Good afternoon and good morning. Thank you all for joining us today and welcome to Traveer Therapeutics Inaugural Research and Development Day. My name is Chris Klein and I have the privilege of hosting today's event. We have an insightful program plan that includes expert perspectives on rare kidney disorders, focal segmental glomerulosclerosis or FSGS and IgA nephropathy as well as a comprehensive overview and outlook for our sparsentan programs in these indications. We will also highlight the latest addition to our pipeline, TBT058, which was previously known as OT58 and is in Phase onetwo development for the treatment of classical and HCU.
We are honored today to be joined by guest speakers Doctor. Jonathan Hogan and Doctor. Jonathan Barrett. Doctor. Hogan is the Assistant Professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania, Clinical Director for the Penn Commerrier Center.
He will be sharing his perspectives on the current unmet needs and landscape in FSGS. Doctor. Barrett joins us from The UK, where he is the Mayor Professor of Renal Medicine at the University of Leicester and John Wall's Renal Unit in Leicester. Doctor. Barrett will share his perspectives on the current unmet needs and landscape in IgA nephropathy.
From Severe Therapeutics, we will be led by our Chief Executive Officer, Doctor. Eric Dubay. Eric will be joined for the presentation by Doctor. Bill Roat, Senior Vice President of Research and Development our Chief Medical Officer, Doctor. Rosenberg and Peter Hammer, our Chief Commercial Officer.
Once we complete the presentation section of the program, we'll move to a moderated Q and A session with all of today's participants. Everyone registered for the webcast should see a question box below the feed the video feed and slides. Please submit your questions here for the group and we'll add them to the queue. We'll do our best to cover as many questions as we can in the allotted time. And for any we don't get to on this session, we'll be sure to follow-up after the event.
Before we begin, we will be making some forward looking statements, about our prospects, product profiles of our investigational products, growth projections, expected time lines, competitive position, potential regulatory filings and agency actions, amongst others. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements, including the results of currently ongoing clinical trials, product competition, market acceptance, the occurrence of adverse safety events with our products or product candidates, regulatory uncertainty and other risk factors and uncertainties that are described in the Risk Factors section of our 10 Qs and 10 Ks filed with the SEC. We refer you to our filings on the SEC website for more information. With that, we will now get started with a brief video of some important perspectives from the nephrology community.
I was in my mid-20s. It was shocking, obviously. It took a long time to get to the diagnosis. A lot of different things were thrown out there of what it could be, what they thought it was, how they would treat it before we finally got there. But overall, it felt like overnight, I went from being a carefree 26 year old to, you know, I was in the prime of my life, I was traveling, I was having fun, to being worried about a fear that I
wasn't even going to see my next birthday. Rare kidney diseases can be extremely aggressive and progress quickly. For example, my daughter went from 100% kidney function to end stage renal disease in eighteen months. When discussing if they were able to receive the needed resources to combat their disease, one of our work group members stated that our rare diseases are not sexy enough to get the attention they deserve. Also, our society has done patients a disservice with the perception that dialysis and transplant are simple and adequate treatments.
But many patients are met with comments like, Can't you just get a transplant? Like, Walmart has kidneys and IL-seven for sale.
Let's put this in perspective. Greater than one in ten Americans, that's roughly 300 excuse me, thirty five million Americans suffer from chronic kidney disease. For patients with the most severe form of chronic kidney disease, these are the rarer forms. There are currently no drugs for these patients, and we're often forced to use off label chemotherapeutics, really high doses of steroids before many of these folks so sadly are forced to go on
to dialysis, transplant, or worse. Providers must not separate science of medicine from the reality of care delivery. Care plans must include the social determinants of health, such as transportation and employment, childcare, food deserts, etcetera. Cost and price should factor in patient reported outcome measures, not only including increased productivity, but also include social contributions as well. And training programs should have a more holistic view of opportunities and challenges of optimizing care with novel therapy.
Take this, ESRD should not be the only and preferred pathway for treatment.
There's nothing worse than living in fear. I cannot imagine a parent having a child that has a disease, and there's nothing that you can do. The fear, the anxiety, the lack of hope, and the desperation, that's that's what living with with with a rare disease is. And then if you have a treatment, it's beyond you with respect to cost. And to to go to a health care professional and be misdiagnosed and the hope that you've had is dashed because maybe what is done is doing more harm than is doing good.
You know,
when I think about advances in other places like cancer, we've definitely seen some improvements in diabetes care. Part of what's made that successful is the messaging of those disease processes as a public health emergency. And so I really think that, you know, as we're moving forward and trying to move the needle on the care of our patients with rare kidney disease, that we've got to get that message across.
I'm Eric Dube, President and CEO of Trevere Therapeutics, and thank you for joining today. The voices that you just heard were from a briefing with members of Congress, HHS, the National Kidney Foundation, and members of the rare renal disease community. Over the last fifty years, glomerular diseases such as FSGS and IgA nephropathy, or IGAN, have had some of the lowest levels of clinical trial activity out of all therapeutic areas. But we, alongside others in the rare renal community, are at a potential tipping point that can change all of that. You will hear today about sparsentan and its potential to become the first treatment indicated for FSGS and IgAN, and to potentially shape the treatment paradigm for these rare disorders if approved.
You will also hear about how we believe that in order to transform the outlook for rare disease, patients must not only change the landscape of clinical trial activity, we must ensure the access to innovation for the patients who are affected. Travere Therapeutics is aiming to change this picture by collaborating with patients, their health care providers, and other stakeholders such as government. We take inspiration from these patient stories and have set an ambition to achieve innovation, not just with therapies, but also in specialty care support, earlier diagnosis and broad access to the care they need. We recently introduced our new corporate name and brand, Travere Therapeutics. Our company has evolved in science and culture and has earned a name that reflects who we are today and our bright future.
I'd like to outline the core elements of this brand and how this reflects our mission and the strengths of our team. The name has two Latin roots, tractus for path and vera for truth. The path in our logo reflects the journey that many rare disease patients are on to seek a diagnosis, better disease understanding, and ultimately a treatment or cure. This path also reflects the scientific progress in delivering innovative treatments. The triangles and mosaic signify the strength that the rare disease community demonstrates on this journey, the diversity within the community, as well as the multiple community members collaborating to support one another.
At the center of all that we do is our culture and our four corporate values. We are inspired by patients. Much like the stories you heard from Alicia, Richard, and Kelly, they inform and drive all we do. We are courageous because the path in rare disease and in rare disease drug development is often uncharted, such as our paving a way to change the historic lack of innovation in rare renal disease. We promote community with a focus on partnering with patients and caregivers in the rare disease community.
And our efforts must reflect the diverse voices and experiences of our patients, employees, the communities we serve. And we are stronger together because we know that the ambition we have set requires the best minds and effort across industry, healthcare providers, government and patients. Next slide, please. Speaking of Stronger Together, what you have seen from Trevere to date and what you will hear from us today should reflect these values and our core strengths as an organization, including a diversified pipeline led by our investigational product candidate, sparsentan, which if approved, we hope will transform the treatment of FSGS and IgAN and the lives of those affected by these rare kidney diseases. And includes TBT058, which we aim to have as a first in class treatment for classical homocystinuria or HCU.
We have demonstrated capabilities in the late stage development of our assets and in the engagement with scientific experts. For example, we have assembled a global renal network, and we have been able to maintain or accelerate our time lines for the DUPLEX and PROTECT trials in the face of the COVID-nineteen pandemic. We have demonstrated industry leading capabilities with our commercialized medicines, such as the ability to identify new patients and help them achieve earlier diagnosis and treatment. You will hear from Peter Hirma, our CCO, today about aspects of our established commercial organization that we believe position us well for successfully bringing sparsentan to patients if approved. All of this is supported by a strong financial foundation, with approximately $456,000,000 as of September 30, which we believe is sufficient to support our expected operations beyond the DUPLEX and PROTECT readouts and will allow us to invest in sparsentan planning activities.
Next slide, please. As I mentioned earlier, leadership in rare disease demands attention beyond innovative medicines. By listening to patients and leaders in the rare disease community, including those who have traditionally been underserved, we are focusing on barriers that prevent some patients from accessing the incredible innovation our industry is delivering. We focus on earlier diagnosis. For example, we provide a cholestasis gene panel to help families gain understanding of their infant's condition.
And the growth of our commercial business reflects the strong capabilities of our commercial and medical teams to work across multiple medical specialties to help patients find a diagnosis. Our efforts include addressing barriers to access, including access to clinical trials and rare disease specialists. Duplex is the only pediatric trial in rare renal disease. We were the founding sponsor of the Rare Disease Diversity Coalition with the Black Women's Health Imperative to address barriers to access amongst communities of color who are disproportionately affected by some rare diseases, including rare renal diseases, or who have worse outcomes in rare disease due to lower access to quality care. Trevere is a founding sponsor of a telehealth model at the Rare Disease Institute at Children's National to ensure that access to rare disease specialists is not dictated by ZIP code or one's ability to travel.
This model was fortuitously established before the COVID pandemic. And since then, we know that telehealth has been a lifeline for so many rare families. And we continue to lead in forging paths in rare renal, hepatic, and metabolic diseases such as the joint HHS and NKF congressional briefings to establish clear policy priorities for rare renal disease. And our leadership in this space is reflected in the science to potentially support proteinuria as a surrogate endpoint. And we are proud of our collaborative research agreements we have between the NCATS at NIH and patient advocacy groups in NGLY1 and Alagille syndrome.
Next slide, please. We have a diversified pipeline that addresses areas of high unmet need in rare renal, hepatic, and metabolic diseases and represents the exciting growth potential of our organization. Our pipeline is funded by our strong balance sheet and commercial revenues. We invest the revenues from our commercial portfolio into our pipeline to hopefully deliver treatments for diseases with no approved therapies. These revenues have grown based on our strong capabilities to find patients and help connect them to a diagnosis and appropriate treatment.
You'll hear more about our lead programs of our pipeline with sparsentan and TVT-fifty eight from Bill Roe and Noah Rosenberg today. Next slide, please. All aspects of Trevere have come together to position 2021 to be a potentially transformational year for the company. We are, of course, continuing to monitor any impacts of the ongoing COVID-nineteen pandemic that might have on achieving these milestones or timelines. With that in mind, in quarter one of next year, we expect to report the headline proteinuria data from our DUPLEX trial in FSGS.
We anticipate data from our Phase III trial in HCU with TBT-fifty eight as well next year. In quarter three, we expect to report proteinuria data from the PROTECT trial in IGAN. And assuming a successful top line data readout, we are planning to file for Subpart H and FSGS by the end of next year. In 2022, we aim to transform the treatment of rare renal disease, starting with the launch of sparsentan and FSGS if approved. Next slide, please.
At Travere Therapeutics, rare disease is personal for us, with many of our employees personally touched by a rare disease. We also regularly invite patients and their families to share their stories with us, patients shown here such as Lily with her mother, Mark and Kevin and many others. We know how difficult it is to live with a rare disease. For Kevin, it took several specialists and years to effectively diagnose his rare kidney disorder. He had to overcome biases by health care providers who said his symptoms were due to poor diet, drug abuse, and steroid use, none of which was true.
And Lily is a teenager with a passion for dance who had to deal with the devastating impact of chronic steroid use because there are no treatments approved for IGAN. These are challenges that Trevere is ideally positioned to tackle, and we are on the precipice of incredible change for patients like Kevin and Lily and Mark. And each of my colleagues at Trevere have a deep commitment to our work in the rare disease community. And I'd like to share with you one more story. In my onboarding for this role last year, I attended a patient summit in Los Angeles, and I sat at a table for lunch with a young family.
While introducing ourselves to one another, the mother of a 10 year old with FSGS heard that I was the CEO of the company developing sparsentan. Her face changed, and she looked at me right in the eye and asked me what I am going to do to bring a treatment for her son and others like him even faster. I and my colleagues show up to work every day with the sense of urgency that this mother so rightly demands. And what you will hear today and should expect from Trevere are three core strengths. One, our external collaboration and scientific rigor have established a foundational science to support sparsentan and its potential future role in glomerular diseases.
Two, we believe sparsentan has the right profile to address the unmet needs of patients with FSGS and IgA nephropathy, and we have designed the ongoing Phase III studies to test this profile. And three, we are the right company to deliver therapies to patients living with rare disease. We operate with the needs of patients at the core and with a sense of urgency that drives our development plans because we know that time matters for these patients. And now it's my pleasure to introduce Doctor. Jonathan Hogan, who is a nephrologist specializing in FSGS at the University of Pennsylvania and is also investigator in our sparsentan programs.
He joins us today to provide a disease overview of FSGS. Doctor. Hogan?
Great. Thanks so much, Eric, for the introduction and that great overview to start. Thanks again for the opportunity to present at this session today. And my name is John Hogan from University of Pennsylvania in Philadelphia, Pennsylvania, and I'm happy to give this talk on FSGS disease state overview. Next slide, please.
So here's my disclosure slide. Next slide, please. So the outline for today is gonna be first to define what FSGS is, then to discuss the epidemiology and pathophysiology of FSGS, then to discuss some of the impacts that FSGS has on kidney health and also on patient health, and finally, discuss some goals and the treatment of FSGS. Next slide, please. Globally, glomerular disease, we know, is a leading cause of chronic kidney disease and end stage kidney disease.
And these glomerular diseases can result from multiple different causes, but the thing that unifies glomerular diseases is really podocyte dysfunction and podocyte damage. This can be caused by genetic, environmental, immunologic factors, and others that are really central to the development of glomerular disease as we see it clinically in the development of protein in the urine. And this scheme on the right displays a spectrum of podocyte diseases and glomerular diseases from a publication from Roger Wiggins back in 2007 and shows the wide variety of different glomerular diseases that we can see in clinical practice. You can see here that both FSGS in green and the the immunologically or inflammatory glomerulonephritis in yellow, that would encompass IgA nephropathy. So both IgA nephropathy and FSGS are included on this.
And together, this group of diseases really comprises ninety percent of the causes of end stage kidney disease worldwide. So this figure and these glomerular diseases and podocyte damage really is at the central nature of the pathogenesis of the major factor driving end stage kidney disease worldwide. Next slide, please. So what is FSGS? So we'll start with the name, focal segmental glomerulosclerosis.
So if you say it five times fast, you get my job. So FSGS is a rare glomerular disorder that's really defined as a histologic pattern. It's based on biopsy findings that are characteristic of various underlying etiologies. There are multiple classification systems whereby we this this diagnosis can be classified. It can be classified based on the way it looks on kidney biopsy.
So this is the histopathologic classification, and that may give clues as to the cause of the disease or how the disease will respond to treatment or how the patient will do for the long term. It can be categorized by the way that a patient presents clinically. For example, if the patient presents with overt nephrotic syndrome, which occurs when you have really heavy protein in the urine, really large amounts of protein in the urine that can lead to severe swelling in the body and other abnormalities. That can also give a clue as to what the disease is caused by and how to best approach, counseling the patient on their prognosis and treatment options. And somewhat by some understanding of the biology of the disease.
This can be categorized as so called primary FSGS or idiopathic FSGS where the disease is really not well understood, secondary FSGS where there is an identified underlying cause that if that cause is addressed, may be able to impact the long term kidney health for these patients. And notably, genetic causes are increasingly recognized as causes or risk factors for the development of FSGS in our patients. Again, going back to the definition, as far as the focal and segmental nature of the lesion that you see on kidney biopsies. So when you're looking at the kidney filters, the glomeruli under a microscope, this diagnosis is made based on focal scarring, which is less than 50% of all glomeruli affected, and that only a part of that glomerulus, only a part of that individual filter is affected. So that's the segmental nature of the lesion.
So together, this comprises our clinical pathologic diagnosis of FSGS, putting together the clinical features as well as the biopsy features. Next slide, please. So FSGS is caused by a continuous and sustained podocyte injury. So these podocyte cells are part of the kidney filtration apparatus, and they really do regulate lots of things including whether or not protein get lost gets lost in the urine. At the beginning of this process, there can be a few different insults or stresses that can cause disease.
These include genetic causes and predispositions. In some patients, there is a hypothesis of a circulating factor, so something that's circulating in the patient's body that's directing directly causing podocyte damage, and I'll give an example of this in just a few slides. Mechanical load for in the example of patients some patients with obesity developing FSGS, Certain toxins and certain viruses as well as other causes have also been either known associations or direct causes of FSGS in our patients. But, again, the common injury pathway always relates to the cell called the podocyte. And with that podocyte injury, you can either have a pathway towards cell repair where that podocyte then becomes functional again, or you can go down this podocyte injury pathway, which results in podocyte detachment from the rest of the filtration apparatus, podocyte cell death, and that leads to podocyte depletion.
All of this, the podocyte damage, podocyte depletion, impaired, function of the rest of the filtration apparatus can lead to the scarring that eventually results in the FSGS lesion that we see on kidney biopsy. So again, we'll be talking specifically about the podocyte in all of these glomerular diseases and specifically in FSGS. Next slide, please. So if we look at a little bit of a schematic of what this podocyte looks like under a high power microscope, like an electron microscope, on the bottom, on the bottom figure, you can see that those little blue semicircles at the top of that bottom figure are the healthy podocytes. But as they become damaged, you can see how as they as we progress to the right into the orange figures, that these podocytes exhibit damage in the in the sense of becoming what we call a faced.
You can see that they become flattened out. They're not standing up nicely, and that is the representative feature that we see on kidney biopsy that shows that there is podocyte damage in glomerular diseases such as FSGS. After the podocyte is damaged, if that damage is continued and sustained over time, we can see that the podocyte will actually detach from the rest of the filtration barrier as represented by the basement membrane and glomerular endothelial layers of the filtration apparatus. And that sets off that cascade that as I mentioned in the previous slide leads to the FSGS lesion and permanent scarring on the kidney filters. Next slide, please.
So a picture really is worth a thousand words, and I I cannot think of a more impressive case that has ever been presented that that really demonstrates this idea of the circulating factor as something that could be key in the pathogenesis of some patients with FSGS. So it's been observed for a very long time that patients with FSGS who develop end stage kidney disease and who require a kidney transplant, they have a high risk of developing recurrent FSGS in their transplanted kidney. It's been shown that up to fifty to eighty percent of these patients have a risk of developing recurrent FSGS in their transplanted kidney. So this is a case of a patient, patient number one, that had FSGS and end stage kidney disease and who received a kidney transplant. And as I'm walking you through this slide, the red, the red part of the graph is going to be the protein in the urine trend, and the blue is gonna be the GFR.
So higher GFR is better kidney function. And you can see there that on day one after receiving the kidney transplant, patient on the protein in the urine just explodes. And to give you some context, you're looking at the right side of the graph here as to the the y axis, And this patient by day one or two has 10,000 milligrams approaching the urine. Normal is 300 milligrams. So really within a very short period of time, developed evidence of recurrent glomerular disease.
And, indeed, on day six, a biopsy was performed that showed recurrent FSGS in the kidney transplant. They started on standard of care treatment for this, but really the investigators and the providers were concerned that the patient was going to lose their kidney. So what they did was they took the kidney out of this patient, and they transplanted it into a different patient who had developed end stage kidney disease from diabetes. And you can see there that immediately upon the transplantation onto the sec into patient two, the proteinuria drops like a rock down towards the normal level, and the kidney function improves towards normal. Really demonstrating this idea that patient one, there's something specific about patient one, something is circulating in that patient that is causing this direct podocyte damage, and again lends a lot of evidence towards this idea of a circulating factor.
Next slide, please. As far as the epidemiology of FSGS, we know that FSGS is the leading glomerular disease cause of end stage kidney disease in The United States, and that the FSGS global incidence is estimated at zero point one per one hundred thousand in children and zero point eight per one hundred thousand adults. We know that there is an increased incidence of primary FSGS over time, for example, three to thirteen fold over the last twenty to thirty years, and that the incidence in adults is almost equal to that of IgA nephropathy, which we know is the most common primary glomerular disease in the world, and is twice as common as something like membranous glomerulonephritis, which is another glomerular disease that we see. Of all nephrotic syndrome cases, FSGS is the cause in twenty percent in children and forty percent in adults showing the burden that almost half of adults with nephrotic syndrome have FSGS on kidney biopsy. And importantly, biopsy results for evaluation of idiopathic nephrotic syndrome have shown that FSGS is seen in up to eighty percent of African American patients.
There have been some exciting discoveries in the last few years with regards to why We know that patients of African ancestry are disproportionately affected by chronic kidney disease and end stage kidney disease. And indeed, the discovery of the APOL one gene, which is highly linked to this increased incidence and prevalence of chronic kidney disease and end stage kidney disease of in patients of recent African ancestry, is a major advancement of understanding of why this patient population is so disproportionately affected. Next slide, please. There certainly is there certainly are many unmet needs in FSGS.
And why is that? Well, fifty percent of patients with severe nephrotic syndrome progress to renal failure within about three years after diagnosis. Forty forty seven percent of children and thirty eight percent of adults, almost half of these patients, do not respond to currently available therapies. And what are these currently available therapies? They're limited and really include conservative type treatments with blood pressure medicines like ACEs and ARBs, ACE inhibitors and angiotensin receptor blockers.
And if those drugs are not effective, then often patients with nephrotic syndrome and FSGS are prescribed immunosuppressive therapy, most notably prolonged courses of high dose steroids, which we know are associated with severe morbidity in these patients. There are other immunosuppressive therapies such as calcineurin inhibitors, are often commonly used. So despite these treatments, we can see the burden of CKD and end stage kidney disease worldwide from FSGS. And so there's a clear unmet need for treatment options to be approved specifically for FSGS. Next slide, please.
Why is it important to treat FSGS associated glomerular disease? Well, we need to know how much the burden is in addition to what we've described already. So we know that the severity of protein in the urine is associated with the risk of developing end stage kidney disease. On this graph, can see that non nephrotic proteinuria, meaning less than three grams a day, has a low risk of developing end stage kidney disease compared to those with nephrotic range proteinuria, which is more than three grams, where it's about a fifty percent risk of developing end stage kidney disease within five to ten years, or patients really malignant type phenotypes with massive proteinuria more than 10 grams, where the average time to end stage kidney disease is around two to three years. And clearly, patients with FSGS are with persistent proteinuria are at increased risk of progressive chronic kidney disease.
And we know that chronic kidney disease and end kidney disease are associated with just unbelievably high risk of cardiovascular morbidity and mortality. So what we target is a remission of proteinuria, which is widely regarded as beneficial in slowing the progression of FSGS. This remission of proteinuria can be categorized as complete remission when the protein in the urine levels go back to normal or a partial remission where they decrease by about 50% and get less than three grams, so below the nephrotic range of proteinuria. And those have been the remission goals for a very long time in improving outcomes in patients with FSGS. Next slide, please.
We also know that this has a significant impact on patient quality of life, and these are some graphs describing the patient reported outcomes in patients with FSGS. We know that this is equally important to to improve the quality of life in patients with FSGS by alleviating symptoms. There are multiple, scales and instruments which have been developed in order to measure quality of life, specifically in patients with kidney disease and FSGS in particular. And so in many clinical trials and in our clinical practice, we have patients utilizing these specific instruments such as symptom diaries and impact questionnaires specific to FSGS in order to gauge this and make sure we're doing the right things by patients by not only improving the protein in the urine, but also affecting their quality of life in a positive way. As you can see here on the right, the percentage of patients experiencing, you know, significant changes in quality of life is really overwhelming, when considering the unmet need that we have in this disease state.
Next slide, please. This slide is to highlight a relatively new, clinically important endpoint in FSGS, and this is called the FSGS partial remission endpoint. It's a robust correlate of kidney survival in patients with primary FSGS, and this is demonstrated by the study published by John Trusz in the last few years, which looked at data from five independent cohorts of patients with FSGS totaling over 400 patients who were analyzed and that established that achieving this modified partial remission endpoint of less than 1.5 grams of proteinuria accompanied with at least a 40% reduction in proteinuria was a robust correlate of kidney survival. And you can see here on this Kaplan Meier curve that those who achieved a complete remission in proteinuria less than 0.3 grams of protein, had the best kidney survival over time. But those who achieved a, FSGS partial remission by this new definition also had significantly improved kidney outcomes over time compared to those who did not achieve a response.
So this is very important, not only that we're thinking about how we're going to achieve our endpoints, but also recognizing novel endpoints that are important to achieve both in clinical practice and in clinical trial settings. Next slide, please. So the treatment strategies for FSGS are varied. In the absence of an approved therapy specifically indicated for FSGS, so we're limited to extrapolating therapies from either off label use, historical use, or or other situations. So we have renin angiotensin system blockade with medications such as ACEs, ARBs, and mineralocorticoid receptor blockers such as spironolactone in order to decrease the pressure within the filters and lower protein in the urine.
We know that blood pressure control is very important. But for those who still have primary or idiopathic FSGS with nephrotic syndrome after those therapies, we're often used we're often forced to prescribe high dose corticosteroids, calcineurin inhibitors, and other immunosuppressive therapies, which again, may be effective in some proportion of patients but have a high morbidity of side effects and have high, high risk of relapse over time. There's also extracorporeal therapies such as plasma exchange therapy and LDL pheresis, which require obtaining access like a large catheter or something similar that's similar to what's used in hemodialysis. And then there's management of complications of chronic kidney disease in nephrotic syndrome, such as the use of lipid lowering agents, diuretics for fluid control, and anticoagulation in some cases. These are blood thinners because we know that patients with nephrotic syndrome at higher risk of developing blood clots, particularly in their veins in their body.
Next slide, please. So to conclude, we know that FSGS is a histologic pattern associated with podocyte injury, which ultimately results in impaired glomerular filtration barrier function and proteinuria. FSGS is an important cause of chronic kidney disease and end stage kidney disease. The pathogenesis of FSGS is heterogeneous and involves genetic causes, secondary stresses, and circulating factors in some patients. The main goal of treatment in FSGS is to reduce proteinuria towards either complete remission or FSGS partial remission of proteinuria in order to improve long term kidney outcomes.
Treatment of FSGS depends on the underlying pathogenesis and may involve renin angiotensin system blockade and immunosuppressive agents, But we definitively know that there still remains a significant unmet need for safe and effective treatments for patients with FSGS. So I'll conclude here and I'm going to be handing off to Doctor. Bill Rhode who's going to give an overview of the mechanism and the mechanistic implications of sparsentan in these glomerular diseases. So I'll hand it off to Bill.
Thank you, doctor. Can I have the next slide, please? I want to share with you a little bit on how we look at kidney injury, how we view the mechanisms at play, and, follow that with some preclinical data that'll make that picture clearer. Doctor. Ho gave us, an excellent overview of FSGS, and I want to build on that by the parallels between FSGS and another glomerular nephropathy, IgA nephropathy, IgAN.
Doctor. Barrett is going to educate us in detail on IgAN later. I want to highlight the similarities that lead us to a common pathway hypothesis. Pathologies behind FSGS and IGAN share many common elements ultimately leading to reductions in glomerular function. FSGS, as you heard from Doctor.
Hogan, can be caused by circulating factor or other elements, and it has the hallmark of damage to the podocytes, followed by increases in proteinuria, glomerulosclerosis, and fibrosis. IgA nephropathy has a completely different etiology, and it's initiated by definition of immune complexes in glomerulus, in podocyte damage, inflammation, stimulating mesangial cell formation, followed by proteinuria, glomerulosclerosis, pheosis. There are many common aspects to both diseases, and central to these and other glomerular diseases are the pathologic roles angiotensin and endothelin. The name, please. Both endothelin and angiotensin are established players in the pathophysiology of kidney disease, and except for their role in renal sodium and water handling, they have similar overlapping and possibly even actions affecting practically all renal cell types and These peptides have been implicated in the control of renal hemodynamics, glomerular pathology, hodocyte structure and functional alterations, and proteinuria, as well as pro inflammatory and fibrogenic signaling.
Angiotensin stimulates growth, cellular proliferation, and fibrosis. It also impacts podocystis cytoskeletal function as well as the secretory activity cell. Endothelin stimulates growth, inflammation, fibrosis, and the release of inflammatory cytokines. Like angiotensin, endothelin also has direct effects on the podocyte cytoskeleton and can cause a reduction in protein synthesis of key slit different proteins and an overall reduction of filtration efficiency. All of the effects in concert and often in a negative way.
And also importantly, significant fractions and crosstalk exist between angiotensin and endothelin. For example, both peptides can stimulate NF kappa B, which is pro inflammatory. But if you block angiotensin, endothelin's still able to activate NF kappa B independently. Similarly, TGF beta is pro fibrotic and is downstream of angiotensin activation, but in the presence of ACE or ARB inhibition, endothelin can activate the bone. Mechanically, blocking both pathways simultaneously will alter the physiology and potential of the pathophysiology.
The bottom line here is that there are two bad actors, and one another is good but insufficient. Blockade of both is ideal. Go to the next slide, please. And sparsentan, with its dual mechanism that inhibits both of key elements playing a key role in the common injury pathway. Sparsentan is designed to inhibit both the antitensin-one endothelin A receptor subtypes.
It's designed to have a high degree of selectivity of endothelin A over endothelin B receptors, and extensive preclinical evidence has demonstrated positive nephroprotective effects in preclinical studies in both FSGS and IgAN. I'll walk you through some of those in just a moment. Finally, sparsentan has been granted ORB designation both US and in Europe. Next slide, please. Linked to this cartoon that describes the role of angiotensin and endothelin in renal disease, it's somehow dual blockade of these two receptors should be beneficial.
Sparsentan provides simultaneous inhibition of pathways that lead to the expansion of injury in glomerular disease, and typically in this case provide protection in both FSGS and IgA nephropathy. I want to now review just a sampling of some of the foundational preclinical data that support this hypothesis. Next slide. Discussed the progression of changes in FSGS and provided us with a good description, actually an excellent description, of glomerulosclerosis. Recall that glomerulosclerosis occurs in both diseases, FSGS and IgA nephropathy.
In each of the animal models presented here, treatment with sparsentan yields a dose dependent and consistent reduction in the degree of glomerular scarring in response to injury. Next slide, please. Central pathology of IgA nephropathy is the perforation of mesangial cells in the glomerulus and the concurrent inflammation that occurs. Treatment with sparsentan in two different animal models of IgA led to a significant reduction in proteinuria, glomerular lesion severity, morphase generation, and importantly, here, mesangial cell activation and proliferation. I want to highlight, in the Thigh one model on the right, in this case we used enalapril, an ACE inhibitor, as a positive control, and that's represented by the black dots on the far right.
Note that ACE inhibition in this setting has a protective effect, but to the same level of protection that's achieved when both endothelin A and angiotensin I receptors are blocked with sparsentan, again reinforcing that maximal benefit is observed when both peptide hormones are antagonized. Next slide, please. Downstream of glomerulosclerosis and such changes at the level of the neuron, proteinuria is a mark of many glomerulonephropathy and is a common element both in FSGS and IgA nephropathy. Here we can see results in animal models of diseases. The inhibition of both endothelin A angiotensin I receptor sparsentan leads to marked reductions in proteinuria.
And as you may note, there's a consistent theme emerging here. Through exploration of the efficacy of sparsentan in animal models, and independent of the models chosen, treatment with sparsentan leads to a consistent dose improvement across multiple models of glomerular disease. Next slide, please. Ultimately, for maximal efficacy, we want to inhibit both endothelin A and AT1 receptors. In these preclinical examples, inhibition of both receptors proved to be superior to blocking only one of these two signaling peptides alone.
When we plot the effect of arsenide in concentration, we can observe a predictable and increased inhibition of proteinuria that correlates with higher plasma concentrations of sparsentan. We factor in the KIs for sparsentan at both the AT1 and ETA receptors, along with the degree of protein binding, we can estimate receptor occupancy and relate that to the outcomes. If you look at the figure, the blue line shows the concentration at which about 50% angiotensin receptors are blocked with only moderate inhibition of endothelin, and we see about half maximal effect. If you move then to BiTE where the red line is on the graph, you've now reached a concentration where greater than 90% of the receptors are occupied and 50 to 60% of the ETA receptors for endothelin are blocked. Now we see the maximal effect when we have this level of occupancy at both receptors.
These are animal data, but if we plotted the DUET Phase II clinical study in the same figure overlay the region described by the blue box. These data translate nicely to what we saw in the clinical program, which Will will walk you through now. Noah?
Thank you, Bill. As Bill nicely laid out the preclinical and scientific foundation, for sparsentan in the use patients with FSGS and IgAN. Next slide, please. I will walk us through initially the overview of the sparsentan clinical program for FSGS. The program has two main components.
The DUET study, which has been completed. It is a Phase II eight week blinded study followed by an open label extension, and we'll walk through that data in patients with primary or genetic FSGS. And the foundation of DUPLEX is DUET. So the learnings we took from DUET, we applied to the longer term DUPLEX Phase III study, looking at patients followed for two years. In both studies, as Bill pointed to, we are testing dual inhibition of ERA and angiotensin with sparsentan versus single, or only angiotensin blockade using the arb irbesartan.
Next slide, please. So, you know, the hypothesis is that this dual blockade will be superior to the single blockade. We heard from Doctor. Hogan about the huge unmet need in patients with FSGS and the need for additional therapies. There are no approved therapies in this condition.
And he also talked about the importance of proteinuria as a marker, as well as an injury causer in patients with FSGS, being directly toxic the tubule. So it's really important that we measure how patients are able to reduce proteinuria using sparsentan, and that's the objective of both DUET, again, in the short term eight week period, as well as the longer term DUPLEX study in a double blinded manner. Next slide, please. DUET was designed, again, as an eight week double blind period, testing two hundred or four hundred or eight hundred milligrams of sparsentan versus matching active irbesartan treatment at 300. These were patients aged eight to 75 years old in The US, so there was a pediatric component, and in The EU, eighteen to seventy five years.
Again, these were biopsy proven FSGS or documented genetic patients, and we did exclude in this study patients with secondary FSGS. The initial UPC to get into the study was greater than or equal to one gram per gram, and they were also required to have an eGFR of greater than 30. Next slide, please. On the left is the primary analysis in proteinuria reduction at eight weeks. You can see clearly from the gray, irbesartan three hundred milligrams at eight weeks achieved an 18.5% reduction in UPC, and that's compared to sparsentan, where we saw a 44.8% reduction in proteinuria.
So clearly, a superior effect with the dual blockade, and that result was significant with a P of 0.006. In terms of overall safety, similar safety between both groups, slightly higher drug related in sparsentan, I'll talk about that in a minute, and slightly higher dose interruption as well. That was related to symptoms of low blood pressure, which were expected with this molecule, and led to changes in the design of the DUPLEX study to accommodate. And again, similar study withdrawal and no deaths in either study. Next slide, please.
So we looked after the eight week period in an open label manner. The study was designed for an open label extension, and what you can clearly see is, and this data was published at ASN two years ago, out to eighty four weeks, there was continued reduction in urinary protein. And this is an interesting slide. If you overlay this on top of what Bill told us about the longer term effects of sparsentan, where it's not just about the initial acute effects, but we've also got reductions in inflammation, fibrosis, apoptosis, along the lines of what Doctor. Hogan spoke to in terms of progression of disease.
So we actually saw a pretty dramatic result going out to eighty four weeks. And again, DUPLEX is going to be a longer term study where we can test this in a double blind manner. I will point out that the gray line are patients who were originally on irbesartan, and they were all switched to sparsentan at eight weeks. So you see the patients who were on ERB got additional incremental reductions, and the patients who were on sparsentan continued to improve, their proteinuria levels. Next slide, please.
So Doctor. Hogan touched upon the important endpoint of FPRE, or FSGS partial remission endpoint, as he said. Say that 10 times fast. FPRE is a unique endpoint to FSGS, and it is an endpoint that has been linked to outcomes, to long term renal outcomes. And in DUET, we used FPRE as a key secondary endpoint, and what you can see is in the eight week double blind period, twenty eight percent of patients in the purple diamonds achieved FPRE in the sparsentan group, and nine percent in the irbesartan group.
So about a threefold increase. And what you see, similar to the overall reductions in proteinuria, that at eighty four weeks, you continue to achieve more achievement of this important endpoint linked to outcome. So this secondary endpoint is the basis of our primary endpoint. It's the primary endpoint for proteinuria in duplex because within the FSGS data set, the truce data that Doctor. Hogan alluded to, this was strongly linked to overall longer term outcomes.
Next slide, please. It's also important to point out that EGFR is an important measure of function, kidney function, and that while there's a short term acute effect, that's expected with these drugs, as you can see, EGFR dips both in the sparsentan group, from time zero to about week four, you see drop and then stabilization. And in the irbesartan switch group, you also see a drop in that gray line, but they all stabilize by week forty eight, and it's important to show that, you know, the drug not only can improve proteinuria, reduce proteinuria, an important marker, but also stabilize EGFR, a key measure of kidney function. Next slide, please. We were asked to look long term in the DUET study in a post hoc manner at the percentage of patients that achieved complete remission.
Now we talked about FPRE, which is a less than 1.5, it was a 1.5 achievement of UPC, combined with a forty percent reduction in proteinuria. But when you talk to academic nephrologists or nephrologists in the community, they don't just treat patients, prior slide please, they don't just treat patients to, 1.5. They want to treat patients to zero. So complete remission is probably closer to what physicians like to try to do in practice, and as you know, there are very limited options out there for these patients. And some of the options, as we talked about, ACEs and ARBs, are somewhat effective, but there's still a lot of residual risk, and steroid therapy is also concerning because of the long term side effects.
It's really limited in how much and how long you can use it. What we did here is we looked at going out in this long term data set. Now DUET is now out to patients followed up to six years, forty two point five months median follow-up. So it's a really nice long term follow-up to have in rare renal disease. We're in a very unique position.
And we were able to look in this data set to say how many patients actually achieved UPC less than 0.3, or the complete remission. And you can see that forty eight percent of patients on the eight hundred, forty on the four hundred, and twenty nine and two hundred. So in a dose related manner, Sparsentan was able to achieve this important endpoint. It just shows the ability of the drug to reduce proteinuria, which again is the fundamental basis of the primary endpoint in DUPLEX. Next slide, please.
