Kesimpta Product Monograph

Recent Major Label Changes

Table of Contents

Certain sections or subsections that are not applicable at the time of the preparation of the most recent authorized product monograph are not listed.

Recent Major Label Changes ................................................................................................... 2

Table of Contents ................................................................................................................... 2

Part 1: Healthcare Professional Information ........................................................................... 4

1. 1.

   Indications ....................................................................................................................... 4

   1.4. Pediatrics .................................................................................................................. 4

   1.5. Geriatrics .................................................................................................................. 4

2. 2. Contraindications ............................................................................................................ 4
3. 4.

   Dosage and Administration ............................................................................................. 4

   4.1. Dosing Considerations .............................................................................................. 4

   4.2. Recommended Dose and Dosage Adjustment ......................................................... 5

   4.4. Administration .......................................................................................................... 6

   4.5. Missed Dose ............................................................................................................. 6

4. 5. Overdose ......................................................................................................................... 6
5. 6. Dosage Forms, Strengths, Composition, and Packaging ................................................... 6
6. 7.

   Warnings and Precautions ............................................................................................... 7

   General ................................................................................................................................. 7

   Hepatic/Biliary/Pancreatic .................................................................................................... 8

   Immune ................................................................................................................................ 9

   Infections .............................................................................................................................. 9

   Reproductive Health ........................................................................................................... 10

   7.1. Special Populations ................................................................................................ 11

   7.1.1. Pregnancy ...................................................................................................... 11

   7.1.2. Breastfeeding ................................................................................................ 11

   7.1.3. Pediatrics ....................................................................................................... 11

   7.1.4. Geriatrics ....................................................................................................... 11

7. 8.

   Adverse Reactions ......................................................................................................... 11

   8.1. Adverse Reaction Overview .................................................................................... 11

   8.2. Clinical Trial Adverse Reactions .............................................................................. 12

   8.3. Less Common Clinical Trial Adverse Reactions ....................................................... 14

   8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data ............................................................................................................... 14

   8.5. Post-Market Adverse Reactions ............................................................................. 14

8. 9.

   Drug Interactions ........................................................................................................... 14

   9.2. Drug Interactions Overview .................................................................................... 14

   9.4. Drug-Drug Interactions ........................................................................................... 15

   9.5. Drug-Food Interactions........................................................................................... 15

   9.6. Drug-Herb Interactions ........................................................................................... 15

   9.7. Drug-Laboratory Test Interactions ......................................................................... 15

9. 10.

   Clinical Pharmacology ................................................................................................... 15

   10.1. Mechanism of Action .............................................................................................. 15

   10.2. Pharmacodynamics ................................................................................................ 16

   10.3. Pharmacokinetics ................................................................................................... 16

   10.4. Immunogenicity ...................................................................................................... 17

10. 11. Storage, Stability, and Disposal ...................................................................................... 17
11. 12. Special Handling Instructions ......................................................................................... 18

Part 2: Scientific Information ................................................................................................ 19

1. 13. Pharmaceutical Information .......................................................................................... 19
2. 14.

   Clinical Trials .................................................................................................................. 19

   14.1. Clinical Trials by Indication ..................................................................................... 20

3. 15. Microbiology ................................................................................................................. 23
4. 16. Non-Clinical Toxicology .................................................................................................. 23

Patient Medication Information ........................................................................................... 26

Patient Medication Information ........................................................................................... 41

Part 1: Healthcare Professional Information

1. Indications

KESIMPTA® (ofatumumab injection) is indicated for:

• the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease defined by clinical and imaging features (see 14 Clinical Trials).

KESIMPTA treatment should be initiated and supervised by health professionals experienced in the treatment of patients with MS and who are familiar with the efficacy and safety profile of KESIMPTA (see 7 Warnings and Precautions).

1.4. Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of KESIMPTA in pediatric MS patients below the age of (<18 years of age) have not been studied. KESIMPTA is not authorized for pediatric use.

1.5. Geriatrics

Geriatrics: Ofatumumab was not studied in patients ≥ 55 years of age.

2. Contraindications

KESIMPTA is contraindicated in patients:

• Who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 Dosage forms, Strengths, Composition and Packaging.
• With active HBV infection (see 4.1 Dosing Considerations and 7 Warnings and Precautions)
• With severe, active infections (see 7 Warnings and Precautions, Infections)
• Who have or have had confirmed progressive multifocal leukoencephalopathy (PML) (see 7 Warnings and Precautions, Infections)
• Who are in a severely immunocompromised state (see 7 Warnings and Precautions, General)
• With known active malignancies

4. Dosage and Administration

4.1. Dosing Considerations

KESIMPTA is intended for patient self-administration by subcutaneous injection. Administration should be performed by an individual who has been trained to administer the product.

