 It's a pleasure and a privilege to introduce Steve Uden, who's the co-founder of a new company called RallyBio. Previously, Steve was a leader in the rare diseases at Alexion. Steve is going to take us through perhaps one of the most exciting areas in all of the biopharmaceutical industry, and that's rare diseases. Steve, with that said, I'll hand it over to you to introduce the panel and kick it off. Thanks very much, Andy. I think seeing we've got quite a challenge, it's been a great meeting despite this being virtual. The conversations have been great. Andy and I are just sharing, just prior to this, how well things are going. Let me introduce the panel that's here today. Many of the panel will be well known to everybody here. In no particular order, David Meeker, currently CEO at Rhythm, but prior to that at KSQ, and then of course was the head of the Genzyme unit at Sanofi for many, many years. David, thanks for joining us. Dan Curran, who leads the rare disease therapeutic area unit at Takeda. Dan and I have interacted quite a lot since we've both been in his team since we've formed RallyBio. It's great to be on a panel with you, Dan, and to catch up. Of course, prior to that, Dan was at Millennium. Al Sandrock needs absolutely no introduction. I think he and I, every time I've been at this meeting, Al and I have been on a panel currently head of R&D at Biogen. When I was doing my rehearsal, I already said you're the CMO, David, forgetting your new role. I think that someone we're really pleased to welcome is Matt Willse. This is Matt's first time at the US India Chamber of Commerce. Interestingly, Matt's background is in Silicon Valley, so I'm hoping he's going to bring a very different view to the whole conversation. He's an entrepreneur and investor, but he's also the founder of the Grace Science Foundation, with a particular focus on our research and supporting patients and their families with NGLY1 deficiency. Anyway, without any more introduction, I think we ought to get on with the discussion. I think we've got a lot of very interesting topics to start with. I think I'm going to start off with perhaps what I think is one of the biggest changes in R&D since I've been in the industry, which is around the engagement of patients and their parents in research and development and the work we do, which certainly when I was joining the industry, I was always saying, if you ever suggested that, you'd say, why on earth would you possibly want to speak to a patient? I think probably rare disease has led the way, so it would be great to perhaps start with you, Matt, with your thoughts about what is the impact of rare disease on families and how families and groups like yours can really contribute to the whole process of bringing new therapeutics to patients with these rare diseases. So, Matt, let's get going. Thanks, Steve, and I'll keep my comments relatively brief at the start, because I'd love to have it be interactive. But Grace's disease is angloid-1 deficiency, as you said, and it's one of the rarest in the world. There are only 70 patients that have been identified. And Grace is 11 years old now, and we were told when she was born that she wouldn't make it past five. And when we started our journey, there weren't many advocates like us, the usual sort of suspects, John Crowley, or Brad Margus, Dine Crescent, Lauren Ang. There weren't many. There was no playbook or plan for us to follow. And now there is an army of sophisticated and highly talented parents, advocates, and organizations jumping into the deep end on basic science, doing animal translation, fundraising, IPOs, IND packages, manufacturing, the list goes on and on. And these new leaders are really driving innovation, and they're getting multiple therapies into the clinic. And these therapies are real. They're improving the lives of the patients. And equally important, they're saving people and their families. These rare diseases are so devastating, so isolating. There's really no one that can relate. Again, only 70 in the angloid-1 world. But I think also importantly is these diseases are unlocking basic biology that is so paramount for all of us and our loved ones. And without that investment in rare, we're not unlocking the more common indications. And the number of organizations has jumped dramatically. But more tools are needed. More collaboration is needed. These organizations are really desperate to work with a lot of the companies that are represented here today. And we sincerely need help. And I just closed my initial comments by saying that these organizations carry a lot of hope. Today, it's a very dark day, obviously, with COVID, and these times are so uncertain. But these organizations, I think, are real beacon for what's possible within science and medicine when silos are broken down. And I think... Sorry, Matt. Sorry, Matt. Just a couple of sources to how quickly it was you sort of had this idea and got moving. I mean, what you say is absolutely spot-on. The number of organizations has blossomed. It just takes my breath away, the way that people like you get motivated. Just a couple of words. What was it that just said, hang on, I can do more than just be a parent of a very sick child? Well, I think early on that there's just the never give up. Obviously, we would do anything for our children, right? And I was fortunate enough to be able to focus on it. Not every parent is. But that's where tools come into place, where you don't have to do this full time to make a difference. And I think my mindset, just as a tech entrepreneur, is, okay, well, we'll build the tools ourselves. If no one else can do it, we'll de-risk the disease and either partner with a pharmaceutical company or we'll build our own pharmaceutical company. There you go. One approach. Definitely a tech entrepreneur. So when we were getting ready, Al, in particular, thought