI75) at week 12 after brodalumab initiation and (2) the proportion of patients achieving a 75% improvement in NAPSI (NAPSI75) at week 24 after brodalumab initiation. Week 24 was chosen as the NAPSI75 endpoint because resolution of nail psoriasis generally takes a longer period of time compared with effects on skin psoriasis [23].

The PSSI score assesses scalp psoriasis based on the sum of physician-assessed scores for severity of erythema, induration and desquamation multiplied by the extent of scalp involvement (range: 0 [no psoriasis] to 72 [severe disease]). Each individual symptom (redness, scaling, and infiltrate) is given a score on a 5-point scale (0 = no symptoms, to 4 = very severe. To determine the total PSSI score, these three values are added and multiplied with a value for the extent of involvement (% of involved area; 0 = 0% to 6 = 90–100%) [24]. NAPSI is calculated on each of the 10 fingernails by assessing the number of quadrants (0–4) in the nail with at least one issue in the nail matrix (nail pitting, leukonychia, red spots in the lunula, and crumbling) and the number of quadrants with at least one issue in the nail bed (onycholysis, oil drop [salmon patch] dyschromia, splinter hemorrhages, and nail bed hyperkeratosis). The nail matrix and nail bed scores are added to give the total NAPSI score on a scale of 0 (no fingernail involvement) to 80 (maximum fingernail involvement) [25]. In addition to evaluating the primary outcome of NAPSI75, we also assessed complete nail clearance (NAPSI 0) in a post hoc analysis.

Secondary endpoints included changes in additional outcome of psoriasis and health-related QoL. PASI captures the degree of disease severity combined with the extent of psoriatic inflammation over the whole body surface in a single score ranging from 0 (no disease) to 72 (worst disease status) [26]. Body Surface Area (BSA) assessments were used to determine the extent of the affected body surface, with one palm corresponding to about 1% of the body surface [27]. The Investigator`s Global Assessment (IGA) represents the investigator`s evaluation of the patient’s current disease activity on a 5-point Likert scale from 0 (no symptoms, best outcome) to 4 (severe state, worst outcome) [28]. The scalp-specific IGA (ssIGA) score uses the same Likert scale but only evaluates lesions on the scalp. The patient’s global assessment of disease activity, pain intensity, and pruritus severity were assessed using a visual analog scale (VAS) ranging from 0 mm (no activity or symptoms) to 100 mm (maximum disease activity/symptoms).

Involvement of the palms and soles was assessed by the use of the Palmoplantar Psoriasis Area Severity Index (PPASI), which provides a measure of the severity of erythema, desquamation, and pustules on palmoplantar surfaces on a scale ranging from 0 (none) to 4 (very severe) (0–4) and adjusted for the percentage of the affected area to give a total score ranging from 0 (no palmoplantar psoriasis) to 72 (severe palmoplantar psoriasis) [29]. The Dermatology Life Quality Index (DLQI) is a measure of health-related QoL in adults suffering from dermatologic conditions. It is composed of 10 questions concerning patients’ perception of the impact of skin diseases on various aspects of their health-related QoL in the past week. Scores range from 0 (no effect) to 30 (extremely large effect) [30, 31]. Treatment satisfaction was assessed on a VAS with 0 defined as “highly satisfied” and 100 as “not satisfied at all.”

This was an exploratory non-interventional study of response to brodalumab; thus, no formal hypothesis testing was performed. The study’s co-primary outcomes were chosen to provide additional information on the effectiveness of brodalumab in treating difficult-to-treat areas during routine care. All efficacy parameters were investigated using descriptive means. Two-sided 95% confidence intervals (CIs) were calculated with the Agresti-Coull method. Due to the exploratory nature of the study, the sample size was based on the number of patients who satisfied inclusion criteria during the recruitment period; a required sample size was not calculated.

The full analysis set (FAS) was defined as all participating patients who received brodalumab and had at least one post-baseline assessment. Primary effectiveness assessments were conducted on the effectiveness analysis set (EAS), defined as patients with a baseline assessment and a post-baseline assessment at week 12. Data from patients who discontinued the study at week 12 or later were included in analyses by use of last observation carried forward (LOCF) for the primary analyses only. Because the PSSI75 co-primary endpoint was based on week 12 data, no LOCF data were used for this analysis; the only analysis with LOCF imputed values was NAPSI75 at week 24. For all other effectiveness assessments, observed data are reported; data were not imputed. Safety analyses were conducted in the safety set, which included all patients who received at least one dose of brodalumab.