The first injection of KESIMPTA should be performed under the guidance of an experienced health professional (see 7 Warnings and Precautions, General).

Assessment Prior to First Dose of KESIMPTA

Hepatitis B Virus Screening

Prior to initiating KESIMPTA, perform Hepatitis B virus (HBV) screening. KESIMPTA is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment (see 7 Warnings and Precaution, Infections).

Serum Immunoglobulins

Prior to initiating KESIMPTA, perform testing for quantitative serum immunoglobulins (see7 Warnings and Precautions, General). For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with KESIMPTA.

Vaccinations

Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all necessary immunizations according to immunization guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines (see 7 Warnings and Precautions, Immune and 10 Clinical Pharmacology).

Liver Function Tests

Prior to initiating KESIMPTA, obtain serum aminotransferases (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), alkaline phosphatase, and bilirubin levels (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic).

Assessment before every injection

Infection Assessment

In case of active infection, delaying injection of KESIMPTA should be considered until the infection resolves (see 7 Warnings and Precaution, Infections).

Premedication

The decision to initiate or continue premedication should be made on an individual patient basis (see 7 Warnings and Precautions, General)).

4.2. Recommended Dose and Dosage Adjustment

The recommended dosage of KESIMPTA is:

• initial dosing of 20 mg by subcutaneous injection at weeks 0, 1 and 2, followed by
• subsequent monthly dosing of 20 mg by subcutaneous injection, starting at week 4.

Special populations

The pharmacokinetics of ofatumumab have not been studied in patients with renal or hepatic impairment, pediatric and geriatric patients (see 10 Clinical Pharmacology, Special population).

4.4. Administration

The usual sites for subcutaneous injections are the abdomen, the thigh and the upper outer arm.

Prior to administration, allow KESIMPTA to reach room temperature for about 15 to 30 minutes.

Visually inspect for particulate matter prior to administration. Do not use if the solution contains visible particles or is cloudy.

Do not freeze. Do not shake.

Comprehensive instructions for the administration of KESIMPTA are provided in the Patient Medication Information.

4.5. Missed Dose

If an injection of KESIMPTA is missed, it should be administered as soon as possible without waiting until the next scheduled dose. Subsequent doses should be reset to administer the next sequential dose at the recommended once a month intervals.

5. Overdose

No cases of overdose have been reported in RMS clinical studies.

Doses up to 700 mg have been administered intravenously in clinical studies with MS patients without dose-limiting toxicity. In the event of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment be instituted as necessary.

1. 6. Dosage Forms, Strengths, Composition, and Packaging

To help ensure the traceability of biologic products healthcare professionals should record both the brand name and the non-proprietary (active ingredient) name as well as other product-specific identifiers such as the Drug Identification Number (DIN) and the batch/lot number of the product supplied.

Table 1 – Dosage Forms, Strengths, and Composition

Description

The single-use solution for injection is sterile, preservative-free, clear to slightly opalescent, and colorless to slightly brownish-yellow.

KESIMPTA is supplied as follows:

• 20 mg/0.4 mL Solution for injection in a pre-filled syringe*
• 20 mg/0.4 mL Solution for injection in a pre-filled Sensoready pen

Each pre-filled syringe and pre-filled Sensoready pen contains 20 mg ofatumumab solution for injection (0.4 mL of 50 mg/mL solution).

*Pre-filled syringes are not available in Canada

7. Warnings and Precautions

General

Injection-related reactions

Injection site reaction (local) symptoms observed in clinical studies included erythema, swelling, itching and pain.

Injection-related reactions with systemic symptoms observed in clinical studies occurred predominantly within 24 hours of the first injection, but were also observed with later injections. Symptoms observed include fever, headache, myalgia, chills and fatigue and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening injection reactions in RMS clinical studies.

Additional systemic injection-related reactions (SIRRs) reported in the post-marketing setting include rash, urticaria, dyspnea, angioedema (e.g., tongue, pharyngeal or laryngeal swelling), and rare cases which were reported as anaphylaxis. Most of the cases were non-serious and occurred with first injection. While there were some cases which were serious and resulted in discontinuation of KESIMPTA treatment, there were also cases where patients were able to continue KESIMPTA treatment.

Some SIRR symptoms may be clinically indistinguishable from Type 1 acute hypersensitivity reactions (IgE-mediated). Patients should be informed that SIRRs generally occur within 24 hours and predominantly following the first injection. SIRRs can be managed with symptomatic treatment, should they occur.

