BRIUMVI- ublituximab injection, solution, concentrate
TG Therapeutics, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BRIUMVI safely and effectively. See full prescribing information for BRIUMVI.
BRIUMVI™ (ublituximab-xiiy) injection, for intravenous use
Initial U.S. Approval: 2022
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
Injection: 150 mg/6 mL (25 mg/mL) in a single-dose vial ( 3)
WARNINGS AND PRECAUTIONS
The most common adverse reactions (≥10%) were infusion reactions and upper respiratory tract infections ( 6.1).
To report SUSPECTED ADVERSE REACTIONS, contact TG Therapeutics at 1-877-848-9462 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
FULL PRESCRIBING INFORMATION: CONTENTS*
BRIUMVI is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
Hepatitis B Virus Screening
Prior to initiating BRIUMVI, perform Hepatitis B virus (HBV) screening. BRIUMVI is contraindicated in patients with active HBV confirmed by positive results for Hepatitis B surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for Hepatitis B core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with BRIUMVI [see Warnings and Precautions ( 5.2)] .
Prior to initiating BRIUMVI, perform testing for quantitative serum immunoglobulins [see Warnings and Precautions ( 5.4)]. For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with BRIUMVI.
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 BRIUMVI for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of BRIUMVI for non-live vaccines [see Warnings and Precautions ( 5.2) and Clinical Pharmacology ( 12.2)] .
Prior to every infusion of BRIUMVI, determine whether there is an active infection. In case of active infection, delay infusion of BRIUMVI until the infection resolves [see Warnings and Precautions ( 5.2)] .
Pre-medicate with 100 mg of methylprednisolone administered intravenously (or an equivalent oral dosage or equivalent corticosteroid) approximately 30 minutes prior to each BRIUMVI infusion to reduce the frequency and severity of infusion reactions [see Warnings and Precautions ( 5.1)] . Pre-medicate with an antihistamine (e.g., diphenhydramine) administered orally or intravenously approximately 30-60 minutes prior to each BRIUMVI infusion to further reduce the frequency and severity of infusion reactions.
The addition of an antipyretic (e.g., acetaminophen) may also be considered.
Administer BRIUMVI under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions, such as serious infusion reactions.
1 Withdraw and discard the required volume of 0.9% Sodium Chloride Injection, USP from the infusion bag following the preparation instructions in Preparation and Administration ( 2.6).
2 Infusion duration may take longer if the infusion is interrupted or slowed.
3 Administer the first subsequent infusion 24 weeks after the first infusion.
|Dose (mg) and Volume (mL) of BRIUMVI||Volume (mL) of 0.9% Sodium Chloride Injection, USP1||Infusion Rate (mL/hour)||Duration2|
|First Infusion||150 mg
(2 weeks later)
(once every 24 weeks) 3
If a planned infusion of BRIUMVI is missed, administer BRIUMVI as soon as possible; do not wait until the next scheduled infusion. Reset the infusion schedule to administer the next sequential infusion 24 weeks after the missed infusion is administered. Infusions of BRIUMVI must be separated by at least 5 months.
Dose modifications in response to infusion reactions depend on the severity.
Life-Threatening Infusion Reactions
Immediately stop infusion and permanently discontinue BRIUMVI if there are signs of a life-threatening or disabling infusion reaction [see Warnings and Precautions ( 5.1)] . Provide appropriate supportive treatment.
Severe Infusion Reactions
Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary [see Warnings and Precautions ( 5.1)] . Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction [see Dosage and Administration ( 2.3)] . If this rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose.
Mild to Moderate Infusion Reactions
Reduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes [see Warnings and Precautions ( 5.1)] . If the reduced rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose.
Only use 0.9% Sodium Chloride Injection, USP to dilute BRIUMVI.
BRIUMVI must be prepared by a healthcare professional using aseptic technique. Prepare the solution for infusion as follows:
Preparation of Solution for First Infusion:
Preparation of Solution for Second Infusion and Subsequent Infusions:
Mix diluted solution by gentle inversion. Do not shake.
Administration of Infusion Solution
Prior to the start of the intravenous infusion, the contents of the infusion bag should be at room temperature [see Dosage and Administration ( 2.7)] .
Administer the diluted infusion solution through a dedicated line.
No incompatibilities between BRIUMVI and polyvinyl chloride (PVC) or polyolefin (PO) bags and intravenous (IV) administration sets have been observed.
