Dupilumab Treatment Normalizes Skin Barrier Function ...
1
Presented at the 3rd Annual Revolutionizing Atopic Dermatitis Conference (RAD 2021); Virtual Conference; December 11–13, 2021. BACKGROUND • Atopic dermatitis (AD) is associated with immunologic and skin barrier dysfunction • Type 2 inflammation, mediated by interleukin-4 and interleukin-13 cytokines, influences keratinization, integrity of tight junctions, composition of lipids, microbiome diversity, filaggrin expression, and natural moisturizing factors 1 • Dupilumab has been shown to suppress cellular and molecular cutaneous markers of type 2 inflammation and to reverse AD-associated epidermal abnormalities in patients with AD, supporting the hypothesis that dupilumab-induced blockade of type 2 inflammation can repair skin barrier alteration in AD 2,3 Dupilumab Treatment Normalizes Skin Barrier Function Measured by Transepidermal Water Loss (TEWL) in Adults and Adolescents With Moderate-to-Severe Atopic Dermatitis Robert Bissonnette 1 , Marco Ramirez-Gama 2 , Shannon Garcia 2 , Patricia Taylor 2 , Amy Praestgaard 3 , Noah A. Levit 4 , Ana B. Rossi 3 , Annie Zhang 3 1 Innovaderm Research, Montreal, QC, Canada; 2 National Jewish Health, Denver, CO, USA; 3 Sanofi Genzyme, Cambridge, MA, USA; 4 Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA References: 1. Hönzke S, et al. J Invest Dermatol. 2016;136:631-9. 2. Guttman-Yassky E, et al. J Allergy Clin Immunol. 2019;143:155-72. 3. Hamilton JD, et al. J Allergy Clin Immunol. 2014;134:1293-300. 4. McNamara PM, et al. Proc SPIE. 2010;7563:75630W. 5. Zhai H et al. Skin Res Technol. 2009;15:14-9. Acknowledgments: Images provided by Quantificare. Rainbow graphics developed by Ana B. Rossi and Marthe Vuillet of Sanofi Genzyme. Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov Identifier: NCT04447417. Medical writing/editorial assistance was provided by Aleksandra Krawczyk, PhD of Excerpta Medica, and was funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc., according to the Good Publication Practice guideline. Disclosures: Bissonnette R: AbbVie, Arcutis, Arena Pharma, Aristea, Asana BioSciences, Bellus Health, Bluefin Biomedicine, Boehringer-Ingelheim, CARA, Dermavant, Eli Lilly, EMD Serono, Evidera, Galderma, GSK, Inmagene, Incyte, Kiniksa, Kyowa Kirin, LEO Pharma, Novan, Pfizer, Ralexar, RAPT, Regeneron, Respivant, Sanofi-Genzyme, Sienna, Target RWE and Vyne Therapeutics– consultant, speaker, grants/research support; Innovaderm Research – employee and shareholder. Ramirez-Gama M, Garcia S, Taylor P: No conflicts of interest. Praestgaard A, Rossi AB, Zhang A: Sanofi Genzyme – employees, may hold stock and/or stock options in the company. Levit NA: Regeneron Pharmaceuticals, Inc. – employee and shareholder. OBJECTIVE • To evaluate the effect of dupilumab on skin barrier function in adults and adolescents with moderate-to-severe AD over 16 weeks of treatment in reference to the barrier function measures in healthy volunteers Figure 2. Example of improvement in target lesion in an AD patient. This individual patient represent the mean value of lesional skin TEWL at baseline and Week 16. Target lesion photos at baseline (A) and Week 16 (B) were analyzed using tissue viability imaging (TiVi) index. TiVi is a colorimetric measurement of the skin, linearly linked to the red blood cells (RBC) concentration within the skin, which allows the quantification of skin erythema (vasodilatation). The red/yellow hues represent a high concentration of RBC, associated with increased erythema, and the blue/green hues represent low concentration of RBC, associated with decreased erythema. 4,5 Mean changes in overall AD population (n = 26) Baseline Week 16 5 2 Sleep quality NRS (0–10) 31 10 EASI (0–72) > 21 severe > 7–21 moderate ≤ 7 mild 7 3 PP-NRS (0–10) 7–10 severe 4–6 moderate 0–3 mild 61 24 SCORAD (0–103) 49–103 severe 10 to < 29 mild 29 to < 49 moderate 0 to < 10 clear 22 8 POEM (0–28) 17–24 severe 25–28 very severe 3–7 mild 8–16 moderate 0–2 clear/ almost clear 12 3 DLQI/CDLQI (0–30) 11–20 very large effect 21–30 extremely large effect 2–5 small effect 6–10 moderate effect 0–1 no effect Figure 3. Changes in clinical and patient reported outcomes from baseline and Week 16. The rainbow graphics display change in absolute values from baseline (red) to Week 16 (blue) for each outcome. Color bands are based on validated thresholds for each outcome. (C)DLQI, (Children’s) Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; POEM, Patient-Oriented Eczema Measure; PP, Peak Pruritus; SCORAD, SCORing Atopic Dermatitis. 