A hypersensitivity reaction may present with any injection, although typically would not present with the first injection. For subsequent injections, more severe symptoms than previously experienced, or new severe symptoms, should prompt consideration of a potential hypersensitivity reaction. Patients with known IgE mediated hypersensitivity to KESIMPTA must not be treated with KESIMPTA (see 2 Contraindications).

Ofatumumab-treated patients who received premedication with methylprednisolone (or an equivalent steroid) experienced fewer symptoms such as fever, myalgia, chills, and nausea. However, in some patients, the use of steroid premedication increased the occurrence of flushing, chest discomfort, hypertension, tachycardia, and abdominal pain even in the absence of ofatumumab treatment (i.e. in patients receiving placebo injections). Therefore, the decision to initiate or continue premedication should be made on an individual patient basis (see 4.1 Dosing Considerations).

The first injection of KESIMPTA should be performed under the guidance of an appropriately trained health professional.

Possible Increased Risk of Immunosuppressant Effects with other Immunosuppressants

When initiating KESIMPTA after immunosuppressive therapy or initiating immunosuppressive therapy after KESIMPTA, consider the potential for increased immunosuppressive effects (see 9.2 Drug Interactions Overview and 10 Clinical Pharmacology).

Hepatic/Biliary/Pancreatic

Liver Injury

Clinically significant liver injury, without findings of viral hepatitis, has been observed in the postmarketing setting in patients treated with KESIMPTA. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from days to months after treatment initiation.

Liver function tests should be performed before initiation of treatment with KESIMPTA, and patients should be monitored for signs and symptoms of any hepatic injury during treatment. Serum aminotransferases, alkaline phosphatase, and bilirubin levels should be measured in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice.

If liver injury is confirmed, discontinue KESIMPTA. If an alternative etiology is identified, treatment with KESIMPTA can be resumed only when the event has been fully resolved.

Immune

Vaccinations

Physicians should review the immunization status of patients before starting treatment with KESIMPTA. All immunizations should be administered according to immunization guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines.

KESIMPTA may interfere with the effectiveness of inactivated vaccines (see 9.2 Drug Interactions Overview).

The safety of immunization with live or live-attenuated vaccines following KESIMPTA therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion (see 10.1 Mechanism of Action).

Vaccination of infants born to mothers treated with KESIMPTA during pregnancy

Due to the potential depletion of B cells in infants of mothers treated with KESIMPTA during pregnancy, live or live-attenuated vaccines should not be administered before the recovery of B-cell counts has been confirmed as measured by CD19+ B cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines (see 16 Non-Clinical Toxicology and 10 Clinical Pharmacology).

Inactivated vaccines may follow the local immunization schedule, but physicians should assess whether a protective immune response was mounted. Physicians may consult vaccination experts as the efficacy of the vaccination of an infant may be decreased following KESIMPTA exposure (see 9.2 Drug Interactions Overview and 7.1.1 Pregnancy).

Infections

Delay KESIMPTA administration in patients with an active infection until the infection is resolved.

It is recommended to evaluate the patient’s immune status prior to initiating therapy (see 4.1 Dosing Considerations).

An increased risk of infections has been observed with other anti – CD20 B-cell depleting therapies. KESIMPTA has the potential for an increased risk of infections, including serious bacterial, fungal, and new or reactivated viral infections; some of these infections have been fatal in patients treated with other anti-CD20 antibodies.

In Study G2301 and Study G2302, the proportion of patients with infections and serious infections was similar in the ofatumumab and the teriflunomide treatment groups (51.6% vs 52.7%, and 2.5 vs 1.8%, respectively).

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the John Cunningham 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 been reported for KESIMPTA in the RMS clinical studies, PML resulting in death has occurred in patients being treated with ofatumumab for CLL (at substantially higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). In addition, JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold KESIMPTA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. 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.

If PML is confirmed, discontinue treatment of KESIMPTA.

Hepatitis B Virus Reactivation

No cases of hepatitis B virus (HBV) reactivation were identified in KESIMPTA RMS clinical studies. However, HBV reactivation has occurred in patients treated with anti-CD20 antibodies, which in some cases resulted in fulminant hepatitis, hepatic failure and death.

Patients with active hepatitis B disease should not be treated with KESIMPTA (see 2 Contraindications). HBV screening should be performed in all patients before initiation of treatment with KESIMPTA (see 4.1 Dosing Considerations). At minimum screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. 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 KESIMPTA. These patients should be monitored and managed following local medical standards to prevent hepatitis B reactivation.

