In recent years, with the deepening of research into the pathogenesis of myelodysplastic syndromes (MDS), many novel drugs have emerged. Currently, the therapeutic drugs for MDS patients include hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, isocitrate dehydrogenase (IDH) inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, spliceosome inhibitors, novel demethylating agents, immune checkpoint inhibitors, drugs targeting TP53 mutations, and monoclonal antibodies.

Related Reading: "Advances in Research on New Therapeutic Drugs for Myelodysplastic Syndromes (Part One)"

5.Spliceosome Inhibitors

Mutations in splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2) are among the most common mutations in myelodysplastic syndromes. SF3B1 inhibitors include pralatrexate analogs (pralatrexate A-G, E7107, and H3B-8800), herboxidienes (GEX1A and other GEX family members), and spliceostatins (FR901463, FR901464, FR901465, spliceostatin A, and sudemycin C, D1, D6, E, F). These compounds were discovered from natural products and demonstrated cytotoxic effects on cancer cells in the low nanomolar range, subsequently being proven to target SF3B1.

H3B-8800, a derivative of pralatrexate B, is an orally bioavailable macrolide small molecule that binds to the SF3b complex and modulates splicing. Phase I trial results showed that H3B-8800 was able to inhibit TMEM14CABRANT splicing in patients with myelodysplastic syndromes. Patients with relatively excessive tTEMM14CAJ transcripts are most likely to benefit from H3B-8800 treatment. The most common side effects of SF3B1 treatment are diarrhea, nausea, fatigue, vomiting, and QTc prolongation. Spliceosome inhibitor E7107, also a semi-synthetic carbamate derivative of pralatrexate B, inhibits spliceosome assembly and regulates protein expression, demonstrating unique broad-spectrum anti-tumor activity in preclinical studies. It exhibits more differential inhibition of splicing in SRSF2 mutant cells. However, E7107 can cause adverse reactions such as optic neuritis and vision loss. The drug is generally well-tolerated, with manageable systemic side effects, but vision loss in a few patients led to the termination of the study. Preclinical studies are ongoing to clarify the causes and mechanisms that affect the optic nerve. Many spliceosome inhibitors, including FD-895 and protein arginine methyltransferase 5 inhibitors (such as GSK3326595, JNJ-64619178), are currently being tested in preclinical and early clinical studies.

6.Immune Checkpoint Inhibitors

Immune checkpoints are inhibitory receptors on immune cells that can allow malignant clonal cells to escape immune surveillance and survive for a long time. Immune checkpoint blockers (ICB) enhance anti-tumor immune responses by blocking the immune system's intrinsic negative factors, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed death receptor-1 (PD-1), and its ligand-1 (PD-L1). Currently, ICB represented by PD-1/PD-L1 antibodies have achieved significant clinical benefits in various solid tumors. PD-1 blockers commonly used in clinical research for hematologic diseases mainly include nivolumab and pembrolizumab, while PD-L1 blockers include atezolizumab, durvalumab, and avelumab. The CTLA-4 blockers mainly include ipilimumab and tremelimumab. Currently, avelumab, durvalumab, and atezolizumab have been developed and approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of myelodysplastic syndromes. Studies have shown that monotherapy with PD-1/PD-L1 and CTLA-4 blockers has limited clinical efficacy, especially when tumor burden is excessive, and monotherapy may not be sufficient to achieve effective treatment outcomes. Immune checkpoint inhibitors have a certain effect on myelodysplastic syndrome patients who have failed demethylating agent treatment. However, according to some studies, the biomarkers of response in myelodysplastic syndrome patients may differ from those in solid tumor phenotypes. Demethylating agent treatment has been shown to upregulate PD1/PDL1 and CTLA-4 levels, providing a rationale for combination therapy.

