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Ameluz: drug evaluation

DRUG EVALUATION
Ameluz® is a new gel formulation containing 10% 5-aminolevulinic acid (ALA) in a nanoscale lipid vesicle formulation that was developed for topical use in photodynamic therapy (PDT) by Biofrontera AG, Leverkusen, Germany, and most recently reached EU-wide market approval by the European Medicines Agency for the treatment of mild and moderate actinic keratosis (AK) of the face and scalp. The active component of Ameluz®, ALA, acts as a prodrug for the formation of protoporphyrin IX, a potent photosensitiser, widely known for its anti-tumour efficacy in photodynamic treatment approaches. Photodynamic therapy using Ameluz® as the photosensitising agent represents a significant new option for the clinical management of AK.
Rolf-Markus Szeimies MD PhD
Department of Dermatology and Allergology
Klinikum Vest Academic Teaching Hospital
Germany
Key words: alitretinoin; dermatology; 
chronic eczema of the hand; unresponsive
Declaration of interest
The author has participated as investigator in a variety of studies with different compounds in the field of epithelial cancers with sponsors including Almirall, Biofrontera, Galderma, Intendis, Photocure and Spirig. He is a member of advisory boards in those companies and has received speakers honoraria and travel grants. 
Actinic keratosis (AK) is a premalignant lesion of the skin that occurs in response to ultraviolet light exposure, mainly from sunlight. Epidemiological studies show that in a Caucasian population the prevalence for developing AK is 15% in men and 6% in women. This disease strongly affects the elderly, with a prevalence of 34% in men and 18% in women suffering from AK.(1)
A considerable risk of a lack of treatment for actinic keratosis is its possible progression to invasive cancerous conditions, namely squamous cell carcinoma (SCC). Estimates for the progression rate of AK to SCC range from 5% to 20% within 10–25 years.(2) 
Photodynamic therapy (PDT) is an efficient treatment option for the clinical management of AK.(3) This treatment combines the topical use of a photosensitiser selectively enriched in neoplastic cells with the illumination of the treated area using an appropriate light source and wavelength, capable of exciting the photosensitiser and consequently generating cytotoxic reactive oxygen species. This reaction results in cell death in the neoplastic cells.(4) 
With Ameluz®, the actual photosensitiser responsible for the photodynamic action is protoporphyrin IX (PpIX), an intermediate of heme biosynthesis. ALA is a naturally occurring precursor of PpIX and increased ALA incorporation into cells may lead to an enhanced PpIX formation, as the physiological control of the amount of heme formation through cellular feedback mechanisms is circumvented in this process. The selectivity of protoporphyrin IX-associated photodynamic agents towards neoplastic lesions is caused by an increased uptake of the prodrug into pathologically altered cells and metabolic and enzymatic alterations in these cells, acting in favour of PpIX production rather than breakdown or conversion to heme.(5,6)
 
Low levels of the photosensitising molecule PpIX are present in every cell, such that reactive oxygen species (ROS) are constantly formed upon light exposure of healthy skin cells. These 'normal' ROS levels are detoxified by the cellular antioxidant capacity. Exposing neoplastic cells to ALA leads to PpIX levels that generate ROS at cytotoxic levels during PDT.(5,6)
Whereas PpIX can be activated at several wavelengths, red light at approximately 630nm is preferentially used in Europe due to its deeper penetration into the tissue compared with shorter wavelengths. Upon excitation, the PpIX molecules will either emit fluorescence or, through a process of intersystem crossing, reach a triplet state at which energy can be transferred to molecular oxygen (O2). This converts oxygen to the highly reactive and cytotoxic singlet oxygen (1O2).
Singlet oxygen has a very short half-life and diffusion range. It therefore elicits cellular damage solely in its immediate surroundings. The selective accumulation of the photosensitiser in neoplastic tissue conveys cytotoxicity preferentially in neoplastic cells. Mitochondria are the major targets since the final steps in PpIX synthesis occur inside these organelles, such that oxidative damage of mitochondria is responsible for the ablation of neoplastic cells.(4,6) 
An important factor for the efficacy of PDT is also the delivery of the prodrug over the stratum corneum, the cornified uppermost layer of the skin. The two mainly used prodrugs of PpIX, ALA and methyl-aminolevulinic acid (MAL) show rather hydrophilic characteristics and are therefore not prone to overcome the epidermal barrier unassisted.(7)
 
Therefore, Ameluz® was developed as a 10% ALA-containing nanoemulsion gel formulation. The emulsion, formed with nanoscale vesicles, not only stabilises ALA in the gel, it also fundamentally increases stratum corneum penetration of the otherwise hydrophilic ALA molecule. The combination of ALA as an efficient and naturally occurring prodrug for the photosensitising of neoplastic lesions with the penetration-enhancing nanoemulsion is now marketed as Ameluz®.
