The material below is Continuing Medical Education sponsored in part by Omeros. Both presenters are consultants for OMER and others, like ALXN, but Laurence is more for OMER. I am going to copy the whole thing for those of you who want to see what they are telling MDs who deal with transplant patients who may exhibit TMA, and what they are telling them about it, and its treatment.
Dr. Laurence, near the beginning, tells the MDs enrolled in this course that about 20% of HSCT patients have this problem. Omeros on the other had, in their presentation slides, estimates it to be 40%.
Omeros admits that there is a problem with defining the disorder because there was never any real approved treatment... yet if you read the course material below, they discuss the treatment of this poorly defined problem... and you can see there are already a number of treatment options (or they'd have nothing to discuss).
Once narso is approved it will be the only approved treatment. But if the addressable market is half the size, so will be the revenue. Perhaps when narso is successful, it will help define the problem better and the addressable market will increase to Omeros' estimate of 40% of allogeneic transplant patients. This is an unknown.
What is not an unknown is that if people treating these patients think there are only half the cases, fewer cases will be treated than we'd estimate going by Omeros's figures (which may be an estimate of AM after it has been better defined). If you are a futurist who doesn't care about the time value of money, the Addressable Market in 2025 or 2030 may be of interest, but it is not to me, because present value declines very substantially over time... and I am interested in what happens soon. This year and next year.
When I try to get an idea of 2021 revenue and 2022 revenue, I care about the current real market size and how much narso will sell.
Will the doctors treating HSCT-TMA give up the non-narso drugs they currently use to adopt narso, right away?
IMO very few will do it right away. They will wait to hear the experience of their colleagues who are brave enough to try something new.
I am concerned whether there is actually 100 eligible patients a week or 200. IOW is it 20% of patients or 40%?
The first earnings report, showing narso revenue is much more likely to be a disappointment and cause massive dumping of shares if there are minimal revenues. The same will happen when Q1'22 revenues are reported, is Omeros estimates are too high and their own consultants are contradicting them (Jeffrey Laurence in this case...Jodele is still not really on the Omeros team).
If you read, or at least skim the educational materials below, you will see that, even though HSCT-TMA has no approved treatment, narsoplimab has and will have competitors they must displace. It will not be as easy as saying "narso is safer and more effective". As we know, for superior market performance, you need to do better than expectations, especially when you are from the wrong side of the tracks, as OMER has been market-love-wise.
Updates in HSCT-TMA: New Therapies and What They May Mean for Patient Care. Authors: Jeffrey Laurence, MD; Sonata Jodele, MD
Jeffrey Laurence, MD: Hello, I'm Jeffrey Laurence, professor of medicine at Weill Cornell Medical College in New York. I want to welcome you to this program titled, "Updates in HSCT-TMAs: New Therapies and What They May Mean for Patient Care." And joining me today is Dr Sonata Jodele. She's a research professor of pediatrics in the Division of Bone Marrow Transplantation and Immune Deficiency at Cincinnati Children's Hospital Medical Center. Welcome.
First, I want to provide an overview of HSCT-TMA. As in all thrombotic microangiopathies, they're characterized by recognition of a microangiopathic hemolytic anemia, thrombocytopenia, and at least 1 damage to an organ. These occur in about 20% of allogeneic stem cell transplants in adults. Dr Jodele is going to talk to you about her experience in children, including autologous stem cell transplants.
Traditionally, we've said that about half of these TMAs may resolve following withdrawal of a calcineurin or mTOR inhibitor. Recently, that has become controversial, and some people believe that you do not need to stop the mTOR or the calcineurin inhibitor, and that there is much less of a chance you're going to get resolution of those TMAs by doing such as a simple maneuver. The most important thing to remember is that outcomes are quite poor when these TMAs persist.
Now, there are multiple risk factors for TMAs occurring in the stem cell transplants: infections, and the big 3 are Aspergillus, cytomegalovirus, and adenovirus, but any infection may trigger one of these TMAs; a high-grade (> grade 2) of graft versus host disease; the use of preconditioning radiation; the use of calcineurin and mTOR inhibitors, as I mentioned before; as well as advanced age, female sex, and the extent of the HLA mismatch. And the most important thing, in terms of recognizing these TMAs and the fact that there is a wide disparity in terms of incidence among different groups reported for these TMAs, is how you define them.
