As the treatment landscape for plaque psoriasis continues to evolve, the dermatology community has another exciting biologic therapy available in its versatile armamentarium. Bimekizumab-bkzx (BIMZELX®) is the first and only dual interleukin-17A (IL-17A) and IL-17F inhibitor biologic approved for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Findings from UCB’s four phase 3 clinical trials in psoriasis (BE READY, BE SURE, BE VIVID, and BE RADIANT) established the efficacy and safety of bimekizumab-bkzx and expanded our understanding of the synergistic role of IL-17A and IL-17F in psoriatic disease.

In summary, the BE READY trial established the rapid and sustained efficacy of bimekizumab-bkzx and showed that it was well-tolerated over 56 weeks compared to placebo. The BE SURE trial evaluated the clinical response of bimekizumab-bkzx over 56 weeks in comparison to adalimumab, a broad-acting tumor necrosis factor (TNF) inhibitor. The BE VIVID trial was a 52-week head-to-head study that reported the relative efficacy and safety of bimekizumab-bkzx compared to ustekinumab, a dual IL-12 and IL-23 inhibitor. Finally, the BE RADIANT trial was a phase 3b, head-to-head study evaluating the efficacy and safety of bimekizumab-bkzx’s inhibition of IL-17A and IL-17F versus secukinumab, which selectively inhibits IL-17A alone.

The implications of the data from bimekizumab-bkzx’s clinical studies are profound. Collectively, these four pivotal clinical studies highlight the rapid-onset, superior skin clearance, durability, and comparative safety of bimekizumab-bkzx in a highly competitive treatment landscape. Additionally, UCB’s extensive trial program for bimekizumab-bkzx raises the bar for the percentage of patients rapidly achieving complete skin clearance and offers a promising outlook to patients suffering with psoriatic disease.

Such head-to-head, comparative studies are essential for making informed decisions about treatment selection in clinical practice at the point of care. Considering the appropriateness of any treatment for our psoriasis patients is central to personalized medicine. As we interpret the data from these phase 3 trials, dermatologists must therefore weigh the exceptional efficacy data against the risk of potential side effects. Moving forward, continuous evaluation of real-world results and vigilance regarding safety data will be key to optimizing patient outcomes with this exciting therapeutic option.

Bimekizumab Efficacy and Safety in Moderate to Severe Plaque Psoriasis (BE READY): A multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial¹

https://pubmed.ncbi.nlm.nih.gov/33549192/

Summary

The phase 3 BE READY trial assessed the efficacy and safety of bimekizumab-bkzx for the treatment of moderate to severe plaque psoriasis as well as the effects of treatment withdrawal over 56 weeks. Conducted across 77 sites in Asia, Australia, Europe, and North America, this trial involved adult patients with an average baseline Psoriasis Area Severity Index (PASI) score of 20. These patients were randomly assigned to receive bimekizumab-bkzx 320 mg or placebo every 4 weeks, with coprimary endpoints measured as the proportion of patients achieving PASI 90 and the Investigator’s Global Assessment (IGA) of 0 or 1 (clear or almost clear skin) at week 16.

Out of 435 patients, those treated with bimekizumab-bkzx showed remarkable disease improvement; 91% achieved PASI 90, and 93% reached an IGA score of 0/1, compared to only 1% of the placebo group. After week 16, patients who achieved PASI 90 on bimekizumab-bkzx were rerandomized to continue the same dose every 4 weeks or every 8 weeks, or to switch to placebo. The therapeutic responses were sustained through week 56 on both bimekizumab-bkzx dosing regimens. For patients randomly assigned back to placebo, the median time to relapse, defined as loss of PASI 75, was 32 weeks from the last dose. These findings are important in real-life situations when patients may miss a dose of medication for reasons outside of their control (eg, surgery or insurance issues).

