Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Horizon Therapeutics Ireland DAC, 70 St. Stephens Green, Dublin 2, D02 E2X4, Ireland
Pharmacotherapeutic group: immunosuppressants, selective immunosuppressants
ATC code: L04AA47
Inebilizumab is a monoclonal antibody that specifically binds to CD19, a cell surface antigen present on pre-B and mature B-cell lymphocytes, including plasmablasts and some plasma cells. Following cell surface binding to B lymphocytes, inebilizumab supports antibody-dependent cellular cytolysis (ADCC) and antibody-dependent cellular phagocytosis (ADCP). B cells are believed to play a central role in the pathogenesis of NMOSD. The precise mechanism by which inebilizumab exerts its therapeutic effects in NMOSD is unknown but is presumed to involve B-cell depletion and may include the suppression of antibody secretion, antigen presentation, B cell–T cell interaction, and the production of inflammatory mediators.
Pharmacodynamics of inebilizumab were assessed with an assay for CD20+ B cells, since inebilizumab can interfere with the CD19+ B-cell assay. Treatment with inebilizumab reduces CD20+ B-cell counts in blood by 8 days after infusion. In a clinical study of 174 patients, CD20+ B-cell counts were reduced below the lower limit of normal by 4 weeks in 100% of patients treated with inebilizumab and remained below the lower limit of normal in 94% of patients for 28 weeks after initiation of treatment. The time to B-cell repletion following administration of inebilizumab is not known.
In the pivotal study of NMOSD patients the prevalence of anti-drug antibodies (ADA) was 14.7% at the end of the OLP; the overall incidence of treatment-emergent ADA was 7.1% (16 of 225) and the occurrence and titer of ADA positive timepoints decreased over time with inebilizumab treatment. ADA-positive status appeared to have no clinically relevant impact on PK and PD (B-cell) parameters and did not impact the long-term safety profile. There was no apparent effect of ADA status on the efficacy outcome; however, the impact cannot be fully assessed given the low incidence of ADA associated with inebilizumab treatment.
The efficacy of inebilizumab for the treatment of NMOSD was studied in a randomised (3:1), double-blind, placebo-controlled clinical trial in adults with AQP4-IgG seropositive or seronegative NMOSD. The study included patients who had experienced at least one acute NMOSD attack in the prior year or at least 2 attacks in the prior 2 years that required rescue therapy (e.g., steroids, plasma exchange, intravenous immunoglobulin), and had an Expanded Disability Severity Scale (EDSS) score ≤7.5 (patients with a score of 8.0 were eligible if the patient was reasonably able to participate). Patients were excluded if previously treated with immunosuppressant therapies within an interval specified for each such therapy. Background immunosuppressant therapies for the prevention of NMOSD attacks were not permitted. A 2-week course of oral corticosteroids (plus a 1-week taper) was administered at the start of inebilizumab treatment in the pivotal study.
Patients were treated with intravenous infusions of inebilizumab 300 mg on Day 1 and on Day 15, or matching placebo, and then followed for a period of up to 197 days or an adjudicated attack, termed the randomised-controlled period (RCP). All potential attacks were evaluated by a blinded, independent, Adjudication Committee (AC), who determined whether the attack met protocol-defined criteria. The attack criteria recognised attacks in all domains affected by NMOSD (optic neuritis, myelitis, brain, and brainstem) and included criteria based exclusively on substantial clinical manifestations, as well as criteria that augmented more modest clinical findings with the use of MRI (see Table 3).
Table 3. Overview of the protocol-defined criteria for an NMOSD attack:
| Domain | Representative symptoms | Clinical-only findings | Clinical PLUS radiological findings |
|---|---|---|---|
| Optic nerve | Blurred vision Loss of vision Eye pain | 8 criteria based on changes in visual acuity or relative afferent pupillary defect (RAPD) | 3 criteria based on changes in visual acuity or RAPD plus presence of corresponding optic nerve MRI findings |
| Spinal cord | Deep or radicular pain Extremity paraesthesia Weakness Sphincter dysfunction Lhermitte’s sign (not in isolation) | 2 criteria based on changes in pyramidal, bladder/bowel, or sensory functional scores | 2 criteria based on changes in pyramidal, bladder/bowel, or sensory functional scores PLUS corresponding spinal cord MRI findings |
| Brainstem | Nausea Intractable vomiting Intractable hiccups Other neurological signs (e.g., double vision, dysarthria, dysphagia, vertigo, oculomotor palsy, weakness, nystagmus, other cranial nerve abnormality) | None | 2 criteria based on symptoms or changes in brainstem/cerebellar functional scores PLUS corresponding brainstem MRI findings |
| Brain | Encephalopathy Hypothalamic dysfunction | None | 1 criterion based on changes in cerebral/sensory/pyramidal functional scores PLUS corresponding brain MRI findings |
Patients who experienced an AC-determined attack in the RCP, or who completed the Day 197 visit without an attack, exited the RCP and had the option to enrol into an OLP and initiate or continue treatment with inebilizumab.
