Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany
Pharmacotherapeutic group: immunosuppressants, interleukin inhibitors
ATC code: L04AC19
Satralizumab is a recombinant humanised immunoglobuline G2 (IgG2) monoclonal antibody (mAb) that binds to soluble and membrane-bound human IL-6 receptor (IL-6R) and thereby prevents IL-6 downstream signalling through these receptors.
IL-6 levels are increased in cerebrospinal fluid and serum of patients with NMO and NMOSD during periods of disease activity. IL-6 functions have been implicated in the pathogenesis of NMO and NMOSD, including B-cell activation, differentiation of B-cells to plasmablasts and production of pathological autoantibodies, e.g. against AQP4, a water channel protein mainly expressed by astrocytes in the CNS, Th17-cell activation and differentiation, T-regulatory cell inhibition, and changes in blood-brain-barrier permeability.
In clinical studies with satralizumab in NMO and NMOSD, decreases in C-reactive protein (CRP), fibrinogen and complement (C3, C4 and CH50) were observed.
The efficacy and safety of satralizumab were evaluated in two pivotal phase III clinical trials in patients with NMOSD (diagnosed as AQP4-IgG seropositive or seronegative NMO [Wingerchuck 2006 criteria], or as AQP4-IgG seropositive NMOSD [Wingerchuk 2007 criteria]). Study BN40898 included adult and adolescent NMOSD patients aged 12-74 years treated with stable IST, with at least 2 relapses in the last 2 years prior screening (with at least one relapse within the 12 months prior to screening) and expanded disability status scale (EDSS) of 0 to 6.5, whereas study BN40900 included adult patients aged 18-74 years on no background IST, with at least 1 relapse or first attack within the last 12 months prior to screening and EDSS of 0 to 6.5. Both studies included approximately 30% AQP4-IgG seronegative NMO patients.
Efficacy in both studies was evaluated based on time to first relapse as adjudicated by an independent Clinical Endpoint Committee (CEC), with relapse defined by pre-specified worsening in the EDSS and functional system score (FSS) criteria, evaluated within 7 days after the patient reported symptoms (adjudicated relapse).
Study BN40898 was a randomised, multicentre, double-blind, placebo-controlled clinical trial to evaluate the effect of satralizumab in combination with stable IST (OCs up to 15 mg/day [prednisolone equivalent], AZA up to 3 mg/kg/day or MMF up to 3000 mg/day, adolescents received a combination of AZA and OCs or MMF and OCs). The double blind period of the study included 83 AQP4-IgG seropositive and seronegative patients (76 adults and 7 adolescents). Patients received the first 3 single doses of satralizumab 120 mg or matching placebo by SC injection in the abdominal or femoral region every 2 weeks for the first 4 weeks and once every 4 weeks thereafter. Study design and baseline characteristics of the study population are presented in table 4.
Table 4. Study design and baseline characteristics in AQP4-IgG seropositive patients for study BN40898:
| Study name | Study BN40898 (AQP4-IgG seropositive: N=55; ITT*: N=83) | |
|---|---|---|
| Study design | ||
| Study population | Adolescent and adult patients with NMO or NMOSD, treated with stable IST Age 12-74 years, ≥2 relapses in the last 2 years prior screening (with at least one relapse in the 12 months prior to screening), EDSS of 0 to 6.5 | |
| Study duration for efficacy evaluation | Event-driven** (26 adjudicated relapses) Median follow-up time: satralizumab 139.4 weeks, placebo 40.2 weeks (in ITT: 115.1 weeks and 42.5 weeks, respectively) | |
| Treatment groups, in 1:1 randomisation | Group A: satralizumab 120 mg SC Group B: placebo | |
| Baseline characteristics of AQP4-IgG seropositive patients | Satralizumab + IST (n=27) | Placebo + IST (n=28) |
| Diagnosis, n (%): NMO NMOSD | 19 (70.4) 8 (29.6) | 14 (50.0) 14 (50.0) |
| Mean age in years (SD) (Min-Max) | 44.4 (15.7) (13–73) | 43.4 (12.9) (14–65) |
| Elderly (≥65 years), n (%) | 3 (11.1) | 1 (3.6) |
| Adolescents (≥12 to <18 years), n (%) | 1 (3.7) | 2 (7.1) |
| Gender distribution, n (%) male / n (%) female | 0/27 (100) | 0/28 (100) |
| Immunosuppressive therapy (IST), n (%): Oral corticosteroids (OCs) Azathioprine (AZA) Mycophenolate mofetil (MMF) AZA + OCs*** MMF + OCs*** | 14 (51.9) 11 (40.7) 1 (3.7) 0 1 (3.7) | 13 (46.4) 11 (39.3) 3 (10.7) 0 1 (3.6) |
* Intention-To-Treat (ITT)
** Patients treated with rescue therapy with no adjudicated relapse were allowed to enter the OLE period of the study and were censored from the primary efficacy analysis
*** Combination allowed for adolescent patients
Study BN40900 was a randomised, multicentre, double-blind, placebo-controlled clinical trial to evaluate the effect of satralizumab monotherapy compared to placebo. The study included 95 AQP4- IgG seropositive and seronegative adult patients. Patients received the first 3 single doses of satralizumab 120 mg or matching placebo by SC injection in the abdominal or femoral region every 2 weeks for the first 4 weeks and once every 4 weeks thereafter.
