Prurigo nodularis: new insights into pathogenesis and novel therapeutics

Viviane Liao; Hannah L Cornman; Emily Ma; Shawn G Kwatra

doi:10.1093/bjd/ljae052

. 2024 Feb 12;190(6):798–810. doi: 10.1093/bjd/ljae052

Prurigo nodularis: new insights into pathogenesis and novel therapeutics

Viviane Liao ¹, Hannah L Cornman ², Emily Ma ³, Shawn G Kwatra ^4,^5,^✉,²

PMCID: PMC11099982 PMID: 38345154

Abstract

Prurigo nodularis (PN) is an inflammatory skin condition characterized by intensely pruritic nodules on the skin. Patients with PN suffer from an intractable itch–scratch cycle leading to impaired sleep, psychosocial distress and a significant disruption in quality of life. The pathogenesis of PN is associated with immune and neural dysregulation, mediated by inflammatory cytokines [such as interleukin (IL)-4, -13, -17, -22 and -31] and neuropeptides (such as substance P and calcitonin gene-related peptide). There is a role for type 2 inflammation in PN in addition to T-helper (Th)17 and Th22-mediated inflammation. The neuroimmune feedback loop in PN involves neuropeptides released from nerve fibres that cause vasodilation and further recruitment of inflammatory cells. Inflammatory cells, particularly mast cells and eosinophils, degranulate and release neurotoxins, as well as nerve growth factor, which may contribute to the neuronal hyperplasia seen in the dermis of patients with PN and neural sensitization. Recent studies have also indicated underlying genetic susceptibility to PN in addition to environmental factors, the existence of various disease endotypes centred around degrees of type 2 inflammation or underlying myelopathy or spinal disc disease, and significant race and ethnicity-based differences, with African Americans having densely fibrotic skin lesions. Dupilumab became the first US Food and Drug Administration-approved therapeutic for PN, and there are several other agents currently in development. The anti-IL-31 receptor A inhibitor nemolizumab is in late-stage development with positive phase III data reported. In addition, the oral Janus kinase (JAK) 1 inhibitors, abrocitinib and povorcitinib, are in phase II trials while a topical JAK1/2 inhibitor, ruxolitinib, is in phase III studies.

Prurigo nodularis is a chronic inflammatory skin condition characterized by extremely pruritic nodules on the extensor arms, legs and trunk. The pathophysiology of the condition involves immune and neural dysregulation promoting a cycle of itching followed by scratching, which exacerbates the immune and neural dysregulation. With an expanded understanding of the pathophysiology, novel therapeutics including biologics, Janus kinase inhibitors and opioid receptor modulators are in various stages of development for treating prurigo nodularis.

Graphical Abstract

Overview

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic nodules often located on the extremities and trunk and an intractable itch–scratch cycle.¹ It is a clinical diagnosis featuring firm, nodular lesions with pruritus lasting greater than 6 weeks and history or signs of repeated scratching.² Patients with PN suffer from impaired sleep, psychosocial distress and severe disruptions in their quality of life.³ Here we highlight advances in our understanding of the biology of PN and focus on an expanding therapeutic pipeline.

Pathogenesis of prurigo nodularis

What is a prurigo nodule?

The characteristic skin lesion of PN is the prurigo nodule, which is characterized histopathologically with hyperkeratotic epidermis with irregular epidermal hyperplasia, focal parakeratosis, fibrosis of the papillary dermis and infiltration of fibroblasts, capillaries and inflammatory cells (Figure 1).⁴ These inflammatory cells include neutrophils, basophils, mast cells, eosinophils and fibroblasts activated by the T-helper (Th) 1, Th2, Th17 and Th22 axes. Mast cells also release inflammatory mediators and neurotrophins that induce itch and neural proliferation.⁵ However, histamine is probably not the major driver of pruritus in PN, as PN is often not responsive to antihistamines.⁶ Eosinophils release neurotrophins, chemokines and cytokines, and eosinophil-specific neurotoxins are increased in PN lesions, which may injure nerves and contribute to the sensation of pruritus.⁷

Histological findings characteristic of prurigo nodularis. (a) Elongated rete ridges, orthohyperkeratosis and hypergranulosis. (b) Dermal lymphocytic infiltrate. (c) Magnified view showing epidermal acanthosis and vertical streaking of collagen in the papillary dermis.

