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Long-term efficacy and safety of ixekizumab: A 5-year analysis of the UNCOVER-3 randomized controlled trial

Open AccessPublished:November 27, 2020DOI:https://doi.org/10.1016/j.jaad.2020.11.022

      Objective

      To report the efficacy and safety of the approved ixekizumab (IXE) dose over 5 years from UNCOVER-3 (NCT01646177).

      Methods

      Patients (N = 1346) were randomized 1:2:2:2 to receive subcutaneous injections of placebo, etanercept 50 mg twice weekly, or IXE 80 mg every 2 weeks or every 4 weeks after an initial dose of IXE 160 mg, respectively. At week 12, patients entered the long-term extension period with dosing of IXE every 4 weeks and could escalate to every 2 weeks after week 60. Efficacy was reported for the IXE every 2 weeks/every 4 weeks group of the intent-to-treat population. Safety was reported for patients who received at least 1 dose of IXE every 2 or every 4 weeks.

      Results

      Using modified nonresponder imputation, 78.8%/67.1%/46.2% of patients receiving the approved dose of IXE every 2 weeks/every 4 weeks (n = 385) achieved ≥75%, ≥90%, or 100% improvement from baseline in the Psoriasis Area and Severity Index, respectively, at week 264; static Physician's Global Assessment score of 0/1 and 0 responses were 69.2% and 45.3%, respectively. Infections were the most observed treatment-emergent adverse event (72.7% of patients).

      Limitations

      Lack of comparison treatment group after week 12.

      Conclusion

      IXE demonstrates sustained efficacy and consistent safety through 264 weeks in patients using the approved dose.

      Graphical abstract

      Key words

      Abbreviations used:

      AE (adverse event), ITT (intention-to-treat), IR (incidence rate), IXE (ixekizumab), LTE (long-term extension), MI (multiple imputation), mNRI (modified non-responder imputation), NRS (Numeric Rating Scale), PASI (Psoriasis Area and Severity Index), SAE (serious adverse event), sPGA (static Physician's Global Assessment), TEAE (treatment-emergent adverse event)
      • Ixekizumab is an efficacious treatment for moderate to severe plaque psoriasis with a well-characterized safety profile.
      • Patients experienced sustained response rates for skin clearance and a consistent safety profile through week 264. Overall, ixekizumab therapy is appropriate for long-term treatment of patients with plaque psoriasis.
      Psoriasis, a chronic immune-mediated disease, usually requires lifelong disease management.
      • Menter A.
      • Strober B.E.
      • Kaplan D.H.
      • et al.
      Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics.
      The efficacy and safety of ixekizumab (IXE), a high-affinity monoclonal antibody that specifically neutralizes interleukin 17A, have been established in up to 4 years of UNCOVER-3 study data for patients with moderate to severe plaque psoriasis.
      • Blauvelt A.
      • Gooderham M.
      • Iversen L.
      • et al.
      Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3).
      • Griffiths C.E.
      • Reich K.
      • Lebwohl M.
      • et al.
      Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.
      • Lebwohl M.G.
      • Gordon K.B.
      • Gallo G.
      • Zhang L.
      • Paul C.
      Ixekizumab sustains high level of efficacy and favourable safety profile over 4 years in patients with moderate psoriasis: results from UNCOVER-3 study.
      • Leonardi C.
      • Maari C.
      • Philipp S.
      • et al.
      Maintenance of skin clearance with ixekizumab treatment of psoriasis: three-year results from the UNCOVER-3 study.
      • Blauvelt A.
      • Papp K.A.
      • Griffiths C.E.M.
      • et al.
      Efficacy and safety of switching to ixekizumab in etanercept non-responders: a subanalysis from two phase iii randomized clinical trials in moderate-to-severe plaque psoriasis (UNCOVER-2 and -3).
      • Gordon K.B.
      • Blauvelt A.
      • Papp K.A.
      • et al.
      Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis.
      Given the chronic nature of psoriasis, additional long-term efficacy and safety data for IXE in patients with moderate to severe plaque psoriasis are essential. Here, we report efficacy and safety over 5 years (264 weeks) of treatment with the approved IXE dose from the UNCOVER-3 study (NCT01646177).

      Methods

       Study design and participants

      UNCOVER-3 was a randomized, double-blinded, multicenter, phase 3 study in patients with moderate to severe plaque psoriasis. Details of the study design and patient population were previously reported.
      • Griffiths C.E.
      • Reich K.
      • Lebwohl M.
      • et al.
      Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.
      ,
      • Blauvelt A.
      • Papp K.A.
      • Griffiths C.E.M.
      • et al.
      Efficacy and safety of switching to ixekizumab in etanercept non-responders: a subanalysis from two phase iii randomized clinical trials in moderate-to-severe plaque psoriasis (UNCOVER-2 and -3).
      ,
      • Gordon K.B.
      • Blauvelt A.
      • Papp K.A.
      • et al.
      Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis.
      Briefly, 1346 patients were randomized 1:2:2:2 to receive subcutaneous injections of placebo, etanercept 50 mg twice weekly or IXE 80 mg every 2 weeks or every 4 weeks after an initial dose of IXE 160 mg. At week 12, all patients were switched to IXE every 4 weeks for the long-term extension (LTE). After week 60, patients could escalate dosing to every 2 weeks at investigator discretion. This report focuses on LTE data from patients who received the approved dosing regimen (initial 160 mg, IXE 80 mg every 2 weeks up to week 12, and IXE 80 mg every 4 weeks thereafter), including patients whose dosage was escalated to every 2 weeks.
      The UNCOVER-3 study was registered on July 18, 2012, with the registration number of NCT01646177. The study protocol was approved by the institutional review board or ethics committee at each participating site and was conducted according to the principles of the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines. All eligible patients provided written informed consent before undergoing study-related procedures.

