Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Propharma Group The Netherlands B.V., Schipholweg 73, 2316ZL Leiden, The Netherlands
Pharmacotherapeutic group: selective immunosuppressants
ATC code: L04AG14
Ublituximab is a chimeric monoclonal antibody that selectively targets CD20-expressing cells.
CD20 is a cell surface antigen found on pre-B cells, mature and memory B cells but not expressed on lymphoid stem cells and plasma cells. The binding of ublituximab to CD20 induces lysis of CD20+ B cells primarily through antibody-dependent cell-mediated cytotoxicity (ADCC) and, to a lesser extent through complement-dependent cytotoxicity (CDC). Due to a specific glycosylation pattern of its Fc region, ublituximab displays an increased affinity for the FcγRIIIa (CD16) and antibody-dependent cellular cytolysis against B cells.
Treatment with ublituximab leads to rapid depletion of CD19+ cells in blood by the first day post treatment as an expected pharmacologic effect. This was sustained throughout the treatment period. For the B cell counts, CD19 is used, as the presence of ublituximab interferes with the recognition of CD20 by the assay.
In the Phase III studies, treatment with ublituximab resulted in a median reduction of 97% of CD19+ B cell counts from baseline values after the first infusion in both studies and remained depleted at this level for the duration of dosing.
In the Phase III studies, between each dose of ublituximab, 5.5% of patients showed B-cell repletion (> lower limit of normal (LLN) or baseline) at least at one time point.
The longest follow up time after the last ublituximab infusion in the Phase III studies indicates that the median time to B-cell repletion (return to baseline/LLN whichever occurred first) was 70 weeks.
Efficacy and safety of ublituximab were evaluated in two randomised, double-blind, double-dummy, active comparator-controlled clinical trials (ULTIMATE I and ULTIMATE II), with identical design, in patients with RMS (in accordance with McDonald criteria 2010) and evidence of disease activity (as defined by clinical or imaging features) within the previous two years. Study design and baseline characteristics of the study population are summarised in Table 3.
Demographic and baseline characteristics were well balanced across the two treatment groups. Patients were to receive either: (1) ublituximab 450 mg plus oral placebo; or (2) teriflunomide 14 mg plus placebo infusion. Oral treatment (active or placebo) was to start on Week 1 Day 1 and treatment was to continue until the last day of Week 95. Infusions (active or placebo) were to begin on Week 1 Day 1 at 150 mg then increase to 450 mg on Week 3 Day 15, and continue at 450 mg on Week 24, Week 48, and Week 72.
Table 3. Study design, demographic and baseline characteristics:
| Study Name | Study 1 (ULTIMATE I) (n=545) | Study 2 (ULTIMATE II) (n=544) | ||
|---|---|---|---|---|
| Study design | ||||
| Study population | Patients with RMS | |||
| Disease history at screening | At least two relapses within the prior two years, one relapse within the prior year, or the presence of a T1 gadolinium (Gd)-enhancing lesion in the previous year; EDSS* between 0 and 5.5, inclusive | |||
| Study duration | 2 years | |||
| Treatment groups | Group A: Ublituximab 450 mg IV Infusion + Oral Placebo Group B: Teriflunomide 14 mg Oral + IV Infusion Placebo | |||
| Baseline characteristics | Ublituximab 450 mg (n=271) | Teriflunomide 14 mg (n=274) | Ublituximab 450 mg (n=272) | Teriflunomide 14 mg (n=272) |
| Mean age (years) | 36.2 | 37.0 | 34.5 | 36.2 |
| Age range (years) at inclusion | 18–55 | 18–55 | 18–55 | 18–55 |
| Gender distribution ( male/ female) | 38.7/61.3 | 34.7/65.3 | 34.6/65.4 | 35.3/64.7 |
| Mean/median disease duration since diagnosis (years) | 4.9/2.9 | 4.5/2.5 | 5.0/3.2 | 5.0/3.7 |
| Patients naïve to previous Disease Modifying Treatment (%)** | 40.2 | 40.9 | 49.3 | 43.0 |
| Mean number of relapses in the last year | 1.3 | 1.4 | 1.3 | 1.2 |
| Mean EDSS* | 2.96 | 2.89 | 2.80 | 2.96 |
| Proportion of patients with Gd-enhancing T1 lesions | 43.2 | 42.3 | 51.8 | 49.6 |
* Expanded Disability Status Scale
** Patients who had not been treated with any RMS medication in the 5 years prior to randomization.
Key clinical and MRI efficacy results are presented in Table 4.
The results of these studies show that ublituximab significantly suppressed relapses and sub-clinical disease activity measured by MRI compared with oral teriflunomide 14 mg.