Why does prurigo nodularis develop?

The first genetic study in patients with PN revealed that there is a unique polygenic risk score for PN, meaning that there is a combination of underlying genetic susceptibility to the disease and environmental factors involved in triggering the disease.⁸ Infections resulting in immune dysregulation, such as tuberculosis and HIV infection, are associated with higher risk of PN.^9–11 Other immune stimuli, such as vaccinations or immunotherapies, have also been reported to trigger PN through a postulated mechanism of enhanced immune system activation leading to increased T-cell recognition of self-antigens.¹² Further research is needed to clarify the role of concomitant conditions in the development of PN and the efficacy of treatments in patients with certain chronic diseases.

The itch transmission pathway of prurigo nodularis

Chronic pruritus is the dominant symptom experienced by patients with PN, and pruritus in PN has been reported to be the highest compared with other inflammatory dermatoses.¹³ While pruritus can be severe in PN nodules, two-thirds of patients experience pruritus both in skin nodules and in normal-appearing adjacent skin.¹⁴ The chronic itch–scratch cycle of PN involves bidirectional neural transmission pathways traversing from unmyelinated C fibres and thinly myelinated A delta fibres in the skin, to the dorsal root ganglion and spinal cord, and the brain.¹⁵ Here we will highlight the roles of immune and neural dysregulation in the pathogenesis of PN (Figure 2).

Immune dysregulation

Type 2 inflammation

The immune dysregulation involved in PN generates robust inflammation through the release of cytokines from Th1, Th2, Th17 and Th22 cells.¹⁶ These cytokines bind receptors on cutaneous nerve fibres, keratinocytes, macrophages, mast cells, eosinophils and keratinocytes, commonly signalling through the Janus kinase–signal transducer and activator of transcription protein (JAK–STAT) pathway that causes upregulation of genes involved in inflammatory responses.¹⁷ With respect to type 2 inflammation, interleukin (IL)-4 and IL-13 directly activate sensory neurons in the skin that drive itch, and also signal through STAT6 to increase the production of pro-inflammatory cytokines, IgE and fibroblasts.¹⁸ IL-31 is another Th2 cytokine whose mRNA is upregulated in PN biopsy samples compared with healthy controls, and patients with psoriasis or atopic dermatitis (AD). It signals through a heterodimeric IL-31 and oncostatin M receptor (OSMR) β to directly activate itch-sensing neurons, stimulate neuronal growth and activate inflammatory cells.^18–20 RNA sequencing demonstrates that OSM, another cytokine that binds to the heterodimeric IL-31 receptor (IL-31R), is also upregulated in PN lesions compared with AD lesions and healthy control skin.²¹ Periostin, an extracellular matrix protein involved in type 2 inflammation that is increased in the dermis and plasma of patients with PN and correlates with increased intensity of pruritus, is also likely to be a key player in the pathogenesis of PN.^22,23 Recent single-cell RNA (scRNA) sequencing studies show that PN lesions have upregulated periostin signalling through the neuronal integrin αVβ3 (ITGAV) receptor, which has been shown in mouse models to directly stimulate the sensation of itch.^22,24,25

T-helper 1, 17 and 22 inflammation

Gene-set variation analysis has also shown upregulation of Th1, Th17 and Th22 markers in lesional PN skin.²⁶ IL-17 induces endothelin-1, a histamine-independent pruritogen, while IL-22 drives epidermal differentiation, cutaneous inflammation and keratinocyte proliferation.^26,27 In a population of patients with PN who are predominantly African American, increased IL-22 release was noted to be from circulating CD4⁺ and CD8⁺ T cells.²⁶

