Uplizna: Package Insert / Prescribing Info

1.1 Neuromyelitis Optica Spectrum Disorder (NMOSD)

UPLIZNA is indicated for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive.

1.2 Immunoglobulin G4-Related Disease (IgG4-RD)

UPLIZNA is indicated for the treatment of Immunoglobulin G4-related disease (IgG4-RD) in adult patients.

2.1 Assessments Prior to First Dose of UPLIZNA

2.2 Assessment and Premedication Before Every Infusion

2.3 Recommended Dosage and Administration

2.4 Preparation and Storage of Infusion Solution

Injection: 100 mg/10 mL (10 mg/mL) clear to slightly opalescent, colorless to slightly yellow solution in a single-dose vial.

5.1 Infusion Reactions

UPLIZNA can cause infusion reactions, including anaphylaxis. Symptoms can include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or palpitations. During the randomized clinical trial period, infusion reactions were observed with the first course of UPLIZNA in 9.3% of NMOSD patients. Infusion reactions of UPLIZNA were observed in 7.4% of IgG4-RD patients during the randomized controlled period. Infusion reactions were most common with the first infusion but were also observed during subsequent infusions.

5.2 Infections

An increased risk of infections has been observed with other B-cell depleting therapies. The most common infections reported by UPLIZNA-treated patients in the randomized and open-label clinical trial periods for NMOSD included urinary tract infection (20%), nasopharyngitis (13%), upper respiratory tract infection (8%), and influenza (7%). In the IgG4-RD randomized controlled and open-label periods, the most common infections reported by UPLIZNA-treated patients were upper respiratory tract infection (11%), nasopharyngitis (10%), urinary tract infection (9%), and influenza (6%). Delay UPLIZNA administration in patients with an active infection until the infection is resolved.

5.3 Reduction in Immunoglobulins

There may be a progressive and prolonged hypogammaglobulinemia or decline in the levels of total and individual immunoglobulins such as immunoglobulins G and M (IgG and IgM) with continued UPLIZNA treatment [see Adverse Reactions (6.1)]. Monitor the levels of quantitative serum immunoglobulins during treatment with UPLIZNA, especially in patients with opportunistic or recurrent infections, and until B-cell repletion after discontinuation of therapy. Consider discontinuing UPLIZNA therapy if a patient with low immunoglobulin G or M develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

5.4 Fetal Risk

Based on animal data, UPLIZNA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to UPLIZNA even after B-cell repletion. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving UPLIZNA and for at least 6 months after the last dose [see Use in Specific Populations (8.1)].

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

7.1 Immunosuppressive or Immune-Modulating Therapies

Concomitant usage of UPLIZNA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when co-administering immunosuppressive therapies with UPLIZNA.

8.1 Pregnancy

8.2 Lactation

8.3 Females of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

12.1 Mechanism of Action

The precise mechanism by which inebilizumab-cdon exerts its therapeutic effects in NMOSD and IgG4-RD is unknown but is presumed to involve binding to CD19, a cell surface antigen presents on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, inebilizumab-cdon results in antibody-dependent cellular cytolysis.

12.2 Pharmacodynamics

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 (14.1)], 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.

In Study 2 [see Clinical Studies (14.2)], CD20+ B-cell counts were reduced below the lower limit of normal by week 2 in 100% of patients treated with UPLIZNA and remained below the lower limit of normal in 85% of patients for up to 52 weeks after initiation of treatment.

12.3 Pharmacokinetics

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.

The pharmacokinetics of inebilizumab-cdon in IgG4-RD patients following intravenous administration of UPLIZNA was biphasic with a mean terminal half-life of 18 days. The mean maximum concentration was 127 µg/mL (300 mg, second dose on Day 15), and the cumulative AUC of the 52-week treatment period in which IgG4-RD patients received two intravenous administrations 2 weeks apart, followed by a third dose at week 26 was 4290 µg×d/mL.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of UPLIZNA.

In Study 1, treatment-emergent antibodies (those that appeared or significantly increased from baseline after administration of UPLIZNA), were detected in 5.6% patients receiving UPLIZNA. Although these data do not demonstrate an impact of anti-inebilizumab-cdon antibody development on the efficacy or safety of UPLIZNA in these patients, the available data are too limited to make definitive conclusions.

In Study 2, the incidence of treatment-emergent anti-inebilizumab-cdon antibodies was 8.8% (6/68) of patients receiving UPLIZNA during the 52-week RCP. Neutralizing antibodies were not directly assessed.

During the treatment periods for Study 1 and Study 2, there was no identified clinically significant effect of anti-inebilizumab-cdon antibodies on pharmacokinetics, pharmacodynamics, safety or effectiveness of UPLIZNA.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Neuromyelitis Optica Spectrum Disorder (NMOSD)

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:

1. 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.
2. 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.
3. 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.

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).

