Multiple Sclerosis and COVID-19

Introduction

From the start of the severe coronavirus disease 2019 (COVID-19) pandemic,¹ there have been concerns for people with multiple sclerosis (MS), an autoimmune disease of the central nervous system.² These concerns include whether people with MS might have more risk for contracting COVID-19 with less ability to combat the disease and greater susceptibility to a more severe disease course.² There has also been concern for whether disease-modifying treatments (DMTs) for MS might convey higher risks, considering they affect the immune system. The Society of Italian Neurologists (SIN) and the Association of British Neurologists (ABN) both published guidelines for use of DMTs during the pandemic as early as March 2020, and calls to revise them were published only 2 months later.³ Efforts to provide current updates from MS organizations have sometimes led to conflicting information, especially early in the pandemic, although the MS International Federation (MSIF) is making efforts to have shared, coordinated information releases.⁴

As with any emerging disease, knowledge and understanding build with time. Recent reports suggest having MS does not confer a higher risk of contracting COVID-19, although this may be a result of higher adherence to social distancing guidelines.^5-7 Data regarding how different DMTs affect risk of infection and the course of COVID-19 are still limited. Recommendations for DMT use are based primarily upon understanding the immune system and the mechanisms through which DMTs act upon it.³

The Innate and Adaptive Immune Systems

The innate immune system is considered the “first responder” of immunity—a nonspecific cytokine-driven inflammatory response—that inhibits viral replication and limits the spread of a pathogen while recruiting white blood cells and other immune affectors to the area.⁸ With respect to the adaptive immune system, antibodies to the specific pathogen are generated by B cell-derived plasma cells in the humoral immune response, and cytotoxic T-cells of the cellular response attack cells invaded by the pathogen specifically. Some of these specifically reactive cells eventually become memory B and memory T cells, allowing a faster specific immune response if the pathogen is encountered a second time.⁹

Both the B and T cells of the adaptive immune system have well-established roles in the immune dysregulation seen in MS. The innate immune system, however, may have a role in MS pathogenesis.¹⁰ B cells also interact with T cells through the immune system mediator interleukin-6¹¹ and may act as antigen presenting cells.¹² Natural killer (NK) cells have a regulatory role for both the innate and adaptive immune systems, and there is evidence that dysfunction of the NK regulation of T cells may play a role in MS.¹⁰ Animal studies suggest macrophages regulate interactions of T cells to shift them from a proinflammatory to anti-inflammatory state, and blocking this effect of macrophages alleviates experimental autoimmune encephalomyelitis, the animal model of MS.^13,14 In addition, several DMTs interact with macrophage-activating interleukins.¹⁵ Data are emerging showing neutrophil dysregulation may also play a role in MS.^16,17

About MAVENCLAD (Cladribine) Tablets

MAVENCLAD® (cladribine) tablets was approved by the Food and Drug Administration (FDA) on March 29, 2019 for the treatment of adults with relapsing-remitting disease (RRMS) and active secondary progressive disease (SPMS). Because of its safety profile, MAVENCLAD is generally recommended for individuals with MS who have had an inadequate response to or are unable to tolerate other DMTs. It is not recommended for treatment of clinically isolated syndrome (CIS). The approved dose of MAVENCLAD is 3.5 mg/kg body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg/year, with each treatment course consisting of 2 treatment weeks about a month apart. The package insert for MAVENCLAD includes a warning for serious side effects, including the risk of malignancies and teratogenicity. Cancer screening, pregnancy tests, and blood tests (complete blood count [CBC] with differential and lymphocyte count) are recommended before starting treatment with MAVENCLAD. Male and female patients should use effective contraception during treatment and for 6 months after their last dose. Blood tests should be repeated during treatment, periodically thereafter, and when clinically indicated.¹⁸

Research has shown MAVENCLAD preferentially targets B and T lymphocytes, with a lesser effect on select innate immune cells.^19-22 In clinical studies of MAVENCLAD, mild-to-moderate decreases in neutrophil counts (27%), hemoglobin levels (26%), and platelet counts (11%) were seen. Severe decreases in neutrophil counts were observed in 3.6% of those treated with MAVENCLAD vs 2.8% of those treated with placebo.¹⁸ Overall, median counts for NK cells, neutrophils, and monocytes remained within the normal range  throughout treatment with MAVENCLAD.

