Description
Romiplostim has been developed and launched for the treatment of
thrombocytopenia in patients with ITP, an autoimmune blood disorder in
which there is autoantibody-mediated platelet destruction. Coating of
the platelets by autoantibodies results in accelerated ingestion by
macrophages. In addition to the destruction component, ITP is also
characterized by impaired platelet production. The primary physiological regulator of platelet production is thrombopoietin (TPO), a growth
factor that orchestrates its effects through the TPO (Mpl) receptor.Agonists of this receptor could, thereby, remediate the platelet production contribution of ITP. By binding to and activating the TPO receptor,
romiplostim serves as a TPO receptor agonist. As a recombinant fusion
protein, in this case coined as a peptibody, it was engineered to contain
two identical single-chain subunits, each consisting of a TPO-binding
domain linked to the C-terminus of a human IgG1 Fc domain designed to
increase the half-life of the protein. Although it binds to the TPO
receptor, romiplostim has no sequence homology to endogenous TPO,
which should mitigate the risks encountered with the first generation
predecessor, recombinant megakaryocyte growth and development
factor (MGDF); this truncated, non-glycosylated form of TPO conjugated
to PEG was halted during clinical studies because of the immunogenicity
of PEG-MGDF resulting in cross-reacting (neutralizing) antibodies
against endogenous TPO and subsequent severe, unrelenting thrombocytopenia. Romiplostim also avoids the side effects associated with the
generalized immunosuppressive agents previously employed for the
treatment of ITP and may prevent splenectomy, another common
treatment option.
Mechanism of action
Romiplostim is a thrombopoietin receptor agonist (TPO-RA) that increases platelet production by activating intracellular transcriptional pathways through c-Mpl. It also acts similarly to thrombopoietin (TPO), an endogenous glycoprotein hormone that regulates platelet production in the bone marrow. Romiplostim is a peptibody that contains four TPO-R binding domains with high affinity for TPO-R (MPL), and a carrier Fc domain with no sequence homology to endogenous TPO. Romiplostim binds to and activates TPO-R on megakaryocyte precursors in the bone marrow in the same manner as endogenous TPO and can displace TPO on its receptor. It may also be able to activate Tregs through two epitopes in the Fc region, called Tregitopes, which in turn promote cell viability, cell growth, intramegakaryocyte mitosis, megakaryocyte maturation, and importantly, platelet production.
Side effects
Common side effects of romiplostim include:
swelling of the face, arms, hands, lower legs, or feet;
body aches,
hearing changes,
chills,
cough,
diarrhea,
trouble breathing,
ear congestion, discharge, or pain,
fever,
headache,
loss of appetite,
loss of voice,
nausea,
pain or tenderness around the eyes and cheekbones;
rapid weight gain,
sneezing,
sore throat,
stomach pain,
stuffy or runny nose,
chest tightness,
tingling in the hands or feet,
unusual tiredness or weakness,
unusual weight gain or loss,
pain in the upper abdomen.
Other side effects that may occur include:
burning, warmth, swelling, or redness in the hands or feet;
fast heartbeat,
hoarseness,
irritation,
joint pain, stiffness, or swelling;
serious allergic reactions (swelling of the face, eyelids, lips, etc., hives, itching, rash, difficulty swallowing) are rare.
