 So now it's a great pleasure to introduce the next panel and our moderator. The panel is Rare Diseases and as a leading company in rare diseases, an area for which I also as a medical geneticist seeing patients with these rare diseases over my clinical career have a great passion for and with 7,000 rare diseases and 400 million people across the world affected by one of these rare diseases. In fact, rare is not so rare with 5% of our population having one of these diseases. 80% of them are genetic and unfortunately, we only have therapies for 5%. So that means 95% of patients who walk around with the rare disease are untreated. 50% of these are kids and 30% of these individuals fail to live beyond their childhood years. It's a really sad area, but it's an exciting area. If you actually combine specialty and rare diseases, about 50% of the investment, 50, 50% of the R&D investment in our industry is targeting these diseases, diseases that for which only 2% of patients take medicine. So there's great hope for the future. And with that said, it gives me a great privilege to introduce the moderator of this panel, an old friend and the chief scientist at Biogen. If there's anybody of all the great people and all the famous people and brilliant scientists that we have today, there's anybody that doesn't need an introduction given the events of the last four to eight weeks. It's Al Sandrock. And I'll say that it's been great to see the dialogue that's ensued with this approval of Adju Kananab and however you feel about this approval, whether you agree with it, whether you disagree with it, however you feel, no one could argue to the great passion and advocacy that Al has brought to the table. And he's championed really what he believes in. So Al, going from a common disease now to rare diseases, I'll hand the panel over to you. Thank you very much, Andy. Thank you for your kind introduction. I have a fantastic panel. And I'm so excited to get going on this discussion. You have their bios, but I think you'll agree that they are fantastic. And I also have two additional people who are going to help me with questions as well, Lina and Tim. And so let me get started. I want to start with the patient and ask Liji to start with, you know, he's the founder of the Lulu Foundation. And what got you, what prompted you to start the foundation? And what would you have to say to the people in the audience here and the folks on the panel in terms of the patient perspective? Thanks, Al, and great to be here and a big thanks to Karun and Andy for making it happen. So I'll just give you a quick summary of our seven-year odyssey just because it's quite representative of many rare disease patient odyssey. So just over seven years ago, our eldest daughter, Alia, was born, was born totally healthy. And then 10 days later, she had 10 seizures. And we went through a diagnostic odyssey that took many months and were finally diagnosed with CDKL5 deficiency disorder, which is a rare neurogenetic disorder causing epilepsy and developmental delays. And I remember at the time, you know, we were distraught. We were in the hospital, my wife and myself and I said, look, 10 years ago, we wouldn't have even known what was wrong. And 10 years from now, hopefully this will be a treatable disorder along with many others. And she said, I want to be 10 years from now. And I said, well, we are the generation of humanity that needs to get from the knowledge of the genomic age that is already there to the ability to implement that therapeutically. So we launched the Lulu Foundation and with clear goals. And I think that's an important first lesson. You have to set your goals and we set treatments in five years, symptomatic treatments and cures plural quote unquote within 10 years. And that was back in 2015. And I think our objective was really kind of laser focused on how to de-risk our indication for industry. We quickly realized that actually it's industry that makes that makes the drugs, but what do they need? And the three elements that we focused on, which I'll just summarize, the first is building a patient community, a one of partnership, one that's cohesive. So when when Ali was born, we were told there were a few hundred patients in the world. We now know many thousand. The incidence rates now well defined at one in 42,000. So it's actually tens of thousands of patients potentially. But then we have a global alliance of patient groups over 20 now. And we really built on some of the excellent work they did. But we learned from from other indications the importance of remaining united and cohesive. The second step was funding the science. And we have a grant program. And we partner with the orphan disease center at the University of Pennsylvania who helps us implement that. And our CSO is based there. But also building the toolkit in parallel. So that might be the models, whether it's cellular models, better animal models, also the clinical infrastructure, better patient registry, an endpoint study in ICD-10 code, educating the regulators on what this disease is, both the FDA and the EMAs. And the third one is engagement in parallel. So the old idea, which has never really been true anyway, that you need to first work on the science and then engage with industry down the line once you get more answers. I don't think that's true of any disorder really, but it's certainly not true in rare disease. So we took the decision to engage early and often with industry, with the regulators. We have a symposium. We host an online app to keep scientists connected. So today there's a better biological understanding. We have the toolkit. We've had multiple trials. Still no approved drug, but hopefully soon. But we also have exciting proofs of concept pre-clinically of mice that have had the condition