Use the prepared infusion solution immediately. If the diluted solution is not administered immediately, store refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours. Do not freeze. If the diluted solution is stored refrigerated, allow it to equilibrate to room temperature prior to administration (approximately 2 hours). The diluted solution can be stored for an additional 8 hours at room temperature up to 25°C (77°F), which includes the equilibration time and infusion time.
Injection: 150 mg/6 mL (25 mg/mL) clear to opalescent, colorless to slightly yellow solution in a single-dose vial.
BRIUMVI is contraindicated in patients with:
BRIUMVI can cause infusion reactions, which can include pyrexia, chills, headache, influenza-like illness, tachycardia, nausea, throat irritation, erythema, and an anaphylactic reaction [see Adverse Reactions ( 6.1)] . In Studies 1 and 2 [see Clinical Studies ( 14)] , patients received methylprednisolone (or an equivalent steroid), an antihistamine, and possibly other pre-medication (i.e., acetaminophen) to reduce the risk of infusion reactions prior to each infusion. The incidence of infusion reactions in Studies 1 and 2 in patients who received treatment with BRIUMVI was 48%, with the highest incidence within 24 hours of the first infusion. In Studies 1 and 2, there were no fatal infusion reactions, but 0.6% of patients treated with BRIUMVI experienced infusion reactions that were serious, some requiring hospitalization.
Observe patients treated with BRIUMVI for infusion reactions during the infusion and for at least one hour after the completion of the first two infusions. Post-infusion monitoring of subsequent infusions is at physician discretion unless infusion reaction and/or hypersensitivity has been observed in association with the current or any prior infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion.
Reducing the Risk of Infusion Reactions and Managing Infusion Reactions
Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions [see Dosage and Administration ( 2.2)] . The addition of an antipyretic (e.g., acetaminophen) may also be considered [see Dosage and Administration ( 2.2)].
Management recommendations for infusion depend on the type and severity of the reaction. For life-threatening infusion reactions, stop the infusion immediately, permanently discontinue BRIUMVI, and provide appropriate supportive treatment [see Dosage and Administration ( 2.5)] . For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
Serious, including life-threatening or fatal, bacterial and viral infections have been reported in patients receiving BRIUMVI. An increased risk of infections, including serious and fatal bacterial, fungal, and new or reactivated viral infections, has been observed during and following completion of treatment with other anti-CD20 B-cell depleting therapies.
In Studies 1 and 2, the overall rate of infections in MS patients treated with BRIUMVI was 56% compared to 54% in patients who were treated with teriflunomide. The rate of serious infections was higher in patients treated with BRIUMVI compared to patients treated with teriflunomide (5% vs 3%, respectively). There were 3 infection-related deaths that occurred in controlled clinical trials in patients with relapsing forms of multiple sclerosis (RMS), all in patients treated with BRIUMVI; the infections leading to death were post-measles encephalitis, pneumonia, and post-operative salpingitis following an ectopic pregnancy. In Studies 1 and 2, the most common infections reported in patients treated with BRIUMVI included upper respiratory tract infection (45%) and urinary tract infection (10%).
Delay BRIUMVI administration in patients with an active infection until the infection is resolved.
Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants
When initiating BRIUMVI after an immunosuppressive therapy or initiating an immunosuppressive therapy after BRIUMVI, consider the potential for increased immunosuppressive effects [see Drug Interactions ( 7.1) and Clinical Pharmacology ( 12.2)] . BRIUMVI has not been studied in combination with other MS therapies.
Hepatitis B Virus (HBV) Reactivation
HBV reactivation occurred in an MS patient treated with BRIUMVI in clinical trials. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies.
Perform HBV screening in all patients before initiation of treatment with BRIUMVI. Do not start treatment with BRIUMVI in patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult a liver disease expert before starting and during treatment.
Progressive Multifocal Leukoencephalopathy (PML)
PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML have occurred in MS patients treated with BRIUMVI, JCV infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold BRIUMVI and perform an appropriate diagnostic evaluation. 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.
Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Following discontinuation of another MS medication associated with PML, lower PML-related mortality and morbidity have been reported in patients who were initially asymptomatic at diagnosis compared to patients who had characteristic clinical signs and symptoms at diagnosis.
It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.
If PML is confirmed, treatment with BRIUMVI should be discontinued.
Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of BRIUMVI for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of BRIUMVI for non-live vaccines.
