Pharmacotherapeutic group: Other dermatological preparations, agents for dermatitis, excluding corticosteroids.
ATC code: D11AH05.
Pharmacology: Pharmacodynamics: Mechanism of action: Dupilumab is a recombinant human IgG4 monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling. Dupilumab inhibits IL-4 signaling via the Type I receptor (IL-4Rα/γc), and both IL-4 and IL-13 signaling through the Type II receptor (IL-4Rα/IL-13Rα). IL-4 and IL-13 are major drivers of human type 2 inflammatory disease, such as atopic dermatitis. Blocking the IL-4/IL-13 pathway with dupilumab in patients decreases many of the mediators of type 2 inflammation.
Pharmacodynamic effects: In atopic dermatitis clinical trials, treatment with dupilumab was associated with decreases from baseline in concentrations of type 2 immunity biomarkers, such as thymus and activation-regulated chemokine (TARC/CCL17), total serum IgE and allergen-specific IgE in serum. A reduction of lactate dehydrogenase (LDH), a biomarker associated with AD disease activity and severity, was observed with dupilumab treatment.
In asthma clinical trials, dupilumab treatment markedly decreased FeNO and circulating concentrations of eotaxin-3, total IgE, allergen specific IgE, TARC, and periostin in asthma subjects relative to placebo. These reductions in type 2 inflammatory biomarkers were comparable for the 200 mg Q2W and 300 mg Q2W regimens. These markers were near maximal suppression after 2 weeks of treatment, except for IgE which declined more slowly. These effects were sustained throughout treatment.
Clinical efficacy and safety in atopic dermatitis: Adults with atopic dermatitis: The efficacy and safety of dupilumab as monotherapy and with concomitant topical corticosteroids were evaluated in three pivotal randomised, double-blind, placebo-controlled studies (SOLO 1, SOLO 2, and CHRONOS) in 2,119 patients 18 years of age and older with moderate to severe atopic dermatitis (AD) defined by Investigator's Global Assessment (IGA) score ≥ 3, an Eczema Area and Severity Index (EASI) score ≥16, and a minimum body surface area (BSA) involvement of ≥10%. Eligible patients enrolled into the three studies had previous inadequate response to topical medication.
In all three studies, patients received an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg once every two weeks (Q2W); an initial dose of 600 mg dupilumab on day 1, followed by 300 mg once weekly (QW); or matching placebo. Dupilumab was administered by subcutaneous (SC) injection in all studies. If needed to control intolerable symptoms of atopic dermatitis, patients were permitted to receive rescue treatment (which included higher potency topical steroids or systemic immunosuppressants) at the discretion of the investigator. Patients who received rescue treatment were considered non-responders.
SOLO 1 enrolled 671 patients (224 to placebo, 224 to dupilumab 300 mg Q2W, and 223 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.
SOLO 2 enrolled 708 patients (236 to placebo, 233 to dupilumab 300 mg Q2W, and 239 to dupilumab 300 mg QW) and had a treatment period of 16 weeks.
CHRONOS enrolled 740 patients (315 to placebo + topical corticosteroid (TCS), 106 to dupilumab 300 mg Q2W + TCS, and 319 to dupilumab 300 mg QW + TCS) and had a treatment period of 52 weeks. Patients received dupilumab or placebo with concomitant use of TCS starting at baseline using a standardized regimen. Patients were also permitted to use topical calcineurin inhibitors (TCI).
Endpoints: In all three pivotal studies, the co-primary endpoints were the proportion of patients with IGA 0 or 1 ("clear" or "almost clear") with a reduction of ≥ 2 points on a 0-4 IGA scale and the proportion of patients with improvement of at least 75% in EASI (EASI-75) from baseline to week 16. Other evaluated outcomes included the proportion of patients with improvement of at least 50% and 90% in EASI (EASI-50 and EASI-90, respectively), reduction in itch as measured by the peak pruritus Numerical Rating Scale (NRS), and percent change in the SCORing Atopic Dermatitis (SCORAD) scale from baseline to week 16. Additional secondary endpoints included mean change from baseline to week 16 in the Patient Oriented Eczema Measure (POEM), Dermatology Life Quality Index(DLQI), and Hospital Anxiety and Depression Scale (HADS) scores. In CHRONOS, efficacy was also evaluated at week 52.
