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Expanded Access to Reblozyl® for Patients with Dr. Guillermo Garcia Manero

This episode focuses on the US Food and Drug Administration expanded access approval of luspatercept or Reblozyl with Dr. Guillermo Garcia-Manero, Chief of the Section of MDS in the Department of Leukemia at MD Anderson Cancer Center in Houston.


Alice Houk:    Hi, everyone. This is podcast for patients with The Aplastic Anemia and MDS International Foundation. And I'm Alice Houk, Senior Director of Patient and Professional Programs. Our podcast series is brought to you, thanks to generous support from patients, families and caregivers like you, and our corporate sponsors. Thanks to everyone for supporting this series. Today, we're talking about the US Food and Drug Administration expanded access approval of luspatercept or Reblozyl with Dr. Guillermo Garcia-Manero, Chief of the Section of MDS in the Department of Leukemia at MD Anderson Cancer Center in Houston, and a member of our AAMDSIF Medical Advisory Board. Welcome, Dr. Garcia-Manero.
Dr. Garcia-Manero    Welcome. Thank you very much, Alice.
Alice Houk:    Reblozyl or luspatercept recently received expanded access approval from the FDA. What does that mean?
Dr. Garcia-Manero    Well  actually, I don't know what expanded access means per se because I think that, uh, what happened is a little bit more than that. So Reblozyl, that I like to refer to as luspatercept, that is  the scientific name of the medication was approved around two years ago for patients with a specific type of myelodysplastic syndrome called, ring sideroblastic anemia that were not benefiting or were not candidates for an erythroid stimulating agent, a drug like, let's say, epoetin alfa. And that was the first label. And that study was called, the MEDALIST trial, gave us the first approval of this drug and then we saw a couple of things. First, that overall, the drug is well-tolerated. And second, that patients with less transfusion needs, did better.
    So this study called, the COMMANDS Trial was designed. And that was a study, phase three, randomized study upfront for any patient with low-risk MDS transition dependent comparing this new drug, luspatercept or Reblozyl to standard of care with epoetin alfa. And the study that was recently published in one of the top journals in the world called, The Lancet and presented at the American Society of Clinical Oncology Meeting and The European Hematology Association Meeting. The results show that this is, really effective therapy when compared to the standard of care. So with that then, this drug now has an approval for patients with low-risk MDS that that transfusion dependent of any phenotype upfront as first-line therapy. And so, yes, it's expanded, but it's not like they decided to expand the access. It's just like there was a very important phase three randomized study upfront for low-risk MDS, patients with anemia needing transfusions where this drug was shown to be superior to the standard of care.
Alice Houk:    And what can patients expect when starting treatment with luspatercept?
Dr. Garcia-Manero    Well, this is very important notes, I think, because we have been using these drugs like epoetin alfa erythropoietin for decades in United States, uh, with actually a formal approval. So these drugs, actually, were never really tested in phase three trials, but it was our workhorse for many, many years. And the write is that they are good drugs and they have helped, uh, our patients for a long time, but the response rate, probably, is around top 30% or so and you know, very few people will have long-lasting responses with these agents. And of course, the drugs were safe. So we needed something better, but nobody had done a front-line randomized study like this. So this is actually very exciting. And, and the data clearly shows that this drug is better for two reasons. First, the response rate was double. It was 60% or so versus 30%. So I think the patient should expect, greater response rate and with the standard, uh, growth factor, but more important to me is per- perhaps, the fact that the duration of response is significantly longer. So in the study, the duration of response was 126 weeks versus around 70 something weeks for the epoetin alfa. So it's almost like a year longer in response. And the response was defined by an increment in hemoglobin level of 1.5 grams, plus transition dependency, that was around 12 to 16 weeks in the first 24-week period. So a very significant amount of transition dependency, increase of hemoglobin. And again, uh, when compared to a standard of care, significant increase, rate of response and duration of response. So hopefully, when we apply this into the real world, we will see the same kind of results where you will have a greater response lasting for a longer period of time. That was, basically, the objective of this study. And this, we hope that in time, will translate into better quality of life and God knows, maybe, some other improvements in the prognosis of this disease, but that, we don't know yet.
Alice Houk:    And what are the common side effects that patients may experience on luspatercept?
Dr. Garcia-Manero    Yeah. So this drug is a subcutaneous injection. It's given every three weeks. It's approved already, as we mentioned, a couple of years ago for specific type of MDS, and also, for non-MDS condition, non-thalassemia, but it's not a type of leukemia or neoplastic process. So you will think that the idea based on that, approved this drug both in first and second-line because it has an excellent, safety profile. This drug is not chemotherapy. It's really not changed the blood counts of our patients. Meaning, making them worse, but, um, a fraction of patients, um, may develop fatigue. And that fatigue sometimes is actually seen in patients that have a good response to the medication. We don't understand that very well, but occasionally, not very frequently but occasionally, the patient may experience some fatigue that, you know, it could be troublesome for the patient.
Alice Houk:    Is there anything else patients should know about luspatercept or how they should speak with their doctor about, uh, possibly considering that as a treatment?
