Fernblock® Scientific & Clinical Support _____________________________________________________________________________

CONTENTS

1. INTRODUCTION 4

2. THE FERNBLOCK TECHNOLOGY 5

3. THE FERNBLOCK CLINICAL EVIDENCE BASE 6

i. MECHANISM OF ACTION 6

ii. FERNBLOCK IN DERMATOLOGIC TREATMENTS 12

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1. INTRODUCTION

Whilst having some beneficial effects on the skin, recurrent exposure to light is the primary cause of skin ageing and a pivotal factor in the development of non-melanoma skin cancer in Caucasian individuals.1 Most available photobiologic studies focus on the ultraviolet (UV) radiation portion of the spectrum, which is considered to be the most damaging form of radiation; however recent studies have also highlighted the deleterious effects of visible light2 and infrared-A exposure. The skin is exposed daily to forms of UV, visible light and infrared-A. In addition, the skin may be intentionally exposed to radiation during the treatment of dermatologic diseases. Topical photoprotection using different kinds of filters to reflect and absorb UV and visible light is a well evidenced and accepted method for reducing their impact on skin ageing and skin health. However, many filters do not protect against high-energy visible light and classical high-level broad-spectrum photoprotection may only reduce free radical or ROS formation by 55%.3 Also, topical photoprotection is often inadequately applied and re-applied. Therefore, there is a need for additional anti-oxidant protection. There is compelling evidence for the role of one particular photoprotector: Fernblock®, a unique and patented extract from the fern, Polypodium leucotomos. Fernblock incorporates potent reactive oxygen species (ROS) inhibitors that demonstrate significant anti-oxidant, anti-inflammatory and photoprotective activity. Its skin-specific broad-spectrum anti-oxidant actions protect the skin architecture, collagen and skin cells from oxidative damage. 1,4 It has been shown to preserve cytoskeletal structure in human fibroblasts and their proliferative capacity after exposure to UVA radiation, in addition to inhibiting lipid peroxidation and matrix metalloproteinase (MMP) expression in fibroblasts and keratinocytes.5,6 Fernblock also enhances skin-health, decreasing the formation of sunburn cells and cyclobutane pyrimidine dimers (CPDs), and preserves Langerhan’s cells after UV exposure.7,8,9,10 In addition to reducing the development of photo-ageing and skin cancers, oral supplementation with Fernblock has been used, either as a standalone or adjunctive therapy, to treat a variety of dermatologic disorders including immunologically-mediated photodermatoses, vitiligo, melasma, psoriasis, atopic dermatitis and actinic keratosis with an excellent safety profile.11 Fernblock is found uniquely in the Heliocare® range. The skin-protecting and skin-enhancing effects of Fernblock, a patented extract from the fern Polypodium leucotomos, have been proven in extensive scientific and clinical studies around the world. This Scientific and Clinical Support Pack summarises the clinical evidence base for Fernblock.

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2. THE FERNBLOCK TECHNOLOGY

Fernblock is a patented natural extract from the fern Polypodium leucotomos that provides a complex of potent anti-oxidants including ferulic and caffeic acids. P. leucotomos originated in Central America as an aquatic plant that adapted to life on land, developing its own natural protective mechanisms against UV radiation. P. leucotomos is known to have been used for centuries in Central America in the treatment of dermatological conditions including psoriasis and atopic dermatitis, leading to investigations into its anti-inflammatory and immuno-modulatory properties. As early as 1967, Horvarth and his team investigated the anti-tumoural effects of P. leucotomos, and following this a team of renowned Dermatologists comprising Gonzales, Fitzpatrick, Pathak and Padilla evidenced its anti-inflammatory properties when used in vitiligo patients receiving PUVA or PUVASOL therapy for repigmentation of vitiligo macules.4 This prompted Gonzales and Pathak to investigate the photoprotective properties of P. leucotomos and evaluate its role in the lipid peroxidation process of skin inflammatory reactions induced by UV radiation. Gonzales and Pathak found that P. leucotomos extract exhibited anti-oxidant and anti-inflammatory as well as photoprotective properties against photo-oxidative stress involving the generation of ROS and lipid peroxidation levels both in vitro and in vivo.4 They also observed significant inhibition of UVB-induced dermal erythemal response following topical application. The photoprotective mechanism of P. leucotomos involving interaction with ROS appeared to have a potential clinical usefulness in preventing cellular and tissue damage within the skin and inhibiting phototoxic skin reactions. Following these initial studies an extensive research programme to achieve the optimum P. leucotomos patented extraction process and finished ingredient took place, along with further clinical investigations conducted in conjunction with the Harvard Medical School and leading experts in the field of photoprotection. The result is the unique and patented extract Fernblock that provides a concentration of essential polyphenols and flavonoids, such as ferulic, caffeic, vanilic and coumaric acid. To date there are over 80 published studies on Fernblock demonstrating the compelling scientific and clinical evidence for its role as a skin protecting agent.

