Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis.
BACKGROUND
Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1.


METHODS
We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12.


RESULTS
In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease.


CONCLUSIONS
In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known. (Funded by Eli Lilly; UNCOVER-1, UNCOVER-2, and UNCOVER-3 ClinicalTrials.gov numbers NCT01474512, NCT01597245, and NCT01646177, respectively.).
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Kenneth B
KB
Gordon
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Andrew
A
Blauvelt
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Kim A
KA
Papp
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Richard G
RG
Langley
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Thomas
T
Luger
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Mamitaro
M
Ohtsuki
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Kristian
K
Reich
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
David
D
Amato
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Susan G
SG
Ball
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Daniel K
DK
Braun
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Gregory S
GS
Cameron
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Janelle
J
Erickson
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Robert J
RJ
Konrad
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Talia M
TM
Muram
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Brian J
BJ
Nickoloff
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Olawale O
OO
Osuntokun
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Roberta J
RJ
Secrest
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Fangyi
F
Zhao
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Lotus
L
Mallbris
From the Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago (K.B.G.); Oregon Medical Research Center, Portland (A.B.); K. Papp Clinical Research and Probity Medical Research, Waterloo, ON (K.A.P.), and the Department of Medicine, Division of Dermatology, Dalhousie University, Halifax, NS (R.G.L.) - both in Canada; the Department of Dermatology, University of Münster, Münster (T.L.), and SCIderm Research Institute and Dermatologikum Hamburg, Hamburg (K.R.) - both in Germany; the Department of Dermatology, Jichi Medical University, Shimotsuke-shi, Japan (M.O.); Lilly Research Laboratories, Eli Lilly, Indianapolis (D.A., S.G.B., D.K.B., G.S.C., J.E., R.J.K., T.M.M., B.J.N., O.O.O., R.J.S., F.Z., L.M.); and the Department of Dermatology, Saint Louis University School of Medicine, St. Louis (C.L.L.).
Craig L
CL
Leonardi
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D002177:Candidiasis / Q000209:etiology; D005260:Female; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D011565:Psoriasis / Q000188:drug therapy*; D012720:Severity of Illness Index
D061067:Antibodies, Monoclonal, Humanized; C549079:ixekizumab