There are several working groups that have listed a variety of criteria. All of these working groups require evidence of hemolytic anemia that's microangiopathic, so recognition of schistocytes is very important on peripheral blood. The teaching point here is just look at the peripheral blood every day when you suspect a TMA. Schistocytes may not appear until many days after an inciting event. Platelet counts should be decreased. Different groups have different criteria about exactly how much a platelet count should be decreased, but most of them say at least about 25% to 50% of the baseline for the patient. LDH should definitely be increased, as evidence of any hemolytic anemia. Haptoglobin, we ordinarily think of as being decreased in a hemolytic anemia. The teaching point here is that haptoglobin is also an acute-phase reactant, so that a haptoglobin of 150 mg/dL, which we may consider within your normal range, could be low for patients whose haptoglobin really ought to be 1000 mg/dL.
There could be an increasing transfusion required, both the red blood cells and platelets, and different groups specify effects on organ function differently. So, some working groups have said that you're required to have an increase in serum creatinine, while other people recognize that might happen a little bit too late in the course of the disease. You should check for proteinuria, microscopic hemoglobinuria, and hypertension -- new hypertension -- as evidence of an incipient TMA. Direct Coombs test, if specified, should be negative, the caveat here being, if you have a multiply transfused patient, the direct Coombs may be positive in the absence of a hemolytic anemia.
Coagulation studies should be normal, and we're not talking about DIC, another type of thrombotic microangiopathy. We're talking about a stem cell transplant-associated TMA. And then, finally, if you measure the ADAMTS13 activity, they should be within the normal range. And virtually all TMAs associated with stem cell transplantation are not of the TTP variety. They're more of a complement-mediated disorder that is much more like an atypical HUS. Therefore, your ADAMTS13 should not be < 5% to 10% of normal. Given that introduction, Sonata, perhaps you can continue. What are some of the unique aspects of stem cell-associated transplantation in your pediatric population?
Sonata Jodele, MD: Thank you, Jeffrey. It's definitely important to discuss the unique aspects of pediatrics vs adults since we're collaborating very nicely on TMA projects at this time. In children, we've been running several prospective studies, and we have some better understanding of the presentation, risk factors, and diagnostic features. As you were mentioning, the diagnostic criteria are slightly updated in the pediatric population. So, in our prospective studies, we noticed that some features like LDH, proteinuria, and hypertension present very early in children with TMA and could give a hint that this problem is evolving. Also, we noted that proteinuria and complement activation serve as the high-risk features in pediatric TMA that currently we use for diagnostics, disease activity assessment, and therapeutics.
It's very important to understand the differences from adults, so we can work together. And in children, we know that disease-specific risk factors exist. Some children's immune deficiencies are at much higher risk of developing TMA, which with adults, technically, transplant occurs in more patients with malignancies. That would be very interesting to assess in the adult population. We also noted clearly that Black race is associated with high risk for TMA. We assume that should be across ages, but we still need to study this. So, I think it's very important for us to work together and to try to replicate some of the information we obtain in pediatrics in the adult population.
Dr Laurence: Thank you. Now, I've mentioned before that the TMAs in the stem cell transplant setting are not of the TTP variety. They're more complement mediated, and we'll delve a little bit more into the complement pathway later, but Sonata, could you provide an overview of the currently available, although they're off-label, approaches for the treatment of stem cell-associated transplant TMAs?
Dr Jodele: Currently, the best we know of the therapies are from complement inhibition. As we showed in our prior work, that complement system is very important in the pathogenesis of TMA. We know that it's not the only pathway that's active in TMA, but it's the pathway that we can intervene. And I will summarize just a couple of sentences. As we know that injury occurs in TMA from many factors in transplantation -- it could be from infections, as you mentioned, from chemotherapies. And when we injure the endothelium, the endothelium tends to activate the complement system, and the terminal complement activation, again, is destructive to the endothelium. So, this is 1 of the systems that we know is involved in pathogenesis. And we now know that all 3 complement pathways -- lectin, classical, and alternative -- are also involved in the pathogenesis of TMA, which is kind of different from other thrombotic microangiopathies.
