UPLIZNA Solution for injection Ref.[10302] Active ingredients: Inebilizumab

Pharmacodynamics of UPLIZNA were assessed with an assay for CD20+ B cells, since UPLIZNA can interfere with the CD19+ B cell assay. Treatment with UPLIZNA reduces CD20+ B cell counts in blood by 8 days after infusion. In Study 1 [see Clinical Studies (14)], CD20+ B-cell counts were reduced below the lower limit of normal by 4 weeks in 100% of patients treated with UPLIZNA and remained below the lower limit of normal in 94% of patients for 28 weeks after initiation of treatment.

The pharmacokinetics of inebilizumab-cdon in NMOSD patients following intravenous administration of UPLIZNA was biphasic with a mean terminal half-life of 18 days. The mean maximum concentration was 108 μg/mL (300 mg, second dose on Day 15), and the cumulative AUC of the 26-week treatment period in which NMOSD patients received two intravenous administrations 2 week apart was 2980 µg•d/mL.

Distribution

Based on population pharmacokinetic analysis, the estimated typical central and peripheral volume of distribution of inebilizumab-cdon was 2.95L and 2.57L, respectively.

Metabolism

Inebilizumab-cdon is a humanized IgG1 monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body.

Elimination

The results of population pharmacokinetic analysis indicated that the estimated inebilizumab-cdon systemic clearance of the first-order elimination pathway was 0.19 L/day. At low exposure levels, inebilizumab-cdon was likely subject to the receptor (CD19)-mediated clearance, which decreased with time presumably because of the depletion of B-cells by UPLIZNA treatment.

Specific Populations

Gender, Race, Geriatric Use

A population pharmacokinetic analysis indicated that there was no significant effect of gender, race, and age on inebilizumab-cdon clearance.

Renal/Hepatic Impairment

No formal clinical studies have been conducted to investigate the effect of renal impairment or hepatic impairment on inebilizumab-cdon pharmacokinetic parameters.

Drug Interaction Studies

Cytochrome P450 enzymes and transporters are not involved in the clearance of inebilizumab-cdon; therefore, the potential risk of interactions between UPLIZNA and concomitant medications that are substrates, inducers, or inhibitors of cytochrome P450 enzymes and transporters is low.

Carcinogenesis

No studies have been conducted to assess the carcinogenic potential of inebilizumab-cdon.

Mutagenesis

No studies have been conducted to assess the genotoxic potential of inebilizumab-cdon.

Impairment of Fertility

Intravenous administration of inebilizumab-cdon (0, 3, or 30 mg/kg/week) to human CD19 transgenic male and female mice prior to and during mating and continuing in females through gestation day 15 resulted in reduced fertility at both doses tested. A no-effect dose for adverse effects on fertility was not identified.

The efficacy of UPLIZNA for the treatment of NMOSD was established in Study 1 (NCT02200770), a randomized (3:1), double-blind, placebo-controlled trial that enrolled 213 patients with NMOSD who were anti-AQP4 antibody positive and 17 who were anti-AQP4 antibody negative.

Patients met the following eligibility criteria:

• A history of one or more relapses that required rescue therapy within the year prior to screening, or 2 or more relapses that required rescue therapy in 2 years prior to screening.
• Expanded Disability Status Scale (EDSS) score of 7.5 or less. Patients with an EDSS score of 8.0 were eligible if they were deemed capable of participating.
• Patients were excluded if previously treated with immunosuppressant therapies within an interval specified for each such therapy.

The use of immunosuppressants during the blinded phase of the trial was prohibited.

The use of oral or intravenous corticosteroids during the blinded phase of the trial was prohibited, with the exception of premedication for investigational treatment and treatment for a relapse.

Of the 213 enrolled anti-AQP4 antibody positive patients, a total of 161 were randomized to receive treatment with UPLIZNA, and 52 were randomized to receive placebo.

The baseline demographic and disease characteristics were balanced between the treatment groups. Females accounted for 94% of the study population. Fifty-two percent of patients were White, 21% Asian, and 9% Black or African American. The mean age was 43 years (range 18 to 74 years). The mean EDSS score was 4.0. The number of relapses in the two years prior to randomization was 2 or more in 83% of the patients.

UPLIZNA was administered according to the recommended dosage regimen [see Dosage and Administration (2.4)].

All potential relapses were evaluated by a blinded, independent, adjudication committee, who determined whether the relapse met protocol-defined criteria. Patients who experienced an adjudicated relapse in the randomized-controlled period (RCP), or who completed the Day 197 visit without a relapse, exited the RCP.

The primary efficacy endpoint was the time to the onset of the first adjudicated relapse on or before Day 197.

The time to the first adjudicated relapse was significantly longer in patients treated with UPLIZNA compared to patients who received placebo (relative risk reduction 73%; hazard ratio: 0.272; p<0.0001). In the anti-AQP4 antibody positive population there was a 77.3% relative reduction (hazard ratio: 0.227, p<0.0001). There was no evidence of a benefit in patients who were anti-AQP4 antibody negative.

Table 4. Efficacy Results in Study 1 in anti-AQP4 Antibody Positive NMOSD Patients:

^a Cox regression method, with placebo as the reference group.

Figure 1. Kaplan-Meier Plot of Time to First Adjudication Committee-Determined NMOSD Relapse in the Randomized-Controlled Period (ITT Population; anti-AQP4 Antibody Positive Patients):

Note: Numbers of patients at risk are shown at each time point.

Compared to placebo-treated patients, patients treated with UPLIZNA who were anti-AQP4 antibody positive had reduced annualized rates of hospitalizations (0.11 for UPLIZNA versus 0.50 for placebo).