The overall safety profile was favorable, with only 2% of bimekizumab-bkzx–treated patients experiencing serious adverse events up to week 16 and similar safety patterns out to week 56. Commonly reported adverse events included nasopharyngitis, oral candidiasis, and upper respiratory tract infections. Hepatic events occurred in 1% to 8% of patients at week 56 and were predominantly transient liver enzyme elevations that did not require bimekizumab-bkzx dose adjustments. There were no instances of death, inflammatory bowel disease, or adjudicated suicidal ideation and behavior throughout the study.

Dr. Hawkes’ Commentary

The BE READY trial study reinforced the premise that IL-17F signaling plays a role in the development of psoriatic disease. Specifically, the selective inhibition of IL-17F, in addition to IL-17A, can improve clinical outcomes for patients experiencing moderate to severe plaque psoriasis. This enhanced clinically efficacy and increased rates of candidiasis compared to IL-17A inhibition alone are presumably the result of more complete suppression of the predominant IL-17 cytokine signaling pathway in the skin.

The trial’s robust, multicentre, randomised, double-blind, placebo-controlled design involved 435 patients across multiple regions, ensuring a comprehensive evaluation of bimekizumab-bkzx’s efficacy and safety. Bimekizumab-bkzx showed remarkable speed and efficacy in the treatment of moderate to severe plaque psoriasis over this 56-week period. The results at week 16 were striking, with 91% of patients on bimekizumab-bkzx achieving PASI 90 compared to only 1% in the placebo group. Furthermore, 93% of bimekizumab-bkzx–treated patients reached an IGA score of 0/1. These clinical observations are profound, not only in the magnitude of the treatment response but also in the rapidity with which improvements were observed. This study adds to our current understanding of the immunopathogenesis of psoriasis and underscores the therapeutic advantage of simultaneously blocking both IL-17A and IL-17F.

Importantly, the observed clinical responses were maintained through week 56, and both maintenance dosing schedules of bimekizumab-bkzx (every 4 or 8 weeks) proved efficacious. The ability to maintain treatment response with an extended dosing interval is particularly noteworthy because it speaks to the durability of bimekizumab-bkzx’s therapeutic effects and offers flexible dosing in clinical practice. Less frequent dosing, compared to other IL-17–inhibiting medications, also has the potential to reduce the treatment burden for patients and improve overall medication adherence.

The safety profile of bimekizumab-bkzx seen in the BE READY trial was comparable to that of other medications in the same therapeutic class. Though the occurrence of treatment-emergent adverse events was higher in the bimekizumab-bkzx group compared to placebo during the initial 16-week period, most of these were mild with no unexpected safety findings over the entire duration of the study. This aspect is critical because long-term safety is a paramount consideration in the management of a chronic condition such as plaque psoriasis. Limitations to the study include the absence of a head-to-head comparison with competing biologic medications and limited racial diversity among participants.

1. Gordon KB, Foley P, Krueger JG, et al. Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY): a multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial. Lancet. 2021;397(10273):475-486. doi:10.1016/S0140-6736(21)00126-4

Bimekizumab Versus Adalimumab in Plaque Psoriasis (BE SURE)²

https://pubmed.ncbi.nlm.nih.gov/33891379/

Summary

In the BE SURE phase 3 trial, the efficacy and safety of bimekizumab-bkzx was compared with those of adalimumab, a TNF inhibitor, for the treatment of moderate to severe plaque psoriasis. The study enrolled 478 patients who were randomly assigned to three groups: bimekizumab-bkzx at a dose of 320 mg every 4 weeks; bimekizumab-bkzx at a dose of 320 mg every 4 weeks for 16 weeks, then every 8 weeks; or adalimumab at a dose of 40 mg every 2 weeks for 24 weeks, followed by bimekizumab-bkzx at a dose of 320 mg every 4 weeks.

The primary end points were a 90% or greater reduction from baseline in the PASI score (PASI 90 response) and an IGA score of 0/1 (clear or almost clear skin) at week 16.

• PASI 90 response: Results showed that 86.2% of patients receiving bimekizumab-bkzx achieved PASI 90 response at week 16 compared to 47.2% in the adalimumab group, demonstrating bimekizumab-bkzx’s noninferiority and superiority.
• IGA 0/1 response: Similarly, 85.3% of bimekizumab-bkzx patients achieved an IGA score of 0/1 compared to only 57.2% for adalimumab.

