FormalPara Key Points

Brodalumab is an effective treatment for psoriasis also for patients with previous failure or intolerance to multiple biologics.

Preliminary results indicate that brodalumab is effective against psoriatic arthritis in a real-world setting.

1 Introduction

Psoriasis is a chronic inflammatory skin disease with an estimated worldwide prevalence of 2–3%. Regional prevalences vary, and Scandinavia is one of the regions with the highest prevalence [1,2,3]. The addition of biological agents to the treatment armamentarium for psoriasis has revolutionised its management. Since the early 2000s, several biologics have been approved. The first generation of biologics was tumour necrosis factor alpha (TNF-α) inhibitors. Since the discovery of the importance of the interleukin 23 (IL-23) and T-helper-17 axis in the pathogenesis of psoriasis, several drugs targeting IL-23 and IL-17 have been developed [4]. They are often referred to as second-generation biologics. Four IL-17 inhibitors have currently been approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA): first secukinumab (2015), then ixekizumab (2016) and brodalumab (2017) and most recently bimekizumab (2021). The mechanism of action of brodalumab differs from that of the selective IL-17A inhibitors secukinumab and ixekizumab. Brodalumab is a human monoclonal antibody that binds to the IL-17 receptor A, thereby blocking the signalling of several IL-17-family cytokines [IL-17A, IL-17C, IL-17E (IL-25), IL-17F and IL17A/F], which may yield a more complete suppression of the inflammatory process in the skin [5,6,7]. Meta-analyses of randomised clinical trials (RCTs) and real-world studies indirectly comparing the effectiveness of the IL-17 inhibitors suggest a comparable or even favourable effectiveness of brodalumab [8,9,10,11,12]. Moreover, both direct and indirect comparisons suggest that brodalumab has a faster onset of action than other biologics[13, 14].

The randomised clinical phase III trials AMAGINE-1, -2 and -3 have shown promising efficacy and safety profile of brodalumab in the treatment of psoriasis [15, 16]. Similar adverse events known to be associated with other IL-17 inhibitors were reported for brodalumab (arthralgia, oropharyngeal pain, headache, fatigue, Candida infections). Up to 30% of patients with psoriasis also develop psoriatic arthritis (PsA) [17]. The phase III AMVISION-1 and -2 trials have also shown promising results for the treatment of PsA with brodalumab [18]. The FDA and the EMA approved brodalumab for moderate to severe psoriasis in 2017 [19, 20]. However, only Japan has currently approved it for the treatment of PsA [21].

Brodalumab became available for clinical use in Denmark in 2018. So far, only limited real-world evidence is available on the drug survival and effectiveness of brodalumab in the treatment of psoriasis and PsA. Thus, the objective of this study was to investigate the drug survival and effectiveness of brodalumab in the treatment of psoriasis and PsA in a real-world setting.

2 Methods

2.1 Design and Study Population

In this observational study, data were retrospectively collected from patients with psoriasis who were receiving out-patient treatment with brodalumab at the Department of Dermatology, Aarhus University Hospital, Denmark. The study included all patients who started treatment with brodalumab due to psoriasis in the period from 30 November 2017 to 17 January 2022. Data were collected until 16 May 2022. Some patients (n = 6) received treatment as part of post-approval investigator-initiated phase IV clinical trials. These patients were included in the study as the inclusion criteria for the trials were in line with indications for initiation of treatment with biologics provided in Danish guidelines, i.e. PASI > 10 and previous inadequate response or intolerance to methotrexate [22]. Among these patients, three resumed brodalumab treatment after initially having discontinued treatment following completion of the trial. The two treatment sequences were merged, meaning that treatment duration for these patients was calculated from the date of the first treatment initiation to the last registered date of active treatment. The interval between the two treatment courses (2.8, 4.0 and 4.5 months) was subtracted from the total treatment duration for each patient.