In the event of HBV reactivation, KESIMPTA and concomitant medications should be discontinued until the active infection is resolved.

Reproductive Health

Females of childbearing potential should use effective contraception (methods that result in less than 1% pregnancy rates) while receiving KESIMPTA and for 6 months after the last treatment of KESIMPTA.

7.1. Special Populations

7.1.1. Pregnancy

No studies have been conducted with KESIMPTA in pregnant women. Human IgG is known to cross the placental barrier; therefore, KESIMPTA may be transmitted from the mother to the developing fetus. Animal studies have shown that ofatumumab may cross the placenta and causes fetal B-cell depletion in monkeys. In addition, in monkeys, in utero exposure to ofatumumab resulted in incidences of B-cell depletion, infection, and deaths in infants. Ofatumumab was also detected in infant monkey blood (see 16 Non-Clinical Toxicology).

Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown (see 7 Warnings and Precautions, Immune and 10 Clinical Pharmacology).

7.1.2. Breastfeeding

• infant, or the effects on human milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KESIMPTA and any potential adverse effects on the breastfed infant from KESIMPTA.

7.1.3. Pediatrics

Pediatrics (< 18 years of age): The safety and efficacy of KESIMPTA in pediatric MS patients below the age of 18 years have not been studied. KESIMPTA is not authorized for pediatric use.

7.1.4. Geriatrics

No studies have been performed in elderly MS patients. Ofatumumab was studied in patients with RMS aged 18 to 55 years.

8. Adverse Reactions

8.1. Adverse Reaction Overview

Approximately 1500 (n=1420 at the date of submission) patients with RMS received ofatumumab in clinical studies. In the two Phase 3 pivotal studies, 1882 patients with RMS were randomized, 946 of whom were treated with ofatumumab for a median duration of 85 weeks; 33% (n=312) of patients receiving ofatumumab were treated for more than 96 weeks (see 14 Clinical Trials).

The proportion of patients with adverse events (AEs) (83.6% versus 84.2%) and the AEs leading to drug discontinuation (5.7% versus 5.2%) were similar in the ofatumumab and teriflunomide groups.

The most common adverse reactions occurring in >10% of patients treated with KESIMPTA, and more frequently than in patients treated with teriflunomide, were upper respiratory tract infections, injection-related reactions (systemic), headache, and injection-site reactions (local). The most common cause of discontinuation in patients treated with KESIMPTA was low immunoglobulin M (3.3%), defined in trial protocols as IgM at 10% below the lower limit of normal (LLN).

8.2. Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. Therefore, the frequencies of adverse reactions observed in the clinical trials may not reflect frequencies observed in clinical practice and should not be compared to frequencies reported in clinical trials of another drug.

Table 2 – Summary of Adverse Reactions associated with KESIMPTA with an incidence of ≥1%) and higher than teriflunomide

Description of selected adverse drug reactions

Upper Respiratory Tract Infections

A higher proportion of ofatumumab-treated patients experienced upper respiratory tract infections compared to teriflunomide-treated patients. In the RMS clinical studies, 39.4% of ofatumumab-treated patients experienced upper respiratory tract infections* compared to 37.8% of teriflunomide-treated patients. The infections were predominantly mild to moderate and mostly consisted of nasopharyngitis, upper respiratory tract infection and influenza.

*Grouping of preferred terms (PTs) was considered for adverse drug reactions frequency determination and includes the following: nasopharyngitis, upper respiratory tract infection, influenza, sinusitis, pharyngitis, rhinitis, viral upper respiratory infection, tonsillitis, acute sinusitis, pharyngotonsillitis, laryngitis, pharyngitis streptococcal, viral rhinitis, sinusitis bacterial, tonsillitis bacterial, viral pharyngitis, viral tonsillitis, chronic sinusitis, nasal herpes, tracheitis.

Injection related reactions and injection site reactions

In patients treated with ofatumumab in the RMS Phase 3 clinical studies, injection related reactions (systemic) and injection-site reactions (local) were reported in 20.6% and 10.9% of patients treated with ofatumumab, respectively.

The incidence of injection-related reactions was highest with the first injection (14.4%), decreasing significantly with subsequent injections (4.4% with second, <3% from third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Only two (0.2%) ofatumumab-treated MS patients reported serious injection-related reactions. There were no life-threatening injection-related reactions. The most frequently reported symptoms (≥2%) included fever, headache, myalgia, chills, and fatigue.

