Taltz (Ixekizumab), IL-17A Antagonist, Receives FDA Approval for Patients with Plaque Psoriasis

Online First - Drug Updates, Online First
Loretta Fala
Medical Writer

An estimated 7.5 million people in the United States have psoriasis, a chronic, inflammatory, autoimmune disease.1 Psoriasis is characterized by thick patches of inflamed, scaly skin resulting from excessive proliferation of skin cells.1 The disease typically affects the scalp, knees, elbows, hands, feet, lower back, and joints; it can also affect nails, the soft tissues of the genitals, and the inside of the mouth.1,2 In some cases, psoriasis can lead to disfigurement and disability.1

Plaque psoriasis, the most common form of psoriasis, affects 80% to 90% of patients with psoriasis.3 Patients with plaque psoriasis have raised, red patches covered with a silver or white, scaly accumulation of dead skin cells.4 The pruritus (severe itching), pain, and, in some cases, bleeding of these patches often require sophisticated medical care.1
Patients with psoriasis face an increased risk for psoriatic arthritis, heart disease, stroke, hypertension, type 2 diabetes, metabolic syndrome, eye disorders, and obesity.4 Up to 30% of patients with psoriasis will have psoriatic arthritis.1

Patients with psoriasis are also at a greater risk for other autoimmune diseases (eg, celiac disease, Crohn’s disease), Parkinson’s disease, and kidney disease.4

Psoriasis has a substantial impact on a patient’s quality of life and self-esteem and can lead to social isolation.4 The National Psoriasis Foundation survey data (2003-2011) show that psoriasis and psoriatic arthritis affect the emotional well-being of 88% of patients and interfere with the enjoyment of life of 82% of patients.5 In addition, 83% of patients report having pain regularly, and 93% have pruritus regularly.5 Furthermore, patients with psoriasis are at an increased risk for depression, anxiety, and suicidality.6

In addition to its detrimental effect on patients’ health and quality of life, psoriasis imposes a financial burden.7 According to a 2015 systematic review of the economic burden of psoriasis in the United States, the total annual cost of psoriasis was $112 billion in 2013.7 The annual direct costs attributed to psoriasis ranged from $51.7 billion to $63.2 billion, indirect costs accounted for $23.9 billion to $35.4 billion, and comorbid conditions accounted for approximately $36.4 billion.7

The goals of psoriasis treatment are to curtail the acceleration of skin growth, thereby reducing inflammation and plaque formation, and to remove scales and smooth the skin.3 The complete clearance of psoriasis plaques has become an increasing role in the treatment paradigm, based on recent studies showing that residual skin disease affects the patient’s quality of life.8-10

Psoriasis therapies, used alone or in combination with other treatments, include topical agents; phototherapy; or systemic therapies, such as cyclosporine, methotrexate, retinoids, and biologic agents.4 Biologic immunomodulator agents approved by the US Food and Drug Administration (FDA) for psoriasis include the tumor necrosis factor-
alpha inhibitors adalimumab (Humira), etanercept (Enbril), and infliximab (Remicade); the interleukin (IL)-12/IL-23 inhibitor ustekinumab (Stelara), and the first IL-17A antagonist secu­kinumab (Cosentyx), which was approved by the FDA in January 2015.4,11

Ixekizumab Approved for Plaque Psoriasis

On March 22, 2016, ixekizumab (Taltz; Eli Lilly), a humanized IL-17A antagonist, became the second IL-17A antagonist to receive approval by the FDA for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, or a combination of both.12 IL-17A antagonists target IL-17, the TH17 cell cytokine that activates inflammation in the pathogenesis of psoriasis.13

“Today’s approval provides patients suffering from plaque psoriasis with another important treatment option to help relieve the skin irritation and discomfort from the condition,” said Julie Beitz, MD, Director of the FDA’s Office of Drug Evaluation III.12

Craig Leonardi, MD, lead study investigator, Clinical Professor of Dermatology, St. Louis University School of Medicine, said, “Complete clearance of skin plaques is an important goal for psoriasis. With Taltz, physicians now have a choice that can help patients achieve virtually clear or completely clear skin; in fact, four out of 10 achieved completely clear skin. With these study results, physicians can reassure patients that consistent results can be maintained with Taltz.”14

Of note, because this drug affects the immune system, the FDA approval stipulates that prescribing ixekizumab must be accompanied by a medication guide to be provided to the patient to inform all patients of the risk for infection, and for an allergic or autoimmune condition associated with this drug.12

Mechanism of Action

Ixekizumab is a humanized immunoglobulin G subclass 4 monoclonal antibody with neutralizing activity against IL-17A, which is a naturally occurring cytokine involved in normal inflammatory and immune responses.8,15 Ixekiz­umab selectively binds to the IL-17A cytokine, thereby inhibiting its interaction with the IL-17A receptor.15

Dosing and Administration

Ixekizumab is administered via a subcutaneous injection.15 The recommended dosage of ixekizumab is 160 mg (ie, two 80-mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks thereafter. Ixekizumab is available in a single-dose prefilled autoinjector or as a single-dose prefilled syringe, both containing 80 mg/mL solution for injection.15

