Tags

Type your tag names separated by a space and hit enter

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 Aug 08; 386(9993):541-51.Lct

Abstract

BACKGROUND

Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis.

METHODS

In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177.

FINDINGS

Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted.

INTERPRETATION

Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option.

FUNDING

Eli Lilly and Co.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Griffiths CE
Dermatology Centre, Salford Royal Hospital, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address: christopher.griffiths@manchester.ac.uk.
Reich K
Dermatologikum Hamburg and SCIderm Research Institute, Hamburg, Germany.
Lebwohl M
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
van de Kerkhof P
Department of Dermatology, Radboud University Nijmegen, Nijmegen, Netherlands.
Paul C
Department of Dermatology, Paul Sabatier University, Toulouse, France.
Menter A
University of Texas, Southwestern Medical School, Dallas, TX, USA.
Cameron GS
Eli Lilly and Company, Indianapolis, IN, USA.
Erickson J
Eli Lilly and Company, Indianapolis, IN, USA.
Zhang L
Eli Lilly and Company, Indianapolis, IN, USA.
Secrest RJ
Eli Lilly and Company, Indianapolis, IN, USA.
Ball S
Eli Lilly and Company, Indianapolis, IN, USA.
Braun DK
Eli Lilly and Company, Indianapolis, IN, USA.
Osuntokun OO
Eli Lilly and Company, Indianapolis, IN, USA.
Heffernan MP
Eli Lilly and Company, Indianapolis, IN, USA.
Nickoloff BJ
Eli Lilly and Company, Indianapolis, IN, USA.
Papp K
Probity Medical Research, Waterloo, ON, Canada.
UNCOVER-2 and UNCOVER-3 investigators
No affiliation info available

MeSH

AdultAnti-Inflammatory Agents, Non-SteroidalAntibodies, Monoclonal, HumanizedChronic DiseaseDouble-Blind MethodDrug Administration ScheduleEtanerceptFemaleHumansImmunoglobulin GMaleMiddle AgedProspective StudiesPsoriasisReceptors, Tumor Necrosis FactorTreatment Outcome

Pub Type(s)

Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26072109

Clinical Trial Links

Clinical trial which this article describes [1]
Clinical trial which this article describes [2]

Citation

Griffiths, Christopher E 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." Lancet (London, England), vol. 386, no. 9993, 2015, pp. 541-51.
Griffiths CE, 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. Lancet. 2015;386(9993):541-51.
Griffiths, C. E., Reich, K., Lebwohl, M., van de Kerkhof, P., Paul, C., Menter, A., Cameron, G. S., Erickson, J., Zhang, L., Secrest, R. J., Ball, S., Braun, D. K., Osuntokun, O. O., Heffernan, M. P., Nickoloff, B. J., & Papp, K. (2015). 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 (London, England), 386(9993), 541-51. https://doi.org/10.1016/S0140-6736(15)60125-8
Griffiths CE, 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. Lancet. 2015 Aug 8;386(9993):541-51. PubMed PMID: 26072109.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. AU - Griffiths,Christopher E M, AU - Reich,Kristian, AU - Lebwohl,Mark, AU - van de Kerkhof,Peter, AU - Paul,Carle, AU - Menter,Alan, AU - Cameron,Gregory S, AU - Erickson,Janelle, AU - Zhang,Lu, AU - Secrest,Roberta J, AU - Ball,Susan, AU - Braun,Daniel K, AU - Osuntokun,Olawale O, AU - Heffernan,Michael P, AU - Nickoloff,Brian J, AU - Papp,Kim, AU - ,, Y1 - 2015/06/10/ PY - 2015/6/15/entrez PY - 2015/6/15/pubmed PY - 2015/9/4/medline SP - 541 EP - 51 JF - Lancet (London, England) JO - Lancet VL - 386 IS - 9993 N2 - BACKGROUND: Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. METHODS: In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov, numbers NCT01597245 and NCT01646177. FINDINGS: Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. INTERPRETATION: Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. FUNDING: Eli Lilly and Co. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/26072109/Comparison_of_ixekizumab_with_etanercept_or_placebo_in_moderate_to_severe_psoriasis__UNCOVER_2_and_UNCOVER_3_:_results_from_two_phase_3_randomised_trials_ DB - PRIME DP - Unbound Medicine ER -