In August 2020, the US Food and Drug Administration approved ofatumumab (brand name, Kesimpta® [Novartis Pharmaceuticals Corporation]), a new therapy for relapsing forms of multiple sclerosis (MS).1 Ofatumumab is a C20-directed cytolytic antibody indicated for the treatment of adult patients with relapsing forms of MS, including clinically isolated syndrome, relapsing–remitting disease, and active secondary progressive disease.
Following subcutaneous administration, ofatumumab is believed to be absorbed predominantly through the lymphatic system. Although the exact mechanism of action is unknown, ofatumumab is presumed to work by binding to CD20, a cell-surface antigen on pre-B and mature B lymphocytes, which induces antibody-dependent cellular cytolysis, complement-mediated lysis, and subsequent B-cell depletion.
The approval of Kesimpta was based on the results of 2 clinical trials, ASCLEPIOS I (ClinicalTrials.gov Identifier: NCT02792218) and ASCLEPIOS II (ClinicalTrials.gov Identifier: NCT02792231), both of which evaluated the efficacy of the drug in patients with relapsing forms of MS. The studies had identical designs: randomized, double-blind, double-dummy, and active comparator-controlled. Patients included in the studies were required to have had at least 1 relapse in the past year, 2 relapses in the past 2 years, or a T1-weighted gadolinium-enhancing (GdE) lesion present in the past year, in addition to an Expanded Disability Status Scale (EDSS) score of 0 to 5.5.
Patients were randomly assigned to receive either Kesimpta or the active comparator, teriflunomide, for a duration that was dependent on when study criteria were achieved. In addition to daily oral placebo, patients assigned to the Kesimpta arm received 20 mg subcutaneously on days 1, 7, and 14, then 20 mg every 4 weeks, starting at week 4. Patients assigned to teriflunomide received 14 mg orally once daily as well as placebo, administered subcutaneously on days 1, 7, 14, then every 4 weeks. Maximum duration of treatment for any one patient in both trials was 120 weeks.
Monitoring during the studies included neurologic evaluation (at baseline, every 3 months during blinded treatment, and at the time of any suspected relapse), as well as magnetic resonance imagining (MRI) scans of the brain (at baseline, 1 year, and 2 years).
The annualized relapse rate during the treatment period was the primary end point of both studies. Secondary outcomes included time until 3-month confirmed disability progression for the pooled populations; the quantity of T1-weighted GdE lesions per MRI scan at weeks 24, 48, and 96; and the annualized rate of new or enlarging lesions on T2-weighted MRI. Disability progression was defined as an increase in EDSS score of at least 1.5, 1, or 0.5 points in patients who had an EDSS baseline of, respectively, 0, 1 to 5, or ≥ 5.5 points.
Of the 927 patients enrolled in ASCLEPIOS I, 465 received Kesimpta and 462 received teriflunomide; 90% of patients receiving Kesimpta and 81% of patients receiving teriflunomide completed the trial. Of the 955 patients enrolled in ASCLEPIOS II, 481 received Kesimpta and 474 received teriflunomide; 83% of patients receiving Kesimpta and 82% of patients receiving teriflunomide completed the trial.
Patient demographics and disease characteristics were balanced across treatment arms in both studies.
In ASCLEPIOS I and ASCLEPIOS II, Kesimpta significantly reduced the annualized relapse rate compared with teriflunomide. Kesimpta also reduced the risk of 3-month confirmed disability progression, the number of T1-weighted GdE lesions, and the rate of new or enlarging T2-weighted lesions compared with teriflunomide. Moreover, Kesimpta was shown to produce a similar effect on these key efficacy results vs teriflunomide during subgroup analyses (by gender, age, body weight, prior nonsteroid MS therapy, disability at baseline, and disease activity).
Safety data were assessed in all patients included in ASCLEPIOS I and ASCLEPIOS II (N=1882). Median duration of treatment for patients in the Kesimpta group (n=946) was 85 weeks; 33% of Kesimpta-treated patients received therapy for as long as 120 weeks.