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3. THE FERNBLOCK CLINICAL EVIDENCE BASE

Fernblock is a patented extract from the fern, P. leucotomos, that is clinically proven to provide skin-ageing protection and enhancement through a broad spectrum skin-specific anti-oxidant activity and protection of the skin architecture, as well as skin-health protection and enhancement through immunological action and cellular DNA protection and repair.1,4-10 Fernblock’s mechanism of action and use in the treatment of a variety of dermatologic disorders, either as a standalone or adjunctive therapy, are summarised below.

i. MECHANISM OF ACTION

Fernblock has four clinically proven mechanisms of action: broad-spectrum skin-specific anti-oxidant activity; immunological action via Langerhans cell protection; cellular DNA protection and repair; and skin architecture, collagen and fibroblast protection and enhancement.1,4-10 a. Anti-oxidant – Broad-spectrum skin-specific antioxidant activity 1,4 ROS can cause structural and functional damage which can accumulate with age and be accelerated by UV exposure. Fernblock is a strong anti-oxidant and has been shown to neutralize ROS in vitro and in vivo, helping to preserve both the cutaneous and plasmatic anti-oxidant systems to reduce the oxidation caused by ROS of essential biological molecules including DNA and lipids.1,4 This can help protect against the adverse effects ROS exposure has on skin-ageing and skin-health. • P. leucotomos extract inhibits superoxide anion production by 55% and lipid peroxidation by 50%

in vitro.4

Graph to show the scavenging effect of P. leucotomos on superoxide anion produced by UVA irradiation of riboflavin.

• P. leucotomos extract administered orally as well as topically reduces lipid peroxidation and cutaneous phototoxic reactions.4

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• P. leucotomos extract administered orally has been shown to effectively reduce glutathione

oxidation in the blood and epidermis.1

Graphs to show oxidised glutathione present in the blood and epidermis following irradiation (red) and irradiation

with P. leucotomos extract (green). • Fernblock prevents the formation of ROS induced by HEVis and IR irradiation in vitro.28

Graphs show reduction in ROS formation after irradiation with visible light and infrared-A when Fernblock is present

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b. Immunological action – Langerhans cell protection7,8 Fernblock reduces the acute phototoxicity induced by high exposure to UVA radiation, as well as its histological consequences.7,8 Langerhans cells in the epidermis are usually caused to migrate upon exposure to UV radiation, lessening the protective impact of the immunological system. In this way, Fernblock helps promote immunological skin-health.

• The oral administration of Fernblock significantly reduces the depletion of epidermal Langerhans

cells upon exposure to UV by PUVA as well as preserving their morphology.7

Histology from paired biopsy specimens of skin treated with PUVA alone (left) and with Fernblock extract (right). PL-treated skin shows: less sunburn cells, maturation disarray, microvesiculation and vacuolisation (A); Langerhans cell numeric and morphologic preservation (B).

• Oral as well as topical administration of P. leucotomos extract preserves epidermal Langerhans

cells.8

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c. DNA – Cellular DNA protection and repair9,10 DNA is essential for normal cellular renewal and functions and maintaining skin health. Pyrimidine dimers caused by UV radiation alter the structure and function of DNA and are the primary cause of skin melanomas. Fernblock is clinically proven to reduce DNA damage and increase repair of damaged DNA, therefore helping to promote cellular DNA skin-health and reduce the risk of cellular mutations.9,10

• The oral administration of Fernblock decreases the production of cyclobutane pyrimidine dimers

(CPDs) induced by stimulation by UV radiation.9 Fernblock inhibits the formation of thymine dimers (p<0.0001), lesions linked to cell mutation and development

of skin cancer. • Fernblock administered orally prevents UV damage including inflammation and enhances DNA

repair.10

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d. Skin architecture – Collagen, ECM and fibroblast protection and enhancement5,6 Fibroblasts and the extracellular matrix (ECM) regulate the structure, elasticity, flexibility and vitality of the skin. ECM and collagen synthesis and degradation is managed by the enzymes matrix metalloproteinases (MMPs) and tissue inhibitors of MMPS (TIMPs). In skin-ageing and photo-ageing, ECM and collagen synthesis is reduced and degradation is accelerated, adversely affecting the structure, elasticity, flexibility and vitality of the skin. Fernblock is clinically proven to help protect and enhance skin architecture and prevent skin-ageing.5,6