Baseline Characteristics: In the monotherapy studies (SOLO 1 and SOLO 2), across all treatment groups, the mean age was 38.3, the mean weight was 76.9 kg, 42.1% were female, 68.1% were white, 21.8% were Asian, and 6.8% were black. In these studies, 51.6% of patients had a baseline IGA score of 3 (moderate AD), 48.3% of patients had a baseline IGA of 4 (severe AD) and 32.4% of patients had received prior systemic immunosuppressants. The baseline mean EASI score was 33.0, the baseline weekly averaged pruritus NRS was 7.4, the baseline mean SCORAD score was 67.8, the baseline mean POEM score was 20.5, the baseline mean DLQI was 15.0, and the baseline mean HADS total score was 13.3.
In the concomitant TCS study (CHRONOS), across all treatment groups, the mean age was 37.1, the mean weight was 74.5 kg, 39.7% were female, 66.2% were white, 27.2% were Asian, and 4.6% were black. In this study, 53.1% of patients had a baseline IGA score of 3 and 46.9% of patients had a baseline IGA of 4 and 33.6% of patients received prior systemic immunosuppressants. The baseline mean EASI score was 32.5, the baseline weekly pruritus NRS was 7.3, the baseline mean SCORAD score was 66.4, the baseline mean POEM score was 20.1, the baseline mean DLQI was 14.5, and the baseline mean HADS total score was 12.7.
Clinical Response:
16-Week Monotherapy Studies (SOLO 1 and SOLO 2): In SOLO 1 and SOLO 2, from baseline to week 16, a significantly greater proportion of patients randomized to dupilumab achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of ≥4 points on the pruritus NRS compared to placebo (see Table 1).
A significantly greater proportion of patients randomized to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as ≥ 4-point improvement as early as week 2; p < 0.01) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 1 and Figure 2 show the mean percent change from baseline in EASI and the mean percent change from baseline in NRS, respectively up to week 16. (See Table 1 and Figures 1 and 2.)
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52-Week Concomitant TCS Study (CHRONOS): In CHRONOS, a significantly greater proportion of patients randomized to dupilumab 300 mg Q2W + TCS achieved an IGA 0 or 1 response, EASI-75, and/or an improvement of ≥ 4 points on the pruritis NRS from baseline to week 16 and week 52 compared to placebo + TCS (see Table 2).
A significantly greater proportion of patients randomized to dupilumab + TCS achieved a rapid improvement in the pruritus NRS compared to placebo + TCS (defined as ≥4-point improvement as early as week 2; p < 0.05) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period. The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis.
Figure 3 and Figure 4 show the mean percent change from baseline in EASI and the mean percent
change from baseline in NRS, respectively, up to week 52 in CHRONOS. (See Table 2 and Figures 3 and 4.)
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Treatment effects in subgroups (weight, age, gender, race, and background treatment, including immunosuppressants) in CHRONOS were consistent with the results in the overall study population.
Clinical Response in Patients Not Adequately Controlled with, Intolerant to, or for whom Ciclosporin Treatment was Inadvisable (CAFE study): CAFE study evaluated the efficacy of dupilumab compared to placebo during a 16-week treatment period, administered with concomitant TCS, in adult patients with AD who are not adequately controlled with, or are intolerant to, oral ciclosporin, or when this treatment is currently contraindicated or not medically advisable.
A total of 325 patients were enrolled, with 210 patients who were previously exposed to ciclosporin and 115 patients who have never been exposed to ciclosporin because ciclosporin treatment was medically inadvisable. The mean age was 38.4 years, 38.8% were female, the baseline mean EASI score was 33.1, the mean BSA was 55.7, the baseline weekly average pruritis NRS was 6.4, the baseline mean SCORAD score was 67.2, and the baseline mean DLQI was 13.8.
The primary endpoint was the proportion of patients with EASI-75 at week 16.
Primary and secondary endpoints for the 16 week CAFE study are summarized in Table 3. (See Table 3.)
