Physiological and Clinical Effect of Romiplostim in the Treatment of ITP
Romiplostim in the treatment of immune thrombocytopenia (ITP) has demonstrated safety and the promise of long-term remission, enabling many pediatric and adult patients to discontinue treatment and maintain a drug-free state.
Thrombopoietin and the Effect of Its Agonists
Thrombopoietin (TPO) plays a key role in the production of platelets, as well as in other hematopoietic pathways. TPO receptor agonists (TPO-RA) lead to increased platelet production and can help reduce the need for additional medication in managing this disease.
The development of the 1st generation of TPO-RA drugs was prematurely terminated due to the formation of neutralizing antibodies that cross-reacted with endogenous TPO. The 2nd generation of TPO-RA, which includes romiplostim, significantly minimizes the risk of neutralizing antibody formation.
Mechanism of Action of Romiplostim
Romiplostim contains 4 TPO-R binding domains with high affinity for TPO-R and one Fc domain. It does not have a homologous sequence with endogenous TPO. Romiplostim binds to TPO-R on megakaryocyte precursors in the bone marrow and activates it. It binds in the same way as endogenous TPO and can displace TPO from the receptor. It triggers a number of activation pathways like TPO, which leads to a sustained increase in platelet count in treated patients with ITP.
Preclinical and clinical data also suggest an immunomodulatory effect of romiplostim. One mouse study indicated that romiplostim not only increases platelet counts but also reduces levels of anti-platelet antibodies. In humans, it has been shown that in cases of chronic ITP, romiplostim improves the function of T-regulatory lymphocytes (Tregs) in vitro. Less information is available about the effect mediated by the Fc region of the molecule, which could contribute to the immune response.
Achieving Sustained Response
A large amount of clinical study data demonstrates the safety and efficacy of romiplostim in terms of increasing platelet counts in both adults and children with ITP. Many patients also achieved a sustained platelet count response even after discontinuing romiplostim treatment. Administration of romiplostim does not necessarily mean long-term or lifelong therapy that cannot be interrupted. On the contrary, a significant proportion of patients achieving a good response may eventually discontinue it and remain off treatment.
Although the original data were obtained from studies concerning patients with chronic ITP, recent findings confirm the efficacy of romiplostim in patients with newly diagnosed (within 3 months) or persistent (3-12 months) disease if there was no response to corticosteroids.
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Sources:
1. Bussel J. B., Soff G., Balduzzi A. et al. A review of romiplostim mechanism of action and clinical applicability. Drug Des Devel Ther 2021; 15: 2243–2268, doi: 10.2147/DDDT.S299591.
2. Newland A., Godeau B., Priego V. et al Remission and platelet responses with romiplostim in primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol 2016; 172 (2): 262–273, doi: 10.1111/bjh.13827.
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