Inebilizumab

1 INDICATIONS AND USAGE UPLIZNA is a CD19-directed cytolytic antibody indicated for the treatment of: Neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive. ( 1.1 ) Immunoglobulin G4-related disease (IgG4-RD) in adult patients. ( 1.2 ) Generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibody positive. ( 1.2 ) 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. 1.3 Generalized Myasthenia Gravis (gMG) UPLIZNA is indicated for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) or anti-muscle specific tyrosine kinase (MuSK) antibody positive.

2 DOSAGE AND ADMINISTRATION Hepatitis B virus, quantitative serum immunoglobulins, and tuberculosis screening is required before the first dose. ( 2.1 ) Prior to every infusion: Determine if there is an active infection ( 2.2 , 5.2 ) Premedicate with a corticosteroid, an antihistamine, and an antipyretic ( 2.2 , 5.1 ) UPLIZNA must be diluted in 250 mL of 0.9% Sodium Chloride Injection, USP prior to administration. ( 2.3 , 2.4 ) UPLIZNA is administered as an intravenous infusion titrated to completion, approximately 90 minutes. The recommended dose is: Initial dose: 300 mg intravenous infusion followed two weeks later by a second 300 mg intravenous infusion. Subsequent doses (starting 6 months from the first infusion): single 300 mg intravenous infusion every 6 months. ( 2.3 ) Monitor patients closely during the infusion and for at least one hour after completion of the infusion. ( 2.3 ) 2.1 Assessments Prior to First Dose of UPLIZNA Hepatitis B Virus Screening Prior to initiating UPLIZNA, perform Hepatitis B virus (HBV) screening. UPLIZNA is contraindicated in patients with active HBV confirmed by positive results for surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with UPLIZNA [see Contraindications (4) and Warnings and Precautions (5.2) ]. Serum Immunoglobulins Prior to initiating UPLIZNA, perform testing for quantitative serum immunoglobulins. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with UPLIZNA [see Warnings and Precautions (5.3) ]. Tuberculosis Screening Prior to initiating UPLIZNA, evaluate for active tuberculosis and test for latent infection. For patients with active tuberculosis or positive tuberculosis screening without a history of appropriate treatment, consult infectious disease experts before initiating treatment with UPLIZNA [see Contraindications (4) and Warnings and Precautions (5.2) ] . Vaccinations Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of UPLIZNA for live or live-attenuated vaccines [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ]. 2.2 Assessment and Premedication Before Every Infusion Infection Assessment Prior to every infusion of UPLIZNA, determine whether there is an active infection. In case of active infection, delay infusion of UPLIZNA until the infection resolves [see Warnings and Precautions (5.2) ]. Premedication Table 1 shows premedication to administer prior to each infusion of UPLIZNA to reduce the frequency and severity of infusion reactions [see Warnings and Precautions (5.1) ]. Table 1. Premedication Prior to Each UPLIZNA Infusion Type of Premedication Route of Administration Examples (or Equivalent) Administration Time Prior to UPLIZNA Infusion corticosteroid intravenous methylprednisolone 80 mg to 125 mg 30 minutes antihistamine oral diphenhydramine 25 mg to 50 mg 30 to 60 minutes antipyretic oral acetaminophen 500 mg to 650 mg 30 to 60 minutes 2.3 Recommended Dosage and Administration NMOSD, IgG4-RD, and gMG UPLIZNA is administered as an intravenous infusion (see Table 2 ). The recommended dosage is: Initial dose: 300 mg intravenous infusion followed 2 weeks later by a second 300 mg intravenous infusion. Subsequent doses (starting 6 months from the first infusion): single 300 mg intravenous infusion every 6 months. Administration UPLIZNA must be diluted prior to administration [see Dosage and Administration (2.4) ]. Prior to the start of the intravenous infusion, the prepared infusion solution should be at room temperature. Administer UPLIZNA under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage potential severe reactions such as serious infusion reactions [see Warnings and Precautions (5.1) ]. Administer the prepared solution intravenously via an infusion pump at an increasing rate to completion, approximately 90 minutes, according to the schedule in Table 2. Administer through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. Table 2. Recommended Infusion Rate for UPLIZNA Administration When Diluted in a 250 mL Intravenous Bag Elapsed Time (minutes) Infusion Rate (mL/hour) 0-30 42 31-60 125 61 to completion 333 Monitor the patient closely for infusion reactions during and for at least one hour after the completion of the infusion. 2.4 Preparation and Storage of Infusion Solution Preparation Visually inspect UPLIZNA solution for particulate matter and discoloration [see Dosage Forms and Strengths (3) ]. If the solution is cloudy, discolored, or it contains discrete particulate matter, do not use and contact the manufacturer (1-800-772-6436). Do not shake the vial. Obtain an intravenous bag containing 250 mL of 0.9% Sodium Chloride Injection, USP. Do not use other diluents to dilute UPLIZNA. Withdraw 10 mL of UPLIZNA from each of the 3 vials contained in the carton and transfer a total of 30 mL into the 250 mL intravenous bag. Mix diluted solution by gentle inversion. Do not shake the solution. Discard the unused portion remaining in the vials. Storage of Infusion Solution UPLIZNA does not contain a preservative. Administer the prepared infusion solution immediately. If not administered immediately, store the infusion solution for a maximum of 24 hours in the refrigerator between 2°C to 8°C (36°F to 46°F) or 4 hours at room temperature between 20°C to 25°C (68°F to 77°F) prior to the start of the infusion.