Study design and baseline characteristics of the study population are presented in table 5.
Table 5. Study design and baseline characteristics in AQP4-IgG seropositive patients for study BN40900:
| Study name | Study BN40900 (AQP4-IgG seropositive: N=64; ITT*: N=95) | |
|---|---|---|
| Study design | ||
| Study population | Adult patients with NMO or NMOSD Age 18-74 years, ≥1 relapse or first attack in the last 12 months prior to screening, EDSS of 0 to 6.5. Patients either received prior relapse prevention treatment for NMOSD or were treatment naïve. | |
| Study duration for efficacy evaluation | Event-driven (44 adjudicated relapses, or 1.5 years after the date of randomisation of the last patient enrolled, whichever comes first) Median follow-up time: satralizumab 96.7 weeks, placebo 60.1 weeks(in ITT: 95.4 weeks and 60.5 weeks, respectively) | |
| Treatment groups, in 2:1 randomisation | Monotherapy: Group A: satralizumab 120 mg SC Group B: placebo | |
| Baseline characteristics of AQP4-IgG seropositive patients | Satralizumab (n=41) | Placebo (n=23) |
| Diagnosis, n (%): NMO NMOSD | 26 (63.4) 15 (36.6) | 15 (65.2) 8 (34.8) |
| Mean age in years (SD) (Min-Max) | 46.0 (12.0) (22–70) | 40.1 (11.5) (20–56) |
| Elderly (≥65 years), n (%) | 1 (2.4) | 0 |
| Gender distribution, n (%) male / n (%) female | 10 (24.4) / 31 (75.6) | 1 (4.3) / 22 (95.7) |
* Intention-To-Treat (ITT)
In AQP4-IgG seropositive patients the relative risk of experiencing an adjudicated relapse in study BN40898 was reduced by 79% (Hazard Ratio, HR [95% CI]: 0.21 [0.06-0.75]), in study BN40900 by 74% (HR [95% CI]: 0.26 [0.11-0.63]) (see Figures 1 and 2). When data across studies BN40898 and BN40900 were pooled, treatment with satralizumab with or without IST led to an overall risk reduction of 75% (HR [95% CI]; 0.25 (0.12-0.50]) in AQP4-IgG seropositive patients. At 48 weeks, 85.7% of satralizumab-treated AQP4-IgG seropositive patients remained adjudicated relapse-free when used in combination with IST or as monotherapy compared to 58.7% in the placebo group. At 96 weeks, 81.4% of satralizumab-treated AQP4-IgG seropositive patients remained adjudicated relapse-free when used in combination with IST or as monotherapy compared to 47.2% in the placebo group. Efficacy was not significant in AQP4-IgG seronegative patients.
Figure 1. Study BN40898 – time to first adjudicated relapse during the double-blind period in AQP4-IgG seropositive patients:
Figure 2. Study BN40900 – time to first adjudicated relapse during the double-blind period in AQP4-IgG seropositive patients:
Treatment with satralizumab in AQP4-IgG seropositive patients reduced the annualized rate of adjudicated relapses (ARR) by 88% (rate ratio [RR]=0.122, 95% CI: 0.027 – 0.546; p=0.0039) in study BN40898 and 90% (RR=0.096, 95% CI: 0.020 – 0.473; p= 0.0086) in study BN40900 compared to treatment with placebo.
As compared to placebo-treated patients, the need for rescue therapy (e.g., corticosteroids, intravenous immunoglobulin, and/or apheresis [including plasmapheresis or plasma exchange]) was reduced in satralizumab-treated AQP4-IgG seropositive patients by 61% (odds ratio [OR]=0.3930, 95% CI: 0.1343-1.1502; p=0.0883) in study BN40898 and by 74% (OR=0.2617, 95% CI: 0.0862-0.7943; p=0.0180) in study BN40900.
Treatment with satralizumab in AQP4-IgG seropositive patients reduced the risk of experiencing a severe relapse defined as an EDSS increase ≥2 points from the previous EDSS assessment by 85% (time to severe adjudicated relapse during the double blind period; HR=0.15, 95% CI: 0.02-1.25; p=0.0441) in study BN40898 and by 79% (HR=0.21, 95% CI: 0.05-0.91; p=0.0231) in study BN40900 compared to treatment with placebo.
Change from baseline to week 24 in pain or fatigue were not met in studies BN40898 and BN40900.
Analyses of longer term data including the OLE period (based on relapse treated with rescue therapy) showed that 58% and 73% of AQP4-IgG seropositive patients treated with satralizumab remained relapse-free after 120 weeks of treatment, when satralizumab was administered as add-on therapy or as monotherapy, respectively.
In phase III study BN40898 (in combination with IST) and in phase III study BN40900 (in monotherapy), anti-drug-antibodies (ADAs) were observed in 41% and 71% of patients receiving satralizumab in the double-blind period, respectively. The ability of ADAs to neutralise satralizumab binding is unknown.
