Briumvi

2.1        Assessments Prior to First Dose of BRIUMVI

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)].

Serum Immunoglobulins

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.

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 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)].

2.2        Assessment and Premedication Before Every Infusion

Infection Assessment

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)].

Recommended Premedication

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. 

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to each infusion with BRIUMVI [see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.1, 8.3)].

2.3     Recommended Dosage and Dose Administration

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.

• First Infusion: 150 mg intravenous infusion
• Second Infusion: 450 mg intravenous infusion administered two weeks after the first infusion
• Subsequent Infusions: 450 mg intravenous infusion administered 24 weeks after the first infusion and every 24 weeks thereafter
• Observe the patient 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 [see Warnings and Precautions ( 5.1)].

2.4        Delayed or Missed Doses

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.

2.5        Dosage Modifications Because of Infusion Reactions

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.

2.6        Preparation and Administration

Preparation

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:

• BRIUMVI should be a clear to opalescent, colorless to slightly yellow solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use the solution if discolored or if the solution contains discrete foreign particulate matter.

Preparation of Solution for First Infusion:

• Prepare infusion bag for First Infusion (150 mg) using one vial (150 mg/6 mL) of BRIUMVI.
  
• Withdraw 6 mL 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.
  
• Withdraw 6 mL BRIUMVI solution from the vial.
  
• Add 6 mL (150 mg) BRIUMVI into the infusion bag containing 0.9% Sodium Chloride Injection, USP.

Preparation of Solution for Second Infusion and Subsequent Infusions:

• Prepare infusion bag for Second Infusion (450 mg) and Subsequent Infusions (450 mg) using three vials (150 mg/6 mL) of BRIUMVI.
  
• Withdraw 18 mL 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag and discard.
  
• Withdraw 18 mL BRIUMVI solution from the vials (6 mL/vial).
  
• Add 18 mL (450 mg) BRIUMVI into the infusion bag containing 0.9% Sodium Chloride Injection, USP.

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.

2.7        Storage Instructions for the Prepared Infusion Solution

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.

8.1        Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to BRIUMVI during pregnancy. Eligible patients are women who become pregnant either while taking BRIUMVI or within 6 months following their last dose of BRIUMVI. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-411-4546 or visiting www.briumvipregnancyregistry.com/.

Risk Summary

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.

Clinical Considerations

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)].

Data

Animal Data

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.

8.2        Lactation

Risk Summary

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.

8.3        Females and Males of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential prior to each infusion

[see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.1)].

Contraception

Females

Females of reproductive potential should use effective contraception while receiving BRIUMVI and for 6 months after the last dose of BRIUMVI [see Warnings and Precautions ( 5.3) and Use in Specific Populations ( 8.1)].

8.4        Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5        Geriatric Use

Clinical studies of BRIUMVI did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.

5.1        Infusion Reactions

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.

5.2        Infections

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.

Vaccinations

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)].

5.3        Fetal Risk

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)].

5.4        Reduction in Immunoglobulins

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.

6.1     Clinical Trials 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 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%).

Infusion Reactions

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)].

Laboratory Abnormalities

Decreased Immunoglobulins

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 109/L. In RMS studies, 3% of patients in the BRIUMVI group had neutrophil counts less than 1.0 x 109/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 109/L, compared to 0% of patients in the teriflunomide group, and these were not associated with an infection.

7.1        Immunosuppressive or Immune-Modulating Therapies

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.

12.1        Mechanism of Action

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.

12.2        Pharmacodynamics

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.

12.3        Pharmacokinetics

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%).

Distribution

The estimated central volume of distribution of ublituximab-xiiy was 3.18 L.

Elimination

The estimated mean terminal half-life of ublituximab-xiiy was 22 days.

Metabolism

Ublituximab-xiiy is a protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.

Specific Populations

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.

Drug Interaction Studies

No studies evaluating the drug interaction potential of ublituximab-xiiy have been conducted.

12.6        Immunogenicity

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.

13.1        Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity studies have been conducted to assess the carcinogenic potential of BRIUMVI.

Mutagenesis

As an antibody, BRIUMVI is not expected to interact directly with DNA.

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 (Cave) approximately 24 times that in humans at the maximum recommended human dose (450 mg).