Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials

Abstract

Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, measured by proportion of patients with a ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included nodule number reduction to ≤5 at week 24. PRIME and PRIME2 enrolled 151 and 160 patients, respectively. Both trials met all the pre-specified primary and key secondary endpoints. A ≥4-point WI-NRS reduction at week 24 in the dupilumab and placebo arms was achieved by 60.0% and 18.4% of patients, respectively, in PRIME (95% confidence interval (CI), 27.8-57.7 for the difference, P < 0.001) and at week 12 by 37.2% and 22.0% of patients, respectively, in PRIME2 (95% CI, 2.3-31.2; P = 0.022). Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions versus placebo in PN. Safety was consistent with the known dupilumab safety profile.ClinicalTrials.gov identifiers: NCT04183335 and NCT04202679 .

Fig. 1. CONSORT diagrams of patient disposition.

a, PRIME. No patients were lost to follow-up at the time of the cutoff date. ^*Low-to-medium potency TCS/TCI as background therapy permitted (maintain dose from screening to end of treatment (EOT)). ^†Patient’s decision (fear of being exposed to Coronavirus Disease 2019 (COVID-19)). ^‡One patient experienced a serious adverse event (SAE) of Hodgkin’s disease; one patient experienced an SAE of duodenal ulcer perforation; and one patient experienced a non-serious event of neurodermatitis. ^§None was related to safety issues, lack of efficacy or COVID-19. ^‖Poor compliance to protocol. b, PRIME2. No patients were lost to follow-up at the time of the cutoff date. ^*Low-to-medium potency TCS/TCI as background therapy permitted (maintain dose from screening to EOT). ^†No discontinuations related to COVID-19. ^‡Patient could not continue the self-administration of investigational medicinal product. ^§None of the ‘other’ reasons for permanent study intervention discontinuation was related to safety or lack of efficacy. All were reported as the reason for withdrawal by the subject.

Fig. 2. Efficacy outcomes.

a, Proportion of patients who achieved WI-NRS improvement (reduction) by ≥4 points from baseline at week 12 and week 24. b, Proportion of patients who achieved IGA PN-S score of 0 or 1 (‘clear’ or ‘almost clear’) at week 12 and week 24. c, Proportion of patients who achieved concomitantly WI-NRS reduction from baseline by ≥4 points and IGA PN-S of score 0 or 1 at week 24 in PRIME and PRIME2. *Endpoint not in the testing hierarchy. Cochran–Mantel–Haenszel test was performed on the association between the responder status and intervention group, adjusted by documented history of atopy (atopic or non-atopic), stable use of TCS/TCI (yes or no), region and baseline antidepressant use (yes or no).

Fig. 3. Patient-reported outcomes.

a, LS mean percent change in WI-NRS (s.e.) from baseline (BL) through week 24. b, LS mean change (s.e.) in DLQI from BL to week 24. c, LS mean change (s.e.) in Skin Pain NRS from BL through week 24 in PRIME and PRIME2. d, LS mean change (s.e.) in HADS from BL through week 24 in PRIME and PRIME2. *P < 0.05, **P < 0.01, ***P < 0.001. Data were presented as mean ± s.e. The imputed complete data were analyzed by fitting an analysis of covariance (ANCOVA) model with the corresponding BL value, intervention group, documented history of atopy (atopic or non-atopic), stable use of TCS/TCI (yes or no), region and BL antidepressant use (yes or no) as covariates. P values at week 24 are multiplicity-controlled except for LS mean change in total HADS in PRIME2. P values for all the other timepoints are non-multiplicity-controlled.

Extended Data Fig. 1. Overview of the trials design.

a, Trial design of LIBERTY-PN PRIME and b, trial design of LIBERTY-PN PRIME2. ^*Low-to-medium potency TCS/TCI as background therapy permitted (dose maintained from screening to EOT). †One patient in the placebo group was randomized but not exposed to study intervention due to patient’s decision (fear of being exposed to COVID-19). EOS, end of study; EOT, end of treatment; R, randomization; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids.

Extended Data Fig. 2. Proportion of patients with WI-NRS score reduction.

Patients with WI-NRS score reduction by ≥4 points over time, by visit, to week 24 in PRIME (a) and PRIME2 (b). *P < 0.05; **P < 0.01; ***P < 0.001. ‘Responder’ was defined as a patient with WI-NRS reduction ≥ 4 from baseline. Cochran-Mantel Haenszel test was performed on the association between responder status and intervention group, adjusted by documented history of atopy (atopic/non-atopic), stable use of TCS/TCI (yes/no), region and baseline antidepressant use (yes/no). P values are non multiplicity-controlled. TCI, topical calcineurin inhibitor; TCS, topical corticosteroids; WI-NRS, Worst Itch Numerical Rating Scale.

Extended Data Fig. 3. Proportion of patients with IGA PN-S score 0 or 1.

Patients with IGA PN-S score 0/1 over time, by visit, to week 24 in PRIME (a) and PRIME2 (b). *P < 0.05; **P < 0.01; ***P < 0.001. ‘Responder’ was defined as a patient with IGA PN-S score of 0 or 1. Cochran-Mantel Haenszel test was performed on the association between responder status and intervention group, adjusted by documented history of atopy (atopic/non-atopic), stable use of TCS/TCI (yes/no), region and baseline antidepressant use (yes/no). P values are non multiplicity-controlled.IGA PN-S, Investigator’s Global Assessment for PN-Stage; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids.

Extended Data Fig. 4. Least-squares mean change in Sleep NRS score over time to week 24 in PRIME (a) and PRIME2 (b).

Data are presented as mean values ± SE. Each of the imputed complete data were analyzed by fitting an ANCOVA model with the corresponding baseline value, intervention group, documented history of atopy (atopic/non-atopic), stable TCS/TCI use (yes/no), region and baseline antidepressant use (yes/no) as covariates. P values are non multiplicity-controlled. LS, least squares; NRS, Numeric Rating Scale; SE, standard error; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids.

Extended Data Fig. 5. Time to first use of rescue medication.

Kaplan–Meier curves of time to first use of rescue medication in PRIME (a) and PRIME2 (b). HR and non multiplicity-controlled P values were derived from Cox proportional hazards model, including intervention, documented history of atopy (atopic/non-atopic), stable use of TCS/TCI (yes/no), region and baseline antidepressant use (yes/no) as covariates. CI, confidence interval; HR, hazard ratio; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids.