 Thank you Sandesh. Can you all hear me? Loud and clear? Okay good morning. Thanks Sandesh. Sandesh has done a fantastic job in putting it together along with the team. Jen is April where are you? Without you this wouldn't be possible at all and thank you for really doing a phenomenal job and we're excited about the program. Clearly I think this is a very unique opportunity for us to come together for the greater good of the community of our patients right? That's what we strive to do every day to make sure that if I was a patient today or tomorrow yes I would like to know you know earlier to detect the disease and then hopefully make an impact with therapeutic strategies and then really have a good outcome. So we're all in the same boat and to that end I believe that today is a very important day and I'm really honored and excited to have a great speakers, great agenda, great moderators. So then let's start off with the moderator introduction. Let's go with Dr. Michael Castro please when I call you, please call upon you, come to the stage. Michael Castro is a great friend of mine. I've known him for 25 years. I've been in the valley here for almost 33 years. I've known him as long as he's been here and he's one of the finest internal medicine practicing doctor both clinical as well as research and in teaching is also a gerontologist. He's done multiple research projects and more recently he's done some research with me doing utilizing technology to actually make a better patient outcome utilizing virtual reality and immersive technology and he was the principal investigator we just presented at the Cardi metabolic Health Congress in Boston that Michael presented recently. So he's done some great work and so honored to have him here. He's also the associate program director for internal medicine program at a brazu and such an honor to have you here Michael. Welcome. And let's, Janice, where are you? Janice Gozman, I'd like to welcome another co-moderator. Janice is a again, a gerontological nurse practitioner based in Tucson. She told me that she's based in Tucson and I heard she's baked in Tucson. Is it okay? We were all baked somewhere or the other but truly she's an amazing nurse practitioner who's doing some good work both in clinical setting as well as doing some very fascinating research. She's actually doing something interesting. She's doing research in remote patient monitoring in veteran population in Tucson at the VA in heart failure. So it's going to be something very different and unique and see whether we can actually make a better impact on patient outcome. So again welcome Janice and again thank you all for coming. I'm going to now hand over to Sandesh to introduce George and then we'll kick off the meeting. Thank you all for coming. Okay, I hope you have a large glass of tea. I have 32 pages of Dr. Post's resume to cover but some of the brief highlights are Dr. George Post is a Regents Professor and Dell Web Chair in Health Innovations Chief Scientist of the Complex Adaptive Systems Initiative. From 2003 to 2009 he built the Biodesign Institute at ASU and since January 21 he assumed leadership of the Institute for Future Health a joint venture of ASU and U of A and he's my boss. From 1992 to 1999 he was a Chief Science and Technology Officer at Smith Klein Beachham now Glaxo Smith Klein and he was also awarded the rank of Commander of the British Empire by Queen Elizabeth II for contributions to research and international security. I think the thing I most admire about George actually is his ability to tell great stories and to integrate knowledge from so many disciplines. So without further ado I'd like to welcome you George Commander. Well good morning everyone thank you for taking time from your busy schedules to come on us on a Saturday and I hope what we will see emerge throughout this meeting is the not only the conceptual framework for the evolving framework for treating this disease but a greater recognition of this disease and the impact for for patients but a full recognition of very much consistent with my role as Director of the Institute for Future Health. We've built in very large-scale programs and collaboration between institutions and I say that as the only non-cardiologist in the session and since the clicker doesn't work I'm going to have to ad-lib here for some reason but the it's completely dead. Where's where's the sensor? Okay great thank you. Still not working. Anyway let me this is a disease which is under-recognized and therefore under-treated. Prevalence is clearly higher than has been recognized hitherto. As a consequence of that there's often an unacceptably long interval between the time a patient first presents and the definitive diagnosis occurs and in that interval a substantial utilization of essentially futile cost before that diagnosis occurs. The prognosis is unfortunately a dire one as this audience certainly knows. More recently we've of course seen the option for new therapeutics whether it be for cardiomyopathy or polyneuropathy but by definition as in most disease states earlier detection actually facilitates effective outcomes. We're having some problems here and I think just one of the sort of simple vignette to show the interest in this subject is simply just the rapid growth in both publications and the references specifically in the last few years to therapeutic intervention. Data is however still fragmented that's not unique in medicine but certainly the data from Arizona against those particular parameters is still a limited data set and to the third bullet there we have very limited data on our Hispanic population and certainly virtually no information on the Native American populations and still most of the data is coming from highly specialized centers such as the ones that you all work in. The clear issue has been most importantly a transition from invasive endomyocardial biopathy to scintographic imaging and but the same time with the increased prevalence of this disease who do you actually then refer to a scintographic workup and we've seen the evolution of a series of risk scores evolving any one of a number of the parameters which are listed they are put together and with the reach of machine learning and artificial intelligence into many domains