Efficacy and clinical activity
A preclinical study using pig skin explants investigated the skin penetration of Ameluz® compared with Metvix® cream (containing 21% methyl-ALA hydrochloride). Microscopic evaluation of PpIX fluorescence revealed a more rapid and deeper action of Ameluz® at every time point tested.(8) The PpIX fluorescence induced by Ameluz® was more pronounced than with Metvix, particularly in the deeper epidermal layers, but no PpIX formation was visible below the basal membrane. This result indicates that Ameluz® is useful for the treatment even of deep epidermal layers, but completely spares dermal regions. The better penetration of Ameluz versus Metvix may cause an improved clinical efficacy.
Clinical efficacy and safety of Ameluz® were analysed in two phase III trials with patients suffering from four-to-eight mild-to-moderate AK lesions on the face or scalp. In these studies, treatment was performed as described below (see Treatment guidelines and recommendations). Lesions were assessed 12 weeks after the first PDT and remaining lesions were retreated. The number of patients with all lesions cleared and the total number of cleared lesions were determined 12 weeks after the final PDT.
A randomised, double-blind, prospective, placebo-controlled phase III trial with 122 patients compared Ameluz® with placebo.(9) The light sources used were either narrow-spectrum or broad-spectrum lamps. The patient complete clearance rates were significantly higher for Ameluz® than for placebo (66.3% versus 12.5%, respectively). The lesion complete clearance rates were 81.1% versus 20.9%, respectively. The use of narrow-spectrum lamps emitting light at 630±9nm resulted in higher efficacy than that of broad-spectrum lamps (96% versus 53%, respectively, for total patient clearance, and 99% versus 70%, respectively, for total lesion clearance). Thus, almost complete clearance could be achieved with the combination of Ameluz and narrow-band PDT lamps. However, the use of narrow-band lamps also resulted in stronger side effects.
In a second pivotal phase III trial10 Ameluz was compared with Metvix and placebo in an investigator-blind setting. A total of 572 patients were treated with PDT using Ameluz®, comparator Metvix®, or placebo at a ratio of 3:3:1. Again, narrow-band and broad-band light sources were used. The primary medical endpoint was the complete recovery of all of a patient's lesions 12 weeks after the last PDT. On average with all lamps, Ameluz® (78.2%) was significantly more efficient than MAL (64.2%) and placebo (17.1%) and the total lesion clearance rates were higher for Ameluz® (90.4%) than for Metvix® (83.2%) and placebo (37.1%). This second study confirmed that the use of narrow-spectrum lamps resulted in greater efficacy, accompanied by stronger side effects. Using this type of lamp, the total patient clearance with Ameluz was 84.8%, with Metvix, 67.5%, and with placebo, 12.8%. The total lesion clearance rates were 93.6% and 89.3% for Ameluz and Metvix, respectively.
Safety
The drug's active component, 5-aminolevulinic acid, is an endogenous molecule occurring in every cell of the body. Ameluz does not lead to an increase in blood or urine ALA concentrations. Thus, it is not surprising that the side effects that occurred in the clinical trials are mostly treatment-related, short-term effects at the application site. Most frequent were erythema, oedema and exfoliation, in most cases disappearing within few days after treatment. In some cases, side effects could persist one-to-two weeks or longer. The most frequent systemic side effect was headache. There was no indication for an allergic potential of Ameluz. Many patients experienced pain at varying intensities during the illumination. 
Despite the significantly increased efficacy of Ameluz, the frequency of pain was not different between Ameluz® (69.4%) and Metvix® (72.8%). 
Application site pain is a well-known adverse effect occurring during PDT with ALA or methyl-ALA. Contradictory reports in the literature attribute stronger pain to either of the two different compounds.(11–14) Authors reporting lower pain intensity for methyl-ALA (as in Metvix) have often hypothesised that ALA, but not methyl-ALA, may enter free sensory nerve endings in the epidermis through GABA transporters(12,14); however, a preclinical study demonstrated that both compounds induced PpIX fluorescence in sensory neurons. Also, both ALA and methyl-ALA are capable of entering nerve endings via the GABA transporter 3.(15) This study rules out the assumption that methyl-ALA might selectively spare nerve terminals, and is in agreement with the data from the direct comparison of Ameluz and Metvix, where no drug-related difference in pain during PDT was observed. 
All side effects of PDT with Ameluz were stronger with narrow-band lamps than with broad-band lamps, and seem to reflect the higher efficacy obtained with narrow-band lamps.
No experience exists for the use of Ameluz in pregnancy, immunosuppressed patients or porphyria. Ameluz should not be used together with UV-sensitising drugs such as St John's wort (hypericine), griseofulvin, thiazide diuretics, sulphonylurea, phenothiazines, sulphonamides, quinolones and tetracyclines, which can increase the phototoxic reaction to PDT. Additionally, the simultaneous application of other topical drugs should be avoided.
Guidelines and recommendations
PDT is recommended as a first-line treatment in a variety of dermatological guidelines on epithelial skin cancers. Ameluz is the first PDT-medicine to be approved for the first-line treatment of mild and moderate AK. 