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In the subgroup of patients resembling the CAFE study population within the 52 week CHRONOS study, 69.6% of dupilumab 300 mg Q2W-treated patients reached EASI-75 vs 18.0% placebo-treated patients at week 16, and 52.4% of dupilumab 300 mg Q2W-treated vs 18.6% placebo-treated at week 52. In this subset, the percent change of pruritus NRS from baseline was -51.4% vs -30.2% at week 16 and -54.8% vs -30.9% at week 52, for the dupilumab 300 mg Q2W and placebo groups respectively.
Maintenance and Durability of Response (SOLO CONTINUE study): To evaluate maintenance and durability of response, subjects treated with dupilumab for 16 weeks in SOLO 1 and SOLO 2 studies who achieved IGA 0 or 1 or EASI-75 were re-randomized in SOLO CONTINUE study to an additional 36-week treatment of dupilumab or placebo, for a cumulative 52-week study treatment. Endpoints were assessed at weeks 51 or 52.
The co-primary endpoints were the difference between baseline (week 0) and week 36 in percent change in EASI from SOLO 1 and SOLO 2 studies baseline and percentage of patients with EASI-75 at week 36 in patients with EASI-75 at baseline.
Patients who continued on the same dose regimen received in the SOLO 1 and SOLO 2 studies (300 mg Q2W or 300 mg QW) showed the optimal effect in maintaining clinical response while efficacy for other dose regimens diminished in a dose-dependent manner.
Primary and secondary endpoints for the 52 week SOLO CONTINUE study are summarized in Table 4. (See Table 4.)
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In SOLO CONTINUE, a trend for increased treatment-emergent ADA positivity with increased dosing intervals was observed. Treatment-emergent ADA: QW: 1.2%; Q2W: 4.3%; Q4W: 6.0%; Q8W: 11.7%. ADA responses lasting more than 12 weeks: QW: 0.0%; Q2W: 1.4%; Q4W: 0.0%; Q8W: 2.6%.
Quality of Life/Patient-Reported Outcomes in Atopic Dermatitis: In both monotherapy studies (SOLO 1 and SOLO 2), both dupilumab 300 mg Q2W and 300 mg QW groups significantly improved patient-reported symptoms and the impact of AD on sleep and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 16 weeks compared to placebo. A significantly larger proportion of patients administered dupilumab groups had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4 points improvement) from baseline to week 16 compared to placebo group. In addition, anxiety and depression symptoms as measured by the HADS total score were significantly reduced in the dupilumab groups compared to placebo at 16 weeks. In a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥ 8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab groups achieved HADS-anxiety and HADS-depression scores < 8 at week 16 compared to placebo (See Table 5).
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In the concomitant TCS study (CHRONOS), dupilumab 300 mg Q2W + TCS and dupilumab 300 mg QW + TCS improved patient-reported symptoms and the impact of AD on sleep and health-related quality of life as measured by POEM and DLQI total scores, respectively, at 52 weeks compared to placebo + TCS. A larger proportion of patients administered dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS had clinically meaningful reductions in POEM and DLQI total score (each defined as ≥ 4-point improvement) from baseline to week 52 compared to the placebo + TCS. In addition, dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS reduced anxiety and depression as measured by the HADS total score at 52 weeks compared to placebo + TCS. In a post-hoc analysis in a subset of patients with HADS-anxiety or HADS-depression subscale scores ≥8 at baseline (the cut-off value for anxiety or depression), a larger proportion of patients in the dupilumab 300 mg Q2W + TCS and 300 mg QW + TCS groups achieved HADS-anxiety and HADS-depression scores < 8 at week 52 compared to placebo + TCS (See Table 6).
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Adolescents with atopic dermatitis: The efficacy and safety of dupilumab monotherapy in adolescent patients was evaluated in a multicentre, randomised, double-blind, placebo-controlled study (AD-1526) in 251 adolescent patients 12 to 17 years of age with moderate-to-severe atopic dermatitis (AD) defined by Investigator's Global Assessment (IGA) score ≥3 in the overall assessment of AD lesions on a severity scale of 0 to 4, an Eczema Area and Severity Index (EASI) score ≥16 on a scale of 0 to 72, and a minimum body surface area (BSA) involvement of ≥10%. Eligible patients enrolled into this study had previous inadequate response to topical medication.