of medicine now apply in those types of deep learning tools to these multi parameters does actually help in a much more important selection but the same time is a need to still validate these evolving test scores risk scores a cost at the spectrum of the disease obviously one goal certainly shared by this audience is to increase the recognition and awareness beyond the specialized amyloid centers there is a paucity of biomarkers which is probably the biggest single area of research opportunity particularly if you could migrate biomarker discovery into easily sample biospecimens such as blood and urine because that would then clearly expand the opportunity to do cost-effective screening for earlier detection at the same time rigorous diagnostic biomarker capabilities would if you had those that could also prognose and predict any progression from polyneuropathy to cardio myopathy biomarkers as in other areas of medicine to monitor therapeutic efficacy disease progression monitoring and the the low cost issue permitting you to screen asymptomatic hereditary variant ATTR cohorts for late onset disease due to the incomplete penetrance of variants in different cohorts we still have any problems here April could someone else advance the slides for me won't do it off the keyboard either then of course in the treatment domain there is still the unresolved issue is efficacy greater for the thyroid routine stabilizers versus the silencers proposals with regard to the use of combination therapeutics and this of course applies in so many areas now one in which I spend a great lot of time is immunotherapy and cancer where combination therapies are increasingly the norm but the same time the of what sequence do you give those agents what is the unit dose titration and then the point which is going to come up in a moment well known to this audience is the fact that the extravagantly high cost of the agents in this arena is certainly problematic another issue which we will eventually wrestle with is other thresholds for irreversible progression which would predict lack of Rx efficacy and that leads of course to the grand challenge question of is is this cardomyopathy reversible will actually then require a new category of myofibril clearance agents next slide please so of course this is the issue of touched on a moment ago the high annual cost of approved therapeutics ranges from a century a quarter of a million to half a million and if you look at the studies by isa and others in the cost effectiveness domain this would require an extravagant reduction in extravagant cost probably of the order of 85 to 90 percent to actually bring you into the quality adjusted segment of 50 to 150 thousand per cost effective quality a threshold next slide please and then of course if you go and look at the pipeline that is evolving in this arena whether it be for neuropathy cardiomyopathy or directly attaching the aberrant TTR this is a burgeoning burgeoning pipeline and one has to then begin to ask the question of what will be the cost effectiveness of these new therapeutic regimens next slide and of course the will we will we in what time frame see a shift in the therapeutic paradigm in this disease that move in from lifelong therapy which is the dilemma today and me is this a bright star on the horizon which is using gene editing technology the work of the Intelliore and Regeneron are doing with the drug it's listed there they've demonstrated initial efficacy in the hereditary polyneuropathy situation and now expanding into cardiomyopathy certainly extrapolating from the studies in polymyopathy and neuropathy there's a thing there is indeed a sustained route knockdown of TTR expression for six to twelve months but the question were how that translates to clinical benefit remains to be seen and of course in any gene therapy framework it is the threshold of transduction efficiency into a target cell population in this case the hepatocyte that will determine all and the dilemma which the FDA is always struggling with is in this emergent arena not just not just for amyloidosis but all gene therapy is what are the off-target effects because they in many instances may be often delayed so it's likely to be the cost of post-approval studies next slide please but that this is just a summary of themes which are well known to this audience what I want to do is put in the context of trying to create this framework for a pan Arizona network because I think there are many elements of what you are facing in this that reflect the same elements that are shaping biomedical R&D and health care delivery at large next slide and that is the fact that we have reflected in my own gray hair and increasingly aged population chronic co-morbidities in that population economically unsustainable treatment regimens and major unmet clinical and social needs as a consequence of that that has to be balanced against what the general public and the politicians think will be an inexorable tsunami of new innovations coming forward at ever lower cost with better clinical outcomes and quality of life but the collision course between those two parameters is going to be with us for some time and then of course in the era of precision medicine we now have multi-omics stratification of diseases into increasingly small cohorts of patients with different underlying molecular to your teleologies and of course that has been the price driver that if you've only got a small patient cohort the recovery of your R&D costs which can be anywhere between 500 million and a billion plus that drives this distorted element of market failure and periphery and the drugs of this category march under the orphan drug status as you know but the threshold for that is 200,000 patients so if indeed the prevalence of ATTR neuropathies and cardiomyopathy is in fact going to quickly move beyond 200,000 patients then that will have to be reexamined and what will that mean them for the price structure and people's willingness to come in and in this of course if you are subsetting patients on the basis of molecular stratification you also need a companion diagnostic so that adds further to the equation next slide and so this of course then leads to something again which this audience lives with the entire time we're living