Table 4. Key clinical and MRI endpoints from studies ULTIMATE I and ULTIMATE II:
| Study 1 (ULTIMATE I) | Study 2 (ULTIMATE II) | |||
|---|---|---|---|---|
| Endpoints | Ublituximab 450 mg | Teriflunomide 14 mg | Ublituximab 450 mg | Teriflunomide 14 mg |
| Clinical Endpoints1 | ||||
| Annualised Relapse Rate (ARR) (primary endpoint) | 0.076 | 0.188 | 0.091 | 0.178 |
| Relative Reduction | 59% (p<0.0001) | 49% (p=0.0022) | ||
| Proportion of patients Relapse-free at 96 weeks | 86% | 74% | 87% | 72% |
| Proportion of patients with 12-week Confirmed Disability Progression2,3 | 5.2% ublituximab vs. 5.9% teriflunomide | |||
| Risk Reduction (Pooled Analysis)4 | 16% (p=0.5099) | |||
| Proportion of patients with No Evidence of Disease Activity (NEDA) | 45% | 15% | 43% | 11% |
| (p<0.0001)7 | (p<0.0001)7 | |||
| MRI Endpoints5 | ||||
| Mean number of T1 Gd-enhancing lesions per MRI scan6 | 0.016 | 0.491 | 0.009 | 0.250 |
| Relative Reduction | 97% (p<0.0001) | 97% (p<0.0001) | ||
| Mean number of new and/or enlarging T2 hyperintense lesions per MRI scan6 | 0.213 | 2.789 | 0.282 | 2.831 |
| Relative Reduction | 92% (p<0.0001) | 90% (p<0.0001) | ||
1 Based on Modified Intent to Treat (mITT) Population, defined as all randomised patients who received at least one infusion of study medication and had one baseline and post-baseline efficacy assessment. ULTIMATE I: ublituximab (N=271), teriflunomide (N=274). ULTIMATE II: ublituximab (N=272), teriflunomide (N=272).
2 Data prospectively pooled from Study 1 and Study 2: ublituximab (N=543), teriflunomide (N=546).
3 Defined as an increase of 1.0 point or more from the baseline EDSS score for patients with baseline score of 5.5 or less, or 0.5 or more when the baseline score is greater than 5.5, Kaplan-Meier estimates at Week 96.
4 Based on Hazard Ratio.
5 Based on MRI-mITT population (mITT patients who have baseline and post-baseline MRI). ULTIMATE I: ublituximab (N=265), teriflunomide (N=270). ULTIMATE II: ublituximab (N=272), teriflunomide (N=267).
6 At Week 96.
7 Nominal p-value.
Serum samples from patients with RMS were tested for antibodies to ublituximab during the treatment period. 81% of ublituximab-treated patients tested positive for anti-drug antibodies (ADA) at one or more timepoints during the 96-week treatment period in clinical efficacy and safety trials. ADA was generally transient (at Week 96, 18.5% of patients were positive for ADA). Neutralising activity was detected in 6.4% of ublituximab-treated patients. The presence of ADA or neutralising antibodies had no observable impact on the safety or efficacy of ublituximab.
The European Medicines Agency has deferred the obligation to submit the results of studies with ublituximab in one or more subsets of the paediatric population in the treatment of multiple sclerosis (see section 4.2 for information on paediatric use).
In the RMS studies, the pharmacokinetics (PK) of ublituximab following repeated intravenous infusions was described by a two-compartment model with first-order elimination and with PK parameters typical for an IgG1 monoclonal antibody. Ublituximab exposures increased in a dose-proportional manner (i.e., linear pharmacokinetics) over the dose range of 150 to 450 mg in patients with RMS. Administration of 150 mg ublituximab by intravenous infusion on Day 1 followed by 450 mg ublituximab by intravenous infusion over one hour on Day 15, Week 24 and Week 48 led to a geometric mean steady-state AUC of 3000 μg/mL per day (CV=28%) and a mean maximum concentration of 139 μg/mL (CV=15%).
Ublituximab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
In the population pharmacokinetic analysis of ublituximab, the central volume of distribution was estimated to be 3.18 L and the peripheral volume of distribution was estimated to be 3.6 L.
The metabolism of ublituximab has not been directly studied, as antibodies are cleared principally by catabolism (i.e. breakdown into peptides and amino acids).
Following intravenous infusion of 150 mg ublituximab on Day 1 followed by 450 mg ublituximab on Day 15, Week 24 and Week 48, the mean terminal elimination half-life of ublituximab was estimated to be 22 days.
No studies have been conducted to investigate the pharmacokinetics of ublituximab in children and adolescents <18 years of age.
There are no dedicated PK studies of ublituximab in patients ≥ 55 years due to limited clinical experience (see section 4.2).
No specific studies of ublituximab in patients with renal impairment have been performed. Patients with mild renal impairment were included in the clinical studies. There is no experience in patients with moderate and severe renal impairment. However, as ublituximab is not excreted via urine, it is not expected that patients with renal impairment require dose modification.
No specific studies of ublituximab in patients with hepatic impairment have been performed.
Since hepatic metabolism of monoclonal antibodies such as ublituximab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification.
Non-clinical data reveal no special hazard for humans based on repeated dose toxicity studies and in vitro mutagenicity studies. Carcinogenicity studies have not been conducted with ublituximab.
In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys were administered weekly intravenous doses of 30 mg/kg ublituximab (corresponding to AUC 26 times the AUC in patients at the maximum recommended dose) during either the first, second or third trimester of pregnancy, which resulted in maternal moribundity and foetal loss. Pathological observations in exposed dams involved multiple organ systems (thrombi in multiple organs, vascular necrosis in the intestine and liver, inflammation and oedema in the lungs and heart) as well as the placenta and these findings were consistent with immune-mediated adverse effects secondary to immunogenicity.
Infant abnormalities were absent in dams exposed during the first trimester of pregnancy. Ublituximab-related external, visceral and skeletal abnormalities were noted in two infants from dams treated during the second trimester of pregnancy. Histopathology evaluations revealed minimal to moderate degeneration/necrosis in the brain. Foetal findings included contractures and abnormal flexion of multiple limbs and tail, shortened mandible, elongate calvarium, enlargement of ears, and/or craniomandibular abnormalities which were attributed to brain necrosis. These findings were potentially related to the immunogenic response of ublituximab in the mothers, which affected the placental exchange of nutrients.
The presence of ublituximab in mother’s milk was not assessed.
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