Patients received an initial dose of 400 mg dupilumab (two 200 mg injections) on day 1, followed by 200 mg once every other week (Q2W) for patients with baseline weight of <60 kg or an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg Q2W for patients with baseline weight of ≥ 60 kg; an initial dose of 600 mg dupilumab (two 300 mg injections) on day 1, followed by 300 mg every 4 weeks (Q4W) regardless of baseline body weight; or matching placebo. Dupilumab was administered by subcutaneous (SC) injection. If needed to control intolerable symptoms, patients were permitted to receive rescue treatment at the discretion of the investigator. Patients who received rescue treatment were considered nonresponders.
In this study, the mean age was 14.5 years, the median weight was 59.4 kg, 41.0% were female, 62.5% were White, 15.1% were Asian, and 12.0% were Black. At baseline 46.2% of patients had a baseline IGA score of 3 (moderate AD), 53.8% of patients had a baseline IGA of 4 (severe AD), the mean BSA involvement was 56.5%, and 42.4% of patients had received prior systemic immunosuppressants. Also at baseline the mean Eczema Area and Severity Index (EASI) score was 35.5, the baseline weekly averaged pruritus Numerical Rating Scale (NRS) was 7.6, the baseline mean SCORing Atopic Dermatitis (SCORAD) score was 70.3, the baseline mean Patient Oriented Eczema Measure (POEM) score was 21.0, and the baseline mean Children Dermatology Life Quality Index (CDLQI) was 13.6. Overall, 92.0% of patients had at least one co-morbid allergic condition; 65.6% had allergic rhinitis, 53.6% had asthma, and 60.8% had food allergies. The co-primary endpoint was the proportion of patients with IGA 0 or 1 ("clear" or "almost clear") least a 2-point improvement and the proportion of patients with EASI-75 (improvement of at least 75% in EASI), from baseline to week 16. Other evaluated outcomes included the proportion of subjects with EASI-50 or EASI-90 (improvement of at least 50% or 90% in EASI from baseline respectively), reduction in itch as measured by the peak pruritus NRS, and percent change in the SCORAD scale from baseline to week 16. Additional secondary endpoints included mean change from baseline to week 16 in the POEM and CDLQI scores.
Clinical Response: The efficacy results at week 16 for adolescent atopic dermatitis study are presented in Table 7. (See Table 7.)
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A larger percentage of patients randomised to placebo needed rescue treatment (topical corticosteroids, systemic corticosteroids, or systemic non-steroidal immunosuppressants) as compared to the dupilumab group (58.8% and 20.7%, respectively).
A significantly greater proportion of patients randomised to dupilumab achieved a rapid improvement in the pruritus NRS compared to placebo (defined as >4-point improvement as early as week 4; nominal p<0.001) and the proportion of patients responding on the pruritus NRS continued to increase through the treatment period (see Figure 5). The improvement in pruritus NRS occurred in conjunction with the improvement of objective signs of atopic dermatitis. (See Figure 5.)
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The dupilumab group significantly improved patient-reported symptoms, the impact of AD on sleep and health-related quality of life as measured by POEM, SCORAD, and CDLQI scores at 16 weeks compared to placebo.
The long-term efficacy of dupilumab in adolescent patients with moderate-to-severe AD who had participated in previous clinical trials of dupilumab was assessed in open-label extension study (AD-1434). Efficacy data from this study suggests that clinical benefit provided at week 16 was sustained through week 52.
Clinical efficacy and safety in asthma: The asthma development program included three randomised, double-blind, placebo-controlled, parallel-group, multi-centre studies (DRI12544, QUEST, and VENTURE) of 24 to 52 weeks in treatment duration which enrolled a total of 2,888 patients (12 years of age and older). Patients were enrolled without requiring a minimum baseline blood eosinophil or other type 2 inflammatory biomarker (e.g. FeNO or IgE) level. Asthma treatment guidelines define type 2 inflammation as eosinophilia ≥ 150 cells/mcL and/or FeNO ≥ 20 ppb. In DRI12544 and QUEST, the pre-specified subgroup analyses included blood eosinophils ≥ 150 and ≥ 300 cells/mcL, FeNO ≥ 25 and ≥ 50 ppb.
