Dupilumab is a fully human monoclonal antibody (mAb) directed against the IL-4 receptor α (IL-4Rα) subunit that blocks both IL-4 and IL-13 signaling.45 IL-4 and IL-13 are highly increased in acute and chronic skin lesions of AD patients,19,46 and its inhibition proved to be very effective in adult patients with moderate-to-severe AD45–50 (figure 1). Dupilumab is the only biologic drug that has progressed to phase III clinical studies for the treatment of moderate-to-severe AD and is also being investigated in asthma, chronic sinusitis with nasal polyposis, and eosinophilic esophagitis.49

Figure 1.

Dupilumab mechanism of action: Dupilumab targets the α-subunit of the interleukin-4 receptor (IL-4Rα). IL-4Rα is a part of type I and type II IL-4 receptors and the IL-13 receptor, therefore, Dupilumab inhibits the downstream signaling of IL-4 and IL-13.

(0.23MB).

Two 4-week randomized, double-blind, placebo-controlled, dose-escalation phase I studies of dupilumab monotherapy were conducted in adult patients with moderate-to-severe AD – M4A and M4B – to evaluate its safety and efficacy.51 In M4A, 30 patients were randomized into 4 groups receiving placebo (n=6) or dupilumab – either 75mg (n=8), 150mg (n=8), or 300mg (n=8) once a week (qw). In M4B, 37 patients were randomized in 3 groups receiving placebo (n=10) or dupilumab – either 150mg/qw (n=14) or 300mg/qw (n=13). In both studies, treatment with dupilumab resulted in a fast, dose-dependent efficacy in all clinical outcomes.51 The achievement of a 50% reduction in Eczema Area and Severity Index score (EASI-50) by day 29 was significantly higher for all dupilumab doses combined compared to placebo (59% vs 19%, respectively; p<0.05). Significant improvement in other clinical endpoints was observed in the combined treatment groups by day 29 when compared with placebo, including the investigator's Global Assessment score (IGA), the Body Surface Area (BSA) percentage and the pruritus numeric rating scale (NRS).

Also, significant rapid dose-dependent changes in the RNA-expression profile in lesional skin were observed after 4 weeks of treatment with dupilumab, approaching non-lesional expression profiles and accompanying EASI improvement. An improvement of 24% and 49% was observed in lesional transcriptome in patients treated with dupilumab 150 and 300mg, respectively, as compared with a 21% shift to a lesional molecular phenotype in the placebo group (p<0.0001 for all groups).49 Also, the suppression in the expression of K16, a keratinocyte proliferation marker and regulator of innate immunity was observed, suggesting that dupilumab reduces epidermal hyperplasia.47

The phase IIb trial was a 16-week randomized, double-blind, placebo-controlled, dose-ranging study in which 380 adult subjects with moderato-to-severe AD were randomized to placebo (n=61) or dupilumab 100mg every 4 weeks (qw4) (n=65), 200mg every 2 weeks (qw2) (n=61), or 300mg/qw (n=63), qw2 (n=64) or qw4 (n=65).52,53 Overall, dupilumab demonstrated higher effectiveness when compared to placebo at all dosing levels. At week 16, EASI scores were significantly improved in the dupilumab groups versus placebo group. The least-squares (LS) mean percent improvement in EASI scores were -74% (300mg/qw), -68% (300mg/qw2), -65% (200mg/qw2), -64% (300mg/qw4), and -45% (100mg/qw4) compared with -18% for placebo (p<0.0001 for all comparison). Moreover, a greater proportion of patients in the dupilumab groups obtained an IGA 0/1. There were also meaningful improvements in the SCORing Atopic Dermatitis (SCORAD) score (up to -56.9% for dupilumab 300mg/qw compared to -13.8% for placebo; p<0.0001 vs placebo) and BSA (up to -65.6% for dupilumab 300mg/qw compared to -7.7% for placebo (p<0.0001 vs placebo).49,52 Additionally, dupilumab was associated with pruritus improvement, as early as week 1. Except for 100mg/qw4, all doses of dupilumab demonstrated LS mean percentage decreases between 32.63% and 46.9% at week 16 (p<0.0001 for each comparison).52 Dupilumab also improved the quality of life of AD patients, with dose-dependent improvement of Dermatology Quality of Life Index (DLQI) from baseline through week 16 for all dose regimens (p<0.0001) besides 100mg/qw4.52(Table 1)

Two 16-week randomized, double-blind, placebo-controlled phase III studies of identical design evaluated dupilumab efficacy and safety.