you'd like to jump in here. So, Al, your thoughts in this whole how patients, groups and their families have really got involved. Yeah, thank you. Well, we believe that the involvement of patients and patient groups is incredibly important and very, very welcome. In the case of spinal muscular atrophy, we found both the SMA Foundation, which was actually founded by parents of a child with SMA, as well as cure SMA to be absolutely crucial in the discovery and development of transformative treatments. All three of the ones that have been currently approved, they had a hand in the discovery and development of those. But another important point was communication with the patient group. Often we have to do controlled trials and sometimes some people have to get placebo or sham control. It's very hard for patients to understand that, but they help to explain why these kinds of trials might be necessary and the hope is that they will lead to more rapid approvals. And that turned out to be the case for SMA. That's cool. Thanks. And in terms of design of study or identifying endpoints of working, those up, was there much contribution from the field? Absolutely. I mean, acceptability of the design, right? I mean, how patients react, but they won't enroll in the trial. It's not going to get done. So absolutely important. Thanks. Dan, am I correct in saying that you've interacted with Matt at some point in recent history? You are absolutely correct. Yeah. So Matt, it's great to see you. You're very, very modest. I think what you've done with the Great Science Foundation is superlative. And obviously, we're pleased to be able to have the opportunity to collaborate with you. We've been collaborating with the Great Science Foundation now for, I think over three years at Takeda, specifically through our Takeda-Syra or T-Syra relationship. And it's absolutely crucial to get the patient voice as we think about how we want to try to discover and develop therapies for such rare diseases. And it's amazing to see that the sort of the humbleness and the power that can be brought to helping to try to develop drugs for rare disease if you interact with patients and their families. And so we'll continue to look forward to collaborate with Grace and the rest of the families that suffer from Anglite I. Thanks. David, as I said earlier, maybe your experience was different at Genzyme, but certainly when I started out in the career, in my sort of R&D career, as I say interacting with families, did you follow that change when you were sort of in Genzyme and leading that group and working your way through? Yes, for sure. Maybe two examples. I started my career very early on, working on a gene therapy approach to cystic fibrosis. This is back in the mid-90s. And as many of you may know, the Cystic Fibrosis Foundation was the convener of that community, if you will. So academics, industry, and obviously the patients themselves, we're all together. And there were these early nascent meetings with all parties represented just trying to solve the problems, multiple industry companies in a sense competing, but working together. And again, it was the patient, which was the foundation of that group. One other example is, we often focus on the U.S. and what these incredible stories of, like Matt's, where people, families have been able to create foundations and motivate a holistic approach to a disease. But outside the U.S. and some of these smaller countries, the way you got the healthcare system's attention was often with one family who was affected, their physician. We as a supplier of a potentially life-saving drug, and the three of us would go to the healthcare system. And they can tell you without that voice of the family. And the physician is there because they're supporting that family and the affected individual. But it was the patient's voice which got the attention. And so I would say doors around the world were open only because that patient voice was there. I think it's a great example. I think many of us have got that experience where that does make such a difference. And the willingness of families to support us in our mission is fabulous. John, just sort of thinking of your role as a lexion and how do you bring in patient groups, any thoughts about how you weave them into the, as you bring programs forward and think about design of programs or move forward? What's your experience in this space? Yeah, Steve, thanks. So as you know, we're breaking new territory and new disease areas for the company. I think one example is ALS where we brought in the patient advocacy organization as well as individual patients to provide input into the design of the study. It took a little more time up front, but I think in the end it ends up being a much more user friendly program and will help to accelerate our enrollment. The other thing I would say is that I want to highlight the role of Nord in actually facilitating patients and families and organizations to provide some of the impetus for doing significant research and leading to drug approvals. And there are many examples that some have already been cited, but Dushan Musco district is another one where the patients were really central in influencing the eventual approval of the first product. Yeah, I think that group in particular has been incredibly active and successful in the work they do. So if we sort of, and Dan touched on this, and this is this whole issue of getting reimbursement and pricing and what have you, and I think particularly in rare disease, we're sort of entering a very interesting period. I mean, one of the earlier questions today is, you know, what's the big new thing in oncology in its cell therapy? I think there's no doubt rare disease is leading the way or certainly neck and neck with oncology in terms of these new modalities over and above sort of proteins and small