We have some targets we can use there for our treatment of TMA. The best we know so far is about terminal complement blockade, and mainly in pediatrics, our most experience is in using eculizumab, which is a C5 blocker. So, this eculizumab, at least in our institution, we treated 64 pediatric patients, and I want to note we only offered this therapy to patients with very high-risk TMA, those who met the high-risk features -- this proteinuria and complement activation.
Those patients, untreated, as based on our prospective studies, had very poor survival. Their 1-year survival was 16.7%, and overall survival was < 10%. So, these patients required some attention, and by using eculizumab in a PK/PD-guided dosing strategy, we were able to improve those survivals up to 66%, which it's a good effort compared with their poor survival, but it's still not ideal because we would like to get better. Again, those were very, very high-risk patients, so not across-the-board all TMAs that were just diagnosed. As you see by the percentage, there was a lack of response in some patients. Definitely, we need to understand better how to use complement blocking agents in our population, and maybe we have to also understand other pathways so that we can do combination therapies, and those studies are currently ongoing.
Dr Laurence: Thank you, Sonata. I want to emphasize 2 important points that you made. The first is that, in the pathophysiology of these disorders, the inciting event appears to be in the fetal cell damage. In fact, if you look at most of the risk factors for these stem cell TMAs, things like the calcineurin and the mTOR inhibitors, things like accompanying radiation, things like graft versus host disease and certain infections, damage to the endothelium is often an inciting event.
The second thing is that you spoke about is that there are 3 parts to the complement pathway: the lectin pathway, the alternative pathway, and the classic pathway. At the moment, most physicians, as you said, have been treating with eculizumab as a C5 inhibitor, blocking the alternate pathway of complement. I'm going to talk now about the lectin pathway of complement because the lectin pathway of complement is activated whenever there's tissue damage, endothelial cell injury. You expose certain molecules, known as DAMPs, which serve as binding sites for proteins called MBL, which binds to an enzyme known as MASP-2, and MASP-2 is a protease, which activates the lectin pathway, which amplifies the alternative pathway of complement.
And so, it not only sets up a proendothelial cell injury milieu, but it also sets up a proinflammatory milieu. And then, finally, MASP-2 is also involved in the activation of prothrombin to thrombin. So not only are you damaging endothelial cells in the process of forming a TMA in the transplant setting, but you're setting off the coagulation pathway, and you're activating a complement component that perpetuates the activation of the clotting system. So, you get this positive feedback loop between endothelial cell injury, complement activation, particularly at the lectin pathway, and activation of blood clotting. And if you can't shut that off, you eventually may develop the disorder that we call a TMA. And that's one of the rationales for looking at specific inhibition of MASP-2 and the lectin pathway of complement in these disorders.
And one of the first studies to look at this was the use of narsoplimab, which is a monoclonal antibody that specifically targets MASP-2 and prevents its activity. And it's already been evaluated in a single-arm, open-label trial. It's given intravenously as a single infusion once a week, and it was either given for a total of 4 weeks or a total of 8 weeks in the setting of a documented stem cell-associated transplant TMA. And these were in adults, with 28 patients so treated. Their mean age was 48, and 71% of these individuals were male.
And the findings from this study, presented earlier this year, was there was a 61% complete response rate in the set that was fully analyzed and a 74% complete response in those patients that stayed and completed the protocol. And for the purposes of this study, a complete response was defined as clinical improvements in laboratory markers, such as platelet count and LDH, and either improvement in an organ function, such as the kidneys or the brain, or freedom from blood and platelet transfusions.
The 100-day survival postdevelopment of a TMA was 68% in all patients in this trial, but 94% among those who completely responded to narsoplimab infusions. The median survival in the full set was about 270 days, and the median survival actually has not yet been reached in those who completely responded to narsoplimab. All of this occurred in the setting of no major adverse events, and there's going to be a follow-up of this at the European Hematology Association meeting this summer in 2021. It also documented the marked increase in platelet counts and the marked decrease in LDH in patients with stem cell-associated TMAs treated with narsoplimab. So, we know that the lectin pathway of complement is an active player in the stem cell-associated TMAs, and that an inhibition of this pathway, an inhibition of MASP-2, appears to be a good thing to do in terms of clinical response and laboratory markers, but there are other potential targets in these TMAs that may also be of interest. And, Sonata, could you summarize for us some of these?
