Phase I Study to Assess Safety of Laser-Assisted Topical Administration of an Anti-TNF Biologic in Patients With Chronic Plaque-Type Psoriasis.

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 via AFL-generated micropores was generally well-tolerated. No special precautions seem necessary in future studies. Clinical benefit will need assessment in sufficiently powered follow-up studies.

Targeted cutaneous delivery of etanercept using Er:YAG fractional laser ablation.

The aim was to investigate the feasibility of using Er:YAG fractional laser ablation to enable topical cutaneous delivery of etanercept (ETA). Preliminary investigations into the effect of fluence on micropore depth, measured by full-field optical coherence tomography, were followed by quantitative experiments to determine ETA delivery and its cutaneous biodistribution from solution and hydrogel formulations. Visualization studies were performed using confocal laser scanning microscopy and an ETA-fluorescein conjugate. Micropore depth was linearly dependent on laser fluence. However, use of a single pulse or "pulse stacking" (i.e. multiple pulses) to apply a given fluence affected pore depth; this was accommodated mathematically by including a "stacking factor". ETA delivery into porated skin from solution and 0.8% Carbopol® formulations was equivalent: increasing ETA content in the gels from 0.5 to 1 and 2% increased ETA delivery linearly (Formulations 7-9: 5.12 ± 0.95 to 7.48 ± 1.45 and 11.2 ± 2.2 µg/cm2, respectively; 10% FAA, 89.9 J/cm2, 5 ppp); occlusion further increased ETA delivery from Formulation 9 to 23.17 ± 6.62 µg/cm2. Cutaneous biodistribution studies demonstrated that ETA was delivered in therapeutically relevant amounts to the epidermis and dermis. Topical laser-assisted delivery of ETA might expand its range of clinical indications to include recalcitrant but not widespread psoriatic plaques (clinical trial underway).

Fractional laser ablation for the targeted cutaneous delivery of an anti-CD29 monoclonal antibody - OS2966.

Monoclonal antibodies targeting cytokines are administered parenterally for the systemic treatment of severe psoriasis. However, systemic exposure to the biologic increases the risk of side-effects including immunosuppression, whereas only a small fraction of the active molecules actually reaches the target organ, the skin. This preclinical study examines the feasibility of delivering a humanized anti-CD29 monoclonal antibody (OS2966) topically to skin using minimally-invasive fractional laser ablation. This approach would enable the targeted use of a biologic for the treatment of recalcitrant psoriatic plaques in patients with less widespread disease while minimizing the risk of systemic exposure. First, the effect of a wide range of laser poration conditions on skin permeation and deposition of OS2966 was tested in vitro to determine optimal microporation parameters. Subsequently, confocal laser scanning microscopy was employed to visualize the distribution of fluorescently-labelled OS2966 in skin. The results demonstrated that delivery of OS2966 into and across skin was feasible. Above fluences of 35.1 J/cm2, skin deposition and permeation were statistically superior to passive delivery reaching values up to 3.7 ± 1.2 µg/cm2 at the most aggressive condition. Selective targeting of the skin was also possible since ≥70% of the OS2966 was delivered locally to the skin. Although nanogramme quantities were able to permeate across skin, these amounts were orders of magnitude lower than levels seen following subcutaneous or intravenous injection and would result in minimal systemic exposure in vivo. The diffusion of fluorescently-labelled OS2966 into the skin surrounding the pores was clearly higher than in intact skin and demonstrated the feasibility of delivering the antibody at least as deep as the dermo-epithelial junction, a critical border region where inflammatory cells cross to promote disease progression. These preliminary results confirm that fractional laser ablation can be used for the cutaneous delivery of OS2966 and now preclinical/clinical studies are required to demonstrate therapeutic efficacy.