Reassuring clinical evidences of dupilumab with targeted MOA

( Chang Ook Park ) 대한피부과학회 2021 대한피부과학회 학술발표대회집 Vol.73 No.1

Dupilumab is the first biologic that blocks IL-4Rα, the shared receptor subunit for IL-4 and IL-13, thus inhibiting signaling of both IL-4 and IL-13. It has shown to be clinically effective and safe in the management of AD both in clinical and real-world aspects. This lecture is intended to zoom on the safety of dupilumab with the latest update. As known, dupilumab, as a monotherapy and with concomitant TCS, resulted in rapid, sustained and clinically meaningful improvements in AD signs, symptoms and QoL in short-term (SOLO 1 & 2 and CAFÉ; through Week 16) and longer-term (CHRONOS; through Week 52) studies in adults with moderate-to-severe AD in its phase 3 clinical trials. Such improvements in AD signs and symptoms were successfully sustained over 3 years (long-term adult OLE study; through Week 148), vouching dupilumab’s long-term efficacy as the maintenance therapy for moderate-to-severe AD. Dupilumab’s clinical efficacy was also consistently demonstrated in the recent pivotal studies targeting patients as young as 6 years old, leading to its recent marketing approval in adolescent and child AD with moderate-to-severe disease severity. To date, improvements in AD signs with dupilumab in real-world clinical practice have been similar to those observed in clinical trials including patients with different AD and difficult-to-treat patients by multiple global registries and real-world data. The latest Korean real-world clinical experiences have been well aligned with global experiences - e.g., recent 52 week single-center retrospective study on dupilumab in Korean (EASI-75: 90.2%, EASI-90: 53.7% in week 52, ISAD oral presentation) Based on real world satisfaction, higher persistence rate of dupilumab has been continuously reported compared to immunosuppressants. The overall safety/tolerability profile of dupilumab is the result of its mode of action as a targeted inhibitor of IL-4 and IL-13 signaling, key and central drivers of type 2 inflammation and the pathogenesis of AD; consequently, dupilumab is not associated with an increased risk of infections, malignancy, or other important adverse reactions that are common with biologics targeting type 1 immunity (eg, anti TNF agents) and with systemic immunosuppressants. In contrast to the traditional systemic immunosuppressants, dupilumab reduced the risk of serious and severe infections, as well as skin infections; no increase in the incidence of overall infections was observed. Dupilumab can also be safely used with non-live vaccines (Tdap and meningococcal polysaccharide) and similar antibody responses to the non-live vaccines were observed in dupilumab-treated and placebo-treated patients; Based on the previous studies and its selected mode of action, dupilumab is thought to have no attenuation of COVID-19 vaccination and can be deemed as safe treatment option in high-epidemic era. The favorable long-term safety/tolerability profile of dupilumab observed in patients treated for up to 3 years in open-label extension study and patients in the Korean real world setting is consistent with that seen in studies of shorter treatment duration. The most common AEs with dupilumab (incidence ≥ 1%) were injection-site reactions, ocular disorders (eg, conjunctivitis, keratitis, and blepharitis), and oral herpes (cold sores). It’s noteworthy that dupilumab can be safely deployed for adolescent and child patients treatment, given its similar/consistent safety/tolerability compared with that observed in adults. Laboratory monitoring, prior to and during treatment, is not required with dupilumab, allowing infrequent clinic visits for treatment monitoring. Dupilumab does not have a clinically meaningful effect on cytochrome P450-mediated drug metabolism, thereby leading to no potential for clinically relevant drug-drug interactions with dupilumab, based on data from a dedicated DDI study. Recent case reports also highlight dupilumab’s reaffirmed safety and efficacy in the high-risk patients including but not limited to the immunosuppressive (eg, HIV), the infected (eg,HBV) and the elderly with various co-morbidities and polypharmacy. With this comprehensive evidence review, dupilumab has favorable long-term safety and tolerability in patients with moderate-to-severe AD as young as 6 years, as supported by data from clinical trials up to 3 years and real world.