molecules, whether it's gene therapy, ASO's like messenger RNA, et cetera, et cetera. It's going to be sort of interesting to think about how payers are going to, how we are going to work with payers in this particular space. So I thought, Dan, you might have a few thoughts about that leading a sort of therapeutic area unit. This must be something on your radar, you know, all of the time. So what's your, you know, how do you see these things evolving as these completely novel therapies coming to play? Yeah, thanks, Steve. And I know it's on all our minds. You know, it used to be in the past, obviously rare diseases were just that and there weren't that many players. And so I think companies could essentially price where they wanted to based on the innovation threshold that they set, because it wasn't really going to hit anybody's radar screen, if you will, at a payer. But now obviously with sort of the explosion of both companies' interests and pursuing rare diseases, it certainly is taking notice of the highest levels of both, certainly the state and the national government level, about the cost of these therapies. And, you know, without waxing philosophical here, it's always been the age old question, what price do you put on innovation? And I think especially, and I hope some of the other panelists can capture as we think about these new modalities, antisense oligonucleotides or certainly gene therapy, and how do we price and how do we capture the value for the innovation that's been created by this industry and indeed by folks on this telecast. It's a real concern, because I think we obviously want to capture value for our shareholders and for our companies, but equally we want to make sure that we ensure access to anyone around the globe for life-saving medicines in many cases. So I think we're going to need to grapple with this even more in rare diseases in the coming days and months as these highly innovative therapies come to market, hopefully, that can truly transform patients' lives. Has Decay to had any sort of specific example to this, or is it something you're just sort of working up as you work on these more innovative modalities, and you're sort of preparing for that? Yeah, I mean, we're definitely preparing for that. We have a number of programs that are in the late stages of clinical development where we think there's an opportunity to truly transform the way a disease is actually treated and essentially become the new standard of care, but these will be lifetime therapies, and we think about the burden of those therapies in terms of cost basis. It's quite astounding, because now it used to be with rare disease, you know, perhaps the patient may live for a few years, and unfortunately would succumb to the disease. With these new therapies, we have the opportunity to essentially completely change the curve of a patient's life. So you hope that you can manage to give a patient 20, 30, 40, even 50 years of life, and the cost of those therapies obviously is one that's going to be borne by the healthcare systems and the national payers. So it's constantly on our mind about how is it that we can actually deliver innovative therapies while at the same time assuring access to patients who so desperately need these therapies. Thanks, thanks. I mean, John, sort of thinking back to my and Dan touched on this, you know, the sort of the U.S. is one particular territory. Thinking back to my time at Alexion, you know, one of the claims to fame was the fact that, you know, Alexion has done such an outstanding job getting reimbursement around the world, you know, revenues almost, you know, there's much revenues outside the U.S. as there are in the U.S. What are your thoughts on this thing? Maybe perhaps taking a more international view of pricing and reimbursement, particularly with these newer modalities. Right. Yeah, so I think it may be worth taking a historical perspective here. If you look at the last 20 to 30 years, every new wave of pharmaceutical innovation has brought significant uncertainty in terms of value, price, budget affordability. And we're going through one of those cycles now with cell and gene therapy. If you will, the first wave may have been chronic mass market drugs like statins and diabetes therapies. They found a way to afford those. Now they're all generic. The second wave were first oncology treatments, again, similar to the first wave. Third wave was targeted therapies, including Perceptin and Avastin. And then the fourth wave was orphan and ultra orphan treatments for chronic disease, including our product for in HNA typical HUS. And, you know, now that's serving as a benchmark for many new products in the orphan space. The fifth wave is really what you're highlighting here, the genetic modalities, the cell and gene therapies. And I would make a distinction between those that are used chronically because some of these like the ASOs and the RNAIs that are used chronically probably are not that different in terms of the reimbursed paradigm compared to, you know, orphan products thus far. But the cell and gene therapies, because there are one time treatment, pose additional and unique considerations. And that's a fundamental distinction because you can apply the traditional outdated approaches to assess the value when you're trying to navigate a number of different pricing and access considerations. And those considerations are different for the U.S. versus international markets. And so the dynamics that they're quite, quite different. U.S. payers are more focused on short permit centers and on their annual budget impact. While in Europe and Japan, many of those countries have single payer systems, they have a very different perspective on long-term incentives. So generally the value of such medicines with long-term benefit is perceived higher. In the U.S., it's difficult to capture