¹School of Medicine, Texas A&M University Health Science Center, Bryan, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, University of Texas Health and Sciences Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Abstract:
Prurigo nodularis and atopic dermatitis are chronic, inflammatory skin conditions characterized by significant pruritus that disrupts daily life. They also involve dysfunction of the T-helper 2 immune response, leading to the over secretion of interleukin-31 (IL-13) in the dermis and serum. Nemolizumab is a new IL-31 receptor antagonist that has shown high efficacy in the treatment of prurigo nodularis (PN) and atopic dermatitis (AD) in multiple phase 3 trials, with a good safety profile. A brief overview of PN and AD including highlights of the findings from three trials of nemolizumab in treating these disorders will be presented herein.

Keywords: atopic dermatitis, interleukin-31, nemolizumab-ilto, prurigo nodularis, pruritus

Introduction

Prurigo nodularis (PN) is a chronic, inflammatory skin condition characterized mainly by pruritus, leading to a disruption of sleep and daily activities.^1,2 The pruritus is often intense, lasting over 6 weeks, and may also present with a burning or stinging sensation.^3,4 Diagnosis is primarily made by clinical examination of the lesions and through the patient’s history, revealing clusters of nodules commonly located on the extremities or trunk.³ Biopsy can also help to confirm the diagnosis in unusual cases, which typically reveals hyperkeratosis, hypergranulosis and increased fibroblasts.³

PN disproportionally impacts individuals of African ancestry and the elderly, although it can affect patients of any age.⁴ Men and women are equally susceptible.⁵ A significant number of patients also suffer from anxiety, depression, and suicidal ideation due to the severity of the condition.^2,4,5 In 2022, dupilumab became the first US Food and Drug Administration approved treatment for PN.⁶ Other conventional treatments have typically been less effective, involve off-label uses of medications and mainly aim to reduce itching by targeting the neural and immunologic aspects of the condition.³

Similarly, atopic dermatitis (AD) is also an inflammatory cutaneous disease commonly manifesting with erythema, papules, edema, and crusting.^7,8 AD most commonly affects the pediatric population, with 90% of cases first presenting with symptoms under the age of 5 years, persisting with episodical outbreaks in adulthood.⁸ AD is highly variable in presentation and current management of the condition depends on its severity.^7,9 First-line therapy involves the use of topical corticosteroids, along with emollients and regular bathing.⁹ Systemic therapies are also commonly used, including ciclosporin, methotrexate, azathioprine, and mycophenolate mofetil.¹⁰ Other treatments include calcineurin inhibitors, crisaborole, rofumilast, ruxolitinib, ultraviolet B phototherapy, and, more recently, dupilumab, tralokinumab, abrocitinib, and upadacitinib, which may be used in more severe or treatmentresistant AD.⁹

IL-31 Pathway and Mechanism of Nemolizumab

T-helper 2 (Th2) cells are primarily responsible for the release of interleukin-31 (IL-31), with CD4+, CD8+, and mast cells also producing IL-31 in the presence of allergens of pathogens.^4,11-13 This leads to the stimulation of eosinophils and contributes to the itching in AD, as well as other inflammatory skin disorders.¹¹ There are multiple proposed mechanisms as to how IL-31 leads to the pruritus in AD and PN, such as the abundance of IL-31 receptors in the dorsal root ganglia (DRG) of cutaneous sensory nerves.¹¹ IL-31 may also activate receptors present in keratinocytes, which subsequently activate unmyelinated C fibers, leading to pruritus.¹¹ Transient receptor potential cation channels in the DRG and chemokine release by keratinocytes due to IL-31 are possible additional mechanisms.¹¹