BRIUMVI may interfere with the effectiveness of non-live vaccines.
The safety of immunization with live or live-attenuated vaccines during or following administration of BRIUMVI has not been studied. Vaccination with live virus vaccines is not recommended during treatment with BRIUMVI and until B-cell repletion.
Vaccination of Infants Born to Mothers Treated with BRIUMVI During Pregnancy
In infants of mothers exposed to BRIUMVI during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19 + B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.
Inactivated or non-live vaccines may be administered as indicated, prior to recovery from B-cell depletion, but an assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted [see Use in Specific Populations ( 8.1)] .
Based on data from animal studies, BRIUMVI may cause fetal harm when administered to a pregnant woman. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. A pregnancy test is recommended in females of reproductive potential prior to each infusion with BRIUMVI. Advise females of reproductive potential to use effective contraception during BRIUMVI treatment and for 6 months after the last dose [see Use in Specific Populations ( 8.1, 8.3)] .
As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed with BRIUMVI. Decrease in immunoglobulin M (IgM) was reported in 0.6% of patients treated with BRIUMVI compared to none of the patients treated with teriflunomide in RMS clinical trials [see Adverse Reactions ( 6.1)] . No decline in immunoglobulin G (IgG) was observed at the end of the studies. Data from clinical studies using other anti-CD20 monoclonal antibody therapies have shown an association between decreased levels of immunoglobulin M (IgM< lower limit of normal [LLN]) and G (IgG<LLN) and increased rates of serious infections. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing BRIUMVI therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
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 clinical practice.
In active-controlled clinical trials (Study 1 and Study 2), 545 patients with RMS received BRIUMVI [see Clinical Studies ( 14)].
The most common adverse reactions in RMS trials (incidence of at least 10%) were infusion reactions and upper respiratory tract infections. Table 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2). The most common cause of discontinuation in patients treated with BRIUMVI was infection (1.3%).
450 mg IVa
14 mg PO
a The first dose of BRIUMVI was given as an intravenous (IV) infusion of 150 mg. The second dose was given as an IV infusion of 450 mg two weeks after the first infusion.
b Includes the following: nasopharyngitis, upper respiratory tract infection, respiratory tract infection, respiratory tract infection viral, pharyngitis, rhinitis, sinusitis, acute sinusitis, tonsillitis, laryngitis, chronic sinusitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection, chronic tonsillitis, pharyngitis streptococcal, sinusitis bacterial, and tonsillitis bacterial.
c Includes the following: bronchitis, pneumonia, tracheitis, tracheobronchitis, COVID-19 pneumonia, bronchitis bacterial, and pneumonia viral.
d Includes several related terms.
|Upper respiratory tract infections b||45||41|
|Lower respiratory tract infections c||9||7|
|Herpes virus-associated infections d||6||5|
|Pain in extremity||6||4|
The incidence of infusion reactions was highest with the first infusion (43%), decreasing with subsequent infusions (10% with second, 8% with third infusion). Three (0.6%) patients treated with BRIUMVI reported serious infusion reactions. Most frequently reported symptoms (greater than 5%) included pyrexia, chills, headache, and influenza-like illness [see Warnings and Precautions ( 5.1)] .
BRIUMVI decreased total immunoglobulins with the greatest decline seen in IgM levels. The proportion of BRIUMVI-treated patients at baseline reporting IgG, IgA, and IgM below the LLN was 6.3%, 0.6%, and 1.1%, respectively. Following treatment, the proportion of BRIUMVI-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 6.5%, 2.4%, and 20.9%, respectively.
Decreased Neutrophil Levels
In Studies 1 and 2, decreased neutrophil counts (<LLN) occurred in 15% of BRIUMVI-treated patients compared to 22% in teriflunomide-treated patients. The majority of decreased neutrophil counts were observed once for a given patient treated with BRIUMVI, and were between 1.0 and 1.5 x 10 9/L. In RMS studies, 3% of patients in the BRIUMVI group had neutrophil counts less than 1.0 x 10 9/L, compared to 2% of patients in the teriflunomide group. Overall, 1% of patients in the BRIUMVI group had neutrophil counts less than 0.5 x 10 9/L, compared to 0% of patients in the teriflunomide group, and these were not associated with an infection.
The concomitant usage of BRIUMVI with other immune-modulating or immunosuppressant drugs, including immunosuppressant doses of corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when co-administering immunosuppressive therapies with BRIUMVI.
