SAPHNELO Concentrate for solution for infusion Ref.[50047] Active ingredients: Anifrolumab

Pharmacotherapeutic group: Immunosuppressants, Selective immunosuppressants
ATC code: L04AA51

Mechanism of action

Anifrolumab is a human immunoglobulin G1 kappa monoclonal antibody that binds to subunit 1 of the type I interferon receptor (IFNAR1) with high specificity and affinity. This binding inhibits type I IFN signalling thereby blocking the biologic activity of type I IFNs. Anifrolumab also induces the internalisation of IFNAR1, thereby reducing the levels of cell surface IFNAR1 available for receptor assembly. Blockade of receptor mediated type I IFN signalling inhibits IFN responsive gene expression as well as downstream inflammatory and immunological processes. Inhibition of type I IFN blocks plasma cell differentiation and normalises peripheral T-cell subsets, restoring the balance between adaptive and innate immunity that is dysregulated in SLE.

Pharmacodynamic effects

In adult patients with SLE, administration of anifrolumab at doses ≥300 mg, via intravenous infusion every 4 weeks, demonstrated consistent neutralisation (≥80%) of a 21 gene type I interferon pharmacodynamic (PD) signature in blood. This suppression occurred as early as 4 weeks posttreatment and was either maintained or further suppressed over the 52-week treatment period. Following withdrawal of anifrolumab at the end of the 52-week treatment period in the SLE clinical trials, the type I IFN PD signature in blood samples returned to baseline levels within 8 to 12 weeks. Anifrolumab 150 mg IV showed <20% suppression of the gene signature at early timepoints, that reached a maximum of <60% by the end of the treatment period.

In SLE patients with positive anti-dsDNA antibodies at baseline, treatment with anifrolumab 300 mg led to numerical reductions in anti-dsDNA antibodies over time through Week 52.

In patients with low complement levels (C3 and C4), increases in complement levels were observed in patients receiving anifrolumab through Week 52.

Clinical efficacy

The safety and efficacy of anifrolumab were evaluated in two 52-week treatment period, multicentre, randomised, double-blind, placebo-controlled, Phase III studies (Trial 1 [TULIP 1] and Trial 2 [TULIP 2]). Patients were diagnosed with SLE according to the American College of Rheumatology (1997) classification criteria.

All patients were ≥18 years of age and had moderate to severe disease, with a SLE Disease Activity Index 2000 (SLEDAI-2K) score ≥6 points, organ level involvement based on British Isles Lupus Assessment Group (BILAG) assessment, and a Physician’s Global Assessment [PGA] score ≥1, despite receiving standard SLE therapy consisting of either one or any combination of oral corticosteroids (OCS), antimalarials and/or immunosuppressants at baseline. With the exception of OCS (prednisone or equivalent) where tapering was a component of the protocol, patients continued to receive their existing SLE therapy at stable doses during the clinical trials. Patients who had severe active lupus nephritis and patients who had severe active central nervous system lupus were excluded. The use of other biologic agents and cyclophosphamide were not permitted during the clinical trials. Patients receiving other biologic therapies were required to complete a wash-out period of at least 5 half-lives prior to enrolment. Both studies were conducted in North America, Europe, South America and Asia. Patients received anifrolumab or placebo, administered by intravenous infusion, every 4 weeks.

Trial 1 (N=457) and Trial 2 (N=362) were similar in design.

In Trial 1 the primary endpoint was SLE Responder Index (SRI-4) response, defined as meeting each of the following criteria at Week 52 compared with baseline:

• Reduction from baseline of ≥4 points in the SLEDAI-2K;
• No new organ system affected as defined by 1 or more BILAG A or 2 or more BILAG B items compared to baseline;
• No worsening from baseline in the lupus disease activity defined by an increase ≥0.30 points on a 3-point PGA visual analogue scale (VAS);
• No use of restricted medication beyond the protocol-allowed thresholds;
• No discontinuation of treatment.

