Imetelstat in Lower-Risk MDS: IMerge Trial Overview and Efficacy Outcomes
An overview of the patient population and study design of the IMerge trial evaluating imetelstat, highlighting its MOA and rationale for its use in MDS, and reviews key efficacy outcomes, including HgB levels and transfusion independence.
Dr. Michael Savona: And now, we're going to talk a little bit about this new drug called imetelstat telomerase inhibitor. And we're really excited about this. And Dr. Zeidan was actually one of the leaders of this, and maybe he can talk a little bit about the patient population for the last phase three study, which is just concluded.
Dr. Amer Zeidan: Yeah, thanks, Mike. So, as you mentioned, I mean, several drugs are currently in the pipeline for lower risk MDS from those which are not approved. Imetelstat is the one that is most advanced, and I think based on the study, is very likely to be approved hopefully in 2024. So, as you mentioned, both of us were involved in the trial and kind of have seen, I think very excellent data with the drug. But just to backtrack on the patient population, so this imetelstat study basically is a phase three randomized study. There was a phase two study that used the drug in a single arm study, and I think in close to 40 patients who had lower risk MDS, who had not responded to ESA, but did not receive HMA or lenalidomide. So it was a second line treatment after ESA failure for anemic patient. And the transfusion independence rate was quite good at 40% and very durable at 88 weeks. So this generated a lot of excitement. This part of the study has been published from the same study from the IMER study. There was a second part, which was the randomized phase three portion in which patients were randomized to receive imetelstat versus placebo. So imetelstat, just to backtrack, is a first in class telomerase inhibitor. It's a reversible and competitive inhibitor. And it has been shown basically to directly impact progenitor MDS cells that have high telomerase activity and potentially restore effective erythropoiesis in those patients. The drug is given intravenously, is given every four weeks, and the starting dose is 7.5 milligram per kilogram. So the trial enrolled patients, adult patients, similar to the phase two who had ESA failure, or unlikely to respond to ESA because their ESA level or their EPO level was high. But I think what was most impressive about this study is that the baseline transfusion burden was very high. The median number of units for patients in the study, six units, imagine six units per eight weeks, that reflects almost a unit every week. So those patients were getting tons of blood. And when you take that about in the sense of the efficacy results that we seen and we'll talk about, this was quite important. Importantly, the endpoint is a common endpoint that we use for these type of trials, which is the eight week transfusion independence, but also the durability was noticeable with this drug. But, I'll let you, Mike, talk about like the efficacy data and then maybe we can discuss the safety and where do it go from here with imetelstat.
Dr. Michael Savona: Yeah. Thanks. And this was a fun study. I mean, we've been, this drug has kind of been around for a while and there was a scare with a potential hepatic toxicity that really was ruled out early in development. But it slowed the development of drug down for several years. And this says, as Amer mentioned, this kind of got revved back up again and because there was so much excitement, it really built the phase two and phase three. [00:21:00] fairly quickly. And IMerge is really a nice study. And you know, if you read IMerge after reading the Medalist study, you can see the themes that the endpoints are built up around conversations with the agency on acceptable surrogates for survival because these patients just have a longer horizon. Transfusion independence is really a rock solid endpoint. And so as Amer mentioned, the primary endpoint was transfusion independence at eight weeks in this study. The difference between, and this was randomized two to one. Two patients with imetelstat for every patient with placebo, to encourage enrollment given such per positive effects we saw with the phase two. The difference with transfusion independence at eight weeks between imetelstat and placebo is 40% versus about 15%, I think. Really striking difference in transfusion independence. And at 28 weeks, about 28% of patients on imetelstat maintained that transfusion independence. Where in the placebo arm as you would imagine, only 3% maintained that. As far as the primary endpoint of transfusion dependence, kind of an impressive result. These weren't necessarily patients who had been through Luspatercept, PSA, and danazol and everything. But as Amer mentioned, they were patients who had previously been exposed to ESA or had high erythropoietin. What's also kind of important to note is that the patients who had transfusion independence on this study maintained that transfusion independence for about a year, 51, 52 weeks versus about 13 weeks for the patients who had transfusion independence in the placebo arm. Illustrating some of the liability that just happens in MDS as it as it progresses. It probably goes without saying transfusion independence is fairly clear. You're either getting transfusions or not. But there's also a transfusion reduction, which is a little softer endpoint. And of course, the important endpoint of hemoglobin improvement in hemoglobin. In the MDS response criteria, we look at something called hematologic improvement, which is a combination of transfusion metrics and a bump in your hemoglobin in the case of red cells. The HI rate, the hematopoietic improvement rate between patients that received imetelstat and placebo is 40% versus 13% echoing kind of what we saw in the transfusion independence. So really fantastic on the key efficacy outcome. Really got us excited.