• P. leucotomos extract promotes fibroblast survival and protects their structure and organisation in

vitro.5

Effect of P. leucotomos extract on the cytoskeleton organisation and adhesion molecule localisation in human

fibroblasts exposed to UVA light compared to non-irradiated and non-treated. • Fernblock inhibits MMPs and stimulates TIMPs, structural ECM collagens (types I,III and V) and

TGF-ß in fibroblasts in vitro.6

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• Fernblock prevents cell damage and the formation of MMP-1 produced by HEVis and IR irradiation in vitro28

Graphs show a reduction in cell death caused by high energy visible light

and infrared-A when Fernblock is used.

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ii. FERNBLOCK IN DERMATOLOGIC TREATMENTS

Fernblock has been shown to provide a broad spectrum of protective activities including anti-oxidant, immunomodulatory and photoprotective effects in vitro as well as in vivo, as summarised above.1,4-10 Whilst topical application of Fernblock has been shown to provide these protective effects, many of the studies utilise an oral form of Fernblock. Oral supplementation with Fernblock has two roles: one is in addition to topical photoprotection, particularly during times of high intensity exposure or high risk such as in patients prone to photodermatoses; the other is as an adjunct to dermatologic treatments, to protect and repair the skin from any negative effects of the treatment and to enhance and prolong the results achieved. Studies are summarised below on the use and potential applications of oral Fernblock in the management of photodermatoses, pigmentary disorders including melasma and vitiligo, inflammatory skin disorders including psoriasis and atopic dermatitis, and actinic keratosis.12-24 a. Photodermatoses protection12-14 Photodermatoses are UV and light-induced skin reactions that affect up to 20% of the population.25 The most common, polymorphic light eruption (PMLE), displays as a dermatitis-like rash of varying degrees, with raised pink or red lesions and an itchy or burning sensation. Recent studies indicate that ROS may play a significant role in the pathogenesis of photodermatoses. Fernblock is clinically proven to reduce the incidence of photodermatoses including polymorphic light eruption (PLE).12-14 Caccialanza et al (2007) demonstrated a reduction in photodermatoses skin reactions and subjective symptoms in 25 patients taking oral Fernblock who were exposed to sunlight.12 Patients with a clinical history of photodermatoses and who had been previously unresponsive to therapy took 480mg/day Fernblock, divided into two doses of 240mg each, orally for 15 days prior to and during the summer months and recorded their photodermatoses symptoms. Twenty out of the 25 patients (80%) found it to be beneficial to consume Fernblock during sunlight exposure, as shown in the table below. Thirty-one percent of patients experienced a complete normalisation in their condition. The two patients in the study with solar urticaria did not report an improvement. The tolerance of oral Fernblock was reported to be excellent. • Oral administration of Fernblock significantly reduces photodermatoses skin reactions and

subjective symptoms.12

Table showing results after sunlight exposure with oral Fernblock

Tanew et al (2011) investigated whether oral Fernblock could prevent or delay the photoinduction of typical PMLE lesions by artificial UV radiation.13 A total of 30 patients with long-standing PMLE were treated with artificial UVB and UVA light to provoke PMLE lesions, after which they commenced oral Fernblock daily. Quantity taken was according to body mass: less than or equal to 55kg, 720mg every

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day; 56 to 70kg, 960mg every day; and more than 70kg, 1,200mg every day. After two weeks of daily oral Fernblock supplementation, a second photoprovocation was performed. Using the same range of UV doses and the same number of UV exposures the phototest was negative in 30% (9 out of 30) of all the UVA-sensitive patients and 28% (5 out of 18) of the UVB-sensitive patients. In the remaining patients the mean number of UVA or UVB exposures required to induce PMLE increased significantly as shown in the table below. Follow-up of 15 patients who took oral Fernblock during the whole summer season revealed that 7 of the 15 patients (47%) experienced no additional PMLE episodes and 4 (27%) developed only a minor rash with a delayed onset. The tolerance of oral Fernblock was excellent in all patients and no adverse events were recorded throughout the study period. • Fernblock administered orally significantly increases the number of UVA and UVB exposures

required to elicit PMLE lesions in susceptible individuals.13

Number of UV exposures needed for elicitation in those patients showing PLE after oral intake of P. leucotomos

In 2011, Caccialanza et al published the results of a second study in which they assessed the results of 57 patients with idiopathic photodermatoses who took 480mg oral Fernblock daily during the summer months.14 Forty-two patients out of 57 (73.68%) found it beneficial to consume oral Fernblock during sunlight exposure and almost 30% had a normalisation. Three out of the 4 patients in the study who were affected with solar urticaria did not improve. No side effects were observed. These clinical studies demonstrate the role of oral Fernblock in improving photodermatoses skin reactions and their subjective symptoms, in particular polymorphic light eruptions, with no to minimal undesirable adverse effects.