Dr Jodele: Yes, several drugs are now in the pipeline, so it's still coming back to complement inhibition. I wanted to mention that there's a phase 3 trial on ravulizumab in pediatric and adult patients, which is a long-acting eculizumab. There's also another terminal complement blocker called nomacopan or Coversin, which is a bifunctional inhibitor of C5 and also leukotriene B4, that also blocks terminal complement activity. There are very few cases of TMA in transplant patients treated with those drugs, so, for both, we should definitely study the pharmacokinetics of these drugs in the bone marrow transplant population, including children and adults, since these medications were not really studied yet in our population, and as we know, our patients usually process and use the drugs in a different way.
I also wanted to mention that there've been some anecdotal data in defibrotide maybe working for TMA. We know it's a good drug for VOD, which is another endothelial injury syndrome. I think we need to understand how to use this drug since patients with TMA have a high risk of bleeding, and one of the side effects of defibrotide is bleeding, but probably if it is used early enough, it could be a drug to study.
Definitely, you would want to mention plasma exchange, a procedure that has been used in the past with some success. I think the main point in our experience with plasma exchange is that, if you use it early, it could be helpful if you use it in certain situations when patients have pretty high cytokine storms. One thing to remember is that plasma exchange removes certain medications, so you cannot combine all therapies with it. You need to be thoughtful about it.
Also, we are now studying and looking to other agents from other pathways since we know, in TMA, the interferon pathways are involved, and also neutrophil extracellular traps are gaining attention to be evaluated as an inciting factor for complement activation in TMA. Hopefully, those studies will be coming in the future, but none of these pathway drugs are yet in the TMA world in the bone marrow transplant population.
Dr Laurence: Thank you, Sonata. Those are very important points. I actually want to add a caveat to the use of plasma exchange in this setting, at least in adults, in that 3 large studies, 3 large international studies that looked at the efficacy of plasma exchange in adults with established TMAs found an excellent response rate in terms of increases in platelet counts, in terms of decreases in LDH, in terms of increases in haptoglobin. The issue was that there was absolutely no difference in survival whether you use plasma exchange or you didn't. So, in the vast majority of these patients, at least the adult patients in these studies, plasma exchange made the numbers look good. The patients died, but they died with normal numbers. And it's an important thing to consider, not only in the transplant-associated TMAs, but also in atypical HUS in general, where the use of plasma exchange has a remarkable ability to change a lot of the hematologic parameters but may not ultimately make an impact on survival.
I think the novel therapies you mentioned are quite important, and they're going to be investigated. People have also looked at the possibility of combinations of therapies, maybe using something affecting the complement pathway in combination with something that may affect platelets, such as defibrotide, which could be of use, but all of this is experimental.
In terms of talking about side effects for some of these interventions in these stem cell-associated TMAs, it's important to recognize that there are certain clear differences. For example, eculizumab requires the use of prophylactic antibiotics to prevent development of certain infections. In adults, these are usually limited to Neisseria meningitidis and N gonorrhoeae, but in the pediatric population, there are also other encapsulated organisms that you may need to prophylax for, and certainly immunize against, both in the adult and pediatric population.
Narsoplimab is a little bit different. Narsoplimab does not require the use of prophylactic antibiotics or vaccinations against these organisms. And, as Sonata had mentioned, defibrotide may be associated with some bleeding risks, so it's something to watch out for. Also, in terms of differentiating the pediatric and the adult populations when it comes to making a diagnosis and potentially predicting outcomes, children are different than adults. And Sonata, could you address that in terms of the stem cell-associated TMAs?
