This document provides information on the treatment of plaque psoriasis with the drug Ixekizumab (Taltz). It discusses that Ixekizumab is an injectable monoclonal antibody that binds to and inhibits the pro-inflammatory cytokine interleukin-17A (IL-17A). IL-17A plays a key role in the pathogenesis of psoriasis by stimulating keratinocyte proliferation and inflammatory responses. The document reviews clinical trial results demonstrating the safety and efficacy of Ixekizumab for plaque psoriasis. It also discusses two other drugs, Brodalumab and Secukinumab, that target the IL-17 pathway as treatment options for psoriasis.
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Treatment for plaque psoriasis: Ixekizumab (Taltz
1. Treatment for
management of plaque
psoriasis: Ixekizumab
(Taltz)
Presented by,
Goh Mei Ying
Lim Tze Shien
Tan Pei Ni
2. Introduction
Ixekizumab (Taltz)
Injectable drug for the treatment of adult patients with moderate-to-severe plaque
psoriasis.
A type of monoclonal antibody acts against the pro-inflammatory cytokine
interleukin-17A (IL-17A).
IL-17A is secreted by Th17 cells which are differentiated from CD4+ cells.
Th17 cells are situated at mucosal barriers.
Function: Trigger pro-inflammatory signals => neutrophil mobilisation to site
of infection
Keratinocytes and psoriatic plaques respond strongly to IL-17A.
Contain high concentrations of Th17 cells => excessive production of IL-17A
=> excessive production of several inflammatory cytokines.
(Committee for Medicinal Products for Human Use (CHMP) 2016)
(Committee for Medicinal Products for Human Use (CHMP) 2016).
6. Figure 5: Thigh injection using autoinjector
(Drugs.com 2016)
Figure 6: Thigh injection using prefilled syringe
(Drugs.com 2016)
7. What is Psoriasis ?
An autoimmune disorder.
Characterized by:
redness, scaly patches, papules and plaques that usually itch
Discolouration or pitting of the nails
Often affects people between the ages of 15 and 35.
family history of the disease
Most common form : plaque psoriasis
affects up to 90% of people with psoriasis
Diagnosis:
physical examination of the skin, scalp and nails
skin biopsy => excessive growth and thickening of the epidermal layer
of the skin
(Committee for Medicinal Products for Human Use
(CHMP) 2016)
(Committee for Medicinal Products for Human Use (CHMP) 2016)
9. Ixekizumab (Taltz)
In three randomized, placebo-controlled clinical trials, with a total of 3,866
patients with plaque psoriasis
Taltz’s safety and efficacy were established
achieved greater clinical response than placebo => skin that was clear or
almost clear
assessed by Psoriasis Area Severity Index (PASI) score and static
Physician's Global Assessment (sPGA)
Affects the immune system => increase the risks of contracting infections
Medication Guide provided
Serious hypersensitive responses
Exacerbation of inflammatory bowel disease
Common side effects:
Upper respiratory infections
Injection site reactions
Nausea
Fungal infections
(Food and Drug Administration 2016)
(Taltz 2016)
10. Properties of protein target
(Genecards.org n.d.)
Protein target: Interleukin-17A
Gene: IL17A gene
Cytogenetic band: 6p12.2 (Genecards.org n.d.)
Pro-inflammatory cytokine
Produced by activated T-cells
Involved in inflammation and immune response
Induce stromal cells to produce pro-inflammatory and hematopoietic
cytokines
Preventing the host from infection (Drugbank.ca 2016)
High level of IL-17A chronic inflammatory disease including
rheumatoid arthritis, psoriasis and multiple sclerosis (Onishi & Gaffen
2010)
11. Mechanism of action of
Ixekizumab
Ixekizumab bind to IL-17A, inhibit the
interaction between IL-17A and its receptor
(IL-17RA)
Hyper-proliferation of keratinocytes is driven by
cytokines from T cells
Keratinocytes amplify the inflammatory response
Psoriatic plaque infiltration of activated T-cells
Activated T cells: Th1, Th17 and Th22
Activated T cells produce other cytokines
IL-17A and IL-17F act on fibroblasts, keratinocytes
etc.
High level of IL-17A and IL-17F hyper-
proliferation of keratinocytes (Lønnberg, Zachariae
& Skov 2014).
Figure 8: Interleuking-17 in the pathogenesis of psoriasis
and targets of Brodalumab, Secukinumab and Ixekizumab
(Lønnberg, Zachariae & Skov 2014).
12. Development of related
analogs
Besides from Ixekizumab, two other drugs that targets IL-17A signalling pathway are
Brodalumab and Secukinumab (Leavitt 1996).