In Trial 2 the primary endpoint was British Isles Lupus Assessment Group based Composite Lupus Assessment (BICLA) response at Week 52, defined as improvement in all organ domains with moderate or severe activity at baseline:

• Reduction of all baseline BILAG A to B/C/D and baseline BILAG B to C/D, and no BILAG worsening in other organ systems, as defined by ≥1 new BILAG A or ≥2 new BILAG B;
• No worsening from baseline in SLEDAI-2K, where worsening is defined as an increase from baseline of >0 points;
• No worsening from baseline in lupus disease activity, where worsening is defined by an increase ≥0.30 points on a 3-point PGA VAS;
• No use of restricted medication beyond the protocol-allowed thresholds;
• No discontinuation of treatment.

The secondary efficacy endpoints included in both studies included maintenance of OCS reduction and annual flare rate. Both studies evaluated the efficacy of anifrolumab 300 mg versus placebo.

Patient demographics were generally similar in both trials; the median age was 41.3 and 42.1 years (range 18-69), 4.4% and 1.7% were ≥65 years of age, 92% and 93% were female, 71% and 60% were White, 14% and 12% were Black/African American, and 5% and 17% were Asian, in Trials 1 and 2 respectively. In both trials, 72% of patients had high disease activity (SLEDAI-2K score ≥10). In Trials 1 and 2 respectively, 47% and 49% had severe disease (BILAG A) in at least 1 organ system and 46% and 47% of patients had moderate disease (BILAG B) in at least 2 organ systems. The most commonly affected organ systems (BILAG A or B at baseline) were the mucocutaneous (Trial 1: 87%, Trial 2: 85%) and musculoskeletal (Trial 1: 89%, Trial 2: 88%) systems.

In Trials 1 and 2, 90% of patients (both trials) were seropositive for anti-nuclear antibodies (ANA), and 45% and 44% for anti-double-stranded DNA (anti-dsDNA) antibodies; 34% and 40% of patients had low C3, and 21% and 26% had low C4.

Baseline concomitant standard therapy medications included oral corticosteroids (Trial 1: 83%, Trial 2: 81%), antimalarials (Trial 1: 73%, Trial 2: 70%) and immunosuppressants (Trial 1: 47%, Trial 2: 48%; including azathioprine, methotrexate, mycophenolate and mizoribine). For those patients taking OCS (prednisone or equivalent) at baseline, the mean daily dose was 12.3 mg in Trial 1 and 10.7 mg in Trial 2. During Weeks 8-40, patients with a baseline OCS ≥10 mg/day were required to taper their OCS dose to ≤7.5 mg/day, unless there was worsening of disease activity.

For BICLA and SRI response, patients who withdrew from treatment prior to Week 52 were considered non-responders. In Trial 1 and 2 respectively, 35 (19%) and 27 (15%) patients receiving anifrolumab, and 38 (21%) and 52 (29%) patients receiving placebo withdrew from treatment prior to Week 52. The results are presented in Table 2.

Table 2 Efficacy results in adults with SLE in Trial 1 and Trial 2:

BICLA: British Isles Lupus Assessment Group-based Composite Lupus Assessment; BILAG: British Isles Lupus Assessment Group, PGA: Physician’s Global Assessment; SLEDAI-2K: Systemic Lupus Erythematosus Disease Activity Index 2000; SRI-4: SLE Responder Index.
All patients received standard therapy.
^* BICLA and SRI are based on the composite estimand where treatment discontinuation or restricted medication use are part of the response criteria.
^† Patients who discontinued treatment or used restricted medications beyond protocol allowed threshold are considered non-responders.
^‡ Subgroup of patients with OCS ≥10 mg/day at baseline. Responders were defined as patients with OCS reduction to ≤7.5 mg/day at Week 40, maintained through Week 52.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with anifrolumab in one or more subset of the paediatric population in treatment of systemic lupus erythematosus (see section 4.2 for information on paediatric use).