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b. Pigmentary disorders15-20 i. Vitiligo15-17 Vitiligo is a common pigmentary skin disorder of unknown aetiology characterised by milk-white depigmented macules resulting from loss of epidermal melanocytes. Its cause is hypothesised to be related to auto-immune processes in which cytotoxic T cells target melanocytes; cytotoxic metabolites of melanogenesis related to oxidative stress have also been linked to its formation.15 Presently, the first choice treatment for vitiligo is narrow-band UVB (NB-UVB); alternative treatment options include psoralens with UVA (PUVA) therapy. NB-UVB and PUVA have similar efficacy rates and whilst NB-UVB is considered to have lower risks than PUVA, they can both increase the risk of melanoma and non-melanoma skin cancers.26 Oral Fernblock has been shown to increase repigmentation rates in patients undergoing NB-UVB and PUVA for vitiligo.15-17 Due to its photoprotective effects, Fernblock could also be useful in preventing or reducing any negative effects associated with NB-UVB and PUVA therapy. Middelkamp-Hup et al (2007) reported on the effects of oral Fernblock capsules of 250mg taken three times daily (morning, noon and evening) or placebo capsules containing the same ingredients except for P. leucotomos extract in 49 patients undergoing NB-UVB for vitiligo vulgaris.15 Repigmentation was higher in the oral Fernblock group vs placebo in the head and neck area (44% vs. 27%, P = 0.06) although this trend did not quite reach statistical significance. Small, non-significant repigmentation increases were observed for the trunk, extremities, and hands and feet for the oral Fernblock group. For those patients who attended more than 80% of the required NB-UVB sessions, there was increased repigmentation in the head and neck area of 50% for the oral Fernblock group vs 19% for the placebo group (P<0.002). Patients with skin types II and III showed more repigmentation in the head and neck area although results for patients with skin types IV and V were inconclusive due to the small numbers of patients of these skin types in the study. • Oral Fernblock in association with NB-UVB increases pigmentation of vitiligo vulgaris affecting the

head and neck area, compared to NB-UVB alone.15

Repigmentation with NB-UVB at W26 in patients following more than 80% of NB-UVB session in oral Fernblock (grey) vs placebo group (white).

A poster presented by Pacifico et al at the American Academy of Dermatology (AAD) annual meeting in 2009 supports these findings.16 Four-hundred and eighty mg oral Fernblock daily in combination with NB-UVB twice weekly was shown to be more effective in repigmentation of patients with generalised vitiligo than treatment with NB-UVB alone (40% vs 22%, P<0.0005). The authors concluded that oral Fernblock in combination with NB-UVB could improve the response to treatment both in terms of extent and rapidity of repigmentation.

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Reyes et al (2006) assessed the effects of oral Fernblock in combination with PUVA compared to PUVA alone in 19 patients with generalised vitiligo.17 They found that the percentage of subjects with a skin repigmentation greater than 50% (moderate to excellent response) was significantly higher in the oral Fernblock group than the placebo group. Additionally, PUVA plus oral Fernblock normalised expression of activation markers by T cells and suppresses proliferation of peripheral blood mononuclear cells versus PUVA alone. It was concluded that the immunomodulatory effects of oral Fernblock might explain the higher rate of patients with moderate to excellent repigmentation and support its beneficial use as an adjuvant to phototherapy in the treatment of vitiligo. Oral Fernblock is clinically proven to increase repigmentation rates in patients undergoing NB-UVB and PUVA for vitiligo.15-17 These effects might be attributed to Fernblock’s immunomodulatory and antioxidant properties, in agreement with the two main hypotheses of vitiligo resulting from an auto-immune process or increased epidermal oxidative stress.15 Fernblock may also help to reduce the risk of negative effects associated with NB-UVB and PUVA therapy, due to its ability to reduce DNA damage, increase DNA repair and protect key skin immune cells, the Langerhans cells.1,7,9,10 ii. Melasma18-19 Melasma is an acquired hyperpigmentation of the forehead and cheeks that occurs on sun-exposed areas and is exacerbated by UV and light exposure. Due to its ability to provide systemic photoprotection there is interest in the use of oral Fernblock as an adjunctive treatment of melasma.18-