Data were retrieved from electronic patient journals and the DERMBIO database of patients with psoriasis who have been treated with biologics in Denmark. The collected data included demographic characteristics, previous and current treatments, presence of PsA, age at onset of psoriasis and disease duration, duration of brodalumab treatment and reasons for discontinuation of brodalumab treatment. Furthermore, the patient’s score on the Dermatology Quality of Life Index (DLQI) was registered at initiation and on the last day of follow-up. The patient’s score on the Psoriasis Area and Severity Index (PASI) was registered at treatment initiation, in weeks 12–17, weeks 40–60 and at the end of follow-up.

Reporting of this study adheres to the standard for reporting of observational studies as defined in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [23].

2.2 Outcomes

The primary outcomes in this study were (1) drug survival, defined as the time patients remained on brodalumab, (2) reasons for discontinuation, (3) the percentage of patients achieving an absolute PASI ≤ 2 at weeks 12–17, weeks 40–60 and at the end of follow-up, and (4) the clinical effectiveness against PsA. PsA response was categorised as described in a recently published study [24]: (1) unknown; (2) remission, defined as no inflammatory joint pain and no clinically active inflammation; (3) partial remission, defined as limited inflammatory activity with a need for non-steroidal anti-inflammatory drugs (NSAIDs) and/or sporadic use of steroid injections; and (4) failure, defined as disease activity with joint swelling and/or disease progression on X-ray or magnetic resonance imaging (MRI).

The secondary outcomes were the percentage of patients having achieved a DLQI of 0 or 1 (DLQI 0/1) at the end of follow-up and the percentage having achieved a 100% or 90% reduction in PASI from baseline (PASI100 and PASI90) to weeks 12–17, weeks 40–60 and the end of follow-up.

2.3 Statistical Analysis

Data were summarised using descriptive statistics. For each variable, only patients without missing data were included in the analysis. Continuous variables were described using mean ± standard deviation (SD). Categorical variables were described by absolute and relative frequencies. The chi-squared and Fisher’s exact tests were used to test for association between categorical variables. Drug survival was assessed by Kaplan–Meier estimates, and drug survival in different subgroups was compared using the log-rank test. Patients were censored if they were still receiving treatment at the analysis cut-off date. Statistical significance was set to α = 0.05. Statistical analyses were performed with Stata/MP 17.0 (StataCorp LLC, College Station, TX, USA).

3 Results

3.1 Study Population

Baseline characteristics of the 83 included patients are presented in Table 1. Among the 83 patients, 49 (59.0%) were male. The patients had a mean disease duration of 25.0 ± 15.1 years, and the age at brodalumab treatment initiation ranged between 17 and 87 years (mean 49.2 ± 17.4 years). Most patients (90.4%) had a previous inadequate response or intolerance to ≥ 1 biologic. The most frequent previous biologic was anti-TNF-α [66 (79.5%)], whereas as many as 43 (51.8%) had tried another IL-17 inhibitor prior to commencing brodalumab treatment. The mean body mass index (BMI) was 30.3 ± 6.2 kg/m2, and 65 out of 80 patients (81.3%) were classified as overweight (BMI ≥ 25 kg/m2). Joint problems associated with psoriasis was a common comorbidity, as PsA was present in 18 (21.7%) of the patients, whereas 24 (28.9%) had psoriatic arthropathy corresponding to inactive psoriatic arthritis, i.e. psoriatic joint and/or entheseal symptoms with no current swollen joints at rheumatologic assessment.

Table 1 Characteristics of the study population
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3.2 Drug Survival

At the end of the study period, 27 patients (32.5%) had discontinued treatment (Table 2). The primary reasons for discontinuation were ineffectiveness on skin and joint symptoms (55.6%) and adverse events (33.3%). Two patients discontinued due to other reasons: one because of hospitalisation with general weakness and urinary tract infections, and one had passed away. We were unable to retrieve data on the cause of death.