Dysregulated fibroblast biology

Cutaneous transcriptomics shows fibroproliferative dysregulation to be unique to PN compared with AD and psoriasis.²⁸ Fibroblasts, which are activated by pro-inflammatory signalling, are elevated in PN skin and have a shift towards a WNT5A⁺ cancer-associated fibroblast-like phenotype.²⁵ WNT5A promotes fibroblast proliferation and resistance to apoptosis, and has also been shown to promote peripheral nerve neuritogenesis.²⁹ Fibroblasts additionally contribute to dermal fibrosis and type 2 inflammation through release of periostin.²²

Neural dysregulation

Neural architecture

PN has been associated with multiple aetiologies of peripheral neuropathies, suggesting neural dysregulation is important in the pathogenesis of the condition.³⁰ PN lesions show thickened and hyperplastic protein gene product 9.5-positive C fibres within the dermis, which may be secondary to mechanical scratching and elevated nerve growth factor (NGF) in patients with PN, and low intraepidermal nerve fibre density that may reflect small-fibre sensory neuropathy.^21,31–34 Neuronal function is also altered in PN, with decreased descending inhibition of pain and NGF-mediated sensitization of cutaneous C fibres.^35,36

Neuropeptides

Upregulation of substance P (SP) and calcitonin gene-related peptide – neuropeptides released from cutaneous nerve fibres that induce inflammation, vasodilation, recruitment of eosinophils and mast-cell degranulation – has also been found in the skin of patients with PN. SP specifically signals through neurokinin 1 receptor (NK1R), which has been targeted in therapeutic development.^37,38 Cortistatin (CST) is another neuropeptide implicated in PN by regulating mast cells through the Mas-related G protein-coupled receptor-X2 (MRGPRX2).⁵ Finally, opioids are endogenous neuropeptides also commonly associated with pruritus.³⁹ Although the mechanism remains unclear, activation of mu opioid receptors (MORs) induces itch while activation of kappa opioid receptors (KORs) inhibits itch, making these receptors promising targets for therapeutic intervention.^15,40

Disease endotypes in prurigo nodularis

In two recent studies, clusters of patients with PN with higher inflammatory plasma biomarkers or rates of myelopathy and spinal disc disease were found.^41,42 The inflammatory cluster demonstrates a bias towards type 2 inflammation and patients were more likely to have a history of atopy. This is supported by other studies identifying subgroups of patients with PN with elevated circulating IL-13 and periostin or gene expression signatures aligning with the Th2 axis on scRNA sequencing of PN lesional skin biopsies.^23,25 This atopic subgroup could be more responsive to novel treatments targeting the Th2 pathway, such as dupilumab or nemolizumab. The myelopathic subgroup, meanwhile, could be more responsive to treatments targeting the neuropathic component of itch, including NK1R antagonists or opioid receptor antagonists. Further characterizing these disease clusters will be vital in better tailoring treatment towards patients with different underlying pathophysiology.

Racial and ethnic differences in the pathogenesis of prurigo nodularis

PN disproportionately affects African American patients and is associated with higher mortality in this group than in any other racial or ethnic group, likely to be due to a higher comorbidity burden.^43–45 African American patients often have a more severe clinical presentation, featuring more nodular, firm lesions that are more recalcitrant to treatment (Figure 3).⁴⁶ This could result in underdiagnosis of PN in White patients, who often have a less severe presentation with more excoriated lesions and suggests the existence of differences in the pathogenesis of PN across races and ethnicities. In one study identifying inflammatory and neuropathic clusters of patients with PN, the inflammatory cluster had a higher percentage of African American patients and in a population-level analysis these patients were shown to have higher erythrocyte sedimentation rate and C-reactive protein, both systemic inflammatory markers.⁴¹ African American patients with PN also have higher levels of renin–angiotensin–aldosterone system dysregulation and more renal comorbidities than other patients with PN, and African American patients with HIV are more likely to have comorbid PN than White patients with HIV.^47,48 The development of a polygenic risk score for PN identifies genetic ancestry as a contributor to the development of PN, although environmental influences also play a substantial role.⁸