Reassuring clinical evidences of dupilumab with targeted MOA

( Chang Ook Park ) 대한피부과학회 2021 대한피부과학회 학술발표대회집 Vol.73 No.-

Dupilumab is the first biologic that blocks IL-4Rα, the shared receptor subunit for IL-4 and IL-13, thus inhibiting signaling of both IL-4 and IL-13. It has shown to be clinically effective and safe in the management of AD both in clinical and real-world aspects. This lecture is intended to zoom on the safety of dupilumab with the latest update. As known, dupilumab, as a monotherapy and with concomitant TCS, resulted in rapid, sustained and clinically meaningful improvements in AD signs, symptoms and QoL in short-term (SOLO 1 & 2 and CAFÉ; through Week 16) and longer-term (CHRONOS; through Week 52) studies in adults with moderate-to-severe AD in its phase 3 clinical trials. Such improvements in AD signs and symptoms were successfully sustained over 3 years (long-term adult OLE study; through Week 148), vouching dupilumab’s long-term efficacy as the maintenance therapy for moderate-to-severe AD. Dupilumab’s clinical efficacy was also consistently demonstrated in the recent pivotal studies targeting patients as young as 6 years old, leading to its recent marketing approval in adolescent and child AD with moderate-to-severe disease severity. To date, improvements in AD signs with dupilumab in real-world clinical practice have been similar to those observed in clinical trials including patients with different AD and difficult-to-treat patients by multiple global registries and real-world data. The latest Korean real-world clinical experiences have been well aligned with global experiences - e.g., recent 52 week single-center retrospective study on dupilumab in Korean (EASI-75: 90.2%, EASI-90: 53.7% in week 52, ISAD oral presentation) Based on real world satisfaction, higher persistence rate of dupilumab has been continuously reported compared to immunosuppressants. The overall safety/tolerability profile of dupilumab is the result of its mode of action as a targeted inhibitor of IL-4 and IL-13 signaling, key and central drivers of type 2 inflammation and the pathogenesis of AD; consequently, dupilumab is not associated with an increased risk of infections, malignancy, or other important adverse reactions that are common with biologics targeting type 1 immunity (eg, anti TNF agents) and with systemic immunosuppressants. In contrast to the traditional systemic immunosuppressants, dupilumab reduced the risk of serious and severe infections, as well as skin infections; no increase in the incidence of overall infections was observed. Dupilumab can also be safely used with non-live vaccines (Tdap and meningococcal polysaccharide) and similar antibody responses to the non-live vaccines were observed in dupilumab-treated and placebo-treated patients; Based on the previous studies and its selected mode of action, dupilumab is thought to have no attenuation of COVID-19 vaccination and can be deemed as safe treatment option in high-epidemic era. The favorable long-term safety/tolerability profile of dupilumab observed in patients treated for up to 3 years in open-label extension study and patients in the Korean real world setting is consistent with that seen in studies of shorter treatment duration. The most common AEs with dupilumab (incidence ≥ 1%) were injection-site reactions, ocular disorders (eg, conjunctivitis, keratitis, and blepharitis), and oral herpes (cold sores). It’s noteworthy that dupilumab can be safely deployed for adolescent and child patients treatment, given its similar/consistent safety/tolerability compared with that observed in adults. Laboratory monitoring, prior to and during treatment, is not required with dupilumab, allowing infrequent clinic visits for treatment monitoring. Dupilumab does not have a clinically meaningful effect on cytochrome P450-mediated drug metabolism, thereby leading to no potential for clinically relevant drug-drug interactions with dupilumab, based on data from a dedicated DDI study. Recent case reports also highlight dupilumab’s reaffirmed safety and efficacy in the high-risk patients including but not limited to the immunosuppressive (eg, HIV), the infected (eg,HBV) and the elderly with various co-morbidities and polypharmacy. With this comprehensive evidence review, dupilumab has favorable long-term safety and tolerability in patients with moderate-to-severe AD as young as 6 years, as supported by data from clinical trials up to 3 years and real world.

청소년과 성인 아토피피부염 환자에서 dupilumab의 임상효과와 순응도: 한국의 단일 알레르기 클리닉의 실제 진료 상황에서의 관찰 결과 분석

이영수,김명은,남동호 대한 소아알레르기 호흡기학회 2023 Allergy Asthma & Respiratory Disease Vol.11 No.2

