Study of Safety, Efficacy and Tolerability of Secukinumab Versus Placebo, in Combination With SoC Therapy, in Patients With Active Lupus Nephritis

This was a pivotal, randomized, double-blind, placebo-controlled trial evaluating at Week 52 the efficacy and safety of secukinumab versus placebo in patients with active lupus nephritis (ISN/RPS Class III or IV, with or without co-existing class V features) also receiving background standard of care therapy (SoC).

The study consisted of the following parts:

* Screening (up to 42 days/6 weeks)
* Run-in period (optional): For subjects who received Mycophenolic acid (MPA) as SoC induction therapy as per investigator's decision and who were not already on MPA at Screening, MPA dosing was initiated during a run-in period before Randomization (for up to 4 weeks prior to the first dose of secukinumab)
* Treatment Period: Duration of 104 weeks of treatment with secukinumab/placebo in addition to SoC treatment (with last dose given at Week 100)
* Secukinumab dosing was started with initial dosing of 300 mg s.c. injections at Baseline, Weeks 1, 2, 3, and 4, followed by dosing every 4 weeks
* Follow-up period: Duration of 8 weeks (last visit performed 12 weeks after last dose of study medication) for all except for subjects entering extension study CAIN457Q12301E1 (NCT05232864).

A total of 275 subjects were enrolled and were randomized to secukinumab 300 mg (n = 137) or placebo (n = 138) until study termination. Recruitment in this study was stopped on 26-May-2023. The CAIN457Q12301 study was terminated early by Novartis due to futile results from interim analysis 1 (IA1). There was no safety related reasons for early termination or concerns for the subjects in the study. The decision was made to terminate both the core and the related extension study in view of treatment futility of the core study.

Eligibility Criteria:
Key inclusion criteria:

1. Adult male and female subjects aged 18 - 75 years old at the time of Baseline.
2. Confirmed diagnosis of:

   * SLE with documented history of at least 4 of the 11 criteria for SLE as defined by the American College of Rheumatology (ACR) (Tan et al 1982) revised by (Hochberg 1997). \[NOTE: The 4 criteria did not have to be present at the time of Screening\], OR
   * LN as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies.
3. Active lupus nephritis, as defined by meeting the 4 following criteria:

   * Biopsy within 6 months prior to Screening visit indicating active glomerulonephritis WHO or ISN/RPS Class III or IV LN \[excluding III (C), IV-S (C) and IV-G (C)\]; patients are permitted to have co-existing Class V. If no biopsy was performed within 6 months of screening, a biopsy was to be performed during the Screening period
   * UPCR ≥ 1 mg/mg at Screening.
   * eGFR \> 30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI).
   * Active urinary sediment (presence of cellular casts (RBC or WBC casts)) or hematuria (\> 5 RBC per high power field or above the laboratory reference range).
4. Subjects must have currently been on MPA, or willing to initiate SoC induction therapy for LN according to the institutional practices using MPA or low-dose CYC in addition to corticosteroids. For guidance, see published guidelines such as by (Bertsias et al 2012, Hahn et al 2012).
5. Subjects must had been treated with anti-malarials (e.g. hydroxychloroquine), unless contra-indicated, and the dose had been stable for at least 10 days prior to Randomization.
6. Able to provide signed informed consent.

Key Exclusion criteria:

1. Severe renal impairment as defined by i.) Stage 4 CKD, or ii.) presence of oliguria (defined as a documented urine volume \< 400 mL/24 h), or iii.) ESRD required dialysis or transplantation.
2. Known intolerance/hypersensitivity to MPA, or oral corticosteroids, or any component of the study drug(s).
3. Subjects received any other biologic immunomodulatory therapy within 6 months prior to Screening, excluding belimumab where 3 months were acceptable.
4. Previous exposure to secukinumab (AIN457) or any other biologic drug targeting IL-17 or the IL-17 receptor.
5. Subjects received any investigational drug within 1 month or five times the half-life of enrollment, whichever was longer.
6. Receipt of more than 3000 mg i.v. pulse methylprednisolone (cumulative dose) within the 12 weeks prior to Baseline.
7. Treatment with a systemic calcineurin inhibitor (e.g. cyclosporine, tacrolimus) within 12 weeks prior to Baseline
8. CYC use (i.v. or oral) within the month prior to Baseline.
9. Subjects requiring dialysis within the previous 12 months before Screening.
10. History of renal transplant.
11. Any severe progressive or uncontrolled concurrent medical condition, including recent severe thromboembolic events, that, in the opinion of the principal investigator, renders the subject unsuitable for the trial.
12. Active ongoing inflammatory diseases that might confound the evaluation of the benefit of secukinumab therapy, including inflammatory bowel disease.
13. Presence of investigator-identified significant medical problems which at the investigator's discretion would prevent the subject from participating in the study, included but not limited to the following: myocarditis, pericarditis, poorly controlled seizure disorder, acute confusional state, depression, severe manifestations of neuropsychiatric SLE (NPSLE).
14. Chest X-ray, computerized tomography (CT) scan, or MRI with evidence of ongoing infectious or malignant process, obtained within 3 months preceding the Screening visit and evaluated by a qualified physician.
15. History of chronic, recurrent systemic infections, active tuberculosis infection, or active systemic infections during the last two weeks (exception: common cold) prior to Randomization.
16. Known infection with human immunodeficiency virus (HIV), hepatitis B or hepatitis C at Screening or Randomization.
17. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system treated or untreated within the past 5 years, regardless of whether there was evidence of local recurrence or metastases (except for skin Bowen's disease or basal cell carcinoma or actinic keratoses that had been treated with no evidence of recurrence in the past 12 weeks, carcinoma in situ of the cervix or non-invasive malignant colon polyps that had been removed).
18. Any of the following abnormal laboratory values on Screening evaluations as reported by Central Laboratory:

    * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or amylase \> 2.5xULN
    * Hemoglobin \< 8g/dL
    * Neutrophils \< 1.0 x 109/L
    * Platelet count \< 50 x 109/L

21. Pregnant or lactating women. 22. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, unless they were using highly effective methods of contraception during the entire study or longer if required by locally approved prescribing information (e.g., in European Union (EU) 20 weeks). Of note: the highly effective methods of contraception were mandated due to SoC medications used as per protocol (MPA and CYC).

In case local regulations deviated from the contraception methods listed above, local regulations applied and were described in the informed consent form (ICF).

If stricter female or male contraception requirements were specified in the country-specific label for induction and maintenance standard of care medications, they had to be followed.

Note: Women were considered post-menopausal and not of childbearing potential if they had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to enrollment. In the case of oophorectomy alone, only when the reproductive status of the woman had been confirmed by follow-up hormone level assessment was she considered not of childbearing potential.