Adverse events include:
Nasopharyngitis
Upper respiratory tract
infection
Nausea
Headache
Pain in the extremities
(Lønnberg, Zachariae & Skov
2014)
(Tse 2013)
13. Brodalumab
Inhibitors of IL-17RA
Humanized chinese hamster ovary cell-
derived immunoglobulin G2(IgG2) anti-
IL-17RA (subunit of IL-17 receptor)
monoclonal antibody.
Inhibit activities of IL-17A, IL-17F, IL-
17E/IL-25.
Target a broader spectrum of IL-17
compare to Secukinumab and
Ixekizumab.
Better efficiency
Increased risk of adverse effects (less
specific) (Mease et al. 2014)
(Brodalumab 2016)
14. Secukinumab
Inhibitors of IL-17A
A human anti-interleukin-17A
monoclonal antibody.
Selectively binds and neutralizes IL-
17A, does not neutralize IL-17F.
This specificity offers the potential of
fewer off target effects.
Achievement of almost clear to clear
skin for the majority of patients (Mease
et al. 2015). (pharmacodia.com 2016)
15. Other related drugs under
development
Interleukin-23 (IL-23) also a causative factor of psoriasis disease
(stimulates survival and proliferation of T-helper 17 cells).
Overproduction of IL-23 by dendritic cells and keratinocytes stimulates
Th17 cells within the dermis to produce IL-17A and IL-22 (Fitch et al. 2007).
Guselkumab
Injectable drug
Monoclonal antibody
Currently in clinical trials III
Estimated to be in the market in year 2018
Targets IL-23 specific intracellular and downstream signalling
90% improvement in the Psoriasis Area Severity Index (McKee 2016)
16. Conclusion
Ixekizumab
A type of monoclonal antibody
Injectable drug
Used for the treatment of moderate-to-severe plaque psoriasis
Acts against pro-inflammatory cytokine IL-17A by binding to it, where it inhibits the interaction
between IL-17A & IL-17RA
Brodalumab
Anti-IL-17RA monoclonal antibody
Targets IL-17RA
Inhibits activities of interleukin-17A, interleukin-17F, interleukin-17A/F, and interleukin-17E
Secukinumab
Anti-IL-17A monoclonal antibody
Selectively binds and neutralizes only IL-17A
Specificity fewer off target effects as compared to Brodalumab
Guselkumab
Besides IL-17A, IL-23 also contributes to psoriasis by stimulating the production of IL-17.
Hence, Guselkumab, which targets IL-23, would be a potential drug for the treatment of psoriasis.
17. References
Brodalumab 2016, viewed 23 November 2016,
<http://www.pharmacodia.com/yaodu/html/v1/biologics/68dad4509908e9a208274a1ca8135221.html>.
Committee for Medicinal Products for Human Use (CHMP) 2016, Assessment report – Taltz, European Medicines
Agency, London, United Kingdom, viewed 4 November 2016,
<http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Public_assessment_report/human/003943/WC500205806.pdf>.
Dr. Makkar 2014, Psoriasis Homeopathic treatment, Dr. Makkar Family Clinic, viewed 18 November 2016,
<http://www.askdrmakkar.com/psoriasis_homeopathic_treatment.aspx>.
Drugbank.ca. 2016, DrugBank: Ixekizumab, viewed 7 November 2016,
<http://www.drugbank.ca/drugs/DB11569#targets>.
Drugs.com 2016, Taltz, viewed 18 November 2016, <https://www.drugs.com/pro/taltz.html>.
Fitch, E., Harper, E., Skorcheva, I., Kurtz, S. E., & Blauvelt, A. 2007, ‘Pathophysiology of Psoriasis: Recent
Advances on IL-23 and Th17 Cytokines’, Current Rheumatology Reports, 9(6), 461–467.
Food and Drug Administration 2016, FDA approves new psoriasis drug Taltz, Food and Drug Administration, United
States, viewed 4 November 2016,
<http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491872.htm>.
Genecards.org. n.d., Genomic Location for IL17A Gene, viewed 7 November 2016, <http://www.genecards.org/cgi-
bin/carddisp.pl?gene=IL17A>.
Haymarket Media 2016, New Drug Product: Taltz, viewed 20 November 2016, <http://www.empr.com/new-drug-
product-taltz/slideshow/3126/>.
Leavitt, M. 1996, Popular advance online, viewed 9 November 2016, <https://www.psoriasis.org/advance/new-
psoriasis-drug-clears-skin-in-one-third-of-patients>.
Lønnberg, A. S., Zachariae, C., & Skov, L. 2014, ‘Targeting of interleukin-17 in the treatment of psoriasis’, Clinical,
18. References
McKee, S. 2016, Janssen’s guselkumab beats Humira in plaque psoriasis trial, viewed 9 November 2016,
<http://www.pharmatimes.com/news/janssens_guselkumab_beats_humira_in_plaque_psoriasis_trial_1151327>.
