Shawn Kwatra, MD

Credit: hopkinsmedicine.org

Nemolizumab reaction is linked to changes in neural, inflammatory, and epithelial signaling compared to placebo, according to new findings, showcasing the distinct impacts of inhibiting interleukin 31 receptor α (IL-31RA) in managing prurigo nodularis (PN).¹

These new findings were the result of a recent study conducted following a prior phase 2 trial on nemolizumab, during with individuals with moderate-to-severe PN showed substantial improvement in their lesion number, their Peak Pruritus Numerical Rating Scale (PP-NRS) scores, their quality of sleep, their investigator’s global assessment (IGA) score, and dermatology life quality index.²

Now, the latest study on PN patients was authored by Shawn G. Kwatra, MD, from the Department of Dermatology at Johns Hopkins University School of Medicine, as well as Valerie Julia, PhD, from Galderma SA in Switzerland.

“Given the significant clinical efficacy of nemolizumab, this study (aimed) to analyze the underlying changes in protein biomarkers and pathways in plasma samples associated with clinical improvement due to nemolizumab treatment,” Kwatra, Julia, and colleagues wrote.

Background and Findings

The investigators conducted their multicenter cohort study across France, Austria, Germany, Poland, and the United States, recruiting adult participants with diagnoses of moderate-to-severe prurigo nodularis and reporting having experienced severe pruritus for a minimum of 6 months. These participants had been recruioted from the previous phase 2 clinical trial.

The original study had sought to determine the effectiveness of nemolizumab, which was a known treatment option for PN. During the current study, the individuals drawn from the nemolizumab group were then selected if they showed a reduction of at least 4 points on the PP-NRS within the initial 12 weeks of nemolizumab therapy.

Conversely, the research team made the placebo controls those who had not exhibited a 4-point decrease in PP-NRS. Through mass spectrometry with tandem mass tags to enhance the detection of skin-specific proteins, the investigators characterized alterations in plasma protein expression among both the nemolizumab and the placebo arms of the study.

The team’s data collection time period took place in the period between November of 2017 and September of 2018, with a subsequent analysis conducted between December of 2019 and April of 2022.

As part of the clinical trial’s protocol, those involved were given a treatment involving 3 total doses of either nemolizumab or a placebo and these were administered at 0, 4, and 8 weeks. The primary aim of the investigators’ research was to investigate changes in both plasma and epidermal protein expression between the nemolizumab-treated arm and the placebo arm.

These changes were assessed at 3 distinct time points: baseline, the 4 week mark, and the 12 week mark. Overall, the investigators noted that their aim was to discern potential variations in protein expression patterns associated with nemolizumab in comparison to the placebo.

In their analysis, the investigators ended up with 38 total participants, with 22 women and 16 men and a mean age of 55.8 years. They had examined biological functions, canonical pathways, and upstream regulators and ended up showing substantial downregulation of terms related to several different aspects.

The research team reported that these had included processes associated with inflammation such as acute-phase response, IL-6, signal transducer and activator of transcription 3, and interferon γ.

Also included were neural functions—including neuritogenesis and synaptogenesis signaling—as well as tissue remodeling and fibrosis—such as transforming growth factor β1 and endothelin-1. Lastly, these included epidermal differentiation, specifically with epithelial mesenchymal transition in the plasma samples of the nemolizumab-treated arm of the study.

“Taken together, these results suggest that IL-31 works through multiple pathways affecting inflammatory, neural, and epithelial regulation to contribute to the pathophysiology of PN,” they wrote. “By targeting signaling downstream of IL-31RA, nemolizumab represents a promising potential new approach for the clinical management of PN.”

The investigators noted that further research should examine the effects of nemolizumab on skin-related outcomes, assessing its influence on neural networks, inflammatory responses, and tissue remodeling pathways.

References

1. ^{Deng J, Liao V, Parthasarathy V, et al. Modulation of Neuroimmune and Epithelial Dysregulation in Patients With Moderate to Severe Prurigo Nodularis Treated With Nemolizumab. JAMA Dermatol. Published online August 09, 2023. doi:10.1001/jamadermatol.2023.2609.}
2. ^{Ständer S, Yosipovitch G, Legat FJ, et al. Trial of nemolizumab in moderate-to-severe prurigo nodularis. N Engl J Med. 2020;382(8):706-716. doi:10.1056/NEJMoa1908316.}