14.2 Immunoglobulin G4-Related Disease (IgG4-RD)

The efficacy of UPLIZNA for the treatment of IgG4-RD was established in Study 2 (NCT04540497), a randomized, double-blind, multicenter, 52-week placebo-controlled trial that enrolled 135 adult patients who met the following eligibility criteria:

• Newly diagnosed or recurrent IgG4-RD that required glucocorticoid (GC) treatment at screening.
• Confirmed history of organ involvement at any time in the course of disease.

The concomitant use of biologic and non-biologic immunosuppressive agents was prohibited during the blinded phase of the trial. Of the 135 enrolled IgG4-RD patients, 68 patients were randomized to receive UPLIZNA and 67 were randomized to receive placebo. The baseline demographic and disease characteristics were generally balanced between the treatment groups. Females accounted for 35% of the study population. Thirty-nine percent of patients were White, 47% Asian, and 1% Black or African American. The mean age was 58 years (range 24 to 80 years). The median disease duration was 0.9 years. Forty-six percent of patients were newly diagnosed with IgG4-RD and 54% had recurrent disease.

Patients were at a uniform 20 mg per day dose of glucocorticoids at the time of randomization and then began a prespecified taper of 5 mg dose every two weeks until discontinuation at the end of 8 weeks. The use of glucocorticoids during the trial was permitted for premedication for investigational treatment, treatment for a relapse and in certain situations other than an IgG4-RD flare. UPLIZNA was administered according to the recommended dosage regimen [see Dosage and Administration (2.4)].

Disease flare was defined as new/worsening signs or symptoms that were positively adjudicated and warranted treatment by the investigator. All potential flares were assessed by the investigator and subsequently reviewed by a blinded, independent, adjudication committee, who determined whether the flare met one or more of the protocol-defined, organ-specific flare diagnostic criteria.

The primary efficacy endpoint was the time to First Treated and Adjudication Committee (AC)-determined IgG4-RD flare within the 52-week RCP. The time to the First Treated and AC determined IgG4-RD flare was significantly longer in the UPLIZNA group, compared with the placebo group (Figure 2). UPLIZNA reduced the risk of treated and AC-determined IgG4-RD flare by 87%, compared with placebo (hazard ratio: 0.13; p < 0.0001) (see Table 6).

Figure 2. Kaplan-Meier Plot of Time to First Treated and Adjudication Committee-Determined IgG4-RD Flare During the Randomized-Controlled Period

Patients who did not complete the RCP and who did not have a treated and AC-determined flare during the RCP were censored at the time of discontinuation.

For all patients in the trial, the mean (SD) total GC use for IgG4-RD control per patient other than the planned GC taper was lower in the UPLIZNA-treated group compared with the placebo- treated group, with a mean (SD) of 118.25 (438.97) mg prednisone equivalent versus 1384.53 (1723.26) mg prednisone equivalent, respectively during the RCP. Forty-two (62.7%) placebo-treated patients and 7 (10.3%) UPLIZNA-treated patients received GC for IgG4-RD control other than the planned GC taper. The mean (SD) total GC use per patient for the 42 placebo-treated patients was 2202.76 (1709) mg prednisone equivalent and for the 7 UPLIZNA-treated patients was 1148.71 (878) mg prednisone equivalent.

16.1 How Supplied

UPLIZNA (inebilizumab-cdon) injection is a clear to slightly opalescent, colorless to slightly yellow solution supplied as:

• One carton containing three 100 mg/10 mL single-dose vials – NDC 75987-150-03

16.2 Storage and Handling

• Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light.
• Do not freeze.
• Do not shake.
• Store vials upright.

Infusion Reactions

Inform patients about the signs and symptoms of infusion reactions, including anaphylaxis, and advise them to contact their healthcare provider immediately if they observe signs or symptoms of infusion reactions [see Warnings and Precautions (5.1)].

Infections

Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or dysuria [see Warnings and Precautions (5.2)].

Advise patients that UPLIZNA may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk [see Warnings and Precautions (5.2)].

Advise patients that PML has happened with drugs that are similar to UPLIZNA and may happen with UPLIZNA. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their healthcare provider if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes [see Warnings and Precautions (5.2)].

Vaccinations

Advise patients to complete any required vaccinations at least 4 weeks prior to initiation of UPLIZNA. Administration of live-attenuated or live vaccines is not recommended during UPLIZNA treatment and until B-cell recovery [see Warnings and Precautions (5.2)].

Pregnancy

Instruct patients that if they are pregnant or plan to become pregnant while taking UPLIZNA, they should inform their healthcare provider [see Use in Specific Populations (8.1)]. Advise females of reproductive potential that they should use effective contraception during treatment and for 6 months after UPLIZNA therapy [see Use in Specific Populations (8.3)]. Advise patients to register with the UPLIZNA pregnancy exposure registry [see Use in Specific Populations (8.3)].