Purpose: Dupilumab (a monoclonal antibody to interleukin-4 receptor alpha) is the first biological agent approved for the treatment of moderate-to-severe atopic dermatitis (AD). We evaluated the clinical efficacy and compliance of dupilumab therapy for AD in real clinical practice. Methods: Medical records of 132 adolescent and adult patients with AD who received at least one dose of dupilumab were retrospectively analyzed. Clinical efficacy of dupilumab was assessed by either changes in eczema area and severity index (EASI) or changes in the requirement of medications from baseline to weeks 16 and 42. Clinical response was determined by the proportion of patients with decreased EASI scores of at least 75% from baseline at week 16 (EASI–75). Clinical remission was defined as a complete withdrawal of all the medications for AD except dupilumab. Results: Dupilumab was administered for 16 weeks (77.3%) and 42 weeks (63.6%) in 132 patients with AD. In patients who received reimbursement from National Healthcare Insurance of Korea (NHIK) for dupilumab therapy, the compliance of dupilumab therapy was 90.2% and 87.8%, and EASI–75 response rate was 92.5% and 100% at weeks 16 and 42, respectively. In patients who received the dupilumab therapy without NHIK reimbursement (self-payment), the compliance of dupilumab therapy was 71.4% and 52.7%, the clinical remission rate was 44.0% and 64.6%, and the median interval of dupilumab therapy was 4 weeks (range, 2–13 weeks) and 5 weeks (2–15 weeks) at weeks 16 and 42, respectively. Conclusion: Dupilumab therapy may be clinically useful in the aspects of efficacy and compliance in patients with AD. .

트랄로키누맙과 두필루맙의 매칭 조정 간접 비교

김태경,신근수,김효진,김유진,최이정,이동훈 한국임상약학회 2023 한국임상약학회지 Vol.33 No.3

Objective: Atopic dermatitis (AD) is a chronic, recurrent inflammatory skin disease. Both tralokinumab and dupilumab have been recommended in the European Guideline for the treatment of adult patients with severe AD. In Korea, dupilumab has been approved for patients with moderate to severe AD, and reimbursed for those with severe AD. Since there is no clinical trial directly comparing tralokinumab and dupilumab, we conducted indirect comparison to assess the clinical usefulness in patients with AD. Methods: We selected clinical trials for indirect comparison through a systematic literature review. Individual patient data were available for the tralokinumab clinical trial, and aggregated data were available for the dupilumab clinical trial. Therefore, we employed the Matching-Adjusted Indirect Comparison (MAIC) method. The treatment efficacy was assessed based on whether patients achieved a 75% reduction on the Eczema Area and Severity Index (EASI 75) after drug administration. Results: The difference in the proportion of patients achieving EASI 75 between tralokinumab and dupilumab was 4.7% (95% CI: −7.9 to 17.3). Considering the non-inferiority margin for the EASI 75 achievement rate is −10%, tralokinumab is deemed non-inferior to dupilumab as the lower bound of the CI for the difference in the EASI 75 achievement rate between tralokinumab and dupilumab was within −10%. Conclusion: We conducted a MAIC analysis comparing tralokinumab and dupilumab based on EASI 75 achievement. The findings of this study show that tralokinumab is non-inferior to dupilumab and can be implemented in Korean clinical settings with a therapeutic position comparable to dupilumab.

중증 아토피피부염 환자에서 dupilumab 치료 도중 발생한 건선 1예

김영찬,김한나,김고은,전지현,백유상 대한건선학회 2022 대한건선학회지 Vol.19 No.2

Dupilumab, a human monoclonal antibody that blocks IL-4 and IL-13 receptors, has been approved for patients with moderate to severe atopic dermatitis. Psoriasiform dermatitis or psoriasis is a rare paradoxical reaction associated with dupilumab. Selectively inhibiting certain type of helper T cell pathway can provoke skewing of T cell polarization to others. Although pathogenesis of dupilumab-induced psoriasis has not been fully elucidated, it is postulated to be caused by shift of balance toward Th17 predominance due to selective suppression of Th2 pathway by dupilumab. A 24-year-old male with severe atopic dermatitis, who had been treated with dupilumab for 9 months, developed multiple well-demarcated erythematous plaques with scales on his back. Histopathology of the lesion revealed typical features of psoriasis, and the diagnosis of dupilumab-induced psoriasis was made. The lesions were significantly improved and well controlled within 3~4 months of applying topical and intra-lesional corticosteroids and topical tacrolimus without discontinuing dupilumab.