Both PN and AD are inflammatory cutaneous conditions that involve impaired IL-31 signaling.⁴ PN skin lesions form as a result of the chronic scratching induced by immunologic and neural dysfunction.⁴ Skin biopsy reveals the presence of T lymphocytes, mast cells, and eosinophils that release IL-31, tryptase, and histamine.⁴ There is also increased nerve fiber density, along with neuropeptides such as substance P and calcitonin gene-related peptide in the dermis, which contribute to the pathogenesis of pruritus in PN.^3,4 Similarly, IL-31 serum levels increase with higher severity of AD, and gene polymorphisms have been linked with the development of the disease.^4,11-13 Nemolizumab is an IL-31 receptor alpha antagonist that has shown potential in treating both PN and AD in multiple phase 3 clinical trials.⁴ These investigations demonstrated that treatment with nemolizumab reduced itch intensity, improved lesion healing and inhibited Th2 (IL-13) and Th17 (IL-17) cells.⁴

Phase 3 Clinical Trials for Prurigo Nodularis

A phase 3 clinical trial of nemolizumab in PN enrolled 274 patients, aged 18 years and older, from 68 sites and 9 different countries, for a 16-week treatment period and subsequent 8-week follow-up.⁵ Patients were selected based on a history of PN for ≥6 months and pruritus classified as severe by the Peak Pruritus Numerical Rating Scale (PP-NRS).⁵ This scale ranges from a score of 0 (no itch) to 10 (worst itch), where a score of 7 or greater is severe and qualified patients for enrollment in the trial.⁵ Patients were also selected for the presence of 20 or more nodules, and a score of 3 or 4 on the Investigator’s Global Assessment (IGA), which assesses the severity of the disease on a scale of 0-4 by the type, size and quantity of lesions.^5,14 Patients with active AD, neuropathic or psychogenic pruritus, or pruritus due to causes other than PN were excluded from the study.⁵

183 patients were randomly chosen to receive nemolizumab and another 91 patients were given a placebo.⁵ Participants were administered an initial dose of 60 mg of nemolizumab, followed by 30 mg or 60 mg based on their starting weight, every 4 weeks over a period of 16 weeks.⁵ Overall, both groups were similar and balanced prior to treatment; only 4.4% of participants were Black.⁵

19.7% and 35% of the nemolizumab group achieved almost complete itch relief at 4 weeks and 16 weeks, respectively.⁵ In the placebo group, 2.2% and 7.7% reported similar itch relief after 4 weeks and 16 weeks, respectively.⁵ 37.2% and 51.9% of patients receiving nemolizumab achieved a decrease in sleep disturbance by 4 and 16 weeks, respectively.⁵ In contrast, only 9.9% and 20.9% of the placebo group reported a clinically significant decrease in sleep disturbance.⁵ 16 week after treatment, 56.3% of the nemolizumab group and 20.9% of the control group achieved a significant decrease in itch intensity, defined as a 4 or greater point decrease on the PP-NRS.⁵ Patients who received nemolizumab demonstrated significant improvements in skin lesions, pruritus, sleep disturbance, pain, global disease assessment, quality of life, and anxiety and depression symptoms compared to the control group.⁵ Improvements in itch, skin lesions, sleep disturbance, and quality of life continued through week 52, with more than two-thirds of patients becoming itch-free or nearly itch-free and 90% reporting clinically meaningful improvement in quality of life.¹⁵ Quality of life was assessed using the Dermatology Life Quality Index (DLQI), which is composed of 10 questions designed to evaluate how patients perceive the impact of their skin condition on different areas of their life, including symptoms/feelings, daily activities, leisure, work/school, personal relationships, and treatment.⁵

61.2% of participants that received nemolizumab and 52.7% of placebo experienced at least one adverse event (AE) (Table 1).⁵ In the treatment group, most AEs were common side effects and included mild AD and headache.⁵ Peripheral or facial edema and asthma were more common in patients receiving nemolizumab, while infections were more prevalent in the control group.⁵ One case of bullous pemphigoid was reported in the nemolizumab group, and a case of generalized exfoliative dermatitis was recorded in the placebo group.⁵ In addition, a higher number of placebo patients required rescue therapy (15.4%) compared to those receiving nemolizumab (4.9%).⁵ 2.2% of patients in each group withdrew from the trial due to adverse reactions.⁵ Long-term data over a 52- week extended study remained consistent with the safety profiles in phase 3 trials.¹⁵