19 A study carried out by Martin et al (2012) investigated the effects of oral Fernblock on the melasma quality of life scale (MELASQOL) and the melasma area and severity index (MASI) in patients with melasma.18 Melasma can have a significant impact on quality of life. The MELASQOL was developed to objectively assess this impact as well as the level of impairment individuals suffer due to their melasma. The MASI is a tool that is used worldwide to measure the area of melasma involvement and the degree of pigmentation and homogeneity in four areas of the face: the forehead, right and left malar regions and the chin. A score is calculated, with a total possible score of 48 for the full face, or 24 for one side of the face. In the study, 21 female subjects with epidermal melasma were randomised to receive oral Fernblock or placebo twice daily for 12 weeks. Each patient also applied SPF45 sunscreen daily. After 12 weeks, patients treated with oral Fernblock had significantly decreased mean MASI (5.7 to 3.3; P<0.05), whereas the placebo group did not (4.7 to 5.7; P=NS). A mild or marked improvement was achieved in 43 and 17 percent of the Fernblock-treated patients, respectively, versus 14 and 0 percent for the placebo-treated patients. Patient self-assessment revealed 50 and 13 percent of the Fernblock-treated patients achieved a mild and marked improvement, respectively, compared to 17 and 0 percent for the placebo-treated patients. On average, MELASQOL parameters were reported as worsened in 50% of placebo compared to 20% of the Fernblock patients, while parameters improved in 59% of the Fernblock patients and only 27% of placebo (P<0.05). These findings indicate that oral Fernblock can reduce melasma severity and could be an important adjunctive treatment option for patients wishing to improve their melasma. A second study carried out in 2013 tested the same hypothesis.19 Thirty-three Hispanic women with melasma were randomised to receive either 240mg oral Fernblock or placebo 3 times daily for 12 weeks. All subjects were given a standard, broad-spectrum, topical sunscreen SPF50 to use every morning. After 12 weeks there was an improvement in the melanin index of 28.8% in the Fernblock group compared to 13.8% improvement in the placebo group. Whilst significant from baseline, the

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intergroup difference was not statistically significant. The MASI scores similarly showed improvement in both groups from baseline, but without significant intergroup difference. It was concluded that whilst oral Fernblock provided an improvement in melasma the improvement was not statistically significant. ii. High-energy visible light induced pigmentation20 More recently, it has been demonstrated that oral Fernblock also appears to provide protective effects against the stimulation of pigmentation induced by high-energy visible light (HEVis) exposure.20 Visible light causes pigmentation as well as erythema and thermal damage; it can worsen photo-exacerbated conditions such as melasma or post-inflammatory hyperpigmentation (PIH), especially in darker skin phototypes. It can also cause DNA damage secondary to the production of ROS. There is currently a study underway at the Henry Ford Hospital, Detroit, USA, to assess the effects of oral Fernblock in protecting against immediate pigment darkening (IPD) and delayed tanning (DT) induced by HEVis.20 Preliminary results were presented at the Skin of Color Society (SOCS) and Photomedicine Society meetings at the AAD 2016, Washington D.C. Twenty-two patients of Fitzpatrick skin types IV-VI were recruited into the study. Each patient took 240mg Fernblock twice daily for 28 days. Assessments included irradiation of skin with visible light (480J/cm2) and skin biopsies to be assessed for changes in skin structure (Hematoxylin & Eosin), pigmentation (Fontana Masson), DNA damage (8-oxoguanine), cellular damage (MMP-1, 2, 9) and inflammation (COX-2). Preliminary results for thirteen of the patients indicate that oral Fernblock can reduce immediate pigment darkening and delayed tanning induced by high-energy visible light.

