Investor Presentation Efficacy of red-light photodynamic therapy with 10% ALA gel in relation to the epidermal extent of atypical keratinocytes in actinic keratosis - Retrospective exploratory analysis of three pivotal phase III trials Authors: E. BIERHOFF1, J.L. COHEN2, R.-M. SZEIMIES3, U. REINHOLD4, T. DIRSCHKA5 References [1] Olsen EA, Abernethy ML, Kulp-Shorten C, et al., J Am Acad Dermatol 1991;24(5 Pt 1):738–43. PubMed PMID: 1869646; [2] Schmitz L, Kahl P, Majores M, et al., J Eur Acad Dermatol Venereol. 2016 Aug;30(8):1303-7. PMID: 26955898 [3] Roewert-Huber J, Patel MJ, Forschner T, et al., Br J Dermatol 2007;156 Suppl 3:8–12. PubMed PMID: 17488400. [4] Cockerell CJ. J Am. Acad. Dermatol 2000;42(1 Pt 2):11–7. PubMed PMID: 10607351. [5] Clinical Study Report (ALA-AK-CT002), study design and results can be accessed via clinicaltrials.gov, see QR-code [6] Clinical Study Report (ALA-AK-CT003), study design and results can be accessed via clinicaltrials.gov, see QR-code [7] Clinical Study report (ALA-AK-CT007), study design and results can be accessed via clinicaltrials.gov, see QR-code [8] AMELUZ® (prescribing information). Woburn, MA: Biofrontera Inc.; 2021. [9] Maisch T, Santarelli F, Schreml S, et al., Exp Dermatol. 2010; Aug;19(8):e302-5. doi: 10.1111/j.1600-0625.2009.01001.x. PMID: 19845760. Methods • Retrospective analysis • Three pivotal phase III studies (ALA-AK-CT002, -003 and -007 [5-7]) • Histological and clinical data from a total of 762 lesions • Punch biopsy at the screening visit • Treatment scheme: • 3 h incubation of either 10% ALA gel, MAL or vehicle • Illumination with broad- or narrow-spectrum red-light lamp • Clinical clearance assessed 12 weeks after the last PDT For this exploratory analysis, lesion clearance was evaluated in relation to the KIN grade of each respective lesion at the screening visit. Red-light PDT appears to be an effective treatment option for AK regardless of the extend of epidermal keratinocyte atypia. AK lesion clearance rates when using red-light PDT with 10% ALA gel or MAL does not seem to depend on KIN grades (I-III). This exploratory analysis also suggests a higher efficacy of 10% ALA gel compared to MAL for all KIN grades, which is consistent with the better penetration of 10% ALA gel. This study is sponsored by Biofrontera Bioscience GmbH (Germany). K IN I II K IN I I K IN I Atypical keratinocytes in the lowest third of the epidermis Figure 1A: Histological classification according to Cockerell [4] Results Lesion clearance rates (PDT with narrow-spectrum red-light LED lamp) • 10% ALA gel: KIN I: 100%, KIN II: 98.1%, KIN III: 94.7% • MAL: KIN I: 92.9%, KIN II: 90.2%, KIN III: 87.5% Data for PDT with 10% ALA gel suggest higher clearance rates for all KIN grades compared to PDT with MAL (see Figure 1B). One limitation of the study is the small number of lesions in some subgroups. 10% ALA gel not clearedcleared MAL Vehicle not clearedcleared not clearedcleared not clearedcleared not clearedcleared not clearedcleared not clearedcleared not clearedcleared not clearedcleared not clearedcleared not clearedcleared not clearedcleared K IN I II K IN I I To ta l ( K IN I -I II ) K IN I 30 2 252 22 13 1 29 4 341 34 17 0 Synopsis Actinic keratosis (AK) • Precancerous epidermal lesions • Predominantly found in chronically sun exposed skin areas Assessment • Clinically (common): thickness and hyperkeratotic status, mild, moderate, or severe (acc. to Olsen [1]) ! BUT: clinical classification is not a conclusive indicator of extent of atypical keratinocytes [1-3] • Histologically: e.g. keratinocyte intraepithelial neoplasia (KIN) grading (acc. to Cockerell [4]), see Figure 1A Treatment • e.g. red-light photodynamic therapy (PDT) with 10% 5-aminolevulinic acid (ALA) gel or methyl aminolevulinate (MAL) cream (not available in US) 98 19 11 3 139 30 155 3 18 1 203 4 Figure 1B: AK lesion clearance rates by treatment and KIN grade Each bar represents the percentage of AK lesions cleared/not cleared with the respective photosensitizing prodrug (10% ALA gel, MAL) or vehicle and red-light illumination, with color code indicating lamp type: The numbers adjacent to the bars correspond to the number of AK lesions considered for the respective subgroup (n). * The three lesions were located on the face/ forehead and were illuminated with the Omnilux lamp; one was of mild and two were of moderate severity. 144 30 83 9 62 21 24 5 14 2 10 3 198 38 110 12 89 24 60 8 30 0 30 8 13 18 6 13 7 3 33 60 17 37 15 23 6 8 3* 0 3 8 52 86 26 50 25 34 EP ID ER M IS EP ID ER M IS EP ID ER M IS D ER M IS D ER M IS D ER M IS Atypical keratinocytes in the lowest two thirds of the epidermis Full thickness atypia 87.9% 92% 88.2% 90.9% 93.8% 82.8% 82.8% 83.9% 42.9% 78.9% 83.8% 78.6% 82.2% 100% 74.9% 76.9% 78.8% 70% 39.5% 100% 98.1% 94.7% 97.1% 92.9% 90.2% 87.5% 89.4% 100% Affiliations: 1 MVZ Corius DermPathBonn GmbH, Heinz-Werner-Seifert-Institute of Dermatopathology Bonn, Germany; 2AboutSkin Dermatology and AboutSkin Research, Greenwood Village and Lone Tree, CO, USA; 3Department of Dermatology and Allergology, Klinikum Vest GmbH, Recklinghausen, Germany; 4MVZ Dermatologisches Zentrum Bonn GmbH, Bonn, Germany; 5CentroDerm GmbH, Wuppertal, Germany and Faculty of Health, University Witten-Herdecke, Witten, Germany Total Broad-spectrum red-light lamp Narrow-spectrum red-light LED lamp Objective The aim was to evaluate if the effectiveness of red-light photodynamic therapy (PDT) for treating AK was influenced by the epidermal extent of keratinocyte atypia. The nanoemulsion-based 5-aminolevulinic acid gel (Ameluz®; 10% ALA gel) in combination with a specific narrow-spectrum red-light LED lamp (BF-RhodoLED® and RhodoLED® XL) is FDA-approved for lesion- and field- directed treatment of mild-to-moderate AKs on the face/scalp [8]. One key advantage of the 10% ALA gel formulation (compared to e.g. MAL): deeper epidermal penetration [9]. What is the 10% ALA gel? CONCLUSION ? ALA-AK-CT002 ALA-AK-CT003 ALA-AK-CT007 27.3% 35.5% 31.5% 41.9% 31.6% 37.7% 42.4% 31%