Summary statistics are reported as mean (standard deviation [SD]) for normally distributed variables and median (interquartile range [IQR]) for variables with a skewed distribution. Exploratory analyses of the impact of baseline PSSI/NAPSI scores used Spearman correlation coefficients. The concordance between NAPSI75 and PASI75 responses was evaluated by use of kappa coefficients.

Between December 8, 2018, and May 18, 2021, 87 patients were enrolled in the study at seven clinical and dermatology centers in Germany (Fig. 1). The last study visit was September 28, 2022. All patients received at least one dose of brodalumab and had at least one post-baseline assessment and were therefore included in both the FAS and the safety set. Sixty-two patients were included in the EAS. During the course of the study, 21 patients discontinued treatment without having reached their treatment goal (9 discontinued due to lack of effectiveness, 3 due to intolerance, 5 lost to follow-up, and 4 for other reasons) and 1 patient achieved their therapy goal at week 36 and did not continue in the study. At week 12, 83 patients (95.4%) remained in the study and this number decreased only slightly at week 24 (77 [88.5%]). Sixty-five patients (74.7%) were treated until the end-of-study visit at week 60.

Previous non-biologic systemic therapy was documented for 41 patients (28 fumaric acid, 27 methotrexate, 7 apremilast, 6 retinoids, 5 cyclosporine; some patients received more than one previous systemic therapy). For 46 patients, data on previous systemic therapy were missing. Previous biological therapy was documented for 22 patients; 13 had one previous biological therapy, 6 had 2, and 3 had >2 previous biological therapies. The most frequently used biologic therapies were adalimumab (n = 9), guselkumab (n = 6), secukinumab (n = 6), ixekizumab (n = 5), and ustekinumab (n = 2). All other biologic therapies were given to only 1 or 2 patients. For 65 patients, data for previous biological therapy were missing.

All patients in the EAS had both nail and scalp psoriasis (defined by a PSSI and NAPSI score >0 at BL). For the FAS there were 7 patients who did not have a medical history of scalp psoriasis, but all of them had a PSSI score >0 at BL. Additionally there were 2 patients who did not have a medical history of any other type of psoriasis other than psoriasis vulgaris, but both patients had a NAPSI and PSSI score >0 at BL. Five patients did not have a NAPSI score documented at BL, but only 1 patient of those did not have a medical history of nail psoriasis. All 5 patients had a PSSI score >0 at BL. One of the patients without a medical history of scalp psoriasis had a NAPSI score of 0 at baseline, but a history of nail psoriasis in their medical records.

The mean (SD) age of the patients in the FAS was 46.8 (14.4) and 28.7% were female (Table 1). Approximately three-quarters (72.4%) of patients had a pre-obese or obese BMI ≥25 kg/m². A history of smoking was common (72.4%) and 40.2% were current smokers. The baseline characteristics of patients in the EAS were similar (mean [SD] age of 47.2 [13.7], 27.4% female; 74.2% with a BMI ≥25 kg/m²). As expected from patients initiating a new psoriasis therapy, disease activity assessments indicated moderate-to-severe disease (Table 1).

The mean (SD) baseline PSSI score in the EAS was 15.2 (9.8), and this decreased to 3.1 (7.4) at week 12 (mean [SD] decrease of 75.1% [62.3]). Of the 62 patients in the EAS, 58 (93.6%) achieved a PSSI75 response at week 12 (95% CI 84.1%, 97.9%), the time point for the co-primary PSSI75 outcome. Improvements occurred rapidly; at week 2, 83.9% of patients had recorded a PSSI75 response (Fig. 2a). High levels of NAPSI75 achievement were also observed in brodalumab-treated patients, although as expected these improvements took longer to occur (Fig. 2b). The mean (SD) baseline NAPSI score was 25.2 (18.3) and this fell to 8.1 (11.6) at week 24 (mean [SD] NAPSI decrease of 60.3% [54.3]). At week 24, the time point for the co-primary NAPSI75 outcome, 56/62 patients (90.3%) achieved a NAPSI75 response (Fig. 2b); this analysis included 5 patients with data imputed by LOCF. Fifty-four patients (87.1%) achieved both primary outcomes. The Cohen’s kappa value was 0.35 (95% CI −0.05, 0.75), indicating moderate concordance between the two responses. No correlation was observed between baseline and week 12 PSSI scores (r = 0.057), but a good correlation was observed between baseline and week 24 NAPSI scores (r = 0.51).

A similar pattern of response to brodalumab as found in the EAS was observed in sensitivity analyses of the FAS, although percentages were lower due to patients with missing data. Of 87 patients, 53 (60.9%) achieved PSSI75 at week 12, 18 (20.7%) did not achieve PSSI75, and data were missing for 16 (18.4%). NAPSI75 was achieved by 59 patients (67.8%) at week 24, 8 (9.2%) did not achieve NAPSI75, and data were missing for 20 (23.0%). Complete nail clearance (NAPSI 0) was achieved by 29 patients with available data at week 24 (n = 67) (43.3%) and 33.3% of all patients in the FAS (n = 87, including 20 with missing data).