When switching from therapies with immune effects, the duration and mechanism of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating BRIUMVI.
There are no data on the developmental risk associated with the use of BRIUMVI in pregnant women. Data from case reports of pregnancies occurring during clinical trials with BRIUMVI are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Although there are no data on ublituximab-xiiy, monoclonal antibodies can be actively transported across the placenta, and BRIUMVI may cause immunosuppression in the in-utero exposed infant [see Clinical Considerations, Warnings and Precautions ( 5.2, 5.3), and Clinical Pharmacology ( 12.1, 12.2)].
Weekly intravenous administration of ublituximab-xiiy to pregnant monkeys during the first, second, or third trimester of pregnancy resulted in embryofetal loss; administration during the second trimester resulted in external, skeletal, and visceral abnormalities in infants (see Data) .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Fetal/Neonatal Adverse Reactions
Transport of endogenous IgG antibodies across the placenta increases as pregnancy progresses and peaks during the third trimester. There are no data on B-cell levels in human neonates following maternal exposure to BRIUMVI. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Avoid administering live vaccines to neonates and infants exposed to BRIUMVI in utero until B-cell recovery occurs [see Warnings and Precautions ( 5.2) and Clinical Pharmacology ( 12.2)].
Weekly intravenous administration of ublituximab-xiiy (0 or 30 mg/kg) to separate groups of pregnant monkeys during the first, second, or third trimester of pregnancy produced a severe immunogenic response in dams, resulting in maternal morbidity and death and embryofetal loss. Dosing was terminated in dams after only two doses during the third trimester because of multiple deaths in dams dosed during the first and second trimesters.
Ublituximab-related external, viscera, and skeletal abnormalities occurred in two infants from dams exposed during the second trimester of pregnancy. Histopathology evaluations revealed minimal to moderate degeneration/necrosis in the brain. Findings in infants 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. Abnormalities were absent in infants of dams exposed during the first trimester of pregnancy. A no-effect dose for adverse effects on embryofetal development in monkeys was not identified.
There are no data on the presence of ublituximab-xiiy in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Human IgG is excreted in human milk, and the potential for absorption of ublituximab-xiiy to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for BRIUMVI and any potential adverse effects on the breastfed infant from BRIUMVI or from the underlying maternal condition.
Ublituximab-xiiy is a recombinant chimeric monoclonal IgG1 antibody with reduced fucose content directed against CD20-expressing B-cells. The molecular weight of the antibody is approximately 147 kDa.
BRIUMVI (ublituximab-xiiy) injection for intravenous infusion is a sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution. Each mL of solution contains 25 mg ublituximab-xiiy, 0.4 mg hydrochloric acid, 0.7 mg polysorbate 80, 9.0 mg sodium chloride, 6.4 mg sodium citrate, and Water for Injection, USP. The pH is 6.5.
The precise mechanism by which ublituximab-xiiy exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ublituximab-xiiy results in cell lysis through mechanisms including antibody-dependent cellular cytolysis and complement-dependent cytolysis.
For B-cell counts, assays for CD19 + B-cells are used because the presence of ublituximab-xiiy interferes with the CD20 assay. Treatment with BRIUMVI reduced CD19 + B-cell counts in blood by the first measured timepoint of 24 hours after infusion. In clinical studies (Study 1 and Study 2), B-cell counts rose to above the LLN or above baseline counts between infusions of BRIUMVI at least one time in 30 of 545 (5.5%) of patients. The median time for CD19 + B-cell counts to return to either baseline or LLN was 70.3 weeks (range 0.1-75.1 weeks) after the last BRIUMVI infusion. Within 1.5 years after the last infusion, B-cell counts rose to either baseline or LLN in 58% of patients.
Ublituximab-xiiy exposures increased proportionally over a dose range of 150 mg (0.33 times approved recommended dosage) to 600 mg (1.33 times the approved recommended dosage) in patients with RMS.
Following administration of the approved recommended dosage of BRIUMVI, the geometric mean steady-state AUC was 3000 mcg/mL per day (CV=28%) and the mean maximum concentration was 139 mcg/mL (CV=15%).
Ublituximab-xiiy is a protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.
There were no clinically meaningful differences in the pharmacokinetics of ublituximab-xiiy based on age, sex, body weight, anti-drug antibodies (ADAs) presence, mild renal impairment, or mild hepatic impairment. The effect of moderate to severe renal impairment or moderate to severe hepatic impairment on the pharmacokinetics of ublituximab-xiiy is unknown.