       Endpoints and outcome assessment

      The efficacy endpoints at week 264 included percentage of patients who achieved at least 75%, 90%, or 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 75/90/100, respectively) and the percentage of patients who achieved a static Physician's Global Assessment (sPGA) score of 1 (minimal) or 0 (clear). For patients who had baseline scalp, nail, or palmoplantar involvement, efficacy was evaluated by the percentage achieving complete resolution based on the Psoriasis Scalp Severity Index, the Nail Psoriasis Severity Index, or the Palmoplantar Psoriasis Area and Severity Index. The patient-administered Itch Numeric Rating Scale (NRS) evaluated patients' quality of life in patients with a baseline Itch NRS of greater than 0, with a score of 0 indicating no itch.
      Safety was evaluated by monitoring of adverse events (AEs), immunogenicity, electrocardiograms, laboratory data, and vital signs collected and reported by study investigators at regular intervals during patient visits. Cytopenias, hepatic-related events, infections, injection site reactions, allergic reactions and hypersensitivities, cerebrocardiovascular events, malignancies, depression, Crohn's disease, ulcerative colitis, pneumocystis pneumonia, and interstitial lung disease were select AEs of special interest. Cerebrocardiovascular events and events possibly indicative of Crohn's disease or ulcerative colitis were adjudicated in a blinded manner by an independent committee of experts.

       Statistical analysis

      The intent-to-treat (ITT) population, defined as all randomized patients regardless of treatment compliance, was analyzed for efficacy. Data from visits in which patients were treated with the approved IXE dosing regimen were included for primary efficacy analysis. Efficacy data were summarized at each post-baseline visit through 264 weeks by using 3 methods: as observed, multiple imputation (MI), and modified nonresponder imputation (mNRI).
      For the as-observed method, only data from patients who completed the visit were analyzed, and no missing data imputation was performed. The MI method handled missing data by estimating what observations would have been if the patient had continued with the hypothetical treatment strategy. The mNRI method analyzed patient response status with a composite strategy: those with missing data due to study drug-related events (e.g., lack of efficacy, adverse events, relapse) were considered nonresponders and were imputed using NRI; all other cases of missing data, considered unrelated to treatment, were imputed by using the MI method as described.
      • Blauvelt A.
      • Gooderham M.
      • Iversen L.
      • et al.
      Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3).
      Response rates using these 3 methods were summarized for categorical efficacy endpoints, and mean PASI percent improvement was summarized using as-observed and MI methods.
      Treatment-emergent AEs (TEAEs), serious adverse events (SAEs), and AEs of special interest were summarized by exposure-adjusted incidence rate (IR) (eg, person-time–adjusted incidence rate per 100 patient-years). Safety events through week 264 for patients on the approved IXE dosing regimen included data collected at visits with every-2-week dosing escalations. The statistical analyses of efficacy and safety measures were performed with SAS, version 9.2 (SAS Institute).

       Availability of data and materials

      Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available on request 6 months after the indication studied has been approved in the United States and European Union and after primary publication acceptance, whichever is later. No expiration date for data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms are provided in a secure data-sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org. Data are also available on clinicaltrials.gov: NCT01646177.

      Results

       Patient characteristics

      Of the 385 patients randomized to the approved dosing regimen (IXE every 2 weeks/every 4 weeks) group, 363 (94.3%), 340 (88.3%), 315 (81.8%), 300 (77.9%), 285 (74.0%), and 255 (66.2%) patients completed weeks 12, 52, 108, 156, 204, and 264, respectively. Reasons for discontinuation by week 264 included AEs (39; 10.1%), patient decision (31; 8.1%), loss to follow-up (18; 4.7%), lack of efficacy (12; 3.1%), and protocol violation (12; 3.1%) (Supplemental Table I; available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2). Baseline demographics and characteristics of patients who received the approved dosing regimen in the ITT population have been previously presented (Supplemental Table II; available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2).
      • Blauvelt A.
      • Gooderham M.
      • Iversen L.
      • et al.
      Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3).
      • Griffiths C.E.
      • Reich K.
      • Lebwohl M.
      • et al.
      Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.
      • Lebwohl M.G.
      • Gordon K.B.
      • Gallo G.
      • Zhang L.
      • Paul C.
      Ixekizumab sustains high level of efficacy and favourable safety profile over 4 years in patients with moderate psoriasis: results from UNCOVER-3 study.
      ,
      • Gordon K.B.
      • Blauvelt A.
      • Papp K.A.
      • et al.
      Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis.