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c. Inflammatory skin disorders21-23 Oral Fernblock has been shown to be an effective adjunct to treatments for inflammatory skin disorders including psoriasis and atopic dermatitis.7,21-23 i. Psoriasis7,21,22 Psoralen and UVA radiation (PUVA) therapy is a very useful tool in the management of psoriasis; however, it has several side effects including sunburn, phototoxic reactions and immunological alterations that could increase the risk of carcinoma.21 The use of oral Fernblock as an adjunct to PUVA has been investigated due to its known photoprotective properties. It was demonstrated that oral Fernblock not only reduced skin phototoxic reactions and protected epidermal cells, it also reduced the accumulated UVA dose required to achieve “bleaching” or whitening of the psoriasis plaques compared to the control.7,21,22 De Las Heras et al investigated the effects of oral Fernblock combined with PUVA compared to PUVA alone in 40 patients with plaque psoriasis (20 patients / group).21 The protocol of the Fernblock + PUVA group was: 720mg Fernblock per day, 3 hours before the 3 weekly PUVA sessions and at doses of 240mg every 8 hours on the remainder of the days, then 240mg every 12 hours following the treatment course. The patients in the Fernblock + PUVA group required a statistically significant lower accumulated dose of UVA to achieve whitening (P<0.0001). Whilst this group also received fewer UVA sessions, no significant difference was detected. The addition of oral Fernblock was also shown to preserve key epidermal immune cells, Langerhans cells, reducing the local immunosuppression and potential carcinogenesis induced by PUVA. The authors concluded that PUVA combined with oral Fernblock could allow a reduction in the UVA dosage required and minimise the risks of PUVA. These findings are supported by studies by Ledo et al (2000) and Middelkamp-Hup et al (2004).7,22 Ledo et al demonstrated that fewer treatment sessions and lower total UVA dose was required to resolve palmoplantar psoriasis in patients taking oral Fernblock alongside PUVA therapy compared to PUVA alone, although the intergroup comparison was not found to be statistically significant.22 There was, however, a significantly lower number of patients experiencing skin phototoxic reactions and hyperpigmentation in the Fernblock group. Middelkamp-Hup et al showed that oral Fernblock lead to a significant reduction of phototoxic reactions, i.e. erythema and oedema, and pigmentary response in PUVA-treated individuals (P<0.005).7 There was also a significantly lower number of sunburn cells (P=0.05) and less depletion of Langerhans cells (P<0.01) when compared to skin treated with UVA alone, confirming Fernblock‘s role as a protective agent against PUVA-induced phototoxicity.

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ii. Atopic dermatitis23 Topical corticosteroids are used to treat inflammation and relieve itching in atopic dermatitis, but their use is limited by adverse reactions.23 The potential benefits of oral Fernblock were investigated in reducing the use of topical corticosteroids in children and adolescents with atopic dermatitis. Oral Fernblock was shown to significantly reduce topical corticosteroid and oral antihistaminic drug use in patients with atopic dermatitis.23 In the study carried out by Ramirez-Bosca et al (2012), 105 patients between the ages of 2-17 years with moderate atopic dermatitis were enrolled.23 All patients were already using topical corticosteroids to alleviate their symptoms. The patients were randomized to receive, in addition to their standard treatment, either oral Fernblock or placebo. The patients were divided into three treatment groups according to age: children aged 6 years or younger received 240mg Fernblock daily; children aged 6 to 12 years received 360mg Fernblock daily (120mg in the morning and 240mg at night); and children aged over 12 years received 480mg Fernblock daily divided into two equal doses; or placebo. Ninety-three patients completed the 6 month study period (the number of withdrawals was similar in the Fernblock group and placebo group). No significant difference in the number of days that topical corticosteroids were used was found. However, the patients in the Fernblock group demonstrated a significant reduction in topical corticosteroid use from the first month to the second month, and from the fourth month to the fifth month (P=0.012); whereas there were no significant differences noted in the placebo group. They also found an overall decrease in oral antihistamine use in the Fernblock group after the first month of treatment, which became statistically significant after the third month of treatment (P=0.038). Clinically, there was a reduction in the number of flares reported by the oral Fernblock group, however this was not statistically significant. These findings indicate that the use of oral Fernblock in addition to standard first-line therapy could have a beneficial effect in the treatment of atopic dermatitis.

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d. Actinic keratosis24 Actinic keratosis (AKs) are the most common form of premalignant skin condition in Caucasian individuals.24 Photodynamic therapy (PDT) is one of the most effective treatments available for AKs; however, PDT can cause DNA damage and immunosuppression, leading to recurrence of AKs and/or treatment failure. Auriemma et al (2015) have demonstrated the ability of oral Fernblock to improve clearance rates of AKs in patients undergoing PDT.24 Thirty-four bald patients presenting with at least two AKs on the scalp were alternatively assigned to two groups. Both groups underwent two PDT sessions one week apart. One week after the last PDT session one group began supplementation with oral Fernblock at a dose of 960mg per day for 1 month followed by 480mg per day for 5 months. Patients from both groups were instructed to use a sun protection product with an SPF ≥50 daily every 2 hours during sun exposure periods. Assessments carried out 2 and 6 months after the first PDT session showed a reduction in AKs in patients in both groups. However, at the 6 month follow up there was a better clearance rate for PDT + supplementation with oral Fernblock compared with PDT alone, as shown in the table below. No major side effects were reported in either treatment group. • Oral Fernblock in association with PDT enhances PDT efficacy in the treatment of AKs, reducing

the number of AKs and preventing recurrence of AKs, compared to PDT alone.24

Median and interquartile range of scalp AKs at baseline and 6 months after treatment for each group.

