A Review of Brodalumab, an IL-17 Receptor Antagonist, for Moderate-to-Severe Plaque Psoriasis

Yun Tong, MD; Andrew J. Peranteau, MD; Zeena Nawas, MD; Stephen K. Tyring, MD, PhD

Disclosures

Skin Therapy Letter. 2017;22(1) 

In This Article

Discussion

IL-17 cytokine pathway plays an important role in psoriasis. Clinical trials validate the role of brodalumab for treating moderate-to-severe plaque psoriasis. By targeting IL-17RA, brodalumab has proven to be exceptionally efficacious with improvement of PASI 75 in over 80%, and approximately 70% of those patients achieved PASI 90 on brodalumab 210 mg by week 12 in 3 large phase 3 clinical trials. Patients with psoriasis experience impairment of their QoL. A PASI 90 response is necessary to achieve a DLQI of 0 or 1. Indeed, the new class of IL-17 antagonists has eminently shifted the expectation of treatment response, such that PASI 90 may be regarded as the new standard.[30] Based on efficacy alone, brodalumab and other IL-17 class biologics could become first-line therapy for moderate-tosevere plaque psoriasis. Safety considerations of depression and suicidality, however, could hamper the use of brodalumab in favor of the other IL-17 biologics secukinumab and ixekizumab.

Il-17 blockade compared to TNF-α or Il-12/23 may be associated with lower potential for broad immune system adverse effects.[9] Il-17RA deficient patients, however, have higher associated recurrent mucocutaneous infections caused by Candida albicans. Two studies reported increased rates of candida infections with brodalumab vs. ustekinumab (5.2 and 5.7 per 100 patientyears vs. 4.1 and 1.6 per 100 patient-years, AMAGINE-2 and AMAGINE-3, respectively). Meta-analysis of several phase 2 trials for IL-17 agents, brodalumab, ixekizumab, and secukinumab, demonstrated no significant difference between biotherapy groups and placebo for adverse events including infections, upper respiratory tract infections, and headaches, excluding nasopharyngitis.[2] Overall, IL-17 agents appear tolerable and are promising therapies with possibly less side effects than current biologics.

While the majority of clinical data points to brodalumab's improvement of depression and QoL, OLE studies of AMAGINE-1, AMAGINE-2, and AMAGINE-3 were terminated in May 2015. Amgen, one of the co-developers with AstraZeneca, withdrew due to fears of gray box labeling requirements that would preclude universal first-line adoption in an increasingly competitive market for psoriasis, which already includes the anti-IL-17 antibodies secukinumab and ixekizumab without restrictive labeling. Valeant Pharmaceuticals, in September 2015, entered into an agreement with AstraZeneca to develop and commercialize brodalumab.[31] Four instances of suicidal ideation among 3180 pooled patients on brodalumab (0.13%) were reported against 1 report out of 613 patients (0.16%) on ustekinumab.[32] Lebwohl28 reported 2 suicides were completed in the 210 mg treatment arm of AMAGINE-2, with 1 during the study and 1 in the OLE compared to none in patients on ustekinumab or placebo. During its own long-term treatment trials, however, 2 suicides (0.06%) in 3117 subjects on ustekinumab were reported.33 Comparatively, no suicides were reported during the treatment periods of secukinumab phase 3 trials.[34] Ixekizumab phase 3 trials UNCOVER-2 and UNCOVER-3 reported no deaths with 2 (0.14%) out of 1469 subjects on ixekizumab attempting suicide.[35] No subjects on placebo (n=361) or etanercept comparator (n=740) attempted suicide.

Theoretically, brodalumab does not cross the intact blood-brain barrier due to its inherent size. The anti-TNF pathway has been associated with central demyelination,[11] of which IL-17 may be significantly involved. Indirect action by brodalumab on the brain may be possible as there is evidence of peripheral cytokine modulation. Alternatively, Danesh and Kimball36 suggest the suicides may be considered within the context of broader suicide trends and attributable to the economic recession. They argue that participants were predominantly middle-aged white males who represent the demographic most at risk for suicide, which as a group has climbed from 20.7 suicides in 2007 to 23.4 per 100,000 in 2013. Before the recession from 1999–2007, suicide mortality increased 0.12 per 100,000 per year whereas an additional 0.51 deaths per 100,000 per year were experienced between 2008–2010 (translating to an additional 1580 suicides annually).[36,37] With the lack of a comparator or placebo during OLE, and more details out of public domain, it remains to be seen what effect IL-17RA inhibition has on suicidality. The key difference in brodalumab's IL-17 inhibition is the receptor target as compared to the IL-17A ligand for secukinumab and ixekizumab. Perhaps this difference has unknown effects on suicidal behavior. Given the substantial improvement in QoL and depression for the majority of subjects in all brodalumab trials, more investigations are warranted.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....