       Efficacy

      Clinical responses were sustained throughout the 5-year treatment period. Excluding every-2-week dosing escalations, 97.4% and 90.7% of patients achieved PASI 75 using the as-observed and MI methods, respectively. Similarly, 90.2% and 75.9% of patients achieved PASI 90, and 66.5% and 51.9% achieved PASI 100, at week 264 using the as-observed and MI methods, respectively. The proportions of patients in the IXE every 2 weeks/every 4 weeks group excluding every-2-week dosing escalations who achieved PASI 75, 90, and 100 at week 264 using the mNRI method were 78.8%, 67.1%, and 46.2%, respectively (Fig 1). Including every-2-weeks dosing escalations, the proportions of patients in the IXE every 2 weeks/every 4 weeks group who achieved PASI 75, 90, and 100 at week 264 using the mNRI method were 81.0%, 67.2%, and 44.6%, respectively (Supplemental Fig 1, A; available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2). At week 264, the mean improvements from baseline PASI were 96.8% using the as-observed method and 82.4% using the MI method (Fig 2, Table I, and Supplementary Video 1, available at jaad.org).
      Figure thumbnail gr1
      Fig 1PASI response rates over time through 264 weeks with the approved IXE dosing regimen. Rate of achievement of a 75% or greater improvement from baseline in PASI (PASI 75), 90% or greater improvement from baseline in PASI (PASI 90), and 100% improvement from baseline in PASI (PASI 100) at each postbaseline visit for the dosing regimen of IXE every 2 weeks/every 4 weeks, excluding data from visits with escalated every-2-weeks dosing. Filled circles indicate PASI 75 response rates, filled squares indicate PASI 90 response rates, and filled triangles indicate PASI 100 response rates. Blue lines indicate use of the as-observed method, red lines indicate use of the multiple imputation (MI) method, and green lines indicate use of the modified nonresponder imputation (mNRI) method. IXE, Ixekizumab; PASI, Psoriasis Area and Severity Index.
      Figure thumbnail gr2
      Fig 2Mean PASI percent improvement over time through 264 weeks with the approved IXE dosing regimen. The mean PASI percentage improvement over time through week 264 with the IXE every 2 weeks/every 4 weeks dosing regimen, excluding data from visits with escalated every-2-weeks dosing. The dark blue line indicates use of the as-observed method, and the light blue line indicates use of the multiple imputation (MI) method. See also Supplementary Video 1, available at jaad.org. CI, Confidence interval; IXE, ixekizumab; PASI, Psoriasis Area and Severity Index; Q2W, every 2 weeks; Q4W, every 4 weeks.
      Table IEfficacy response rates (as-observed, MI, and mNRI methods) in the UNCOVER-3 study (approved dosing regimen patient population, without escalations)
      ParameterIXE 80 mg every 2 weeks/IXE every 4 weeks (n = 385)
      Results are reported as n/total (%) (95% CI) unless noted otherwise. As-observed percentages are calculated by using the number of patients with nonmissing data at weeks 60, 108, 156, 204, and 264 as the denominator. MI and mNRI results are reported as % (95% CI) based on the average response rate across multiple imputed data sets.
      Year 1Year 2Year 3Year 4Year 5
      sPGA of 0/1
       As observed287/335 (85.7)

      (81.9-89.4)
      256/305 (83.9)

      (79.8-88.1)
      212/248 (85.5)

      (81.1-89.9)
      197/222 (88.7)

      (84.6-92.9)
      176/194 (90.7)

      (86.6-94.8)
       MI82.4 (78.5-86.4)78.4 (73.9-82.8)72.8 (67.5-78.1)76.0 (70.3-81.7)79.4 (73.3-85.6)
       mNRI79.3 (75.1-83.4)73.6 (69.0-78.2)67.4 (62.2-72.6)68.4 (63.0-73.8)69.2 (63.3-75.1)
      sPGA of 0
       As observed212/335 (63.3)

      (58.1-68.4)
      179/305 (58.7)

      (53.2-64.2)
      160/248 (64.5)

      (58.6-70.5)
      153/222 (68.9)

      (62.8-75.0)
      129/194 (66.5)

      (59.9-73.1)
       MI60.5 (55.5-65.5)53.9 (48.6-59.1)52.2 (46.6-57.8)54.4 (48.6-60.3)50.9 (44.8-57.0)
       mNRI58.3 (53.3-63.3)50.7 (45.6-55.9)48.5 (43.1-53.8)49.6 (44.1-55.1)45.3 (39.7-51.0)
      PASI 75
       As observed321/335 (95.8)

      (93.7-98.0)
      287/305 (94.1)

      (91.5-96.7)
      241/248 (97.2)

      (95.1-99.2)
      218/222 (98.2)

