Ixekizumab (Taltz)

Treatment for management of plaque psoriasis: Ixekizumab (Taltz)

Presented by,Goh Mei Ying Lim Tze Shien

Tan Pei Ni

IntroductionIxekizumab (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).

Figure 1: Taltz (Ixekizumab) (Haymarket Media 2016)

Figure 2: Taltz autoinjector

Figure 3: Taltz prefilled syringe(Drugs.com 2016) (Drugs.com 2016)

Figure 4: Injection site for Taltz (Drugs.com 2016)

Figure 5: Thigh injection using autoinjector (Drugs.com 2016) Figure 6: Thigh injection using

prefilled syringe

(Drugs.com 2016)

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)

Figure 7: Signs & symptoms of psoriasis (Dr. Makkar 2014)

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)

Properties of protein target

(Genecards.org n.d.)

Protein target: Interleukin-17AGene: IL17A geneCytogenetic 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)

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). 

Development of related analogsBesides 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)

BrodalumabInhibitors 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)

SecukinumabInhibitors 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)

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)

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-17ESecukinumab 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.

ReferencesBrodalumab 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, Cosmetic and Investigational Dermatology, 7, 251–259, viewed 9 November 2016, <http://doi.org/10.2147/CCID.S67534>. 

ReferencesMcKee, 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. 

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