Edited by: Satyaki Ganguly, All India Institute of Medical Sciences Raipur, India
Reviewed by: Jose-Manuel Carrascosa, Hospital Germans Trias i Pujol, Spain; Irina Khamaganova, Pirogov Russian National Research Medical University, Russia
This article was submitted to Dermatology, a section of the journal Frontiers in Medicine
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Ablative fractional laser treatment facilitates epidermal drug delivery, which might be an interesting option to increase the topical efficacy of biological drugs in a variety of dermatological diseases. This work aims at investigating safety and tolerability of this new treatment approach in patients with plaque-type psoriasis. Eight patients with plaque-type psoriasis were enrolled in this study. All patients received (i) ablative fractional laser microporation (AFL) of a psoriatic lesion with an Er:YAG laser + etanercept (ETA; Enbrel® solution for injection) (AFL-ETA), (ii) ETA alone on another lesion, and, if feasible, (iii) AFL alone on an additional lesion. Overall, all treatment arms showed a favorable safety profile. AFL-ETA improved the lesion-specific TPSS score by 1.75 vs. baseline, whereas ETA or AFL alone showed a TPSS score improvement of 0.75 points, a difference that was not statistically significant and might be attributable to differences in baseline scores. Topical administration of ETA to psoriatic plaques
Psoriasis is a chronic remitting-relapsing, inflammatory disease of the skin, affecting about 2% of the general population (
During the last few years, biologics have revolutionized the treatment of moderate-to-severe psoriasis patients. However, there is still a lack of treatment options especially for patients with mild, localized disease when they do not sufficiently respond to, or are intolerant to, topical treatments. Detailed knowledge about the pathogenesis of chronic plaque psoriasis and the central role for the TNF/IL-23/TH17 pathway has led to the development of therapies targeting the pathogenic cytokines, including anti-TNFs, anti-p40 (IL-12/IL-23), anti-p19 (IL-23 specific), anti-IL-17A, and anti-IL-17 receptor antibodies (
Etanercept (Enbrel®), a genetically-engineered fusion protein acting as a soluble decoy receptor, has been approved as a safe and efficacious treatment option for patients with moderate-to-severe plaque psoriasis in the US, Europe, and a number of other countries. Mechanistically, etanercept binds to the pro-inflammatory cytokines TNFα and lymphotoxin-α (LT-α, also known as TNF-β), thereby neutralizing their biological activity. Etanercept thus mimics the inhibitory effects of naturally occurring soluble TNF receptors, while offering a greatly extended half-life in circulation which allows superior therapeutic activity (
In view of the potential synergy between laser microporation and topical etanercept administration, we performed a phase I clinical trial to assess safety and efficacy of ablative fractional laser microporation and topical occlusive application of etanercept in patients with chronic plaque-type psoriasis.
This partially observer-blinded, lesion-randomized, intra-patient controlled, 3-arm, monocentric phase I study to assess safety and efficacy of a localized, laser-assisted topical administration of etanercept in patients with plaque-type psoriasis was conducted over 1 year between January 2019 and January 2020.
The study was performed in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guidelines and its amendments. The study was registered under EudraCT no. 2018-001093-19 and EUDAMED no. CIV-AT-20-06-033310, and approved by the local ethics committee and competent authority. All study participants received oral and written information about the study and provided their written informed consent before study enrolment.
Lesions were selected based on similar characteristics, size, and similar location. Treatment was randomly assigned to the respective lesion areas on the first day of treatment. The treatment procedures (etanercept as well as laser) were repeated twice weekly over 6 weeks on the respective lesions. All patients received (i) ablative fractional laser microporation (AFL) of psoriatic lesions + etanercept (ETA; Enbrel® 25 or 50 mg solution for injection in pre-filled pen, marketing authorization holder for Europe: Pfizer Europe) and (ii) ETA alone on another lesion. Four out of eight participants additionally received (iii) AFL microporation alone to treat another lesion (this was only applicable if three comparable lesions could be randomized).
The Er:YAG laser P.L.E.A.S.E.® Professional (Pantec Biosolutions AG, Ruggell, Liechtenstein), with a wavelength of 2'940 nm, a repetition rate of 100 Hz and a pulse length of 225 μs, was used to generate micropores in a 4 or 8 cm2 area of a designated plaque. Etanercept (50 mg) solution at a dose of 30 μl/4 cm2 or 60 μl/8 cm2 was applied to the previously microporated or native surface of the plaque. The treated areas were covered with a transparent dressing for 4 h (occlusion). Patients were asked to document local reactions, adverse events and co-medications in a patient diary. After the screening period, the use of concomitant treatment for psoriasis in all body regions (excluding the three randomized lesions) was restricted to emollients (not supplied), with no pharmacologically active ingredients such as lactic acid, salicylic acid, urea, α-hydroxy acids or fruit acids allowed.
Eligible patients were aged ≥ 18 years with chronic plaque-type psoriasis diagnosed at least 6 months prior to baseline who were candidates for topical therapy or phototherapy with at least 2 lesions. Main exclusion criteria were other forms of psoriasis, drug-induced psoriasis, ongoing use of topical corticosteroids, other topical treatments or phototherapy involving study treatment areas and any biological medicinal product (for full in- and exclusion criteria see the above-indicated registries).
Safety assessments included the continuous assessment of the incidence and severity of adverse events (AE), Administration Site Reactions (ASR, defined as itching, redness, swelling, pain, or ulceration), Adverse Device Effects (ADE), local tolerability at the treatment area, laboratory values (blood chemistry, hematology, and lipid panels), monthly pregnancy tests for females of child-bearing potential, and electrocardiograms (ECG) and vital signs.