      (96.4-99.9)
      189/194 (97.4)

      (95.2-99.7)
       MI93.7 (91.0-96.4)90.5 (87.2-93.8)91.2 (87.5-95.0)94.6 (91.2-97.9)90.7 (86.0-95.5)
       mNRI88.8 (85.6-92.1)84.2 (80.4-87.9)82.4 (78.3-86.6)82.6 (78.4-86.8)78.8 (74.1-83.6)
      PASI 90
       As observed282/335 (84.2)

      (80.3-88.1)
      247/305 (81.0)

      (76.6-85.4)
      215/248 (86.7)

      (82.5-90.9)
      195/222 (87.8)

      (83.5-92.1)
      175/194 (90.2)

      (86.0-94.4)
       MI81.0 (76.8-85.1)75.0 (70.3-79.6)74.6 (69.5-79.8)72.9 (67.3-78.5)75.9 (70.4-81.5)
       mNRI77.8 (73.5-82.1)70.6 (65.9-75.4)68.9 (63.9-74.0)66.3 (60.9-71.6)67.1 (61.6-72.6)
      PASI 100
       As observed213/335 (63.6)

      (58.4-68.7)
      177/305 (58.0)

      (52.5-63.6)
      160/248 (64.5)

      (58.6-70.5)
      149/222 (67.1)

      (60.9-73.3)
      129/194 (66.5)

      (59.9-73.1)
       MI60.8 (55.7-65.9)52.6 (47.4-57.8)52.2 (46.5-57.9)52.5 (46.6-58.4)51.9 (46.1-57.7)
       mNRI58.6 (53.5-63.7)49.7 (44.6-54.9)48.6 (43.1-54.0)48.2 (42.7-53.8)46.2 (40.7-51.8)
      PASI % improvement from baseline
       As observed, total, mean (95% CI)335, 95.9 (95.0-96.8)305, 94.9 (93.8-96.0)248, 96.4 (95.5-97.3)222, 96.8 (96.0-97.7)194, 96.8 (95.9-97.8)
       MI, mean (95% CI)93.6 (92.1-95.1)91.1 (89.3-92.9)89.7 (87.4-92.1)86.2 (81.9-90.4)82.4 (76.4-88.5)
      NAPSI of 0
      NAPSI of 0, PSSI of 0, and PPASI 100 response rates are determined for patients with baseline fingernail, scalp, or nonpustular palmoplantar psoriasis, respectively. For nail psoriasis assessments, only fingernail psoriasis was assessed in UNCOVER-3.
      (n = 229)
       As observed143/211 (67.8)

      (61.5-74.1)
      130/184 (70.7)

      (64.1-77.2)
      121/154 (78.6)

      (72.1-85.1)
      110/145 (75.9)

      (68.9-82.8)
      98/127 (77.2)

      (69.9-84.5)
       MI66.7 (60.4-73.1)68.6 (62.1-75.1)76.2 (69.7-82.7)75.1 (68.7-81.5)75.5 (68.9-82.1)
       mNRI64.7 (58.4-71.0)64.6 (58.0-71.2)69.7 (63.1-76.2)59.9 (52.8-67.1)64.4 (57.5-71.3)
      PSSI of 0
      NAPSI of 0, PSSI of 0, and PPASI 100 response rates are determined for patients with baseline fingernail, scalp, or nonpustular palmoplantar psoriasis, respectively. For nail psoriasis assessments, only fingernail psoriasis was assessed in UNCOVER-3.
      (n = 349)
       As observed265/306 (86.6)

      (82.8-90.4)
      237/273 (86.8)

      (82.8-90.8)
      193/220 (87.7)

      (83.4-92.1)
      174/199 (87.4)

      (82.8-92.0)
      151/173 (87.3)

      (82.3-92.2)
       MI84.7 (80.8-88.7)84.5 (80.4-88.6)82.5 (78.1-86.9)83.0 (78.5-87.6)81.8 (76.9-86.7)
       mNRI80.5 (76.3-84.8)77.8 (73.2-82.4)74.0 (69.1-78.9)64.2 (58.4-70.0)69.4 (63.8-75.1)
      PPASI 100
      NAPSI of 0, PSSI of 0, and PPASI 100 response rates are determined for patients with baseline fingernail, scalp, or nonpustular palmoplantar psoriasis, respectively. For nail psoriasis assessments, only fingernail psoriasis was assessed in UNCOVER-3.
      (n = 96)
       As observed71/82 (86.6)

      (79.2-94.0)
      66/71 (93.0)

      (87.0-98.9)
      48/56 (85.7)

      (76.5-94.9)
      46/48 (95.8)

      (90.2-100.0)
      37/41 (90.2)