Dr. Garcia-Manero    06:30    Yeah. So, um, there are two issues. First, going back to the toxicity question, when we compared the toxicity profile of luspatercept versus the standard growth factor, there were no significant differences. So, this is, I think, reassuring. I think, because MDS is not that frequent a disorder, it is possible that a lot of the physicians in the community may not be familiar, yet, with the drug or with the fact that this drug, now, is approved for first-line indication. And actually, sometimes the patients are the ones reaching to the doctors in the community saying, you know, there's this compound do you think I'm a good candidate or not? The second issue with this medication is, uh, because it can be quite potent, it can increase the hemoglobin level significantly up. There are some boundaries in terms of, basically, how to dose the medication, and it was based on the original studies and FDA mandates. So there's, basically, like a titration scale in terms of how we do this. So you start at a dose of one milligram per kilo and then you do a couple of doses. Basically, six weeks. And if there is no response, you can increase the dose to 1.33. And then you could do that again to a dose of 1.75. I think, most doctors and patients are familiar with this, but occasionally, I see patients that, are still at a low dose, not really responding. And, this is something to consider. Sometimes, also, what you have is, the patient has a great response at, let's say, one milligram per kilo and then you know, a few months later you start losing a little bit in response. You could increase the dose at that time. So you have like, basically, two steps up with the dose of the medication.
Alice Houk:    Thank you. And, and are there other, developments in MDS that you foresee in addition to this important approval, which is the first in many years for a low-risk MDS? Are there other things on the horizon or other adjustments that patients might be seeing in the future?
Dr. Garcia-Manero    And we're seeing, gradual, uh, push to new therapies in low-risk MDS. So one concept is this idea of starting treatment early. Meaning, in patients that are transfusion independent. There were some nice data from Europe, uh, showing, for instance, in del 5q minus MDS patients that they start low dose lenalidomide early having really good outcomes. So it's something that is starting to take some traction. There is no data with the hypomethylating agents. Particularly, the new oral hypomethylating agents. Drug like this, oral decitabine/cedazuridine with nice activity in some group of patients with low-risk MDS. And then, not yet with us, but maybe, at some point soon, we hear about the new drug called, imetelstat. That could be a potential second-line drug for patients that fail and ESA like erythropoietin alfa or maybe luspatercept. We will know next summer whether this drug is approved or not by the FDA. And actually the EHA Meeting, uh, last summer or I should say, this past summer, uh, we saw, already, data from what we call second generation drugs like luspatercept or the drug called,  KER-050 with some nice response also. So that's interesting that we'll have, also, kind of second generation drugs like that. And I can tell you that MD Anderson, in the phase one program, we have like around five or six new compounds that target different angles of low-risk MDS. It's early, but is very excited to have this kind of drugs for this patient population where in the past, actually, we didn't really have access to any significant, you know, studies or new entities, for group of patients with low-risk disease. So it's actually quite exciting, right now, for clinical research in low-risk MDS and the fact that, you know, we have big important approval with Reblozyl and maybe good drugs coming in the pipeline for second-line drug, imetelstat, and some of these other phase one, two drugs that are ongoing. So I think it's really good times for low-risk MDS.
Alice Houk:    Thank you. And one final question, these drugs, Reblozyl, luspatercept and the others that you mentioned are all being developed through patients participating in clinical trials. Can you talk about the importance of patients considering clinical trials if they are eligible?
Dr. Garcia-Manero    First of all, we should be grateful to the patients for agreeing to participate on, on those studies. They are cumbersome and it's a huge effort for them. So we are very grateful to the patients and their families for this, but the reality is, they cannot be progress in this disease unless we develop these drugs. In other words, we cannot have these new agents unless the physicians design and conduct good studies, and the patients and their families, you know, agree to do this, of course. And do we use something that is safe and logical, and every patient is different, so we need to target those studies for a specific clinical situations, but I think that for a disease that they saw heterogeneous as MDS, that's probably one of the main issues where we’re so slow developing , uh, drugs. And the fact that the disease affects a little bit older population, sometimes not in the best, um, condition to travel to one academic center or some place where they can do this kind of research that, maybe a little bit of hesitation in terms of participating on those trials that I totally understand, but if you think about, for instance, the effort that the patients that were part of the COMMANDS trial or the MEDALIST trial did, and realizing that this was a randomized study where some of the patients actually got into the control, it was not placebo. It was, in this case, with epoetin alfa, but the fact that then this drug now is approved worldwide and  I hope this is gonna have for all our patients with low-risk MDS, it tells you how important is to be on those studies. So we should be thankful to, to the patients, but they need to recognize, also, how important it is to consider those studies. So we can move the field and provide them with the drugs that they deserve for their betterment.
Alice Houk:    Thank you, Dr. Garcia-Manero, for sharing your time and expertise with all of us. You can find out more-
Dr. Garcia-Manero    It's my pleasure.
Alice Houk:    You can find out more about MDS treatments on our website at www.aamds.org, by following us on Facebook, Instagram and Twitter or by calling our helpline at 800-747-2820. This concludes our program.