Assessment of treatment efficacy was based on the established Target Plaque Severity Score (TPSS). To this end, the target plaque was assessed separately for induration, scaling and erythema using a five-point severity scale (0, none; 1, slight; 2, moderate; 3, marked; 4, very marked), and the scores were summed up to yield the TPSS sum score [13-point scale = 0 (no severity), 12 (high severity)]. Assessments were done before the treatment on day 1 (baseline), as well as on days 4, 8, and 13.
Treatment safety as assessed by ASR and AE/ADE was the primary study objective. Treatment efficacy as assessed by TPSS evolution served as the secondary study outcome.
Treatment was randomly assigned on the first day of treatment to eligible psoriatic lesions.
The sample size of this study (
Eight participants (4 females) with a mean age of 43 ± 14 years and a baseline TPSS of 6.9 ± 2 (range 4-10) were included into the study. Detailed patient characteristics are given in
Patient characteristics at baseline.
Participants (female), |
8 (50) |
Age (years), mean (SD) | 43 (14) |
Range | 23–67 |
Race, |
|
Caucasian | 8 (100.0) |
Other | 0 |
Weight (kg), mean (SD) | 89 (37) |
Range | 55–177 |
Duration of psoriasis since first diagnosis (years), mean (range) | 8 (0.6–19) |
Fitzpatrick Score, mean (SD) | 3 (1) |
TPSS, mean (SD) | 6.9 (2.0) |
Range | 4.0–10.0 |
BSA (%), mean (SD) | 13.7 (6.6) |
Range | 1.5–23.0 |
A total of 64 ASR, all of mild (
Adverse site reactions.
8 (25.00) | 17 (53.13) | 3 (9.38) | 4 (12.50) | 32 | |
4 (28.57) | 8 (57.14) | 1 (7.14) | 1 (7.14) | 14 | |
8 (44.44) | 9 (50.00) | 1 (5.56) | 0 (0.00) | 18 | |
20 | 34 | 5 | 5 | 64 |
A total of eleven AE of mild or moderate severity were documented for five out of the eight study participants, of which most were classified as unrelated to the study procedures: influenza, contact dermatitis on the neck, gastrointestinal bleeding, abdominal cramps (twice in the same subject), headache, constipation, arterial hypertension, hyperlipidaemia, bleeding at laser application site, common cold (two subjects). Furthermore, one serious AE (hospitalization due to arterial hypertension) was recorded and classified as unrelated to the study procedures. No ADE was observed. In addition, one subject experienced two episodes of bleeding at the AFL only laser application site (classified as moderate ASR). No clinically significant deviations in lab results were observed.
The evolution of the TPSS for the respective treatment over the study period is given in
TPSS values (mean ± SD). TPSS was assessed before the respective twice weekly treatments [Er:YAG laser microporation, etanercept (ETA) or combination] over the 6 week study period.
Efficacy analysis showed no significant differences between the treatments AFL + ETA and ETA only. However, five patients (62.5%) had higher V1-minus-V13 differences under AFL + ETA than under ETA only, two patients (25%) had the same changes over time in both treatments and only one patient (12.5%) showed a higher difference under ETA than under AFL + ETA (
Individual TPSS values at visit 1 and visit 13 for the respective treatment areas. TPSS for etanercept (
The raw data from TPSS Total-Score by visit and treatment are listed in
Plaque lesions selected for treatment of a representative subject are displayed in
Results from this study suggest that laser-assisted epidermal delivery of ETA to psoriasis lesions is generally safe and well-tolerated. A comprehensive assessment of risks and benefits associated with either treatment arm (AFL + ETA, ETA only, AFL only) is naturally hampered by the low sample size of a phase I study.
A total of 64 ASR were documented throughout the study. In areas treated with the combination of AFL and ETA 32 ASR, thereof mainly redness (
A comparison of all three treatment groups showed the mean TPSS Total Score evolution (
The strategy of enhancing drug delivery through skin micropores has recently been extensively used for various applications including vaccination (
The drug formulation was not optimized and due to high fluidity special attention was needed during topical administration. In our case ETA doses of 30 μl/4 cm2 or 60 μl/8 cm2 was applied to the treatment area of 4-8 cm2 in comparison to 50 mg dose in 1 ml needed for systemic efficacy. The lowered economic burden afforded by localized delivery system has been demonstrated in other medical fields as well, most notably with the case of systemic bevacizumab adapted for local intra-ocular delivery for wet age-related macular degeneration (AMD) (
Based on the favorable safety profile of the here investigated laser-medicinal product combination, no special precautions seem necessary for future studies.
In summary, topical administration of ETA to psoriatic plaques
The original contributions presented in the study are included in the article/
The studies involving human participants were reviewed and approved by Ethics Committe of the Medical University of Vienna. The patients/participants provided their written informed consent to participate in this study.
CB, WB, RB, MBo, and MZ designed the study. MBa, EL, PM, VA, SP, and PB conducted the study. MBa, PB, and MZ discussed the data. MBa, VL, MBo, PB, and MZ wrote the manuscript. MZ supervised the study. All authors agreed on publication of this manuscript.
VL is employed by Takeda, CB is consultant to Takeda. WB and RB are founders of Pantec Biosolutions AG and MBo serves as an advisor for Pantec Biosolutions AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at:
Plaque lesions selected for treatment with the respective TPSS scores at baseline and before the last treatment on visit 13 (AFL, ablative fractional laser microporation; ETA, etanercept). Each treated area is about 4 cm2.