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We thank Dr Zhao and Dr Huang for their interest in our article.1 2
The approved dosage of brodalumab for plaque psoriasis includes a loading treatment of 210 mg every week at weeks 0, 1 and 2 followed by a dose of 210 mg every 2 weeks thereafter.3 The brodalumab dosage administered in patients with axial spondyloarthritis (axSpA) in our study1 was the same as that approved for plaque psoriasis. Therefore, the rapid improvement in Assessment of SpondyloArthritis International Society 40/20 as early as week 2 in patients with axSpA in our study and similar to the improvement observed in Psoriasis Area and Severity Index in patients with plaque psoriasis4 could be attributed to the loading treatment. However, the study5 that Zhao et al have referred to in their correspondence2 was conducted in patients with psoriatic arthritis and not in those with plaque psoriasis and included a loading treatment of brodalumab 210 mg every week at weeks 0, 1 and 2.
With regard to the comment on safety, we believe that the short study period of 16 weeks is insufficient to investigate safety appropriately, specifically safety aspects that may develop over the longer term. The 16-week results from our study showed no safety signals with respect to an increase in the risk of suicide and/or depression with brodalumab, although safety among patients at high risk of suicide or depression could not be assessed. Moreover, the small sample size in our study was a limitation for the identification of risk signals for suicide and/or depression. However, it is common practice to conduct clinical trials in low-risk patients before expanding studies to medium-risk and high-risk patients as well as specialty populations to provide protection from potentially severe adverse events (AEs). Incidentally, the decision to discontinue the AMAGINE-2 and AMAGINE-3 trials was based on events of suicidal ideation and behaviour in the brodalumab programme, which necessitated restrictive labelling.6
While it is known that interleukin (IL)-17 plays a role in the pathway involved in liver inflammation,7 it is not surprising that results from studies in humans and mouse models are inconsistent. Liver-related events (standardised Medical Dictionary for Regulatory Activities queries: ‘hepatotoxicity [narrow]’) were observed in seven patients who received brodalumab treatment in our study by week 16; the severity of these events was grade 1 or 2. However, the incidence of hepatotoxicity/liver function abnormality may vary depending on the indication and concomitant medications. Moreover, there is an increased possibility of such AEs occurring with the use of non-steroidal anti-inflammatory drugs (NSAIDs) and non-biological disease-modifying antirheumatic drugs (DMARDs), which were permitted in our study, but not in previous studies that assessed patients with plaque psoriasis. All seven patients who reported liver-related events in our study were using NSAIDs and/or non-biological DMARDs alone or in combination with other medication. Therefore, concomitant use of NSAIDs or non-biological DMARDs may have impacted the incidence of liver-related events. Furthermore, the short study period of 16 weeks limited the investigation of liver-related events and inflammatory bowel disease (IBD).
In addition, the incidence of IBD, reported as ‘treatment-emergent AEs of interest’ in our study, cannot be compared with that in previous studies of brodalumab or other IL-17 inhibitors because the definition of IBD was specific to this study, as described in the original publication and in table 1. No cases of ulcerative colitis or Crohn’s disease were reported by week 16 in our study.
Definition of inflammatory bowel disease in the phase 3 study of brodalumab in patients with axial spondyloarthritis
As mentioned earlier, our study presents only short-term results up to week 16, which limits the interpretation of safety results. However, the open-label extension part of our study further investigates brodalumab in patients with axSpA up to week 68. We look forward to answering your questions on safety based on the long-term results from our study.
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Acknowledgments
Medical writing support was provided by Dr Deepali Garg, MBBS, PGDHA, of Cactus Life Sciences (part of Cactus Communications) and was funded by Kyowa Kirin.
Footnotes
Handling editor Josef S Smolen
Contributors All authors reviewed and approved the response to the correspondence for publication.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests JC-CW reports grant from Kyowa Kirin Co for the work under consideration for publication; grants from AbbVie, BMS, Celgene and UCB pharma; personal fees from TSH Taiwan; and grants and personal fees from Janssen, Novartis and Pfizer, outside the submitted work. T-HK reports grants from Kyowa Kirin Co for the work under consideration for publication. MK reports personal fees from Kyowa Kirin Co for the work under consideration for publication; personal fees from AbbVie, Amgen-Astellas BioPharma, Asahi-Kasei Pharma, Astellas, Ayumi Pharma, BMS, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Kyowa Kirin, Novartis, Ono Pharma, Pfizer, Tanabe-Mitsubishi and UCB Pharma, outside the submitted work. NO is an employee of Kyowa Kirin Co. HJ is an employee of Kyowa Kirin Korea Co. SK reports personal fees from Kyowa Kirin Co for the work under consideration for publication; personal fees from AbbVie, Bristol-Myers Squibb Co, Eisai Co, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Novartis Pharma, Eli Lilly Japan and Asahikasei Pharma Co, outside the submitted work.
Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.
Provenance and peer review Commissioned; internally peer reviewed.