Advances in Research on New Therapeutic Drugs for Myelodysplastic Syndromes (Part one)

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies characterized by defective normal hematopoiesis leading to a reduction in blood cells, with a risk of transformation into acute myeloid leukemia. Currently, demethylating agents such as azacitidine and decitabine, as well as hematopoietic stem cell transplantation, are the primary treatment options for MDS patients. In recent years, with the deepening of research on the pathogenesis of MDS, many novel drugs have emerged. Current 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.

1. HIF Prolyl Hydroxylase Inhibitors

HIF is a heterodimeric transcription factor that regulates cellular responses to hypoxic conditions by upregulating several genes crucial for erythropoiesis, including erythropoietin, erythropoietin receptor, and proteins involved in iron metabolism. The HIF transcription factor consists of two subunits: an oxygen-sensitive α subunit and a constitutively expressed β subunit. Under normal oxygen conditions, the α subunit degrades in the presence of molecular oxygen, but under hypoxic conditions, it translocates to the nucleus and forms a heterodimer with HIF-β, thus activating HIF-1 and HIF-2 gene transcription. Under normoxic conditions, HIF can degrade the prolyl residue on the HIF-α subunit through HIF prolyl hydroxylase. Therefore, preventing HIF degradation by inhibiting HIF prolyl hydroxylase has become a promising target for promoting erythropoiesis.

Roxadustat is an oral HIF prolyl hydroxylase inhibitor that has been studied in over 400 patients with chronic kidney disease and has been approved in China for the treatment of anemia in chronic kidney disease patients. Roxadustat is also being studied in patients with myelodysplastic syndromes. Currently, a randomized, double-blind, placebo-controlled phase III clinical trial (NCT03263091) is ongoing to investigate the efficacy of roxadustat in non-del(5q) myelodysplastic syndrome patients with low transfusion burden. Among the 24 patients recruited, 38% achieved transfusion independence within at least 8 weeks, and 58% reduced their transfused red blood cell units by at least 50% within 8 weeks. After 28 weeks of treatment, the response rate was 54%, and the transfusion independence rate was 38%. Roxadustat is currently a highly regarded oral therapy for managing anemia, with an initial response rate higher than monotherapy with erythropoiesis-stimulating agents. Clinical trial results have shown significant improvements in the clinical efficacy of roxadustat, making it a potential treatment option for patients with myelodysplastic syndromes in the future.

2.IDH Inhibitors

IDH is a key enzyme involved in the tricarboxylic acid cycle of cells. Among the identified cancer genes in humans, IDH1 and IDH2 are the most frequently mutated tumor metabolic genes, and approximately 5% of patients with myelodysplastic syndromes have IDH1/IDH2 gene mutations. It is currently believed that IDH1/IDH2 mutations promote the synthesis of 2-hydroxyglutarate (2-HG), and elevated levels of 2-HG can lead to increased reactive oxygen species (ROS), which is associated with gene mutations and carcinogenesis. Ivosidenib (AG-122) and enasidenib (AG-LH) are oral small-molecule inhibitors of IDH1 and IDH2, currently used as monotherapy or combined with azacitidine for the treatment of acute myeloid leukemia. A phase III clinical trial showed that the complete response rate for patients with relapsed/refractory IDH2-mutated acute myeloid leukemia treated with enasidenib was 38.6%. Another study showed that Ivosidenib could effectively extend the median survival time of patients with acute myeloid leukemia who achieved complete remission (CR) or hematological remission. In a phase I study using two drugs to treat patients with myelodysplastic syndromes, the objective response rate was 92% for Ivosidenib and 59% for enasidenib. Currently, a phase II clinical trial of Ivosidenib for IDH1-mutated myelodysplastic syndromes is ongoing (NCT03503409).

IDH inhibitors have demonstrated significant single-agent activity in acute myeloid leukemia, leading to the FDA approval of Ivosidenib and enasidenib for the treatment of this disease. According to current research, IDH inhibitors also show promise in treating patients with myelodysplastic syndromes. Therefore, there is hope that better results will be achieved in future phase II/III trials, enabling more patients with myelodysplastic syndromes to benefit.

3.Telomerase Inhibitors

Telomeres play a crucial role in maintaining normal hematopoiesis, and telomere shortening and telomerase dysregulation are considered significant in the development of myelodysplastic syndromes and acute myeloid leukemia. Telomerase is a protein complex that includes human telomerase reverse transcriptase, an RNA template, and specific proteins that have the function of extending and maintaining telomere length. Telomerase is inactive in normal cells but its levels increase in many cancers, leading to significant proliferation. Studies have shown that patients with myelodysplastic syndromes who have high telomerase activity levels tend to have worse survival rates.

Imetelstat is an effective and specific telomerase inhibitor. It is an oligonucleotide that complements the template region of telomerase and binds with high affinity, resulting in competitive inhibition. Preclinical studies have shown that imetelstat has extensive inhibitory effects on tumor growth in multiple human tumor xenograft animal models, including myeloma and breast cancer. Since tumor cells in patients with myelodysplastic syndromes have high telomerase activity, a phase I to III trial showed that 22% of patients achieved transfusion independence after 24 weeks, and approximately 66% of patients had hematological improvement. The IMerge trial (NCT02598661) is currently studying the use of imetelstat in phase II to III patients, with 68% of patients showing hematological improvement. At weeks 8 and 24, the transfusion independence rates were 45% and 26%, respectively, and the median duration of response was approximately 20 months. Imetelstat is a promising new drug for patients with refractory low-risk myelodysplastic syndromes, but it has certain adverse reactions. During the treatment of myeloproliferative neoplasms, thrombocytopenia, neutropenia, and anemia are relatively common adverse reactions that require further monitoring during treatment.

4.Tyrosine Kinase Inhibitors

Rigosertib binds to the Ras-binding domain of several kinases, including RAF and PI3K, primarily acting by inhibiting the Ras pathway, leading to mitotic arrest and apoptosis. Phase I trials conducted among patients with myelodysplastic syndromes have achieved satisfactory results, with an objective response rate of up to 53%. Phase II trial data suggests that the combination of azacitidine and rigosertib may have a synergistic effect, showing a response rate of 62% among patients refractory to demethylating agents. Randomized phase III trials are ongoing, comparing the combination of rigosertib with azacitidine to azacitidine alone for the treatment of newly diagnosed patients with high-risk myelodysplastic syndromes, in anticipation of its synergistic effects.

References:

[1] Wang Geng, Tian Zhiliang. Research Progress in Therapeutic Drugs for Myelodysplastic Syndromes [J]. Modern Drugs & Clinical, 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 Clinical Medicine in Practice, 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.