Local reactions at the administration site were very common. Injection-site reactions were all mild to moderate in severity and non-serious in nature. The most frequently reported symptoms (≥2%) included erythema, pain, itching, and swelling (see 7 Warnings and Precautions, General).

8.3. Less Common Clinical Trial Adverse Reactions

In RMS clinical trials, there are no adverse reactions that occurred at an incidence rate of <1%.

8.4. Abnormal Laboratory Findings: Hematologic, Clinical Chemistry, and Other Quantitative Data

Clinical Trial Findings

Immunoglobulins

In Study G2301 and Study G2302, a decrease in mean level of immunoglobulin M (IgM) was observed in KESIMPTA-treated patients, but was not associated with risk of infections. In 14.3% of patients in Study G2301 and Study G2302, treatment with KESIMPTA resulted in a decrease in a serum IgM that reached a value below 0.34 g/L. KESIMPTA was associated with a decrease of 4.3% in mean IgG levels after 48 weeks of treatment and an increase of 2.2% after 96 weeks.

Neutropenia

The overall incidence of neutropenia-related AEs was low in ofatumumab group (9 patients, 1.0%), as compared to 32 patients (3.4%) in the teriflunomide group and were mostly grade 1 or 2 and transient in nature. Causality to KESIMPTA has not been established.

8.5. Post-Market Adverse Reactions

The following adverse drug reactions have been derived from postmarketing experience with KESIMPTA via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known.

Immune system disorders: Hypersensitivity reaction (see 7 Warnings and Precautions, General).

Hepatobiliary disorders: Liver injury (see 7 Warnings and Precautions, Hepatic/Biliary/Pancreatic)

9. Drug Interactions

9.2. Drug Interactions Overview

Ofatumumab does not share a common clearance pathway with chemical drugs that are metabolized by the cytochrome P450 system or other drug metabolizing enzymes. Additionally, there is no evidence that CD20 monoclonal antibodies (mAbs) are involved in the regulation of the expression of drug metabolizing enzymes. Interactions between KESIMPTA and other medicinal products have not been investigated in formal studies.

Vaccinations

The safety of and the ability to generate a primary or anamnestic (recall) response to immunization with live, live-attenuated or inactivated vaccines during ofatumumab treatment has not been investigated. The response to vaccination could be impaired when B-cells are depleted. It is recommended that patients complete immunizations prior to the start of KESIMPTA therapy (see 7 Warnings and Precautions, Immune).

Other Immunosuppressive or Immune-Modulating Therapies

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

When switching from therapies with prolonged immune effects, such as ocrelizumab, cladribine, fingolimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate, the duration and mode of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating KESIMPTA.

Patients in a severely immunocompromised state must not be treated until the condition resolves (see 2 Contraindications).

9.4. Drug-Drug Interactions

Interactions with other drugs have not been established.

9.5. Drug-Food Interactions

Interactions with food have not been established.

9.6. Drug-Herb Interactions

Interactions with herbal products have not been studied.

9.7. Drug-Laboratory Test Interactions

Interference of KESIMPTA with laboratory and/or diagnostic tests has not been studied.

10. Clinical Pharmacology

10.1. Mechanism of Action

B-cells play an important role in MS pathogenesis due to production of pro-inflammatory cytokines, release of auto-reactive antibodies and activation of pathogenic T cells. Ofatumumab is a human monoclonal antibody (IgG1κ) that binds specifically to a distinct epitope encompassing both the small and large extracellular loops of the CD20 molecule. The CD20 molecule is a transmembrane phosphoprotein expressed on B lymphocytes from the pre-B to mature B lymphocyte stage. The CD20 molecule is also expressed on a small fraction of activated T cells.

The binding of ofatumumab to CD20 induces lysis of CD20+ B-cells primarily through complement-dependent cytotoxicity (CDC) and to a lesser extent, through antibody-dependent cell-mediated cytotoxicity (ADCC). Ofatumumab has also been shown to induce cell lysis in both high and low CD20-expressing cells. CD20-expressing T cells are also depleted by ofatumumab.

10.2. Pharmacodynamics

B-cell depletion

For B-cell counts, assays for CD-19+ B-cells are used because the presence of KESIMPTA interferes with CD20 assay. In Study G2301 and Study G2302, KESIMPTA administered as recommended, resulted in a reduction of CD19+ B-cells to below the LLN in 77% and 78.8% of patients, respectively, one week after treatment initiation, and 95% and 95.8% of patients, respectively, two weeks after treatment initiation (see 4 Dosage and Administration and 14 Clinical Trials). In Study G2301 and Study G2302, at week 12, 99.3% to 99.5% of patients had CD19+B-cell counts below LLN. The CD19+B-cell counts remained below LLN for approximately 97% of patients in Study G2301 and 92% of patients in Study G2302 from 12 weeks through 120 weeks while on KESIMPTA treatment.