Racial differences in the clinical presentation of prurigo nodularis (PN). (a–d) PN in African American patients typically features firmer, nodular lesions with a fibrotic appearance. (e–h) PN in White patients typically features more shallow, ulcerative lesions.

Prurigo nodularis as a systemic disease

PN is associated with several systemic comorbidities, including type 2 diabetes, chronic kidney disease (CKD), chronic obstructive pulmonary disease, congestive heart failure and chronic hepatitis C.⁴⁹ These comorbidities may predispose patients to PN, and PN may additionally lead to subsequent development of new comorbidities through chronic systemic inflammation.^23,26,42 Novel therapeutics in development for PN decrease systemic inflammation through a variety of pathways, allowing for tailoring of therapy choice based on the disease context and comorbidity burden.

Novel therapeutics for prurigo nodularis

There is currently only one therapy, dupilumab, that has been approved by the US Food and Drug Administration (FDA) for PN. PN is also treated with locally acting agents, phototherapy, systemic immunomodulators and systemic neuromodulators, although these have variable efficacy and significant side-effect profiles.⁵⁰ There is ongoing development of novel targeted therapeutics for PN; however, the majority of trials targeting patients with moderate-to-severe PN exclude patients with underlying neuropathic aetiologies, comorbid pruritic dermatoses, hepatitis B, hepatitis C, HIV, tuberculosis or CKD (Figures 4 and 5). AD is the most common pruritic dermatosis comorbid with PN, with a prevalence of approximately 15.5%. Despite the high prevalence, patients with AD were excluded from almost all trials except those for dupilumab and vixarelimab, which later stratified patients with or without atopy. Similarly, chronic hepatitis C (prevalence of 6.4% in patients with PN), HIV (7.4%) and CKD (29.4%) are highly prevalent in patients with PN. The lack of inclusion of patients with PN and these comorbid conditions limits the generalizability of a significant portion of ongoing PN trials.⁴⁹ The primary endpoint of these trials most often reflects change in itch, as measured by Worst-Itch Numeric Rating Scale (WI-NRS) with a greater than 4-point reduction being considered clinically meaningful improvement. Secondary endpoints include measures of pain, number of pruriginous lesions, severity of lesions, sleep disturbance, work impairment, anxiety and depression.

Novel therapeutics in development for prurigo nodularis target various aspects of itch pathogenesis. Each therapeutic in development targets a different aspect of itch pathogenesis. Dupilumab, nemolizumab and vixarelimab all target receptors that activate the JAK–STAT signalling pathway in multiple cell types, including sensory neurons, keratinocytes, macrophages, eosinophils, mast cells and T cells. Abrocitinib and povorcitinib target intracellular JAK–STAT signalling. Nalbuphine targets opioid receptors found on cutaneous nerve terminals, and barzolvolimab affects the mast cell KIT receptor, serving to block migration and activation of mast cells. Serlopitant and aprepitant target NK1Rs, acting to block activation of sensory neurons and mast cells by SP.

IL, interleukin; IL-…Rα, IL-… receptor α; JAK, Janus kinase; KOR, kappa opioid receptor; MOR, mu opioid receptor; NK1R, neurokinin 1 receptor; OSMRβ, oncostatin M receptor β; SCF, stem cell factor; SP, substance P; STAT, signal transducer and activator of transcription; TYK, tyrosine kinase.

