Thrombopoietin receptor agonists (TPO-RA) and ITP therapy

Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder characterized
by isolated peripheral platelet count reduction without a clear cause.
Based on three large retrospective studies in Europe and a study in Korea, the annual incidence of adult ITP is about
1~6/100,000.
The peak incidence is over 60 years old, and women of childbearing age are slightly higher than men
of the same age.
In terms of treatment, the emergence of thrombopoietin receptor agonists (TPO-RA) in recent years is a new class of ITP treatment drugs, to a certain extent to enrich the choice of ITP treatment, create a new situation in treatment, in order to have a deeper understanding of the past and present life of TPO-RA and ITP treatment, "Tumor Lookout" specially invited Professor Ma Jun of Harbin Institute of Hematology and Oncology to give a detailed interpretation
of this topic.

Since the first discovery and recognition of primary immune thrombocytopenia (ITP) in 1735, the pace of exploration of its treatment has never stopped, and treatment options have been continuously enriched, such as glucocorticoids, human immunoglobulin (IVIg), recombinant human thrombopoietin (rh-TPO), rituximab and splenectomy, etc.
, to a certain extent, good efficacy progress
has been achieved.

However, on the other hand, there are still many challenges and thorny problems in the treatment of ITP, mainly reflected in the following aspects: (1) As a first-line treatment, glucocorticoids have poor long-term efficacy and may lead to a lot of treatment-related adverse reactions, such as hormone-related diabetes, osteoporosis, femoral head necrosis, infection and thrombosis, which are problems
that cannot be ignored 。 In a Canadian meta-study, 1138 patients with ITP from nine RCTs were included, and the results showed that long-term high-dose dexamethasone can lead to a series of adverse reactions, mainly gastrointestinal events (peptic ulcer, etc.
, 6%), hyperglycemia (6%), weight gain (5%), hypertension (3%) and Cushing's syndrome (2%), as shown in Figure 1
below.

(2) The recurrence of ITP patients is still very tricky, and studies have shown that based on the premise of first- and second-line treatment of ITP such as glucocorticoids and recombinant human thrombopoietin (rh-TPO), most patients relapse after stopping the drug, and the 10-year survival rate is only 15%, see Figure 2
below.

(3) Recombinant human thrombopoietin (rh-TPO) drugs need to be injected every day, and the response rate is low and cannot be used
for a long time.
A multicenter RCT study in China included 140 patients with ITP who had failed glucocorticoid therapy, and the results showed that the primary response rate (MRR) and overall response rate (TRR) of rhTPO were only 38.
4% and 60.
3%, respectively (see Figure 3).

In another clinical study, rh-TPO monotherapy was shown to be unable to maintain efficacy in the long term, and platelet counts in patients with ITP dropped to baseline within 1 week of stopping rh-TPO therapy (see Figure 4).

(4) Some of the existing small molecule drugs have liver damage problems, and they also need to be paid attention to
in clinical treatment.

In recent years, with the entry of TPO-RA into medical insurance, providing access to medication for many patients, ITP is a long-term treatment disease, and it is good news
that more drugs can be approved for the treatment of ITP patients.
Therefore, under the background that the efficacy of previous treatment strategies has failed to meet the needs of patients, the treatment of ITP still urgently needs the emergence of new drugs, in order to break through the bottleneck of current ITP treatment and further improve the efficacy of ITP treatment

The goal of ITP treatment is to maintain a safe level of platelet count to prevent clinically significant bleeding and is a common aspiration
of clinicians and patients.
Second-line therapy should be used when first-line therapy (e.
g.
, glucocorticoids) does not raise platelet counts to safe levels, or when the dose of first-line therapy
is tapered below safe levels.

According to ITP guidelines or expert consensus at home and abroad, second-line treatment mainly includes thrombopoietic drugs (rh-TPO and TPO-RA), rituximab, splenectomy, etc.
, among which thrombopoietin receptor agonists (TPO-RA) have become an important choice for second-line treatment of ITP, mainly including small molecule peptides and non-peptides
.
Its mechanism of action is to stimulate megakaryocyte production in the bone marrow and ultimately stimulate platelet production
in the bone marrow by binding to and activating TPO receptors.

