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Iron Metabolism in Myelodysplastic Syndrome (MDS) · EHA Unplugged

• 0:06
  Greetings and welcome to EHA Unplugged, the official podcast
• 0:10
  channel of the European Hematology Association EHA.
• 0:14
  Hello, today we are going to have a discussion on iron
• 0:19
  metabolism and its role in EO 2 processes in MD's and we're
• 0:25
  lucky to have two experts in the field here, Elena Ginsburg and
• 0:30
  Amit Verma. And please, Elena and Amit, will
• 0:33
  you please introduce yourself? I'm a physician scientist at the
• 0:37
  I Can School of Medicine at Mount Sinai in New York.
• 0:41
  I study iron biology in the laboratory and it's crosstalk
• 0:46
  with erythropoiesis both in normal and dysregulated
• 0:50
  conditions, and I see patients in the iron disorders and
• 0:55
  erythropoiesis disorders spectrum, both anemia and
• 1:00
  polycythemia there. Yes, thank you.
• 1:04
  Good. Morning Amit Verma.
• 1:07
  I'm at the Albert Einstein College of Medicine in
• 1:10
  Montefiore Medical Center. I work in MD's both clinically
• 1:14
  and in the lab, and we have worked on the role of various
• 1:19
  oncogenes, stem cell alterations, and iron overload
• 1:23
  in MD's models. Thank you very much.
• 1:28
  So I think just to get started because we we're different types
• 1:34
  of people listening here. So I think, I think I would like
• 1:38
  to start with the clinical question.
• 1:40
  So, so in which patients would you actually MD's patients,
• 1:45
  would you recommend iron chelation and, and how do you
• 1:48
  consider that with respect to the effects and and the cost and
• 1:52
  so on? How would you prioritize?
• 1:54
  Do we have a an opinion on this? Yeah, I can start and take a
• 2:01
  stab at this. So MD's patients can broadly be
• 2:05
  grouped into two major categories, a lower risk form of
• 2:09
  MD's and a higher risk form. The lower risk patients mainly
• 2:13
  suffer from low blood counts and anemia is the predominant
• 2:18
  clinical presentation which effects 95% of patients.
• 2:21
  With MD's we have some drugs that help with anemia but none
• 2:27
  of these are curative and most patients relapse.
• 2:31
  So transfusions becomes a mainstay of treatment for these
• 2:35
  patients and with transfusions these patients develop iron
• 2:40
  overload. So iron overload is a big
• 2:43
  problem for MD's clinicians and in lower and intermediate risk
• 2:49
  patients we have this problem very significantly.
• 2:55
  We face this problem because of the need for transfusion
• 2:59
  dependence. So iron collation does present a
• 3:05
  very attractive therapeutic modality, especially for lower
• 3:08
  risk patients, because these patients are going to be
• 3:10
  dependent on transfusions for many, many years and they face
• 3:15
  prospects of end organ damage from iron overload.
• 3:20
  Yes, which gives us an opportunity also to discuss how
• 3:24
  to select patients for iron chelation.
• 3:27
  And so firstly, one would need to consider the diagnosis of
• 3:32
  iron overload, which of these patients are iron overloaded and
• 3:36
  which less so and the standard discussion in the clinical
• 3:41
  field. And Ahmed, please also add that
• 3:46
  transfusions in the range of 20 or ferritin above 1000 tend to
• 3:53
  be clinical markers that are easily accessible and in the
• 3:58
  centers where MRI is available or other more specific
• 4:04
  modalities that allow us to directly measure organ iron
• 4:08
  concentrations, these become more attractive direct measures
• 4:14
  to diagnose iron overload when they are available.
• 4:19
  And then the other are things like life expectancy and the
• 4:23
  expectation of survival for one to two years is the minimum to
• 4:30
  bring the the bring up this therapeutic modality to attempt
• 4:36
  to treat these patients. Yeah.
• 4:40
  I think this is also what I'm sort of used to.