Mease, P.J., Genovese, M.C., Greenwald, M.W., Ritchlin, C.T., Beaulieu, A.D., Deodhar, A., Newmark, R., Feng, J.,
Erondu, N. & Nirula, A. 2014, ‘Brodalumab, an Anti-IL17RA monoclonal antibody, in Psoriatic arthritis’, New England
Journal of Medicine, 370(24), pp. 2295–2306. doi: 10.1056/nejmoa1315231.
Mease, P.J., McInnes, I.B., Kirkham, B., Kavanaugh, A., Rahman, P., van der Heijde, D., Landewé, R., Nash, P.,
Pricop, L., Yuan, J., Richards, H.B. & Mpofu, S. 2015, ‘Secukinumab inhibition of Interleukin-17A in patients with
Psoriatic arthritis’, New England Journal of Medicine, 373(14), pp. 1329–1339. doi: 10.1056/nejmoa1412679.
Onishi, R & Gaffen, S 2010, ‘Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease’,
IL-17-MEDIATED PATHOGENESIS I AUTOIMMUNE DISEASE, vol. 129, no. 3, pp. 331-321, viewed 13 November
2016, <https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826676/>.
pharmacodia.com 2016, Secukinumab, Pharmacodia Holding Ltd., viewed 23 November 2016,
<http://en.pharmacodia.com/web/drug/1_719.html>.
Taltz 2016, Important Safety Information, Eli Lilly and Company, USA, viewed 4 November 2016,
<https://www.taltz.com/>.
Tse, M.T. 2013, ‘IL-17 antibodies gain momentum’, Nature Reviews Drug Discovery, 12(11), pp. 815–816. doi:
10.1038/nrd4152.
Th17 cells are situated at the mucosal barriers and functions to trigger pro-inflammatory signals which lead to neutrophil mobilisation and responses that constitute to an antimicrobial response
Keratinocytes and psoriatic plaques respond strongly to IL-17A, where these cells contain high concentrations of Th17 cells and this would lead to the excessive production of IL-17A (Committee for Medicinal Products for Human Use (CHMP) 2016). Over 40 genes in keratinocytes can be activated by IL-17A, leading to excessive production of several inflammatory cytokines.
Single-use prefilled autoinjector—1, 2, 3; Single-use prefilled syringe—1, 2, 3
TALTZ
1 autoinjector of 80mg/ml cartons (Qty:3)
appx. Price $13, 422.00
http://www.empr.com/taltz/drug/34558/
Taltz comes in an autoinjector and a prefilled syringe that you or your caregiver may use at home to give injections. Your healthcare provider will decide which type of Taltz is best for you to use at home.
Taltz is given as an injection under your skin (subcutaneous injection), in your thighs or stomach area (abdomen) by you or a caregiver. A caregiver may also give you an injection of Taltz in the back of your arm.
https://www.drugs.com/pro/taltz.html
https://www.drugs.com/pro/taltz.html
For Subcutaneous Use Only
The most common form where it affects up to 90% of people with psoriasis is plaque psoriasis which appears on elbows, knees, scalp and back (Committee for Medicinal Products for Human Use (CHMP) 2016).
Occasionally skin biopsy is obtained where it typically shows excessive growth and thickening of the epidermal layer of the skin due to keratinocyte hyper-proliferation with an inflammatory infiltrate of T-cells (Committee for Medicinal Products for Human Use (CHMP) 2016).
In these studies, the co-primary efficacy endpoints at 12 weeks were a 75 percent improvement in the composite Psoriasis Area Severity Index (PASI) score and static Physician's Global Assessment (sPGA) 0 or 1 and at least a 2-point improvement from baseline. PASI measures the extent and severity of psoriasis by assessing average redness, thickness and scaliness of skin lesions (each graded on a zero to four scale), weighted by the body surface area of involved skin, while the sPGA is the physician's assessment of severity of a patient's psoriasis lesions overall at a specific point in time and is a required measure the FDA uses to evaluate effectiveness.
In all three studies, at 12 weeks, 87 to 90 percent of patients treated with Taltz saw a significant improvement of their psoriasis plaques (PASI 75). In addition, 81 to 83 percent of patients treated with Taltz achieved sPGA 0 or 1. The majority of patients treated with Taltz, 68 to 71 percent, achieved virtually clear skin (PASI 90) and 35 to 42 percent of patients saw complete resolution of their psoriasis plaques (PASI 100, sPGA 0). Among those patients treated with placebo, 7 percent or fewer achieved PASI 75, 7 percent or fewer achieved sPGA 0 or 1, 3 percent or fewer achieved PASI 90 and 1 percent or fewer achieved PASI 100 and sPGA 0.
Figure above: Location of IL17A gene on human chromosome 6 (Genecards.org n.d.)