Secondary endpoints, PASI 100 response (complete skin clearance) and PASI 75 response, also favored bimekizumab-bkzx. These efficacy levels were maintained through week 56 regardless of the bimekizumab-bkzx dosing regimen.

Patients initially treated with adalimumab who switched to bimekizumab-bkzx at week 24 showed increased clinical responses, reaching levels similar to those who received bimekizumab-bkzx at the outset. This finding is important for patients who may need to switch therapies owing to an inadequate treatment response or intolerance. Bimekizumab-bkzx demonstrated higher efficacy than adalimumab in for the treatment of moderate to severe plaque psoriasis over 24 weeks with clinical responses maintained for up to 56 weeks. Although bimekizumab-bkzx was associated with a higher frequency of oral candidiasis (9%–17%) and diarrhea (1%–5%), most adverse events were considered mild and did not lead to treatment discontinuation. Of note, no deaths, major adverse cardiac events, or inflammatory bowel disease events were associated with bimekizumab-bkzx treatment.

Dr. Hawkes’ Commentary

The BE SURE phase 3 trial represents an advance over traditional TNF inhibitors such as adalimumab. The trial’s results provide valuable comparative treatment data on the efficacy of bimekizumab-bkzx against a well-established biologic for the treatment of psoriatic disease. In my opinion, such comparative studies are essential for making informed decisions with our patients about treatment selection in clinical practice.

The study’s results at week 16 showed that bimekizumab-bkzx was not only noninferior but also superior to adalimumab in achieving PASI 90 and IGA 0/1. This superiority was evident in both the 4- and 8-week maintenance dosing regimens of bimekizumab-bkzx (320 mg).

Of note, bimekizumab-bkzx’s rapid and sustained improvements in psoriasis manifestations and symptoms were observed in patients as early as 2 to 4 weeks. This rapid onset of action, coupled with sustained efficacy up to week 56, aligns well with the goals of achieving rapid symptom relief and long-term disease control for psoriasis.

For patients initially on adalimumab, switching to bimekizumab-bkzx after 24 weeks led to improved clinical outcomes. This finding is particularly relevant for patients not responding adequately to TNF inhibitors, indicating that switching to a dual IL-17A and IL-17F inhibitor represents a viable therapeutic strategy.

The effectiveness of two different dosing regimens of bimekizumab-bkzx is advantageous because it offers flexibility in personalizing treatment plans based on patient needs and preferences and individual clinical responses. This flexibility can enhance patient adherence and overall satisfaction with treatment.

The BE SURE trial revealed a higher frequency of oral candidiasis and diarrhea with bimekizumab-bkzx. Given the innate protective role of IL-17 in the skin and mucosa, particularly against Candida, this side effect profile is not unexpected following more complete blockade of IL-17 cytokine signaling. Dermatologists should be aware of these potential treatment-related adverse events and educate patients accordingly, with an emphasis on the importance of infection surveillance and appropriate medical management, which is relatively simple and straightforward.

Overall, the BE SURE trial’s findings affirm the role of bimekizumab-bkzx as a highly effective treatment for moderate to severe plaque psoriasis. It offers a superior alternative to traditional, broad-acting TNF inhibitors, which have been largely replaced by newer IL-17 and IL-23 inhibitors for skin disease control. These results have the potential to modify conventional treatment strategies in psoriasis patients who have both skin and joint disease.

2. Warren RB, Blauvelt A, Bagel J, et al. Bimekizumab versus adalimumab in plaque psoriasis. N Engl J Med. 2021;385(2):130-141. doi:10.1056/NEJMoa2102388

Bimekizumab Versus Ustekinumab for the Treatment of Moderate to Severe Plaque Psoriasis (BE VIVID): Efficacy and safety from a 52-week, multicentre, double-blind, active comparator, and placebo-controlled phase 3 trial³

https://pubmed.ncbi.nlm.nih.gov/33549193/

Summary

The BE VIVID phase 3 trial was conducted to evaluate the efficacy and safety of bimekizumab-bkzx compared to placebo and ustekinumab for the treatment of moderate to severe plaque psoriasis over 52 weeks.