Photodynamic therapy is a well-established treatment for actinic keratosis, with clearance rates ranging from 60 to 90%. However, it has a recurrence rate of 20% at 12 months, and clearance rate is lower in immunosuppressed patients. This indicates an important role of UV-induced immunosuppression in treatment outcomes and recurrence rates. Fernblock is clinically proven to reduce DNA damage, increase DNA repair and protect key skin immune cells, the Langerhans cells.1,7,9,10 In this study, Auriemma et al demonstrate that oral Fernblock supplementation after PDT treatment reduces the recurrence of AKs in high-risk individuals.24 A review article by Choudry, Lim et al published in the Journal of Drugs in Dermatology in 2014 summarises the use and potential applications of Fernblock in the treatment and management of dermatologic disorders including photodermatoses, vitiligo, melasma, psoriasis and atopic dermatitis. 11 The authors conclude that Fernblock has multiple mechanisms of action, ranging from anti-inflammatory and immunomodulatory to antioxidant and photoprotective. Due to these multiple mechanisms of action, Fernblock may play a role as a new adjunctive option in the treatment of these conditions.

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As demonstrated in the clinical studies summarised above, oral supplementation with Fernblock has been used as an adjunct in the treatment of dermatologic conditions with promising results and an excellent safety profile. It has been shown to improve photodermatoses symptoms as well as improving outcomes or reducing side effects when used as an adjunct in the treatment of conditions including vitiligo, melasma, psoriasis, atopic dermatitis and actinic keratosis. Fernblock is available in an oral form with the Heliocare Oral Supplements.

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References: 1. Polypodium leucotomos extract inhibits glutathione oxidation and prevents Langerhans cell depletion induced by UVB/UVA radiation in a hairless rat model. Mulero, Rodriguez-Yanes, Nogues, Giralt, Romeu, Gonzalez & Mallol. Exp Dermatol 2008;17:653-658. 2. Effects of Visible Light on the Skin. Mahmoud, Lim et al. Photochem Photobiol, 2008. 84:450-462. 3. The role of antioxidants in photoprotection: a critical review. Chen et al. J Am Acad Dermatol. 2012;67:1013-24. 4. Inhibition of ultraviolet-induced formulation of reactive oxygen species, lipid peroxidation, erythema and photosensitization by Polypodium leucotomos. Gonzalez & Pathak. Photodermatol Photoimmunol Photomed 1996;12:45-56. 5. Photoprotective properties of a hydrophilic extract of the fern Polypodium leucotomos on human skin cells. Alonso-Lebrero, Dominguez-Jiminez, Tejedor, Brieva & Pivel. J Photochem Photobiol B: Biol 2003;70:31-37. 6. Beneficial regulation of matrixmetalloproteinases and their inhibitors, fibrillar collagens and transforming growth factor-ß by Polypodium leucotomos, directly or in dermal fibroblasts, ultraviolet radiated fibrolblasts, and melanoma cells. Philips, Conte, Chen, Natrajan, Taw, Keller, Givant, Tuason, Dulaj, Leornardi & Gonzalez. Arch Dermatol Res 2009. 7. Orally administered Polypodium leucotomos extract decreases psoralen-UVA-induced phototoxicity, pigmentation and damage of human skin. Middelkamp-Hup, Pathak, Parrado, Garcia-Caballero, Rius-Diaz, Fitzpatrick & Gonzalez. J Am Acad Dermatol 2004;50:41-49. 8. Topical or oral administration with an extract of Polypodium leucotomos prevents acute sunburn and psoralen-induced phototoxic reactions as well as depletion of Langerhans cells in human skin. Gonzales, Pathak, Cueva, Villarubia & Fitzpatrick. Photodermatol Photoimmunol Photomed 1997: 13;50-60. 9. Oral Polypodium leucotomos extract decreases ultraviolet-induced damage of human skin. Middelkamp-Hup, Pathak, Parrado, Goukassian,