Specialty Pharmacy Distribution

Ixekizumab is distributed to physicians and patients through several specialty pharmacy and/or network partners, including Accredo, Amber Specialty Pharmacy and Hy-Vee Pharmacy Solutions, Avella, BioPlus, BriovaRx, Cardinal, Cigna Specialty Pharmacy, CVS/Specialty, Diplomat, EnvisionSpecialty, Humana, Prime Therapeutics Specialty Pharmacy, Senderra, TLC, US Bioservices, and Walgreens.16

The 3 Pivotal Clinical Trials

The FDA approval of ixekizumab was based on 3 pivotal phase 3 clinical trials—UNCOVER-1, UNCOVER-2, and UNCOVER-3—that included more than 3800 patients with moderate-to-severe plaque psoriasis.8,15,17 Enrolled patients had a minimum body surface area involvement of 10%, a static Physician Global Assessment (sPGA) score of ≥3 in the overall assessment of psoriasis (severity scale, 0-5), a Psoriasis Area Severity Index (PASI) score ≥12, and were candidates for phototherapy or systemic therapy.15

In all 3 studies, patients were randomized to placebo or to ixekizumab 80 mg every 2 weeks for 12 weeks, after a 160-mg starting dose.15 In the UNCOVER-2 and UNCOVER-3 studies (both active comparator clinical trials), patients were also randomized to receive etanercept 50 mg twice weekly for 12 weeks.15,17 Table 1 outlines patients’ baseline characteristics in the 3 clinical trials.15

Table 1

The co-primary end points at 12 weeks included a composite PASI score of 75 (ie, patients who achieved ≥75% reduction in the composite score) and an sPGA of 0 (clear) or 1 (ie, the proportion of patients with an sPGA of 0 or 1 and at least a 2-point improvement). The other efficacy end points were the proportion of patients with an sPGA score of 0; ≥90% reduction in PASI (ie, PASI 90); a 100% reduction in PASI (ie, PASI 100), representing a complete resolution of psoriasis plaques; and an improvement in itch severity, as measured by a reduction of at least 4 points on an 11-point itch rating scale.15

Overall, 87% to 90% of patients receiving ixekizumab achieved PASI 75 versus 2% to 7% of those receiving placebo; 81% to 83% of patients achieved an sPGA of 0 or 1 with ixekizumab versus 2% to 7% with placebo (Table 2).15

Table 1

Complete resolution of psoriatic plaques was seen in 35% to 40% of patients receiving ixekizumab who had a PASI 100 response and an sPGA of 0 compared with 0% to 1% of those receiving placebo. In addition, 68% to 71% of patients in the ixekizumab group achieved nearly complete resolution (PASI 90) versus 1% to 3% in the placebo group.15

At week 12, no differences in response to ixekizumab treatment were observed based on variables such as age, sex, race, body weight, and previous biologic treatment. An integrated analysis of the 2 studies comparing ixekizumab and etanercept demonstrated that ixekizumab 80 mg once every 2 weeks was superior to etanercept 50 mg twice weekly in sPGA and PASI scores at 12 weeks.15,17

Maintenance and Durability of Response

In the UNCOVER-1 and UNCOVER-2 studies, patients who responded at week 12 were rerandomized to an additional 48 weeks of ixekizumab 80 mg every 4 weeks or placebo. Nonresponders at week 12 and patients whose disease relapsed during the maintenance period received ixekiz­umab 80 mg every 4 weeks.15

In these 2 clinical trials, 75% of patients in the ixekizumab group maintained their response at week 60 compared with 7% of those in the placebo group. Among patients who were rerandomized to placebo at week 12, the median time to disease relapse was 164 days in the 2 studies; 66% of patients regained an sPGA response of at least 0 or 1 within 12 weeks of restarting treatment with ixekizumab.15

In the UNCOVER-3 study, 73% of patients who received ixekizumab 80 mg every 2 weeks maintained a PASI 90 response at 60 weeks, and 55% of patients maintained a PASI 100 response at 60 weeks.8

Adverse Events

The most common adverse reactions reported in ≥1% of patients in the ixekizumab group and more often than in the placebo group through week 12 included injection-site reactions (17%); upper respiratory tract infections, including nasopharyngitis and rhinovirus infection (14%); nausea (2%); and tinea infections (2%).15

In 2 active comparator clinical trials, ixekizumab treatment resulted in 2% of serious adverse events and 2% of treatment discontinuation compared with 0.7% with etanercept for each category.15,17

Contraindications

Ixekizumab is contraindicated in patients with a serious hypersensitivity reaction to ixekizumab or to any of its excipients.15

Drug Interactions

Live vaccines. Completing age-appropriate immunizations should be considered before starting ixekizumab treatment. Live vaccines should be avoided in patients who receive ixekizumab.15