The study involved 567 patients across 105 sites in 11 countries who were randomly assigned to receive bimekizumab-bkzx 320 mg every 4 weeks; ustekinumab 45 or 90 mg (dosed according to the label) at weeks 0 and 4, then every 12 weeks; or placebo every 4 weeks. After week 16, placebo recipients were switched to bimekizumab-bkzx. The primary outcomes were PASI 90 and an IGA score of 0/1 at week 16.

At week 16, bimekizumab-bkzx showed superior efficacy, with 85% of patients achieving PASI 90 compared to only 50% and 5% for ustekinumab and placebo, respectively. Similarly, 84% of bimekizumab-bkzx patients reached an IGA score of 0/1 compared to 53% and 5% for ustekinumab and placebo, respectively. Over the 52-week period, serious adverse events were reported in 6% of patients in the bimekizumab-bkzx group (including those switched from placebo) and 8% of the patients in the ustekinumab group.

The trial concluded that bimekizumab-bkzx significantly outperformed placebo and ustekinumab, confirming bimekizumab-bkzx’s robust efficacy in achieving skin clearance in psoriasis compared to dual IL-12 and IL-23 blockade. The safety profile of bimekizumab-bkzx was consistent with previous phase 3 studies, suggesting it is a well-tolerated and effective long-term treatment option for patients with moderate to severe plaque psoriasis.

Dr. Hawkes’ Commentary

What stands out from the BE VIVID trial is not just the efficacy but also the speed of onset and durability of the therapeutic effect of bimekizumab-bkzx. Meaningful clinical responses were again observed within the first 2 weeks of bimekizumab-bkzx treatment, and more than 50% of patients achieved PASI 100 between weeks 8 and 12.

Through 52 weeks, bimekizumab-bkzx continued to show a favorable and consistent efficacy and safety profile. The safety profile of bimekizumab-bkzx was in line with previous phase 3 studies with no unexpected safety signals. Most common adverse events included nasopharyngitis, oral candidiasis, and upper respiratory tract infections. Rates of transaminitis, inflammatory bowel disease, major adverse cardiac events, cancer, and adjudicated suicidal ideation and behavior were rare and similar between the two treatments. Two deaths occurred in the bimekizumab-bkzx treatment arm but were not deemed related to treatment.

These study findings represent clinical improvements associated with increased blockade of IL-17 signaling inhibition and could significantly modify our treatment approach to psoriatic disease. The higher rate of complete skin clearance with bimekizumab-bkzx may further translate into improved patient quality of life and overall treatment satisfaction, which is essential for patients living with this chronic, debilitating condition. Long-term, real-world data will further illuminate the drug’s safety profile and provide insights into less common or rare adverse events that might not have been fully elucidated in the phase 3 clinical trial program. Additional head-to-head trials with other available biologics and long-term cost-effectiveness analyses will inform the positioning of bimekizumab-bkzx within the psoriasis treatment algorithm.

3. Reich K, Papp KA, Blauvelt A, et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial. Lancet. 2021;397(10273):487-498. doi:10.1016/S0140-6736(21)00125-2

https://pubmed.ncbi.nlm.nih.gov/33549193/

Study Bimekizumab Versus Secukinumab in Plaque Psoriasis (BE RADIANT)⁴

https://pubmed.ncbi.nlm.nih.gov/33891380/

Summary

The BE RADIANT trial was a phase 3b study that investigated the efficacy of bimekizumab-bkzx against secukinumab, a selective inhibitor of IL-17A.