      (81.2-99.3)
       MI84.6 (76.9-92.3)88.3 (81.0-95.7)83.3 (74.7-91.9)92.2 (85.7-98.8)91.0 (84.0-98.0)
       mNRI78.0 (69.5-86.5)79.3 (70.9-87.7)71.7 (62.2-81.2)77.9 (69.3-86.5)75.4 (66.2-84.6)
      CI, Confidence interval; IXE, ixekizumab; MI, multiple imputation; mNRI, modified multiple imputation; NAPSI, Nail Psoriasis Severity Index; PASI, Psoriasis Area and Severity Index; PASI 75, 75% improvement from baseline in Psoriasis Area and Severity Index; PASI 90, 90% improvement from baseline in the Psoriasis Area and Severity Index; PASI 100, 100% improvement from baseline in the Psoriasis Area and Severity Index; PPASI 100, 100% improvement from baseline in the Palmoplantar Psoriasis Area and Severity Index; PSSI, Psoriasis Scalp Severity Index; sPGA, static Physician's Global Assessment.
      Results are reported as n/total (%) (95% CI) unless noted otherwise. As-observed percentages are calculated by using the number of patients with nonmissing data at weeks 60, 108, 156, 204, and 264 as the denominator. MI and mNRI results are reported as % (95% CI) based on the average response rate across multiple imputed data sets.
      NAPSI of 0, PSSI of 0, and PPASI 100 response rates are determined for patients with baseline fingernail, scalp, or nonpustular palmoplantar psoriasis, respectively. For nail psoriasis assessments, only fingernail psoriasis was assessed in UNCOVER-3.
      Response rates were also consistent for an sPGA score of 0/1 (Supplemental Fig 2, A; available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2) and 0 (Supplemental Fig 2, B) throughout the 5-year treatment period. Excluding every-2-week dosing escalations, responses using the as-observed, MI, and mNRI methods were, respectively, 90.7%, 79.4%, and 69.2% for sPGA of 0/1 and 66.5%, 50.9%, and 45.3% for sPGA of 0. Including every-2-week dosing escalations, the proportions of patients in the IXE every 2 weeks/every 4 weeks group who achieved sPGA of 0/1 and sPGA of 0 at week 264 using the mNRI method were 65.8% and 44.1%, respectively (Supplemental Fig 1, B).
      Complete resolution during the 5-year treatment period was observed in patients with baseline nail (n = 229), scalp (n = 349), and palmoplantar (n = 96) involvement (Table I and Supplemental Fig 3; available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2). The percentages of patients reporting no itch (Itch NRS of 0) at week 264 for patients with an itch score of greater than 0 at baseline (n = 376) were 57.7%, 50.8%, 44.1% using the as-observed, MI, and mNRI methods, respectively, excluding every-2-week dosing escalations (Supplemental Fig 5; available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2).
      Sustained efficacy responses were also observed in patients using the approved dosing regimen when including data from visits where dosing was escalated to every 2 weeks (Supplemental Fig 4; available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2). Between week 60 and week 264, 86 (22.3%) patients on the approved dose escalated to every-2-weeks dosing. At the visit before dosing escalation, 49 (57.0%) of the patients with every-2-weeks dosing escalations reported PASI 75 or better, 16 (18.6%) patients reported PASI 90 or better, and 1 (1.2%) patient reported PASI 100; 37 (43.0%) patients had mild disease activity (sPGA, ≤2). After escalating dosing to every 2 weeks, 31 (83.8%) of the 37 patients who had at least 1 postescalation visit achieved PASI 75 responses at least once after every-2-weeks dosing escalation. Of the 86 patients with every-2-weeks dosing escalations, 22 (25.6%) patients discontinued the study treatment by week 264. Reasons for discontinuation were patient decision (6; 7.0%), loss to follow-up (5; 5.8%), adverse event (3; 3.5%), lack of efficacy (3; 3.5%), clinical relapse (2; 2.3%), sponsor decision (2; 2.3%), and investigator decision (1; 1.2%).