The observed incidence of ADAs is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the studies described below with the incidence of ADAs in other studies, including those of ublituximab-xiiy or of other ublituximab products.
In clinical studies (Study 1 and Study 2), serum samples from patients with RMS were tested for antibodies to ublituximab-xiiy during the 96-week treatment period. Of the 534 BRIUMVI-treated patients, 434 (81%) tested positive for ADAs at one or more timepoints, and 34 (6.4%) tested positive for neutralizing antibodies (NAbs). However, the assay used to measure NAbs is subject to interference from serum ublituximab-xiiy, possibly resulting in underestimation of the incidence of NAb formation and limiting the ability to characterize the clinical impact of NAbs.
The presence of ADAs had no observable impact on the safety or efficacy of BRIUMVI.
No carcinogenicity studies have been conducted to assess the carcinogenic potential of BRIUMVI.
Impairment of Fertility
No studies in animals have been conducted to assess the effects of BRIUMVI on male or female fertility. No adverse effects on male or female reproductive organs were observed at the only dose level evaluated (30 mg/kg) in a 26-week intravenous toxicity study in monkeys, which was associated with plasma exposures (C ave) approximately 24 times that in humans at the maximum recommended human dose (450 mg).
The efficacy of BRIUMVI was demonstrated in two randomized, double-blind, double-dummy, parallel group, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks [Study 1 (NCT03277261) and Study 2 (NCT03277248)]. Patients were randomized to receive either BRIUMVI, given as an IV infusion of 150 mg for the first infusion, 450 mg two weeks after the first infusion for the second infusion/second dose, and 450 mg every 24 weeks after the first infusion for subsequent doses (third infusion and beyond) with oral placebo administered daily; or teriflunomide, the active comparator, given orally as a 14 mg daily dose with IV placebo administered on the same schedule as BRIUMVI. Both studies enrolled patients who had experienced at least one relapse in the previous year, two relapses in the previous two years, or had the presence of a T1 gadolinium (Gd)-enhancing lesion in the previous year. Patients were also required to have an Expanded Disability Status Scale (EDSS) score from 0 to 5.5 at baseline. Neurological evaluations were performed at baseline, every 12 weeks, and at the time of a suspected relapse. Brain MRI scans were performed at baseline and at Weeks 12, 24, 48, and 96.
The primary outcome of both Study 1 and Study 2 was the annualized relapse rate (ARR) over the treatment period. Additional outcome measures included: the total number of MRI T1 Gd-enhancing lesions by Week 96, the total number of new or enlarging MRI T2 hyperintense lesions by Week 96, and time to confirmed disability progression for at least 12 weeks. Disability progression was defined as an increase of greater than or equal to 1.0 point from the baseline EDSS score that was attributable to MS when the baseline score was 5.5 or less, and greater than or equal to 0.5 points when the baseline score was above 5.5. Confirmed disability progression was evaluated in a pooled analysis of Studies 1 and 2. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit 12 weeks after the initial documentation of neurological worsening.
In Study 1, 274 patients were randomized to BRIUMVI and 275 to teriflunomide. Of those randomized to BRIUMVI, 88% completed the 96-week treatment period; of those randomized to teriflunomide, 92% completed the 96-week treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age was 37 years, 97% were White, and 63% were female.
In Study 2, 272 patients were randomized to BRIUMVI and 273 to teriflunomide. Of those randomized to BRIUMVI, 93% completed the 96-week treatment period; of those randomized to teriflunomide, 88% completed the 96-week treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age was 35 years, 99% were White, and 65% were female.
In Study 1 and Study 2, BRIUMVI significantly lowered the ARR compared to teriflunomide. BRIUMVI statistically significantly reduced the number of T1 Gd-enhancing lesions and the number of new or enlarging T2 lesions in both studies compared to teriflunomide. There was no statistically significant difference in disability progression confirmed at 12 weeks between BRIUMVI-treated and teriflunomide-treated patients.
Results for Study 1 and Study 2 are presented in Table 3.
1 Based on Modified Intent-to-Treat (mITT) Population, defined as all randomized patients who received at least one infusion of study medication and had one baseline and post-baseline efficacy assessment. Study 1: BRIUMVI (N=271), teriflunomide (N=274). Study 2: BRIUMVI (N=272), teriflunomide (N=272).
