BENLYSTA® (belimumab): FDA-Approved Treatment for Lupus

BENLYSTA® (belimumab)

 

Belimumab (trade name Benlysta, previously known as LymphoStat-B) is a human monoclonal antibody that inhibits B-cell activating factor (BAFF). It is approved in the U.S., Canada and Europe for treatment of systemic lupus erythmatosis (SLE), and is under investigation for use in other autoimmune diseases.

Uses:

#Systemic lupus erythematosus

Belimumab successfully met the primary endpoints in its phase III clinical trials for SLE. Benlysta was the first new drug to treat lupus after 56 years. Industry analysts expect the drug to be a blockbuster, with annual sales exceeding $2.2 billion by 2014. GlaxoSmithKline will be the producer and marketer of the drug. It will sell for about US$35,000 per year per patient.


#Rheumatoid arthritis

Belimumab has also undergone phase II clinical trials for rheumatoid arthritis. Preliminary results in November 2005 were encouraging



The most common side effects of BENLYSTA include:

    Nausea
    Diarrhea
    Fever
    Stuffy or runny nose
    Cough (bronchitis)
    Trouble sleeping
    Leg or arm pain
    Depression
    Headache (migraine)
    Sore throat
    Urinary tract infection
    Decreased white blood cell count (leukopenia)
    Vomiting
    Stomach pain

Mechanism of action

Three membrane receptors are involved in the interaction of BLyS with B lymphocytes:

- BCMA (B cell maturation antigen)
- TACI (transmembrane activator and calcium modulator and cyclophylin ligand interactor)
- BAFF-R (also known as BR3)

These receptors are not present in early B cell precursors or in pre-B cells (stage at which CD20 receptors appear). They are present in primary mature B cells and in plasma B cells (in this last stage, CD20 receptors have disappeared).

BLyS is secreted, sometimes under the influence of interferon-gamma, by a variety of cells: monocytes and macrophages, bone marrow stromal cells, astrocytes, synoviocytes during rheumatoid arthritis, salivary epithelial cells during Sjögren's syndrome, astrocytes in certain glioblastomas.

Lymphocyte apoptosis may be decreased by BLyS because stimulation of BAFF-R and BCMA increases levels of Bcl-2, which is a key anti-apoptotic mediator. Stimulation of all 3 BLyS receptors increases intranuclear levels of NF kappa B, active on differentiation and proliferation.

BLyS is not the only activator of B lymphocytes. APRIL (a proliferation-inducing ligand) also plays a key role, but is only active on BCMA and TACI.

It is possible that belimumab binds primarily to circulating soluble BLyS, therefore not inducing antibody-dependent cellular cytotoxicity that could be expected from this IgG1-type antibody. Belimumab does reduce the number of circulating B cells, but seemingly less deeply and durably than anti-CD20 monoclonal antibodies. Only comparative trials will clarify this impression.
 

Other drugs addressing B lymphocyte hyperactivity

Atacicept is a recombinant fusion protein built with the extracellular ligand binding portion of TACI. It blocks activation of TACI by April and BLyS. It failed a phase II trial for multiple sclerosis.

BR3-Fc is a recombinant fusion protein built with the extracellular ligand-binding portion of BAFF-R. It blocks activation of this receptor by BLyS, and is in early stage pharmaceutical development.

Anti-CD20 monoclonals: Rituximab has been approved for some indications. Ocrelizumab, ofatumumab and third generation anti CD20 monoclonals are in development.