Adult patients with moderate to severe plaque psoriasis for at least 6 months were enrolled and had a baseline mean PASI score greater than 20, indicating more severe disease. Study patients were randomly assigned to receive bimekizumab-bkzx (320 mg every 4 weeks) or secukinumab (300 mg weekly to week 4, followed by one injection every 4 weeks). The primary endpoint was complete skin clearance (PASI 100) at week 16. Secondary endpoints included PASI 75 at week 4, PASI 100 at week 48, and quality-of-life assessments through the Dermatology Life Quality Index.

At week 16, 61.7% of bimekizumab-bkzx–treated patients achieved complete skin clearance versus 48.9% of patients who received secukinumab, with bimekizumab-bkzx demonstrating superiority (adjusted risk difference of 12.7 percentage points). At week 48, 67% of patients treated with bimekizumab-bkzx maintained a PASI 100 response compared to only 46.2% of those receiving secukinumab. Additionally, bimekizumab-bkzx’s efficacy was evident in both the 4- and 8-week dosing regimens, with no significant difference between the two.

Regarding the relative safety of these two biologics, the incidence of adverse events was similar between groups, although bimekizumab-bkzx compared to secukinumab was associated with a higher rate of Candida infections (21% vs 5%, respectively, through 48 weeks). Serious adverse events were comparable, and the overall safety profile was consistent with known effects of IL-17 blockade. Importantly, the incidence of other adverse events of interest, including inflammatory bowel disease, cancer, and major adverse cardiac events, was less than 1% and similar between the two treatments.

In summary, the BE RADIANT trial concluded that bimekizumab-bkzx’s dual inhibition of IL-17A and IL-17F provided a more effective treatment for moderate to severe plaque psoriasis compared to inhibition of IL-17A alone.

Dr. Hawkes’ Commentary

The BE RADIANT phase 3b clinical trial represents a significant step forward in the treatment of moderate to severe plaque psoriasis. The trial’s focus on the dual inhibition of IL-17A and IL-17F stems from a growing body of evidence underscoring the importance of these two cytokines in the immunopathogenesis of psoriatic disease. The prospective study design also begins to tease out the individual contribution of IL-17F via this head-to-head comparison of bimekizumab-bkzx (IL-17A and IL-17F dual blockade) versus secukinumab (IL-17A alone). This is essential to our understanding of the pathophysiology of psoriasis given that both IL-17A and IL-17F contribute to the formation of psoriatic plaques, though higher levels of IL-17F are detected in plaque psoriasis tissue samples.

The superior efficacy of bimekizumab-bkzx compared to secukinumab, a well-established and commonly used IL-17A inhibitor, suggests that dual inhibition of IL-17A and IL-17F may offer a more robust attenuation of the IL-17 signaling cascade that drives the development of mature psoriatic plaques. The trial’s rigorous design, which included a substantial number of study participants and a lengthy follow-up period, lends credence to its findings.

In line with other phase 3 studies with bimekizumab-bkzx, the primary efficacy endpoint—complete skin clearance or PASI 100 at week 16—was achieved by approximately two-thirds of patients on bimekizumab-bkzx compared to about half of secukinumab patients. This is a remarkable achievement given that only two current FDA-approved treatments for plaque psoriasis (bimekizumab-bkzx and brodalumab) have resulted in complete skin clearance in the majority of patients at the primary study endpoint in a phase 3 study. The trial also demonstrated the durability of bimekizumab-bkzx’s efficacy with a significant proportion (67%) of patients maintaining PASI 100 response at week 48.

The increased incidence of Candida infections in patients treated with bimekizumab-bkzx is a treatment-related adverse event that warrants attention and further discussion. Although most cases were mild in nature and responsive to oral antifungal treatments, the risk of opportunistic infections is an important consideration for patient selection and monitoring. This specific side effect reflects the innate, protective role of IL-17 cytokines in the skin and mucosa, particularly against fungal pathogens such as Candida.