• 4:45
  I think we have slightly higher limits like 1500 for Ferton and
• 4:50
  and and but also the two years life expectancy.
• 4:54
  What about do you have any age limit to when you iron chelate?
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  MD's is a disease that predominantly affects the
• 5:04
  elderly. So we don't in our practice, we
• 5:08
  don't necessarily have any age limits.
• 5:12
  The chelating agents are generally well tolerated.
• 5:15
  You know, they they are associated with some side
• 5:17
  effects which we can talk about, but they are generally well
• 5:21
  tolerated, especially when given in the oral form.
• 5:24
  So we don't really have an age limit for their use.
• 5:30
  What is the major side effect that you worry about actually
• 5:34
  with these drugs? Yeah.
• 5:37
  So you have to be careful that you're not dosing patients who
• 5:41
  have renal compromise. And also some formulations may
• 5:47
  have some gastrointestinal side effects and may also be
• 5:52
  associated with a dry mouth. Some newer formulations do have
• 5:58
  less of these side effects, but generally overall they're
• 6:02
  they're well tolerated. Yeah.
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  So, so it gives us an opportunity to kind of go
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  through the list perhaps there are three, four approved oral
• 6:14
  iron chelators at least in the US There's death for all the
• 6:19
  parental administration. There's deferral prone which is
• 6:23
  an oral agent dosed three times a day which is not approved for
• 6:28
  MD's at the moment as well as defroxy defrocerax.
• 6:36
  So there the and that is dosed once a day and I think Ahmed
• 6:41
  that's the one you were already alluding to defrocerax in it's
• 6:45
  two formulations, one with the gastrointestinal added benefit
• 6:50
  of lower side effects as well as the original one.
• 6:55
  Yeah. So do you experience good
• 6:57
  compliance for with these drugs? Is that the same for all three
• 7:01
  formulations? Because I think that's
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  important. I think since patients are
• 7:06
  having this for a long, long time, compliance become more and
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  more. That's a very important
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  question. We generally don't have problems
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  with compliance. These patients do understand
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  that I don't overload can be deleterious to their health.
• 7:23
  The pills are relatively easy to take.
• 7:27
  That's the main step for treatment in our clinics
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  presently and we don't have major problems with compliance.
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  The issue is the the efficacy, you know, the problem is if a
• 7:39
  patient is transfusion dependent and is on a regular transfusion
• 7:45
  schedule, for example, gets 2 units of RBCS every two weeks,
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  they get a massive, I don't overload every time they get a
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  transfusion and the iron chelators do work, but they work
• 7:58
  quite gradually. So you have a slight decrease
• 8:02
  with sustained dosing and then suddenly you get a transfusion
• 8:08
  and then it goes up again. So overall, it's, you know, a
• 8:12
  tough problem to solve because these agents do work, but they
• 8:18
  don't work dramatically rapidly. Secondly, yeah, that's very,
• 8:23
  that's very important to think up for also when you treat us as
• 8:26
  a physician, maybe we should so, so you have touched upon the low
• 8:31
  risk MD's. Are there any situations where
• 8:35
  ironculation is recommended and high risk or where you would
• 8:39
  recommend the ironculation and high risk?
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  Now high risk patients, the the main problem for them is
• 8:48
  transformation to acute leukemia.
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  So the goals of therapy become, how can we prevent this
• 8:55
  transformation to acute leukemia phenotypes.
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  And the mainstay of treatment presently in the US includes
• 9:04
  hypomethylating agents decytobine and azocytidine.
• 9:08
  The BCL 2 inhibitor venetoclax is being used even though the
• 9:12
  phase three trial, we are still waiting for the results, but
• 9:14
  it's being used and the goals of therapy as I mentioned are
• 9:21
  improving overall survival, reducing the blast count and
• 9:26
  eventually preventing the transformation to acute myeloid
• 9:29
  leukemia. Yeah.