In a study of bioequivalence using the same dosing regimen as in Study G2301 and Study G2302, before initiation of the maintenance phase, total CD19+B-cell levels below the defined threshold of 10 cells/µL were achieved in 94% of patients starting week 4 and 98% of patients at week 12.

B-cell repletion

Data from the two RMS Phase 3 studies indicate a median time to B-cell recovery to either LLN or baseline value of 24.6 weeks post treatment discontinuation. PK and PD (B-cell) modelling and simulation for B-cell repletion corroborate these data, predicting median time to B-cell recovery to LLN of 23 weeks post treatment discontinuation.

10.3. Pharmacokinetics

Ofatumumab exhibits a long half-life and low volume of distribution similar to that of other monoclonal antibodies. Ofatumumab is eliminated through a non-linear target-mediated route as well as a target-independent route mediated by non-specific endocytosis followed by intracellular catabolism. Higher baseline B-cell count results in greater component of target-mediated elimination clearance and shorter ofatumumab half-life at the start of therapy. Subsequent ofatumumab dosing leads to potent depletion of B-cells resulting in reduced overall clearance.

Absorption

A monthly subcutaneous dose of 20 mg leads to a mean AUCtau of 483 µg·h/mL and a mean Cmax of 1.43 µg/mL at steady state.

After subcutaneous administration, ofatumumab is believed to be predominantly absorbed via the lymphatic system similarly to other therapeutic monoclonal antibodies.

Distribution

The volume of distribution at steady-state was estimated to be 5.42 L following subcutaneous administration of repeated KESIMPTA 20 mg dose.

Metabolism

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

Elimination

Ofatumumab is eliminated by a target-independent catabolic pathway and a target (i.e. B-cell)-mediated pathway. At the beginning of ofatumumab treatment, the B-cells counts at baseline result in a greater component of B-cell-mediated clearance of ofatumumab. Following depletion of B-cells by ofatumumab administration, the overall clearance is reduced as it is primarily driven by the catabolic pathway. The half-life at steady state was estimated to be approximately 16 days following repeated subcutaneous administration of KESIMPTA at a dose of 20 mg.

Special populations and conditions

• Pediatrics: No studies have been conducted to investigate the pharmacokinetics in pediatric patients below the age of 18 years.
• Geriatrics: No studies have been performed in elderly MS patients. Ofatumumab was studied in patients with RMS aged 18 to 55 years.
• Sex: Gender had a modest (12%) effect on ofatumumab central volume of distribution in a cross-study population analysis, with higher C_max and AUC values observed in female patients (48% of the patients in this analysis were male and 52% were female); these effects are not considered to have a significant change in the pharmacokinetics of ofatumumab.
• Hepatic Insufficiency: No formal pharmacokinetic study has been conducted. Since hepatic metabolism of monoclonal antibodies such as ofatumumab is negligible, hepatic impairment is not expected to impact its pharmacokinetics.
• Renal Insufficiency: No formal pharmacokinetic study has been conducted. Ofatumumab is not excreted via urine; therefore, no significant change in the pharmacokinetics of ofatumumab is expected in patients with renal impairment.

10.4. Immunogenicity

All therapeutic proteins have the potential for immunogenicity.

As a fully human monoclonal antibody, ofatumumab has a low potential of inducing anti-drug antibodies (ADA). In RMS Phase 3 studies, the overall incidence of ADAs was very low: treatment induced ADA were detected in 2 of 914 ofatumumab treated patients and no patients with treatment enhancing or neutralizing ADA were identified. There was no impact of positive ADA titers on PK, safety profile or B-cell kinetics in any patient.

1. 11. Storage, Stability, and Disposal

Store between 2°C to 8°C.

Do not freeze. Do not shake.

Store in the original carton to protect from light.

If necessary, KESIMPTA may be stored unrefrigerated for a single period of up to 7 days at room temperature (not above 30°C). If not used during this period, KESIMPTA can then be returned to the refrigerator for a maximum of 7 days.

KESIMPTA must be kept out of the reach and sight of children.

12. Special Handling Instructions

Any unused product or waste material should be disposed of in accordance with local regulations.

