2. Psoriasis
• Psoriasis is an autoimmune disease that leads to chronic
inflammation of the skin.
• This inflammation causes increased proliferation of the
epidermal cells at a rate that is faster than that of natural skin
shedding
• Chronic plaque psoriasis, also known as psoriasis vulgaris is the
most common type of the disease, where the lesions appear
symmetrically on the scalp, elbows and knees.
• Leads to psychological problems such as anxiety and
depression
(Richards and Fortune 2006), (Vakirlis, kastanis and loannides 2008)
3. Treatment of Psoriasis
• Treatment of Psoriasis is based around the severity of the disease measured as psoriasis area and severity index
(PASI) (Gisondi, Del Giglio and Girolomoni 2017).
Toxicity
Effectiveness
Tropical
Systemic
Photochemotherapy
• Taclonex
• Davobet
• Enstilar
• Biologics
• Methotrexate
• Cyclosporine
• Adalimumab
• PUVA
4. Pathogenesis
• The pathogenesis of psoriasis is divided
into two phases, initiation phase and
maintenance phase .
• In the initiation phase, certain triggers
cause keratinocytes to release DNA in
addition to cathelicidin forming a
complex with pathogen derived DNA, the
complex would then bind to TLR-9 on
dendritic cells.
• This would start a signalling cascade that
leads to the release of cytokines from T-
cells that would stimulate increase
keratinocyte proliferation and altered
differentiation.
• Maintenance phase involves a loop of
chronic inflammation in effected areas.
(Rønholt and Iversen 2017).
Figure 1: Targets for biologics within psoriasis immunological
process (Rønholt and Iversen 2017).
5. Enstilar
• Enstilar is the brand name of a topical treatment for
psoriasis.
• The active ingredients of Enstilar are betamethasone
dipropionate, a potent corticosteroid and
calcipotriene, a synthetic analogue of vitamin D3
• Enstilar is a topical treatment for psoriasis that is
applied directly to the lesions, thus avoiding the side
effects of systemic treatments.
(Simonsen et al. 2004).
6. Discovery Pathway - Betamethasone
• Betamethasone dipropionate (Corticosteriods) is a C-16 steroids found by scientist at Merck & Co. and at
Schering Corp. at the year 1962.
• It have been used for decades in treatment of various disease due to their anti-inflammatory and
antiproliferative properties.
• Their anti-inflammatory properties are attributed gnomically to cortisol’s activation of the glucocorticoids
receptors, of which following it’s accumulation in the cytoplasm would eventually migrate into the nucleus,
dimerizing and binding to the promoter sequence transcribing genes with anti inflammatory functions such as
TAT and IL-7.
Figure 2: Structures of Betamethasone
Dipropionate (Simonsen et al. 2004).
(Uva et al. 2012)
7. Discovery Pathway - Calcipotriene
Figure 3: 1,25-
Dihydroxyvitamin D3
(Kragballe 1992).
Figure 4: Chemical
structures of Calcipotriene
(Kragballe 1992).
• Calcipotirene usage in the treatment of psoriasis is attributed to vitamin D3 immunomodulating
properties.
• Calcipotriene has an analogue of 1,24-dihydroxyvitamin D containing a double bond and a
cyclopropane ring in a side chain, it would preserve the cell regulating function while being 200 times
less likely to produce hypercalcemia than oral vitamin 1,25(OH)2D3 .
• Vitamin 1,25(OH)2D3 causes decreased proliferation and increased differentiation of keratinocytes by
increasing intracellular calcium rapidly.
• Reducing the cell sensitivity to growth factors in addition to enhancing the transcription of the
transforming factor TGF β1 which in turn reduces the cell growth rate.
(Kragballe 1992).
9. Clinical Development
- Success rate of clinical phase 2 for LEO 90100-35 is 51.4% which is
higher than Taclonex oilment, foam vehicle and ointment vehicle.
- Success rate of clinical phase 2 for LEO 90100-7 is 45% which is higher
than Betamethasone and Calcipotriol
- Success rate of clinical phase 3 for LP0053-1001 is 53.3% which
higher than foam vehicle.
- Clinical phase 4 is still undergoing as they going to test on skin colour
(and its change with Enstilar treatment) as well as the effect of
Enstilar on post-inflammatory hyperpigmentation.
(Kim & Frampton 2016).
10. Conclusion
• While Enstilar is an effective treatment for Psoriasis that combine two potent
ingredients, the adherence to topical therapy in patients is generally low,
particularly in the long term, and this could impair its effectiveness in real life.
• Further advancement such as Nano structure lipid carries for betamethasone
dipropionate and calcipotriene can enhance skin retention, reduce systemic
absorption and skin irritation of the active ingredients (Kong et al. 2016)
• This advancement should be adopted in order to reduce the irritation by
reducing the number of daily application required, increasing patient adherence
to the topical medicine Enstilar.
11. References
• Gisondi, P, Del Giglio, M & Girolomoni, G 2017, ‘Treatment approaches tomoderate to severe psoriasis’, International Journal of Molecular Sciences,
vol. 18, no. 11.
• Jullien, D & Lyon-, UCB 2015, ‘Psoriasis physiopathology’, BIOalternatives, vol. 20, pp. 5–6.
• Kim, ES & Frampton, JE 2016, ‘Calcipotriol/Betamethasone Dipropionate Foam: A Review in Plaque Psoriasis’, Drugs, vol. 76, no. 15, pp. 1485–1492.
• Kong, X, Zhao, Y, Quan, P & Fang, L 2016, ‘Development of a topical ointment of betamethasone dipropionate loaded nanostructured lipid carrier’,
Asian Journal of Pharmaceutical Sciences, vol. 11, no. 2, pp. 248–254.
• Kragballe, K 1992, ‘Treatment of psoriasis with calcipotriol and other vitamin D analogues’, Journal of the American Academy of Dermatology, vol. 27,
no. 6, pp. 1001–1008.
• Monograph, ND & Panel, MA 2016, ‘Calcipotriene and Betamethasone Dipropionate’, no. July.
• Richards, HL & Fortune, DG 2006, ‘Psychological distress and adherence in patients with psoriasis’, Journal of the European Academy of Dermatology
and Venereology, vol. 20, no. SUPPL. 2, pp. 33–41.
• Rønholt, K & Iversen, L 2017, ‘Old and new biological therapies for psoriasis’, International Journal of Molecular Sciences, vol. 18, no. 11.
• Simonsen, L, Høy, G, Didriksen, E, Persson, J, Melchior, N & Hansen, J 2004, ‘Development of a new formulation combining calcipotriol and
betamethasone dipropionate in an ointment vehicle’, Drug Development and Industrial Pharmacy, vol. 30, no. 10, pp. 1095–1102.
• Uva, L, Miguel, D, Pinheiro, C, Antunes, J, Cruz, D, Ferreira, J & Filipe, P 2012, ‘Mechanisms of action of topical corticosteroids in psoriasis’,
International Journal of Endocrinology, vol. 2012, no. iv.
• Vakirlis, E, Kastanis, A & Ioannides, D 2008, ‘Calcipotriol/betamethasone dipropionate in the treatment of psoriasis vulgaris’, Therapeutics and Clinical
Risk Management, vol. 4, no. 1, pp. 141–148.
• Valley, N 1984, ‘Editorials PUVA therapy for psoria’, vol. 77, pp. 70537–70539.