We talked about it's not only important to get proteinuria down, it's important in the longer term to help, as a predictor, to stave off some of the longer term complications to stabilize eGFR. And what you see here is that patients, who were complete remitters, so they were able to achieve complete remission by one year, had a slower progression of eGFR, versus patients who did not achieve UPC. Again, within this data set, again, sparsentan long term data set linking proteinuria to eGFR, proteinuria in duplex again being the primary proteinuria endpoint, and then EGFR being a confirmatory endpoint. This really gives a strong case for the link between those two, not just in a large external data set, but also within patients treated with sparsentan. Next slide, please.
In terms of edema, I just want to highlight that it is a common occurrence in patients living with FSGS, As it's a renal disease, these patients, as Doctor. Hogan said, are pretty sick. It's also an adverse event of interest that we, are looking at carefully because it is a potential ERA class effect. I want to point out here that edema was treatment related edema events were well managed with diuretics, and what you can see here is that the rates were relatively low, and especially when you look at drug related, at the two point seven percent. Again, this is in the eight week period, and I think when you apply this to the open label extension, you see similar findings.
I also just want to point out that in hypotension or orthostatic hypotension dizziness, so the second and third rows, if you look at those, they're elevated in these patients, and that was related to the acute blood pressure drop that we saw with the eight hundred milligram dose. And I'll talk about how we have adjusted Duplex to help overcome some of that change in blood pressure. Next slide, please. So here are what have we learned from DUET? Number one, we raised the UPC inclusion criteria from one to 1.5.
And that may be fairly obvious, but it's important to state because the UPC base is below 1.5, so we wanted to allow all patients the opportunity to achieve that less than 1.5. We're also going, instead of eight weeks in a double blind period, out to thirty six weeks of treatment, comparing scorcenta versus irbesartan. And I think with regards to the eight hundred milligram dose, in order to avoid some of the blood pressure related effects that led to patients dropping from 800 to 400 in duet, we actually have a two week titration period, which we believe gives us confidence in our ability to achieve eight hundred milligrams DUPLEX, and we'll talk about design in a minute. And finally, the confirmatory EGFR endpoint is in a double blind manner followed out to one hundred and eight weeks of treatment. Next slide, please.
So this all leads us to the design of DUPLEX, and hopefully I've made the case for this study, and why we're thinking about it this way. I'll just highlight that, you know, again, patients are started on four hundred, they're titrated up to eight hundred after two weeks if they tolerate, then irbesartan is also similarly titrated. Again, it's a matching pills, they're basically one hundred fifty thousand three hundred or four hundred thousand eight hundred. Patients are followed out to week 36. So the thirty six week interim analysis, the first 190 patients will serve as the basis of the subpart H filing, and we'll talk about timing there.
We know that that's in the first quarter of this coming year. In addition, at one hundred and eight weeks, we talked about 300 patients will be followed for the confirmatory endpoint in terms of the slope of EGFR. So the hope is that patients, we can actually get the approval based on the FPR endpoint, that's the subpart H surrogacy and the surrogacy of proteinuria predicting, and then that the, this change in slope at 300 subjects will occur once the patient's already approved, if all things work out, and then be able to confirm the effect of the drug on the functional level of EGFR. Now, I just want to point out that we're over 90% powered to detect the difference on the FPRE response between the two groups, and we're also 90% powered to detect low single digit differences in eGFR at that one hundred and eight week analysis between irbesartan and sparsentan. So where are we?
This is, you know, exciting because, as you know, we've really spent a considerable amount of effort, and I want to give some, you know, a good deal of credit to the team at Trevere, to our investigators, such as those esteemed colleagues who joined us today, and also the sites and the patients and their support staff and the advocacy groups for making this happen. We are thrilled that, you know, we've achieved the three hundredth randomization, and completed new patient enrollment. I will add that toward the end, once we announced the end of screening, we had a really tremendous upsurge in the patients, that were interested. And as Eric pointed out, we're just a very patient focused company. Felt we wanted to give everyone the opportunity, and so we've actually over enrolled on this study as a result, and I'm very happy and proud to be part of a company that's willing to do that for patients.
Duplex had four independent data monitoring committee assessments of safety, all with proceed as planned. I would also point out that it's not just the Duplex data monitoring committee, it's the DuPRO. So they actually see Duplex and PROTECT together. So they have the totality of data, that gave us, it was expected, but again, us great confidence going forward. We also did, for DUPLEX specifically, sample size reassessment was completed with no increase in sample size recommended.
And I'll also touch a little bit, I mean, we're still finalizing the data set. As you know, some of the patients are still moving through the final procedures from screening to randomization, but in terms of our interim initial baseline characteristics, they're in line with our expectations. As you followed us, and you know well, the DUET, as I talked about in Neptune databases, were really used to design the DUPLEX and power the DUPLEX study. We've seen no clinically meaningful difference in the baseline distribution of UPC compared to DUET. The blinded baseline range of EGFR is also consistent, and the blinded variability is in line with expectations.
I'm also narrowing a little bit of our timing here for first quarter. I've said it so many times, it's like automatic, but now we're able to say the top line data from interim analysis is anticipated in February 2021, and the teams are very actively involved in the final steps of monitoring and collecting data and working with the sites to ensure a high quality readout. Next slide, please. So that's my spiel, that's my section. I have the privilege of, introducing Doctor.
Jonathan Barrett from University of Leicester, who really needs no introduction, but just to say that he is an expert and pioneer in the field of IGAN, and, really appreciate him taking the time to spend some time with us today. Thanks so much, Doctor. Barrett.
Thanks, Noah, and thanks for that introduction. It's a real pleasure to be talking to everyone today about IgA nephropathy, another rare disease with a massive unmet need, which hopefully we will see some real movement on in the next few years. In could I have my next slide, please? So what do we know about IgA nephropathy? Well, if we think of all glomerular diseases, and we've heard about FSGS already, IgA nephropathy is the most common form of primary glomerulonephritis in the world.
If we think about what that means for patients, what that means is that, these patients have a progressive chronic kidney disease, which in up to fifty percent of cases will result in that patient ending up on dialysis with end stage kidney disease. And this is a a massive burden for patients because these patients are predominantly young adults when they're first diagnosed in their twenties, late teens, early thirties, at a critical period in their life where they are starting a career, wanting to start a family, buy a house, develop their lives for the next, forty, fifty years. And they're given a diagnosis of a disease that we have no clear understanding of its cause, and we have no treatments available. And all we can tell our patients is that there's a risk that you may well develop end stage kidney disease when you're in your forties or early forties, fifties, and that, we can really do very little about that at the moment. We know that globally, this is a massive, health problem because up to ten percent of all patients on dialysis in the world are on dialysis because of IgA nephropathy.
And we know that that prevalence increases as we move from the West to the East. Not only does the disease become more common, it becomes more severe and more likely to put you on dialysis. Now a kidney transplant is the holy grail for people with end stage kidney disease, and we know that of those patients who develop end stage kidney disease, sixty percent will get a kidney transplant, but actually a significant number of those will lose their kidney because the disease comes back in the kidney, allograft. And we have no way of preventing that at the moment. So we have patients in their twenties being told they have this devastating disease.
There's little we can do about it in 2020 other than watch their kidney function deteriorate until they end up on dialysis. If they're fortunate enough to get a kidney transplant, which is what we plan in all our IgA patients if we can, then there is a risk that that kidney will go through exactly the same process, and these patients will be back on dialysis ten or fifteen years later. And this is a real challenge if we're talking about a 20 year old. Not so much of a challenge if people get this disease in their seventies because they do not have the length of time left to live that a 20 year old does, but this has a massive impact on on young people. It really should not be underestimated.
We go to the next slide. So these are the estimated numbers of cases of IgA nephropathy in different parts of the world, and these are estimates. So there's up to two hundred thousand patients with IgA in in The US, an equivalent number across Europe, eight hundred thousand at least in China, and I think this is a significant underestimate, and at least a hundred and thirty thousand in Japan. We know this disease very rarely affects affects, individuals of African descent, so it is very much a disease of, Caucasians and Asians, and you can see that the disease increases as we move from the West to the East. Can I have the next slide, please?
And I just want to reiterate, in twenty twenty, fifty years after the commonest glomerulonephritis in the world was first described, we still have no approved therapies to treat IgA nephropathy. And this really, takes us back to Eric's first presentation talking about the massive unmet need and the reasons for that unmet need in rare disease. And I'll be perfectly honest with you. I've studied IgA nephropathy and studied my PhD a fair few years ago, and it's only really in the last five years or so that companies like Trever have have come onto the scene with a real interest in wanting to study rare diseases. And it's absolutely fantastic both in terms of understanding the disease, but also providing new potential treatments for our patients, in terms of looking at new ways we can address this very, very challenging area of rare kidney diseases.
If we go to the next slide.
And so what I'm going
to talk about in the remainder of the session is the recent update to the international guidelines on how to manage IgA nephropathy, and these are have been developed by KDIGO, which is an international organization that covers all aspects of kidney disease, from the glomerular nephritis through to how to deliver dialysis, how to manage acute kidney injury. And I was fortunate enough to lead the guideline committee reviewing the evidence of how to treat IgA nephropathy.
And I'm just gonna give
you some highlights as to where we are in, 2020 in terms of how we should address and treat this disease. Next slide. And the best evidence we have for this slowly progressive kidney disease is that the primary focus of management should at the moment be on optimized supportive care. And this essentially is a management of the patient looking at a holistic approach to general lifestyle advice, dietary sodium restriction, which we know is important in any disease, proteinuria kidney disease, stopping smoking, weight control, exercise as appropriate. We need to ensure we assess cardiovascular risk because that is a very significant problem for all patients with chronic kidney disease.
But what you will see here is no mention of any specific immunotherapies, and that's because we just don't have them. Where we are at the moment is general lifestyle advice. It has the best level of evidence as to how to slow the rate of progression of kidney disease and IgA nephropathy. And this is very much supported by this European study called the STOP IgA study, which now has over ten years follow-up, and this shows how important it is to get these basic things right, because we know they will not only slow down the rate of kidney progression, but but are also, infective in other for in other manifestations of disease, particularly cardiovascular disease. If we go to the next slide.
And the central tenant of supportive care is to control the blood pressure and reduce proteinuria. So if you have high blood pressure, we want to be able to treat our patients with a maximum tolerated dose of ACE inhibitor or ARB, particularly if they have more than half a gram of proteinuria for twenty four hours. Even if the patient doesn't have high blood pressure, we still want to reduce proteinuria if it's above half a gram for twenty four hours because we know in these patients they are at increased risk of progressive kidney disease. This really isn't rocket science, and it's not specific to IgA nephropathy. It is what we do in every patient with proteinuria kidney disease.
If we go to the next slide. So this is how we approach IgA. We do a kidney biopsy because it can only be diagnosed following a kidney biopsy. We assess for other causes of IgA deposition in the kidney, and assuming we've excluded these, we come up with a diagnosis of IgA. We score the kidney biopsy.
And if you're interested in IgA nephropathy, we use something called the Oxford score. We now have a web based or phone based prediction tool where we can input data from the kidney biopsy and the clinical data to give us the risk of significant changes in kidney function up to five years following the biopsy. And ideally, we would want to enroll the patient in a disease registry where one is available. And then we commence supportive care as I've mentioned here, and you can see all of these things here. Next slide, please.
What defines a patient who remains at high risk of progressive kidney disease? Well, we have defined that as those patients who have more than one gram per twenty four hour proteinuria despite at least ninety days of optimized supportive care. And this is important because this is the group of patients we think warrant additional therapy, and these are exactly the patients that are included in the PROTECT clinical study. So these we have in the PROTECT study design specifically focused on the significant unmet need in the IgA population by studying those patients who remain at high risk despite good quality supportive care. And we make a specific recommendation in the guidelines that you should not be considering immunosuppressive drugs if you wish to use them in patients who have not met this criteria.
So it is not appropriate to be putting patients with IgA nephropathy immediately on immunosuppression before you have maximized supportive care for at least ninety days. If you go to the next slide. We believe that the evidence out there for safety and efficacy of current immunosuppressive choices, and I'll touch on those in a little min little while, remain unclear. And we believe and strongly recommend that any patient who remains at high risk, their first port of call should be to be offered an opportunity to take part in a clinical trial. And that is exactly what I do in my clinical practice.
So every patient who continues to be at high risk despite good quality supportive care is offered an opportunity to to go into a clinical trial. In those patients and those nephrologists who wish to use immunosuppression, we feel that a very detailed discussion of the risks and benefits of each drug should be undertaken with the recognition that adverse treatment effects are much more likely if the eGFR is below 50. If we go to the next slide. The only other recommendation we make in the guidelines, and this pertains to immunosuppression, is there is some evidence, it is low quality, that a six month course of corticosteroids may be beneficial in IgA nephropathy. But I want to draw your attention, and we do in the KDIGO guidelines very particularly, that this therapy is associated with sick a significant risk of treatment emergent toxicity, particularly in patients with an eGFR below 50 mils per minute.