중등증-중증의 한국인 아토피피부염 환자에서 Dupilumab의 효과와 안전성에 관한 연구

김종욱,김연아,원상현,배경남,이정수,신기혁,김훈수,고현창,김문범,김병수 대한피부과학회 2023 대한피부과학회지 Vol.61 No.7

Background: Dupilumab is a human monoclonal antibody against interleukin-4 receptor α. Several clinical trials have demonstrated the rapid and excellent therapeutic effects of dupilumab. Although a growing number of studies have reported data on the real-world efficacy and safety of dupilumab for the treatment of atopic dermatitis, data on real-world experiences in Korea are limited. Objective: To evaluate the real-world efficacy and safety of dupilumab for the treatment of moderate-to-severe atopic dermatitis in Korean patients. Methods: This was a retrospective, single-center study. A total of 179 patients treated with dupilumab for at least 16 weeks were enrolled in this study. Based on electronic medical records, the clinical characteristics, Eczema Area and Severity Index (EASI) score, and adverse events were investigated. Results: The mean baseline EASI score (26.5±7.2) significantly decreased at weeks 16, 40, 52, and 112 (p<0.05). All and 55.2% of patients achieved EASI75 and EASI90 responses at week 52, and all and 75.0% of patients achieved EASI75 and EASI90 responses at week 112, respectively. Common adverse events were facial erythema (31.8%), conjunctivitis (24.0%), and herpes simplex virus infection (11.2%). Three serious adverse events of severe conjunctivitis, mycosis fungoides, and mesenteric venous thrombosis resulted in discontinuation of dupilumab. Conclusion: Dupilumab was effective in real-world clinical practice with a favorable safety profile in Korean patients with moderate-to-severe atopic dermatitis.

Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis (AD) in the Korean population: a phase 3 clinical trial (SOLO 2) substudy

( Hyun Jung Kwon ),( Seong-jun Seo ),( Young Lip Park ),( Jooyoung Roh ),( Chun Wook Park ),( Moon Bum Kim ),( Gwang Seoung Choi ),( Dong-ho Nahm ),( Hyo Hyun Ahn ),( Young Min Park ),( Kwang Hoon Lee 대한피부과학회 2017 대한피부과학회 학술발표대회집 Vol.69 No.2

Background: Dupilumab, a fully human anti-IL-4Rα mAb, inhibits signaling of IL-4/IL-13, key drivers of type 2/Th2-mediated diseases, such as AD/asthma. Objectives: We report efficacy and safety of dupilumab in Korean patients (pts) with moderate-to-severe AD in a randomized, placebo (PBO)-controlled, multinational phase 3 trial (SOLO 2: NCT02277769). Methods: Pts were randomized 1:1:1 to subcutaneous dupilumab 300mg every 2 weeks (wks; q2w), weekly (qw), or PBO qw, for 16 wks. Results: 708 pts were randomized; 80 were Korean. In the Korean population, more dupilumab-treated pts achieved Investigator’s Global Assessment 0/1 vs PBO at Wk 16 (primary endpoint; q2w/qw vs PBO: 33.3%/33.3% vs 0.0%; both P=0.0018), ≥75% improvement in Eczema Area and Severity Index (29.6%/40.7% vs 7.7%; P=0.0764/P=0.0091) and peak pruritus numerical rating scale ≥4-point improvement from baseline at Wk 16 vs PBO (33.3%/34.6% vs 3.8%; P=0.0113/P=0.0109) (key secondary). Dupilumab also improved Patient Oriented Eczema Measure and Dermatology Life Quality Index vs PBO at Wk 16 (both P<0.01) (secondary). Adverse events (AEs) were reported in 12/27 (q2w) and 8/27 pts (qw) vs 17/26 pts (PBO), none were serious. AD was the most common AE, occurring less frequently in the dupilumab groups vs PBO (4/27 and 4/27 pts vs 16/26 pts). Conclusion: The efficacy and acceptable safety profile of dupilumab in Korean pts were generally consistent with the overall study population.

Dupilumab facial redness: association with hypersensitization to Malassezia species