DRI12544 was a 24-week dose-ranging study which included 776 patients (18 years of age and older). Dupilumab compared with placebo was evaluated in adult patients with moderate to severe asthma on a medium-to-high dose inhaled corticosteroid and a long acting beta agonist. The primary endpoint was change from baseline to week 12 in FEV1 (L). Annualized rate of severe asthma exacerbation events during the 24-week placebo controlled treatment period was also determined. Results were evaluated in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophils count.
Dupilumab compared with placebo was evaluated in 107 adolescent and 1,795 adult patients with persistent asthma on a medium-to-high dose inhaled corticosteroid (ICS) and a second controller medication. Patients requiring a third controller were allowed to participate in this trial. Patients were randomised to receive either 200 mg (N=631) or 300 mg (N=633) Dupixent every other week (or matching placebo for either 200 mg (N = 317) or 300 mg (N= 321) every other week) following an initial dose of 400 mg, 600 mg or placebo respectively. The primary endpoints were the annualized rate of severe exacerbation events during the 52-week placebo controlled period and change from baseline in pre-bronchodilator FEV1 at week 12 in the overall population (unrestricted by minimum baseline eosinophils or other type 2 inflammatory biomarkers) and subgroups based on baseline blood eosinophils and FeNO.
VENTURE was a 24-week oral corticosteroid-reduction study in 210 patients with asthma unrestricted by baseline type 2 biomarker levels who required daily oral corticosteroids in addition to regular use of high dose inhaled corticosteroids plus an additional controller. After optimizing the OCS dose during the screening period, patients received 300 mg dupilumab (n=103) or placebo (n=107) once every other week for 24 weeks following an initial dose of 600 mg or placebo. Patients continued to receive their existing asthma medicine during the study; however their OCS dose was reduced every 4 weeks during the OCS reduction phase (week 4-20), as long as asthma control was maintained. The primary endpoint was the percent reduction in oral corticosteroid dose assessed in the overall population, based on a comparison of the oral corticosteroid dose at weeks 20 to 24 that maintained asthma control with the previously optimized (at baseline) oral corticosteroid dose.
The demographics and baseline characteristics of these 3 studies are provided in Table 8 as follows. (See Table 8.)
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Exacerbations: In the overall population in DRI12544 and QUEST subjects receiving either dupilumab 200 mg or 300 mg every other week had significant reductions in the rate of severe asthma exacerbations compared to placebo. There were greater reductions in exacerbations in subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (see Table 9 and Table 10).
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In the pooled analysis of DRI12544 and QUEST, hospitalizations and/or emergency room visits due to severe exacerbations were reduced by 25.5% and 46.9% with dupilumab 200 mg or 300 mg every other week, respectively.
Lung Function: Clinically significant increases in pre-bronchodilator FEV
1 were observed at week 12 for DRI12544 and QUEST. There were greater improvements in FEV
1 in the subjects with higher baseline levels of type 2 inflammatory biomarkers such as blood eosinophils or FeNO (Table 11 and Table 12).
Significant improvements in FEV
1 were observed as early as week 2 following the first dose of dupilumab for both the 200 mg and 300 mg dose strengths and were maintained through week 24 (DRI12544) and week 52 in QUEST (see Figure 6). (See Figure 6 and Tables 11 and 12.)
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Quality of Life/Patient-Reported Outcomes in Asthma: Pre-specified secondary endpoint of ACQ-5 and AQLQ(S) responder rates were analysed at 24 weeks (DRI12544 and VENTURE) and at 52 weeks (QUEST). The responder rate was defined as an improvement in score of 0.5 or more (scale range 0-6 for ACQ-5 and 1-7 for AQLQ(S)). Improvements in ACQ-5 and AQLQ(S) were observed as early as week 2 and maintained for 24 weeks in DRI12544 study and 52 weeks in QUEST study. Similar results were observed in VENTURE. The ACQ-5 and AQLQ(S) responder rate results in patients with elevated baseline biomarkers of type 2 inflammation in QUEST at week 52 are presented in Table 13. (See Table 13.)