MAVENCLAD is thought to exert effects on MS by interfering with DNA synthesis in B and T lymphocytes, resulting in depletion of these cells.¹⁸ MAVENCLAD treatment is associated with reduced lymphocyte counts.²² In clinical studies, 87% of participants treated with MAVENCLAD experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course.¹⁸ Although a majority of participants treated with MAVENCLAD in clinical trials experienced mild-to-moderate lymphopenia, most had cell counts return to a normal range. It may take several months or more for the recovery of the T and B cells, which may not go back to pretreatment levels. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematologic effects. Lymphocyte counts should be monitored before and during treatment, periodically thereafter, and when clinically indicated.¹⁸

In addition to those noted above, MAVENCLAD has the risk of other serious adverse events including an increased risk of malignancies and infections, such as herpes zoster and pyelonephritis, hematologic toxicity, graft-versus-host disease with blood transfusions, liver injury, hypersensitivity to cladribine, and cardiac failure.¹⁸

MAVENCLAD and COVID-19 Data

Updated safety analysis of data from the first 18,463 patients who received MAVENCLAD postapproval, as of July 2020, was presented at MSVirtual2020.²³ This analysis included findings from 46 people treated with MAVENCLAD who then presented with confirmed (n=18) or suspected (n=28) COVID‑19. The majority had mild-to-moderate respiratory symptoms; 4 were hospitalized, and no deaths had occurred. Real-world data will continue to help further understand outcomes in those affected by COVID-19 while on MAVENCLAD.

Summary

As physicians evaluate various treatment options for their MS patients there are many factors to consider, including the immune system effects. MAVENCLAD treatment affects the innate immune system to a lesser extent and preferentially targets B and T cells. MAVENCLAD may not be right for every patient. Visit MAVENCLAD.com/HCP for more information.

INDICATION

MAVENCLAD® (cladribine) tablets is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS.

Limitations of Use: MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile.

IMPORTANT SAFETY INFORMATION
WARNING: MALIGNANCIES and RISK OF TERATOGENICITY

•Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD

• MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the potential for fetal harm. Malformations and embryo lethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant

CONTRAINDICATIONS

• Patients with current malignancy.

• Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during and for 6 months after the last dose in each treatment course. May cause fetal harm.

• Patients with human immunodeficiency virus (HIV).

• Patients with active chronic infections (e.g., hepatitis or tuberculosis).

• Patients with a history of hypersensitivity to cladribine.

• Women intending to breastfeed while taking MAVENCLAD tablets and for 10 days after the last dose.

WARNINGS AND PRECAUTIONS

• Malignancies: Treatment with MAVENCLAD may increase the risk of malignancy. After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. In clinical studies, patients who received additional MAVENCLAD treatment within 2 years after the first 2 treatment courses had an increased incidence of malignancy. The risk of malignancy with reinitiating MAVENCLAD more than 2 years after the completion of 2 treatment courses has not been studied. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.

• Risk of Teratogenicity: MAVENCLAD may cause fetal harm when administered to pregnant women. In females of reproductive potential, exclude pregnancy before initiation of each treatment course of MAVENCLAD and prevent by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment.

• Lymphopenia: MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects. Monitor lymphocyte counts before and during treatment, periodically thereafter, and when clinically indicated.

• Infections: MAVENCLAD can reduce the body's immune defense and may increase the likelihood of infections. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of patients treated with placebo in clinical studies. The most frequent serious infections included herpes zoster and pyelonephritis. Single fatal cases of tuberculosis and fulminant hepatitis B were reported in the clinical program. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. In patients treated with parenteral cladribine for oncologic indications, cases of progressive multifocal leukoencephalopathy (PML) have been reported. No case of PML has been reported in clinical studies of cladribine in patients with MS.

• Hematologic Toxicity: In addition to lymphopenia, decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. In general, mild to moderate decreases in neutrophil counts, hemoglobin levels, and platelet counts were observed. Severe decreases in neutrophil counts were observed in 3.6% of MAVENCLAD-treated patients, compared to 2.8% of placebo patients. Obtain complete blood count (CBC) with differential including lymphocyte count before and during treatment, periodically thereafter, and when clinically indicated.

• Risk of Graft-versus-Host Disease With Blood Transfusions: Transfusion-associated graft- versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications.

• Liver Injury: In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) compared to 0 placebo patients. Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment. Discontinue if clinically significant injury is suspected.

• Hypersensitivity: In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD, occurred in 0.5% of MAVENCLAD-treated patients, compared to 0.1% of placebo patients. If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine.

• Cardiac Failure: In clinical studies, one MAVENCLAD-treated patient experienced life- threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis.

Adverse Reactions

The most common adverse reactions with an incidence of >20% for MAVENCLAD are upper respiratory tract infection, headache, and lymphopenia.

Drug Interactions/Concomitant Medication

Concomitant use of MAVENCLAD with immunosuppressive or myelosuppressive drugs and some immunomodulatory drugs (eg, interferon beta) is not recommended and may increase the risk of adverse reactions. Acute short-term therapy with corticosteroids can be administered. Avoid concomitant use of certain antiviral and antiretroviral drugs. Avoid concomitant use of BCRP or ENT/CNT inhibitors as they may alter bioavailability of MAVENCLAD.

Use in Specific Populations

Studies have not been performed in pediatric or elderly patients, pregnant or breastfeeding women. Use in patients with moderate to severe renal or hepatic impairment is not recommended.

Please see the full Prescribing Information, including boxed WARNING for additional information.