Rory Shallis Explains New Therapy for Patients with Low-Risk MDS, Imetalstat

Leigh Clark:    Hi everyone. Welcome to Podcasts for Patients. My name is Leigh Clark, Director of Patient Services and I'll be moderating the podcast today. Before we get started, I'd like to thank our diamond level sponsors, Alexion and Novartis. And of course our patients and families and caregivers who support our educational programs. Today, I have the pleasure of speaking with Rory Shallis who is a physician at Yale Cancer in New Haven, Connecticut. Thank you so much, Doctor Shallis, for joining us today.
Rory Shallis:    It's a pleasure. Thanks for the invitation.
Leigh Clark:    Imetelstat was recently approved for treating MDS. and can you tell us a little bit about what is the new therapy?
Rory Shallis:    Sure. It's an important question. Imetelstat uses what we're calling novel mechanisms where it works in a new way. It's a first in class competitive inhibitor of telomerase which is an enzyme that works to, has a couple of functions, it works to protect and even make more telomeres or the caps, if you will, on the end of chromosomes which is kind of like these large structures of genetic material that all of our cells have. It protects them from a sort of cellular retirement, and from damage for those that have not yet retired, if that's the way you can think about it.
    Now malignant cells, like those found in MDS, uh, appear to rely upon this enzyme, to protect them so it not only makes sense to try and target this aspect of the malignant cellular machinery in these cells, and just to kind of develop and study a drug that did just that. Imetelstat was shown in early experiments to inhibit telomerase activity and the proliferation or growth of these cells in various cancers, including MDS. Imetelstat showed promising results in an initial Phase II trial that were, as you might be aware, confirmed in a randomized Phase II trial that eventually led to its approval on June 6th of this year.
Leigh Clark:    What patients would most benefit from the treatment?
Rory Shallis:    Sure. this is a good question and I think it's still being debated as to who exactly, to whom it might exactly apply. I can tell you the randomized trial studied imetelstat patients with lower risk MDS that had already been failed by what we call an erythropoiesis stimulating agent or ESA. So at a minimum these patients,  you know, for whom the treatment would be reasonable, and for whom the drug was approved, particular subgroups may be more attractive for this treatment but this requires, a bit more research and we wait to say in all honesty how the NCC and guidelines may respond to this as well.
Leigh Clark:    How is the treatment given and what are the known side effects?
Rory Shallis:    Of course. Imetelstat is  administered as a two-hour-ish, infusion intravenously or IV through the pains. It's given every four weeks. The side effect profile is largely navigable, I'd say. It does require some vigilance o-on the part of providers and patients. Uh, the key side effect that, you know, did get some press, uh, is a lowering of blood counts including low white blood cell count, uh, low platelet count in the majority of patients, where at least, at least weekly monitoring, in some cases more often is recommended with consideration perhaps for, growth factors, mind you myeloid growth factors, some maybe prophylactic antibiotics and uncommonly a platelet transfusion or two.
    However, the vast majority of patients had this as a short-lived side effect, in the order of, uh, maybe four weeks or so and limited episodes of recurrence beyond the first cycle, or so. Other side effects include liver irritation, headache, fatigue, muscle aches but these are, I would argue, like-likewise fairly manageable and acceptable given the benefits that have been thus demonstrated.
Leigh Clark:    Can you tell us a little more about the clinical trial that led to the approval?
Rory Shallis:    Of course. This is the IMerge trial, uh, which was a Phase III randomized double-blind placebo controlled trial, uh, of this drug imetelstat or placebo, uh, you know kind of like the gold standard of trials to really demonstrate whether a drug is truly working. Fhis was, amongst patients with lower risk MDS, just under 200 patients were on the trial. Treatment norms were by design balanced for patients who have certain degrees of red blood cell transfusion burden, and a certain measure of MDS disease risk. So it was a cleanest kind of appraisal of how this drug is really doing compared to placebo.
    The specific target for how well this drug worked was an eight-week period, protected eight-week period, of not needing a red blood cell transfusion. Forty percent of patients receiving imetelstat hit this target compared to 50% of patients receiving placebo, So clearly, indicating the effect of the drug.
Leigh Clark:    What is the difference between Luspatercept and imetelstat?
Rory Shallis:    A lot. Luspatercept is what we, uh, know now as an erythroid maturation agent or we still, you know, or Ken called it TGF beta ligand trap, you know, fancy terminology for a drug that works in somewhat of a-a new way or new ways. It's a subcutaneous, or under the skin injection, every three weeks and appears to have a much better effect for patients whose disease harbors what we call ring sideroblasts. We've been using this drug for a few years now and, tend to recommend it for patients with this exact situation, so MDS with ring sideroblasts, different ways of defining it, although it does have some effect in patients with disease outside of this particular subset. There's likely to be some overlap in the particular patients that may have a path to being recommended for particular treatment like Luspatercept and or imetelstat, and it may take some time in all honesty to really sort out which one is more attractive for particular patients 'cause we, as of yet, do not have a-a comparative study. There's no randomized Phase III trial comparing Luspatercept to imetelstat.
    But we certainly for the time being welcome new additions to our toolkit to help patients with this disease which, you know, is, um, is in need of newer therapies for sure.
Leigh Clark:    What else is important for patients to know about imetelstat?
Rory Shallis:    This regimen can be navigated safely. You know, you get through the side effects. There are other options that can be considered for the patient being considered for imetelstat including lenalidomide, Luspatercept, as we talked about, or in some cases hypomethylating agent. Um, but these options should be weighed against each other and  against imetelstat hopefully, with the assistance of an MDS specialist. So, I would probably just counsel patients to ask their provider for a second, if not third opinion if you're not already seeing one.
Leigh Clark:    Well, thank you very much, Doctor Shallis for sharing your time and your expertise with us today. And if you'd like more information about MDS and other treatments, please feel free to visit our website at AAMDS dot org. Or give us a call at 800-747-2820 and if you're looking to find an MDS specialist, please feel free to let us know and we can help you with that as well. Thank you so much, Doctor Shallis, for sharing your time today. Have a great day.
Rory Shallis:    Thank you so much. You as well. Take care.