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Oral Corticosteroid Reduction Study (VENTURE): VENTURE evaluated the effect of dupilumab on reducing the use of maintenance oral corticosteroids. Baseline characteristics are presented in Table 8. All patients were on oral corticosteroids for at least 6 months prior to
the study initiation. The baseline mean oral corticosteroid use was 11.75 mg in the placebo group and 10.75 mg in the group receiving dupilumab.
In this 24-week trial, asthma exacerbations (defined as a temporary increase in oral corticosteroid dose for at least 3 days) were reduced by 59% in subjects receiving dupilumab compared with those receiving placebo (annualized rate 0.65 and 1.60 for the dupilumab and placebo group, respectively; rate ratio 0.41 [95% CI 0.26, 0.63]) and improvement in pre-bronchodilator FEV
1 from baseline to week 24 was greater in subjects receiving dupilumab compared with those receiving placebo (LS mean difference for dupilumab versus placebo of 0.22 L [95% CI: 0.09 to 0.34 L]). Effects on lung function, on oral steroid and exacerbation reduction were similar irrespective of baseline levels of type 2 inflammatory biomarkers (e.g. blood eosinophils, FeNO). The ACQ-5 and AQLQ(S) were also assessed in VENTURE and showed improvements similar to those in QUEST.
The results for VENTURE by baseline biomarkers are presented in Table 14. (See Table 14.)
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Long-term extension trial (TRAVERSE): The long-term efficacy of Dupilumab in 2282 adults and adolescents with moderate-to-severe asthma, and adults with oral corticosteroid-dependent asthma, who had participated in previous clinical trials of Dupilumab, was assessed in the open-label extension study (TRAVERSE). In this study, the clinical benefit of Dupilumab, including reduction in exacerbations and improvement in lung function, was sustained up to 96 weeks. In the population with oral-corticosteroid-dependent asthma, there was sustained reduction in exacerbations and maintained improvement in lung function, despite continued decrease or discontinuation of oral corticosteroid dose up to 96 weeks. Similar maintenance of effect was also observed for ACQ-5 and AQLQ(S) at week 48 (see Table 15). Consistent results were also observed in the subgroup of patients on high dose ICS. (See Table 15.)
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Paediatric population: A total of 107 adolescents aged 12 to 17 years with moderate to severe asthma were enrolled in QUEST study and received either 200 mg (N=21) or 300 mg (N=18) dupilumab (or matching placebo either 200 mg [N=34] or 300 mg [N=34]) every other week. Efficacy with respect to severe asthma exacerbations and lung function was observed in both adolescents and adults. For both the 200 mg and 300 mg every other week doses, significant improvements in FEV
1 (LS mean change from baseline at week 12) were observed (0.36 L and 0.27 L, respectively). For the 200 mg every other week dose, patients had a reduction in the rate of severe exacerbations that was consistent with adults. Safety and efficacy in paediatric patients (< 12 years of age) with severe asthma have not been established. The adverse event profile in adolescents was generally similar to the adults.
The European Medicines Agency has deferred the obligation to submit the results of studies with dupilumab in one or more subset of the paediatric population in atopic dermatitis and asthma (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: The pharmacokinetics of dupilumab is similar in patients with atopic dermatitis and asthma.
Absorption: After a single subcutaneous (SC) dose of 75-600 mg dupilumab, median times to maximum concentration in serum (t
max) were 3-7 days. The absolute bioavailability of dupilumab following a SC, ranging between 61% and 64%, as determined by a population pharmacokinetics (PK) analysis.
Steady-state concentrations were achieved by week 16 following the administration of 600 mg starting dose and 300 mg dose every other week. Across clinical trials, the mean ±SD steady-state trough concentrations ranged from 73.3±40.0 mcg/mL to 79.9±41.4 mcg/mL for 300 mg dose administered every other week.