Nevertheless, the precise relationship between IL-17 inhibition and Candida infections is not fully understood. For example, broad inhibition of IL-17 cytokine signaling, such as brodalumab’s blockade of the IL-17 receptor, does not appear to be associated with the same increased rate of Candida infections as seen with bimekizumab-bkzx despite brodalumab’s blockade of IL-17A, IL-17C, IL-17E, and IL-17F cytokine signaling. Additionally, nearly all the patients treated with bimekizumab-bkzx who developed Candida infections were limited to one to two isolated events, often occurring early in the treatment course, and they rarely developed persistent or chronic candidiasis despite ongoing bimekizumab-bkzx therapy during the study. Most importantly, few candidiasis infections led to treatment discontinuation. Further study of the precise relationship between candidiasis, IL-17 inhibition, and the innate, protective effects of IL-17 expression is warranted.

In summary, the BE RADIANT trial’s findings suggest that bimekizumab-bkzx is a valuable addition to our therapeutic armamentarium for patients with moderate to severe plaque psoriasis. The dual inhibition of IL-17A and IL-17F appears to offer more complete suppression of IL-17–related immune signaling driving psoriatic plaque development, leading to better skin clearance and patient-reported outcomes. Compared to other IL-17 inhibitors, bimekizumab-bkzx offers a more favorable dosing schedule with dosing every 8 weeks along with flexible dosing for patients who may require monthly dosing and weigh more than 120 kg. Data from ongoing psoriatic arthritis clinical studies and a possible head-to-head study of bimekizumab-bkzx versus an IL-23 inhibitor will certainly be of interest to the medical dermatology community at large. In the meantime, bimekizumab-bkzx is an impressive and welcome addition to an ever-growing and improving arsenal of targeted biologic therapies available for the treatment of moderate to severe plaque psoriasis.

Dr. Jason Hawkes is a medical dermatologist at the Pacific Skin Institute’s Integrative Skin Science and Research Center in Sacramento, CA. He received his medical degree and completed his residency training at the University of Utah. He also completed a fellowship in translational immunology at the National Institutes of Health and received a master’s degree in clinical investigation from Rockefeller University, where he was the chief clinical scholar and principal investigator on multiple human research protocols in the Laboratory for Investigative Dermatology.

Dr. Hawkes was an associate professor and faculty member in the Departments of Dermatology at the University of California, Davis; Icahn School of Medicine at Mount Sinai; and University of Utah School of Medicine. He is a councilor in the International Psoriasis Council and currently serves on the medical board and scientific advisory committee of the National Psoriasis Foundation.

Dr. Hawkes is also an National Science Foundation- and National Institutes of Health-funded investigator and the recipient of many teaching awards, including the National Psoriasis Foundation Outstanding Educator in Psoriatic Disease and the Exceptional Teacher of the Year in the Department of Dermatology at Mount Sinai.

4. Reich K, Warren RB, Lebwohl M, et al. Bimekizumab versus secukinumab in plaque psoriasis. N Engl J Med. 2021;385(2):142-152. doi:10.1056/NEJMoa2102383

STUDIES BEING REVIEWED:

Gordon KB, Foley P, Krueger JG, et al. Bimekizumab efficacy and safety in moderate to severe plaque psoriasis (BE READY): a multicentre, double-blind, placebo-controlled, randomised withdrawal phase 3 trial. Lancet. 2021;397(10273):475-486. doi:10.1016/S0140-6736(21)00126-4

Warren RB, Blauvelt A, Bagel J, et al. Bimekizumab versus adalimumab in plaque psoriasis. N Engl J Med. 2021;385(2):130-141. doi:10.1056/NEJMoa2102388 [[BE SURE]]

Reich K, Papp KA, Blauvelt A, et al. Bimekizumab versus ustekinumab for the treatment of moderate to severe plaque psoriasis (BE VIVID): efficacy and safety from a 52-week, multicentre, double-blind, active comparator and placebo controlled phase 3 trial. Lancet. 2021;397(10273):487-498. doi:10.1016/S0140-6736(21)00125-2

Reich K, Warren RB, Lebwohl M, et al. Bimekizumab versus secukinumab in plaque psoriasis. N Engl J Med. 2021;385(2):142-152. doi:10.1056/NEJMoa2102383 [[BE RADIANT]]