And that is exactly what the two best studies thus far published in IgA nephropathy showed. So in the European STOP IgA study, they showed a very significant increase in treatment emergent toxicity associated with corticosteroids. And in the testing study, which was a Chinese a prominent Chinese study, this study actually had to be stopped by the data safety monitoring committee because of the increased risk of deaths in the steroid treated arm, and this was a steroid versus placebo randomized controlled trial. That was in addition to the increase in steroid related side effects associated with weight gain, with increased blood pressure, impaired glucose tolerance, and bone disease. And so this study again highlights the importance of the risks associated with corticosteroids, and I'll come on to that again a little bit later.
If we go to the next slide, we make specific clarity that clinical benefit of corticosteroids is not established and should be used with extreme caution or avoided entirely in these conditions here. So very low GFR, preexisting diabetes, obesity, latent infections, uncontrolled psychiatric illness particularly. If we go to the next slide. And so here you will see the algorithm for how we suggest you approach IgA nephropathy, again, defining that high risk group despite optimized supportive care and consider enrollment in a clinical trial, and that is exactly how the PROTECT entry criteria work. As with all other clinical trials recruiting at the moment, we are selecting this group of patients because they remain at high risk of progression.
If a nephrologist or a patient does not wish to go into a clinical trial, then if their GFR is above 30, the nephrologist must discuss very, very carefully with each patient after making a decision on their risk of steroid related adverse events, whether they are going to offer a six month course I will tell you now, I have never used corticosteroids for IgA nephropathy because I think they are very toxic, and I think the evidence for that benefit is very poor. There are some specific recommendations we make, which I'll touch on in a minute. If we go to the next slide. The list of KDIGO guidelines in IgA are actually more full of lists of drugs we shouldn't you shouldn't use, and here you can see a variety, particularly cyclophosphamide, calcineurin inhibitors, rituximab, and azathioprine.
These are all drugs commonly used in immune mediated kidney diseases, but have shown that there is no evidence for their use in IgA nephropathy. There is the beginnings of an understanding that the disease may behave differently to treatments in different parts of the world, and this data here suggests that MMF may be useful in a Chinese population, particularly in this study as a steroid sparing a agent. So so in this study, there was no add additional benefit of of MMF, but what it did allow the investigators to do was to get away with a lower dose of steroids, and therefore, the steroid related side effects were far less in the combination arm. And so we do draw this attention for those Chinese nephrologists who wish to use steroids is that we would strongly recommend MMF because it will reduce the risk of steroid related side effects. There is no evidence for MMF utility in non Chinese patients.
If we go to the next slide. The other piece of clinical trial work that has come out of China is the potential benefit of hydroxychloroquine. Again, this has been delivered in small studies, so there is no definitive evidence, but we do recognize that hydroxychloroquine may be of use in high risk patients, high risk Chinese patients, but it does require further study. And here we again highlight that hydroxychloroquine has not been evaluated in non Chinese patients. So if we go to the next slide.
Tonsillectomy, you may or may not have heard about, is very popular in Japan. We do not recommend it is used outside of Japan and simply acknowledge that it is performed in Japan based on low quality evidence from retrospective studies. And in fact, the only randomized controlled trial ever conducted in Japan did not show benefit, but the Japanese still perform this regularly. If we go to the next slide. So how do we assess the effectiveness of a new drug?
Well, this is where in IgA. Well, this is where there's been great strides over the last three to five years, and the initial paper was this paper by Leslie Inca that reported an individual patient level meta analysis looking at clinical trials that had both an early assessment of proteinuria change, and that was in six to twelve months after starting a new treatment, and a longer term EGFR based endpoint three to five years later where an assessment could be made about changes in kidney function or the development of end stage kidney disease. And if we can go to the next slide. This was updated, and this is the same diagram with a couple with the testing and the stop IgA studies added that that was produced as part of the KHI working group that I was part of, which is a collaboration between the FDA and the American Society of Nephrology. And here we specifically wanted to identify surrogate biomarkers that could be used for registration of new therapies in IgA nephropathy.
And I just want to carefully take you through this graph because this is really critical to the whole landscape of IgA nephropathy clinical trial design and the PROTECT trial design in in 2020. So what you can see here is the change in proteinuria between six to twelve months after starting a new therapy compared to placebo. And here you can see the hazard ratio for the risk of an endpoint three to five years later, and the endpoint here was a doubling of serum creatinine end stage kidney disease or death. And what you can see is there is a linear relationship between the quantity of proteinuria reduction you achieve early on and the future protection of kidney function three to five years later. And this led the FDA to agree that an early reduction in proteinuria is a reasonably likely surrogate for future renal protection.
And in the case of IgA nephropathy, therefore proteinuria reduction at between six and twelve months after starting a new treatment can be used for for an accelerated approval of a new therapy in IgA nephropathy with a longer term study to for for full approval based on an EGFR endpoint. But this has really transformed how we approach clinical trial design in IgA because we can now have an interim analysis in a randomized controlled trial looking at a six to twelve month time point for proteinuria change to give us clear indications of drug efficacy and to be used for an an accelerated approval pathway. And just as an example here, if we assume a third the drug produces a 30% reduction in proteinuria compared to placebo at, for instance, nine months, then what you will see is an almost halving of the hazard ratio for a hard kidney endpoint of doubling serum creatinine end stage kidney disease or death three to five years later. And if we go to the next slide, this is data this really shows you what this means. So this is data from Lester, from my unit, and here in red, you have the outcomes of patients who had more than one gram of proteinuria and eGFR greater than 30 mils despite maximal supportive care.
And here you can see the proportion of patients without an event, and this event in this case is end stage kidney disease or a GFR below 15, and here you can see over time in years on the horizontal axis the trajectory of that patient group. If we assume a new therapy results in a thirty percent reduction in proteinuria, as I showed you in that previous table, this is what it means for the hazard ratio for that population. And here you can see we are expanding out by over a decade the time to, fifty percent of those patients hitting a GFR below 50 out to twenty four years, and this has massive implications to the quality of life and the outlook for a 20 year old where we can realistically start to tell them about what's going to happen to them and how much we can delay the progression of their kidney disease. I'm sure there may be questions on this in the q and a, so I'm just going to move quickly on now. If we just go to the next slide.
So
part of
the KD Go work is to identify the key unmet need, and the key unmet need in IgA nephropathy guideline, but also in every other glomerular disease guideline, is we must evaluate therapeutic strategies that minimize or avoid systemic corticosteroid exposure. And as you'll have told, probably told from my talk, I am no fan of systemic corticosteroids, and this is particularly important in IgA nephropathy. So we need to be under we need to understand the use of nonimmunosuppressive comprehensive supportive care. And the great news is we have the possibility to do that in the PROTECT trial with sparsentan, which is a really interesting drug because it allows patients to receive both maximal renin angiotensin system blockade while also offering endothelin receptor antagonism in a single tablet. And I think that's particularly exciting because my patients really don't want to take many tablets.
And if they're able to just take one tablet, that is potentially an advantage for them. And, of course, the other endothelin receptor antagonist antagonist that is being evaluated in IgA is atrocentin in the ALIGN trial. We also have heard some data from the recent ASN about SGLT two inhibitors and their potential cardio and renal protective effects. And, again, we need to see more data. This may well be another facet to our non immunosuppressive treatment regimen in IgA nephropathy in the future.
If we go to the next slide, I've already mentioned we need to think more about MMF and hydroxychloroquine, particularly in different racial groups. If we go to the next slide. And finally, have a number of other therapies currently being evaluated in IgA nephropathy, the gut directed steroid Neficon. We have a number of complement inhibitors being evaluated, and we have direct therapies targeting B cell activation and survival. And these are all non steroid non corticosteroid systemic corticosteroid based therapies offer us an opportunity to get away from the highly toxic systemic corticosteroids that are are used in a range of glomerular diseases at the moment.
So if we go to the next slide. So where are we gonna be in the next ten years? If we go to the next slide. I think we are going to have transformed the landscape for IgA nephropathy. We are going to have hopefully safe and effective treatments that will allow us to give patients the opportunity for enhanced non immunosuppressive care through endothelin receptor antagonism, possibly SGLT two inhibitors, and we are going to be able to target the fundamental disease and inflammatory processes in IgA nephropathy by directing therapies against B cells that generate the pathogenic IgA, the mucosal immune system, which is where we believe this pathogenic IgA originates from, and target inflammation in the kidney with complement inhibition.
So I'm going to finish there. I think it's really exciting, and I'm very pleased to be associated with Traverse who really have, made their, made set their stall out as a company wanting to address the issues affecting patients with rare kidney diseases. So I'm going to hand back to Noah now, and I look forward to his questions later on in the session.
Thank you so much, John, for that excellent overview. I'm going to sort of try to build upon what, doctor Barry, said about IGAN, the, unmet need, and the link between proteinuria and outcomes, and translate that into our our clinical, program for IGAN, in other words, the PROTECT study. Next slide, please. So we've already heard from Doctor. Hogan and from Bill wrote earlier about the common injury pathways, the link across diseases.
And so regardless of which diseases accounts for ninety percent of all end stage kidney disease, they lead to the common pathway, portal site pathology, activation, ultimately kidney failure, transplant dialysis. But an important link in there is proteinuria. And as we've established, you know, sparsentan has this phase two duet data where we've been able to establish key reductions in FSGS, and Bill showed you some data also in ADM models in reducing fibrosis and apoptosis and inflammation. Next slide, please. But with regard to the ERA class and IGAN, I think one of the most compelling pieces that speaks to dual inhibition versus single or just the angiotensin inhibition is this data set.
So here, in this data set, combined RAS and selective ET inhibition was compared against nifedipine, a calcium channel blocker which lowers blood pressure. And what you can see here is clearly, that the effects on blood pressure, and this is sort of in the text, were similar, between both groups. And pulse wave velocity as well, which is a measure of endothelial dysfunction or the stiffness of the wall. But what was different, and you can see in the angled bars, is cytisinicline was able to lower proteinuria. And so there is a suggestion here of a beyond blood pressure effect, again speaking perhaps to why we saw in DUET the eight week data, and then continue to see an effect longer term, some of the things we talked about, inflammation, and again, and reduction of apoptosis, anti inflammatory and anti apoptosis.
So selected ETA antagonism similar here to sparsentan may provide additional cardiovascular renal protection by reducing proteinuria, blood pressure, and arterial stiffness. Next slide, please. Doctor. Hogan spoke to the link in his lab between proteinuria and long term outcomes, and I think he presented some very compelling data, which he's generous enough to share with this group. Here we have a large recent analysis of trial level data from about 1,000 patients at IGAN, and you can clearly see similarly a relation between reductions in proteinuria were associated with stabilization of eGFR, and there's additional data further to Doctor.
Barrett's point linking it to overall outcomes. So it's important to reduce proteinuria. I think we've established that there's harm there, and I think that's really the basis of, again, the PROTECT study. Next slide, please. So how do we design PROTECT?
It's very similar to Duplex, and I'll highlight the similarities and then one key difference. Patients come in, many of these patients are on background of ACE ARP therapy. One thing I neglected to mention earlier is regardless of whether it's FSGS in DUPLEX or PROTECT, I think it's important to note that most of these patients will be on ACE ARB therapy. And in some ways you can think of these as ACE ARB failure studies, because clearly they were able to get patients on these drugs, which are important, but not below 1.5. So you still got a lot of room to go.
Here within PROTECT, it's one. The bar, the UPC bar was one versus 1.5. And that relates to the key data set that I alluded to and where the line was drawn in terms of overall improvement with patients. But I think that that's one key difference. The key similarity is that at thirty six weeks, we will be measuring a primary endpoint for UPC in a similar subpart H manner.
That's your surrogate endpoint. Instead of 190 patients in DUPLEX, you have two 80 patients for that initial read in PROTECT. And then instead of three 100 in DUPLEX, you have three eighty. And all this has to do with the modeling the populations that we use as the basis of the modeling within each specific disease state. I think a key difference is you can see, in PROTECT, it's a slightly lower dose, about half a dose at four hundred milligrams.
I just want to make a couple points here, and these patients actually start at two hundred and titrate to four hundred. It's a similar titration step. IGAN, as Doctor. Barrett alluded to, is a slower progressing disease than FSGS in general, although there are high risk groups, but also, IgAN, is a less potent neurotic disease. And so we know the four hundred milligram dose was effective in the DUET study.