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  The patients that respond to these agents, we do get a good
• 9:37
  response duration and then iron becomes important.
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  So I would say in the acute setting where you're worried
• 9:44
  about blast transformation, iron may take a backseat, iron
• 9:48
  chelation may take a backseat. But as these patients respond to
• 9:51
  therapies, iron overload does become important.
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  And what emerging issue in these patients is if they have bone
• 9:59
  marrows that are quite heavily iron overloaded, there is
• 10:04
  science that shows that they have an increased amount of
• 10:07
  reactive oxygen species. And these and other iron
• 10:13
  metabolic products may actually accelerate the condition, may
• 10:19
  actually make the transformation to leukemia, may make cytopenias
• 10:23
  worse. So iron chelation may actually
• 10:27
  help with that. So scientifically it makes
• 10:32
  perfect sense to do iron chelation even for high risk
• 10:35
  disease, but it has not been borne out yet in in big phase
• 10:40
  three trials. Just to add to that, there is
• 10:44
  also some emerging data that correlatory that the outcomes of
• 10:52
  transplant stem cell transplant are worse in heavily iron loaded
• 10:57
  patients. And I mentioned the the word
• 11:01
  correlation because the more severe the disease, the higher
• 11:04
  the transfusion burden, the higher the likelihood of iron
• 11:07
  overload. And the question still remains
• 11:10
  if you control that iron overload, whether trans trans
• 11:14
  transplant outcomes would in fact be improved.
• 11:18
  But that concept is an important one to look at, as Amit is
• 11:22
  saying, whether the iron overload itself is contributing
• 11:25
  in the niche, in the bone marrow niche that contributes to worse
• 11:30
  transplant outcomes in the patients who are eligible.
• 11:34
  Yeah, Doctor Ginsburg brings up a very important point.
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  You know, there are a bunch of studies that have shown that I
• 11:40
  don't overload is associated with it adverse outcomes post
• 11:44
  transplantation and the few patients with MD's that we can
• 11:48
  actually offer an allergenic transplant and a curative
• 11:52
  therapy with an allergenic transplant.
• 11:54
  This becomes an extremely important point.
• 11:56
  Yeah, that is also how we we look at it here, I think.
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  So transplantation and of course the the, the, the low risk that
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  really needs transfusion for years.
• 12:07
  That's the main Yeah, OK. So of course, one of the major
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  concerns we have about iron is, is that the organ damage how,
• 12:22
  how, how, what, what, how did, why does it happen and, and what
• 12:25
  are the consequences and, and can you please elaborate a bit
• 12:29
  on that? Sure.
• 12:31
  I can give you a clinical perspective and Doctor Ginsburg
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  can elaborate on this. These patients with MD's who are
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  I don't overloaded are generally, you know, elderly and
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  they do have comorbidities that include heart conditions, liver
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  conditions, kidney conditions. I don't overload can
• 12:52
  particularly affect the heart as well as the liver.
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  So we we encounter situations where patients may develop
• 13:02
  progressive heart failure. We also encounter conditions
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  where liver function tests may become abnormal.
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  And both of these have a big impact on the patient's, you
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  know, total outcomes as well as prognosis.
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  And how do you follow that? Because now you say, is it so
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  gradually that you can actually just wait and follow the the
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  heart condition or or do you really need to to be aware that?
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  It's a very important point. We, we usually do
• 13:36
  echocardiograms to assess for contractility and ejection
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  fractions. But a lot of times the patients
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  present with symptoms of, you know, heart morbidity and that
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  may be, you know, features of heart failure, but also chest
• 13:54
  pain, which the anemia doesn't help, right.
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  And also, you know, some some fatigue, you know, loss of
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  quality of life. All of these may be linked with
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  slowly progressive heart failure.
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  Yeah. So it's so, So maybe do we have
• 14:15
  to follow them regularly, you think?
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  Or can we just wait until the symptoms are there?