       Safety

      Safety profiles of the primary study populations in UNCOVER-3 through 204 weeks of treatment with ixekizumab have been previously published.
      • Blauvelt A.
      • Gooderham M.
      • Iversen L.
      • et al.
      Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3).
      ,
      • Lebwohl M.G.
      • Gordon K.B.
      • Gallo G.
      • Zhang L.
      • Paul C.
      Ixekizumab sustains high level of efficacy and favourable safety profile over 4 years in patients with moderate psoriasis: results from UNCOVER-3 study.
      A yearly overview of AEs from year 1 to year 5, as well as AEs during the LTE period in the approved dosing regimen patient population are presented in Table II. TEAEs occurred in 323 patients (IR per 100 patient years, 21.6) during the LTE period. Most events reported were mild or moderate in severity, and the most frequently reported TEAEs were nasopharyngitis and upper respiratory tract infection. A total of 55 patients (IR, 3.7) reported SAEs during the LTE period. The most frequently reported SAEs were infections (15 patients; IR, 1.0). The IR for SAEs remained consistent for year 1 through year 5 (range, 3.5-5.2). Thirty-three patients (IR, 2.2) discontinued from study drug due to an AE over the entire LTE period.
      Table IIOverview of AEs, LTE period (approved dosing regimen patient population), n (IR)
      ParameterIXE 80 mg every 2 weeks/IXE every 4 weeks
      Patients were allowed to escalate to every-2-weeks dosing after week 60 during the LTE period. Patients who increased dosing to 80 mg IXE every 2 weeks remained on this dosage until they completed or discontinued the study. These data comprise all patients in the approved dosing regimen, including those who escalated to every-2-weeks dosing during the LTE period.
      Year 1
      Year 1 included the 12-week induction period.
      (355.5 total PY
      Total patient years indicates the total time patients were in the treatment period.
      )
      Year 2 (326.7 total PY
      Total patient years indicates the total time patients were in the treatment period.
      )
      Year 3 (310.2 total PY
      Total patient years indicates the total time patients were in the treatment period.
      )
      Year 4 (291.6 total PY
      Total patient years indicates the total time patients were in the treatment period.
      )
      Year 5 (273.1 total PY
      Total patient years indicates the total time patients were in the treatment period.
      )
      LTE period (1493.8 total PY
      Total patient years indicates the total time patients were in the treatment period.
      )
      Any TEAEs
      An AE is considered a TEAE if it first occurred or worsened during the LTE treatment period. AEs reported here are cumulative.
      297 (83.5)220 (67.3)177 (57.1)158 (54.2)140 (51.3)323 (21.6)
      SAEs18 (5.1)17 (5.2)11 (3.5)15 (5.1)13 (4.8)55 (3.7)
      Deaths1 (0.3)01 (0.3)01 (0.4)3 (0.2)
      Discontinued because of AEs4 (1.1)11 (3.4)6 (1.9)6 (2.1)6 (2.2)33 (2.2)
      Frequently reported TEAEs
      Frequently reported AEs included any AE occurring at a rate of 5% or greater in the approved IXE dosing group of IXE every 2 weeks/every 4 weeks.
       Nasopharyngitis64 (18.0)44 (13.5)32 (10.3)30 (10.3)29 (10.6)112 (7.5)
       Upper respiratory tract infection26 (7.3)5 (1.5)11 (3.5)9 (3.1)13 (4.8)42 (2.8)
      TEAE severity
      For patients with more than 1 occurrence of the same event, severity was categorized based on the event of highest severity.
       Mild120 (33.8)104 (31.8)86 (27.7)84 (28.8)62 (22.7)80 (5.4)
       Moderate158 (44.4)100 (30.6)77 (24.8)64 (21.9)62 (22.7)186 (12.5)
       Severe19 (5.3)16 (4.9)14 (4.5)10 (3.4)16 (5.9)57 (3.8)
      AESIs
       Infection187 (52.6)125 (38.3)103 (33.2)89 (30.5)77 (28.2)263 (17.6)
      Serious infection3 (0.8)4 (1.2)2 (0.6)5 (1.7)1 (0.4)15 (1.0)
       Injection-site reaction67 (18.8)10 (3.1)2 (0.6)3 (1.0)3 (1.1)33 (2.2)
       Allergic reactions/hypersensitivities
      Nonanaphylaxis39 (11.0)18 (5.5)9 (2.9)7 (2.4)9 (3.3)56 (3.7)
      Potential anaphylaxis01 (0.3)1 (0.3)002 (0.1)
       Hepatic events15 (4.2)7 (2.1)8 (2.6)7 (2.4)3 (1.1)30 (2.0)
       Cytopenias8 (2.3)4 (1.2)3 (1.0)2 (0.7)1 (0.4)14 (0.9)
