Brodalumab for the Treatment of Psoriasis: A Review of Phase III Trials

Psoriasis is a common chronic immune-mediated skin disease that occurs in 3–4% of the adult US population [1]. Symptoms of psoriasis, which include redness, scaling, flaking, pruritus, skin tightness, pain, and bleeding, have a significantly negative impact on patients’ physical and mental functioning [2]. Psoriasis also leads to impairment of quality of life, psychological well-being, and work productivity [2, 3]. Despite the rapid development of novel treatment modalities over the past 2 decades, surveys conducted by the National Psoriasis Foundation reveal that a significant portion of patients with psoriasis remain undertreated relative to the severity of their disease [3]. These patients will require new medications with superior long-term efficacy and safety for the treatment of moderate-to-severe psoriasis.

Brodalumab is one of three biologic agents, in addition to secukinumab and ixekizumab, which targets the interleukin (IL)-17 cytokine pathway, which has been implicated in the pathogenesis of psoriasis. IL-17A is one of six subsets of IL-17 and is regarded as the most significant subtype in psoriasis development [4, 5]. The cytokine applies its effect by binding the IL-17 receptor type A (IL-17RA) [6]. TH17 cells are increased in psoriatic lesions and are activated by IL-23 to release IL-17 [7‐11]. IL-17 plays a part in the stimulation and recruitment of neutrophils, the defense of neutrophil apoptosis, and the provocation of psoriasis angiogenesis [5, 12‐14]. Proof of increased levels of IL-17 mRNA [15] and IL-17 in psoriatic lesions and in the serum of psoriasis patients further supports the role of IL-17 in the pathogenesis of psoriasis [8, 16‐19]. Brodalumab is a human immunoglobulin G (IgG) 2 monoclonal antibody that acts by specifically inhibiting IL-17RA, thus decreasing the downstream effect of IL-17 [20]. It binds with high affinity to IL-17RA and blocks the biological activity of IL-17A, IL-17F, and IL-25 (IL-17E) [20].

In the following article, we review the results of the clinical phase III trials establishing the efficacy and safety of brodalumab in patients with moderate-to-severe plaque psoriasis. Two co-primary end points were examined: a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) and static physician global assessment (sPGA) of 0 (clear) or 1 (almost-clear) on a five-point scale by week 12 of treatment. sPGA is a method employed by investigators to document their assessment of disease severity, with scores ranging from 0 (clear) to 4 (severe disease). We also report long-term efficacy results up to 52 weeks in the clinical trials that have been completed to date.

We conducted a systematic English-language literature search of PubMed, MEDLINE, and Cochrane databases from January 2003 to May 2016 to identify and evaluate all phase III randomized clinical trials on efficacy and safety of brodalumab for plaque psoriasis. Key search terms included “brodalumab,” “psoriasis,” and “phase III” or “IL-17,” “psoriasis,” and “phase III.” We also reviewed citations within articles to identify relevant resources. Studies that were not in English, were not phase III, or did not conduct a randomized controlled trial for plaque psoriasis on humans were excluded from the review. This left three phase III clinical trials that were included in this assessment: AMAGINE-1, AMAGINE-2, and AMAGINE-3. Pooled measures of efficacy and incidence of adverse events were calculated by tabulating values from independently conducted studies. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Three major phase III clinical trials, AMAGINE-1, AMAGINE-2, and AMAGINE-3 (ClinicalTrials.gov identifiers: NCT01708590, NCT01708603, and NCT01708629, respectively), were conducted to determine the efficacy and safety of different doses of brodalumab compared to placebo [20, 21]. AMAGINE-2 and AMAGINE-3 also compared brodalumab to ustekinumab. The comparisons in baseline demographics are shown in Table 1, while the results from each of these trials are displayed in Table 2. All three trials were eventually terminated prematurely by the study sponsor (Amgen) prior to obtaining long-term extension data.

Results from the examined phase III clinical trials demonstrated that brodalumab is a very potent agent in the treatment of plaque-type psoriasis. At week 12, the proportions of patients achieving PASI 75 or sPGA scores of 0 or 1 were higher in the brodalumab 210 mg arm compared to the brodalumab 140 mg arm, and both were far superior to the portion of patients that received placebo (Table 2; Fig. 1). Brodalumab 210 mg was also found to be statistically superior to ustekinumab at 12 weeks with respect to PASI 90, PASI 100, and sPGA 0 or 1. While current long-term results seem encouraging, further long-term trials are needed. The advantage in brodalumab is most distinct in regards to the percentage of patients who attain PASI 90 and PASI 100 (Table 2). Based on evidence that patients who reach PASI 90 or PASI 100 experience greater improvement in quality of life than PASI 75 responders [22], we can estimate that these efficacy achievements are more significant than PASI 75 from a patient perspective. In comparison to secukinumab and ixekizumab, brodalumab achieves similar treatment results at 12 weeks. However, brodalumab appears to deliver greater PASI 100 rates at 12 weeks and better overall maintenance at 52 weeks, although no head-to-head studies have been conducted and research is still in its early states [23]. In any case, the development of this unique, highly effective class of biologic therapy provides optimism for patients whose psoriasis remains refractory to older biologic agents.