We weren't able to show a difference between four hundred and eight hundred, which may be because of that blood pressure effect, and we had to back titrate, down to four hundred. So we felt comfortable using the four hundred milligram dose here because, again, effective in DUET, less proteinuria disease, and so that's why we chose the four hundred milligram dose here. I also want to make the point that we've got a 90% power to show the primary proteinuria percent reduction, a 30% difference in proteinuria between the spar and the irbesartan arms on percent reduction in UPC. Next slide, please. So in terms of status, again, tremendous effort, to Duplex, through COVID, through all sorts of challenges, tremendous grit.
The team, investigators, our sites, the coordinators are often the unsung heroes at the sites, and the patients and the families who really have gone to heroic efforts to get patients in during these times. So we're very excited that we achieved the first two eighty patients to support the UPC reduction after 36 this year. We continue to enroll towards that three eighty patients and completion of enrollment expected next year. Top line data from the thirty six week interim analysis expected in 2021. If successful, expected to support the accelerated approval submissions in The U.
S. And the EU. Next slide. I think I now turn it over. So we've talked a lot about the clinical focus.
If is positive, if this is positive, Peter Herma, our head of commercial, is going to walk us through how we plan to change the therapeutic treatment paradigm.
Good morning. Thank you, Noah. It is my pleasure to present to you how we are planning towards this farsentan launch if approved. My name is Peter Hirma and I joined Traveer Therapeutics as Chief Commercial Officer a little over a year ago. The reason for me to join Traveer was the promise of sparsentan for patients combined with an ambitious organization with established commercial capabilities in rare disease.
Before walking you through how we see the opportunity for sparsentan, let me talk to you about the impact of progressive kidney disease on patients, their caretakers, their healthcare system and the associated cost for society. As you heard earlier today, end stage kidney disease is a severe condition causing more death than many cancer types. In fact, about one out of four patients die within the first year of dialysis and these are the ones that make it. Many patients disease before reaching late stage kidney disease due to kidney related cardiovascular events. Think about the impact dialysis has on quality of life of patients and their caretakers.
I have seen this firsthand with a family member. Every other day these patients need a four hour blood filtering session. Basically, this means losing three days a week. In the days after dialysis, patients often need to rest as the dialysis has been wearing their mouths. And I'm not even mentioning the impact dialysis has on the limitations of water intake and dietary restrictions.
Additionally, progressive kidney disease has a dramatic impact on health care costs. It accounts for about twenty percent of all Medicare spending. A dialysis patient is among the most expensive patients for society and the costs associated with end stage kidney disease reached almost $50,000,000,000 in The U. S. In 2018.
And this number is growing with over one hundred and twenty five thousand new patients starting dialysis each year. The number of patients that require renal replacement therapy like dialysis or transplant are disproportionately coming from FSGS and IgA. These patients are on the fast course to end stage kidney disease and we believe we have the potential to delay or possibly avoid the devastating impact of end stage kidney disease by slowing the disease progression for these patients with sparsentan if approved. If you can have the next slide. You heard earlier today from Doctor.
Hogan and Doctor. Barrett and I want to reiterate some of their statements about the burden of disease. Primary FSGS generally affects patients in their mid 40s to 50s. High levels of proteinuria often in the nephrotic or sub nephrotic range is hallmark of the disease and these leaking proteins are directly toxic for the kidneys. But it's also strongly prognostic for kidney disease loss.
Of those patients managed to get into remission or partial remission, the majority of patients do relapse and about half of the FSGS patients progress to end stage kidney disease within five to ten years. And as we heard earlier transplantation is often not an option with about forty percent of the patients having recurrence of disease in their aircraft sometimes even within days. The incidence of IgA peaks among young adults likely requiring renal replacement in their 40s or early 50s. Although the disease is generally not advancing as rapidly as FSGS, about thirty to forty percent develop a progressive form of disease. The prognosis for those patients is worse with persistent proteinuria.
Can I have the next slide? In his introduction Erik was telling you how the Travea logo represents the rare disease patient pass and we have done quite some research this year in gaining understanding on the patient journey. We learned that about fifty percent of the patients have already progressed to stage three by the time they are referred to a nephrologist. This because the path to diagnosis and treatment for these patients is largely uncharted. Signs and symptoms are not well recognized and not directly related to potential kidney disorders.
And patients express frustration with initial PCP assessments and note significant room for improvement in time to referral. Once patients are under the care of the nephrologist, the biopsy may be performed to confirm the diagnosis. Our research indicates that about sixty to ninety percent of the suspected glomerular nephropathies are confirmed through biopsy. Patients treated in academic institutions are more likely to get an earlier biopsy compared to those treated in community centers. And while a biopsy is required to confirm the presence of IgA, nephrologists may only presume IgA nephropathy in patients with minimal proteinuria and stable eGFR without confirmatory diagnosis, given the limited impact of a biopsy on the anticipated treatment approach.
We also saw that RAS inhibition is the backbone treatment and basically all patients get an ACE or an ARB even before the biopsy. Some of those patients are already on ACE or an ARB when they are referred to the nephrologist. Nephrologists are generally more comfortable in prescribing steroids or other immune suppressant agents on top of RAS inhibition in FSGS driven by the need for an immediate response to lower the peaks of nephrotic proteinuria ranges. These nephrotic ranges of proteinuria as often seen in FSGS is less common in IgA and immunosuppression has limited efficacy in these patients while there are tolerability and safety concerns. If we can have the next slide.
Let me now share some insights from our external research how nephrologists see the unmet need within the different kidney disorders they treat on a daily basis. Across renal diseases nephrologists generally recognize FSGS and IgA as the most challenging to manage and to treat. When probed on this they mention the lack of effective treatment options, the overall scarcity of any treatment option and the progressive nature of these two nephropomies. In fact nephrologists predict that only eighty percent of their FSGS patients are optimally managed. And though for IgA nephropathy this is a little bit better, still the prevailing view among nephrologists is that over eighty percent of these patients are not optimally managed today.
Let's hone a little bit further on what the limitations of the current treatment options are. First of all, as Doctor Hogan and Doctor Barrett emphasized earlier, there are no approved treatments today. Nephrologists express a strong need for evidence based medicine that will be addressing the limited efficacy of RAAS inhibition. It avoid or delay the need of adding an immune suppressant agent like steroids. Particularly steroid minimization is articulated as a key goal when treating these patients as steroid therapy is often not benign.
So what are the attributes of a desired product profile to treat these patients better And how do nephrologists see the promise of the molecules that are currently in development? What you see here are the results of a syndicated market research that was conducted this past summer with over 100 participating nephrologists in The US. Slowing progression of disease, reducing proteinuria levels, improving the duration of remission supported by strong clinical data were articulated as the most desired attributes for a novel pharmacologic treatment for both FSGS and IgA nephropathy. When reacting to the different product profiles of molecules that are in clinical development for these indications nephrologists participating in this external research expressed the most interest and optimism about sparsentan. So let me now transition towards the value that sparsentan may present if approved and how pending the phase three data we are planning to model this into a potential value proposition.
There are four value components that we believe are relevant for payers and we are seeking evidence around all these four value drivers. First of all, as Bill mentioned earlier, sparsentan's novel mode of action is addressing a common injury pathway potentially allowing for a nephropotactic proposition. This is in particular relevant for the impact that sparsentan may have in slowing or possibly halting the progression of disease. As Doctor. Barrett presented, models based on real world evidence and patient level data demonstrate that a 30% reduction of proteinuria and IgA may potentially allow for a ten year delay in progression towards end stage kidney disease.
And I showed you earlier what the impact of end stage kidney disease is for patients and the cost associated with renal replacement therapies like dialysis or transplantation. So this would be a significant value driver. Doctor. Hogan was talking about quality of life this morning. One aspect that I want to mention here is productivity.
As you saw before, primary FSGS and IgA affect generally younger patients who are in the midst of their active and productive lives. So this is a view of socio economic importance. Having an ability to decrease worker productivity loss but also lower disability benefits could be relevant value components. The last driver I want to mention is safety and tolerability. Earlier I mentioned how nephrologists and patients seek for a steroid sparing option and we are also looking into how this may add value in a proposition for sparsentan if approved.
We can have the next slide. Let me continue in sharing how we see the market in the eligible number of patients and the potential for sparsentan. As is common in rare diseases it is often difficult to get a clear picture of the epidemiology and the number of patients that are directly addressable. This past year we have spent considerable efforts in gaining understanding here. We have done systematic literature research, extensive market research both internally as well as externally through syndicated research and we initiated collaborations with third parties in assessing large data sets.
We looked at ICD 10 codes and biopsy rates in these databases and asked nephrologists in three separate market research projects about the number of unique FSGS and IgA patients they are managing. Based on this, we estimate that the addressable patient population for sparsan would be about one hundred and ten to one hundred and eighty five zero patients in The US and Europe at launch. As additional approved treatments become available, we expect this number may increase over time as there may be more attention and educational efforts both at the physician and at the patient level and this may result in earlier symptom recognition and potentially an earlier and increased diagnosis rates. So far I have been talking about the external environment and I would like to continue now to our organization. With our established rare disease capabilities and proven commercial infrastructure, I believe we are building on strengths in preparing for sparsentan launch, pending the Phase three data and if approved.
Over the past six years, we have been delivering continuing organic growth in number of patients treated with Strabir products. We know how to collaborate with scientific and patient communities to support new patient identification and ensure that these patients are getting the right treatment. We are also able to provide rare disease patients with the support and services they need to comply with their treatment recommendation. Additionally, we have the experience in planning and execution of a successful product launch. With the recent introduction of Thiola EC, we outperformed benchmark launches and secured a rapid uptake with two thirds of the patients using the new EC formulation within six months of launch.
Important to mention here, nephrology is already an important goal point for Thiola and our field force has a established relationship with about 2,000 nephrologists in The US. You have heard a lot this morning about these glomerular nephropathies, our clinical programs and how we see the Spar Syndrome opportunity. Let me try to summarize what I see as some of the key takeaways. Nephrologists generally consider FSGS and IgA as the most challenging kidney disorders to manage with the highest unmet needs. There are currently no approved therapies and current treatment options are associated with limited efficacy, safety and tolerability issues and limited duration of response.
Nephrologists surveyed in an external market research generally considered sparsentan as the most desired product profile among nodules in development for FSGS and IgA nephropathy. We believe the high burden and progressive nature of disease may allow for the support of a solid value proposition. There is a considerable amount of patients that are in need for better treatment options that may be candidates for sparsentan. Our estimate is in the range of one hundred and ten to one hundred and eighty five zero patients across The US and Europe. And we believe that we at Travea Therapeutics are well positioned to bring sparsentan to market if approved.
As we are building from a position of strengths by utilizing our established commercial rare disease capabilities and nephrology footprint in The US. Thank you for your attention and I will forward to your questions in the Q and A session. I will now turn the microphone to Bill who will talk to you about our new Morpheus, TBT058.
Thank you. Orphan Technologies was acquired by Trevere earlier this quarter and with it, TBT058 program. We've been studying this program for some time and have been impressed with both the work of the team, at Orphan Technologies and their collaborator as well as by the results produced to date. And I'll take just a few minutes, at the close of the program here to review this. Could I have the next slide, please?
Classical homocystisuria, or HCU, is a rare metabolic disorder with significant mixed threatening complications. The cause of the disease is a mutation in the cystathionine bisynthase gene, leading to a reduction in the activity, the CBS enzyme, causing toxic accumulation of homocysteine and to other metabolic arrangements that also have negative effects on and I'll speak to those in a moment. Patients with HCU significantly elevated risk thromboembolic events. For example, untreated patient will have approximately a twenty five percent risk of death by the age of 30 for cardiovascular complications. Additionally, the metabolic derangement from HCUs to severe vision issues, skeletal abnormalities, developmental delay, intellectual disabilities.
This is the no approved treatments aimed at correcting the underlying genetic defect, with current treatment modalities aimed at primarily minimizing protein intake. Epidemiology evidence suggests that there are three thousand five hundred diagnosed HC patients in The U. S. And a similar number in Europe. Go to the next slide please.
Normal homocysteine levels are in the low double digits, and HCU patients will be north of 100 to 200, with some much higher. Standard medical diets low protein are the standard of care, and they're difficult to adhere to, certainly not very eligible, and they represent a significant challenge both patients and for caregivers. As children age to adolescence, their diet becomes their responsibility rather than their parent, and quite predictably compliance suffers. Key to all of this is an accumulation of damage due to periods of high homocysteine, and this represents a cumulative impact and translates to lifelong risks. Next slide please.
To understand the value of TBT058, it's important to understand the biochemistry that's relevant in
the
setting. Methionine cycles to homocysteine, creating a pathway to donate methyl groups other proteins. Homocysteine, in turn, is converted either back to methionine or to cystathionine and subsequently to cysteine as part of the pathway that manages sulfur containing amino acids. TBT05 is a recombinant modified CBS enzyme. It's a dimer versus the tetramer that occurs in nature, and it's pegylated to increase its circulating half life.