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  Or how do you see it? So as Doctor Ginsburg mentioned,
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  if we have a high ferritin and a patient is transfusion
• 14:28
  dependent, we usually start them on chelation in our practice,
• 14:31
  especially in low intermediate one patients.
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  And we do the heart check UPS as needed.
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  If they start showing symptoms, you are treating them with
• 14:41
  chelation. So you're doing what you can.
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  And you know, if if they do develop symptoms of heart
• 14:49
  failure, then you push the chelation even more aggressively
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  if possible. The the liver, though, is
• 14:56
  usually the first organ to get loaded, and at least from
• 15:01
  thalassemia literature, the the heart is rarely the first loaded
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  organ. But I think what Doctor Verma is
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  is saying is that many of them will have evidence of liver iron
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  overload and then the cardiac symptoms are overlaid more after
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  iron overload progresses over time.
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  And that becomes a new plateau that really does require pushing
• 15:32
  iron chelation to its maximal effect, because the the lower
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  level is attempting, perhaps unsuccessfully, to manage at
• 15:41
  least the liver iron loading, which we follow with pretty
• 15:45
  standard blood tests for ALTAST and synthetic function.
• 15:54
  And you also sometimes do fibre scans, don't you?
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  Or do you, do you use other, do you use other kinds of scanning?
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  So things for for looking at the iron levels.
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  I my personal preferences MRI that really allows you a
• 16:11
  quantitative measure over time to see if you're progressing
• 16:16
  iron overload, decreasing iron overload, or steady prevention
• 16:22
  of exacerbation of iron overload in the liver.
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  But I think your your point may be also about how do you look at
• 16:30
  the consequence of the iron loading in the organ.
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  And sure, fibro scans would be one additional way.
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  So I remember 1 younger patients with bad compliance who actually
• 16:44
  came in into the ward. You know, we did, we had did on
• 16:47
  an echo few few weeks before and he comes in with a complete
• 16:51
  heart failure, 10% EF. And, and, and it's actually what
• 16:56
  I remember there was, it was actually possible to, to draw
• 16:59
  out all the, the iron again by using high doses of intravenous
• 17:04
  yes for all. So, so I think you know, it's
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  important to understand that that this isn't reversible to at
• 17:09
  least to some extent also in the severe cases reversible
• 17:12
  condition. Absolutely, but it's quite acute
• 17:16
  and so one wouldn't want to wait until.
• 17:18
  No, it was awful. Right, you one wouldn't want to
• 17:21
  wait until these peak exacerbations to initiate
• 17:25
  therapy. Absolutely not good.
• 17:32
  How do you so, So can you explain a little bit more detail
• 17:36
  how this iron overload pushes the inefficient Hymatopoiesis?
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  Because that's for me a little bit more complicated to
• 17:46
  understand. And I, I wish we had some slides
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  here actually, because I think we're digging into some very
• 17:51
  complicated mechanisms and maybe you can explain that.
• 17:56
  Well, I can, I can try. So the the general consensus is
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  that iron overload correlates with ineffective erythropoiesis.
• 18:08
  And this is partly due to the consequence of, again, high
• 18:13
  transfusion requiring patients being those that load iron most
• 18:20
  with the correlated increased morbidity and mortality of the
• 18:24
  iron overload that we've already been talking about.
• 18:27
  What we don't know is whether iron overload also directly
• 18:32
  worsens an effective erythropoiesis.
• 18:33
  And Dr. Verma already started alluding to these, these
• 18:38
  partially known elements like the in vitro work and the mouse
• 18:45
  work that has been done that has shown that both iron overloaded
• 18:51
  serum in patients can suppress the proliferation of erythroid
• 18:57
  early progenitors in vitro. And that mouse models with iron
• 19:01
  overload are correlated with worse anemia and instability,
• 19:07
  chromosomal instability in in vivo as well as in vitro.
