A Rapidly Changing Landscape in Prurigo Nodularis Signals New Directions and Opportunities for Treatment

Prurigo nodularis (PN) is a chronic skin disorder characterized by multiple nodules predominately found on extensor surfaces. A defining feature of PN is severe itch that causes patients to scratch and further inflame the condition. Historically, PN has been difficult to treat, as patients often find the itch uncontrollable even after trying multiple over-the-counter and prescription treatment options.

When the FDA approved dupilumab, an inhibitor of interleukin (IL)-4 and IL -13, for adults with PN in 2022, the treatment landscape for the disease shifted dramatically. In 2024, the second systemic agent, the IL-31 inhibitor nemolizumab, won FDA approval for the treatment of adults with PN. Now that 2 systemic agents with unique mechanisms are available for the treatment of PN, clinicians can consider various disease, pharmacologic, and patient factors as they decide on treatment.

Dupilumab

Dupilumab targets the IL-4 receptor-α, which plays an important role in type-2 inflammation.¹ It inhibits the signaling of both IL-4 and IL-13 to help reduce type-2 inflammation and, in turn, reduce itch and promote nodule clearance.^2-4 It is administered via injection once every 2 weeks; it can be given via a prefilled pen or syringe.

In the LIBERTY-PN PRIME (NCT04183335) and PRIME 2 (NCT04202679) trials, 32% and 25.6%, respectively, of dupilumab-treated patients with 20 or more nodules showed a reduction to 5 nodules or fewer at 12 weeks; among the placebo groups, such a reduction was found in 11.8% and 12.2%, respectively.⁵ Beyond 12 weeks, treated patients continued to show improvement, with 48% and 44.9% of patients achieving 5 nodules or fewer by 24 weeks; among those given placebo, 18.4% and 15.9%, respectively, showed this continued improvement.

During the Society of Dermatology Physician Associated Annual Fall Dermatology Conference, additional results from the PRIME trials highlighted the reduction in lesion burden across numerous lesion types in patients treated with dupilumab.⁶ According to the 24-week findings, dupilumab-treated patients experienced a marked reduction in average lesion count from 26.3 to 8.8 lesions. Complete lesion resolution was achieved in 26.1% of patients, and 73.8% of patients achieved healing of at least 50% of their lesions. Safety data were consistent with clinical trial data.

Nemolizumab

Approved by the FDA in August 2024 for the treatment of PN in adults, nemolizumab is a monoclonal antibody that blocks IL-31, a pathway that is active in signaling itch within the nerves.⁷ Nemolizumab is administered once every 4 weeks via a prefilled self-injector pen.

The results of the OLYMPIA 1 trial (NCT05061693) were published in November 2024.⁸ The findings showed an improvement of 4 points or more from baseline in the weekly average Peak Pruritus Numerical Rating Scale (PP-NRS) score among 58.4% of nemolizumab-treated patients and 16.7% of patients given placebo. Additionally, 26.3% of patients receiving nemolizumab achieved an Investigator's Global Assessment (IGA) score of 0/1 (clear/almost clear) and a 2-grade improvement from baseline as compared with 7.4% of the placebo group.

In an ad hoc analysis, an improvement in the PP-NRS of at least 4 points was noted among 58.3% of the nemolizumab treatment group and 20.4% of the placebo group; further, IGA success was noted in 30.5% of the nemolizumab group versus 9.4% of the placebo group.

Regarding safety, nemolizumab was generally well tolerated.

In the Pipeline

As researchers and clinicians learn more about the pathogenesis of PN, efforts to target key pathways in the itch cycle may yield new therapeutic approaches through the development of novel treatments. One agent currently in development is povorcitinib, a selective oral JAK1 inhibitor that is also being evaluated for the treatment of nonsegmental vitiligo, hidradenitis suppurativa, asthma, and chronic spontaneous urticaria.

Results of a phase 2 study (NCT05061693) of povorcitinib that were presented at the 2024 American Academy of Dermatology annual meeting showed that oral use of this small-molecule, selective JAK1 inhibitor resulted in significant improvement in the itch NRS score (NRS4) at 16 weeks when compared with administration of placebo.⁹

Current Opportunities and Future Directions

Despite the availability of multiple systemic agents with indications for PN, a notable need remains for increased awareness regarding the disease itself and the importance of early intervention. As efforts for education and awareness regarding the impact of itch continue, more patients may be able to benefit from available systemic treatments that target the pathways of itch. In a recent video interview with Dermatology Times, Melodie Young, MSN, A/GNP-C, noted that earlier diagnosis may lead both to earlier interventions with these agents and to their increased use. “The sooner we can intervene,” Young noted, “the sooner we can give [patients] a proper diagnosis and we [can] get them on [systemic agents] that are FDA approved for the first time ever for this condition. And they get relief from it. Then you can talk to them about how their skin is going to heal.”

References

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2. Williams KA, Huang AH, Belzberg M, Kwatra SG. Prurigo nodularis: pathogenesis and management. J Am Acad Dermatol. 2020;83(6):1567-1575. doi:10.1016/j.jaad.2020.04.182
3. Oetjen LK, Mack MR, Feng J, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell. 2017;171(1):217-228. doi:10.1016/j.cell.2017.08.006
4. Serezani APM, Bozdogan G, Sehra S, et al. IL-4 impairs wound healing potential in the skin by repressing fibronectin expression. J Allergy Clin Immunol. 2017;139(1):142-151.e5. doi:10.1016/j.jaci.2016.07.012
5. Yosipovitch G, Mollanazar N, Stander S, et al. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nature Med. 2023;29(5):1180-1190. doi:10.1038/s41591-023-02320-9
6. Ständer S, Yosipovitch G, Kim B, et al. Dupilumab improves skin lesions of varying clinical morphologies in adult patients with prurigo nodularis. Abstract presented at: the Society of Dermatology Physician Associates (SDPA) 22nd Annual Fall Dermatology Conference 2024; November 13-17, 2024; Las Vegas, Nevada.
7. Williams KA, Roh YS, Brown I, et al. Pathophysiology, diagnosis, and pharmacological treatment of prurigo nodularis. Expert Rev Clin Pharmacol. 2021;14(1):67-77. doi:10.1080/17512433.2021.1852080
8. Ständer S, Yosipovitch G, Legat FJ, et al; for the OLYMPIA1 Investigators. Efficacy and safety of nemolizumab in patients with moderate to severe prurigo nodularis: the OLYMPIA 1 randomized clinical phase 3 trial. JAMA Dermatol. Published online November 27, 2024. doi:10.1001/jamadermatol.2024.4796
9. Martin M. Efficacy and safety of oral povorcitinib in patients with prurigo nodularis: results from a randomized, double-blind, placebo-controlled phase 2 study. Abstract presented at: the 2024 American Academy of Dermatology Annual Meeting; March 8-12, 2024; San Diego, CA.