Ixekizumab


Article Author:
Charles Preuss


Article Editor:
Judy Quick


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


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Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Radia Jamil
Patrick Le
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Heba Mahdy
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James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/11/2019 12:27:21 AM

Indications

Ixekizumab is FDA-indicated for the adult treatment of moderate to severe plaque psoriasis.[1] These adult patients are also candidates for systemic therapy or phototherapy. Safety and effectiveness have not been determined in pediatric patients. Next, psoriasis will be briefly discussed to better understand ixekizumab's mechanism of action and its therapeutic use. 

Psoriasis is a common skin disease which affects about 2% of US population. The most common form is the plaque-type. Examples of forms of psoriasis are inverse, guttate, and pustular. Plaque-type psoriasis is a chronic inflammatory skin disease with the following clinical characteristics: erythematous plaques with mica-like scales, sharply demarcated, that predominately affect the elbows, knees, gluteal cleft, and scalp. The skin plaques can be pruritic and slowly enlarge which last for long periods of time. Approximately 30% of patients with psoriasis have psoriatic arthritis in which there are five subtypes: arthritis mutilans, asymmetric, distal interphalangeal predominant, spondylitis, and symmetric. Arthritis mutilans which account for less than 5% of psoriatic arthritis cases is severe and can deform the small joints of the hands and feet. Asymmetric arthritis can affect any joint and may appear as sausage digits or dactylitis. Distal interphalangeal predominant can involve the fingers and toes, and it occurs in about 5% of psoriatic arthritis cases. Spondylitis or spondyloarthritis can affect the spine or pelvis, and it accounts for about 5% of psoriatic arthritis cases. Symmetric arthritis can present as a milder form of rheumatoid arthritis. The pathophysiology of psoriasis is not well understood. There is a genetic aspect to the disease with about 50% of the patients having a family history. Activated T cells are thought to produce cytokines which lead to hyperproliferation of keratinocytes and endothelial cells. Interleukin 17A (IL-17A) is an example of a cytokine which ixekizumab selectively inhibits. This hyperproliferation of keratinocytes and endothelial cells causes the erythematous plaques with mica-like scales to form on the elbows, knees or scalp. Interleukin 17 is a key mediator in the mammalian immune system. It has six subtypes: IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F. Drugs which inhibit T cell activation, clonal expansion, or release (or activity) of proinflammatory cytokines can be effective in treating psoriasis.

Mechanism of Action

Ixekizumab is a humanized monoclonal antibody (IgG) that selectively binds to interleukin 17A (IL-17A). This prevents interleukin 17A from binding to its receptor, the IL-17 receptor. Thus, this attenuates an inflammatory response mediated by interleukin 17A.[2]  Psoriasis is caused by upregulated immune-related mechanisms that result in the activation of myeloid dendritic cells, which release interleukin 17A and other cytokines to activate T cells, including helper T cell T17. Along with other immune cells, T17 produces interleukin 17A. This proinflammatory cascade causes proliferation of keratinocytes, angiogenesis, and movement of immune cells in psoriatic skin lesions. Thus, ixekizumab disrupts the pathogenic inflammatory cascade of psoriasis. Ixekizumab was studied in three clinical phase three trials: UNCOVER-1, UNCOVER-2, and UNCOVER-3.[3] UNCOVER-1 compared ixekizumab treatment in 1296 patients with psoriasis. Patients were randomly assigned to one of three groups. The two-week group received 160 mg starting dose at week zero, 80 mg every two weeks for a duration of 12 weeks. The four-week group received 160 mg starting dose at week zero, 80 mg every four weeks for a duration of 12 weeks. The placebo group received placebo for a duration of 12 weeks. Therapeutic efficacy was measured via the psoriasis area and severity index (PASI) score. A psoriasis area and severity index (PASI) score of 90 means that there was a 90% reduction in the psoriasis skin lesion area. At the end of 12 weeks, the two-week, four-week, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 70.9%, 64.6%, and 0.5%, respectively which were statistically significant when the two treatment groups were compared to placebo. UNCOVER-2 compared ixekizumab treatment in 1224 patients with psoriasis. The same UNCOVER-1 treatment regimens were used with the additional treatment group of etanercept 50 mg twice a week for the duration of 12 weeks. At the end of 12 weeks, the two-week, four-week, etanercept and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 70.7%, 59.7%, 18.7%, and 0.6%, respectively which were statistically significant when ixekizumab treatment groups were compared to etanercept and placebo. UNCOVER-3 compared ixekizumab treatment in 1346 patients with psoriasis. The same treatment regimens were used as in UNCOVER-2. At the end of 12 weeks, the two-week, four-week, etanercept, and placebo groups had the following psoriasis area and severity index (PASI) 90 scores: 68.1%, 65.3%, 25.7%, and 3.1%, respectively which were statistically significant when ixekizumab treatment groups were compared to etanercept and placebo. Etanercept (Enbrel) binds to and inhibits the inflammatory cytokine, tumor necrosis factor (TNF). It is a synthetic TNF receptor.