       Depression4 (1.1)3 (0.9)3 (1.0)2 (0.7)011 (0.7)
      Suicidal ideation01 (0.3)0001 (0.1)
       Cerebrocardiovascular events
      Cerebrocardiovascular events were included only if they were confirmed by adjudication.
      2 (0.6)4 (1.2)2 (0.6)2 (0.7)5 (1.8)13 (0.9)
       Malignancies2 (0.6)1 (0.3)1 (0.3)2 (0.7)3 (1.1)9 (0.6)
       Crohn's disease
      Medical Dictionary for Regulatory Activities (MedDRA) preferred term.
      00002 (0.7)2 (0.1)
       Ulcerative colitis
      Medical Dictionary for Regulatory Activities (MedDRA) preferred term.
      1 (0.3)00001 (0.1)
       Pneumocystis pneumonia000000
       Interstitial lung disease000000
      AE, Adverse event; AESI, adverse event of special interest; IR, incidence rate per 100 patient years; IXE, ixekizumab; LTE, long-term extension; PY, patient-years; SAE, serious adverse event; TEAE, treatment-emergent adverse event.
      Patients were allowed to escalate to every-2-weeks dosing after week 60 during the LTE period. Patients who increased dosing to 80 mg IXE every 2 weeks remained on this dosage until they completed or discontinued the study. These data comprise all patients in the approved dosing regimen, including those who escalated to every-2-weeks dosing during the LTE period.
      Year 1 included the 12-week induction period.
      Total patient years indicates the total time patients were in the treatment period.
      § An AE is considered a TEAE if it first occurred or worsened during the LTE treatment period. AEs reported here are cumulative.
      ǁ Frequently reported AEs included any AE occurring at a rate of 5% or greater in the approved IXE dosing group of IXE every 2 weeks/every 4 weeks.
      For patients with more than 1 occurrence of the same event, severity was categorized based on the event of highest severity.
      # Cerebrocardiovascular events were included only if they were confirmed by adjudication.
      ∗∗ Medical Dictionary for Regulatory Activities (MedDRA) preferred term.
      With respect to AEs of special interest during the LTE period, infection was the most frequently reported (263 patients; IR, 17.6). Seventeen patients (IR, 1.1) in the approved dosing regimen patient population reported 25 Candida events during the LTE period. All Candida events were mild (12 AEs) to moderate (13 AEs) in severity, and oral candidiasis events (11 AEs) were predominately reported. Five cases of vulvovaginal mycotic infections, 5 cases of vulvovaginal candidiasis, 2 cases of oral fungal infections, 1 case of skin Candida, and 1 case of nail Candida were also observed. No patient discontinued because of an AE of candidiasis. The IR of allergic reactions and hypersensitivities was 11.0 during year 1 and decreased to 3.3 during year 5. Two potential cases of anaphylaxis were reported during the LTE period but after medical review did not meet anaphylaxis criteria. Potential anaphylaxis terms were identified as per standardized Medical Dictionary for Regulatory Activities queries for anaphylactic reaction and as defined by Sampson et al.
      • Sampson H.A.
      • Munoz-Furlong A.
      • Campbell R.L.
      • et al.
      Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium.
      The overall IR of injection site reactions was 2.2 (33 patients) over the entire LTE period; the IR was 18.8 at year 1 and decreased to 1.1 in year 5. Adjudicated cerebrocardiovascular events were reported by 13 patients (IR, 0.9). Two reported cases of Crohn's disease (IR, 0.1) were adjudicated as probable and occurred in year 5. Both of the cases were moderate in severity, and 1 of the patients discontinued because of the event. One case of ulcerative colitis (IR, 0.1) was adjudicated as probable and occurred in year 1. The event was moderate in severity and was not resolved; the patient discontinued treatment because of the AE. During the LTE period, 3 (IR, 0.2) deaths were noted. Causes of death were hemorrhagic cerebral infarction, complication due to postoperative situation, and death due to unknown cause. In all 3 cases, deaths were judged as not related to IXE by the treating physician. AE data of all IXE-exposed patients during the LTE period are presented in Supplemental Table III (available via Mendeley at http://doi.org/10.17632/rgrg58szs6.2).