Among the phase III trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. The majority of adverse events were mild or moderate in severity. Less than 2% of patients experienced either neutropenia or candida infection while on brodalumab 210 mg or brodalumab 140 mg through the first 12 weeks. Neutropenia was transient and without associated infections, and candida infections were mild to moderate in intensity and resolved without discontinuation of treatment. Anti-IL-17 therapeutics, including brodalumab, have the theoretical risk of increasing the incidence of mucocutaneous candidiasis infection, based on genetic studies of patients lacking IL-17 immunity [24, 25]. Candida infections were more common among patients taking brodalumab than in those taking placebo among the studies we examined. In comparison to secukinumab and ixekizumab, no substantial differences were noted in the safety profile, with nasopharyngitis, upper respiratory infection, and headache comprising the most common adverse events [23]. Both neutropenia and candida infections generally occurred more frequently, although not significantly, in patients on the three therapeutics. Of utmost significance, the AMAGINE-2 trial included two patients who completed suicide (one within 52 weeks and another one beyond 52 weeks) while on brodalumab. Although concerning, these events do not necessarily constitute a causative relationship between brodalumab and suicidal ideation, especially given that patients with psoriasis are already at higher risk for depression, suicidal ideation, suicide attempt, and completed suicide [26, 27]. Regardless, Amgen, the company involved in the devlopment of brodalumab, has decided to withdraw from co-development of the drug because of worries of a potential black box warning about suicide, citing “events of suicidal ideation and behavior in the brodalumab program” [19]. Valeant Pharmaceuticals has since assumed a lead role in the further development of brodalumab [28].

Brodalumab is a human IgG2 monoclonal antibody that may better achieve full clearance (PASI 100) relative to the other IL-17A cytokine specific agents, secukinumab and ixekizumab, because it is the only treatment in development that inhibits the IL-17 receptor (IL-17RA). Although IL-17A is recognized as the most significant IL-17 isotype in the pathogenesis of psoriasis [5], IL-17F and IL-25 also interact with the IL-17 receptor to provoke inflammatory signaling [4, 20]. The ability of brodalumab to block the effects of all cytokines that interact with IL-17RA is likely to contribute to the higher efficacy observed with brodalumab compared to ixekizumab and secukinumab, whose antagonistic effects are limited to IL-17A [29]. Both secukinumab and ixekizumab have passed phase III trials and are FDA approved, with ixekizumab obtaining approval most recently on 22 March 2016, while brodalumab remains in development. Both brodalumab and secukinumab are fully human monoclonal antibodies, whereas ixekizumab is a humanized antibody. A humanized antibody contains nonhuman regions, but still behaves very similarly to a fully human antibodies. In regards to injection frequency, brodalumab provides a more advantageous option with only four syringes injected by the end of the first month for the 210-mg regimen compared to secukinumab, which necessitates the injection of ten syringes by the end of the first month for the 300-mg regimen (both dosing regimens are the highest for the respective drug). Thus far, there have been no head-to-head comparisons of brodalumab against secukinumab and ixekizumab.

In addition to treating psoriasis, brodalumab has the potential to offer further systemic benefits. With regards to psoriatic arthritis, which affects between 5% and 30% of those with psoriasis, anti-IL-17 agents may have a critical role, as higher levels of IL-17 and IL-17RA have been observed within the synoviocytes and synovial fluid of psoriatic arthritis patients [30‐33]. Consequently, a phase III clinical trial has shown that brodalumab was statistically superior to placebo in the treatment of patients with active psoriatic arthritis at 12 weeks, as measured by the proportion of patients achieving an American College of Rheumatology 20% improvement response (ACR20) and 50% improvement response (ACR50) [34]. Brodalumab is also being tested as a treatment for asthma and axial spondyloarthritis [35, 36]. Additionally, treatment of the inflammatory state underlying psoriasis has the ability to reduce the incidence of cardiovascular disease [37]. Increased IL-17 has been detected in atherosclerotic plaques [38] and is believed to pair with other inflammatory signals in forming plaques [39]. These observations together convey the possibility of using IL-17 pathway antagonists to treat not only psoriasis, but also psoriatic arthritis and to reduce the risk of cardiovascular disease in those with psoriasis [40].

Brodalumab has generated encouraging data for efficacy and safety in the treatment of chronic plaque psoriasis. The phase III clinical trials results suggest that brodalumab 210 mg and brodalumab 140 mg dosed every 2 weeks are far superior statistically to placebo in all categories at 12 weeks and better able to achieve complete clearance compared to the contemporary biologic agent ustekinumab. Further results from open-label extension studies are required to validate the promising long-term efficacy and safety profile of this unique therapeutic.