Cytochrome (CY) P450 substrates. Ixekizumab could normalize the development of CYP450 enzymes. Therefore, when ixekizumab therapy is started or discontinued in patients who are receiving CYP450 substrate drugs, monitoring for effect (eg, for warfarin) or drug concentration (eg, for cyclosporine) should be considered, as well as dosage modification of the CYP450 substrate drug.15

Warnings and Precautions

Infections. Serious infections have been reported with ixekizumab therapy. Ixekizumab should be discontinued if a serious infection occurs until resolution of the infection.15

Hypersensitivity. Serious hypersensitivity reactions, including angioedema and urticaria, occurred in patients who received ixekizumab. Ixekizumab should be immediately discontinued if a serious hypersensitivity reaction occurs.
Tuberculosis. Patients should be evaluated for tuberculosis before starting ixekizumab treatment, and monitored for active tuberculosis.15

Inflammatory bowel disease. Crohn’s disease and ulcerative colitis occurred more often with ixekizumab than with placebo. Patients with inflammatory bowel disease who are receiving ixekizumab should be closely monitored.15

Use in Specific Populations

Data on the presence of ixekizumab in human milk are not available. The mother’s clinical need for ixekizumab should be weighed against potential adverse effects on the breast-fed infant.

No differences in the safety or effi­cacy of ixekizumab were reported between patients aged ≥65 years and younger patients; however, the number of older patients was not sufficient to determine any potential difference in their response to treatment.15

Conclusion

With the FDA approval of ixekiz­umab, an IL-17A antagonist, for patients with moderate-to-severe plaque psoriasis, an important new treatment option was added to the current treatment armamentarium for this patient population. The safety and efficacy of ixekizumab were demonstrated in 3 pivotal clinical trials including 3866 patients with plaque psoriasis. Results showed that patients who received ixekizumab had greater clinical responses than those who received placebo; skin was clear or nearly clear.

Ixekizumab’s dosing schedule every 2 weeks through week 12 and every 4 weeks thereafter, and its formulation as prefilled autoinjector or prefilled syringe, may provide a convenient management option for appropriate patients with plaque psoriasis.

References
1. National Psoriasis Foundation. Psoriasis and comorbid conditions issue brief. www.psoriasis.org/sites/default/
files/advocacy/PsoriasisandComorbidConditionsIssueBriefonepager20140225.pdf. Accessed August 10, 2016.
2. American Academy of Dermatology. Psoriasis. www.aad.org/media/stats/conditions/psoriasis. Accessed August 9, 2016.
3. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. 2008;58:826-850.
4. Mayo Clinic staff. Diseases and conditions: psoriasis. June 17, 2015. www.mayoclinic.org/diseases-conditions/psoriasis/basics/definition/con-20030838. Accessed August 10, 2016.
5. Armstrong AW, Schupp C, Wu J, Bebo B. Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011. PLoS One. 2012;7:e52935.
6. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-based cohort study. Arch Dermatol. 2010;146:891-895.
7. Brezinski EA, Dhillon JS, Armstrong AW. Economic burden of psoriasis in the United States: a systematic review. JAMA Dermatol. 2015;151:651-658.
8. Gordon KB, Blauvelt A, Papp KA, et al; for the UNCOVER-1 Study Group; UNCOVER-2 Study Group; and UNCOVER-3 Study Group. Phase 3 trials of ixekizu­mab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016;375:345-356.
9. Viswanathan HN, Chau D, Milmont CE, et al. Total skin clearance results in improvements in health-related quality of life and reduced symptom severity among patients with moderate to severe psoriasis. J Dermatolog Treat. 2015;26:235-239.
10. Takeshita J, Callis Duffin K, Shin DB, et al. Patient-reported outcomes for psoriasis patients with clear versus almost clear skin in the clinical setting. J Am Acad Dermatol. 2014;71:633-641.
11. US Food and Drug Administration. FDA approves new psoriasis drug Cosentyx. Press release. January 21, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm430969.htm. Accessed August 10, 2016.
12. US Food and Drug Administration. FDA approves new psoriasis drug Taltz. Press release. March 22, 2016. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm491872.htm. Accessed July 25, 2016.
13. Krueger JG, Fretzin S, Suárez-Fariñas M, et al. IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis. J Allergy Clin Immunol. 2012;130:145-154.e9.
14. Eli Lilly and Company. Lilly’s Taltz (ixekizumab) receives U.S. FDA approval for the treatment of moderate-to-severe plaque psoriasis. Press release. March 22, 2016. https://investor.lilly.com/releasedetail.cfm?ReleaseID=961838. Accessed July 28, 2016.
15. Taltz (ixekizumab) injection [prescribing information]. Indianapolis, IN: Eli Lilly and Company; March 2016.
16. Lilly. Taltz (ixekizumab): specialty pharmacy network partners. 2016. www.taltz.com/_Assets/pdf/Taltz_Contracted_Specialty_Pharmacy_List.pdf. Accessed July 28, 2016.
17. Griffiths CE, Reich K, Lebwohl M, et al; for the UNCOVER-2 and UNCOVER-3 Investigators. Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Lancet. 2015;386:541-551.

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