• 19:12
  So there. And and then of course there's
• 19:15
  iron chelation data that both in prospective and retrospective
• 19:20
  studies that has shown that there is a sub group of patients
• 19:25
  who can increase their hemoglobin and decrease their
• 19:30
  transfusion requirements when treated with iron chelation.
• 19:35
  So but what makes the the responders different from the
• 19:40
  non responders is poorly understood.
• 19:43
  And the randomized controlled trial using deferasirax, the
• 19:50
  Telesto trial actually did not show a decrease in transfusion
• 19:56
  requirements and an increase in in hemoglobin in low and
• 19:59
  intermediate risk MD's patients. So there is data that is
• 20:06
  incompletely doesn't show a complete picture yet about both
• 20:12
  weather and if. How iron overload impacts
• 20:18
  ineffective erythropoiesis. Because there are certain
• 20:22
  pathways you have been looking into, right?
• 20:25
  Could you just quickly say a few words about which pathways are
• 20:28
  important? I mean.
• 20:31
  Doctor Verma. So MD's, you know, the, the main
• 20:36
  problem in MD's, as Doctor Ginsburg said, is ineffective
• 20:40
  hematopoiesis, predominantly erythropoiesis, but also
• 20:44
  myelopoiesis. So the patients have low blood
• 20:46
  counts. We have and others have studied,
• 20:50
  you know, the molecular pathways that may cause this blocking
• 20:54
  differentiation and suppression of normal hematopoiesis.
• 20:59
  And there's a lot of inflammatory pathways involved
• 21:01
  in this problem. And one of the pathways that's
• 21:04
  involved in this is the transforming growth factor beta
• 21:08
  pathways. So TG of beta pathways.
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  We and others have shown that TG of beta signaling, namely smash
• 21:16
  signaling is over activated in MD's bone marrows.
• 21:20
  And when you interrupt that, you can relieve the differentiation
• 21:23
  blocks and cause increases in blood counts, at least in
• 21:26
  experimental models. And there's emerging data that
• 21:30
  iron overload may also interfere in this process via different
• 21:34
  mechanisms. So there are investigational
• 21:39
  papers that show that iron overload can increase reactive
• 21:43
  auction species, which can be damaging, lead to chromosomal
• 21:46
  instabilities like Doctor Ginsberg mentioned.
• 21:50
  But also there are pathways involving mediators such as
• 21:55
  hepcidin and Dr. Ginsberg can elaborate more on that.
• 21:59
  That can also modulate the SMAD signaling pathways and does lead
• 22:04
  to further bone marrow suppression.
• 22:07
  Yeah, that's what what I sort of was thinking you would talk
• 22:11
  about. So maybe, Doctor Ginsberg, could
• 22:13
  you please tell us a little bit about this?
• 22:15
  So Doctor Verma and I recently published a paper looking at the
• 22:20
  effects of defer prone, specifically the iron chelator
• 22:24
  defer prone in a myelodysplastic syndrome mouse model, the one
• 22:29
  that's if extensively used, sort of the the favorite model in the
• 22:35
  field that showed that we could target how iron is delivered and
• 22:43
  trafficked and sensed within the erythroblasts.
• 22:47
  So we can see that ferroprone decreases reactive oxygen
• 22:53
  species, specifically in erythroblasts.
• 22:55
  We can see that it changes the delivery of iron, transferring
• 23:00
  bound iron to the erythron. And we hypothesize that iron
• 23:08
  chelation as a group, of course all lower ferritin and iron
• 23:16
  loading in the parenchyma. But the affinity of the iron to
• 23:21
  the chelator may be additionally important, so that rather than
• 23:27
  binding iron and removing iron, which they all do, the the goal
• 23:33
  may be rather to bind iron, remove it from an intracellular
• 23:38
  compartment, and deliver it to transferrin.
• 23:42
  With now emerging data that the the kind of transferon that is
• 23:48
  found in circulation when bound to transferring receptors on
• 23:54
  erythroblasts can alter the EPO responsiveness in a different
• 23:59
  way. And so modulating specifically
• 24:02
  the compartment in which that iron is contained and how it's
• 24:07
  delivered can alter how the erythroblasts themselves
• 24:13
  proliferate, differentiate, and apoptose as a consequence.