Table 2 Reasons for discontinuation
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Figure 1 shows the drug survival rate during the study period. At the end of follow-up, the mean (SD) treatment duration was 51.9 (47.8) weeks, ranging from 2 weeks to 233 weeks. Kaplan–Meier survival at 12 weeks, 24 weeks and 52 weeks was estimated as 91.6%, 81.3% and 65.7%, respectively. After 77 weeks and until 233 weeks, the probability of survival remained at 57.2%, and median drug survival was not reached.

Fig. 1
figure 1

Kaplan–Meier-estimated drug survival of brodalumab

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No statistically significant association was found between drug survival, baseline PASI ≥ 10 (P = 0.91), BMI ≥ 30 (P = 0.70), previous treatment with > 2 biologics (P = 0.64) or previous use of other IL-17 inhibitors (P = 0.64) (Fig. 2).

Fig. 2
figure 2

Drug survival of brodalumab by a previous treatment with ≤ or > 2 biologics (log-rank test, P = 0.64), b previous treatment with other IL-17 inhibitors (P = 0.64), c BMI < 30 or ≥ 30 (log-rank test, P = 0.70), and d Baseline PASI ≥ 10 or < 10 (log-rank test, P = 0.91). BMI body mass index, IL interleukin, PASI Psoriasis Area and Severity Index

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3.3 Psoriasis Area and Severity Index

PASI response was analysed in patients with available data (Table 3). Mean (SD) PASI was reduced from 10.9 (6.9) at baseline to 2.1 (3.8) at the end of follow-up. An absolute PASI ≤ 2 was achieved by 68.2% of patients. A PASI100 response was achieved by 55.8%, whereas 65.4% achieved a PASI90 response at the end of follow-up.

Table 3 Effectiveness of brodalumab at the end of follow-up and weeks 12–17 and 40–60
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PASI response was also assessed after 12–17 weeks and 40–60 weeks of treatment. After 12–17 weeks, the mean (SD) PASI had decreased to 1.6 (2.4), 70.0% had a PASI of 2 or less, whereas PASI100 and PASI90 response rates were 57.9% and 73.7%, respectively. After 40–60 weeks of treatment, the mean (SD) PASI was 1.2. PASI ≤ 2, PASI100 and PASI90 were achieved by 76.2%, 63.2% and 68.4%, respectively.

Neither at the end of follow-up nor at the two timepoints was there any statistically significant association between achieving PASI ≤ 2, PASI90 or PASI100 and having a baseline PASI ≥ 10, BMI ≥ 30 or previously having received treatment with > 2 biologics or other IL-17 inhibitors (P > 0.05). At weeks 12–17, a tendency was observed towards fewer patients with BMI ≥ 30 achieving PASI100 compared with patients with BMI < 30. However, this trend did not reach significance (P = 0.07) and was not seen at weeks 40–60 or at follow-up. Furthermore, a lower percentage of patients having previously received more than two biological treatments achieved PASI90 and PASI100 at follow-up (Fig. 3). This difference between the groups was not observed at weeks 12–17 or 40–60 or for PASI ≤ 2, and it did not reach significance at follow-up (P = 0.07).

Fig. 3
figure 3

Percentage of patients achieving PASI90, PASI100 and PASI ≤ 2 at the end of follow-up in patients who have previously received ≤ 2 versus > 2 biologics

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3.4 Psoriatic Arthritis

Eighteen patients (21.7%) had PsA. Among these, eight (44.4%) experienced complete remission of their PsA, whereas two patients (11.1%) experienced partial remission. Treatment failure in terms of PsA response was registered in five patients (27.7%). In two patients, the PsA response was difficult to evaluate as the patients experienced joint pain, but rheumatologists deemed it likely that the pain was a side effect of the brodalumab treatment. One patient experienced back pain, which doctors thought was more likely due to the patient’s daily physical activities. However, an MRI was pending at the cut-off date for this analysis.

