Dupilumab improves pruritus and skin lesions in patients with prurigo nodularis: Pooled results from 2 phase 3 trials (LIBERTY-PN PRIME and PRIME2)

Background Phase 3 PRIME/PRIME2 trials independently demonstrated efficacy and an acceptable safety profile of dupilumab adults with moderate-to-severe prurigo nodularis. Objective To obtain a more precise estimate of onset and magnitude of treatment effect using PRIME/PRIME2 pooled data. Methods In PRIME/PRIME2, patients were randomized to dupilumab or placebo for 24 weeks. Pooled analysis assessed proportion of patients achieving clinically meaningful improvement in itch, clear/almost-clear skin, or both; at weeks 12 and 24; overall and by demographic subgroups and changes from baseline to week 24 in symptoms, signs, and quality of life. Results Patients receiving dupilumab (n = 153) vs placebo (n = 158) experienced significant improvements in all tested endpoints. At week 24, 90 (58.8%) dupilumab-treated vs 30 (19.0%) placebo-treated patients achieved clinically meaningful improvement in itch, 71 (46.4%) vs 27 (17.1%) clear/almost clear skin, and 54 (35.3%) vs 14 (8.9%) achieved both (P < .0001 for all). Treatment benefits were independent of baseline demographics. Safety to week 36 was generally consistent with the known dupilumab safety profile. Limitations On-treatment data limited to 24 weeks. Conclusions Pooled analysis confirmed improvements reported in individual trials and revealed earlier effect onset in itch and skin pain. Dupilumab treatment showed benefits across demographics.


INTRODUCTION
][3][4][5][6] Topical therapies and systemic immunosuppressants or neuromodulators are used off-label, but often fail to control PN. 7,8 The US Food and Drug Administration recently approved dupilumab as the first systemic PN therapy. 9upilumab is a fully human VelocImmune-derived monoclonal antibody that blocks the shared receptor component (interleukin 4 receptor alpha [IL-4Ra]) for interleukin (IL)-4 and IL-13, 10,11 thus inhibiting signaling of these central drivers of type 2 inflammation.
LIBERTY-PN PRIME and PRIME2 were 2 similarly designed phase 3 trials of dupilumab in adults with moderate-to-severe PN. 12 In each trial, dupilumab demonstrated significant improvements compared with placebo on prespecified endpoints, including itch, skin lesions, QoL, skin pain, and anxiety/ depression, with safety generally consistent with its known safety profile. 12In the current study, to further explore the robustness and onset of dupilumab action in PN, we assessed changes from baseline to week 24 in skin symptoms, signs, QoL, anxiety/depression, and sleep, using pooled data from PRIME/PRIME2 trials.Additionally, we used the increased power of the pooled analysis to assess treatment effect by baseline demographic subgroups, and we report safety results up to week 36.Plain Language Summary available via Mendeley at https://data.mendeley.com/datasets/75xwz2849j/1.

METHODS
Details of individual PRIME/PRIME2 (NCT04183335/ NCT04202679) trials have been published previously. 12RIME and PRIME2 were randomized, placebocontrolled, phase 3 trials, conducted independently in 16 countries in North and South America, Europe, and Asia.Each trial included a 2 to 4-week screening period, a 24-week intervention period, and a 12-week posttreatment follow-up period (Supplementary Fig 1, available via Mendeley at https://data.mendeley.com/datasets/75xwz2849j/1).The studies were conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Good Clinical Practice guideline, and applicable regulatory requirements.All patients provided written informed consent before participating.

Study design
This was a pooled analysis by treatment group of data from PRIME/PRIME2.

Patients
Patients were adults (18-80 years) with moderate-tosevere PN inadequately controlled with topical therapies or for whom those therapies were inadvisable.
Key inclusion criteria were: PN diagnosed for $3 months prior to screening; average Worst Itch Numerical Rating Scale (WI-NRS) score $7 in the 7 days prior to day 1 (assessed daily); $20 pruriginous nodules at screening and day 1 (Investigator's Global Assessment for PN-Stage [IGA PN-S] of 3 or 4), with involvement of at least 2 body areas; history of failure of a 2-week course of medium-to-superpotent topical corticosteroids (TCS), or TCS were not advisable.Detailed inclusion and exclusion criteria have been reported previously. 12

