Imetelstat Shows Potential to Transform QOL in Lower-Risk MDS

The unique ability of the telomerase inhibitor imetelstat to significantly reduce transfusion dependence and potential to modify disease in patients with lower-risk myelodysplastic syndrome (MDS) who cannot receive standard erythropoiesis-stimulating agents (ESAs) may lead to improved quality of life (QOL) in this setting, according to Sunil Iyer, MD.

In August 2023, the FDA accepted for review a new drug application (NDA) seeking the approval of imetelstat for the treatment of transfusion-dependent anemia in adult patients with International Prognostic Scoring System (IPSS) low- to intermediate-1–risk MDS who have not responded to, have lost response to, or are ineligible for ESAs.¹ The NDA is supported by phase 3 data from the phase 2/3 IMerge/MDS3001 trial (NCT02598661), in which 8-week red blood cell (RBC) transfusion independence (TI) was improved with imetelstat (n = 118), at 39.8% (95% CI, 30.9%-49.3%) vs 15.0% (95% CI, 7.1%-26.6%) with placebo (n = 59; P <.001). Similarly, 24-week RBC-TI was achieved by 28.0% of patients on imetelstat vs 3.3% of those on placebo (P ≤.001).²

On March 14, 2024, the FDA’s Oncologic Drugs Advisory Committee voted in favor of the risk-benefit profile of imetelstat in this population.^2,3 Although the committee agreed on the benefit-risk profile of the agent, they questioned the magnitude and duration of RBC-TI in the absence of an improvement in overall survival, response, and patient-reported outcomes (PROs).

“For patients who may have [SF3B1] mutations or ASXL1 mutations, which are not taken into account in the IPSS-R, we may soon have medications like imetelstat approved,” said Iyer following his participation in an OncLive® State of the Science Summit™ on hematologic malignancies. “This [agent] may be disease modifying, and we may be able to reduce the variant allele frequencies for patients with this disease, improve their cytopenia, and prolong or prevent the transformation to acute myeloid leukemia [AML].”

In an interview with OncLive, Iyer, who is an assistant professor of medicine at Columbia University Irving Medical Center in New York City, explained how the unique mechanism of action of imetelstat could address unmet needs in MDS, detailed the design and key findings of the IMerge trial, and emphasized the agent’s potential impact in this population. Iyer expanded further on the impact of luspatercept-aamt (Rezboyl) in lower-risk MDS in a related interview.

OncLive: What is unique about the mechanism of action of imetelstat?

Iyer: Imetelstat is a telomerase inhibitor. Our chromosomes contain telomeres, which are lengths of new nucleotide sequences. Every time the cells divide, our telomeres get shorter. Once the telomeres reach a critical level of shortness, there are DNA damage signals that are produced so the cells can no longer reproduce. They go into senescence, and eventually apoptosis. Some cells in the body express an enzyme called telomerase, which [engenders the] lengthening of telomeres, [thereby allowing cells to] reproduce and not go into apoptosis. Our hematopoietic stem cells express telomerase as do some immune cells, but generally, most of our somatic cells do not express telomerase, which is why our cells have an expiration date. However, MDS does contingently express telomerase, [which] is why telomerase was chosen as a drug target.

You might think, “Won’t this lead to cytopenia because a telomerase inhibitor is also going to inhibit hematopoietic stem cells?” [However], there is a differential effect in the malignant cells and your normal cells, because normal cells only transiently express telomerase. This leads to less apoptosis, and only transient cytopenia, because the MDS cells are expressing telomerase more and therefore taking more damage.

Please describe the design and methodology of the IMerge trial.

The IMerge trial is evaluating the first-in-class telomerase inhibitor imetelstat vs placebo in patients with lower-risk MDS who are RBC transfusion dependent. A major difference from the phase 3 COMMANDS trial [NCT03682536] is that these patients are relapsed/refractory to ESAs.These are patients without deletion 5q who were naive to lenalidomide [Revlimid] and hypomethylating agents. In the phase 3 portion of this trial, the rates of RBC-TI at 8 weeks, 24 weeks, and 1 year [were evaluated] to see whether there were durable responses.

Could you expand on the key safety and efficacy findings reported from the IMerge trial?

As expected, there were some cytopenias with this medication. There was a high rate of grade 3/4 neutropenia but [the rates of] neutropenic fever, bleeding, and bruising were quite low. When the drug was held, these cytopenias were [mitigated]. The variant allele frequency of some of the common mutations you see in MDS, such as DNMT3A, SF3B1, TET2, and ASXL1, was reduced with imetelstat. This leads us to think that the medication may be disease modifying, which we know medications like ESAs and [potentially] luspatercept are not. Similar to the COMMANDS trial, the primary outcome of the IMerge trial was 8-week RBC-TI. This [end point] was met in 39.8% of patients receiving imetelstat and only 15% of patients receiving placebo. Looking at 24-week RBC-TI, 3.3% of patients on placebo maintained RBC-TI vs 28% of patients on imetelstat. Looking at 1-year [RBC-TI], 17.8% of patients on imetelstat maintained RBC-TI vs 1.7% of patients on placebo.

If approved, how might imetelstat benefit patients with lower-risk MDS?

Reducing transfusion dependence is a huge boon to patients who are requiring transfusions, as it improves QOL. [Patients will undergo] fewer visits and have a lower risk of [experiencing] adverse effects from transfusions. What you must accept up front is that there is a risk of cytopenias; it may depend on your patient and how frail they are. There’s also the possibility that imetelstat is disease modifying. Down the line, [we may see a] reduced rate of transformation to AML. [Hopefully,] this medication will be approved soon for this indication.

References

1. Geron announces FDA acceptance of new drug application for imetelstat for the treatment of lower risk MDS. News release. Geron. August 21, 2023. Accessed March 28, 2024. https://ir.geron.com/investors/press-releases/press-release-details/2023/Geron-Announces-FDA-Acceptance-of-New-Drug-Application-for-Imetelstat-for-the-Treatment-of-Lower-Risk-MDS/default.aspx
2. Zeidan AM, Platzbecker U, Santini V, et al. IMerge: results from a phase 3, randomized, double-blind, placebo-controlled study of imetelstat in patients (pts) with heavily transfusion dependent (TD) non-del(5q) lower-risk myelodysplastic syndromes (LR-MDS) relapsed/refractory (R/R) to erythropoiesis stimulating agents (ESA). J Clin Oncol. 2023;41(suppl 16):7004. doi:10.1200/JCO.2023.41.16_suppl.7004
3. March 14, 2024, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. Accessed March 28, 2024. https://www.youtube.com/watch?v=Om-cKKBsMS4