3.5 Quality of Life

Following brodalumab treatment, DLQI was reduced from a mean (SD) of 8.2 (5.5) at baseline to 2.9 (4.4) at the end of follow-up. Furthermore, 60.8% of the patients obtained a DLQI of either 0 or 1.

4 Discussion

This study confirms that brodalumab is an effective treatment of psoriasis and PsA in difficult-to-treat patients. Apart from a small case series, we are, to our knowledge, the first to present real-world data regarding the effectiveness of brodalumab against PsA [25].

In this study, 1-year drug survival was estimated at 65.7%. We have previously investigated the drug survival of IL-23 inhibitors at the Department of Dermatology, Aarhus University Hospital. IL-23 inhibitors as a group had a 1-year survival of 81.0%. As data in the two studies originate from the same centre, the results are appropriate for comparison. In addition to the lower overall drug survival of brodalumab compared with IL-23 inhibitors, the survival of brodalumab rapidly decreased until week 31, whereafter the survival declined at a slower rate and became constant after week 77. The lower survival rate of brodalumab and the steep fall in survival may be due to the effectiveness and mode of action of the drug itself, but other factors also need to be considered. Brodalumab has previously been recommended as a second-line biologic treatment option in Denmark. This may potentially have caused clinicians to switch patients more readily to other treatment options if the response was suboptimal [26]. Furthermore, brodalumab is considered to have a rapid onset of action, which may also expedite the decision of moving on to other treatment options in case of a suboptimal response [13].

The observed drug survival was also lower than what has been reported in other real-world studies. A Greek multi-centre study of 180 brodalumab-treated patients found a 1-year drug survival of 91.8%, whereas a smaller study (n = 24) reported a 1-year survival rate of 73.0% [27, 28]. Other studies have reported 1-year survival rates within this range [8, 29,30,31,32,33]. Data on 2-year survival rates are not as readily available. However, Torres et al. reported a survival rate similar to ours, whereas Tampuratzi et al. and Papadavid et al. reported very high drug survivals of 83.8% and 78.8%, respectively [27, 30, 32]. One important difference between the patient populations in the mentioned studies is the percentage of bio-naïve patients. This percentage was markedly lower in our study (9.6%) than in most of the other studies (37.5–58.3%) [8, 27, 28, 30,31,32].

The AMAGINE-1/2/3 trials reported PASI90 and PASI100 response rates at week 12 of 68.9–70.3% and 36.7–44.4%, respectively [15, 16]. After 52 weeks, the AMAGINE-2/3 trials reported PASI90 response rates of 73% and 75% for patients who had received continuous 210 mg brodalumab, whereas the results for PASI100 were 56% and 53%, respectively. Our results are difficult to compare with the results from these two trials due to the manner in which missing data were handled and due to the inherent differences between the setup of RCTs and real-world clinical practice. The population in the present study represented difficult-to-treat patients who had tried multiple biologic treatments prior to brodalumab. The baseline PASI in the RCTs was higher than the baseline PASI in our study, which may potentially also explain some of the observed differences as a high baseline PASI is a known predictor of achieving PASI90 [34]. Furthermore, an absolute PASI ≤ 2 has been suggested as a meaningful and favourable treatment goal [35, 36]. We therefore chose absolute PASI ≤ 2 to evaluate the effectiveness of brodalumab. At the end of follow-up, 68.2% of patients had achieved PASI ≤ 2. Results from other real-world studies are somewhat varying, as PASI ≤ 1 has been reported in 31.0–76.2% and PASI ≤ 3 or < 3 in 55.2–86% of patients after 12 weeks of treatment [28, 31, 32, 37,38,39]. We found PASI ≤ 2 in 70.0% of patients after 12–17 weeks of treatment. Three studies have reported PASI ≤ 3 or < 3 to fall in the 82.7–92.2% range after 48 weeks of treatment, which is higher than our findings for PASI ≤ 2 after 40–60 weeks of treatment (76.0%) [31, 32, 37]. Some of the variances may be explained by the diverse complexity of the patients in the studies. Additionally, the manner in which missing data were handled at the timepoints differed between some of the studies. Fargnoli et al. and Galluzzo et al. used the last observation carried forward method, whereas we only included patients with available data in the analyses at weeks 12–17 and 40–60 [37, 38].

