FDA Accepts NDA for Imetelstat in Lower-Risk MDS

The FDA has accepted a new drug application (NDA) seeking the approval of imetelstat for the treatment of transfusion-dependent anemia in patients with lower-risk myelodysplastic syndrome (MDS).¹

The NDA is supported by findings from the phase 3 IMerge trial (NCT02598661), which demonstrated that patients treated with imetelstat (n = 118) experienced an 8-week red blood cell transfusion independence (RBC-TI) rate of 39.8% (95% CI, 30.9%-49.3%) compared with 15.0% (95% CI, 7.1%-26.6%) for patients treated with placebo (n = 59; P < .001).²

The FDA has assigned a standard review to the NDA with target action date of June 16, 2024, under the Prescription Drug User Fee Act.³

“The FDA’s acceptance of our NDA is an important landmark along our steadfast journey to bring telomerase inhibition with imetelstat to the market,” John A. Scarlett, MD, chairman and chief executive officer of Geron, stated in a news release.¹ “We look forward to continuing our collaboration with the FDA toward the goal of bringing imetelstat to the many patients for whom we believe this treatment could make a significant difference.”

IMerge was a randomized, double-blind, phase 3 trial that enrolled patients with International Prognostic Scoring System (IPSS) low- or intermediate 1–risk MDS that was relapsed/refractory to an erythropoiesis-stimulating agent (ESA) or erythropoietin of more than 500 mU/mL if they were ineligible for an ESA.2 Patients also needed to be transfusion dependent, defined as requiring at least 4 units of RBCs per 8 weeks over a 16-week pre-study. Patients could not have 5q deletions or prior treatment with lenalidomide (Revlimid) or hypomethylating agents.

Patients were randomly assigned 2:1 to receive 7.5 mg/kg of imetelstat once every 4 weeks or matching placebo. Stratification factors included transfusion burden (4-6 units vs >6 units) and IPSS risk category (low vs intermediate 1).

The rate of 8-week RBC-TI served as the trial’s primary end point. Secondary end points included 24-week RBC-TI, duration of transfusion independence, hematologic improvement–erythroid (HI-E), and safety.

Additional data showed the 16-week RBC-TI rates were 31.4% (95% CI, 23.1%-40.5%) for patients treated with imetelstat compared with 6.7% (95% CI, 1.9%-16.2%) for those given placebo (P < .001). The 24-week RBC-TI rates were 28.0% (95% CI, 20.1%-37.0%) for imetelstat vs 3.3% (95% CI, 0.4%-11.5%) for placebo (P< .001). The 1-year RBC-TI rates were 13.6% (95% CI, 8.0%-21.1%) and 1.7% (95% CI, 0.0%-8.9%), respectively (P = .012).

The median duration of RBC-TI was 51.6 weeks (95% CI, 26.9-83.9) compared with 13.3 (95% CI, 8.0-24.9) for placebo (HR, 0.23; 95% CI, 0.09-0.57; P < .001).

Among evaluable 8-week RBC-TI responders, those given imetelstat (n = 47) experienced median hemoglobin rise of 3.6 g/dL (range, –0.1 to 13.8) vs 0.8 g/dL (range, –0.2 to 1.7) for those treated with placebo (n = 9). The median hemoglobin peak was 11.3 g/dL (range, 8.0-21.9) vs 8.9 g/dL (range, 7.9-9.7), respectively.

Regarding HI-E, 42.4% (95% CI, 33.3%-51.8%) of patients in the imetelstat arm experienced hematologic improvement per International Working Group 2018 criteria vs 13.3% (95% CI, 5.9%-24.6%) of patients in the placebo am (P < .001).

Regarding safety, the most common any-grade hematologic adverse effects (AEs) reported in at least 10% of patients in the experimental arm included thrombocytopenia (imetelstat, 75%; placebo, 10%), neutropenia (74%; 7%), anemia (20%; 10%), and leukopenia (10%; 2%). In the imetelstat arm, the rates of grade 3/4 thrombocytopenia and neutropenia were 62% and 68%, respectively, and these AEs were most often reported during the first 3 cycles of treatment.

The median duration of thrombocytopenia was 1.4 weeks (range, 0.1-12.6) in the imetelstat arm vs 2.0 weeks (range, 0.3-11.6) in the placebo arm. Thrombocytopenia resolved within 4 weeks for 86.3% of patients in the experimental arm vs 44.4% of patients in the control arm. The median duration of neutropenia was 1.9 weeks (range, 0-15.9) and 2.2 weeks (range, 1.0-4.6) for the imetelstat and placebo arms, respectively. Neutropenia resolved within 4 weeks for 81.0% of patients in the experimental group vs 50.0% of patients in the control group.

The most common any-grade non-hematologic AEs included asthenia (imetelstat, 19%; placebo, 14%), COVID-19 (19%; 14%), headache (13%; 5%), diarrhea (12%; 12%), increased alanine transaminase (12%; 7%), peripheral edema (11%; 14%), hyperbilirubinemia (9%; 10%), pyrexia (8%; 12%), and constipation (8%; 12%).

AEs led to dose modifications in approximately 75% of patients in the imetelstat arm; however, less than 15% of patients discontinued treatment due to treatment-emergent AEs.

Grade 3 or higher bleeding events occurred in 2.5% of patients in the imetelstat arm vs 1.7% of patients in the placebo arm. The rates of grade 3 or higher infections were 11.0% and 13.6%, respectively. One patient (0.8%) in the imetelstat arm experienced grade 3 febrile neutropenia.

“FDA acceptance of our NDA is a significant milestone for both Geron and the MDS community, as there remain few treatment options and significant unmet needs, particularly for patients with difficult-to-treat subtypes of this cancer,” Faye Feller, MD, executive vice president and chief medical officer of Geron, said.1“We believe that the IMerge phase 3 data reflect the truly unique attributes of imetelstat, and, if approved, we expect imetelstat will change the standard of care in lower risk MDS.”

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 August 21, 2023. 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. Geron announces PDUFA date for imetelstat NDA in lower risk MDS. News release. Geron. August 22, 2023. Accessed August 22, 2023. https://ir.geron.com/investors/press-releases/press-release-details/2023/Geron-Announces-PDUFA-Date-for-Imetelstat-NDA-in-Lower-Risk-MDS/default.aspx