reversed with gene therapy. Also some theoretical transgenic approaches. But we've always seen that ultimately our customer is industry, but what do we need to bring together to make it happen? Thank you, Majid. That's very compelling. Beautifully articulated the ecosystem that you figured out how to navigate essentially. And I think what you just said for the Lulu Foundation applies to many, many other rare diseases. It's very similar to what I heard from the SMA Foundation in the early days as well. And so thank you very much for that. I'd like to ask each panelist, Majid mentioned the revolution and genomic medicine and Andy did too. But what has enabled us to actually tackle rare diseases from the technology point of view? Maybe I'll start and then maybe you can list some of the successes as well. So I'll start with Kathy. Well, thanks. And I think I would name as a critical foundation scientifically the human genome project and the ability to identify the genes that cause so many of these rare diseases. And I think part of the hope of the human genome project had been that that by identifying these diseases, we would greatly expand therapeutic options for people born with serious inherited diseases and at least part of that hope had also centered on gene therapy. And of course, as you know, in the in the event, it took a good deal longer to work out successful gene therapy than it did to sequence the human genome. But I do think that now with a handful of approved products for serious genetic diseases, approved gene therapy products for serious genetic diseases, what seems especially exciting to me is that over the last couple of years, we've begun to hear about very promising data in late phase clinical trials for what I would call the more common rare diseases. For example, sickle cell disease, thalassemia, hemophilia, Duchenne muscular dystrophy. And so some of these diseases that really affect very large numbers of people are in phase three testing with promising results. And so I think we are poised to move from gene therapy as a treatment for a handful of ultra rare disorders, pediatric neurodegenerative diseases, inherited retinal dystrophies and so forth, to more common inherited diseases. And so I see that as a sign of progress for the field. Thank you, Kathy Frank. Do you have any thoughts on this? Yeah, I would add to what Kathy said. I think the Human Genome Project was really a landmark for giving us the encyclopedia of the human genome and the genes. And I think another really important technology events that's enabled us to be where we are today is the sequencing technologies. I think it's amazing today that we can sequence a person's genome for a few thousand dollars. And that gives us a tremendous amount of information and has probably, you know, been watershed in our ability to diagnose these rare diseases. And, you know, the implementation of that is, I think we're really at the tip of the iceberg as far as seeing what we can do with that. And my hope is that that would lead to newborn screen sequencing basically at birth so that we can treat patients prophylactically rather than treating them, you know, after they have symptoms on sets. And then, you know, the other aspect is, you know, drug discovery technologies. And, you know, my field has been in antisense oligonucleotides. And, you know, the sequence information has been critical for us to really leverage the technology that we've been working on for 30 years and applying it now to these rare diseases. And as you know, we're beginning to see some success come out of that effort there. Thanks, Frank. John and David, do you have anything to add in terms of what has enabled us to tackle rare diseases? Yeah, I would just add, Al, in addition to the new technologies and sequencing of the human genome, which has clearly accelerated our understanding of the biology and therefore new targets in rare disease, I'd like to highlight the Orphan Drug Act itself because that was really revolutionary in terms of the investment creating incentives for developing new therapies. Prior to its authorization in 1983, there were only less than 10 therapies actually that had come to market. Since its approval in 1983 to the end of 2020, we've had 599 Orphan products developed and approved to treat rare diseases. So that's absolutely tremendous. And it's interesting that over the past 15 years, Big Pharma has really jumped into the fray of their dominant force in this sector right now, clearly for various reasons, including addressing their pipeline and engineering competition. Thanks, John. David? Yeah, Al, the only thing I would add is non-scientific, but the internet. And again, it's many things. But with all this amazing science and ability to diagnose, understand the biology, the challenge for many of these communities is that they're just not organized and they're too small. So whether you're the patient being diagnosed and you're suddenly alone and who do you talk to, how to get information, whatever, that's all been enabled. And importantly from a clinical development standpoint, as many conversations with patient organizations, if you can do anything to increase your chance of having a cure, it's organize yourself and the internet's been foundational to that. Thanks, David. Well, one thing that was sort of was touched on but not really talked about was prices, drug prices. And each one of you in the industry are aware of this, but how important is that to enable this or to continue to sustain it? And are there any clouds on the horizon that you'd like to highlight that may impede our progress? You know, we talked about successes, but is this assured? Is this sustainable? Who wants to start? David? Maybe I'll dive in. I think I fanged up early. I mean, we all, I think we're all concerned