The treatment involves the prior removal of crusts and scales by slight curettage. Subsequently, lesions should be wiped with ethanol using a gauze wipe. The gel is then spread on the lesioned areas and surrounding healthy skin parts, carefully sparing the eye region and mucosal parts by at least 1cm. The gel is left to dry before an occlusive covering of the areas is applied for three hours. The red light illumination is performed at 75–200 J/cm² with broad-spectrum lamps or at 37 J/cm² with narrow-spectrum devices. Eye protection must be worn by the patient and health personnel throughout the illumination.
Treatment should include the AK lesions and the surrounding areas. Three months after PDT, the whole procedure should be repeated for lesions that are not entirely cleared. The clinical study showed that >50% of the patients are cleared from all lesions after one PDT with Ameluz and a narrow-spectrum lamp, whereas the combination of Metvix and narrow-band lamps reached the same result in <40% of the patients only.
Cost effectiveness
AK mainly affects the elderly. Approximately 10% of the Caucasian population is affected by AK. Its incidence has been doubling every ten years during the last decades. Given the 10–15% risk of transformation into SCC, AK should always be treated. Several authors compared the economic impact of AK treatment by PDT with those of other treatment options and concluded that PDT is the most cost-effective treatment option. Ameluz is the PDT drug approved for AK with the highest efficacy and the broadest label. Thus, it should be considered as first-line treatment for AK.
Conclusions
Ameluz® offers an effective treatment opportunity for actinic keratosis. It provides a safe, highly efficacious and economically reasonable treatment option. No phase III trials with any other treatment option for AK resulted in similarly high clearance rates as those obtained with Ameluz. PDT with Ameluz is safe, and pain during the illumination is not increased compared to other PDT drugs. The cosmetic outcome was shown to be excellent. 
Key points
  • Ameluz® is a new drug for the photodynamic therapy of mild and moderate actinic keratosis.
  • Ameluz® contains 5-aminolevulinic acid in a nanoscale lipid vesicle formulation that greatly improves tissue penetration.
  • Efficacy of PDT with Ameluz® was significantly higher than with Metvix.
  • Application site adverse effects and pain are not different between Ameluz® and Metvix.
References
  1. Memon AA et al. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol 2000;142:1154–9.
  2. Braathen LR et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology, 2005. J Am Acad Dermatol 2007;56:125–43.
  3. Babilas P et al. Photodynamic therapy in dermatology: state-of-the-art. Photodermatol Photoimmunol Photomed 2010;26:118–32.
  4. Agostinis P et al (2011) Photodynamic therapy of cancer: an update. CA Cancer J Clin 2011;61:250–81.
  5. Peng Q et al. 5-aminolevulinic acid-based photodynamic therapy – Clinical research and future challenges. Cancer 1997;79:2282–308.
  6. Calzavara-Pinton PG, Venturini M, Sala R. Photodynamic therapy: update 2006. Part 1: Photochemistry and photobiology. J Eur Acad Dermatol Venereol 2007;21:293–302.
  7. Uehlinger P et al. 5-Aminolevulinic acid and its derivatives: physical chemical properties and protoporphyrin IX formation in cultured cells. J Photochem Photobiol B 2000;54:72–80.
  8. Maisch T et al. Fluorescence induction of protoporphyrin IX by a new 5-aminolevulinic acid nanoemulsion used for photodynamic therapy in a full-thickness ex vivo skin model. Exp Dermatol 2010;19:e302–e305.
  9. Szeimies RM et al. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a prospective, randomized, double-blind, placebo-controlled phase III study. Br J Dermatol 2010;163:386–94.
  10. Dirschka T et al. Photodynamic therapy with BF-200 ALA for the treatment of actinic keratosis: results of a multicentre, randomized, observer-blind phase III study in comparison with a registered methyl-5-aminolaevulinate cream and placebo. Br J Dermatol 2012;166:137–46.
  11. Wiegell SR et al. Pain associated with photodynamic therapy using 5-aminolevulinic acid or 5-aminolevulinic acid methylester on tape-stripped normal skin. Arch Dermatol 2003;139:1173–7.
  12. Kasche A et al. Photodynamic therapy induces less pain in patients treated with methyl aminolevulinate compared to aminolevulinic acid. J Drugs Dermatol 2006;5:353–6.
  13. Moloney FJ, Collins P. Randomized, double-blind, prospective study to compare topical 5-aminolaevulinic acid methylester with topical 5-aminolaevulinic acid photodynamic therapy for extensive scalp actinic keratosis. Br J Dermatol 2007;157:87–91.
  14. Gholam P et al. Treatment with 5-aminolaevulinic acid methylester is less painful than treatment with 5-aminolaevulinic acid nanoemulsion in topical photodynamic therapy for actinic keratosis. Dermatology 2011;222:358–62.
  15. Novak B, Schulten R, Lubbert H. delta-Aminolevulinic acid and its methyl ester induce the formation of Protoporphyrin IX in cultured sensory neurones. Naunyn Schmiedebergs Arch Pharmacol 2011;384:583–602.

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