What are the long-term side effects of Kesimpta (ofatumumab) as a Disease-Modifying Therapy (DMT)?

Long-Term Side Effects of Kesimpta (Ofatumumab)

Kesimpta demonstrates a favorable long-term safety profile with up to 3.5 years of continuous treatment data showing no new safety signals, stable immunoglobulin levels in most patients, and manageable infection risks. 1

Most Common Long-Term Adverse Events

The most frequently reported adverse events during extended ofatumumab treatment include:

• Upper respiratory tract infections occur commonly, along with nasopharyngitis, headache, and urinary tract infections 2
• Injection-related reactions affect approximately 20% of patients (versus 15% with placebo), with 99.8% being mild to moderate in severity 3
• These injection reactions typically decrease over time—from 86% during the first infusion to 42% during subsequent infusions in observational data 4

Infection Risk Profile

The overall infection rate with ofatumumab is comparable to other disease-modifying therapies:

• Infections occurred in 51.6% of ofatumumab-treated patients versus 52.7% with teriflunomide in phase 3 trials 3
• Serious infections remain low at 2.5% in the ofatumumab group versus 1.8% with teriflunomide 3
• No opportunistic infections or progressive multifocal leukoencephalopathy (PML) cases have been identified in patients with up to 3.5 years of exposure 1
• Six patients required hospitalization for infections in one observational cohort over a median 2.2 years of treatment 4

Immunoglobulin Changes and Monitoring

A critical long-term consideration is the impact on immunoglobulin levels:

• Mean IgG levels remain stable throughout extended treatment 1
• Mean IgM levels decrease but typically remain above the lower limit of normal in most patients 1
• Decreased immunoglobulin levels were not associated with increased serious infections after 3.5 years of treatment 1
• Regular monitoring of IgM and IgG levels is recommended, as low IgM can increase risk of infections with encapsulated bacteria 5

Malignancy Risk

• The risk of malignancies remains low with extended ofatumumab exposure 1
• This represents an important safety distinction from some other immunosuppressive therapies

Immunogenicity and Antibody Formation

Ofatumumab has an exceptionally low immunogenic risk:

• Only 2 of 914 patients (0.2%) developed anti-drug antibodies in the ASCLEPIOS I/II trials 3
• This low rate is attributed to ofatumumab's fully human monoclonal antibody structure 3
• The minimal immunogenicity contributes to sustained efficacy and reduced risk of infusion reactions over time 3

Cardiovascular and Other Systemic Effects

Unlike some other disease-modifying therapies, ofatumumab does not carry warnings for:

• Cardiac toxicity or QT prolongation (concerns seen with some tyrosine kinase inhibitors) 6
• Hepatotoxicity (a concern with some oral DMTs)
• Thrombocytopenia (unlike efalizumab, which required platelet monitoring) 6

Key Clinical Pitfalls to Avoid

Live-attenuated vaccines are contraindicated during ofatumumab treatment:

• Complete all two-dose vaccine regimens at least 4-6 weeks before starting therapy 7
• This is a critical consideration for long-term treatment planning

Do not discontinue effective therapy prematurely:

• Switching from stable ofatumumab therapy risks disease reactivation during washout periods 7
• The subcutaneous formulation allows convenient long-term adherence 3

Comparison to Other Anti-CD20 Therapies

The long-term safety profile of ofatumumab appears consistent with the broader class effect of anti-CD20 monoclonal antibodies, with some advantages:

• Lower systemic injection-related reactions compared to intravenous formulations due to the low-dose subcutaneous route (20 mg monthly) 3
• No increased infection risk compared to ocrelizumab, which also shows good long-term tolerability over ≥7.5 years 7
• The fully human structure may contribute to better long-term tolerability compared to humanized antibodies 3

Duration of Safety Data

Current evidence extends to 3.5 years of continuous treatment from the ALITHIOS extension study, with 1,292 patients continuously treated (3,253 patient-years of exposure) 1. This represents robust medium-term data, though longer follow-up beyond 5 years will be important for detecting rare late complications.