Part 2: Scientific Information

13. Pharmaceutical Information

Drug Substance

Non-proprietary name of the drug substance:

Ofatumumab

Chemical name:

Fully human monoclonal immunoglobulin G1 antibody (IgG1-kappa) against human CD20

Molecular formula and molecular mass:

C6480H10022N1742O2020S44

146062 Da

Structural formula:

Ofatumumab consists of two IgG1 heavy chains and two kappa light chains. Both heavy chains of Ofatumumab contain oligosaccharide chains linked to the protein backbone at Asn302.

Physicochemical properties:

The drug substance (DS) is a clear to opalescent, colorless to pale yellow aqueous solution of Ofatumumab. The pH of the aqueous solution is in the range of 5.3 – 5.7.

Product Characteristics:

Ofatumumab is a recombinant fully human monoclonal immunoglobulin G1 (IgG1) antibody against human CD20 expressed on B-cells. Ofatumumab is produced in a murine cell line (NS0) by recombinant DNA technology.

14. Clinical Trials

The efficacy and safety of KESIMPTA were evaluated in two randomized, double-blind, double-dummy, active-controlled Phase 3 pivotal studies of identical design (G2301 (ASCLEPIOS I) and G2302 (ASCLEPIOS II)) in patients with relapsing forms of MS (RMS), aged 18 to 55 years, a disability status at screening with an Expanded Disability Status Scale (EDSS) score from 0 to 5.5, and who had experienced at least one documented relapse during the previous year or two relapses during the previous two years or a positive gadolinium (Gd)-enhancing MRI scan during the previous year.

14.1. Clinical Trials by Indication

Table 3 - Summary of Trial Design and patient demographics for clinical trials in RMS

In the two studies, 927 and 955 patients with RMS, respectively, were randomized 1:1 to receive either KESIMPTA 20 mg subcutaneous injections every 4 weeks starting at Week 4 after an initial dosing regimen of three weekly 20 mg doses in the first 14 days (on Days 1, 7 and 14) or teriflunomide 14 mg capsules orally once daily. Patients also received matching placebo corresponding to the other treatment arm to ensure blinding (double-dummy design). The treatment duration for individual patients was variable based on when the end of study criteria were met. The maximal duration of treatment for an individual patient was 120 weeks. Neurologic evaluations were performed at baseline, every 3 months during blinded treatment, and at the time of a suspected relapse. Brain MRI scans were performed at baseline, 1 and 2 years.

In Study G2301, a total of 927 patients were randomized to receive KESIMPTA (n = 465) or teriflunomide (n = 462). Of those randomized to KESIMPTA, 89.5% completed the study; of those randomized to teriflunomide, 81.4% completed the study. In Study G2302, a total of 955 patients were randomized to receive KESIMPTA (n = 481) or teriflunomide (n = 474). Of those randomized to KESIMPTA, 82.5% completed the study; of those randomized to teriflunomide, 82.1% completed the study.

Patients with active disease were enrolled in the studies. These included both newly diagnosed patients and patients switching from their current treatment due to lack of efficacy, safety or tolerability considerations. Demographics and baseline characteristics were well-balanced across treatment arms and both studies (Table 3).

The primary efficacy endpoint of both studies was the annualized rate of confirmed relapses (ARR) based on EDSS. Key secondary efficacy endpoints included the time to disability worsening on EDSS (confirmed at 3 months and 6 months), defined as an increase in EDSS of ≥1.5, ≥1, or ≥0.5 in patients with a baseline EDSS of 0, 1 to 5, or ≥5.5, respectively. Further key secondary endpoints were the number of Gd-enhancing T1 lesions per MRI scan, and the annualized rate of new or enlarging T2 lesions. Disability-related key-secondary endpoints were evaluated in a pooled analysis of combined data from studies G3201 and G2302, as defined in the study protocols.

In both studies, KESIMPTA significantly lowered the ARR compared to teriflunomide.

KESIMPTA significantly reduced the risk of 3-month confirmed disability worsening and 6-month confirmed disability worsening compared to teriflunomide based on a pooled analysis of both studies.

In both studies, KESIMPTA significantly reduced the number of Gd-enhancing T1 lesions and the rate of new or enlarging T2 lesions.

The efficacy results for both studies are summarized in Table 4 and Figure 1.

Table 4 – Results of Key Clinical and MRI Endpoints from the Phase 3 studies in RMS

Figure 1 Time to first 3-month confirmed disability worsening by treatment (G2301 and G2302 combined, full analysis set)

15. Microbiology

No microbiological information is required for this drug product.