Ropsilostim is a peptide TPO-RA consisting of 2 human IgG1κ heavy chain constant regions (Fc fragments) linked by disulfide bonds, each of which is covalently bound
to two peptides with the same sequence by polyglycine at the 228th amino acid residue.
Four binding sites combined with natural TPO to rapidly and safely elevate platelet counts in healthy people, ITP patients and MDS patients, the drug was first marketed in Australia in July 2008 and subsequently approved by the FDA and EMA for second-line treatment
of immune thrombocytopenia 。 Based on its good clinical efficacy, the official website of the China National Medical Products Administration (NMPA) announced on January 11, 2022 that Ropilostim for injection was approved in China for the treatment of immune thrombocytopenia (ITP), which will provide a new option
for patients with ITP who are intolerant or have a poor response to glucocorticoids.

Structural advantages lead to better platelet promoty

As a kind of TPO-RA, ROPSTEIN has many advantages: (1) It can activate more downstream signaling pathways that promote the proliferation of megakaryocytes: compared with small molecule non-peptide TPO-RA, ROMUSTINE can phosphorylate TPO receptors and activate more downstream signaling pathways, including JAK2-STAT5, STAT3, PI3K/AKT, etc.
, which have a stronger activation effect on AKT and JAK-STAT pathway than small molecule non-peptide TPO, This is of great value in promoting the proliferation and maturation of megakaryocytes, while the small molecule drug eltrombopag does not have AKT and STAT3 signaling pathways
.
In addition, compared with non-peptide TPO-RA (such as eltrombopag, hydrotrombopag, etc.
), the signal strength is higher and the speed is twice as fast (30minvs60min)
when the JAK2 and STAT5 pathways are activated by ropsipin and rhTPO.

(2) Compared with rhTPO, which is also a recommended drug, TPO-RA does not compete with endogenous TPO, does not induce TPO antibodies, and can achieve stable and predictable platelet count rise
.

(3) Long half-life and low frequency of medication: Roprostim belongs to the TPO peptide mimetic and is an Fc peptide fusion protein synthesized by recombinant DNA technology in
Escherichia coli.
The fusion protein consists of 1 IgG1Fc vector domain and 4 TPO-R binding domains composed of 4 polypeptide sequences with high affinity for TPO-R, in which the antibody Fc segment can bind to the nascent Fc receptor (FcRn) and recirculate with endothelial cells to prolong the half-life of the drug in vivo, which can be extended to 120-140 hours, thereby reducing the frequency of medication to once a
week.

Clinical studies have shown that roprostim has a fast and good platelet lifting effect

A study conducted in the USA included 340 patients with ITP, all treated
with roprostiem.
Results showed that over 80% of patients with ITP had rapidly elevated platelets
after starting treatment with roprostim within 24 weeks of follow-up, regardless of the course of the disease in patients with ITP.

In a prospective study conducted in Europe, 356 patients with ITP treated with roprostim were included with a baseline platelet count of only 20×109/L, but platelets in patients with ITP rose rapidly and significantly after 2 weeks of roprostim treatment, and remained above
50×109/L for a medium to long term during the subsequent 104 weeks of treatment.

In a 6-month, prospective, multicenter, randomized, double-blind, placebo-controlled phase III clinical +3-year follow-up study, results showed a significant reduction in the incidence of grade 2 bleeding events in patients with ITP in the roprostim group by 15% (Roprostim group) vs.
34% (placebo group)
compared with placebo.

In addition, ROPROSTIM is a long-acting TPO-RA, which is convenient and long-lasting, and only needs to be once a week to achieve long-lasting good results
.
Good safety: studies have shown that ropremim does not impair liver function, does not affect the duration of diet, and has a good
safety profile for long-term treatment.

In fact, at present, the recommended status of TPO-RA in domestic and foreign guidelines is increasing, and in the "Adult Primary Immune Thrombocytosis-2018 Edition", it is clear that the TPO-RA recommended position represented by Roprostim is an important choice for ITP second-line treatment, and it should be pointed out that the guidelines on ITP in ASH in 2019 also clearly state that for adult ITP patients who have not responded to glucocorticoid therapy for more than 3 months, ASH recommends TPO-RA instead of rituximab
。 In addition, the 2019 ITP International Consensus Report also clearly recommends (Ib grade, class A recommendation) TPO-RA as a key drug for the second-line treatment of
ITP.

Thrombopoietin receptor agonist (TPO-RA) has a unique mechanism of action in the treatment of ITP, creating a new era of ITP platelet enhancement therapy, roprostim as a new generation of TPO-RA, because of its good efficacy and safety shown in clinical studies, has been approved for the second-line treatment of ITP, with four significant advantages of fast onset, ultra-high response rate, long-lasting efficacy/convenient application, and good safety, making it one of the good choices for the clinical treatment of ITP
。