Imetelstat Offers Potential New Therapy for Lower-Risk MDS

Amer Zeidan, MBBS

Treatment with imetelstat generated statistically significant and clinically meaningful efficacy data, meeting the primary end point of the phase 3 IMerge trial (NCT02598661) in patients with heavily transfusion dependent, non-del(5q) lower-risk myelodysplastic syndrome (MDS) that is relapsed or refractory to erythropoiesis stimulating agents (ESAs).¹

As of October 2022, 118 patients received imetelstat in the study, a first-in-class direct and competitive telomerase inhibitor. Patients treated with imetelstat achieved 8-week red blood cell transfusion independence at a rate of 39.8% (95% CI, 30.9%-49.3%) vs 15.0% (95% CI, 7.1%-26.6%) for the 59 patients who received placebo (P <.001).

Additionally, 16-week transfusion independence was also improved with imetelstat at 31.4% (95% CI, 23.1%-40.5%) vs 6.7% (95% CI, 1.9%-16.2%) with placebo, respectively (P <.001). The 24-week transfusion independence rates were 28.0% (95% CI, 20.1%-37.0%) vs 3.3% (95% CI, 0.4%-11.5%), respectively (P <.001), and at 1 year, transfusion independence rates were 13.6% (95% CI, 8.0%-21.1%) and 1.7% (95% CI, 0.0%-8.9%; P =.012).

“Importantly, this transfusion independence was seen across the genetic mutational spectrum, so, all kinds of genetic alterations responded. It's a drug that works across the spectrum for lower-risk patients with MDS patients after ESA failure,” Amer Zeidan, MBBS, told Targeted Oncology^TM, in an interview.

In the interview, Zeidan, Yale Cancer Center, further discussed the IMerge study and next steps for imetelstat for patients with lower-risk MDS.

Targeted Oncology: Can you describe imetelstat and how it works?

Zeidan: Imetelstat is a first-in-class telomerase inhibitor. It works by inhibiting the telomerase and early phase data suggested that this could have selective pressure on the clonal cells within patients with MDS, leading to the killing of the MDS clone and the recovery of the count in those patients.

What was the rationale behind the IMerge study?

The rationale for the IMerge randomized, phase 3 trial was based on the phase 2 trial, which is part of the same trial, but it was a single-arm part where 40 patients with lower-risk MDS who had heavy transfusion dependence but had no previous exposure to lenalidomide or to hypomethylating agents were enrolled in the phase 2 part of the study. Importantly, the transition dependence rate was quite good at around 40%. Those patients had durable responses.

We presented an update looking at the long-term outcome of the 11 patients who had transfusion independence lasting more than 1 year, and the response rate was high, and it was durable. Importantly, we saw early evidence of disease modification, which we inferred by a reduction in the allele frequency of several genes that are involved in the pathogenesis of MDS. On the adverse effect side, the main effects were liver enzyme abnormalities, but most of those were grade 1 and grade 2, and generally reversible, as well as thrombocytopenia and neutropenia, and while those were grade 3 and grade 4, most of them are reversible and manageable, meaning that when you hold the drug, they basically go back to grade 2 or less 80% of the time within 4 weeks. There was [also] no increase in the rates of significant clinical consequences, for example, severe infection or bleeding with the drug.

What can you tell me about the methods and design of the phase 3 portion of the study?

The phase 3 trial of IMerge basically was built on the phase 2, and the patients were randomized. There was a total of 178 patients and they were randomized into 2 arms in a 2:1 fashion to receive either imetelstat or placebo. That was given intravenously every 4 weeks, and the patients had to have lower-risk MDS and to have transfusion dependence, meaning that they are needing more than 4 units of blood every 8 weeks. The median transfusion dependence on the trial was 6 units, and they had to have not received drugs beyond the ESA, so they could not have received lenalidomide [Revlimid] or hypomethylating agents.

The trial was double-blind, meaning that the investigators and the patients did not know which patient was receiving the drug or a placebo. The primary end point was the 8-week transfusion independence, but there were a number of secondary end points looking at the durability of transfusion independence, the 24 week transfusion independence, and a number of other secondary end points.

What were the top-line results from the study?

The efficacy was similar to what was seen on the phase 2 part of the study where the transfusion independence rate was also 40%. Again, remembering that those patients had a significant burden of transfusion at baseline, this is quite impressive. Most of those patients had sustained 1 episode of transfusion independence and the median duration was 51 weeks. The rate of transfusion dependence in the placebo arm was only 15%, and it was not durable. Importantly, this transfusion independence was seen across the genetic mutational spectrum, so all kinds of genetic alterations responded. It's a drug that works across the spectrum for lower-risk patients with MDS patients after ESA failure.

Can you discuss the safety of the drug?

The findings were similar to phase 2 in the sense that the main 2 adverse effects were liver enzyme abnormalities, which again, were mostly grade 1 and grade 2, largely reversible, and cytopenias with thrombocytopenia and neutropenia. But again, [they were] largely reversible when withholding the drug, most of the time coming back lessened to grade 2 within 4 weeks. When withholding the drug, severe cytopenias, such as infection or bleeding that were grade 3 or higher were not different between the 2 arms. Generally, the drug was well-tolerated with a manageable adverse effect profile.

How are these updated findings going to influence the future of this space and research?

The next step will be submitting these findings to the regulatory agencies, the company is already doing this, and this will be reviewed by the FDA. My expectation is that the drug will hopefully get regulatory approval based on the efficacy and safety data, and if that happens, it will be an important option for our patients because while we have other agents that we can use in this space, such as lenalidomide. Generally, those drugs do not lead to responses in all patients. Actually, less than 50% of patients do not respond and their responses are not durable, so most patients need additional options. I think having a drug that's very active, well-tolerated, and potentially can modify the disease's natural course would be an important option to give to our patients.

REFERENCE:

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