Geron Submits NDA for First-in-Class Therapy for MDS

Geron has submitted a new drug application (NDA) to the FDA for imetelstat to treat adult patients with transfusion-dependent anemia. If approved, it would indicated for patients with low- to intermediate-risk for myelodysplastic syndromes (MDS) who have failed to respond to erythropoiesis-stimulating agents (ESAs). The FDA had previously granted fast track designation to imetelstat.

Myelodysplastic syndromes are a group of cancers in which blood stem cells do not mature. This can lead to anemia, infection or bleeding.

Imetelstat is a first-in-class therapy that targets telomerase to inhibit uncontrolled proliferation of malignant stem and progenitor cells in myeloid hematologic malignancies.

Telomerase is a naturally occurring enzyme that maintains telomeres. Telomere is the protein structure that at both ends of each chromosome that protects the chromosome from becoming frayed. Each time a cell divides, the telomeres become shorter; telomerase stops this from happening.

Telomerase expression has been found to be present in about 90% of biopsies taken from a broad range of human cancers, according to Geron. This drives cancer cells to continue to divide and grow. Imetelstat was designed to inhibit telomerase, selectively killing the malignant stem and progenitor cells in the bone marrow.

The submission is based on results from the phase 3 study IMerge to evaluate imetelstat versus placebo, which were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The primary endpoint of transfusion independence was significantly at eight weeks was met with high statistical significance for imetelstat-treated patients (39.8%) vs. placebo (15.0%). Key secondary endpoint of 24-week transfusion independence and hematologic improvement erythroid were also met with high statistical significance.

Additionally, mean hemoglobin levels in imetelstat-treated patients increased significantly over time compared to placebo patients.

Amer Methqal Zeidan, MBBS

The most common grade 3/4 adverse events were thrombocytopenia and neutropenia, with similar rates of grade ≥3 bleeding and infections on imetelstat and placebo. In patients treated with imetelstat, cytopenias were manageable, of short duration, and > 80% were reversible to grade ≤2 within four weeks.

“The IMerge phase 3 results are especially encouraging because of the significant unmet need in lower risk MDS patients with symptomatic anemia needing regular red blood cell transfusions, especially with less than half of such patients responding to frontline ESA therapy, and most of those who do respond losing that response in less than two years,” Amer Methqal Zeidan, MBBS MHS, associate professor of Internal Medicine (Hematology) and director of hematology Early Therapy Research at Yale School of Medicine and Yale Cancer Center, said in a press release. Zeidan is a lead investigator on the IMerge trial and presented the data at ASCO.

Imetelstat is also being studied in a phase 2 trial in higher risk myelodysplastic syndromes and relapsed/refractory acute myeloid leukemia (AML).