Biologics

Dupilumab

Dupilumab is the first drug to be approved by the FDA for treatment of PN, gaining approval in September 2022.⁵¹ It is a monoclonal antibody (mAb) that targets IL-4Rα, which mediates IL-4 and IL-13 signalling through the JAK–STAT pathway, which induces the release of pro-inflammatory cytokines and IgE.^52,53 As IL-4 and IL-13 stimulate pruritus after intradermal injection in mice both together and individually, ⁵⁴ targeting IL-4Rα may be effective for chronic itch conditions like PN and AD that are strongly associated with the Th2 axis.⁵³ Its efficacy was confirmed in two phase III trials demonstrating clinically significant reduction of itch at weeks 12 and 24.^55–57 However, the trials did allow continuation of low-to-moderate-potency topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI) if patients had been on a stable regimen when enrolled, and allowed for inclusion of up to 10% of patients with mild AD, potentially representing confounding factors that were not present in trials for other agents. Despite this, dupilumab indeed shows substantial promise across patients with and without atopy in phase III trials and as the first FDA-approved drug for PN.

Nemolizumab

Nemolizumab is a mAb that targets IL-31RA, one component of the heterodimeric IL-31R.¹⁹ Overexpression of IL-31 has been associated with sensory neuronal overgrowth and stimulation, as well as increased sensitivity to itch-inducing stimuli.¹⁹ Higher levels of IL-31 were found in PN lesions compared with normal skin of healthy individuals, suggesting inhibition of IL-31-mediated pathways may be an effective treatment strategy.²⁰ RNA sequencing of PN skin biopsies and proteomic analysis of plasma collected before and after treatment with nemolizumab demonstrates suppression of Th2 and Th17 responses, as well as neural development and epithelial differentiation, downstream of IL-31.^58,59 A phase III trial comparing nemolizumab against placebo in 274 patients demonstrated clinically significant reduction in itch at 16 weeks in 56% of nemolizumab-treated patients compared with 21% of those in the placebo arm (P < 0.001).^60,61 These results suggest comparable efficacy and speed of onset with dupilumab, but with no TCS nor TCI use. Three other phase III trials are currently underway to further assess long-term durability of response, long-term safety, and efficacy at different doses.^62–64

Vixarelimab

Vixarelimab is a mAb that targets OSMRβ, which mediates both IL-31 and OSM signalling.^19,65 OSM is upregulated in PN lesions, contributing to pruritus by potentiating neural responses to pruritogens and enhancing inflammation through matrix metalloproteinase-mediated degradation of extracellular structures.^21,66 In a phase IIa trial with 49 patients with PN, the proportion of patients with clinically meaningful decrease in itch at week 8 was significantly greater in the vixarelimab group (–50.6%) compared with the placebo group (–29.4%) (P < 0.05).⁶⁷ Unlike other studies, this trial included patients with AD to assess for impact of atopy on treatment response. This could represent a possible confounder, particularly because the vixarelimab group was noted to have an increased proportion of patients with history of atopy and elevated IgE as a result of small sample size. A larger phase IIb trial was recently completed to assess efficacy, safety and pharmacokinetics for four different doses of the drug. No results are available yet.⁶⁸

Barzolvolimab

Barzolvolimab is a mAb targeting the KIT receptor, a tyrosine kinase receptor found on mast cells and activated by stem cell factor to regulate differentiation, migration and activation of mast cells.⁶⁹ As an increased number of mast cells is seen in the lesional epidermis of patients with PN and mast cells mediate neurogenic inflammation through pro-inflammatory chemokine release onto nearby peripheral nerve fibres, targeting KIT could alleviate pruritus by suppressing mast-cell activation and differentiation.^70,71 A completed phase Ib trial of 24 patients with PN has demonstrated safety and tolerability of the drug as well as clinically meaningful reduction in itch among 57% of patients with PN treated with 3.0 mg kg^–1 barzolvolimab, 43% with 1.5 mg kg^–1 barzolvolimab and 25% treated with placebo. This was accompanied by a dose-dependent reduction in serum tryptase, a marker of mast-cell activation.⁷² Although this was a small study and, unlike other studies, patients were required to apply topical emollients twice daily, the dose-dependent nature of the clinical effects and reduction in mast-cell activation suggest that barzolvolimab and inhibition of mast-cell degranulation are indeed promising options for the treatment of PN. Therapeutics targeting other mediators of mast-cell activation, such as MRGPRX2 or CST, may also be considered for development.