• 24:18
  Very interesting. So will that sort of be a new
• 24:21
  target for therapy, you think, or can it can can that be
• 24:24
  modulated in some way? Well, we're certainly aiming in
• 24:29
  that direction, but this is preliminary mouse data and it
• 24:34
  requires being viewed in that context that this is, we're not
• 24:41
  by any means suggesting that we have novel therapy, but I think
• 24:45
  it opens a door for a deeper understanding perhaps for how
• 24:51
  iron chelation in a subset of patients does in fact reverse
• 24:56
  ineffective erythropoiesis in low and intermediate risk MD's
• 25:01
  that's. Very interesting.
• 25:04
  Yeah. So about your mouse model, can I
• 25:10
  just can you just elaborate a little bit on that?
• 25:12
  So, so I know you say it's the most commonly used, but it's
• 25:16
  also develops into AML quite quickly, is that correct?
• 25:21
  So it's really a good model for low risk MPs.
• 25:25
  Is it so it the it's a very important question.
• 25:28
  It therefore it allows us the opportunity to look at a early
• 25:34
  phase as well as a later phase. So the literature suggests that
• 25:39
  the mouse model transforms and not in all cases, but the the
• 25:43
  likelihood of transformation increases at the seven month
• 25:47
  mark, which is about half the life expectancy of a normal
• 25:51
  mouse. And so then therefore we analyze
• 25:55
  our animals at the five and six month mark prior to the
• 26:00
  transformation to AML. Another caveat that is a vagary
• 26:05
  of animal models is these are not transfusion dependent mice.
• 26:12
  And it is also true in MD's that prior to transfusion, the
• 26:17
  mechanism of the communication between ineffective
• 26:21
  erythropoiesis and iron metabolism leads to an iron
• 26:25
  overload phenotype that can be observed most clearly in the
• 26:30
  ring sitter blast subtypes of MD's, but is occurring in all
• 26:35
  the different IPSS categories. So that this model, this mouse
• 26:44
  model mimics in some ways the earlier phases of MD's, the less
• 26:50
  severe forms and in other ways the more severe forms, and can
• 26:56
  be used as a model not in a vacuum of other kinds of data,
• 27:02
  but to to discover for discovery and for testing.
• 27:10
  So So what is the genetic defect in that mouse?
• 27:12
  I forgot about it. It's it's called the NUP Hawks 3
• 27:19
  model. Doctor Verma, do you recall
• 27:22
  offhand? Yeah, Yeah.
• 27:23
  This is a translocation between NHD 13 and Hawks.
• 27:29
  And you know, this is a genetic defect that's seen in some some
• 27:35
  patients with MD's. It's predominantly seen more in
• 27:38
  pediatric cases. Yeah, but we do see some adults
• 27:42
  with this particular. So it's not the classical MD's,
• 27:46
  you know, defense we know no, because it's very difficult with
• 27:50
  mouse models in MD's. Isn't that correct?
• 27:52
  Absolutely. So that's a very important
• 27:55
  point. We do not have great mouse
• 27:58
  models that recapitulate the phenotype of MD's and this
• 28:03
  probably is one of the best ones to model MD's in in vivo
• 28:08
  setting. Very interesting.
• 28:11
  Yeah. So, yeah.
• 28:15
  So based on all of this, do you think we, well, we talked about
• 28:19
  a little bit before, you might think about new targets for, for
• 28:23
  ironculation or new targets for MD's therapy?
• 28:26
  I think it's two different things maybe, but but still if,
• 28:29
  if this is does really does improve hematopoiesis.
• 28:35
  So do you think we can we can come up with new suggestions,
• 28:39
  not now maybe, but in time, full time your suggestions for
• 28:44
  treatment, do you foresee any new treatments in low risk MD's?