( Su Min Kim ),( Chang Ook Park ) 대한피부과학회 2019 대한피부과학회 학술발표대회집 Vol.71 No.2

Background: Dupilumab is widely used to treat patients with atopic dermatitis who are not controlled well with topical medications and systemic immunosuppressants. Dupilumab facial redness (DFR) is an adverse event which is not described in the dupilumab clinical trials. According to the recent reports which propose the etiology of the DFR, DFR might have a relationship with the sensitization status on the Malassezia species. Objectives: To describe the prevalence of DFR in dupilumab-treated atopic dermatitis patients, and to suggest the relationship between the DFR and sensitization status to Malassezia species. Methods: Retrospective chart review of 30 atopic dermatitis patients who treated with dupilumab was done. Every patients underwent the blood test including MAST or CAP test, and CAP test for Pityrosporum orbiculare (P. orbiculare). DFR patients who show hypersensitivity to the P. orbiculare was informed to take itraconazole (Sporanox®) 100mg twice daily for 7days, and clinical improvement was evaluated by photography review. Results: Total 5 patients had DFR, their average onset was 8 weeks. The patients who have DFR showed much higher rate of sensitization to P. orbiculare (100% vs. 24%, p<0.01). All 5 patients who have DFR showed significant improvement by itraconazole (Sporanox®) 100mg twice daily for 7days. Conclusion: This study demonstrated that DFR might be originated from the sensitization to Malassezia species, thus the oral itraconazole can be a effective treatment option.

Long-term dupilumab treatment improves signs and symptoms in Korean patients with moderate-tosevere atopic dermatitis

( Joo Young Roh ),( Young Lip Park ),( Chun Wook Park ),( Joo Hee Lee ),( Zhen Chen ),( Brad Shumel ),( Ana B. Rossi ) 대한피부과학회 2020 대한피부과학회 학술발표대회집 Vol.72 No.1

Background: Dupilumab provided clinical improvement and favorable safety in patients with moderate-to-severe atopic dermatitis (AD) not controlled with topical medications. Objectives: To evaluate the effect of long-term dupilumab in adult Koreans with moderate-to-severe AD. Methods: LIBERTY AD OLE (NCT01949311) is a phase 3 study assessing 300mg weekly open-label dupilumab in adults with moderate-to-severe AD who previously participated in controlled (parent) studies of dupilumab. Results: 96 Korean patients were treated (65.6% male; mean age 30.2 years). At Week 124 (n=40), 57.5% of patients had Investigator’s Global Assessment ≤1, and 85.0% of patients had ≥75% improvement in Eczema Area and Severity Index (EASI-75); 46.9% had EASI-75 by Week 2 (n=96). Mean percent change of weekly averaged Peak Pruritus Numerical Rating Scale (PP-NRS) from parent study baseline to Week 124 (n=35) was -59.31%. In the total OLE population (n=2,677), 9.6% patients had serious treatment-emergent adverse events (TEAE). Most common TEAEs were nasopharyngitis (28.1%), AD exacerbation (16.4%), upper respiratory tract infection (13.1%), conjunctivitis (9.7%), headache (8.1%), oral herpes (7.0%). There was no increase in TEAE rates or new safety signals compared with the parent studies. Conclusion: Dupilumab treatment provided a sustained, multidimensional control in Korean patients with moderate-to-severe AD with the safety profile supporting dupilumab as long-term treatment option.

FC 1-1 : Facial erythema in patients with atopic dermatitis treated with dupilumab

( Jiyoung Ahn ),( Dong Heon Lee ),( Chan Ho Na ),( Dong Hyun Shim ),( Yu Sung Choi ),( Hye Jung Jung ),( Eric L. Simpson ) 대한피부과학회 2021 대한피부과학회 학술발표대회집 Vol.73 No.-

Background: The development of an eczematous rash on face and neck, which was not described in phase 3 clinical trials, is being reported in the literature in patients treated with dupilumab. Little is known regarding the causes or features of the facial dermatitis. Objectives: We conducted surveys of 162 severe AD patients treated with dupilumab to describe its clinical features, morphology, and etiology. Methods: A multicenter prospective cohort study was conducted from January 1, 2020, to December 31, 2020. A total of 162 patients under dupilumab treatment were asked to complete a questionnaire and patients were evaluated by dermatologists. Results: Out of all 162 patients, 84.6 percent had pre-existing facial dermatitis PRIOR to dupilumab therapy. 121 (88.3 %) patients of them got better after the treatment, 9 (6.6 %) patients of them had no change after the treatment, but 7 (4.3 %) patients of them got worse after the treatment. Out of 25 patients who had not pre-existing facial dermatitis PRIOR to the therapy, 6 (3.7 %) patients of total experienced new-onset facial erythema after the treatment. A large proportion of the patients in both groups had a history of TCS use. Conclusion: In severe AD patients treated with dupilumab, additional or new-onset development of an eczematous rash on face and neck after dupilumab treatment did not frequently occur. Although the mechanisms of this adverse event remains unclear, the possibility of topical corticosteroids withdrawal cannot be excluded.