2 Data prospectively pooled from Study 1 and Study 2: BRIUMVI (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 point 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). Study 1: BRIUMVI (N=265), teriflunomide (N=270). Study 2: BRIUMVI (N=272), teriflunomide (N=267).
6 At Week 96.
7 BRIUMVI dosing by intravenous infusion: first dose of 150 mg, second dose 450 mg two weeks after the first; subsequent doses 450 mg every 24 weeks; teriflunomide dosing: 14 mg by mouth once daily.
|Study 1||Study 2|
|Annualized Relapse Rate (Primary Endpoint)
49% (p = 0.002)
|Proportion of Patients with 12-week Confirmed Disability Progression
|5.2% BRIUMVI vs. 5.9% teriflunomide
16% (p = 0.510)
|Mean number of T1 Gd-enhancing lesions per MRI
|97% (p<0.001)||97% (p<0.001)|
|Mean number of new or enlarging T2 hyperintense lesions per MRI
In exploratory analyses of Study 1 and Study 2, a similar effect of BRIUMVI on the ARR was observed in subgroups defined by gender, prior non-steroid MS therapy, baseline disability (EDSS 3.5 or lower versus greater than 3.5), the number of relapses in the 2 years prior to study enrollment, and number of Gd-enhancing lesions at baseline.
BRIUMVI (ublituximab-xiiy) injection is a sterile, clear to opalescent, colorless to slightly yellow, preservative-free solution for intravenous use supplied as a carton containing one 150 mg/6 mL (25 mg/mL) single-dose vial (NDC 73150-150-06).
Advise the patient to read the FDA-approved patient labeling ( Medication Guide).
Inform patients about the signs and symptoms of infusion reactions and that infusion reactions can occur up to 24 hours after infusion. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions [see Warnings and Precautions ( 5.1)] .
Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last infusion. Signs can include fever, chills, constant cough, or dysuria [see Warnings and Precautions ( 5.2)] .
Advise patients that BRIUMVI 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 BRIUMVI and may happen with BRIUMVI. 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 doctor 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)] .
Advise patients to complete any required live or live-attenuated vaccinations at least 4 weeks and, whenever possible, non-live vaccinations at least 2 weeks prior to initiation of BRIUMVI. Administration of live-attenuated or live vaccines is not recommended during BRIUMVI treatment and until B-cell recovery [see Warnings and Precaution ( 5.2)] .
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with BRIUMVI and for 6 months after the last BRIUMVI dose. Advise patients to notify their healthcare provider if they are pregnant during treatment with BRIUMVI [see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.1, 8.3)] .
TG Therapeutics, Inc.
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BRIUMVI is a trademark of TG Therapeutics, Inc.
©TG Therapeutics, Inc. 2021-2022. All rights reserved.
This Medication Guide has been approved by the U.S. Food and Drug Administration
for intravenous use
|These infusion reactions can happen over 24 hours after your infusion. It is important that you call your healthcare provider right away if you get any of the signs or symptoms listed above after each infusion. If you get an infusion reaction, your healthcare provider may need to stop or slow down the rate of your infusion.
|What is BRIUMVI?
BRIUMVI is a prescription medicine used to treat adults with relapsing forms of multiple sclerosis (MS), including:
|It is not known if BRIUMVI is safe or effective in children.|
|Do not receive BRIUMVI if you:
|Before receiving BRIUMVI, tell your healthcare provider about all of your medical conditions, including if you:
|Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.|
|How will I receive BRIUMVI?
|What are the possible side effects of BRIUMVI?
See “ What is the most important information I should know about BRIUMVI?”
The most common side effects of BRIUMVI include:
|These are not all the possible side effects of BRIUMVI. Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.
|General information about the safe and effective use of BRIUMVI.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. You can ask your pharmacist or healthcare provider for information about BRIUMVI that is written for health professionals.
What are the ingredients in BRIUMVI?
Principal Display Panel - 6 mL Carton Label
150 mg/6 mL
For Intravenous Infusion
Discard Unused Portion.
Attention: Dispense the enclosed Medication
Guide to each patient.
Contains one 6 mL
ublituximab injection, solution, concentrate
|Labeler - TG Therapeutics, Inc. (117372682)|
|Packaging Coordinators, LLC||078525133||label(73150-150) , pack(73150-150)|
|Samsung Biologics Co., Ltd.||557810567||api manufacture(73150-150) , manufacture(73150-150)|