Ofatumumab

Introduction to Ofatumumab

Ofatumumab (brand names: Arzerra for intravenous use, Kesimpta for subcutaneous use) is a fully human monoclonal antibody targeting the CD20 antigen on B cells. It was initially approved by the FDA in 2009 for the treatment of chronic lymphocytic leukemia (CLL). In 2020, a subcutaneous formulation of ofatumumab (Kesimpta) was approved for the treatment of relapsing forms of multiple sclerosis (MS) in adults.

Mechanism of Action

Ofatumumab is a type I anti-CD20 monoclonal antibody that targets a unique epitope on the CD20 molecule. Its mechanism of action includes:

B-cell depletion:
- Binds to both the small and large loops of the CD20 molecule
- Results in rapid and efficient depletion of CD20-expressing B cells
Complement-dependent cytotoxicity (CDC):
- Highly effective at inducing CDC, even in cells with low CD20 expression
- More potent CDC activity compared to rituximab
Antibody-dependent cellular cytotoxicity (ADCC):
- Induces ADCC through interaction with Fc receptors on immune effector cells
Antibody-dependent cellular phagocytosis (ADCP):
- Enhances phagocytosis of targeted B cells by macrophages

In multiple sclerosis, the depletion of B cells is thought to reduce inflammation and the progression of the disease by limiting the presentation of antigens to T cells and reducing the production of pro-inflammatory cytokines and antibodies.

Indications

Ofatumumab is FDA-approved for the following indications:

Chronic Lymphocytic Leukemia (CLL) - Arzerra:
- In combination with chlorambucil, for previously untreated CLL patients for whom fludarabine-based therapy is considered inappropriate
- In combination with fludarabine and cyclophosphamide for relapsed CLL
- For extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL
- For refractory CLL in patients who have failed treatment with fludarabine and alemtuzumab
Multiple Sclerosis (MS) - Kesimpta:
- For the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults

While not FDA-approved, ofatumumab has shown promise in clinical trials for other B-cell malignancies, including:

Follicular lymphoma
Diffuse large B-cell lymphoma
Waldenstrom's macroglobulinemia

Dosage and Administration

The dosing regimen for ofatumumab varies depending on the indication and formulation:

For CLL (Arzerra - intravenous infusion):

Previously untreated CLL:
- 300 mg on day 1, followed by 1000 mg on day 8 (Cycle 1)
- 1000 mg on day 1 of subsequent 28-day cycles for a minimum of 3 cycles
Relapsed CLL:
- 300 mg on day 1, followed by 1000 mg on day 8 (Cycle 1)
- 1000 mg on day 1 of subsequent 28-day cycles for a maximum of 6 cycles
Extended treatment in CLL:
- 300 mg on day 1, followed by 1000 mg 1 week later
- 1000 mg every 8 weeks for up to 2 years

For Multiple Sclerosis (Kesimpta - subcutaneous injection):

Initial dosing: 20 mg at weeks 0, 1, and 2
Subsequent dosing: 20 mg monthly starting at week 4

Premedication with acetaminophen, antihistamine, and glucocorticoids is recommended to reduce the risk of infusion-related reactions for intravenous administration.

Efficacy

Ofatumumab has demonstrated significant efficacy in clinical trials:

Chronic Lymphocytic Leukemia:

COMPLEMENT-1 trial: Ofatumumab + chlorambucil vs. chlorambucil alone in treatment-naive CLL
- Significantly improved progression-free survival (PFS) (median PFS: 22.4 vs. 13.1 months)
- Improved overall response rate (82% vs. 69%)
COMPLEMENT-2 trial: Ofatumumab + fludarabine + cyclophosphamide vs. fludarabine + cyclophosphamide in relapsed CLL
- Improved PFS (median PFS: 28.9 vs. 18.8 months)
- Higher overall response rate (84% vs. 68%)

Multiple Sclerosis:

ASCLEPIOS I and II trials: Ofatumumab vs. teriflunomide in relapsing MS
- Significantly reduced annualized relapse rate (0.11 vs. 0.22)
- Reduced risk of 3-month confirmed disability progression (10.9% vs. 15.0%)
- Reduced number of gadolinium-enhancing T1 lesions and new or enlarging T2 lesions on MRI

Safety Profile

The safety profile of ofatumumab varies somewhat between its use in CLL and MS:

Common adverse events in CLL treatment:

Infusion-related reactions (especially with first and second infusions)
Neutropenia
Pneumonia
Pyrexia
Cough
Diarrhea

Common adverse events in MS treatment:

Injection-related reactions
Upper respiratory tract infections
Headache
Urinary tract infections
Back pain

Serious adverse events (for both indications):

Hepatitis B virus reactivation
Progressive multifocal leukoencephalopathy (PML)
Serious infections
Tumor lysis syndrome (in CLL patients)
Cytopenias (in CLL patients)

Ofatumumab carries boxed warnings for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy.

Pediatric Considerations

While ofatumumab is not currently FDA-approved for pediatric use, several points are relevant for pediatricians:

Potential applications: Given its efficacy in adult CLL and MS, ofatumumab may have potential in pediatric B-cell malignancies and autoimmune disorders.
Ongoing research: Clinical trials are evaluating the safety and efficacy of ofatumumab in pediatric patients with conditions such as nephrotic syndrome and multiple sclerosis.
Dosing considerations: Pediatric dosing would need to be carefully determined, considering differences in pharmacokinetics and pharmacodynamics in children.
Route of administration: The availability of both intravenous and subcutaneous formulations could offer flexibility in pediatric applications.
Long-term effects: The impact of B-cell depletion on the developing immune system would need careful evaluation, particularly regarding infection risk and long-term effects on immune function.
Safety profile: Special attention would be needed for infusion/injection-related reactions and the risk of serious infections in pediatric patients.

As research continues, pediatricians should stay informed about the potential applications of ofatumumab in pediatric B-cell mediated diseases, both malignant and autoimmune.