Adverse reactions experienced by greater than 10% of Kesimpta-treated patients and occurring more frequently than in teriflunomide-treated patients were upper respiratory tract infection (39% in Kesimpta-treated patients and 38% in teriflunomide-treated patients), systemic injection-related reaction (21% and 15%), headache (13% and 12%), and injection-related local reaction (11% and 6%). The most common reason for discontinuation of Kesimpta was a low serum level of immunoglobulin M (IgM) in 3.3% of patients, defined as 10% below the lower limit of normal.
The highest incidence of a systemic injection-related reaction occurred at first injection (14.4%), decreasing to 4.4% at second injection and less than 3% at third injection. More common (≥2%) symptoms associated with a systemic injection-related reaction were fever, headache, myalgia, chills, and fatigue. The severity of almost all (99.8%) systemic injection-related reactions was considered mild or moderate. Serious injection-related reactions occurred in 2 Kesimpta-treated patients (0.2%); no life-threatening injection-related reactions were reported.
Although local injection-related reactions were common in Kesimpta-treated patients, all were considered of mild or moderate severity. More common (≥2%) symptoms associated with a local injection-related reaction were erythema, pain, itching, and swelling.
A decrease in the average IgM level was observed in patients treated with Kesimpta in ASCLEPIOS I and ASCLEPIOS II, but this decrease was not associated with an increased risk of infection. In 14.3% of patients in ASCLEPIOS I and ASCLEPIOS II, treatment with Kesimpta was associated with a serum IgM value of less than 0.34 g/dL. Kesimpta was also found to be associated with a reduction of 4.3% in the average IgG level after 48 weeks and a 2.2% increase after 96 weeks.
Dosage and Administration
Kesimpta is supplied as a 20-mg/0.4-mL solution in a single-dose, prefilled Sensoready® pen. The recommended dosage of Kesimpta is 20 mg subcutaneously at weeks 0, 1, and 2, followed by 20 mg subcutaneously once a month starting at week 4. A missed dose should be administered as soon as possible, and subsequent doses should be administered at recommended intervals.
The first Kesimpta injection should be performed under the supervision of a health care professional; subsequent doses can be self-administered by the patient. Kesimpta should be administered subcutaneously in the thigh, abdomen, or outer upper arm. Areas with a mole, scar, or stretch mark, or where skin is damaged, should be avoided. Kesimpta Sensoready® pens are for 1-time use only.
Contraindications, Warnings, Precautions, and Adverse Reactions
Kesimpta is contraindicated in patients with an active HBV infection. At higher dosages, Kesimpta has caused HBV reactivation and, subsequently, fatal infection. HBV screening should be performed in all patients prior to initiating Kesimpta. Screening should include tests of hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (HBcAb), at minimum. A liver disease expert should be consulted prior to initiating and during treatment with Kesimpta in patients who are HBsAg- and positive for HBV core antibody (HBcAb+) or who are an HBV carrier (HBsAg+).
Kesimpta has the potential to increase the risk of bacterial, fungal, and new or reactivated viral infections. Findings from ASCLEPIOS I and ASCLEPIOS II revealed that the overall rates of infection and serious infection were similar for patients who received Kesimpta and those who received teriflunomide (51.6% and 52.7% for infection and 2.5% and 1.8% for serious infection, respectively). The more common infections experienced by Kesimpta-treated patients in ASCLEPIOS I and ASCLEPIOS II were upper respiratory tract infection (39%) and urinary tract infection (10%). For patients who have an active infection, treatment with Kesimpta should be delayed until infection has resolved.
Progressive multifocal leukoencephalopathy (PML), caused by the JC virus (human polyomavirus), has occurred in patients taking Kesimpta at a higher dosage or taking other anti-CD20 antibody and MS therapies. As such, treatment should be withheld at the first sign or symptom of PML and appropriate diagnostic evaluation performed; MRI findings might be evident prior to clinical signs or symptoms. Kesimpta should be discontinued if PML is confirmed.
With regard to vaccinations, the effectiveness of inactivated vaccines might be altered by Kesimpta; the safety of live and live-attenuated vaccines after treatment with Kesimpta has not been studied. Vaccination with live or live-attenuated vaccines should be avoided during treatment with Kesimpta and until repletion of the B-cell population following discontinuation.
