Objective To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care.
Methods Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering.
Results IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduced the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN-K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable.
Conclusions IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering.
Trial registration number NCT02665364.
- systemic lupus erythematosus
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Handling editor Josef S Smolen
Presented at The results of the phase IIb in systemic lupus erythematosus were presented at the 13th International Congress on Systemic Lupus Erythematosus (LUPUS 2019), San Francisco, California, USA (abstract #198).
Contributors FH drafted the manuscript and AT, MT and TC were involved in revising it critically for important content. All other authors were involved in revising the article prior the submission. FH had full access to all data in the study and takes the responsibility for the integrity of the data and the accuracy of the data analyses. FH, AT, MT and TC were responsible for study conception and design. All authors, except TC, were involved in data acquisition, while FH, AT, MT and TC were responsible for data analysis and interpretation.
Funding This study was funded by Neovacs S.A.
Competing interests FH reports grants from Neovacs during the conduct of the study and outside the submitted work. AT reports personal fees from Neovacs during the conduct of the study. MT reports grants and personal fees from Neovacs during the conduct of the study. TC was an employee and shareholder of Neovacs at the time of the conduct and analyses of the data.
Patient consent for publication Not required.
Ethics approval Argentina: CEIC Larrea; ID: 1254/63/2015. Belgium: CEC Hospitalo-Facultaire; ID: 2015/12JUI/339. Chile: (1) CE-Cientifico Adultos, ID: EC692186/15; (2) Comite de Evaluacion Etico-Cientifico, ID: 13/August/2015. Colombia: (1) CEI Riesgo de Fractura, ID: 22 959; (2) CE en el Área de la Salud, ID: #129; (3) CEIC-CAIMED; ID: CEIC-CAIMED/#016/15; (4) Comité de Investigaciones y Ética en investigación Hospital Pablo Tobón Uribe, ID: #09/2016; (5) Comité de Ética en Investigación del Oriente, ID: #4. Croatia: CEC, ID:530-07/15-01/47. France: CPP Nord-Ouest IV, ID: CPP 15/35. Georgia: (1) EC of Ltd 'National Institute of Endocrinology', ID: Letter of 19/June/2015; (2) EC of Ltd 'Medulla', Chemotherapy and Immunotherapy, ID: Letter of 5/June/2015; (3) EC of Ltd 'Medicore', ID: Letter of 04/June/2015; (4) EC of 'Mediclub', ID: Letter of 02/June/2015. Germany: (1) EC der Justus Liebig-Universität, ID: 122/15; (2) EC des Landes Berlin, ID: 122/15; (3) Geschäftsstelle Ethikkommission Universität zu Köln Gebäude, ID:122/15; (4) EC der Landesärztekammer Rheinland-Pfalz, ID:122/15; (5) EC bei der LMU München, ID: 122/15; (6) Medizinische Hochschule Hannover Ethikkommission, ID: 1122/15. Italy: (1) Comitato Etico Milano, ID: 50 372 of 28/October/2015; (2) Nucleo Ricerca Clinica AOUI di Verona, ID: 688CESC; (3) Comitato di Bioetica/Bioethics Committee, ID: E_20160020098; (4) Comitato Etico dell’Università “La Sapienza” di Roma, ID: 2912/15 (ref. 3890); (5) Segreteria Scientifica CE per Ia Sperimentazione clinica della Provincia di Padova, ID: 3662/AO/15; (6) CE-AVEC, ID:180/2015/0/Sper; (7) CE di Area Vasta Nord Oves, ID: 754/2015. Mexico: (1) CE en Investigación de la Unidad Medica de Diagnostico y Tratamiento S.A., ID: Control 006; (2) CE en Investigación Clinbor, ID: N° 06/2015; (3) CECEI BAC, ID: CECEI BAC 21/August/15; (4) CE en Investigación de la Clínica Bajío CLINBA, S, ID: 15–034; (5) MCCR, ID: MCCR-15/1213 (v) Comité de Investigación del Antiguo Hospital Civil de Guadalajara, ID:234/15; (6) CE en Investigación de la Unidad Medica de Diagnostico y Tratamiento S.A de C.V, ID: Letter of 06/Aug/2015; (7) CE en Investigación del