Distribution: A volume of distribution for dupilumab of approximately 4.6 L was estimated by population PK analysis, indicating that dupilumab is distributed primarily in the vascular system.
Biotransformation: Specific metabolism studies were not conducted because dupilumab is a protein. Dupilumab is expected to degrade to small peptides and individual amino acids.
Elimination: Dupilumab elimination is mediated by parallel linear and nonlinear pathways. At higher concentrations, dupilumab elimination is primarily through a non-saturable proteolytic pathway, while at lower concentrations, the non-linear saturable IL-4R α target-mediated elimination predominates.
After the last steady state dose, the median time for dupilumab concentrations to decrease below the lower limit of detection, estimated by population PK analysis, was 10 weeks for the 300 mg Q2W regimen and 13 weeks for the 300 mg QW regimen.
Linearity/non-linearity: Due to nonlinear clearance, dupilumab exposure, as measured by area under the concentration-time curve, increases with dose in a greater than proportional manner following single SC doses from 75-600 mg.
Special populations: Gender: Gender was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis.
Elderly patients: Of the 1,472 patients with atopic dermatitis exposed to dupilumab in a phase 2 dose-ranging study or phase 3 placebo-controlled studies, a total of 67 were 65 years or older. Although no differences in safety or efficacy were observed between older and younger adult atopic dermatitis patients, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients.
Age was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab determined by population PK analysis. However, there were only 61 patients over 65 years of age included in this analysis.
Of the 1,977 patients with asthma exposed to dupilumab, a total of 240 patients were 65 years or older and 39 patients were 75 years or older. Efficacy and safety in this age group were similar to the overall study population.
Race: Race was not found to be associated with any clinically meaningful impact on the systemic exposure of dupilumab by population PK analysis.
Hepatic impairment: Dupilumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of dupilumab.
Renal impairment: Dupilumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of dupilumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of dupilumab. Very limited data are available in patients with severe renal impairment.
Body Weight: Dupilumab trough concentrations were lower in subjects with higher body weight with no meaningful impact on efficacy.
Paediatric population: The pharmacokinetics of dupilumab in paediatric patients (< 12 years of age) with atopic dermatitis has not been studied.
For adolescents 12 to 17 years of age with atopic dermatitis receiving every other week dosing (Q2W) with either 200 mg (<60 kg) or 300 mg (≥60 kg), the mean ±SD steady state trough concentration of dupilumab was 54.5±27.0 mcg/ml.
A total of 107 adolescents aged 12 to 17 years with asthma were enrolled in QUEST study. The mean ±SD steady-state trough concentrations of dupilumab were 107±51.6 mcg/mL and 46.7±26.9 mcg/mL, respectively, for 300 mg or 200 mg administered every other week. No age-related pharmacokinetic difference was observed in adolescent patients after correction for body weight.
The long-term safety and efficacy of Dupilumab was assessed in 89 adolescent patients who were enrolled in an open-label extension study in moderate-to-severe asthma (TRAVERSE). In this study, patients were followed for up to 96 weeks, resulting in 99 patient-years cumulative exposure to Dupilumab. The safety profile of Dupilumab in TRAVERSE was consistent with the safety profile observed in asthma pivotal studies for up to 52 weeks of treatment. No additional adverse reactions were identified. In this study, the clinical benefit of Dupilumab, including reduction in exacerbations and improvement in lung function observed in pivotal asthma studies, was sustained up to 96 weeks
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity (including safety pharmacology endpoints) and toxicity to reproduction and development.
The mutagenic potential of dupilumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with dupilumab. An evaluation of the available evidence related to IL-4Rα inhibition and animal toxicology data with surrogate antibodies does not suggest an increased carcinogenic potential for dupilumab.
During a reproductive toxicology study conducted in monkeys, using a surrogate antibody specific to the monkey IL-4Rα, no fetal abnormalities were observed at dosages that saturate the IL-4Rα.
An enhanced pre- and post-natal developmental study revealed no adverse effects in maternal animals or their offspring up to 6 months post-partum/post-birth.
Fertility studies conducted in male and female mice using a surrogate antibody against IL-4Rα showed no impairment of fertility (see Use in Pregnancy & Lactation).