A total of 230 patients were enrolled: 213 patients were AQP4-IgG seropositive patients and 17 were seronegative patients were enrolled; 174 patients were treated with inebilizumab and 56 patients were treated with placebo in the RCP of the study. Of the 213 AQP4-IgG seropositive patients, 161 were treated with inebilizumab and 52 were treated with placebo in the RCP of the study. Baseline and efficacy results are presented for the AQP4-IgG seropositive patients.
Baseline demographics and disease characteristics were balanced across the 2 treatment groups (see Table 4).
Table 4. Demographics and baseline characteristics of the AQP4-IgG seropositive NMOSD patients:
| Characteristic | Placebo N=52 | Inebilizumab N=161 | Overall N=213 |
|---|---|---|---|
| Age (years): mean (standard deviation [SD]) | 42.4 (14.3) | 43.2 (11.6) | 43.0 (12.3) |
| Age ≥65 years, n (%) | 4 (7.7) | 6 (3.7) | 10 (4.7) |
| Sex: Male, n (%) | 3 (5.8) | 10 (6.2) | 13 (6.1) |
| Sex: Female, n (%) | 49 (94.2) | 151 (93.8) | 200 (93.9) |
| Expanded disability status scale (EDSS): mean (SD) | 4.35 (1.63) | 3.81 (1.77) | 3.94 (1.75) |
| Disease duration (years): mean (SD) | 2.92 (3.54) | 2.49 (3.39) | 2.59 (3.42) |
| Number of prior relapses: ≥2, n (%) | 39 (75.0) | 137 (85.1) | 176 (82.6) |
| Annualised Relapse Rate: mean (SD) | 1.456 (1.360) | 1.682 (1.490) | 1.627 (1.459) |
Rescue therapy was initiated as needed for NMOSD attacks. All patients were pre-medicated prior to investigational product administration to reduce the risk of infusion-related reactions.
The primary efficacy endpoint was time (days) from Day 1 to onset of an AC-determined NMOSD attack on or before Day 197. Additional key secondary endpoint measures included worsening from baseline in EDSS at last visit during the RCP, change from baseline in low-contrast visual acuity binocular score measured by low-contrast Landolt C Broken Rings Chart at last visit during the RCP, cumulative total active MRI lesions (new gadolinium-enhancing or new/enlarging T2 lesions) during the RCP, and the number of NMOSD-related in-patient hospitalisations. A patient was considered to have a worsening in EDSS score if one of the following criteria was met: (1) worsening of 2 or more points in EDSS score for patients with baseline score of 0; (2) worsening of 1 or more points in EDSS score for patients with baseline score of 1 to 5; (3) worsening of 0.5 points or more in EDSS score for patients with baseline score of 5.5 or more. Although no comparator was available during the OLP, the annualised attack rate across both randomised and open-label treatment was determined.
Results in AQP4-IgG seropositive patients are presented in Table 5 and Figure 1. In this study, treatment with inebilizumab statistically significantly reduced the risk of an AC-determined NMOSD attack as compared to treatment with placebo (hazard ratio: 0.227, p<0.0001; 77.3% reduction in risk of AC-determined NMOSD attack) in AQP4-IgG seropositive patients. There was no treatment benefit observed in AQP4-IgG seronegative patients.
In the inebilizumab group EDDS worsening was significantly less than placebo group (14.9% versus 34.6% of the subjects). There were no differences in the low-contrast visual acuity binocular score between the study arms. The mean cumulative number of total active MRI lesions (1.7 versus 2.3) and mean cumulative number of NMOSD related hospitalisations (1.0 vs 1.4) were reduced in the inebilizumab study group.
