Romiplostim

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.

Originator

Amgen (United States)

brand name

Nplate

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.

Clinical Use

Fc-peptide fusion protein:
Treatment of chronic immune (idiopathic) thrombocytopenic purpura (ITP)

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.

Metabolism

Mainly renal clearance.