Clinical Trials

Date: 2016-03-07

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results at the American Academy of Dermatology (AAD) Annual Meeting in Washington, D.C.

Company: Eli Lilly (USA -IN)

Product: ixekizumab

Action mechanism:

• monoclonal antibody. Ixekizumab is a monoclonal antibody with high affinity and specificity that binds to and neutralizes the pro-inflammatory cytokine interleukin-17A (IL-17A). In psoriasis, IL-17A plays a major role in driving excess keratinocyte (skin cell) proliferation and activation. Ixekizumab does not bind to cytokines IL-17B, IL-17C, IL-17D, IL-17E or IL-17F. Ixekizumab is administered via subcutaneous injection (under the skin). Ixekizumab is also in clinical development for the treatment of psoriatic arthritis.

Disease: moderate-to-severe plaque psoriasis

Therapeutic area: Autoimmune diseases - Dermatological diseases

Country: Argentina, Australia, Austria, Bulgaria, Canada, Chile, Czech Republic, Denmark, France, Germany, Hungary, Italy,Japan, Mexico, The Netherlands, Poland, Romania, Russian Federation, Spain, UK, USA

Trial details:

• In the three UNCOVER studies, patients were assigned to receive either placebo or ixekizumab (80 mg every two or four weeks) for 12 weeks, following a 160 mg starting dose. In the two active comparator studies (UNCOVER-2 and 3), patients could be assigned to receive etanercept 50 mg twice weekly for 12 weeks. In UNCOVER-1, responders to treatment were assigned to continue treatment on either placebo or ixekizumab (80 mg every 4 or 12 weeks) for up to 60 weeks. Patients enrolled in the UNCOVER studies had a confirmed diagnosis of chronic plaque psoriasis for at least six months prior to randomization. Additionally, at screening and at randomization they demonstrated at least 10 percent Body Surface Area (BSA) of psoriasis, an sPGA score of at least 3 and PASI score of at least 12. UNCOVER-1 compared the safety and efficacy of different dosing regimens of ixekizumab to placebo after 12 weeks and 60 weeks of treatment. UNCOVER-2 and 3 evaluated different dosing regimens of ixekizumab compared to either placebo or etanercept for 12 weeks.(NCT01474512, NCT01597245, NCT01646177)

Latest news:

• • On March 7, 2016, Eli Lilly announced that JAMA Dermatology has published detailed results from three pivotal Phase 3 trials that evaluated the effect of ixekizumab on work productivity in patients with moderate-to-severe plaque psoriasis. Specific results from the UNCOVER-1 study were also presented during the American Academy of Dermatology (AAD) Annual Meeting in Washington, D.C.
• In an analysis of the UNCOVER-1, UNCOVER-2 and UNCOVER-3 studies, the effect of ixekizumab on work productivity was evaluated by the change from baseline as measured by Work Productivity and Activity Impairment-Psoriasis (WPAI-PSO) scores at 12 weeks. The validated, self-reported WPAI questionnaire is used to measure impairment of work activities due to general health or a specific condition. In all three studies, patients treated with ixekizumab reported improved work productivity compared to patients treated with placebo. In UNCOVER-1, improvements in work productivity were also sustained up to 60 weeks in those who demonstrated initial clinical response to ixekizumab at 12 weeks. In all three studies, patients treated with ixekizumab every two weeks demonstrated the following results at 12 weeks:
• - In UNCOVER-1, patients treated with ixekizumab showed significantly greater improvement compared to placebo in all WPAI-PSO scores: absenteeism, presenteeism, work productivity loss and activity impairment (p < 0.001 for all comparison scores). - In UNCOVER-2, patients treated with ixekizumab showed significantly greater improvement compared to placebo in all WPAI-PSO scores: absenteeism (p=0.016), presenteeism (p < 0.001), work productivity loss (p < 0.001) and activity impairment (p < 0.001). Patients treated with ixekizumab also showed significantly greater improvement in the following WPAI scores compared to those treated with etanercept: presenteeism, work productivity loss and activity impairment (p < 0.001 for all comparison scores). - In UNCOVER-3, patients treated with ixekizumab showed statistically significant improvements compared to placebo in all WPAI-PSO scores: absenteeism (p=0.012), presenteeism (p < 0.001), work productivity loss (p < 0.001) and activity impairment (p < 0.001). Patients treated with ixekizumab also showed significantly greater improvement in activity impairment scores compared to those treated with etanercept (p=0.009).
• Improvements in WPAI scores were also sustained through 60 weeks among patients who achieved clinical response with ixekizumab at 12 weeks. In UNCOVER-1 and UNCOVER-2, significant improvements from baseline were sustained through 60 weeks among patients treated with ixekizumab for presenteeism, work productivity loss and activity impairment scores. The majority of treatment-emergent adverse events were mild or moderate. The most frequently reported adverse drug reactions were injection site reactions and upper respiratory tract infections (most frequently nasopharyngitis) and generally did not lead to treatment discontinuations.
• Eli Lilly also announced that detailed results of the UNCOVER-2 study were presented during the American Academy of Dermatology (AAD) Annual Meeting. In UNCOVER-2, 64 percent (229/358) of patients treated with bi-weekly etanercept did not respond (static Physician's Global Assessment score [sPGA] ?2) to treatment at 12 weeks. These nonresponders were treated with placebo at 12 weeks, then received ixekizumab every four weeks from Weeks 16 through 60. This study's co-primary efficacy endpoints at 12 weeks of ixekizumab therapy were PASI 75 and sPGA 0 or 1. 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.
• Among those patients who did not respond to etanercept, the following was observed at 24 weeks of the study, 12 weeks following treatment with ixekizumab:
• 83.5 percent of patients achieved PASI 75; 57.0 percent of patients achieved PASI 90; 22.0 percent of patients achieved complete resolution of psoriasis plaques (PASI 100).
• At 48 weeks following treatment with ixekizumab, the following was also observed at week 60 of the study among those who did not respond to etanercept:
• 82.5 percent of patients achieved PASI 75 68.5 percent of patients achieved PASI 90; 43.5 percent of patients achieved complete resolution of psoriasis plaques (PASI 100). Additionally, 73 percent of those patients who did not respond to etanercept achieved sPGA 0 or 1 12 weeks after starting treatment with ixekizumab.
• The majority of treatment-emergent adverse events were mild or moderate. The safety profile after receiving ixekizumab treatment was comparable among patients who initially received etanercept and patients who initially received placebo in this clinical trial. In UNCOVER-2, patients who did not respond to etanercept after 12 weeks of treatment demonstrated high levels of improvement in their moderate-to-severe plaque psoriasis after receiving treatment with ixekizumab.
• • On August 21, 2014, Eli Lilly announced results of the three UNCOVER studies evaluating ixekizumab in moderate-to-severe plaque psoriasis. Ixekizumab was statistically superior to etanercept and placebo on all skin clearance measures in these Phase 3 studies. Patients treated with both dosing regimens of ixekizumab had significantly greater levels of skin clearance compared to placebo and to etanercept at the 12-week endpoint. Skin clearance was measured by standard primary endpoints for psoriasis studies: the Psoriasis Area and Severity Index (PASI) and the Static Physician Global Assessment (sPGA). For patients treated with ixekizumab either every four weeks or every two weeks, between 78 to 90 percent of patients achieved at least a 75 percent reduction in PASI score (PASI 75) at 12 weeks. Additionally, 31 to 41 percent of these patients achieved PASI 100, or clear skin, at week 12. For comparison, between 5 to 7 percent of patients treated with etanercept in the UNCOVER-2 and 3 studies achieved PASI 100.
• Statistically significant improvements in skin clearance measures for patients treated with ixekizumab were observed as early as the first week when compared to either placebo or etanercept, and continued through week 12. In the UNCOVER-1 study, high levels of response were maintained through 60 weeks of treatment. Adverse events were comparable for patients receiving ixekizumab in the 12-week, randomized control portion across all three studies. The overall rates and severities of adverse events observed were comparable to those for etanercept in the two active comparator trials. The most frequently reported events (more than five percent across all three studies) were nasopharyngitis and injection site reaction. Most injection site reactions were mild, and most patients who experienced an injection site reaction continued treatment with ixekizumab. Lilly plans to submit full data from the UNCOVER studies for disclosure at scientific meetings and in peer-reviewed journals in 2015. The company intends to submit ixekizumab to regulatory authorities in the first half of 2015.

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