On January 11, 2022, the official website of the State Drug Administration (NMPA) announced that the roplastim (former name: romistim) of Concord Kirin (China) Pharmaceutical Co., Ltd. was approved for the treatment of immune thrombocytopenia (ITP).
Roppestine is the first second-generation long-acting thromboplastin receptor agonist (TPO-RA) in China, after which lopsimide has been approved for marketing in 69 countries and regions around the world. Not only was it approved for ITP indications, the U.S. FDA also granted ropplistatim as an orphan drug for the treatment of aplastic anemia and chemotherapy-induced thrombocytopenia. In 2009, Roppsting was selected as the "Best Biotechnology Product" by the Galen Prize, known as the "Nobel Prize of the Pharmaceutical Industry". With this domestic approval, lopestine will bring new treatment options to ITP patients in China[1].
From: NMPA official website
New drugs are online, and the ITP treatment pattern has changed
Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder characterized by isolated peripheral platelet count reduction without a clear cause, the main pathogenesis is the loss of platelet autoantigen immune tolerance, resulting in abnormal activation of humoral and cellular immunity, which together mediate accelerated platelet destruction and platelet insufficiency of megakaryocytes. The annual incidence of ITP in adults is (2 to 10)/100,000, and the elderly over 60 years old are the highest incidence group. The clinical manifestations of the disease vary greatly, and asymptomatic thrombocytopenia, mucocutaneous bleeding, severe visceral bleeding, and fatal intracranial hemorrhage can occur. The risk of fatal bleeding is significantly higher in elderly patients than in younger patients. Patients with ITP often have symptoms of fatigue and anxiety, which also greatly affect the quality of life [2].
First-line treatment for ITP is primarily glucocorticoids and immunoglobulins, and if first-line therapy fails or recurs, second-line therapy is indicated. In recent years, with the in-depth study of the pathogenesis of ITP, pro-thrombocytopoiesis drugs have developed rapidly and been applied clinically to reduce or ineffective thrombopoiesis. The first generation of TPO drugs, polyethylene glycolated human megakaryocyte growth and development factor (PEG-rhMGDF) and recombinant human thrombopoietin (rhTPO), responded 36.5% with danazole alone in rhTPO clinical studies, 60% response rate to rhTPO combined with danazole, and still 40% of patients treated without response [3].
The second-generation TPO receptor agonists are mainly lopestine and edopopapitanolamine. Edlopapethanolamine needs to be taken daily and is prone to liver function damage, and has been warned by the FDA that liver function needs to be closely monitored, affecting the safety of its long-term application.
Unlike rhTPO and edopapi, roppestine is a human TPO mimics peptide produced by RECOM DNA, a 4 peptide domain formed by disulfide bonds linking the Fc constant region of the human Kappa light chain to the IgG1 heavy chain, which binds to the TPO receptor on the surface of the megakaryocyte and activates its endogenous pathway to promote platelet production in megakaryocytes. The Fc constant zone prolongs the half-life of the drug, so lopestine only needs to be administered once a week. In addition, roppredim does not have endogenous TPO homology sequences and therefore does not cause cross-reactions to produce neutralizing antibodies [4].
Studies have confirmed that lopestine has a fast onset of action, and the efficacy and safety are excellent
Lopestine in patients with ITP: a double-blind, randomized controlled Phase III clinical study[5]
The study, which included 34 PATIENTs with ITP from 11 research centers in Japan, was designed to evaluate the efficacy and safety of lopestine. In the study, patients received lopestine or placebo for 12 weeks at a starting dose of 3 μg/kg per week. The primary endpoint was the number of weeks of platelet response (defined as a platelet count ≥50×109/L).
The results of the study showed that after 1 week of the first administration, the platelet response rate of the roprestimide group reached 77% and 91% after 2 weeks, and the vast majority of patients could obtain platelet response within 1 week, and the response rate remained stable throughout the treatment period. The overall platelet response rate was as high as 96% in the roppestine group compared to 8.3% in the placebo group, and the number of intermediate platelet response weeks in the roppestine group was 11 weeks during the total 12-week treatment period, compared with 0 weeks in the placebo group. All treatment-related events were mild in severity and there were no serious treatment-related events.
Lopsudine treatment of patients with ITP, a 3-year randomized controlled and extended study[6]
Following a phase III randomized controlled 24-week roppestine treatment study, an open-label extended study was continued, with all patients receiving roppestimide in the extended study, with some patients receiving lopestine for up to 3 years.
The results of the study showed that during the randomized controlled study, the percentage of patients in the roppestin-treated group who experienced moderate or severe bleeding adverse events was significantly lower than that in the placebo group (P<0.05). In the extended study, the incidence of moderate or greater adverse bleeding events decreased from 23% at the beginning of the extended study to ≤6% after the application of lopestine. After lopsimide treatment, the platelet count of most patients increased to more than 50×109/L, which significantly reduced the proportion and severity of bleeding events, and followed up to 3 years, suggesting that roplastim was safe.
Roproxtin, a brand new choice for ITP therapy
In summary, lopestine can quickly promote platelet production, long-term maintenance of platelet count to a safe range, good tolerability, and roppestine is a long-acting TPO-RA, only need to be administered once a week, improving the quality of life of patients. As a second-generation TPO receptor agonist, lopestine has been approved for marketing in 69 countries and regions around the world, with fast onset of action, high efficiency, low frequency of administration, better safety and other characteristics, most patients can reduce or discontinue other ITP drugs, make up for the lack of existing therapeutic drugs, a large number of clinical studies confirmed and clinical guidelines also fully affirmed the excellent efficacy and safety of lopestine [7-8]. Approved in China, lopestine will improve drug accessibility for thrombocytopenia-related diseases in China and provide a new treatment option for ITP patients.
bibliography:
[1] Nplate® （romiplostim） Now Approved For Earlier Use In Adults With Immune Thrombocytopenia. Retrieved Oct. 18, 2019 , from http://investors.amgen.com/news-releases/news-release-details/nplater-romiplostim-now-approved-earlier-use-adults-immune.
[2] Chinese guidelines for the diagnosis and treatment of primary immune thrombocytopenia in adults (2020 edition). Chinese Journal of Hematology. August 2020 Vol. 41, Issue 8: 617-624.
Wang Shujie et al., a multicenter randomized controlled trial of recombinant human thromboplastin in the treatment of idiopathic thrombocytopenic purpura. Thrombosis and Hemostasis, Vol. 16, No. 4, 2010 149-153.
WANG Meiling. Evaluation of the safety and efficacy of romitine and placebo in the treatment of ITP in adults[D]. Zhengzhou University,2018.
[5] Shirasugi Y, Ando K ,Miyazaki K , et al. romiplostim for the treatment of chronic immune thrombocytopenia in adult Japanese patients: a double-blind, randomized Phase III clinical trial[J]. International Journal of Hematology, 2011, 94(1): 71-80.
[6] Gernsheimer T B , George J N , Aledort L M , et al. Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP). Journal of Thrombosis & Haemostasis Jth, 2010, 8(6):1372-1382.
[7] Kuter D J , Bussel J B , Lyons R M , et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. [J]. Lancet, 2015, 371（9610）:395-403.
[8] Cindy Neunert, et al. American Society of Hematology 2019 guidelines for immune thrombocytopenia. Blood Adv. 2019 Dec 10;3(23): 3829-3866.