7. Targeting TP53 mutant drugs

Among 10% of patients with myelodysplastic syndromes (MDS), TP53 mutations have been observed, which are associated with poor prognosis. Patients with a high frequency of TP53 mutations tend to have worse prognosis than those with a low frequency of mutations. Research shows that, compared with patients with single-allele mutations, MDS patients with more than one TP53 alteration (mutations and/or deletions) have a poorer prognosis. Eprenetapopt, a novel drug, can reconstruct the p53 protein, reactivating its apoptosis-promoting and cell cycle arrest functions, restoring the wild-type p53 function in TP53 mutant cells. The combination of eprenetapopt with azacitidine has demonstrated good tolerability in treating TP53 mutant MDS, producing high clinical response and remission rates with relatively acceptable toxicity, making further research of this drug in non-mutated TP53 diseases highly anticipated.

8.New Demethylating Agent

Guadecitabine (SGI-110) is a second-generation demethylating agent, which is a dinucleotide of decitabine and deoxyguanosine, addressing the shortcomings of the first-generation demethylating agents. Guadecitabine is less susceptible to deamination by cytidine deaminase in multiple organs in the body, and has a longer half-life compared to the first-generation demethylating agents. Guadecitabine is more resistant to cytidine deaminase, resulting in improved stability, which can enhance the ability of DNA to integrate into dividing cells.

9.Monoclonal Antibody

The anti-CD47 monoclonal antibody, Magrolimab (Hu5F9), functions as a macrophage checkpoint inhibitor. CD47 is an immune regulatory molecule overexpressed on cancer cells, and Magrolimab can interfere with the recognition of CD47 by the SIRPα receptor on macrophages, thereby blocking the self-protection signal used by cancer cells to avoid phagocytosis by macrophages. A Phase I study on the tolerability and efficacy of Magrolimab combined with azacitidine in patients with myelodysplastic syndrome and acute myeloid leukemia showed an objective response rate of 91% and a complete response rate of 42% for the combination therapy. Phase II/III clinical trials are ongoing.

Tomaralimab (OPN-305): Toll-like receptors (TLRs) belong to a family of pattern recognition receptors that are expressed in various hematopoietic cell types such as dendritic cells, macrophages, and lymphocytes, as well as non-hematopoietic cells like endothelial and epithelial cells. They have the function of recognizing foreign pathogen-associated molecular patterns and endogenous byproducts of cellular damage, playing a central role in the innate immune response to infection and tissue damage. Enhanced TLR signaling in CD34+ stem cells and progenitor cells can lead to the activation of NFkB and histone demethylase JMJD8, resulting in the expression of various cytokines. Studies have shown that high TLR expression can lead to ineffective hematopoiesis and impair the function of normal hematopoietic stem cells. Recent research suggests that enhanced TLR expression may be involved in the pathogenesis of myelodysplastic syndromes (MDS).

Tomaralimab is a human-derived antibody that blocks TLR and is currently being tested as a treatment for MDS patients who have failed demethylating agent therapy. The results of a phase I-II multicenter clinical trial showed that, among low-to-intermediate-risk patients with early treatment failure after demethylating agent therapy, the use of tomaralimab led to a reduction in the average blood transfusion volume during treatment, with an overall response rate of 52%. Therefore, tomaralimab represents a novel treatment option for low-risk MDS patients who have failed to respond to demethylating agent therapy.

In summary, the treatment of myelodysplastic syndromes has entered a new era of novel drugs, and the use of new drugs alone or in combination with chemotherapy will be one of the main research directions in the future. With the deepening of research into the genetic mutations and immune microenvironment of myelodysplastic syndromes, the ability to prioritize the most effective and safest single drug or combination therapy will become crucial. By providing personalized treatment plans for myelodysplastic syndrome patients through genetic testing, it is believed that with further research, more effective new drugs will be applied to the clinical treatment of myelodysplastic syndromes.

References:

[1] Wang Geng, Tian Zhiliang. Research Progress in Therapeutic Drugs for Myelodysplastic Syndromes [J]. Modern Drugs and Clinical Remedies, 2022, 37(02): 433-438.

[2] Li Na, Zhang Runze, Yao Haiying. Research Progress in the Treatment of Myelodysplastic Syndromes in the Era of New Drugs [J]. Journal of Practical Clinical Medicine, 2021, 25(07): 128-132.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.