14.8 12.3 P = 0.163 30 20 10 40 50 60 70 80 0 Day 1 (BL) (A) Lesional skin of AD patients treated with dupilumab vs skin of healthy volunteers Day 15 Day 29 Day 57 Day 85 Week 16 TEWL (g/m 2 /h) after 5 STS, LS mean (95% CI) Baseline TEWL after 5 STS, mean (95% CI) AD lesional skin (n = 26) 62.50 (53.9, 71.1) 12.07 (10.0, 14.1) Healthy skin (n = 26) 15 10 5 20 25 30 35 40 0 Day 1 (BL) (B) Non-lesional skin of AD patients treated with dupilumab vs skin of healthy volunteers Day 15 Day 29 Day 57 Day 85 Week 16 TEWL (g/m 2 /h) after 5 STS, LS mean (95% CI) Baseline TEWL after 5 STS, mean (95% CI) AD non-lesional skin (n = 26) 21.24 (15.7, 26.8) 12.07 (10.0, 14.1) Healthy skin (n = 26) 19.1 14.9 P = 0.225 Figure 1. Adjusted mean (95% CI) TEWL after 5 STS over time. BL, baseline; CI, confidence interval; LS, least squares. CONCLUSIONS • Dupilumab treatment significantly improved TEWL in AD patients as early as day 15 and sustained through Week 16, demonstrating normalization of epidermal barrier function • This significant improvement in skin barrier function reflects the improvement observed in signs, symptoms, and quality of life in patients with moderate-to-severe AD METHODS • The dupilumab skin BArrier function and LIpidomics STudy in Atopic Dermatitis (BALISTAD [NCT04447417]) was an open-label, exploratory study on skin barrier function • Transepidermal water loss (TEWL [g/m 2 /h]) was measured in lesional and non-lesional (n = 26) skin of adolescents and adults with moderate-to-severe AD and the skin of 26 matched healthy volunteers • TEWL was measured after 5 skin tape strippings (STS) repeatedly performed over 16 weeks of dupilumab therapy • Adjusted mean values of TEWL over time were estimated with analysis of covariance (ANCOVA) models, of log-transformed TEWL values that included log-transformed baseline TEWL, skin type, age, and gender RESULTS B. Target lesion at week 16 (TiVi on right) A. Target lesion at baseline (TiVi on right)
Transcript of Dupilumab Treatment Normalizes Skin Barrier Function ...
Presented at the 3rd Annual Revolutionizing Atopic Dermatitis Conference (RAD 2021); Virtual Conference; December 11–13, 2021.
BACKGROUND• Atopic dermatitis (AD) is associated with immunologic and skin barrier dysfunction• Type 2 inflammation, mediated by interleukin-4 and interleukin-13 cytokines, influences keratinization,
integrity of tight junctions, composition of lipids, microbiome diversity, filaggrin expression, and natural moisturizing factors1
• Dupilumab has been shown to suppress cellular and molecular cutaneous markers of type 2 inflammation and to reverse AD-associated epidermal abnormalities in patients with AD, supporting the hypothesis that dupilumab-induced blockade of type 2 inflammation can repair skin barrier alteration in AD2,3
Dupilumab Treatment Normalizes Skin Barrier Function Measured by Transepidermal Water Loss (TEWL) in Adults and Adolescents With Moderate-to-Severe Atopic Dermatitis
Robert Bissonnette1, Marco Ramirez-Gama2, Shannon Garcia2, Patricia Taylor2, Amy Praestgaard3, Noah A. Levit4, Ana B. Rossi3, Annie Zhang3
1Innovaderm Research, Montreal, QC, Canada; 2National Jewish Health, Denver, CO, USA; 3Sanofi Genzyme, Cambridge, MA, USA; 4Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
References: 1. Hönzke S, et al. J Invest Dermatol. 2016;136:631-9. 2. Guttman-Yassky E, et al. J Allergy Clin Immunol. 2019;143:155-72. 3. Hamilton JD, et al. J Allergy Clin Immunol. 2014;134:1293-300. 4. McNamara PM, et al. Proc SPIE. 2010;7563:75630W. 5. Zhai H et al. Skin Res Technol. 2009;15:14-9. Acknowledgments: Images provided by Quantificare. Rainbow graphics developed by Ana B. Rossi and Marthe Vuillet of Sanofi Genzyme. Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov Identifier: NCT04447417. Medical writing/editorial assistance was provided by Aleksandra Krawczyk, PhD of Excerpta Medica, and was funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc., according to the Good Publication Practice guideline. Disclosures: Bissonnette R: AbbVie, Arcutis, Arena Pharma, Aristea, Asana BioSciences, Bellus Health, Bluefin Biomedicine, Boehringer-Ingelheim, CARA, Dermavant, Eli Lilly, EMD Serono, Evidera, Galderma, GSK, Inmagene, Incyte, Kiniksa, Kyowa Kirin, LEO Pharma, Novan, Pfizer, Ralexar, RAPT, Regeneron, Respivant, Sanofi-Genzyme, Sienna, Target RWE and Vyne Therapeutics– consultant, speaker, grants/research support; Innovaderm Research – employee and shareholder. Ramirez-Gama M, Garcia S, Taylor P: No conflicts of interest. Praestgaard A, Rossi AB, Zhang A: Sanofi Genzyme – employees, may hold stock and/or stock options in the company. Levit NA: Regeneron Pharmaceuticals, Inc. – employee and shareholder.