In patients with no history of asthma, 6 of 156 in the nemolizumab group and 2 of 77 in the placebo group had decreased expiratory flow below 80% during the treatment period.⁵ In those with a history of asthma, 5 of 22 patients receiving nemolizumab showed peak expiratory flow under 80% of the predicted value during the treatment period, however, only 2 of these were confirmed as worsening asthma.⁵ In comparison, 1 of 13 patients with a history of asthma in the placebo group experienced a peak expiratory flow under 80% of the expected value during the treatment period.⁵ An increased eosinophil count was reported in 7.7% of the nemolizumab group and 4.4% of the placebo group.⁵ Moreover, 5.8% of nemolizumab patients developed antidrug antibodies.⁵

Table 1.

Phase 3 Clinical Trials for Atopic Dermatitis

In two identical phase 3 trials of nemolizumab for the management of AD, ARCADIA 1 and ARCADIA 2, 1142 patients over the age of 12 years received 30 mg of nemolizumab (after a loading dose of 60 mg), while 586 participants were given a placebo every 4 weeks over a period of 16 weeks.¹⁶ The Eczema Area and Severity Index (EASI), which assesses the surface area of the skin affected by AD and the severity of lesions, as well as the IGA, were used to characterize the severity of AD.^16,17 Primary endpoints were defined as an IGA score of 0 or 1 with a ≥2-point improvement from baseline and at least 75% improvement in EASI.¹⁶ Patients in the nemolizumab group who successfully achieved these endpoints were then randomly reassigned in a 1:1:1 ratio.¹⁶ They were to receive either 30 mg of nemolizumab every 4 weeks, 30 mg of nemolizumab every 8 weeks, or a placebo every 4 weeks in a maintenance period.¹⁶

In the nemolizumab group, 36% of patients in ARCADIA 1 and 38% in ARCADIA 2 achieved IGA success, compared to 25% (ARCADIA 1) and 26% (ARCADIA 2) of patients in the control group.¹⁶ 75% improvement in EASI was observed in 44% (ARCADIA 1) and 42% (ARCADIA 2) of patients in the nemolizumab group, compared to 29% (ARCADIA 1) and 30% (ARCADIA 2) of those receiving placebo.¹⁶ Improvements in pruritus were observed from week 1 in the nemolizumab group, with additional improvements reported in quality of life, sleep, and a decrease in pain by 16 weeks.¹⁶ Additionally, clinically meaningful improvements in itch, skin lesions, and sleep disturbance persisted through week 56 of an extended study.¹⁸ Overall, the study showed that a statistically significant proportion of patients with moderate to severe AD achieved clinically meaningful improvements in symptoms of pruritus and inflammation with nemolizumab (Table 2).¹⁶

Table 2.

In terms of safety, 50% of patients in ARCADIA 1 and 41% in ARCADIA 2 receiving nemolizumab reported an AE, with serious effects occurring in 1% and 3% of patients in each respective trial.¹⁶ Worsening of AD was the most commonly reported adverse effect, occurring in a total of 112 patients receiving nemolizumab from both trials, compared to 49 patients in the control group. Worsening of asthma was reported in 1% of patients in ARCADIA 1 and 5% of patients in ARCADIA 2 in the nemolizumab group; however, there was no significant difference compared to those receiving placebo.¹⁶ Serious drug-related AEs were rare, reported in 5 patients in ARCADIA 2, and included infection, peripheral edema, eosinophilic colitis, and small intestinal obstruction.¹⁶ Additionally, AEs resulting in treatment discontinuation occurred in a total of 24 patients in the nemolizumab group, compared to 6 patients in the control group across both trials.¹⁶ Safety results of nemolizumab after 56 weeks aligned with previous findings, supporting its use in adolescents and adults with moderate-to-severe AD.¹⁸