Live or live-attenuated vaccines should not be administered to infants of mothers treated with Kesimpta during pregnancy before it is confirmed that the B-cell count has recovered. Inactivated vaccines can be administered prior to repletion of the B-cell population; however, assessment of the immune response to any vaccine should be considered to determine whether a protective immune response occurred.
In ASCLEPIOS I and ASCLEPIOS II, 21% of patients who received Kesimpta reported a systemic injection-related reaction compared with 15% of patients who received a matching placebo injection plus teriflunomide. In addition, local injection-related reactions were reported in 11% and 6% of the Kesimpta and placebo injection arms, respectively.
Systemic injection reactions typically occurred within 24 hours after the first Kesimpta injection but were reported with subsequent injections as well. Symptoms of a systemic injection reaction were predominantly mild or moderate in severity and included fever, headache, myalgia, chills, and fatigue. No life-threatening injection reactions occurred during ASCLEPIOS I or ASCLEPIOS II. Local injection reactions included erythema, swelling, itching, and pain.
Symptomatic treatment is recommended for patients who experience an injection-related reaction. In clinical trials, premedication with a corticosteroid, antihistamine, or acetaminophen was found to have limited benefit. Administration of the first injection of Kesimpta should be performed under the supervision of an appropriately trained health care professional.
Reduction in Immunoglobulins
In clinical trials, 7.7% of Kesimpta-treated patients experienced a decrease in serum IgM level compared with 3.1% of teriflunomide-treated patients. Furthermore, 3.4% of patients who received Kesimpta discontinued treatment due to decreased immunoglobulin levels compared with 0.8% of patients who received teriflunomide. A decrease in IgG level was not observed at the end of the study.
Levels of quantitative serum immunoglobulins should be monitored during treatment, especially in patients who are at higher risk for opportunistic or recurrent infection. Serum immunoglobulin levels should also be monitored after Kesimpta is discontinued until repletion of the B-cell population.
Discontinuation of Kesimpta should be considered in patients with low immunoglobulin levels who develop a serious opportunistic infection or recurrent infection. Discontinuing treatment should also be considered in patients with prolonged hypogammaglobulinemia that requires intravenous immunoglobulin treatment.
Kesimpta can cause fetal harm, based on animal data. Women with reproductive potential should be counseled to use effective contraception while taking Kesimpta and for at least 6 months after their last dose.
Concomitant administration of Kesimpta with immunosuppressant medications can have additive immunosuppressive effects and increase the risk of infection. When initiating Kesimpta, the duration, mechanism of action, and immune system effects of each immunosuppressive therapy should be considered.
Considerations for Specific Populations
There are insufficient data on the developmental risk associated with administration of Kesimpta in pregnant women. Animal studies analyzing the effect of administering high doses of ofatumumab to pregnant monkeys revealed (1) increased mortality, (2) B-cell population depletion, and (3) impaired immune function in offspring without resulting in maternal toxicity. Effective contraception should be used by women of childbearing age during treatment with Kesimpta and for 6 months after the last dose.
Based on findings from animal studies, ofatumumab might cross the placenta and result in fetal B-cell depletion. Live vaccines should not be administered to newborns and infants exposed to ofatumumab in utero until the B-cell population has recovered.
No data exist on the presence of ofatumumab in breast milk, its effect in a breastfed child, or its effect on milk production. Benefits of breastfeeding, a mother’s clinical need for ofatumumab, and potential adverse effects of ofatumumab and the underlying maternal condition on the breastfed child should be considered.
Efficacy and safety of Kesimpta have not been established in pediatric patients. Additionally, there were an insufficient number of geriatric patients in ASCLEPIOS I AND ASCLEPIOS II clinical trials to determine whether efficacy and safety is different in this population than in younger patients.
The effects of Kesimpta in patients with renal or hepatic impairment have not been studied.
- Kesimpta is approved in adults for relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
- Kesimpta is contraindicated in patients with active HBV infection.
- Prior to initiating Kesimpta, HBV screening, testing for quantitative serum immunoglobulins, and required vaccinations should be completed.
- Kesimpta is intended to be administered by the patient by subcutaneous injection.
1. Kesimpta [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; August 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125326s070lbl.pdf. Accessed November 4, 2020.
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Reviewed November 2020