Janus kinase inhibitors

Ruxolitinib

Ruxolitinib is a JAK1 and JAK2 inhibitor that blocks activation of the JAK–STAT pathway by inflammatory cytokines; this pathway leads to an exaggerated inflammatory response, activation of eosinophils, and suppression of regulatory T cells.⁷³ Thus, blocking the pathway allows for suppression of multiple inflammatory pathways involved in PN. Topical ruxolitinib is already approved for use in AD and a phase III trial is currently recruiting to evaluate its safety and efficacy in PN.⁷⁴

Abrocitinib

Abrocitinib is an oral JAK1 inhibitor that blocks activation of the JAK–STAT pathway through JAK1, which is involved in mediating IL-2, -4, -6, -13, -15, -22, -31, thymic stromal lymphopoietin, interferon (IFN)-γ and IFN-α signalling.⁷⁵ Given the success of abrocitinib in treating AD, a phase II trial assessing the efficacy of abrocitinib in 10 patients with PN and 10 patients with chronic pruritus of unknown origin is underway.⁷⁶

Povorcitinib

Povorcitinib is another oral JAK1 inhibitor in phase II clinical trials for PN. The trial underway tests three doses of the drug and enrols a total of 140 patients with PN.⁷⁷

Opioid receptor antagonists

Nalbuphine

Nalbuphine is a partial MOR antagonist and KOR agonist approved for pain management.⁷⁸ It is also used to treat pruritus because inhibition of MORs and activation of KORs has been successful in inhibiting itch mediated by endogenous opioids.^78,79 Nalbuphine elicited clinically significant reduction in itch in 25% of patients treated with nalbuphine compared with 14% treated with placebos in a recently completed phase IIb/III trial among patients with PN (P = 0.0157).^80,81 However, the study excluded patients with major psychiatric comorbidities, which represents a significant proportion of patients with PN.⁸² There was also substantial attrition from 36 to 16 patients in total, largely due to lack of efficacy or treatment-emergent adverse events. Although nalbuphine has shown mild efficacy in these trials, careful consideration must be taken in prescribing it for long-term management of PN, given its habit-forming potential.^83,84 Data are still being gathered for the open-label extension portion of the trial.⁸⁵

Neurokinin 1 receptor antagonists

Aprepitant

Aprepitant is an NK1R antagonist that blocks SP-mediated signalling for inflammation, vasodilation, recruitment of eosinophils and mast-cell degranulation. This was promising for the treatment of PN because patients have elevated serum SP and NK1R, as well as increased SP-positive nerve fibres in the dermis.^37,86 However, in a phase II crossover trial, aprepitant failed to elicit greater pruritus reduction than placebo.^86,87

Serlopitant

Serlopitant, another NK1R antagonist, succeeded in eliciting significantly greater reduction in pruritus compared with placebo in phase II clinical trials but failed in two phase III studies.^88,89 Vyne (previously known as Menlo) Therapeutics Inc. has since terminated development of serlopitant for PN.^90–92 While it is unlikely that NK1R antagonists will be effective for a large majority of patients with PN, given the failure of two separate NK1R antagonists in clinical trials, the success of aprepitant and serlopitant in smaller case studies suggests that NK1R antagonists may be effective for some patients whose itch aetiology involves greater neural than immune dysregulation.