about this. You know, it's under the sustainability of the model. And if you go back to the early nineties, I'm being one of the pioneers here. At that point, when we were discussing, you know, the treatment of precochet that one of the first rare disease treatments that came forward, it was a price at a very high level, you know, for the world, it was, you know, sort of unbelievable, how could that work? But society really embraced that. They understood that the pricing was a function of rarity that, you know, if there wasn't a price that allowed a company to recover on the work that went into it, and acknowledging there's a very small number of individuals who might benefit, in a sense, society had to step up. So the foundation was laid there, but we've come a long way. And I think it's, you know, this model, it's not guaranteed, it's not magic. And increasingly, the rules around rare diseases are the same as the rules elsewhere, meaning that we have to demonstrate value. There has to be clear value. Just because you have a treatment for a rare disease doesn't mean that you should be, you know, reimbursed. It's what is the value you have created for that individual patient or that individual community. The second thing I think we need to be thoughtful about is industry pricing in general. I think from an industry perspective, there's this societal contract, which says, yes, you're going to pay more for the drug when it's first approved and over its patent life, but then it will go off that. And you, society, we will all have that drug for a fraction of the cost forever more. And I think in the rare disease world, that evolution hasn't fully played out, in part because many of these are biologics and they have their own challenges in terms of going generic. But I think as a community, we have to think about how do we fulfill our side of that societal contract that says you're going to pay more in the beginning, but it's not a lifetime contract at that same price. That's a really good. Yeah, go ahead. If I could just jump in here and just add something to what David said. You know, I do think as a society, we have a challenge here. If we applied the current model to the remaining 7,000 or so rare diseases that still have no treatment, we'd have a big problem because healthcare budgets are finite and we're already experiencing some challenges with pricing and market access. So we need to come up with innovative market access solutions and maybe that involves some kind of public-private partnerships that takes the onus off the private sector entirely or partially. That also keeps the incentives for developing new therapies for rare disease. And the model for gene therapies is of course evolving rapidly, but we shouldn't apply traditional or outdated approaches to assess the value there. The most important distinction here being that gene or cell therapies or other regenerative therapies are intended to be given as a one-time treatment with long-term benefits versus the traditional product therapy that requires recurring payments. So the value of these new one-time therapies needs to be demonstrated using non-traditional approaches. So standard cost-effectiveness frameworks don't fairly represent the overall value of these treatments. Thanks, John. Before we move on to the next question, I wondered if Brigitte had a patient perspective on what we just talked about. Yeah, so I totally agree with John's point. There does need to be innovation. I'll take it away from the paying side to the approval process and the regulatory side. I just think that the way the trial design and the hurdles, certainly efficacy still has to be proven up, but the way it's done for smaller populations like rare diseases just has to be different. It's too much of a burden now relative to the population size, and that's what drives the cost up, which ultimately affects the price and of course the time to development. The other thing I would add is I think with some of these new technologies, gene therapy, gene editing, there are some common infrastructure needs which government can step into. It's starting to. There's an NIH initiative that was announced a couple of years ago, but beyond just sort of vector manufacture, actually trying to crack the knot of delivery into key organ systems. Once you've done it overall, then hopefully it's not going to be quite as straightforward as plug and play, but you will see an acceleration of progress for multiple indications. So there are some areas where government spending can really move the needle quickly as we've seen it can with COVID-19. Thank you very much. I want to now move on to ultra rare diseases, and I'm even though Tim is here to be a questioner, I'm going to also treat him sort of like a panelist, but we talked about rare diseases, but then we have the ultra rare and sort of the end of one, if you will, or the end of a few. What are the issues associated with that? I'm going to ask Tim to start how he thinks about that as he practices medicine, but also how he approaches thinking about therapeutic therapeutics, and then maybe also ask Frank to talk about and more. Excellent. It's a pleasure to be on this panel and to follow up all these distinguished guests here. I think that as a geneticist and neurologist at Boston Children's, we get approached a lot by families, especially those with disorders that no one has ever heard of that haven't made it to perhaps the stage of having a foundation like Majeed's that haven't made it to the target profile portfolios of companies like yours, Al. And they're in that early stage of looking for help, looking for scientists and looking for industry partners. And I wanted to come back to the point that John made about public-private partnerships, that as we think about this long tail of ultra