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Infusion Reactions [see Warnings and Precautions (5.1) ] Infections [see Warnings and Precautions (5.2) ] Reduction in Immunoglobulins [see Warnings and Precautions (5.3) ] The most common adverse reactions (at least 10% of patients treated with UPLIZNA and greater than placebo) were NMOSD: urinary tract infection and arthralgia. ( 6.1 ) IgG4-RD: urinary tract infections and lymphopenia. ( 6.1 ) gMG: headache and infusion-related reactions. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Adverse Reactions NMOSD The safety of UPLIZNA was evaluated in Study 1, in which 161 patients were exposed to UPLIZNA at the recommended dosage regimen during the randomized, controlled treatment period; during which 52 patients received placebo [see Dosage and Administration (2.1) and Clinical Studies (14) ] . Subsequently, 198 patients were exposed to UPLIZNA during an open-label treatment period. Two-hundred and eight patients in the randomized and open-label treatment periods had a total of 324 person-years of exposure to UPLIZNA, including 165 patients with exposure for at least 6 months and 128 with exposure for one year or more. Table 3 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 1. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were urinary tract infection and arthralgia. Table 3. Adverse Reactions in Patients with NMOSD with an Incidence of at Least 5% with UPLIZNA and a Greater Incidence than Placebo in Study 1 Adverse Reactions UPLIZNA N = 161 % Placebo N = 52 % Urinary tract infection 11 10 Arthralgia 10 4 Headache 8 8 Back pain 7 4 Across both the randomized and open-label treatment in Study 1, the most common adverse reactions (greater than 10%) were urinary tract infection (20%), nasopharyngitis (13%), infusion reaction (12%), arthralgia (11%), and headache (10%). IgG4-RD The safety of UPLIZNA was evaluated in Study 2, in which 68 patients were exposed to UPLIZNA at the recommended dosage regimen during the randomized, controlled treatment period; during which 67 patients received placebo [see Dosage and Administration (2.1) and Clinical Studies (14) ] . Table 4 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 2. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were urinary tract infection and lymphopenia. Table 4. Adverse Reactions in Patients with IgG4-RD with an Incidence of at Least 5% with UPLIZNA and a Greater Incidence than Placebo in Study 2 Adverse Reactions UPLIZNA N = 68 % Placebo N = 67 % Lymphopenia 19 Lymphopenia includes both lymphopenia and lymphocyte count decreased. 9 Urinary tract infection 12 6 Pyrexia 9 5 Neutropenia 6 5 Myalgia 6 0 Additional adverse reactions during the randomized controlled period in Study 2 were infusion related reactions, influenza, and pneumonia. gMG The safety of UPLIZNA was evaluated in Study 3, in which 119 patients were exposed to UPLIZNA at the recommended dosage regimen and 119 patients received placebo during the randomized, placebo-controlled treatment period. The randomized controlled treatment period was 52 weeks for patients who were anti-AChR antibody positive (n=95 each group) and 26 weeks for patients who were anti-MuSK antibody positive (n=24 each group) [see Dosage and Administration (2.1) and Clinical Studies (14) ] . References to adverse reaction frequency in the overall population in the randomized controlled period of Study 3 are reflective of 52-week data for the anti-AChR antibody positive population, and 26-week data for the anti-MuSK antibody positive population that were available at the time of the primary analysis. Table 5 lists adverse reactions that occurred in at least 5% of patients treated with UPLIZNA and at a greater incidence than in patients who received placebo in Study 3. The most common adverse reactions (incidence of at least 10% in patients treated with UPLIZNA and at a greater incidence than placebo) were headache and infusion-related reaction. Table 5. Adverse Reactions in Patients with gMG with an Incidence of at Least 5% with UPLIZNA and a Greater Incidence than Placebo in Study 3 Adverse Reactions Based on the overall randomized controlled period, comprised of 52 weeks for the anti-AChR antibody positive population and 26 weeks for the anti-MuSK antibody positive population UPLIZNA N = 119 % Placebo N = 119 % Headache 15 7 Infusion-related reaction Infusion-related reaction was defined as any sign or symptom experienced by patients during the infusion of study drug, or any adverse event occurring within 24 hours of study drug administration for which an alternative explanation was not evident. 