Rius-Diaz, Mihm, Fitzpatrick & Gonzalez. J Am Acad Dermatol 2004;51:910-918. 10. Polypodium leucotomos Extract Decreases UV-Induce Cox-2 Expression and Inflammation, Enhances DNA Repair, and Decreases Mutagenesis in Hairless Mice. Zattra, Coleman, Arad, Helms, Levine, Bord, Guillaume, El-Hajahmad, Zwart, van Steeg, Gonzalez, Kishore & Goukassian. Am J Pathol 2009;175(5):1952-1961. 11. Role of Oral Polypodium Leucotomos Extract in Dermatologic Diseases: A Review of the Literature. Choudry, Bhatia, Ceilley, Hougeir, Lieberman, Hamzavi & Lim. JDD 2014;13(2):611-616. 12. Photoprotective activity of oral Polypodium leucotomos extract in 25 patients with idiopathic photodermatoses. Caccialanza, Percivalle, Piccinno & Brambilla. Photodermatol Photoimmunol Photomed 2007;23:46-47. 13. Oral administration of a hydrophilic extract of Polypodium leucotomos for the prevention of polymorphic light eruption. Tanew, Radakovic, Gonzalez, Venturini & Calzavara-Pinton. J Am Acad Dermatol, 2011. 14. Oral Polypodium leucotomos extract photoprotective activity in 57 patients with idiopathic photodermatoses. Caccialanza, Recalcati & Piccinno. G Ital Dermatol Venereol 2011;146:85-7. 15. Treatment of vitiligo vulgaris with narrow-band UVB and oral Polypodium leucotomos extract: a randomized double-blind placebo-controlled study. Middelkamp-Hup MA et al. J Eur Acad Dermatol Venereol. 2007;21(7):942-50. 16. Combined treatment of narrowband ultraviolet B light (NBUCB) phototherapy and oral Polypodium leucotomos extract versus NBUVB phototherapy alone in the treatment of patients with vitiligo. Pacifico et al. J Am Acad Dermatol. 2009;3(Suppl 1):AB154. 17. Systemic immunomodulatory effects of Polypodium leucotomos as an adjuvant to PUVA therapy in generalised vitiligo: A pilot study. Reyes, Jaen & Cuevas. J Dermatol Sci. 2006; 41(3):213-216. 18. A randomized double-blind placebo controlled study evaluating the effectiveness and tolerability of oral Polypodium leucotomos in patients with

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melasma. Martin LJ, Caperton C, Woolery-Lloyd H, Avashia N. J Am Acad Dermatol, 2012. 19. A randomized, double-blinded, placebo-controlled trial of oral Polypodium leucotomos extract as an adjunct to sunscreen in the treatment of melasma. Ahmed et al. JAMA Dermatology. Aug 2013;149(8):981-2. 20. Mohammad TF, Lim HW et al. Henry Ford Hospital, Detroit. Presentations SOCS & Society of Photomedicine, AAD 2016 21. Polypodium leucotomos extract as adjuvant to PUVA therapy in the treatment of Plaque Psoriasis. De La Heras ME et al. Med Cután Iber Lat Am. 1997;XXV/97:103-107. 22. Treatment of palmoplantar psoriasis with topical puva and polypodium leucotomos (Difur). Ledo et al. Med Cutan Iber Lat Am 2000;28(1):18-22. 23. Polypodium leucotomos Extract in Atopic Dermatitis- A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Ramirez-Bosca et al. Actas Dermosifilogr. 2012;103(7):599-607. 24. Polypodium Leucotomos Supplementation in the Treatment of Scalp Actinic Keratosis: Could It Improve the Efficacy of Photodynamic Therapy?

Auriemma, Di Dicola, Gonzales, Piaserico, Capo & Amerio. Dermatol Surg 2015;41:898-902. 25. Photodermatoses: Diagnosis and Treatment. Lehmann & Schwarz. Dtsch Arztebl Int. 2011 Mar; 108(9): 135-141. 26. Concise review of recent studies in vitiligo. Allam & Riad. Qatar Med J. 2013: 2013(2): 1-19. 27. Vitamin D Fact Sheet for Health Professionals. U.S Department of Health & Human Services. National Institutes of Health. Office of Dietary Supplements. https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/ 28. Fernblock Prevents Dermal Cell Damage Induced by Visible and Infrared A Radiation. Zamarrón, Lorrio, González and Juarranz. Int. J. Mol. Sci. 2018, 19, 2250

Date of preparation: 8 May 2019 AesthetiCare, a division of Ferndale Pharmaceuticals, is distributor for Heliocare 360° in the UK and Ireland Heliocare® is a registered trademark of Cantabria Labs, Spain Fernblock® is a registered trademark of Cantabria Labs, Spain 0800 019 5322

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