rare diseases, and there are many, the great majority of the 7,000 different genetic diseases have incredibly tiny populations. How do we see, it's clear that the populations are so small, the patients that are coming to us often will tell us that there may be only three or four other patients like them that their doctors are aware of in the world. And so how do we incentivize the activities of these public-private partnerships? How do we band these groups together? What we try to connect a lot of these families to one another, and there's been ideas floated, for instance, by Andrew Lowe at MIT of forming a national CRO to coalesce under an umbrella many ultra rare diseases. Do you see, how do you see that working? Given that we have experts here who have seen single disease efforts really well incentivized under their current system, how do you imagine this working under a larger umbrella organizations like that? John, I think he was asking you. Well, you know, I do think we need something like that, a framework that creates this umbrella so that we can sort of defray and share the cost of developing therapies for these ultra ultra rare diseases. At Alexia, we kind of, you know, some of this is related to pricing strategy, and when you are able to capture more patients in a particular platform, obviously, you have a lot more flexibility on the pricing side. So that's the direction we've taken because there hasn't been something like this in place to incentivize us to go into those ultra ultra rare conditions. So absolutely endorse the need for that. I don't exactly know what the solution is, but honestly, but it's something that we need to apply some effort to. Go ahead, Frank. Yeah, so one thing to consider is how expensive it is to identify and develop a drug. And, you know, one area that we really haven't talked about is ways that we can increase the efficiency of the process. And, you know, it's, you know, just the discovery of the molecule that you're going to be using for a drug consumes teams of people to partake in that. And, you know, one of the areas that we're really interested in is really, you know, thinking about machine learning technologies that we can really capitalize on past experiences to be able to make it a much more efficient process for the discovery. That's just really the starting point. And I think everybody on the panel recognizes that the discovery of the drug is actually the cheap part of the process. And the expensive part is the development and showing that it has clinical utility. And, you know, I think that the point is that, you know, for these rare, ultra rare diseases, we need to think differently about how we're going to demonstrate efficacy. And, you know, maybe even go back to the point where we may not need to demonstrate efficacy. What we have to demonstrate is no harm to the patient and, you know, or reframe how we're trying to approach going forward with the technology. And, you know, we have a foundation that our CEO, XCO started staying pro called Enlorum Foundation. And we spent quite a bit of time thinking through this issue about the benefit risk and how do we, you know, continue patients where there may be just one patient on treatment and Tim had to deal with this. How do you justify continuing to treat that patient with a medicine that could have some adverse effects and getting that balance right. And I think those are the kinds of discussions we need to have to really advance the field and advance where we can treat many more of these patients out there. Al, one additional thought there just to pile on here. I think the disease foundations and the patient advocacy organizations can do a lot to support drug development and rare disease more broadly maybe not the ultra ultra rare, but somewhere in between by creating disease registries that will bring a better understanding of the natural history and disease progression because with a lot of these diseases we don't really understand and we have to define and refine clinical endpoints, PROs that can serve as a basis for regulatory and approval and market access. And so there's a clear gap there that is quite a challenge for companies to pursue if that hasn't been, that groundwork hasn't been laid. That's a good point. Sorry, David, did you want to say something? Yeah, just one quick point. I just want to go back to Frank. So the risk benefit issue, I think this is, you know, back to regulatory frameworks. We do think there's a bit of a cookie cutter and, you know, you have to have and Tim's already, you know, this standard, you know, expensive approach and Tim's already proven, well, that's not true. You know, it can be done and risk benefit, of course, and small populations, you can think absolutely differently, right, about the overall risk benefits. So that's a key component. And the other thing I think about is for these ultra rare organisms, entities, it works if we can leverage something. And the question is, how do we incentivize the party that has something to leverage to allow it to be used? And so you can think of R&D tax credits and the like, right, which is to say, you know, if I've got a technology delivery, Majid, you mentioned delivery is an issue, right? I mean, I might be a company that has, you know, I don't have anything to do with rare, but I see that I could contribute to that. And if somebody told me I could get a significant tax credit, you know, align R&D tax credit, I might throw my hat in the ring. Somebody else has got manufacturing expertise and, you know, they can devote a reactor and get a tax credit. I might do that. Yeah, I know it's like, those are good points, David. It seems also that all these innovations and genomics and in terms of therapeutic modalities, gene therapy is Kathy pointed out and all you can do