Administration

Ixekizumab is administered subcutaneously. It should be stored at 2 to 8 degrees Centigrade (36 to 46 degrees Fahrenheit). The ixekizumab dosage form should not be frozen, and it should be protected from light. The unused portion of the dosage from should be discarded. The patient should remove ixekizumab from the refrigerator and let it warm to room temperature which will take approximately 30 minutes. Next, the patient should visually inspect the ixekizumab liquid which should be free of particles and clear in color to a slightly yellow color. The patient should not shake the autoinjector or prefilled syringe. Lastly, the patient should inject ixekizumab subcutaneously at the directed dose. Recommended sites of injection are the thighs, upper arms, or abdomen which should be rotated to prevent damage to the skin. The patient should avoid injecting sites which are affected by psoriasis, bruised or damaged.

The recommended dosing is the following:

  • 160 mg once on week 0
  • 80 mg during weeks 2, 4, 6, 8, 10 and 12
  • 80 mg every four weeks

There are no documented maximum doses for indicated use. Dosage adjustment has not been studied in patients with renal or hepatic impairment.

Adverse Effects

Commonly observed (> 10%) adverse drug reactions in patients who were treated with ixekizumab are: neutropenia, hypersensitivity reactions, e.g., urticaria and angioedema, infections, injection site reactions, e.g., pain. Less commonly observed (< 10%) adverse drug reactions are: fungal skin infections (tinea), nausea, thrombocytopenia, and antibody development. The antibody development can decrease the concentrations of ixekizumab and decrease drug efficacy. Less than 1% observed adverse drug reactions are: Crohn disease, ulcerative colitis, oral candidiasis (Candida albicans infection), influenza, conjunctivitis, and rhinitis. The Crohn disease and ulcerative colitis include exacerbations in susceptible patients. [4][5]

Contraindications

A patient contraindication is a severe hypersensitivity reaction, for example, anaphylaxis to the ixekizumab dosage form.

Monitoring

It is recommended that patients receiving treatment with ixekizumab should be monitored for signs of infection, for example, tuberculosis, and inflammatory bowel disease including exacerbations.

Toxicity

There are no specific antidotes for an overdose of ixekizumab.

Enhancing Healthcare Team Outcomes

The healthcare team, e.g., physicians, nurses, pharmacists, etc. needs to work together to ensure the safety and efficacy of ixekizumab therapy. The patient needs to be taught on how to correctly self-administer and store ixekizumab. Importantly, the healthcare needs to monitor for signs of serious infection as well as exacerbation of inflammatory bowel disease. re team


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Ixekizumab - Questions

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A 31-year-old man is receiving treatment with ixekizumab. Which of the following is most likely being treated in this patient?



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A 35-year-old woman with severe plaque psoriasis receives treatment with ixekizumab. Ixekizumab selectively binds to and inhibits the action of which of the following?



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A 38-year-old man with moderate plaque psoriasis receives treatment with ixekizumab. Which of the following is the most clinically important side effect of ixekizumab?



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A 39-year-old woman is diagnosed with severe plaque psoriasis. Which for the following would be the most effective treatment?



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Ixekizumab - References

References

New biologics in psoriasis: an update on IL-23 and IL-17 inhibitors., Dong J,Goldenberg G,, Cutis, 2017 Feb     [PubMed]
Ixekizumab: A Review in Moderate to Severe Plaque Psoriasis., Syed YY,, American journal of clinical dermatology, 2017 Feb     [PubMed]
Blegvad C,Skov L,Zachariae C, Ixekizumab for the treatment of psoriasis: an update on new data since first approval. Expert review of clinical immunology. 2018 Dec 27;     [PubMed]
Deodhar A,Poddubnyy D,Pacheco-Tena C,Salvarani C,Lespessailles E,Rahman P,Järvinen P,Sanchez-Burson J,Gaffney K,Lee EB,Krishnan E,Santisteban S,Li X,Zhao F,Carlier H,Reveille JD, Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: 16 Week Results of a Phase 3 Randomized, Double-Blind, Placebo Controlled Trial in Patients with Prior Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis     [PubMed]
Philipose J,Ahmed M,Idiculla PS,Mulrooney SM,Gumaste VV, Severe de novo Ulcerative Colitis following Ixekizumab Therapy. Case reports in gastroenterology. 2018 Sep-Dec;     [PubMed]

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