Treatment and procedures
Patients were randomized 1:1 to receive subcutaneous dupilumab 300 mg every other week (600 mg loading dose on day 1) or placebo for 24 weeks.Use of high-potency/superpotency TCS, systemic immunosuppressive and immunomodulating drugs, intralesional corticosteroid injections, and cryotherapy, phototherapy, opioid-receptor antagonists, gabapentin, pregabalin, and thalidomide were prohibited from 4 weeks prior to screening to the end of the trial.Patients on a stable regimen of low-to-medium potency TCS and topical calcineurin inhibitors prior to screening were allowed to continue their use throughout the trial.Patients on stable doses of antidepressants for 3 months prior to enrollment were eligible if they kept medication unchanged throughout the trial.
Atopy was defined as having a medical history of or ongoing atopic dermatitis (AD), allergic rhinitis/ rhinoconjunctivitis, asthma, or food allergy.Atopic and nonatopic PN populations were capped at 60% of the trial population.Patients with ongoing mild

CAPSULE SUMMARY d
Similarly designed PRIME and PRIME2 randomized, placebo-controlled trials supported approval of dupilumab as the first systemic therapy in prurigo nodularis.

d
The present pooled analysis of PRIME and PRIME2 data confirmed, with increased power, efficacy, onset of treatment effect, and acceptable safety profile of dupilumab in patients with moderate-to-severe prurigo nodularis.
AD were eligible; their enrollment was capped to 10% of the atopic population.

Instruments used to assess efficacy
WI-NRS (0, ''no itch'' to 10, ''worst imaginable itch'') is validated in PN, and a reduction of 4 points is considered clinically meaningful in patients with baseline WI-NRS $7. [13][14][15] Patients reported a daily score; the average of the previous 7 days was used as the trial weekly WI-NRS score.
IGA PN-S, also validated in PN, 16 is the clinician-assessed stage based on approximate number of palpable pruriginous nodules on a scale of 0-4 (0

Study endpoints
Efficacy endpoints addressing pruritus and skin lesions included proportion of patients with $4-point reduction from baseline in WI-NRS, or achieving IGA PN-S score 0 or 1, or both, at week 12 and week 24, and percent change in WI-NRS from baseline to week 24.Other efficacy endpoints included changes from baseline to week 24 in the Dermatology Life Quality Index (DLQI), Skin Pain-NRS, total Hospital Anxiety and Depression Scale, and Sleep Quality-NRS, as well as proportion of patients who used rescue medication through week 24.
Subgroup analyses included proportion of patients with $4-point reduction in WI-NRS, or IGA PN-S score 0/1, or both, at week 24, by age, sex, region, race, and baseline body mass index (BMI).
Safety was assessed up to week 36, including the treatment and follow-up periods.

Statistical analysis
Efficacy analyses were performed on the full analysis set, including all randomized patients.For categorical endpoints, P-values and the response rate difference vs placebo (95% CI) were calculated by Cochran-Mantel-Haenszel test performed on the association between the responder status and intervention group, adjusted by randomization stratification factors (documented history of atopy [atopic/ nonatopic], stable use of TCS or topical calcineurin inhibitors [yes/no], region, baseline antidepressant use [yes/no], and study indicator [PRIME/PRIME2]).Patients who received prohibited medications/ procedures, rescue medication, or with missing data at the analysis timepoint were considered nonresponders.For continuous endpoints, data were analyzed by fitting an analysis of covariance model with the corresponding baseline value, intervention group, and randomization stratification factors as covariates.Data collected after study discontinuation were included.Data collected after prohibited medications/procedures, use of rescue medication, or study discontinuation due to lack of efficacy were set to missing and imputed by worst observation carried forward.Other missing data were imputed by multiple imputation.For subgroup analyses, odds ratios (OR) and 95% CI were derived from the Mantel-Haenszel estimator.ORs or 95% CIs for some specific subgroup categories could not be calculated due to either empty cell(s) or high imbalance within 1 or more cells of the 2 3 2 table (treatment vs improvement status) at each level of the stratification factors used in the analysis model.All reported P values are nominal.
All analyses were conducted using SAS software version 9.4.
Prior to enrollment, all patients had used topical medications for PN, and 66.2% had used systemic medications.Despite prior therapies, at baseline, all patients had moderate or severe disease as defined by pruriginous nodule count, severe or very severe itch, skin pain, and impaired sleep.The overall mean (SD) WI-NRS score was 8.5 (1.0).Among enrolled patients, 66.3% had 20-99 nodules (IGA PN-S = 3), and 33.7% had $100 nodules (IGA PN-S = 4).Mean (SD) Skin Pain-NRS was 7.2 (2.4), and Sleep Quality-NRS was 4.3 (2.4).Mean (SD) DLQI score was 17.5 (7.0), indicating a very large effect of disease on QoL.x Defined as having a medical history of atopic dermatitis, allergic rhinitis/rhinoconjunctivitis, asthma, food allergy.Population with history of atopy was capped at 60% of the trial population.
k Mild ongoing atopic dermatitis population was capped at 10% of the atopic population.The cumulative rate of symptom breakthrough requiring TCS rescue medication separated early for dupilumab vs placebo (week 2) and was significantly lower for the dupilumab group vs placebo over the remainder of the 24-week treatment period (Fig 3).