the benefits you're going to have five, 10, even 20 years downstream. We don't have the infrastructure to that. So we need to take a look at the valuation of these therapies, very different than traditional therapies. That's a really interesting insight, John. I mean, it kind of almost makes you wonder whether this is something as an industry that we could work on in terms of in the U.S., what could we do to sort of gather those data? Because you make an excellent point, you know, without having the centralized health cases that they have in many European countries. So one thing that Karun put in, one thing for us to address, and I'm going to pick on David to open this one up, because I mean, I think Genzyme really did sort of set the pace in terms of pricing. But there was a report which I'm sure we're all aware of the Institute of Clinical and Economic Review. I had a review and they suggested that some cost-effectiveness of these are therapies is not as high as one would suggest, or as the value they create. And I just wonder, you know, I think David, Genzyme, more than anybody's been looking across, you know, for many, many years, it's been interesting, your thoughts on that, that particular report, and the view of, you know, value and what have you in rare disease. So David, putting you on the spot. In one minute, I'm going to answer that question. I think, you know, I'll just give you a brief history on, you know, Genzyme and Henry Tamir, you know, who was responsible for pricing that first product. And, you know, there's a lot of discussion around, you know, the value of the Orphan Drug Act, which is tremendous, right? I mean, brought attention and, you know, some rights that go with being, getting a drug approved. But arguably, but maybe not even arguably, I think the most transformative event for the Orphan Disease Space was when Henry priced that Saturdays for, you know, the treatment for grocery disease. And he priced it at a level which people found, you know, unbelievable astronomical $20,000 for a full course of treatment at the heaviest weight. But what that did was it suddenly signaled to the world that you could create a business. And, you know, from that moment forward, there was just, I think, a, you know, spiraling increase of, you know, people willing to invest in the different diseases and the like. So that's point number one. Number two is over time, you know, this concept that orphan disease pricing, you know, that's actually, I think, been misunderstood and in some cases abused. The fact that you qualify as an orphan drug doesn't mean you quote unquote, you get orphan drug pricing. The whole principle behind those early drugs pricing was a function of rarity. And so if you're living at the ultra rare end of the orphan spectrum, so, you know, a few thousand patients, that's a very different number of patients who might be served. Then if you're up at 100 to 200,000, and both of those would be categorized as orphan drugs. And so I don't think we've done a great job of recognizing that over time. And so we're in a sense at risk of breaking the contract that we have implicitly with the healthcare systems. And your last part of that, an important part of the question is ICER and how you think about value. So early on, again, Jen's on, you know, we volunteered. We had a discussion with NICE and Michael Rollins, who's had NICE at that time, and we worked with them to test and see whether you could apply the methodology cost-effectiveness to an orphan disease space. And there was a mixed conclusion coming out of that. I can tell you inside NICE, the general conclusion was you could not, at least in that case, because as with many rare diseases, you just lack the data. You lack the national history data. You lack the data on what the healthcare system is spending to care for those patients. They don't live. They die early. Like I said, nobody's paid attention. I mean, it's just there's a fundamental gap in terms of being able to apply the methodology. That said, and what the analysts who did the work would tell you is, it's absolutely not cost-effective. And what Sir Michael Rollins said was he stood up at the end of the day and basically said, look, whether you agree or disagree about the cost-effective analysis, society needs to step up and pay. But his message to industry was you don't have a blank check. And so I think that's a good summary. These will never be cost-effective in a classic sense just because they almost can't be. And so I'll leave you with one anecdote to think about it with. I often ask people, how much did it cost to get the Chilean miners out of the ground? Remember that famous event, 100 people in the ground and people go, I don't know. And that's the point. Given the opportunity to save a life, and we're working in a world that wants to work with us in that context, but we cannot abuse that sentiment. That's a great tour of the force, David. Thanks for that. I mean, I think the great thing that Genzyme did was to completely break this whole paradigm. And I'm certainly speaking for myself, stepping back and looking at the logic that was put in place in terms of pricing. It actually makes sense. And all congratulations. And then the other point that you've made about, this isn't just a blank check for any old Tom Dick and Harry to jump on. And sadly, we have seen that happen. But that's life, I guess. Matt, I mean, it'd be great to get your thoughts, because in two ways. One is, this is your first time here at this meeting. So, but you've come at this in a very, you've come looking at this as a parent and as a you know, a founder of a foundation and from a very different industry. So, I'm just wondering whether, you know, just as an outlier outside looking in, yeah, or an outlier putting on outsider, that's very unfair, an outlier or a yes. I mean, from wearing my tech