• 28:49
  Because low risk MD's is really difficult.
• 28:52
  Yeah, yeah. So there's a lot of research
• 28:54
  happening right now. I can give you a very brief
• 28:57
  treatment landscape of low risk MD's.
• 28:59
  So we have the erythro pointing based treatments which can
• 29:05
  include EPO as well as the long acting form which is known as
• 29:10
  Aranes. These are used for patients that
• 29:14
  have a low baseline EPO. We also have Revlimid which is
• 29:20
  Lenalidomide which is only used for patients with five Q minus
• 29:25
  deletion. And then we have lispateracept,
• 29:29
  which was initially approved for patients with refractory anemia
• 29:33
  with ring cytoplast or with an SF3B1 splicing mutation, but now
• 29:38
  has a broader approval for MD's for all subtypes.
• 29:43
  And very recently, a drug called imelistat, which is a telomerase
• 29:49
  inhibitor was also approved by the FDA.
• 29:52
  That being said, the hypermethylating agents,
• 29:55
  decitabine and azacitidine are also sometimes used by
• 29:59
  clinicians and maybe in slightly lower regimens, lower intensity
• 30:05
  regimens than what we use for aggressive MD's.
• 30:09
  But that's, that's basically the treatment landscape.
• 30:12
  There's a lot of research going on and patients, people you know
• 30:16
  P is, are trying a lot of investigational therapies that
• 30:20
  are being in used in trials that are targeting inflammation, you
• 30:25
  know cytokine signaling as well as the inflammasome.
• 30:28
  But we don't really have robust clinical results yet.
• 30:32
  So these are not FDA approved? No SO.
• 30:36
  I also think that the the targeting of ineffective
• 30:39
  erythropoiesis is really the niche more so than direct iron
• 30:45
  chelation. If we're going to research how
• 30:49
  to manipulate iron, it would be only from my perspective, with
• 30:53
  an eye towards the communication between the erythroid
• 30:58
  compartment and the iron metabolism compartment, because
• 31:01
  the real target is ineffective erythroporesis.
• 31:05
  The chelators that we currently have are doing a great job
• 31:08
  chelating. Can we push them to be more
• 31:11
  potent so that we canmore effectively decrease the iron
• 31:15
  load of the transfusion burden? Of course, that would be a
• 31:19
  wonderful unmet need, but I would still venture that
• 31:24
  targeting the ineffective directly to enable avoiding
• 31:29
  transfusion or reducing transfusion burden would be the
• 31:33
  direction that I would take for development in the field.
• 31:37
  Yeah. That sounds like a very good way
• 31:40
  to go, I think. Yeah, because we've been doing
• 31:44
  the other thing for many, many years actually.
• 31:46
  And this is probably where there is something to that can also
• 31:49
  improve the disease itself. So that sounds nice.
• 31:53
  Yeah. So do you think are there any
• 31:56
  important questions we haven't touched up on that you would
• 31:59
  like to discuss? I think we've done a great job
• 32:06
  bringing out the important clinical and translational
• 32:09
  issues with our insulation. It continues to be a very big
• 32:13
  problem and a problem that's not easy to fix in our field.
• 32:18
  So I would encourage, you know, scientists and industry to come
• 32:24
  up with better and more powerful solutions for our elation
• 32:29
  because it continues to be a massive unmet need in in our
• 32:33
  patient population. Exactly.
• 32:36
  And it's and it's a growing patient population really.
• 32:38
  So yes, yes. And do you have something to
• 32:43
  add? I think you've done a great job.
• 32:46
  I'm very happy. Very good.
• 32:50
  But then, then I want to thank you both of you, Doctor Ginsburg
• 32:53
  and Dr. Obama for taking the time and on behalf of ESAI
• 32:57
  really want to to thank you for participating in this very
• 33:01
  interesting discussion. So thank you very much.
• 33:03
  Thank you. Thank you, Doctor Grombeck.