three times as Frank did. And even potentially do efficacy type studies with registry comparisons to natural history. It's exposed some of the bottlenecks, though. One of the, I think, frankly, you were telling me that one of the most costly and time-consuming aspects is the pre-clinical safety. And that has a major innovation in toxicology that I know of anyway, and maybe I just don't know, in a long time. And I know that the FDA has put new guidelines in that has reduced some of the hurdles, but it still takes a long time and it's pretty costly. Yeah, me for, in Lawn Foundation, we're trying to develop individual therapies for patients free of cost to the patient. The most expensive part of the whole process is the IND or the talk studies that would support treating the individual patients. And as I'll point it out, there really hasn't been any change from doing, luckily the FDA has reduced it to a single species, instead of having to do two species and they'll allow rodents for the single species. But you still have to do extensive talks work that adds cost to individual patients. And we're getting to the point where patients are having bake cells to raise money for talk studies. And I know Tim said to deal with that a bit as well. Thanks, Frank. Look, we only have five minutes left. It's amazing how quickly time flies. I wanted to ask Lena if there were some questions that she would want to ask the panelists at this point. Yeah, so, you know, our focus in TMA Precision Health, which is a company representing here, which we created based on our experience, because I'm a patient with a rare disease, and a scientist and an entrepreneur and all that. So, but something that I have realized is that, yes, 80% of rare diseases are monogenic and probably targeted therapies are going to be good for those. But there is something that we rarely think about and is that rare diseases and many of them are syndromes. And they are present with different types and different, yeah, that the patients are confronted to different development of the disease. So, what we are doing integrating now information, you know, and then basically what we can understand is analyze the patient journey and then identify the segment, you know, segment the patients and really understand how they move forward and how what are the patterns of disease presentation that we can anticipate how to control and better treat those patients. And I think that we came to realize that information that we gather is crucial for drug development and for clinical utility as one of the panelists was mentioning. So, what I want to raise here is the how can we use that information that companies like ours are gathering from the primary care before we actually go to the before the disease is totally identified because we actually help as well to identify the disease and if there is a gene involved etc. But what is most important is these patterns of presentation and these patterns of presentation allow us to understand better diseases that academics can do more work in terms of understand targets and then pharma can do a better approach of patient to take a therapy rather than molecule to therapy. So, I would like to sort of put that information on the table and get the discussion trigger for that. How can we use better than information in pharma? Precision phenotyping perhaps. Frank touched on something that he talked about newborn screening and he wondered whether that could really improve things, accelerate this area. And you know, we have only now just finally gotten the last few states to do newborn screening for spinal muscular atrophy even though drugs have been available for years. And that's sort of the catch point too that you can't get newborn screening until you have therapy. But I wonder whether Frank you were suggesting that you could accelerate this whole process if we had newborn screening that was more comprehensive and I wondered whether each of the panelists would have a view on that. You know just one thought is you know as I mentioned the sequencing cost or getting to the point where we can consider sequencing at birth for every every baby born. And you know the issue that I think we struggle with is that there's a lot of sequence information that's not actionable today. But yet the sequence isn't changing. And so maybe one way to approach this is that you have a book with your sequence information and every few years when there's scientific advances you kind of go back into the book or your physician goes back into the book and identifies maybe you know at this point you need to get more exercise or you need to change something in your lifestyle that could impact your health you know 20 or 30, 40, 50 years from now as you know science advances. And it seems silly not to do you know new total genome sequencing rather than do a piecemeal for only the diseases that are actionable today. Or maybe not if not newborns at least some systematic process whereby for example any unknown rare disease any patient that presents with something that's unknown perhaps should at least be considered for genetic testing or for... Yeah, may I just add I think it's more related to natural history of the disease what I'm mentioning rather than pre-screening and genotyping everybody especially for underserved communities that you know that's probably an impossibility to get genotype everybody but natural history is so important. So can we follow those patients learn from it and then try to better type rare diseases and then identify the target. But you can combine the two where you're you're collecting a rich natural history that's sort of tied to your your genome history. Right. And you know I think that will be actionable at some point in the future. And just to follow up on Al's point about genome sequencing