Conclusions

PN is a chronic, neuroimmune-mediated skin condition that greatly impacts patient quality of life. Th1, Th2, Th17 and Th22 immune dysregulation, as well as alterations in neuron density, neuron sensitization and neuropeptides are implicated in its pathogenesis. Recent studies have also pointed to the existence of various endotypes of PN with unique clinical manifestations and inflammatory biomarker profiles. There are several novel therapeutic agents undergoing assessment for treatment of PN, including biologics, JAK inhibitors and opioid modulators (trial information is shown in Tables 1 and 2). While few trials have assessed the treatment efficacy of these agents based on disease endotype, thorough characterization of PN disease endotypes and associated differences in pathogenesis will provide increasing clarity on targeting of immunomodulatory or neuromodulatory treatments towards specific subgroups and help to usher in precision medicine for patients with PN.

Table 1.

Summary of novel therapeutics in development for prurigo nodularis

Candidate	Manufacturer	Mechanism of action	Route of administration	Trial identifiers	Trial status	References
Dupilumab	Sanofi Genzyme, Regeneron Pharmaceuticals	mAb targeting IL-4 receptor α	SC	NCT04202679, NCT04183335	FDA approved	51–57
Nemolizumab	Galderma	mAb targeting IL-31 receptor A	SC	NCT04501666, NCT04501679, NCT04204616, NCT05052983	Phase III completed	58–64
Vixarelimab	Kiniksa Pharmaceuticals	mAb targeting oncostatin M receptor β	SC	NCT03816891	Phase IIb completed	65–68
Barzolvolimab	Celldex Therapeutics	mAb targeting KIT receptor	IV	NCT04944862	Phase I ongoing	69–72
Ruxolitinib	Incyte Corporation	JAK1/2 inhibitor	Topical	NCT05755438	Phase III ongoing	73,74
Abrocitinib	Pfizer Inc.	JAK1 inhibitor	Oral	NCT05038982	Phase II ongoing	75,76
Povorcitinib	Incyte Corporation	JAK1 inhibitor	Oral	NCT05061693	Phase II ongoing	77
Nalbuphine	Trevi Therapeutics	Partial MOR antagonist, KOR agonist	Oral	NCT02174419, NCT02174432, NCT03497975	Phase IIb/III completed	78–85
Aprepitant		NK1R antagonist	Oral	N/A	Failed at phase II	86,87
Serlopitant	Menlo Therapeutics^a	NK1R antagonist	Oral	NCT02196324, NCT03677401, NCT03546816	Failed at phase III	88–92

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^aMenlo Therapeutics is now Vyne Therapeutics Inc.

FDA, US Food and Drug Administration; IV, intravenous; JAK, Janus kinase; KOR, kappa opioid receptor; mAb, monoclonal antibody; MOR, mu opioid receptor; NK1R, neurokinin 1 receptor; SC, subcutaneous.

Table 2.

Itch relief in the most recently completed clinical trials for novel therapeutics in development for prurigo nodularis