OBJECTIVE
• To evaluate the effect of dupilumab on skin barrier function in adults and adolescents with moderate-to-severe AD over 16 weeks of treatment in reference to the barrier function measures in healthy volunteers
Figure 2. Example of improvement in target lesion in an AD patient.
This individual patient represent the mean value of lesional skin TEWL at baseline and Week 16. Target lesion photos at baseline (A) and Week 16 (B) were analyzed using tissue viability imaging (TiVi) index. TiVi is a colorimetric measurement of the skin, linearly linked to the red blood cells (RBC) concentration within the skin, which allows the quantification of skin erythema (vasodilatation). The red/yellow hues represent a high concentration of RBC, associated with increased erythema, and the blue/green hues represent low concentration of RBC, associated with decreased erythema.4,5
Mean changes in overallAD population (n = 26)
Baseline
Week 16
5
2
Sleep qualityNRS
(0–10)
31
10
EASI
(0–72)
> 21severe
> 7–21moderate
≤ 7 mild
7
3
PP-NRS
(0–10)
7–10severe
4–6moderate
0–3 mild
61
24
SCORAD
(0–103)
49–103severe
10 to < 29mild
29 to < 49moderate
0 to < 10clear
22
8
POEM
(0–28)
17–24severe
25–28very severe
3–7mild
8–16moderate
0–2 clear/almost clear
12
3
DLQI/CDLQI
(0–30)
11–20 verylarge effect
21–30 extremely large effect
2–5small effect
6–10moderate effect
0–1 no effect
Figure 3. Changes in clinical and patient reported outcomes from baseline and Week 16.
The rainbow graphics display change in absolute values from baseline (red) to Week 16 (blue) for each outcome. Color bands are based on validated thresholds for each outcome. (C)DLQI, (Children’s) Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; POEM, Patient-Oriented Eczema Measure; PP, Peak Pruritus; SCORAD, SCORing Atopic Dermatitis.
14.8
12.3P = 0.163
30
20
10
40
50
60
70
80
0Day 1 (BL)
(A) Lesional skin of AD patients treated with dupilumab vs skin of healthy volunteers
Day 15 Day 29 Day 57 Day 85 Week 16
TE
WL
(g/m
2 /h)
aft
er 5
ST
S, L
S m
ean
(95%
CI)
Baseline TEWL after 5 STS, mean (95% CI)
AD lesional skin (n = 26) 62.50 (53.9, 71.1)
12.07 (10.0, 14.1)Healthy skin (n = 26)
15
10
5
20
25
30
35
40
0Day 1 (BL)
(B) Non-lesional skin of AD patients treated with dupilumab vs skin of healthy volunteers
Day 15 Day 29 Day 57 Day 85 Week 16
TE
WL
(g/m
2 /h)
aft
er 5
ST
S, L
S m
ean
(95%
CI)
Baseline TEWL after 5 STS, mean (95% CI)
AD non-lesional skin (n = 26) 21.24 (15.7, 26.8)
12.07 (10.0, 14.1)Healthy skin (n = 26)
19.1
14.9P = 0.225
Figure 1. Adjusted mean (95% CI) TEWL after 5 STS over time.
BL, baseline; CI, confidence interval; LS, least squares.
CONCLUSIONS
• Dupilumab treatment significantly improved TEWL in AD patients as early as day 15 and sustained through Week 16, demonstrating normalization of epidermal barrier function
• This significant improvement in skin barrier function reflects the improvement observed in signs, symptoms, and quality of life in patients with moderate-to-severe AD
METHODS• The dupilumab skin BArrier function and LIpidomics STudy in Atopic Dermatitis (BALISTAD
[NCT04447417]) was an open-label, exploratory study on skin barrier function• Transepidermal water loss (TEWL [g/m2/h]) was measured in lesional and non-lesional (n = 26)
skin of adolescents and adults with moderate-to-severe AD and the skin of 26 matched healthy volunteers
• TEWL was measured after 5 skin tape strippings (STS) repeatedly performed over 16 weeks of dupilumab therapy
• Adjusted mean values of TEWL over time were estimated with analysis of covariance (ANCOVA) models, of log-transformed TEWL values that included log-transformed baseline TEWL, skin type, age, and gender
RESULTS
B. Target lesion at week 16 (TiVi on right)
A. Target lesion at baseline (TiVi on right)