Observed median (IQR) PSSI scores in the FAS decreased from 14.0 (8, 24) at baseline (n = 87) to 0 (0, 3) at week 12 (n = 71) and 0 (0, 2) at week 24 (n = 68) (Fig. 3a). Observed median (IQR) NAPSI scores decreased from 19 (9, 36) at baseline (n = 82) to 9 (2, 24) at week 12 (n = 75) to 2 (0, 8) at week 24 (n = 67) (Fig. 3b). For both outcomes, low scores were maintained for the duration of the 60-week study.

There were no clear differences in baseline demographic characteristics between PSSI75 responders and non-responders. Although there was a higher proportion of males in the responder group (73.6% vs. 61.1% for non-responders), males and females had comparable PSSI75 response rates at week 12 (13/25 [52.0%] females with 5 missing values; 39/61 [63.9%] males with 11 missing values) and week 24 (16/25 [64.0%] females with 6 missing values; 39/61 [63.9%] males with 13 missing values). Comparable response rates were also observed for patients with BMI <25 kg/m² compared with BMI ≥25 kg/m² (59.1% vs. 61.9% at week 12; 68.2% vs. 61.9% at week 24).

Other measures of psoriasis, including PASI, BSA, IGA, and ssIGA, provided further confirmation of the reduction in disease activity in brodalumab-treated patients during the first 24 weeks of the study and continuing to week 60 (Table 2). Mean PASI values dropped rapidly and a PASI100 response was achieved by >90% of patients starting at week 2 and continuing up to week 60. Differences in PPASI values were less noticeable as only 17 patients in the FAS had palmoplantar psoriasis. Patient-reported outcomes, including DLQI, pruritus, pain, and patient’s assessment of psoriasis disease activity, showed strong improvements from baseline. Treatment satisfaction improved markedly from baseline to week 60 of brodalumab treatment (Table 2).

During the 60-week study, 43 adverse events were documented in 29/87 patients (33.3%). Adverse events could not be rigorously summarized due to lack of adequate medical coding and frequent use of free text entries. Based on the available information, 7 patients had a fungal infection (identified as Candida in 3 cases) and 4 patients had a viral or bacterial infection. Six patients reported fatigue, 4 reported pruritus, and 1 had an injection site reaction.

In this exploratory observational study, brodalumab was highly effective in reducing psoriasis symptoms in difficult-to-treat areas, specifically the scalp and nails. More than 90% of patients achieved a PSSI75 at week 12 (95.2%) and NAPSI75 at week 24 (90.3%), the co-primary endpoints. High levels of improvement in both outcomes were observed at the earliest time point, week 2. As has been demonstrated in phase 3 trials [12, 32, 33], other measures of psoriasis also showed strong improvements. Although our study did not include a control group, given the low PASI75 response rate of the placebo arms (2–10%) observed in brodalumab phase 3 clinical trials [12, 32, 33] it is reasonable to assume that the clinical effectiveness observed in the study patients is largely due to treatment with brodalumab.

The 87 patients enrolled in this study were generally representative of those with moderate-to-severe psoriasis initiating treatment with a new therapeutic agent. Although data on previous treatments were missing for the majority of patients, at least 41 patients had one or more previous non-biologic systemic therapies and at least 22 patients had at least one previous biological treatment. Patients reported a mean of 19 years since diagnosis. Elevated BMIs and current smoking or a history of smoking were common. Significant disease activity for overall psoriasis and for symptoms related to the nails and scalp were reported.

Psoriasis in difficult-to-treat or impactful areas is associated with increased psoriasis disease activity, as indicated by BSA, PASI, and IGA scores, and reduced health-related QoL [16, 34]. Management of difficult-to-treat areas can be challenging, but there is some evidence that IL-17 inhibitors may result in better outcomes than other biologics [20]. In our study, brodalumab, which binds to IL-17 receptor subunit A and inhibits signaling of four subunits of IL-17 including IL-17A and −17F, proved to be highly effective in reducing overall psoriasis symptoms as well as symptoms specific to the scalp and nails. This finding is consistent with secondary analyses from randomized trials of patients with psoriasis [22] and with other recent exploratory studies of brodalumab during “real-world use” [14, 35‒37]. In the phase 3 AMAGINE trials, PSSI75 was achieved by 89.0% of brodalumab-treated patients [22], which is similar to the 93.6% observed in our study. NAPSI75 was not reported, but the mean improvement in NAPSI between baseline and week 24 was 76.9% [22], which is somewhat higher than the 60.3% improvement observed in our study. However, the nail clearance (NAPSI 0) rate observed in our study (43.3% of patients with data) is higher than the corresponding rates for continuous brodalumab (31.6%) or continuous ustekinumab (18.8%) in the AMAGINE trials [22]. Our data suggest that the effectiveness of brodalumab reported in clinical trials is maintained during routine clinical care; lower treatment effectiveness during routine care versus clinical trials has been observed for some psoriasis therapies [38].