58 addresses the primary defect in the disease by replacing the damaged enzyme. It shifts the metabolic balance back toward more normal physiology. Additionally, TBT058 has orphan drug designation in The U. S. And in Europe, and it also has rare pediatric disease and fast track designation from the FDA.
Next slide, please. The team at Orphan Technologies and their collaborators have demonstrated impressive preclinical efficacy in multiple animal models of HCU. In CBS knockout mice, administration of the recombinant enzyme had a profound effect on reduction of homocysteine in plasma as one would anticipate, given that these mice lack the enzyme required to metabolize homocysteine. Importantly, while the native CBS enzyme resides in tissues, replacement enzyme is administered subcutaneously and circulates in plasma. The data here clearly demonstrate that by lowering plasma homocysteine concentration, this works to create a concentration gradient that pulls homocysteine tissues into the circulation where it can be metabolized by the replacement enzyme.
This is the basis of the metabolic sync mechanism that allows for a reduction in homocysteine throughout the body while the enzyme itself circulates in the blood. Next slide, please. Simply reducing concentrations of homocysteine in the body, when replacing the defective enzyme we can observe meaningful changes in the clinical sequelae in animals. Mice that like the CVS enzyme don't survive their first months of life. However, survivals dramatically improve with TBT058 administrative own health in this lifelong issue for homocystinuria patients is improved with treatment as bone mineralization is normalized.
And finally, we can clearly see the difference that restoration of the metabolic balance makes on the cellular fibers of the eye. This defect is a direct result of the combination of high homocysteine and low cysteine. Without sufficient cysteine to form these structural proteins, they become weak and are unable to maintain the position of the lens in the eye. Next slide, please. Currently, this compound is being evaluated in an ongoing phase onetwo dose ranging study.
Cohorts one through four have been completed. Cohort five is enrolling now. Also, the study is designed in such a way that as the dose escalates, subjects on earlier cohorts on lower doses are also allowed to increase their dose following DMC review of the safety and efficacy data of an individual cohort. The goal of the study is dose optimization both for effect and for optimal dose frequency. The primary endpoint is safety, with secondary endpoints focused on changes in plasma homocysteine, cognitive function, assessments of vision function, bone mineral density, and patient quality of life.
Also in parallel, a natural history study is underway. This study has been running for over three years now and has enrolled 60 patients with about nearly an even fiftyfifty split between adult and pediatric patients. The goal of the study is to evaluate clinical course and treatment effectiveness for the current standard of care. We expect this study will be helpful in designing trials going forward and is also supportive of the regulatory strategy. And for the dose ranging study, we will continue to evaluate if additional cohorts in that study will be added.
Our assessment of the number of cohorts will be based on achieving the right dose and dose regimen for optimal effect against the backdrop of the clinical and biomarker data as it's correlated from the natural history study. We plan to provide further updates next year on when we expect to provide data for the phase onetwo study in the natural history study, as well as what we see as the password registration for this program. Ultimately, we want to set this program up for success. And at this point, I'm going to hand back to Eric for his closing comments.
All right. Thank you, Bill. With the addition of TBT-fifty eight to our exciting sparsentan program and our established commercial business, we're poised for a transformational year in 2021. I am proud of every one of my colleagues who has helped to get Trevyr where we need to be going into such an important year. So to summarize here on the slide, you can expect the headline proteinuria data from DUPLEX and FSGS in February, with the headline proteinuria data from PROTECT in IGAN in quarter three.
Also next year, we expect to provide data from our Phase III program in HCU. In all, 2021 is going to be a busy but pivotal year for us at Trevere and for the rare renal communities we aim to serve. So now let me turn it back over to Chris for Q and A. Thank you very much. Chris?
Great. Thanks, Eric. And, thank you to all the presenters. At this point, I'm going to ask you all to come back on camera so that we can go through, the list of questions that we have. Now we've gotten quite a few questions from, from our analysts and investors.
So thank you very much for the, the attention throughout the presentation. I'm going to go through and answer as or ask as many as we can to our our panelists, and we'll get through as many as we can in in the allotted time. And any of the rest, we'll be sure to follow-up. So the the first set of questions comes from Joe Schwartz at at SVB Leerink. Thanks for the questions, Joe.
And I'll first direct these to Doctor. Hogan and Doctor. Barrett. What is the spectrum of severity in FSGS and IgA nephropathy? And what proportion of patients need a treatment option beyond what's currently available?
Maybe Doctor. Hogan, I'll start with you in, FSGS and how you see that.
Yeah. Thanks for the question. So, you know, with regards to severity of disease, I think we generally stratify it by how bad their kidney function is around the time of diagnosis, how bad their proteinuria is, and then subsequently what their rate of response to those endpoints that we discussed. So it's hard to know exactly because there have been these studies over the years, but if looking at, you know, this truce study, which combined multiple different clinical cohorts and studies, it looks like there are about a third of patients are definitively in the nephrotic range, a third of the patients have lower levels of proteinuria, and a third are in the middle. So it seems like it's kind of a third, a third, a third split, at least based on that type of data.
And with regards to who will require additional therapies, so if you think if we think that getting to complete remission is associated with the best overall outcomes, then as has been stated in other talks today, we we know that probably less than twenty percent of patients in these cohorts have achieved that complete remission endpoint. And so we know that there's sort of a longitudinal relationship, continuous relationship between reduction of proteinuria and improving kidney outcomes. If we're really shooting for that complete response, then you're really looking at are looking at probably more than eighty percent of patients with FSGS for whom there's an unmet need for a drug such as farsentrine, just as an example, in order to try to get them to that complete response.
Thanks, Doctor. Hogan. Doctor. Barrett, maybe on IgA nephropathy?
Yeah. I think if we think about those patients who I described who remain at high risk of progression despite maximal supportive care, in my clinical practice that if we take all patients who have a kidney biopsy diagnosis, I can get roughly forty percent to fifty percent of those patients under control with proteinuria less than a gram with maximal supportive care. So it's at least fifty percent of the patients I see continue to have more proteinuria than I would like to see and would be people I would be wanting to give an additional therapy to. And at the moment, as I said, they all go into clinical trials. But if sparsentan is shown to be safe and effective, then those would be the patient population I would want to to use, that drug in.
So I think and this this is fifty percent of of my cohort, which I think is very typical for European, and Jonathan may want wish to comment on the North American cohorts. I think it will be higher as we move towards the East because they have far far more, aggressive disease. And I think the likelihood of just supportive care working in a Chinese population, for instance, or a Japanese population is less likely than in a Caucasian. But I think from a European perspective, fifty percent of my cases, I cannot get below a gram with maximal supported care and good blood pressure, including good blood pressure control.
Great. Thank you, doctor Barrett. The next question from Joe is I'm I'm gonna direct this to Bill. How important is it that patients reach a higher dose with sparsentan
Certainly.
With respect to the four hundred versus eight hundred, I tend to look at it this way. The DUET study data suggested that both four hundred and eight hundred were both efficacious. It's important to note that the two doses are at the top of the sigmoidal dose response curve. So while there's a large apparent numerical difference in practical usage, the two doses are closer together than they might appear. Post hoc review of the DUET study data that was presented at ASN in November showed a benefit of the eight hundred versus four hundred with respect to the percentage of patients who achieved a complete response.
Ultimately, we believe that the eight hundred milligram dose in FSGS may give patients a better chance at responding and we want to give all that opportunity, but we believe the four hundred is also very efficacious.
Great. Thanks, Bill. Our next couple set of questions comes from Lisa Baco at Evercore ISI. Thanks for the question, Lisa. This one is directed towards Doctor.
Hogan. How much edema is acceptable and how much is too much?
So edema is a, you know, a common topic in all talks of glomerular disease. We know that edema is associated with significant quality of life problems for patients with glomerular disease, particularly those with overt nephrotic syndrome. I think that for patients in our disease cohort, for FSGS, for example, it's very common to need to use diuretics for the management of edema. So, you know, edema, it's very dependent on the patient. But edema is not a barrier from the perspective of an adverse event or a side effect profile in our realm, in my opinion.
Certainly in other cohorts where there are older patients with other comorbidities and heart failure, it can be a problem. But symptomatic edema requiring the use of diuretics is very common in patients with nephrotic syndrome and proteinuria kidney disease in general. And so it's it's very common. How much is acceptable is really dependent on the patient, and we do wind up titrating either the prescription or the use of diuretics in general to the patient preference and how their blood pressure is doing. But I don't see this being a barrier to the use of to therapies that we are demonstrating good outcome data with, particularly in our patient population, which tends to be younger and with less comorbidities compared to the populations that I discussed previously where edema could be a problem with regards to heart failure, etcetera.
So I think it's a hard question to answer with specifics, but suffice to say, and I I I'm not I'm interested to hear what doctor Barrett has to say about this as well, but that in our realm of patients with proteinuria kidney disease and patients with renal insufficiency, the use of diuretics for management of blood pressure and edema is extremely routine and so it's not a barrier to therapy.
Doctor. Barrett, since Doctor. Hogan put you on the spot, anything from the IgA landscape with that? Yeah. Thanks, Jonathan.
I thought that
was a difficult question, well answered. I think comparing IgA with FSGS, edema is far less of a problem because we don't have the nephrotic presentation. But as Jonathan mentioned, anyone with proteinuria disease is is likely to have some element of edema. It's not really something that we see as a critical issue in IgA. And as as has been mentioned, I'm a an investigator on the PROTECT study, and both PROTECT and DUPLEX have been forensic in their approach to looking for edema and looking for the potential effects of that edema on those patients.
And and my experience as an investigator, of course, I'm I'm completely blinded to the therapies, and I'm recruiting for both DUPLEX and PROTECT, is we have looked very, very hard for symptomatic edema in patients in this clinical trial and have not found any, certainly in my clinical experience of the study, patients to both. So we are looking very, very hard. There will be very clear data in the studies, but for me personally, it has not been an issue for my patients in either study. And as Jonathan mentions, edema is commonplace. Nephrologists are using diuretics all the time to both treat edema and to improve management of blood pressure.
So so it's it's really not it's part and parcel of our daily activity looking at edema and treating it. So it's not really a a key red flag sign that would make us concerned. And you've got to remember, as Jonathan mentioned, we're dealing with a young group of pay patients here. We're not dealing with elderly diabetic multi comorbid patients where potential edema may influence, the cardiac status, for instance. That's not really something that we come across in the groups of patients that we're studying in PROTECT and DUPLEX.
Great. Thank you, doctor Barrett. And I'll actually stick with you two for Lisa's next question, which is where in the treatment paradigm for FSGS and IgA do you see sparsentan fitting in? And and maybe I'll I'll stay with you, doctor Barrett, and start in the IgA landscape.
Yeah. So so it's very simple as far as I'm concerned is that we know patients who have more than one gram of proteinuria are at increased risk of progression, and we have nothing safe to offer them at the moment. And these are the patients that are recruited to the PROTECT study. If the PROTECT study, which I hope it does, shows that the drug is safe and efficacious, then that group of patients will be the patients I would want to use this drug in. So so it is very straightforward for me in terms of the the the patient group are already identified.
We already know there is an unmet need for a safe and effective treatment, and, that is the group of patients that need an additional therapy. So so in terms of where the results of the PROTECT study will fit, it will be that that will be a treatment choice for those patients. And as I said, that's fifty percent of the patients I see with a new diagnosis who I cannot get under control with maximal supportive care.
Thank you, doctor. Doctor Hogan, would that be yes?
Yeah. With that, I think it's it kind of goes back to our our question earlier around what's the goal of treatment. And if the goal of treatment is really to drive proteinuria down to the complete remission, range, which is the normal range of proteinuria, then you are looking at, you know, again, the vast majority of patients that would require this. And as far as where in the treatment algorithm, I think similarly to ACE inhibitors and ARBs being upfront therapy, that's arsentan would fit in that paradigm. Would be used early and it would be used in combination with any other therapies that were being prescribed for for FSGS at that time.
So I think it would be it would not be the necessarily where you would choose this or immunosuppression, and if you had a patient that was perceived to need immunosuppression, just like the uses of ACEs and ARBs, you would be looking to use it in combination. So it'd be used, I think, pretty early on in many patients, and I think it would be used chronically thereafter just as ACEs and ARBs are in order to try to achieve that complete remission endpoint.
Great. Thank you, Doctor. Hogan. Our next couple set of questions comes from Maury Raycroft from Jefferies. Thanks for the questions, Maury.
Doctor. Hogan, one's coming back to you. Why has primary FSGS increased so much in the last twenty to thirty years? Is it a function of an increase in diagnosis or are there some environmental factors that are contributing to that?
I'm on the hot seat with the tough questions now. Okay. So I see doctor Barrett feeling a soft relief that he did not get that one. So I don't think we really know. I think that there is there are various hypotheses around this.