16. Non-Clinical Toxicology

General Toxicology: Repeated intravenous administration of ofatumumab to cynomolgus monkeys at doses of 20 and 100 mg/kg over 7 months (administered weekly in first 2 months and monthly thereafter) resulted in CD20+ B cell-depletion, attenuation of the humoral immune response to keyhole limpet hemocyanin (KLH), and atrophy of lymphoid organs,

10.9%

15.0%

24

22

20

18

16

14

12

10

8

6

4

2

0

944

Ofatumumab

908

878

844

810

784

533

319

176

49

1

0

932

Teriflunomide

901

841

804

756

718

477

297

146

41

1

0

Study month

Number of patients at risk

0

3

6

9

12

15

18

21

24

27

30

33

Kap^l an _-Meⁱe^r es_tima^t e o^f cumula^tiv e ev en_t ra^te (% )

Ofatumumab (N= 944)

Teriflunomide (N= 932)

Risk reduction (RR): 34.3%, p=0.003 which are consistent with the pharmacological effects of ofatumumab. Partial or complete recovery was observed within 6 months of dosing cessation. The following mortalities occurred in this study: two deaths were considered subsequent to gastrointestinal infection possibly exacerbated by immunosuppression; and three other deaths were considered related to the immunogenic response in monkeys (hemolytic anemia or immune-complex disease) The dose of 100 mg/kg was considered to be the no- observed- adverse -effect level (NOAEL) and is associated with an AUC-based safety margin of 118-fold when compared with the human exposure following subcutaneous administration at the therapeutic dose of 20 mg monthly.

In cynomolgus monkeys administered ofatumumab subcutaneously at 20 or 100 mg/kg or intravenously at 100 mg/kg on Days 1 and 15 of a 2-dose study, the expected pharmacological effect of B cell-depletion, as well as the rate of B cell recovery during the off-dose phase, were similar between the subcutaneous and intravenous routes of administration. There were no significant local effects at the intravenous and subcutaneous injection sites.

Carcinogenicity: No carcinogenicity studies have been performed to assess the carcinogenic potential of ofatumumab.

Genotoxicity: No genotoxicity studies have been performed to assess the genotoxic potential of ofatumumab. As an antibody, ofatumumab is not expected to interact directly with DNA.

Reproductive and Developmental Toxicology: Fertility, embryo-fetal development (EFD) and enhanced pre-/post-natal development (ePPND) studies were conducted in cynomolgus monkeys using the intravenous route of administration.

In the 13-week fertility study, the dosing regimen consisted of an initial dose of 10 or 100 mg/kg given weekly for the first 5 weeks followed by a dose of 3 or 20 mg/kg given every 2 weeks. Male and female fertility-related endpoints were unaffected by administration with ofatumumab. The NOAEL for fertility-related endpoints was therefore the 100/20 mg/kg dose, resulting in male and female AUC-based safety margins of 335-fold and 257-fold, respectively, when compared with the human exposure following subcutaneous administration at the therapeutic dose of 20 mg monthly.

In the EFD study, weekly administration of ofatumumab at 20 or 100 mg/kg to pregnant monkeys during organogenesis (gestation day [GD] 20 to 50; total of 5 doses) caused no maternal toxicity, no teratogenicity, and no adverse effects on embryofetal development. The pharmacologically expected depletion of CD20+ B cells was seen in maternal animals and their fetuses, which also had decreased spleen weights at 100 mg/kg without histological correlates. The dose of 100 mg/kg was considered to be the NOAEL, resulting in a maternal AUC-based safety margin of 1288-fold when compared with the human exposure following subcutaneous administration at the therapeutic dose of 20 mg monthly.

In the ePPND study, pregnant monkeys were administered ofatumumab starting from GD20 with an initial dose of 10 or 100 mg/kg given weekly for the first 5 weeks, followed by a maintenance dose of 3 or 20 mg/kg given every 2 weeks until parturition. Exposure to ofatumumab during gestation caused no maternal toxicity. The expected depletion of CD20+ B-cells was seen in maternal animals and their infants, along with a reduced humoral immune response to KLH in infants at 100/20 mg/kg. All were reversible during the 6-month postnatal period. In infants, early postnatal mortality was observed at 100/20 mg/kg and was likely due to potential infections secondary to immunomodulation. No other adverse effects were observed in surviving infants. The dose of 10/3 mg/kg was considered to be the NOAEL for infants, resulting in a maternal AUC-based safety margin of 22-fold when compared with the human exposure following subcutaneous administration at the therapeutic dose of 20 mg monthly.

Ofatumumab was detected in cord blood (EFD study) and in infant blood (ePPND study), supporting that ofatumumab crosses the placental barrier.