Dr Jodele: Yes. I wanted to mention about our experiences with predisposing genetics, especially at complement genes. In pediatrics, we performed a prospective study looking at complement genetics and fingerprints in predisposing patients to TMA. We noted that quite a few patients, about 65% of those who developed TMA, had at least 1 variant in the complement gene panel, and we specifically structured the gene panel for 17 genes from what we usually test in HUS and other diseases. An interesting observation was that it was not 1 particular gene that predisposes patients to TMA, but a clustering of those variants. So, it's important to note that probably this variance, in regular life when you're not undergoing such a procedure as a transplant, would be irrelevant to life or cause any illness, but under such acute stress like a transplantation procedure, those variants increase susceptibility to TMA. And patients, especially of Black race, there's multiple complement variants, and they have very severe TMA, and they usually succumb to this disease.
So, clustering of the variants, and the more variants you have, the more susceptible you are to this complication. In adult teams, very nice work from Dr Gavriilaki in Greece has shown that in the adult population, there are similarities. There are also complement variants and ADAMTS13 gene variants in the adult population. Interestingly, both studies showed that the recipient DNA, and not the donor DNA, is what matters. So, I think this is important to remember since when we transplant our patients, then later when they engraft the donor cells, the blood is already from the donor. So, the 1 obstacle and 1 challenge, looking at genetics, is that you need the recipient's DNA, and that DNA either must be obtained prior to transplant like when we do an HLA typing or a buccal swab, but it still could be contaminated with donor cells.
But, interestingly, adult and pediatric studies showed kind of similar findings that complement genetics predispose those patients to TMA. In patients with multiple variants in the complement or in ADAMTS13 genes, there is increased risk for toxicity from TMA and transplant. So, this is something to keep in mind, but I think we are striving to find some functional studies that would be reflecting genetics that could be done quickly and at any time after the transplant, so we don't have to go back to genetics, which is a much more cumbersome test to do. So, we're striving to identify such a test.
Dr Laurence: Thank you. I think the last point that you mentioned is especially important because in our own study here at Cornell of adults who develop persistent TMAs after allogeneic transplants, we found no reported published mutations in complement or complement regulatory genes, but we found multiple unpublished polymorphisms in both ADAMTS13 and in the complement-related genes. It's just, in the absence of functional studies, we don't really know what their meaning is. And 1 more thing, the only time where you may also need to do not just the recipient genetics pre-transplant, but the donor genetics, is in the face of a complement regulatory protein that is on cell membranes -- that is perhaps a donor who had an MCP mutation where you transplant that kidney, and that potentially, I guess, could be at risk.
Dr Jodele: Interestingly, you mentioned about the published vs not published variants. And when we did the in silico modeling and when we looked at our patients, some of these variants were very functionally active in our RNA-seq studies, even though, in the databases, they're listed as nonpathogenic. So, I think we still need to learn what's important in our patient population. And, again, it's a stress vs susceptibility balance. In HUS, for example, you have a high genetic predisposition, and you don't need much stress to present with disease. Well, probably in the transplant setting, you have an underlying predisposition, and this very severe transplantation stressor provokes it much better than regular life events. So, I think it's still to be confirmed, and even though we don't do genetic testing as of yet as a standard procedure, or we might not do it in the future, I think it just teaches us a lot about functionality and what to expect in certain populations.
Dr Laurence: Very important points. Thanks.
At the moment, I would say that our key takeaway is that 1 of the most important things you can do in terms of exposure to a transplant-associated TMA is to make that diagnosis early. Recognition of this disease will permit earlier intervention. As you mentioned, perhaps using the plasma exchange early on will do something when later studies have not found benefit. So, recognizing the signs and the symptoms of a stem cell-associated TMA and how they may be different in adults and pediatric cases, as you've pointed out, Sonata, is very critical.
The second thing is, because these are so unusual -- and even many transplant surgeons that I talk to who have referred patients to our unit are not familiar with these TMAs -- seek expert opinion. If you have a difficult case, talk to all of us, people who have had more experience maybe than you do in your particular center in terms of the recognition and treatment of these disorders. And, again, additional trials with agents that block various parts of the complement pathway and continuing trials with narsoplimab are very important to the ultimate cure of this disease.
Sonata, thank you for this great discussion, and thanks to the audience. Thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.
original content ©2020 to 2021 by Alan Robert Ross
Founder, Trust Intelligence
The foregoing is not investment advice.