Conclusion

Nemolizumab demonstrated high efficacy in the treatment of PN and AD in phase 3 trials, yielding marked improvements in symptom control with an overall favorable safety profile.^5,16 In the PN trial, a significant number of patients receiving nemolizumab exhibited improvements in pruritus, sleep disturbances, and quality of life based on the DLQI compared to the control group.⁵ The most common side effects were nasopharyngitis, AD, and headaches.⁵ In the AD trials, similar improvements in pruritus, sleep quality, and a decrease in pain levels were observed with the most common side effect being worsening of AD.¹⁶ Overall, nemolizumab has shown promising results in reducing pruritus and is particularly useful in treating severe or therapy-resistant PN and AD.^4,5,16

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¹Schulich School of Medicine and Dentistry, Western University, Windsor, ON, Canada
²Department of Health Sciences, Brock University, St. Catharines, ON, Canada
³Windsor Clinical Research Inc, Windsor, ON, Canada

Conflict of interest: Karen Michael, Jaefer Mohaad and Nuha Nasir have no conflicts. Jerry Tan is an advisor, consultant, speaker and/or trialist for Bausch, Cipher, Cutera, Galderma and Sun Pharma.

Funding sources: None.

Abstract: Clindamycin phosphate 1.2%/benzoyl peroxide 3.1%/adapalene 0.15% (IDP-126) is a novel fixed-dose triad gel combination approved by the US FDA October 2023 and by Health Canada August 2024 for the treatment of acne vulgaris in patients aged 12 years and older. IDP-126 was efficacious in moderate to severe acne compared to vehicle and component topical dyads in phase 2 and to vehicle in phase 3 randomized controlled studies. Efficacy outcomes were inflammatory and noninflammatory lesion counts and Evaluator’s Global Severity Score. IDP-126 also had a favorable tolerability and safety profile.

Keywords: acne, topical, triple combination, fixed-dose, clindamycin, adapalene, benzoyl peroxide, treatment, Cabtreo™

Introduction

The pathogenesis of acne involves different mechanisms including follicular proliferation of Cutibacterium acnes (C. acnes), follicular hyperkeratinization, inflammation, and increased sebum production.¹ Current topical medications include retinoids, benzoyl peroxide, antibiotics, azelaic acid, and dapsone – either as monads or dyads. Recently, a novel topical fixed-dose triad, combining clindamycin phosphate 1.2%/benzoyl peroxide (BPO) 3.1%/adapalene 0.15% (IDP-126) has been developed. Herein, we summarize pivotal trials leading to regulatory approval in the US and Canada.

Phase 2 Studies

The phase 2 study, conducted in the US and Canada, was randomized, controlled and double-blinded involving participants 9 years or older with moderate [Evaluator’s Global Severity Score (EGSS) of 3] to severe (EGSS 4) facial acne.² Participants were randomized to one of five different treatment groups for 12 weeks: vehicle, IDP-126 (triple combination), and the following dyad formulations: benzoyl peroxide 3.1%/adapalene 0.15% gel (BPO/ ADAP), clindamycin phosphate 1.2%/benzoyl peroxide 3.1% (CLIN/BPO), or clindamycin phosphate 1.2%/adapalene 0.15% gel (CLIN/ADAP).

Treatment success, defined by achievement of ≥2-grade reduction in EGSS and clear/almost clear (EGSS 0 or 1), was achieved by 52.5% of participants at week 12 with IDP-126. This was significantly greater than the three dyad gels (range 27.8-30.5%; P ≤ 0.001, all) and vehicle (8.1%; P < 0.001). IDP-126 resulted in significant mean reductions in inflammatory (29.9) and noninflammatory lesions (35.5) from baseline to week 12 (P < 0.05, all) compared to all dyad treatments and vehicle (Figure 1). Overall, IDP-126 demonstrated over 70% reductions in both inflammatory and noninflammatory lesions.

Phase 3 Studies

Two identical randomized, double-blind, vehicle-controlled 12-week trials were conducted in subjects aged 9 years and older in moderate to severe acne.³ Participants were randomized to IDP-126 or vehicle gel, at a 2:1 ratio. Co-primary outcomes were ≥2-grade reduction from baseline and achievement of clear/almost clear on EGSS, and changes in inflammatory and noninflammatory lesion counts.