DISCUSSION
The present analysis confirms individual trial results, adds information on efficacy by demographic subgroups, and extends previously reported  safety up to week 36.Dupilumab demonstrated efficacy vs placebo in all tested efficacy endpoints, including clinically meaningful reduction in itch, reduction in pruriginous nodule number to #5, reduction in skin pain and anxiety/depression, and improvement in sleep quality and QoL.Pooling data from the 2 PRIME studies allowed for greater precision in delineating the onset of action and revealed earlier differentiation from placebo in WI-NRS mean percent change from baseline (week 3, consistent with PRIME) than that seen in the PRIME2 trial (week 4), as well as in Skin Pain-NRS mean change from baseline (week 2, compared with week 3 in PRIME and week 4 in PRIME2).Additionally, consistent with results in PRIME, but in contrast to PRIME2, the pooled analysis showed nominally significant improvements in sleep quality from week 4 to week 24. 12nalyses by baseline demographic subgroups showed a consistent trend of dupilumab benefit compared with placebo in achieving $4-point reduction in WI-NRS, IGA PN-S 0 or 1, or both, at week 24, with comparable effect size in all demographic subgroups that included sufficient patients for meaningful testing.Racial differences have been demonstrated in PN, with more males affected in the Asian population and more females affected in White and African-American populations. 17,180][21] In our study, the magnitude of the treatment effect on itch improvement and skin nodule clearance was comparable between White and Asian patients.The percentage of responders vs placebo in the Black patient subgroup also showed dupilumab benefit (45.5% vs 12.5% for itch and 36.4% vs 12.5% for skin lesions); however, ORs could not be calculated due to the small sample size.
3][24][25] There were no keratitis events.The incidence of conjunctivitis in dupilumab-treated patients was 3.9% (including 1 patient with comorbid mild AD).This incidence is lower than that reported in AD trials (9.3% in AD 16-week monotherapy trials with 300 mg dupilumab every 2 weeks; 13.6% in 52-week CHRONOS and 28% in 16-week CAF E AD trials of dupilumab with concomitant TCS), 26 which is in line with previous studies showing higher incidence of ocular surface disorders in AD clinical trials compared with other dupilumab indications. 26Consistent with previous dupilumab trials for AD, [27][28][29] in this analysis, fewer patients in the dupilumab group vs placebo developed non-herpetic skin infections (7 [4.6%] vs 14 [8.9%]).This may be explained by the rapid effect of dupilumab in breaking the itch/scratch cycle, 30 its restorative effect on skin barrier integrity, 31 and its targeted IL-4/IL-13 inhibition without broad immunosuppression.
3][34][35] Signaling through IL-4Ra, which is expressed on various subsets of itch sensory neurons, 33,34 was shown to sensitize neurons to other pruritogens released in inflamed skin. 33,35Therefore, IL-4Ra blockade with dupilumab is expected to alter the itch-scratch cycle in PN.Dupilumab may also impact the activity of IL-31, an important driver of pruritus, as IL-4 stimulation upregulates IL-31 receptor A expression and is the central driver of T helper 1 or 2 cell precursor polarization.As T helper 2 cells are the main source of IL-31, IL-4/IL-13 blockade with dupilumab could potentially prevent activation of sensory neurons by reducing IL-31 signaling. 33imitations of this study include the relatively short treatment duration and the small representation of the Black/African-American population (6.1%).Given that all tested efficacy endpoints improved progressively over 24 weeks, longer treatment may lead to a sustained itch-free state, which in turn may curb emergence of nodules and allow skin remodeling and healing.
In conclusion, this pooled analysis confirmed findings from individual trials and, through its increased power, supported improvements in sleep quality, pointed to earlier onset of action in itch y One patient included in the PRIME2 trial was not treated with IMP due to participant's decision.
z One event each of Hodgkin's disease, duodenal ulcer perforation, and neurodermatitis, considered IMP unrelated, and 1 event of urticaria, considered IMP related.
x Accidental overdose, defined as twice the intended dose during an interval of 11 days, was reported as a TEAE in 7 (4.5%)placebo-and 9 (5.9%) dupilumab-treated patients; these events represented shorter interval between injection administration than the interval stated in the protocol and not an increased dose.None of the events was symptomatic, and none associated with medical consequences.k Skin infections TEAE (excluding herpetic infections) were identified based on blinded medical review of all reported TEAEs identified as possible skin infections using CMQ30067 (Company MedDRA Query).This search included PTs under MedDRA High Level Group Term skin and subcutaneous tissue infections and infestations, all PTs under HLT skin structures and soft tissue infections, all PTs of ''wound infection,'' and PTs of chalazion, hordeolum, and skin papilloma.
# Herpes viral infections (HLT) includes the PTs oral herpes, herpes zoster, ophthalmic herpes zoster, genital herpes simplex.**In the placebo group, 1 event of severe COVID-19 and 1 event of cellulitis, considered IMP unrelated, and one event of sepsis, considered IMP related; in the dupilumab group, 1 event of moderate COVID-19 pneumonia and one event of pyelonephritis acute, considered IMP unrelated; none of the infections led to permanent discontinuation.yy In the placebo group, 2 events considered IMP related, 1 nonserious event of moderate urticaria, not leading to study discontinuation, and 1 nonserious event of mild urticaria, which led to permanent discontinuation; in the dupilumab group, 1 nonserious event of mild dermatitis allergic, considered IMP unrelated and not leading to discontinuation.zz In the placebo group, 1 event of Hodgkin's lymphoma, and 1 event of cutaneous T cell lymphoma; in the dupilumab group, 1 event of papillary thyroid carcinoma; all were considered IMP unrelated and led to permanent study drug discontinuation.