Candidate drug	Trial identifier	Trial phase	Trial design	Number of subjects	Measure of itch improvement	Outcome	TEAE rate
Dupilumab^a	NCT04202679 (PRIME2)	III	2-arm parallel group study in patients with uncontrolled PN	Drug: n = 78 Placebo: n = 82	Percentage of patients with WI-NRS reduction of ≥ 4 points at 12 weeks^b	Drug: 37% of patients (P < 0.05) Placebo: 22% of patients	Drug: 54.5% Placebo: 46.3%
	NCT04183335 (LIBERTY-PN PRIME)	III	2-arm parallel group study in patients with uncontrolled PN	Drug: n = 75 Placebo: n = 76	Percentage of patients with WI-NRS reduction of ≥ 4 points at 24 weeks^b	Drug: 60% of patients (P < 0.0001) Placebo: 18% of patients	Drug: 65.3% Placebo: 56.0%
Nemolizumab	NCT04501679 (OLYMPIA2)	II	2-arm parallel group study in patients with moderate-to-severe PN	n = 274	Percentage of patients with PP-NRS reduction of ≥ 4 points at 16 weeks^b	Drug: 56% of patients (P < 0.001) Placebo: 21% of patients	Drug: 68% Placebo: 67%
Vixarelimab	NCT03816891	IIa	2-arm parallel group study in patients with moderate-to-severe PN	Drug: n = 23 Placebo: n = 26	Percentage change from baseline in WI-NRS at 8 weeks^b	Drug: 50.6% decrease (P < 0.05) Placebo: 29.4%	Drug: 91.3% Placebo: 76.9%
Barzolvolimab	NCT04944862	Ib	3-arm parallel group study in patients with PN	Drug, 3.0 mg kg^–1: n = 9 Drug, 1.5 mg kg^–1: n = 7 Placebo: n = 8	Percent change from baseline in WI-NRS at 8 weeks^b	Drug, 3.0 mg kg^–1: 57% of patients Drug, 1.5 mg kg^–1: 43% of patients Placebo: 25% of patients	Results not yet available
Ruxolitinib	NCT05755438	III, ongoing	2-arm parallel group study in patients with PN	Drug, 1.5% cream: n = 100 Placebo: n = 100	Percentage of patients with WI-NRS reduction of ≥ 4 points at 12 weeks^b	Results not yet available	Results not yet available
Abrocitinib	NCT05038982	II, ongoing	Nonmasked study in patients with PN	n = 10	Percentage change from baseline in PP-NRS at 12 weeks^b	Results not yet available	Results not yet available
Povorcitinib	NCT05061693	II, ongoing	4-arm parallel group study in patients with PN	n = 140	Percentage of patients with Itch-NRS reduction of ≥ 4 points at 16 weeks^b	Results not yet available	Results not yet available
Nalbuphine	NCT03497975 (PRISM)	IIb/III	2-arm parallel group study in patients with moderate-to-severe PN	Drug: n = 168 Placebo: n = 176	Percentage of patients with WI-NRS reduction of ≥ 4 points at 14 weeks^b	Drug, 162 mg: 25% of patients (P = 0.0157) Placebo: 14% of patients	Drug: 48% Placebo: 45%
Aprepitant	N/A	II	2-arm cross-over study in patients with PN	Drug then placebo: n = 19 Placebo then drug: n = 19	Difference between first and second treatment periods in the change in average 24-h Itch-VAS score during each treatment period	Drug change minus placebo change: –11.1 (P = 0.7) Placebo change minus Drug change: –12.7	Drug: 55.2% Placebo: 65.5%
Serlopitant	NCT03546816	III	2-arm parallel group study in patients with PN	Drug: n = 142 Placebo: n = 143	Percentage of patients with WI-NRS reduction of ≥ 4 points at 10 weeks^b	Drug: 26.45% of patients (P = 0.229) Placebo: 20.31% of patients	Drug: 17.1% Placebo: 5.7%
	NCT03677401	III	2-arm parallel group study in patients with PN	Drug, 5 mg oral daily: n = 148 Placebo: n = 147	Percentage of patients with WI-NRS reduction of ≥ 4 points at 10 weeks^b	Drug: 25.90% of patients (P = 0.158) Placebo: 18.95% of patients	Drug: 24.5% Placebo: 23.7%

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All parallel group studies were randomized, double-blinded and placebo-controlled.

^aDupilumab has been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of PN.

^bPrimary outcome of the study.

NRS, Numeric Rating Scale; PN, prurigo nodularis; PP, Peak-Pruritus; TEAE, treatment-emergent adverse event; VAS, Visual Analog Scale; WI, Worst-Itch.

Contributor Information

Viviane Liao, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Hannah L Cornman, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Emily Ma, Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Shawn G Kwatra, Department of Dermatology; Maryland Itch Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Funding sources

S.G.K. is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under Award Number K23AR077073-01A1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Data availability

No data were generated.

Ethics statement

Not applicable.

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