All coprimary efficacy endpoints were achieved in both trials with IDP-126 gel outperforming vehicle at week 12. Significantly greater percentages of participants achieved a 2-grade reduction in EGSS and clear/almost clear at week 12 with IDP-126 vs. vehicle (Study 1: 49.6% vs. 24.9%, P ≤ 0.01; Study 2: 50.5% vs. 20.5%; P ≤ 0.001).

When comparing IDP-126 vs. vehicle at week 12, greater reductions were also observed in inflammatory (Study 1: 27.7% vs. 21.7%, P ≤ 0.01; Study 2: 30.1% vs. 20.8%; P ≤ 0.001) and noninflammatory (Study 1: 35.4% vs. 23.5%, P ≤ 0.01; Study 2: 35.2% vs. 22.0%; P ≤ 0.001) lesion counts (Figure 2). Significant differences in inflammatory and noninflammatory lesion counts with IDP-126 vs. vehicle were noted by week 4 (P < 0.05).

Treatment-emergent adverse events (TEAEs) were observed with greater frequency in the IDP-126 group (Study 1: 24.6% vs. 8.2%; Study 2: 30.0% vs. 8.3%) and considered related in a smaller proportion (Study 1: 18.0% vs. 0%; Study 2: 21.7% vs. 3.3%). These were primarily mild-moderate in severity and attributed to application site pain (Study 1: 10%; Study 2: 15.0%), erythema (Study 1: 4.9%; Study 2: 2.5%), dryness (Study 1: 1.6%; Study 2: 4.2%), irritation (Study 1: 0.8%; Study 2: 3.3%), exfoliation (Study 1: 3.3%; Study 2: 0%) and xerosis (Study 1: 0%; Study 2: 2.5%). Three severe adverse events were reported, all in the IDP-126 cohorts (Study 1: application site burn, n = 1, led to study withdrawal; Study 2: application site pain and dryness, n =1; application site pain, n = 1; related). No serious adverse events were reported.

Network Meta-Analysis

A network meta-analysis compared the relative efficacy of commercially available acne treatments for moderate to severe acne.⁴ Inclusion criteria were randomized controlled trials (RCTs) with minimum duration of 4 weeks involving subjects aged 9 years and older. Notably, isotretinoin studies were excluded from this analysis due to either absence of global assessments in current use for regulatory approval, or non-randomized designs. Primary outcomes evaluated were percentage of patients achieving a ≥2-grade reduction in acne severity, almost clear/clear for global severity score, and changes in inflammatory lesion (IL) counts, and noninflammatory (NIL) counts. Treatments were ranked using surface under cumulative ranking (SUCRA) values. SUCRA scores rank treatments based on their effectiveness across studies, simplifying comparison by assigning higher scores to more consistently effective treatments. The top treatments across these outcomes were: (1) IDP-126, a combination of topical antibiotics/ BPO/retinoids (SUCRA 0.96 for Global Assessment, 0.90 for inflammatory lesions, and 0.91 for noninflammatory lesions), (2) fixed-dose dyad topical treatments with oral antibiotics (SUCRA 0.88, 0.98, and 0.99, respectively), and (3) topical retinoid/ BPO combinations (SUCRA 0.74, 0.79, and 0.79, respectively). These rankings highlight the strong overall performance of these treatment combinations across different acne efficacy outcome measures. In addition to efficacy, IDP-126 showed a favorable safety and tolerability profile with lower discontinuation rates (2.8%). It also had fewer patients with TEAEs than dyads.

Conclusion

The topical fixed-dose triad of clindamycin phosphate 1.2%/BPO 3.1%/adapalene 0.15% gel (IDP-126) represents an effective and well-tolerated novel topical treatment option for moderate to severe acne. In comparison to currently available topical and systemic treatments (except for oral isotretinoin), it ranks within the top three of the most effective treatments for moderate to severe acne.

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