you know I do think that in pediatric genetics people are moving to this more and more quickly to avoid the kind of diagnostic odyssey that Majid talked about for his daughter and so I you know I think that's that's not so far away. Application to the entire population you know I'm not sure we're going to see that right away. So just just just to add to that I mean it totally would be just our example our disorder you know it used to be 10 years plus the age of diagnosis in our case it was about six months now it's a matter of weeks more and more and there are more hospitals applying that you know any child into the NICU they do the sequencing first before the whole odyssey but actually the UK government this week is having a public debate on whether every newborn child should be sequenced. So it's not that that's beyond the realm of the possible but certainly every child with something clearly wrong at birth that's becoming far more straightforward and unusual. Thank you. Well it's 1022 I don't know whether Andy and Caloon are going to let us keep talking because I think we could talk all day about this very exciting area. Why don't you end at 1025 and then we'll move on. Okay all right wonderful. Are there any do you in terms of gene therapy Cathy do you see any advances that could sort of replace the current therapies for example I'm thinking about gene editing. Well I think that actually some of the results that are coming out from clinical studies using gene editing and I would cite for example the sickle cell results from CRISPR and others to me are proving the the worth of gene editing approaches and I think that base editing is not far behind and I think that what will be important for people interested in gene-based therapeutics is to understand the best ways to combine and utilize or choose among the options that we have and everything from mRNA, anti-sensical nucleotides and gene replacement and gene knockdown to gene editing and base editing and so I think the proliferation of gene-based strategies is only a good thing for people with rare disease. Thanks Cathy I was thinking that you know there must be criteria at each company on which diseases to tackle and put into their pipeline and you know for us at Biogen for example we have taken on SOD1 mediated ALS along with IONUS even though only one or two percent of patients with ALS have it we estimated the prevalence to be about 500 or so when we started the program in the US. Tim talked about the ultra rare you know the ends of one to five to ten that and Lauren I think is tackling is there a gap in between the ultra rare and the 500 to a thousand plus that we haven't addressed? I think one of the age old beliefs about rare diseases was it was an entry point to larger diseases I think A that may be true I mean you know we may be able to apply a gene therapy to a rare disease and run a maybe a quicker trial I think that's better than misnomer but but I do think that the expansion so for example rhythm right now the company I'm at we're looking at rare genetic diseases of obesity the first genes that we are studying literally there's you know tens of people that we are pursuing for you know in the US at the current time but the number of genes that may be benefited is much larger and so the whole research plan is to work through those different genes and try to understand that incremental opportunity so I think a company has to decide are they are they in that disease and trying to pursue it to its natural end following the science or they in it to simply get to something else and there are two different things I just wanted to I'll just you know sort of a message of hope as Andy said that you know just five years ago and we started none of these things were approved and now we already have multiple approved gene therapies as well as for rare disorders such as your own for for SMA and even I remember that conversation with my wife being told that you know Alia was missing one letter from one copy of this gene and she said can't we put it back and I said honey that's not how DNA works and today we're actually working with a lab with prime editing to do precisely that and the field has moved so far in just these few years I think it is very exciting and hopeful well on that positive note it's past 10 25 it begins and ends with the patient thank you very much Majid and I want to thank all my panelists for very stimulating and wonderful conversation I'll turn it back over to Andy thank you very much Alan thanks to all the panelists and I'm going to hand this to Karun to kick off our polling thank you Andy thank you Al wonderful panel can you put the polling slide please for the rare diseases writes what measures are most needed to accelerate drug development in rare diseases Paul starts we have 50 seconds to Paul please go ahead the question is what measures are most needed to accelerate drug development in rare diseases next year Karun will need some elevator music during this one minute period yep or the jeopardy song exactly yeah for them well everybody and welcome back thank you for participating in our polling if we could please please bring up the polling results so that we can share them with the audience and I'm just going to bring this up on my screen so I can read it there we go great so the question that each of you addressed was what measures are most needed to accelerate drug development in rare diseases and actually I was suspecting that this one would be more even than the results have turned out and it looks like the majority in almost 50 percent of you Paul believe that the most needed activity is to more use of real-world data for rare disease patients to understand natural history of disease and disease heterogeneity so thank you very much for participating in that poll