hat, being a tech entrepreneur, the price of things comes down over time. I mean, as I think about like gene therapy for end-by-one deficiency, it's going to be very, very expensive initially. Not only the R&D cost, but the manufacturing costs. But as manufacturing processes improve, that cost should come down. So, the thing that I have trouble with within the biotech space is that the price should not be static over time. And I think a lot of the discussion that I see actually in the press is not taking that into account. I mean, the first supercomputer cost a fortune. Now, our laptop that I'm speaking to you from today is more high-powered than that. And it's, you know, it's the $1,000 device from Apple. So, where is the savings on the actual cost of goods? And I think that ultimately will make these things that are game-changing, like gene therapy or base editing, are going to be much, much cheaper, long-term. So, I think that's forgotten at least from my perspective in the conversation that I see. Yeah. So, that is a very good point. And then, of course, eventually, you know, the IP, the interesting thing is going to be with these rare diseases. As the IP works out, you know, will they ever generalize? But it's probably, you know, it would have to watch that space. So, Alan, unless you're bouncing up and down in your seat to sort of jump into the pricing discussion, it would be good to sort of move on to it. I think we should now sort of, we've looked at two ends really. We've looked at, you know, the patients and the, you know, the huge demand and desire to do great things. We've looked at the sort of business realities. There is always that thing in the middle, which, of course, is going through the approval process. And it would be, I think it would be good to sort of just open up a discussion about, you know, is the process becoming more complex and, you know, what are your, and how are things evolving in rare disease in general? So, Alan, I thought you might be great guys, just get that conversation going. Sure, sure. I'll begin with by noting that, you know, although FDA is generally very consistent and follows precedence within a given division, there are big differences sometimes between, say, CBER and CEDR and perhaps across divisions. So, my colleagues on the panel may have different views from mine. But I'll say that FDA as well as other regulators really do have a shared sense of urgency, especially for serious and life-threatening diseases. But they're very reluctant to lower the evidentiary bar for approval, just because of the rarity of a condition. For example, we found that there's little to no flexibility on the use of surrogate endpoints that are not clinical endpoints. There are exceptions to this, of course, but that's what we found. With respect to statistical methods, they still require an alpha 0.05 with a two-sided test. And while they recognize the feasibility challenges of enrolling patients into rare disease trials, they do expect you to enroll an adequate sample size to conduct a well-powered study and usually a well-controlled study. Now, having said that, we do think that there's some flexibility. For example, the use of an outcome measure that is completely novel and may not have checked every single validation box, I think they're open to that, although they must be at least based in content validity. There's opportunities for early assessments, for example, by doing interim analyses. And then they welcome enrichment approaches, for example, studying a subset of patients. But when the approval comes, they may actually approve for a broader population than actually study leaving treatment decisions to physicians. So for example, in the case of Stenraza, our ASO for spinal muscular atrophy that was approved in December of 2016, FDA was very collaborative and met with us numerous times to guide our thinking on how to conduct a pivotal study with a novel endpoint and to perform an interim analysis. And moreover, after there was evidence of clear efficacy based on a well-controlled study, they acted very, very quickly approving the drug within three months of completing the submission. So I think they're very collaborative, they're open, but they won't lower the evidentiary bar too much, perhaps slightly. Yeah, I think that's a great point. Although, I would say perhaps another big change in industry and it has been the approach that the FDA is taking. I mean, I don't know if that's your experience, David, but certainly when I joined the industry, it was sort of a combative relationship. I think they are, and I'd be interested in your views, David, but again, you've been through this for quite some time. How is the review process going with all of the complexity around rare disease? Yeah, I agree with Ali. I think it's highly case-specific. I'll just give two quick examples. So CFG therapy in the mid-90s, I talk to my reviewer every week. I mean, it was like the two of us were developing the drug together. And more recently, much more formal, much more difficult to access and get that kind of interaction, despite the new regs that give you special access, etc. And at the end of the day, it comes down to who's sitting across the table from you. It's just people and you get like everywhere else in life. Some people have a view, which is, I'll call it enlightened. They just might call it more open and others are more conservative. And that's the FDA. But you do have the opportunity to appeal up. And that's what I try to get people in my regulatory group to think about is one, it's just people and two, we have more than one shot. You make a great point. The number of, I think we often forget the people aspect of this. I remember talking to a very interesting guy and asking him, but he was sort of a lobbyist and he made the point that one of the failings of particularly R&D colleagues