Our results for the clinical effectiveness of brodalumab were comparable to our results for IL-23 inhibitors in terms of achieving PASI ≤ 2 at the end of follow-up, but the percentage of patients achieving PASI ≤ 2, PASI100 and PASI90 at the end of follow-up and at weeks 12–17 and 40–60 was higher for brodalumab [24].

The response to the treatments that are available for psoriasis varies from patient to patient, and many patients will try multiple biologics and other systemic treatments during the course of their disease. We did not find drug survival or clinical effectiveness against psoriasis in terms of achieving PASI ≤ 2 or PASI90/100 to be associated with either previous treatment with more than biologics or having previously been treated with any other IL-17 inhibitor. Our results regarding clinical effectiveness are consistent with the literature [40]. Other studies have reported an association between bio-experience and lower drug survival and lower response rates [8, 28, 30, 39]. Our findings suggest that brodalumab is a valuable option also for patients with previous failure or intolerance to other biological therapies.

The effectiveness of some biologics is known to be influenced by body weight [41, 42]. The systemic exposure of brodalumab has been shown to be lower in patients with a higher body weight [43]. Additionally, an association between body weight, brodalumab serum levels and clinical response has been reported [44, 45]. A phase II trial reported declining PASI response rates with increasing body weight [46]. Meanwhile, a post hoc analysis of the AMAGINE-2/-3 trials did not find BMI to be significantly associated with brodalumab efficacy. In the present study, we saw a trend towards fewer patients with a BMI ≥ 30 achieving PASI100 after 12–17 weeks of treatment. An ongoing phase IV trial is currently investigating if increasing the dosage of brodalumab will improve its the efficacy in patients with a higher body weight (NCT04306315).

Up to 30% of patients with psoriasis also suffer from PsA, making treatment options that can help both conditions desirable. The phase III trials AMVISION-1 and AMVISION-2 have shown brodalumab to be effective in improving PsA signs and symptoms [18]. In the trials, brodalumab was demonstrated to be superior to placebo until week 24 as significantly more patients treated with brodalumab achieved the American College of Rheumatology 20 (ACR20) response. Data assessing the long-term efficacy profile of brodalumab is lacking. Furthermore, real-world data regarding the effectiveness of brodalumab against PsA are scarce. In the present study, we found that more patients experienced improvement than failure. These preliminary findings are promising but must be underpinned by more real-world evidence.

We found no new serious AEs to be associated with brodalumab in addition to the AEs previously reported in RCTs [15, 16, 47, 48].

The limitations to this study include its retrospective nature and the relatively small sample size. A washout period before initiating brodalumab treatment was not required for study inclusion. This could confound the reported PASI response rates. Another limitation is that only patients with available data were included in the analysis of PASI response, which leaves a risk of survival bias. The strengths of this study include the long follow-up time (up to 233 weeks) and the thorough evaluation of the effectiveness of brodalumab through several clinical measures. Real-world evidence is important to fully comprehend the effectiveness and potential limitations of new treatments. The complex patients in real-world studies would often not meet the inclusion criteria for RCTs, which investigate the efficacy of drugs under ideal circumstances. Thus, the results from the present study may complement the findings from RCTs as they add to the available knowledge on the use of brodalumab in real-world settings.

5 Conclusions

In summary, this real-world study showed brodalumab to be an effective treatment for psoriasis, with a high percentage of patients achieving PASI ≤ 2. The drug survival rate was lower than previously reported. In most parts of the world, brodalumab is not yet approved for PsA treatment. However, the results found in this study are promising but need to be supported by studies with larger sample sizes.