It can be misleading to compare data across studies due to variations in patient populations and study designs, but results from other studies can help provide important context for the data reported here. The PSSI75 response rate observed in our study was almost identical to the rate reported at 12 weeks in the ixekizumab UNCOVER trials (93.6% vs. 93.0%), while the 75.1% improvement in PSSI values observed in our study was slightly higher than the 71.0% improvement observed in the secukinumab SCALP study [39]. The mean NAPSI improvement of 60.3% at 24 weeks observed in our study was lower than reported for ixekizumab at 24 weeks (77.5%) but higher than the 52.6% improvement reported at 32 weeks in the secukinumab TRANSFIGURE study, despite the fact that nail improvements generally increase over time [40]. The rate of nail clearance (NAPSI 0) in our study was also slightly lower than for ixekizumab (43.3% vs. 52.0%) [40].

Although safety assessments are better suited to clinical trials, we did not observe unexpected adverse events over the 60 months of this study. The favorable tolerability of brodalumab is further suggested by the 24.1% discontinuation rate over 60 months in this observational study. This rate is in line with the 1-year discontinuation rate of 23.4% observed for first-line biologics during routine clinical care in patients with psoriasis [41]. In addition, treatment satisfaction increased markedly after brodalumab initiation and remained favorable throughout the 60-month study.

Limitations of our study are representative of those encountered in observational studies, including deficiencies in reporting prior and concomitant medication and missing data points for outcomes at some visits. We used LOCF to impute data for the co-primary analysis of NAPSI75 at week 24, which may have over- or under-influenced our estimation of brodalumab effectiveness. Outcome assessments may have been affected by responder bias, in which patients who are doing well on an intervention are more likely to continue in the study. However, it is notable that strong improvements in psoriasis outcomes were already observed at 2 weeks, prior to any study discontinuations.

Based on the data reported here, we conclude that brodalumab is highly effective in patients with psoriasis and scalp or nail involvement during routine clinical care. The improvements associated with brodalumab continued to be observed throughout the 60-month study. Brodalumab thus provides a rapid, effective, long-term option for management of psoriasis affecting difficult-to-treat areas.

In everyday clinical practice, brodalumab is effective for patients with psoriasis affecting difficult-to-treat body regions.

We thank the patients and medical staff who participated in this study and Sharon L. Cross, PhD, who provided medical writing support under the direction of the authors with funding from the Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.

The study protocol was reviewed and approved by the Ethics Committee of the University Hospital Frankfurt on November 11, 2018 (No. 56/18). Additional ethical approvals were obtained from each of the study centers that participated in the study. The study was conducted in accordance with the Declaration of Helsinki and all patients provided written informed consent for study participation.

S.D., A.C.F., K.H., C.K., A.K., I.H., M.K., and C.M. do not have any conflicts of interest to disclose. A.P. has served as an advisor, and/or paid speaker, and/or participated in clinical trials sponsored by: AbbVie, Almirall-Hermal, Amgen, Biogen Idec, Biontec, BMS, Boehringer-Ingelheim, Celgene, Celltrion, GSK, Eli-Lilly, Eva Pharma, Galderma, Hexal, Incyte, Janssen-Cilag, Klinge Pharma LEO Pharma, MC2, Medac, Merck Serono, Mitsubishi, Moonlake, MSD, Novartis, Pascoe, Pfizer, Tigercat Pharma, Regeneron, Roche, Sandoz Biopharmaceuticals, Sanofi-Genzyme, Schering-Plough, UCB Pharma, and Züllig Pharma.

Financial support for this study was provided by LEO Pharma, which holds the license to develop and market brodalumab in Europe.

M.K., A.P., S.D., A.C.F., and A.K. were involved in conceptualizing the clinical study. A.C.F., K.H., and C.K. performed statistical analyses. C.M. provided coordination support for the clinical study. I.H. recruited, supervised, and processed patients for the study center in Frankfurt. A.C.F., K.H., C.K., A.P., and S.D. interpreted the data. S.D. drafted the manuscript. All authors reviewed the manuscript draft and approved the manuscript for submission.

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author [A.P.] upon reasonable request.