Hospital Aranda de la Parra, ID: Letter of 20/August/2015; (8) CE en Investigación de la Clínica Bajío CLINBA, ID:15–034. Peru: (1) CIEI-USMP-CCM, ID: #1030–2015; (2) CIEI-USMP-CCM, ID: 1031–2015; (3) CIEI-USMP-CCM, ID: 1029–2015; (4) Comité de Etica en Investigacion del Hospital Nacional Guillermo Almenara Irigoyen, ID: Letter N°245 CEI-OCID-G-RAA-ESSALUD-2015; (5) Comité Institucional de Etica en Investigación de la Universidad de San Martin de Porres, ID: 1032–2015-CIEI-USMP-CCM. Philipines: (1) EC of Medical Center of Manila; ID: MMERC 2015–05; (2) EC of Chong Hua Hospital, ID: IRB-2615–08; (3) EC of St. Luke's Medical Centre, ID: CT-15074; (4) EC of Southern Philippines Medical Centre, ID: P15091101. Poland: CEC Komisja Bioetyczna przy Okręgowej Radzie Lekarskiej Wielkopolskiej Izby Lekarskiej, ID: Poland 121/2015. Russia: (1) Kemerovo Regional Clinical Hospital LEC, ID: SBEI HPE OSMU/#123; (2) CEC: Ministry of Healthcare of the Russian Federation, Ethics LEC of State Budgetary Healthcare Institution, ID: 23; (3) Ministry of Healthcare of the Russian Federation, Ethics Council-Ethics Committee of State Budgetary Healthcare Institution of Sverdlovsk Region 'Sverdlovsk Regional Clinical Hospital #1', ID: RSEC/#117; (4) CEC: Ministry of Healthcare of the Russian Federation, Ethics Council; LEC: EC of State Budgetary Educational Institution of Higher Professional Education 'Saratov State Medical University', ID: EC of SBEI Saratov SMU/# 1; (5) Local Independent Ethics and Evidence of Medical Scientific Trials Committee of State Autonomous Healthcare Institution of Kemerovo Region 'Kemerovo Regional Clinical Hospital', ID: SAHI/KRCH/ #1; (6) EC of Central Clinical Hospital of Russian Academy of Sciences CCH RAS, ID: Ethics Committee of CCH/RAS/#92; (7) EC of State Budget Healthcare Institution of Kemerovo region 'Regional Clinical Hospital for War Veterans', ID: #103/2; (8) LEC of North-Western State Medical University, ID: LEC of SBE HPENWSMU Mechnikov/#8; (9) LEC of 'Medical-Sanitary Unit #157', ID: #7; (10) Russia EC of Budgetary Healthcare Institution of Omsk Region 'Regional Clinical Hospital', ID: EC of BHIOR‘RCH’/#15; (11) Russia LEC of 'Clinical-Diagnostic Center ' Ultramed, ID: #4. South Korea: (1) IRB of The Catholic University, ID: SC15BGGS0112; (2) IRB of Boramae Medical Centre, ID: 20150714/16-2015-97/081; (3) IRB of Eulji University Hospital, ID: 2015-07-012-001; (4) IRB of Konkuk University Medical Centre, ID: KUH1010693; (5) IRB of Ajou University Hospital, ID: AJIRB-MED-BDR-15–302. Spain: CE de la Investigación con Medicamentos, ID :Act N° 392. Switzerland: Commission cantonale (VD) d'éthique de la recherche sur l'être humain, ID: 388/15. Taiwan: (1) REC, China Medical University Hospital, ID: 104-REC2-127; (2) IRB, ID: 1-105-05-019; (3) IRB, Taipei Veterans General Hospital, ID: 2016–02 004BU; (4) IRB, Chang Gung Medical Foundation, ID: 104-5919A; (5) Research Ethics Committee, National Taiwan University Hospital, ID: 201 602 031MSD; (6) IRB, Chung Shan Medical University Hospital, ID: CS2-15110. Thailand: (1) Siriraj IRB, ID :450/2558; (2) Research EC3, ID: 499/2015; (3) CREC, Rajavithi Hospital, ID: 025/58BPs. Moldova: Comitetul Naţional de Etică pentru studiul clinic al medicamentelor şi metodelor noi de tratament, ID: 199. USA: (1) Schulman/Advarra IRB, ID: Pro00025952; (2) Columbia Research Human Research Protection Office IRB, ID: IRB-AAAQ8645; (3) University of California, San Diego USCD-HRPP, ID: 170 273. Tunisia: CPP SE prêtant à l’expérimentation médicale ou scientifique des médicaments destinés à la médecine humaine, ID: TN2016-INT-IND-31.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available in a public, open access repository. Additional study design details are available on clinical trial.gov (NCT02665364) and clinicaltrialsregister.eu (EudraCT 2015-001341-86). Per regulation, main study results will be posted on the same registries.