In SOLO 1, 671 subjects were randomized to receive placebo (n=224), dupilumab 300mg/qw (n=224) or the same dose of dupilumab qw2 alternating with placebo (n=223).54 IGA scores of 0/1 at week 16 were achieved in 38 and 37% of the patients receiving dupilumab qw2 and qw, respectively, as compared to 10% of the patients in placebo group (p<0.001). The mean improvement of EASI score was approximately 70% in both groups of dupilumab, with 51 and 52% achieving EASI-75 at week 16 in the dupilumab qw2 and qw groups, respectively (p<0.001 vs placebo).54 Also, the LS mean percentage change from baseline at week 16 were -51.0% and -48.9% in peak pruritus NRS score, -57.7 and -57.0% in SCORAD score at week 16 in the dupilumab qw2 and qw groups, respectively (p<0.001 vs placebo).54

In SOLO 2, a total of 708 patients were randomized into 3 groups receiving placebo (n=236), dupilumab 300mg/qw (n=239) or the same dose of dupilumab qw2 alternating with placebo (n=233).54 At week 16, the endpoint IGA 0/1 was achieved in 36% in both dose regimen of dupilumab groups, compared to 20% in the placebo group (p<0.001). EASI-75 at week 16 was reported in 44 and 48% patients receiving dupilumab qw2 and qw, respectively (p<0.001 vs placebo). The LS mean percentage change from baseline were –44.3% and -48.3% in peak pruritus NRS score and -51.1 and -53.5% in SCORAD score at week 16 in the dupilumab qw2 and qw groups, respectively (p<0.001 vs placebo). Additionally, BSA and DLQI scores had great improvements at week 16 with all dupilumab dose regimens, in both studies.

In both SOLO trials a major impact in patients’ quality of life was observed, with significant reduction of symptoms of anxiety and depression using the Hospital Anxiety and Depression Scale (HADS).54(Table 1)

A 52-week randomized, double-blind, placebo-controlled phase III study was conducted in adult patients with moderate-to-severe AD to evaluate safety and efficacy of dupilumab in association to TCS. 740 patients were randomized into 3 groups receiving placebo (n=315) or dupilumab 300mg/qw (n=319) or q2w (n=106), plus TCS. IGA 0/1 at week 16 was observed in 39% of patients in both dupilumab groups versus 12% of patients in the placebo group (p<0.0001 vs placebo); EASI-75 at week 16 was achieved by 64% of patients treated with dupilumab qw and 69% of patients receiving dupilumab q2w, versus 23% of patients of the control group (p<0.0001 vs placebo)55; peak pruritus NRS improvement of 4 or higher at week 16, was achieved by more than one-half of patients in both dupilumab groups versus 20% of patients receiving placebo (p<0.0001 vs placebo). Identical effectiveness was observed at week 52 for these 3 clinical endpoints. Dupilumab also improved all other indices at weeks 16 and 52, including SCORAD, BSA and DLQI scores. (Table 2) Dupilumab was also associated with more days free of TCS, lower rates of rescue medication use, and reduction of the AD flares over the 52-week treatment period compared to placebo.55

Dupilumab was well tolerated and had a favorable safety profile across all studies, with the majority of adverse events (AEs) being classified as mild or moderated in severity and transient in duration. Serious AEs (SAEs) were globally infrequent across all studies.51,52,54(Tables 3, 4).

In phases I-III studies, the most common AEs were nasopharyngitis, injection-site reactions, headache, exacerbation of AD and skin infections. In all these trials, nasopharyngitis’ incidence was balanced across dupilumab and placebo groups, whereas exacerbations of AD and skin infections were more common in patients receiving placebo.54

SAEs were more common with placebo than dupilumab across all studies, as well as SAEs of skin infections, with an incidence across all phase I and IIa studies 4-times as high as the incidence in the dupilumab groups (0.20 vs 0.05, respectively).51 In phase IIb study, serious exacerbations of AD (2% in both groups) and serious infections (<1% with dupilumab vs 0% with placebo) were similar and rare in both groups.52 In SOLO-1 and -2, skin infections occurred in approximately 6% of patients receiving dupilumab, and in 8 to 11% of those receiving placebo, whereas dupilumab was not associated with increased overall risk of infections in CHRONOS.54,55

Herpes viral infections were more common in subjects receiving dupilumab than in those receiving placebo in phase IIb study (8% vs 2%, respectively), SOLO-1 and -2 (5% in both studies vs 4% and 3%, respectively), and CHRONOS (7% vs 8%, respectively). This finding was not reported in phases I and IIa trials.

A higher incidence of conjunctivitis was observed among treatment groups compared to placebo in phase IIb study (7% vs 3%, respectively), SOLO-1 and -2 (8% and 5% vs 2% and 1%, respectively), and CHRONOS (18% vs 8%, respectively), and most cases were mild-to-moderate.52,55 Solely 2 patients receiving dupilumab discontinued study treatment due to conjunctivitis.56

No deaths were reported in phase I and II studies, while 3 deaths were reported in the phase III studies, although none appeared to be associated with dupilumab.

SAEs that led to drug and study discontinuation were low across all studies, with the majority occurring with placebo, except in phase IIb study (7% with dupilumab vs 5% with placebo). In CHRONOS, one-half of patients withdrew from the study due to AD flares in the placebo group, and one due to conjunctivitis in the dupilumab qw group.