Exposure was lower in ADA positive patients, however there was no impact of ADAs on safety and no clear impact on efficacy nor pharmacodynamic markers indicative of target engagement.
Treatment with satralizumab led to a similar reduction in the risk of experiencing an adjudicated relapse in patients in the phase III studies despite different ADA rates between those studies.
In study BN40898, there were 7 adolescent patients enrolled during the double blind period. Their mean age was 15.4 years and the median body weight was 79.6 kg. The majority were female (n=6). Four patients were White, 2 were Black/African American, and 1 was Asian. Three (42.9%) adolescent patients were AQP4-IgG seropositive at screening (2 in the placebo group and 1 in the satralizumab group). During the double-blind period, 1 of 3 adolescents in the placebo group and 1 of 4 adolescents in the satralizumab group experienced an adjudicated relapse. Due to the small sample size, the hazard ratio for the primary endpoint of time to first adjudicated relapse in this subgroup was not calculated. Two additional adolescent patients were enrolled in the open-label period of the study.
The European Medicines Agency has deferred the obligation to submit the results of studies with Enspryng in one or more subsets of the paediatric population in treatment of NMOSD (see section 4.2 for information on paediatric use).
The pharmacokinetics of satralizumab have been characterised both in Japanese and Caucasian healthy volunteers, and in NMO and NMOSD patients. The pharmacokinetics in NMO and NMOSD patients using the recommended dose were characterised using population PK analysis methods based on a database of 154 patients.
The concentration-time course of satralizumab in patients with NMO or NMOSD was accurately described by a two-compartment population PK model with parallel linear and target-mediated (Michaelis-Menten) elimination and first-order SC absorption. Satralizumab clearance and volume parameters allometrically scaled by body weight (through power function with the fixed power coefficient of 0.75 and 1 for clearance and volume parameters, respectively). Bodyweight was shown to be a significant covariate, with clearance and Vc for patients weighing 123 kg (97.5th percentile of the weight distribution) increased by 71.3% and 105%, respectively, compared to a 60 kg patient.
Steady state pharmacokinetics were achieved after the loading period (8 weeks) for Cmin, Cmax and AUC as follows (mean (±SD): Cmin: 19.7 (12.2) mcg/mL, Cmax: 31.5 (14.9) mcg/mL and AUC: 737 (386) mcg. mL/day.
The absorption rate constant of satralizumab was 0.0104/h equating to an absorption half-life of around 3 days (66 hours) at the recommended dose (see section 4.2). The bioavailability was high (85.4%).
Satralizumab undergoes biphasic distribution. The central volume of distribution was 3.46 L, the peripheral volume of distribution was 2.07 L. The inter-compartmental clearance was 14 mL/h.
The metabolism of satralizumab has not been directly studied, as monoclonal antibodies are principally cleared by catabolism.
The total clearance of satralizumab is concentration-dependent. Linear clearance (accounting for approximately half of the total clearance at steady state using the recommended dose in NMO and NMOSD patients) is estimated to be 2.50 mL/h. The associated terminal t1/2 is approximately 30 days (range 22-37 days) based on data pooled from the phase 3 studies.
Population pharmacokinetic analyses in adult patients with NMO or NMOSD showed that age, gender, and race did not meaningfully influence the pharmacokinetics of satralizumab. Although body weight influenced the pharmacokinetics of satralizumab, no dose adjustments are recommended for any of these demographics.
Data obtained in 8 adolescent patients [13-17 years of age] who received the adult dosing regimen show that population PK parameters for satralizumab are not significantly different from those in the adult population. Therefore, no dose adjustment is necessary.
No dedicated studies have been conducted to investigate the PK of satralizumab in patients ≥65 years of age, however patients with NMO or NMOSD between 65 and 74 years of age were included in the BN40898 and BN40900 clinical studies.
No formal study of the effect of renal impairment on the PK of satralizumab has been conducted. However, patients with mild renal impairment (creatinine clearance ≥50 mL/min and <80 mL/min) were included in the phase III studies. Based on population PK analysis there is no impact of renal impairment on the PK of satralizumab which is in line with the known mechanisms of clearance for satralizumab. Therefore no dose adjustment is required.
No formal study of the effect of hepatic impairment on the PK of satralizumab has been conducted (see section 4.2).
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and toxicity to reproduction and development.
No rodent carcinogenicity studies have been performed to establish the carcinogenic potential of satralizumab. Proliferative lesions have not been observed in a chronic cynomolgus monkey 6-month toxicity study.
No studies have been performed to establish the mutagenic potential of satralizumab. Antibodies are not expected to cause effects on DNA.
Prenatal treatment and postnatal exposure with satralizumab in pregnant monkeys and their offspring did not elicit any adverse effects on maternal animals, foetal development, pregnancy outcome or infant survival and development including learning ability.
The concentrations of satralizumab in breast milk were very low (<0.9% of the corresponding maternal plasma levels).
No effects on male or female reproductive organs were seen with chronic treatment of satralizumab in monkeys.
Based on in vitro studies with human blood, the risk of the release of pro-inflammatory cytokines with satralizumab is considered low in terms of incidence and increase in cytokines.
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