Table 5. Efficacy results in pivotal trial in AQP4-IgG seropositive NMOSD:
| Treatment group | ||
|---|---|---|
| Placebo N=52 | Inebilizumab N=161 | |
| Time to adjudication committee-determined attack (primary efficacy endpoint) | ||
| Number (%) of patients with attack | 22 (42.3%) | 18 (11.2%) |
| Hazard ratio (95% CI)a | 0.227 (0.1214, 0.4232) | |
| p-valuea | <0.0001 | |
a Cox regression method, with Placebo as the reference group.
Figure 1. Kaplan-Meier plot of time to first AC-determined NMOSD attack during the RCP in AQP4-IgG seropositive patients:
AC adjudication committee; AQP4-IgG anti-aquaporin-4 immunoglobulin G; CI confidence interval; NMOSD neuromyelitis optica spectrum disorders; RCP randomised control period.
Across the RCP and OLP, the annualised AC-determined NMOSD attack rate was analysed as a secondary endpoint and in AQP4-IgG seropositive patients treated with inebilizumab the result was 0.09.
The European Medicines Agency has deferred the obligation to submit the results of studies with inebilizumab in one or more subsets of the paediatric population in NMOSD (see section 4.2 for information on paediatric use).
Inebilizumab is administered as an intravenous infusion.
Based on population pharmacokinetic analysis, the estimated typical central and peripheral volume of distribution of inebilizumab was 2.95 L and 2.57 L, respectively.
Inebilizumab is a humanised IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body.
In adult patients with NMOSD, the terminal elimination half-life was approximately 18 days. From population pharmacokinetic analysis, the estimated inebilizumab systemic clearance of the first-order elimination pathway was 0.19 L/day. At low pharmacokinetic exposure levels, inebilizumab was likely subject to the receptor (CD19)-mediated clearance, which decreased with time presumably due to the depletion of B cells by inebilizumab treatment.
Inebilizumab has not been studied in adolescents or children.
Based on population pharmacokinetic analysis, age did not affect inebilizumab clearance.
A population pharmacokinetic analysis indicated that there was no significant effect of gender and race on inebilizumab clearance.
No formal clinical studies have been conducted to investigate the effect of renal impairment on inebilizumab. Due to the large molecular weight and hydrodynamic size of an IgG monoclonal antibody, inebilizumab is not expected to be filtered through the glomerulus. From population pharmacokinetic analysis, inebilizumab clearance in patients with varying degrees of renal impairment was comparable to patients with normal estimated glomerular filtration rate.
No formal clinical studies have been conducted to investigate the effect of hepatic impairment on inebilizumab. In clinical studies, no subjects with severe hepatic impairment have been exposed to inebilizumab. IgG monoclonal antibodies are not primarily cleared via the hepatic pathway; change in hepatic function is, therefore, not expected to influence inebilizumab clearance. Based on population pharmacokinetic analysis, baseline hepatic function biomarkers (AST, ALP, and bilirubin) had no clinically relevant effect on inebilizumab clearance.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Inebilizumab was evaluated in a combined fertility and embryo-foetal development study in female and male huCD19 Tg mice at intravenous doses of 3 and 30 mg/kg. There was no effect on embryo-foetal development, however, there was a treatment-related reduction in fertility index at both tested doses. The relevance of this finding to humans is unknown. Additionally, there was a decrease in B-cell populations at the site of B-cell development in foetal mice born to inebilizumab-treated animals as compared to the offspring of control animals, suggesting that inebilizumab crosses the placenta and depletes B cells.
Only sparse toxicokinetic samples were collected in the combined fertility and embryo-foetal development study; based on first dose maximum concentration (Cmax), the exposure multiples of 3 and 30 mg/kg in female huCD19 Tg mice were 0.4-fold and 4-fold respectively for the 300 mg clinical therapeutic dose.
In a pre-/postnatal development study in transgenic mice, administration of inebilizumab to maternal animals from Gestation Day 6 to Lactation Day 20 resulted in depleted B-cell populations in offspring at postnatal Day 50. B-cell populations in offspring recovered by postnatal Day 357. The immune response to neoantigen in offspring of animals treated with inebilizumab was decreased relative to offspring of control animals, suggestive of impairment of normal B-cell function.
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