in an environment of escalating scientific and clinical complexity and in short how do each of us stay current with our responsibilities it's not it's the pace and diversity of innovation new concepts new technologies and an overwhelming burgeoning of large-scale data and the world in which I live is basically a fusion of three previously separate domains namely medicine with engineering and computing and then we're seeing new combination products diagnostics therapeutics devices and data algorithms coming together and at the same time with the pervade with the pervasive and rapid acceleration of machine learning and AI technologies in all areas of medicine regulatory validation through the FDA so-called software as medical device will become an increasingly challenging issue and then back again to price increasingly and if you look at the inflation reduction act it's very clear that the FDA's mandate which is currently limited to safety and efficacy is going to extend to value and so with or without ICES insertion into the equation CMS will become an equally potent blunt weapon in this debate next slide and so it's what I colloquially refer to as the S4 to M4 paradigm shift particularly if you're in academia for the most part academia is still trapped in single scientific disciplines or single clinical specialties but increasingly the problems we wrestle with our multidisciplinary and multi-speciality often conducted in single institutions where as the scale and sophistication was required requires multi-institutional collaborations often if one is dependent upon the federal purse the resources are subcritical and at the same time you then got to manage the scale of these much larger enterprises and it is still frustratingly slow to translate innovation into patient benefit and we have to do better next slide and so another way of putting that is in fact silo subvert solutions and so the whole metiae for the incident which I run and many others around the country is actually making this transition from the S4 to the M4 next slide and so a quick vignette about Arizona for those of you who don't live here where the third fastest growing state in the nation Metro Phoenix is now overtaken Philadelphia and Houston as the fifth largest urban complex in the country we have unique demographics almost a quarter of our population is Hispanic we have the largest population of Native American tribes in the country constitute 5.6% of our population an intriguing feature is that in this five and a half million Metroplex health care is largely provided by only seven major health care providers whereas if you compare that with Philadelphia or Houston you're talking about 35 to 40 major health care providers so the question of herding cats in those situations is a lot more complex and trying to get seven major provider organizations to work together in Arizona and there has been very rapid growth in both universities ASU U of A NAU with now 1.5 billion in annual grant revenues next slide and as a consequence of that we've had a momentum in the last few years to do exactly what we're trying to do here these are consortia which have been established in the last two to three years by bringing everyone together across Arizona that's listed there the topics are self-explanatory but it's a momentum and so it is the question of what we've done here in these other consortia which have been built over the last two to three years the penultimate one of course there was catalyzed by COVID but nonetheless it is this S4 to M4 transition next slide and so if one were to define theoretically what one would like to see in this network is the capability to build a substantial biobank a longitudinal registry of patients ethnic diversity in that patient group different stages multi-organ amyloidosis for sampling both cardiac and non-cardiac and as mentioned earlier the ability to migrate to much more minimally invasive low-cost biospecimens at the same time in the world ever increasing world of omics the last time I checked there were 400 omics prefix suffixes attached but certainly a whole exome whole transcriptome sequencing is now quite routine there are people in this audience who have published on proteomics circulating micro vesicles or exosomes are becoming an intriguing analyte class and have been shown to be altered in ATTR and then of course what is the nature of the structural biology that gives rise to the altered protein folding then a whole series of analytical platforms which are needed to support that and in the end you get to data high-performance data computing ASU has the is now in the top 100 fastest computers super computers in the country we're we're one of only six worldwide Dell high-performance computing capabilities that puts us in the top 10 of any university high-performance computing capability and as we said when we talked about multi parameter risk or is bringing together all this complex phenotypic data yet alone the multi omic data is going to require that type of analytical framework and last but not least is this again back to this issue of pharmacopharmacoeconomic analysis next side and so the idea would be that the people in this audience could in fact be the catalyst to begin to build this statewide network of capabilities in the detection and treatment of ATTR amyloidosis we need to generate much more sophisticated epidemiological data in the state of Arizona analyze what are the barriers and the promoters to implement evidence-based care apologies for the type evidence-based practice and at the same time clearly we're not an island we would like to see Arizona migrate into a national framework as a leading enterprise within this important area of biomedicine next slide and so just my disclosures and the most important thing is if any of you want access to the slides it's also a prompt to remind you that the slides from everyone's presentations are available but I hope at least with this superficial surf across a large landscape you've at least got a sense of what we hope will be an aspirational framework for Sam Desh and his colleagues in helping us build this so again thank you so much for taking time from your schedules on the Saturday and I'm looking forward to a stimulating and productive symposium thank you