in, again, someone outside looking in is we are hardcore scientists and we're very logical, but we forget that, you know, people like, yeah, they're human beings and they have other agendas and you I think we should never lose sight of that. And they have a tough job, right? And again, this is a science world that's exploding. I mean, we're struggling and you know, quote unquote, if you're buried in it in the expert and they're, they just see everything and how can you be expert in everything? So it's a challenging job. Yeah, I think it's especially true, David, for rare diseases, right? Many of the colleagues at the FDA, they don't know what these diseases even are, much less the course disease. So there is a very significant educational component that needs to come into every interaction with regulatory authorities, not just the FDA, but obviously other regulatory bodies around the globe as well. Because of this, the lack of knowledge in many cases about some of these very rare diseases. I'm so looking at my dashboard, and I can sort of see that, you know, in the people wishing to join the conversation, we've got Tim, you out there who is bouncing up and down as far as I can tell, hoping to join the call. And as usual, we're running out of time. I apologize to everybody. This is always much more interesting. I wish they'd just sort of leave us to discuss it. But Tim, I believe you've got some thoughts about this whole whole space and, you know, some areas Tim. Thank you. Yeah, thanks so much for having me, Tim, you Boston children. So for my question, I want to bring the focus back for a second on patient communities like MAPS, like the NGLY1 community. And it represents lots of others with lots of other communities like it that might have conditions with individuals numbering in the dozens. And even though it's fantastic that we're moving more towards rare and rare indications, we're still at a difficult point with these smaller communities. And so I wanted to ask to our folks on this fantastic panel, do these super rare diseases, are they really the structural blind spots that they seem to be? Do the incentives that we're putting in place, do they allow us to reach, are they going to allow us to reach down further into these ultra rare conditions, ultra ultra rare conditions? If not, are there real practical changes, and some of which you've touched on regulatory financing, reimbursement, clinical, whatever it is, are there real practical changes that would help your organizations go after these even more effectively? Well, I think I know just the person to pull in this, because we were discussing it a week or so, I said, Al, I know you've got some thoughts in this space about ultra rare and how industry can work, or not the ultra rare, I'm calling it the Pico rare. So Al, have you got some thoughts? Well, we've addressed the ultra, ultra rare, perhaps a bit with MLauram that Tim and I are both involved in, where if it's less than a certain number, Ionis has started this thing called MLauram with Biogen, and we will make ASOs for people to try and their patients. It's that intermediate sort of range between, I would say, probably 50 patients to 500 patients that I think Tim might be most concerned about, where you don't have enough of a business case perhaps for a profit, making a corporation to address, and so you either have to reduce costs or increase the revenue, and I don't know how we do that, because we just talked about the payers, and so the increasing revenue piece seems capped, so reducing costs, and that's probably why you bring up regulatory process and other things, but yeah, I think we need more creative solutions. Yeah, and I think that's a great example. Can I add a comment to that? Please do, John, yes. Yeah, I think this is something that probably not just industry shouldn't have to tackle. There has to be greater partnership across other folks like government agencies, patient advocacy organizations, which already stepped up to the plate in many cases, but also academia, at a minimum, preserving the current incentives in the Orphan Drug Act are important signals for the industry to continue to invest in ultra orphan diseases, but it's not enough, because as Al said, the ROI is not there, so we need other partners to help us contribute to the effort. That includes you understanding the disease with registries, natural history, data sets, endpoints that otherwise all fall on industry. It's a big investment to have to do all that legwork, investment in basic research, regulatory requirements could be reduced to a certain extent to that could be more flexibility there. I mean, there are many good examples where, and again, it comes down to people where the agency has been very flexible in allowing you to design programs. In other cases, they've been a little more rigid requiring you to placebo control studies when you're talking about a handful of patients, which doesn't make a lot of sense. And then, you know, helping even in finding patients across the globe to do the trials, that's also a really important aspect of this. Thanks, John. I'm sort of cognizant of the time here because I'd love to carry on with this conversation, but we don't want to sort of ruin Karun's carefully choreographed meeting. So I think we're sort of coming to the natural pause here. Tim, thanks for joining us and thanks to all of the panel. As with the other sessions, there is going to be some polling questions, which we'd love you to answer. So I think they're going to be coming on immediately after this session ends. But I'd like to just take this opportunity to thank everybody on the panel, Dan, John, David, Al and Tim for jumping in to help with the discussion. It's a shame we can't carry on. We've all got a lot of thoughts I'm sure we'd like to share. So with that, I'll hand back to Andy, I presume, at this point.