Fig 1 .
Fig 1. Prurigo nodularis.Proportion of patients with $4-point reduction from baseline in WI-NRS, IGA PN-S score 0 or 1, or both, at week 12 and week 24 in the pooled analysis (top), and comparison with individual trials (bottom).Cochran-Mantel-Haenszel test was performed on the association between the responder status and intervention group, adjusted by documented history of atopy (atopic or nonatopic), stable use of TCS/TCI (yes or no), region, baseline antidepressant use (yes or no), and study indicator (PRIME and PRIME2).ORs were derived from the Mantel-Haenszel estimator.CI, Confidence interval; IGA PN-S, Investigator's Global Assessment for PN-Stage (range 0-4); OR, odds ratio; q2w, every 2 weeks; RD, raw difference; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids; WI-NRS, Worst Itch Numerical Rating Scale (range 0-10).

Fig 2 .
Fig 2. Prurigo nodularis.Patient-reported outcomes over time in the pooled analysis (left) and comparison of results at week 24 with individual trials (right).*P \.05; **P \.01; ***P \.001; ****P \ .0001.Each of the imputed complete data were analyzed by fitting an analysis of covariance model with the corresponding baseline value, intervention group, documented history of atopy (atopic or nonatopic), stable use of TCS/TCI (yes or no), region, baseline antidepressant use (yes or no), and the study indicator (PRIME or PRIME2) as covariates.DLQI, Dermatology Life Quality Index; HADS, Hospital Anxiety and Depression Scale; LS, least-squares; NRS, Numerical Rating Scale; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids; WI-NRS, Worst-Itch Numerical Rating Scale.

Table I .
Demographic and clinical characteristics of the patient population at baseline AD, Atopic dermatitis; DLQI, Dermatology Life Quality Index; HADS, Hospital Anxiety and Depression Scale; IGA PN-S, Investigator's Global Assessment for PN-Stage; NRS, Numerical Rating Scale; PN, prurigo nodularis; q2w, every 2 weeks; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids; WI-NRS, Worst Itch Numerical Rating Scale.*36.4% (16/44) of US patients were Black or African American.y Including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, unknown.z Asia: China, Japan, South Korea, Taiwan; Eastern Europe: Hungary, Russia; Latin America: Argentina, Chile, Mexico; Western countries: USA, Canada, France, Italy, Portugal, Spain, and UK.

Table II .
Safety overview for the 36-week treatment and follow-up periods AE, Adverse event; HLT, MedDRA High Level Term; IMP, investigational medicinal product; MedDRA, Medical Dictionary for Regulatory Activities; PT, MedDRA Preferred Term; SAE, serious adverse event; TEAE, treatment-emergent adverse event.*One patient included in the PRIME trial was randomized but not treated with IMP due to fear of being exposed to COVID-19.