Romiplostim (Nplate)

Romiplostim is a recombinant fusion protein peptibody composed of 2 IgG1 constant regions (Fc fragments) linked to a peptide domain containing 4 binding sites for the TPO receptor.

A thrombopoietin receptor agonist.

Administered in weekly subcutaneous injections.

It is an antibody heavy chain containing a human immunoglobulin IgG1 Fc domain covalently linked at each of its 2C-terminals to two 14-amino acid peptides that bind to and stimulate the thrombopoietin receptor.

Does not share the amino acid sequence homology of endogenous thrombopoietin, so it is associated with a decreased risk of developing cross reactive antibodies thrombopoietin (TPO).

Binds to the thrombopoietin receptor and activates intracellular signaling pathways, JAK-STAT and MAP kinase pathways, which stimulates platelet production.

Binding of romiplostim to the TPO receptor results in activation of intracellular signalling cascades (JAK-STAT and MAP kinase pathways) that lead to increased platelet production.

Unlike first-generation thrombopoietin does not cause the development of antibodies against endogenous thrombopoietin.

Stimulates production of platelets via a peptide fragment that shares no sequence homology with natural thrombopoeitin, preventing the production of neutralizing antibodies.

Utilized for chronic immune idiopathic thrombocytopenia when the response to corticosteroids, immunoglobulin or splenectomy are insufficient.

Following a single intravenous or subcutaneous dose, there is a dose-dependent increase in platelet count within 5 to 8 days which returns to baseline by day 28.

Approved for the treatment of pediatric patients aged ≥1 year with immune thrombocytopenia for at least 6 months who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Should be used inpatients with a degree of thrombocytopenia and clinical condition that are associated with an increased the risk of bleeding.

Should not be used to normalize platelet counts.

Long-term use may cause increased reticulin in the bone marrow.

Starting dose of 1 mcg/kg with increased dose as needed to target a platelet count of 50,000/mcL-200,000/mcL.

 

Romiplostim recommended initial dose of is 1 μg/kg administered subcutaneously once per week and then titrated to a maximum of 10 μg/kg to achieve a platelet count ≥50,000/μL.

A single dose results in an increase in the platelet count after 5-8 days in a dose-dependent fashion, with peak platelet count reached between days 12-16, and by 28 the platelet count falls to baseline.

In a randomized controlled study for ITP patients platelet count of 50,000 per cubic millimeter was achieved in romiplostim treated patients was 38% in splenectomized patients and 61% in non-splenectomized patients (Kuter DJ et al).

An open extension of the above study, more than 50% had a platelet count of at least 50,000 per cubic millimeter during at least 90% of all visits at a median of 78 weeks (Kuter DJ et al).

Overall response rate in nonsplenectomized patients 88% compared to response rate of 14% in nonsplenectomized patients treated with placebo.

Response rate 79% in splenectomized patients compared to a 0% response rate in splenectomized patients treated with placebo.

Continuous treatment increases platelet counts in patients with ITP for up to five years with few adverse effects.

For myelodysplastic syndrome azacitidine 75 mg/m2/day for 7 days of a 28 day cycle plus placebo or subcutaneous romiplostim 500 mg or 750mg per week on a randomized basis: incidence of thrombocytopenia events per cycle higher in placebo group (85%) than in the romiplostim 500 mg (69%) and 750 mg (64%) groups, also 69% of placebo group received platelets, in comparison to 46% and 36% for the romiplostim 500 mg and 750 mg, respectively (Kantarijian ).

In a 52-week study randomly assigning 234 adult patients with immune thrombocytopenia, who had not undergone splenectomy, received standard care or weekly subcutaneous injections of romiplostim: the rate of platelet response in the treatment group was 2.3 times that of standard care group (Kuter DJ et al).

In the above ITP study patients receiving romiplostim had a significant lower incidence of treatment failure of 11% compared to those receiving standard of care, 30%.

In the above ITP study splenectomy was also performed less frequently in patients receiving romiplostim,9%, versus 36% in those receiving standard of care.

In the above ITP study the romiplostim group had a lower rate of bleeding events, blood transfusions, and great improvement in quality of life than the standard of care group.

In the above ITP study serious adverse events in patients receiving romiplostim was 23% compared to 37% in patients receiving standard of care.

In a randomized, double blind, placebo controlled study adult chronic ITP patients with insufficient response to corticosteroids, immunoglobulins, or splenectomy randomized to receive subcutaneous romiplostim weekly or placebo weekly for 24 weeks: 61% of the patients receiving romiplostim achieves a durable platelet response compared with 5% of those receiving placebo, with an overall response rate of 88% (Kutler DJ).

In the above study platelet counts of 50,000 were achieved by 50% of non-splenectomized patients after 2-3 weeks.

Romiplostim is a recombinant fusion protein “peptibody” composed of 2 IgG1 constant regions (Fc fragments) linked to a peptide domain containing 4 binding sites for the TPO receptor.

 

 

Romiplostim binds to the TPO receptor and results in activation of intracellular signalling cascades (JAK-STAT and MAP kinase pathways) that lead to increased platelet production.

 

Following a single intravenous or subcutaneous dose, there is a dose-dependent increase in platelet count within 5 to 8 days which returns to baseline by day 28.

 

A retrospective analysis showed a significant decrease in corticosteroid use from 35% to 20% after 3 years of treatment with romiplostim.

 

Patients with ITP who previously completed a romiplostim study were enrolled in an open-label extension study in which romiplostim was administered weekly for a median of 78 weeks, A platelet count of ≥50,000/μL was achieved in 94.5% of patients during the study. More than 50% of patients had platelet counts of ≥50,000/μL on ≥90% of all visits.

 

In a 52-week open-label study, non-splenectomized patients with ITP were treated with romiplostim or standard of care: platelet response was 2.3 times higher in the romiplostim group than the standard of care group.

 

 

Treatment failure occurs  less frequently in romiplostim-treated patients compared to standard of care.

Discontinuance may result in progressive thrombocytopenia worse than that present before treatment of the agent.

Weekly blood counts are required after discontinuation of Romiplostim.

Weekly dosing schedule, subcutaneously.

Weekly CBCs should be performed during the dose adjustment phase of therapy and then monthly following establishment of a stable dose.

In pateints with myelodysplastic syndrome with lower risk disease and with platelet counts <30,000/mm3, use associated with a 45% complete or major platelet responses with subcutaneously weekly treatment (Kantarijian).

Not approved for use in myelodysplastic disorders.

Portal vein thrombosis may occur in patients with chronic liver disease.

Poor responsiveness or failure to maintain a platelet response should prompt for surgical causative factors including neutralizing antibodies to romiplostim.

Failure of the platelet count to increase to a sufficient level to avoid bleeding after 4 weeks at the highest dose level of 10 mcg/kg, the agent should be discontinued.

Headache is most common reported adverse drug reaction, currently 35% patients.

Headaches are usually mild to moderate in severity.

Most common adverse reactions are arthralgias, dizziness, insomnia, myalgias, pain in the extremities, abdominal pain, shoulder pain, dyspepsia and paresthesias.

Promising for chemotherapy induced thrombocytopenia, but is not yet approved for such an indication.