10 6 Nasopharyngitis 7 3 Cough 7 3 Urinary tract infection 7 3 Laboratory Abnormalities Decreased Immunoglobulins NMOSD At the end of the 6.5-month randomized, controlled period, relative to baseline, the total immunoglobulin level was reduced approximately 8% from baseline for patients treated with UPLIZNA as compared to an increase of 6% in patients treated with placebo. The mean decreases from baseline in immunoglobulin G (IgG) and immunoglobulin M (IgM) were approximately 4% and 32%, respectively, in patients treated with UPLIZNA, whereas IgG was increased by 6% and IgM was increased by approximately 13% in placebo-treated patients. The proportion of patients treated with UPLIZNA who had IgG levels below the lower limit of normal at year 1 was 7% and at year 2 was 13%. The proportion of patients treated with UPLIZNA who had IgM levels below the lower limit of normal at year 1 was 31% and at year 2 was 42%. IgG4-RD At the end of the 12-month randomized, controlled period, relative to baseline, the total immunoglobulin level was reduced approximately 12% from baseline for patients treated with UPLIZNA as compared to an increase of 21% in patients treated with placebo. The mean decreases from baseline in IgG and IgM were approximately 9% and 32%, respectively, in patients treated with UPLIZNA, whereas IgG was increased by 26% and IgM was increased by approximately 3% in placebo-treated patients. gMG At the end of the 26-week randomized, controlled period, relative to baseline, the total immunoglobulin level was reduced approximately 13% from baseline for patients treated with UPLIZNA as compared to an increase of 15% in patients treated with placebo. The mean decreases from baseline in IgG and IgM were approximately 8% and 30%, respectively, in patients treated with UPLIZNA, whereas IgG was increased by 18% and IgM was increased by approximately 5% in placebo-treated patients. The proportion of patients treated with UPLIZNA who had IgG and IgM levels below the lower limit of normal at the end of the 26-week randomized, controlled period was 29% and 16%, respectively, compared to 8% and 4%, respectively, in the placebo group. Decreased Neutrophil Counts NMOSD Neutrophil counts between 1.0-1.5 × 10 9 /L were observed in 7% of UPLIZNA-treated patients versus 2% of patients who received placebo. Neutrophil counts between 0.5-1.0 × 10 9 /L were observed in 2% of patients treated with UPLIZNA compared to no patients who received placebo. At the end of the 6.5-month randomized, controlled period, the proportion of patients with a neutrophil count below the limit of normal was 12% for patients treated with UPLIZNA compared to 4% for patients who received placebo. IgG4-RD During the 12-month randomized, controlled period, neutrophil counts between 1.0-1.5 × 10 9 /L were observed in 8% of UPLIZNA-treated patients versus 3% of patients who received placebo. Neutrophil counts between 0.5-1.0 × 10 9 /L were observed in 2% of patients treated with placebo compared to no patients who received UPLIZNA. gMG During the 26-week randomized, controlled period, neutrophil counts between 1.0-1.5 × 10 9 /L were observed in 3% of patients who received placebo compared to no patients who received UPLIZNA. Neutrophil counts between 0.5-1.0 × 10 9 /L were observed in 1% of patients treated with UPLIZNA compared to no patients who received placebo. Decreased Lymphocyte Counts NMOSD A reduction in lymphocyte counts was observed more frequently in patients treated with UPLIZNA compared to those who received placebo. At the end of the 6.5-month randomized, controlled period, the proportion of patients with a lymphocyte count below the limit of normal was 5% for patients treated with UPLIZNA compared to 4% for patients who received placebo. IgG4-RD A reduction in lymphocyte counts was observed more frequently in patients treated with UPLIZNA compared to those who received placebo. During the 12-month randomized, controlled period, the proportion of patients with a lymphocyte count below the limit of normal was 42% for patients treated with UPLIZNA compared to 36% for patients who received placebo. gMG A reduction in lymphocyte counts was observed more frequently in patients treated with UPLIZNA compared to those who received placebo. During the 26-week randomized, controlled period, the proportion of patients with a lymphocyte count below the limit of normal was 35% for patients treated with UPLIZNA compared to 31% for patients who received placebo.

12.3 Pharmacokinetics The pharmacokinetics of inebilizumab-cdon in patients with NMOSD, IgG4-RD, and gMG was similar, and was biphasic with a mean terminal half-life of 18 days. In patients with NMOSD, the mean maximum concentration was 108 µg/mL (following the second 300 mg 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. In patients with IgG4-RD, the mean maximum concentration was 127 µg/mL (following the second 300 mg 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. In patients with gMG, the mean maximum concentration was 139 µg/mL (following the second 300 mg dose on day 15) for the overall population. The cumulative AUC of the 52-week treatment period in which anti-AChR antibody positive patients (n = 84) received two intravenous administrations 2 weeks apart, followed by a third dose at week 26 was 4240 µg×d/mL. The cumulative AUC of the 26-week treatment period in which anti-MuSK antibody positive patients (n = 17) received two intravenous administrations 2 weeks apart was 3740 µg×d/mL. Distribution Based on population pharmacokinetic analysis, the estimated typical central and peripheral volume of distribution of inebilizumab-cdon was 2.95 L and 2.57 L, 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.