      Discussion

      The sustainability of response and absence of serious adverse effects with chronic use are crucial factors for consideration when optimizing therapy for patients with psoriasis.
      • Kaushik S.B.
      • Lebwohl M.G.
      Psoriasis: which therapy for which patient: psoriasis comorbidities and preferred systemic agents.
      ,
      • Kaushik S.B.
      • Lebwohl M.G.
      Psoriasis: which therapy for which patient: focus on special populations and chronic infections.
      This report evaluated treatment efficacy with an approved IXE dose (IXE every 2 weeks/every 4 weeks) over 5 years from the UNCOVER-3 study. Results illustrated sustained efficacy responses through 5 years of treatment with the approved IXE dose, consistent with findings previously reported in patients with moderate to severe psoriasis. Approximately half of the patients receiving the approved dose reported complete resolution of psoriasis (ie, PASI 100 or sPGA of 0). A majority of patients had near-complete resolution (PASI 90) of psoriasis at week 264. Sustained high responses were observed with the efficacy parameters of PASI 75, 90, 100 and sPGA of 0 or 0/1 regardless of the statistical method used (as-observed, MI, or mNRI), supporting consistency of the results. Efficacy results for the approved dosing group with every-2-weeks dosing escalations were similar to that of the group without dosing escalations. However, given that the dosage was escalated at the investigator's discretion and at different times for each patient, the patterns of overall dosing escalation efficacy are difficult to discern. During the LTE period, discontinuation due to loss of efficacy was 3.1%, which further supports the long-term efficacy of IXE. In addition, high clearance rates of scalp, fingernail, and palmoplantar psoriasis were observed through 264 weeks of treatment, with the majority of patients achieving complete resolution. Moreover, 57.7% of patients also reported no itch (Itch NRS, 0), which correlates with improvements in patients' quality of life.
      • Leonardi C.L.
      • Blauvelt A.
      • Sofen H.L.
      • et al.
      Rapid improvements in health-related quality of life and itch with ixekizumab treatment in randomized phase 3 trials: results from UNCOVER-2 and UNCOVER-3.
      The safety profile of the approved IXE dosing regimen over 5 years was similar to those of previous reports, with no unexpected safety outcomes and no new adverse events.
      • Blauvelt A.
      • Gooderham M.
      • Iversen L.
      • et al.
      Efficacy and safety of ixekizumab for the treatment of moderate-to-severe plaque psoriasis: results through 108 weeks of a randomized, controlled phase 3 clinical trial (UNCOVER-3).
      ,
      • Lebwohl M.G.
      • Gordon K.B.
      • Gallo G.
      • Zhang L.
      • Paul C.
      Ixekizumab sustains high level of efficacy and favourable safety profile over 4 years in patients with moderate psoriasis: results from UNCOVER-3 study.
      ,
      • Leonardi C.
      • Maari C.
      • Philipp S.
      • et al.
      Maintenance of skin clearance with ixekizumab treatment of psoriasis: three-year results from the UNCOVER-3 study.
      ,
      • Leonardi C.
      • Reich K.
      • Foley P.
      • et al.
      Efficacy and safety of ixekizumab through 5 years in moderate-to-severe psoriasis: long-term results from the UNCOVER-1 and UNCOVER-2 phase 3 randomized controlled trials.
      The majority of the TEAEs were mild to moderate in nature, and overall discontinuation due to AEs was low (IR, 2.2). Infections, such as nasopharyngitis and upper respiratory tract infection, were the most frequently reported AEs but decreased after year 1 and remained stable. Crohn's disease and ulcerative colitis events were low during the LTE period and consistent with background rates.
      • Ng S.C.
      • Shi H.Y.
      • Hamidi N.
      • et al.
      Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies.
      • Langley R.G.
      • Kimball A.B.
      • Nak H.
      • et al.
      Long-term safety profile of ixekizumab in patients with moderate-to-severe plaque psoriasis: an integrated analysis from 11 clinical trials.
      • Armstrong A.
      • Paul C.
      • Puig L.
      • et al.
      Safety of ixekizumab treatment for up to 5 years in adult patients with moderate-to-severe psoriasis: results from greater than 17,000 patient-years of exposure.
      Similar to prior findings,
      • Bobonich M.
      • Young M.
      • Parker P.
      • Xu W.
      • Ridenour T.
      Candida infections in clinical trials of ixekizumab (Taltz), an interleukin-17A Monoclonal antibody, in patients with psoriasis or psoriatic arthritis.
      Candida events remained low during the LTE period, and no severe or systemic Candida events were reported. These findings demonstrate the consistency in the safety profile of the approved IXE treatment regimen over time.
      The UNCOVER-3 study was multicenter and included a geographically diverse demographic population that was overall representative of the affected patient population, which increases the generalizability of the results. However, the LTE period was open label and lacked head-to-head comparisons to placebo or etanercept, which were included during the first 12 weeks of UNCOVER-3. The results reported here illustrate the consistency of the safety profile for the approved dosing regimen of IXE as well as sustained long-term efficacy through 5 years of treatment in patients with moderate to severe plaque psoriasis.

      Conflicts of interest

      Dr Blauvelt has served as a scientific advisor and/or clinical study investigator for AbbVie, Aclaris, Almirall, Arena, Athenex, Boehringer Ingelheim, Bristol Myers Squibb, Dermavant, Dermira, Eli Lilly and Company, Forte, Galderma, Janssen, Leo, Novartis, Ortho, Pfizer, Rapt, Regeneron, Sandoz, Sanofi Genzyme, Sun Pharma, and UCB Pharma and as a paid speaker for AbbVie. Dr Lebwohl is an employee of Mount Sinai; receives research funds from AbbVie , Amgen , Arcutis , AstraZeneca , Boehringer Ingelheim , Celgene , Clinuvel , Eli Lilly , Incyte , Janssen Research and Development, LLC , Kadmon Corp, LLC , Leo Pharmaceuticals , MedImmune , Novartis , Ortho Dermatologics , Pfizer , Sciderm , UCB , and Vida ; and is a consultant for Allergan, Almirall, Arcutis, Inc, Avotres Therapeutics, BirchBioMed Inc, Boehringer Ingelheim, Bristol Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Evelo, Foundation for Research and Education in Dermatology, Inozyme Pharma, LEO Pharma, Meiji Seika Pharma, Menlo, Mitsubishi, Neuroderm, Pfizer, Promius/Dr. Reddy's Laboratories, Theravance, and Verrica. Dr Mabuchi has served as a paid speaker for Eli Lilly, Maruho, Kyowa Kirin, Celgene, and Janssen and has received research funds from Kyowa Kirin , Torii , Maruho , Taiho , and Leo Pharma . Author Leung is an employee of Syneos Health, on behalf of Eli Lilly. Dr Garrelts, Author Crane, Drs ElMaraghy and Patel, Author Ridenour, and Drs See and Gallo are employees of Eli Lilly and Company and own stock. Dr Paul is a consultant and investigator for Amgen, AbbVie, Almirall, Boehringer Ingelheim, Celgene, Dermira, Janssen-Cilag, Leo Pharma, Eli Lilly and Company, GlaxoSmithKline, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi Genzyme, and UCB Pharma.
      The authors would like to thank the patients, their families, and the study personnel who participated in this clinical trial. The authors would also like to thank Chenyun Tan, PharmD, an employee of Eli Lilly and Company, for writing support.

      Supplementary data

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