Certainly, recognition of FSGS could be something that is happening, although the diagnosis of FSGS and kidney biopsy is is is an old diagnosis. It's not like other rarer glomerular diseases where there's maybe some increased recognition by by pathologists over time because they're now recognizing entities that are being put out by by kind of experts around the world. So I'm not sure if it's about recognition on kidney biopsy, and I don't think we have great data that more patients are being biopsied. That could be the case in some areas and at some centers. Certainly, the genetics part is playing a role recently where now the the use of genetic testing in in the clinical realm the absence of a kidney biopsy could increase your ability to detect FSGS in patients with a strong family history of FSGS, for example.
And certainly environmental factors and how they relate to these genetics is a hot topic. If I could answer the question, I'd probably I wouldn't get the Nobel Prize, but I would certainly be, you know, getting some award. But I think certainly think some people think that that obesity, other changes in diet, and other environmental pressures could be at play. But because FSGS is so heterogeneous in its ideologies, it's really hard to make a statement about, you know, one or even two factors that are driving this. So I think I'll have to hedge a little bit on that one.
Great. Thanks for that. Next question from Maury, and I'll direct this one to maybe it's a two part for Noah and Eric. First, Noah, in terms of expectations for response, FPRE response at thirty six weeks, what do you think for or what do you expect for the study for both sparsentan and then irbesartan? The next question for Eric, what data do we anticipate providing at top line?
And would we go into detail about that in the first quarter when that becomes available? Benoit, I'll start
with you. Yes. Thanks, Chris. I think the way that we have powered Duplex is on the basis of Duet, the eight week data. So essentially, what we expect to see in DUPLEX between arms and the achievement of FPRE is what we saw at the eight week projected out to nine months.
So with regard to our data readout next quarter, really what we're looking to provide is sufficient level of data to help you assess the quality of the data on efficacy and tolerability and safety when it comes to the Subpart H submission and the regulatory pathway. We all have to keep in mind that this is an ongoing trial and that the endpoint, particularly the confirmatory eGFR endpoint, will not be mature next quarter. That really will come, in two years' time. And so there will be a limited data set that we will provide next quarter, but it should be sufficient for you to assess the high level profile of sparsentan and FSGS.
Thanks, Eric. And the next question comes from Greg Harrison at Bank of America. Thanks for the question, Greg. This one, Doctor. Barrett, I push over to you.
There's a fair amount going on in the IgA landscape in terms of development. Where do you view the positioning of sparsentan in the future treatment paradigm relative to the other programs that are ongoing?
So I think the beauty of what's happening in IgA at the moment, particularly with my last slide, a lot of people view the situation as we're going to have to choose between these drugs and
that
you can only have one or the other, and that I think is completely wrong. I think we will be moving to combination therapies. I think we will be adding to our understanding of RAS inhibitors by adding an endothelin receptor antagonism, but that's not gonna stop us also wanting to target the gut's production of IgA or target B cells, reduce inflammation in the kidney by targeting complement inhibitors by using complement inhibitors or even SGLT two inhibitors. So so while we put all the companies who have their own drug development programs in silos and assume that they're all competing against one another, In my perspective, the only thing I'm interested in is getting new therapies for my patients. And it is incredibly exciting because if each each of these drugs is shown to be safe and effective, I will be using them in combination because I want to get the maximal effect, in the kidney to protect my patients against end stage kidney disease.
And I can see great synergisms between the drugs that I've talked about in terms of using them together. So I think it is a real misperception that we are gonna have to choose one or the other because that is just not how medicine works. So I'm sure Jonathan will speak to this. We we want the best for our patients, which means we will be using combinations whether that's what people think will happen or not. I guarantee you, we will be using, for instance, sparsentan with Nefecom, potentially with a complement inhibitor.
We will be coming up with ways to treat this disease. I've had nothing to give my patients for the last I've not been around fifty years, but since I qualified. And I'm gonna have these new drugs, and I'm gonna want to use them together to maximize the effectiveness for my patients in the safest possible way. And so I don't view any of these drugs as competitors against one another. I use I view these drugs as drugs that are going to increase the ability for me to look after my patients.
So I hope I I can't say this strongly more strongly enough. It is not an either or, a winner and a loser. We are going to be having drugs that will be added together to improve, the the life of our patients. And just as Jonathan said, in terms of sparsentan plus an immunomodulatory therapy, why wouldn't we want to use those two together? It makes complete sense to me.
They may be made by different companies in different stages of drug development, but it's complete sense to me we will be using these together. So I would strongly advise the analysts on the call not to think you have to pick one or another. You know, if you have one, you're not gonna be allowed the other. That's not how it's going to work in the fullness of time.
Great. Thanks, doctor Barrett. And doctor Hogan, do you have, any views in FSGS with regard to develop other development programs?
Yeah. There's a lot. I mean, I think IgA and FSGS are the two glomerular diseases for which there is the most activity and excitement around clinical drug development, which is a great great thing, as doctor Barrett has mentioned, for us to kinda look forward to and being a new in a new era of being able to treat our patients with with with drugs that have shown to be efficacious in helping them. But I do agree. I think it's not an either or in many cases.
It's, you know, particularly in FSGS, again, driving down towards that complete remission, which we know is best. That's beyond the design of the clinical trial. This is this is real life, you know, prescription of drugs to patients. So if other drugs are available and have been shown to be efficacious, then this can be used in combination with them. And so it's kind of an it's it's the perception of what could be an embarrassment of riches from a clinical perspective, and we would be in a very nice place as a field to have that in order to tailor our therapies for our patients.
But again, I do think that agreeing with Doctor. Barrett that in many of these cases, will be combination therapies, which is similar to what we've seen in other chronic diseases and other fields. So it's really nothing new. It's just the application of this concept of layering on therapies that are hopefully additive for the benefit of our patients and drive them towards those real most important endpoints, which will hopefully translate to to long term kidney benefit.
Thanks, doctor Hogan. The next question comes from Michelle Gilson at at Canaccord. For your question, Michelle. Noah, this one's going to come to you. Given the thirty six week endpoint in DUPLEX, and this is building on one of the earlier questions, is there any reason to believe that there would be an increase in the response in the control arm?
Great question, Michelle. So in terms of the overall population, I want to go back to something that I mentioned earlier, is duet and duplex are essentially, and END for TAT are essentially ACE ARB failure studies, right? These patients are coming in with about a 1.5 in DUPLEX, you know, or above, and they've been on these drugs for a period of time. So the expectation is that the irbesartan arm, which is an ARB, and these patients are going to have been on some ACE or ARB, many of them optimized, will have a limited effect throughout that thirty six week period. That's not to say that they won't have any effect.
And when we powered the study from eight weeks out to thirty six weeks, we have accounted for some effect of the drug. And even if we see, again, similar delta at eight weeks projected out to thirty six weeks, we still are confident that we'll be able to show positive results. So hopefully addresses the question.
Great. Thanks, Noah. And another one from Michelle. This one is directed towards Doctor. Hogan, but maybe it's both Doctor.
Hogan and Doctor. Barrett. How long would you anticipate keeping your patients on therapy if approved? And I'll start with you, Doctor. Hogan.
Yeah. That's a good question. I mean, these are chronic diseases. We know that for sure. And so I think that similar to the uses ACE and heart, again, just to distinguish this from immunosuppressive therapy, where you don't want to keep people on long term therapy, that a drug like sparsentan, is not immunosuppressive, and I think in a chronic disease, would probably intend to keep them on it indefinitely, given the data that we're seeing.
And so I think this would be a very similar extrapolation from the uses of ACEs and ARBs would be to use it as a chronic therapy.
Thanks, doctor Hogan. Doctor Barrett?
Completely agree. This is a lifelong therapy for me, for patients with IgA. We want to continually suppress proteinuria and protect the glomerulus, that is lifelong. So, so it would be a chronic, continuous therapy.
Thank you. The next set of question comes from, Laura Chico at at Wedbush. Laura, thanks for the the questions. Doctor Hogan, how would you characterize distribution of proteinuria severity amongst your current FSGS patients? And with this in mind, which which ones would would you believe would be candidates for for sparsent if approved?
Yeah. So in my patients, I'm a bit biased because I am at a referral center, so I tend to see the the more extreme patients, either those with lower GFRs or, you know, higher degrees of proteinuria that have not responded to first or second line therapy. So I probably have, you know, instead of, like, the third, the third, the third that I described previously from, you know, previously described cohorts, you know, if you look at so I would probably say I'm more on, like, the two thirds are in the more extreme group and one third in the less extreme group of proteinuria. However, if you if you rely back on, like, the Neptune cohort, other cohorts of patients that have been described, if you go by the third, the third, the third, again, I do think that it's it would be a drug that would be appealing across all of the different ranges of proteinuria. And so I think, you know, in my in my practice, it would be appealing across all patients because by definition coming to me, they will have been deemed to be quote unquote resistant.
Right? Nobody's gonna send me a patient in complete remission for a for a second or third opinion. So for me, in my practice, it would be pretty much everybody with FSGS. I would think about using drug like sparsentan because it's showing that ability to reduce proteinuria further in in these patients. But even going back to a more general practice where if it is a third, a third, a third, the only patients for whom you would not think about a drug spar who who who you would not think about using sparsentan would be those that have already achieved complete remission.
And, again, like I said, that's less than twenty percent of patients.
Alright. Thank you. Another one from Laura is, what impact and this is for you, doctor Hogan. What impact does having a titration period mean for for sparsentan the real world setting? How challenging will this be to manage if if if you would have to do that?
I don't think that's a barrier at all. I mean, I think that's standard of care for the use of many drugs, including ACEs and ARBs. Right? We don't start people on the maximum dose. We dose titrate.
We check safety labs in those in in calcineurin inhibitors. And, you know, the the difference between general nephrology practice and when you manage patients with glomerular disease is that you're used to titrating a lot of medicines at the same time. Actually, FSGS and IgA are some of the less intensive ones compared to the other diseases. So but every time we we titrate the ACE or the ARB, we have to check a lab. And so this is this is well within the general scope of not only in glomerular disease practice, but also within general nephrology practice.
I don't think that's gonna be an issue at all because it's standard of care for the way that we use, you know, our most relied upon drugs to begin with. As as a that's not as a specialist within glomerular disease, that's just as a field in general. So I don't think it will be a barrier at all.
Thank you. Our next set of questions comes from Tim Bugo at William Blair. Thanks for the question, Tim. This one is going to Noah for the edema events in DUET. Can you provide a little bit more detail on the difference between drug related versus non and maybe any anecdotes for, how that was determined?
Great question, Tim. So, you know, the fundamental question is how does it become drug related or not? And what's the termination there? And it really comes down to investigator judgment. We really try to be minimally involved in that, and it really is on a site and investigator level.
So it's likely that the seven that were unrelated were considered by the investigator to be expected as part of the patient's disease. We talked about edema being common in this disease state, and there's prevalent, and I think John Hogan talked a little bit about that in FSGS. So, you know, were the two related, were down to the fact that, you know, those patients likely hadn't presented with edema in the past, or we know there's a class effect with ERAs and there may have been a heightened awareness of the PI there as well. So having said that, I think it's important to sort of, we've got this data out to six years, forty two point five months median, and I can say that across to date, across the dataset, all the patients who've experienced edema has been mild or moderate edema, and not all patients even need a diuretic therapy. And I think to Doctor.
Perhogut's point, I mean, not everyone's going to need it. Edema is expected in this population. And I think where intervention is necessary, I think to his point, you know, we're seeing that they're well managed with diuretic therapy.
Great. Thanks, Noah. Another one from Tim, and this one is directed to Doctor. Hogan. Regarding the circulating factor theory for FSGS, what's the estimated percent of patients which may have FSGS driven by this factor or other causes?
And is there any leading theory as to the competition circulating factor?
Another Nobel Prize type question. These are the good ones. This is when patients ask me these questions. They it it keeps you sharp. So we do not know.
I think that, you know, our best guess is that, you know, patients if you were to try to break it down and if I was to get if I was to, you know, sort of hypothesize, certainly, the patients with higher levels of proteinuria in that, like, one third of patients that really have, you know, extreme proteinuria, certainly nephrotic range, and even moving towards that massive proteinuria range that I described would be the the ones that we would think would be most enriched for the circulating factor being a part of their pathogenesis. And certainly those that recur after kidney transplantation, we would think so as well. But it's really impossible to say for sure. I think that we're just with the moving of genetics into genetic testing into not only clinical research but also clinical practice, we're just seeing that this is even more of a complicated story than we thought to begin with. So I don't really know if anybody could give a true if we don't even know what the circulating factor is and I can't measure it, I couldn't give you an accurate percentage.
As far as a candidate, there's been many candidates since, I think, the 1996 New England Journal paper that came out after doctor Virginia Sabin's lab. And I think that we still do not know. I mean, every few years, a new candidate comes up, most recently with Supar, but that has not quite panned out as the pathogenic circulating factor to date. I think the field would agree with me on that in general. And so I think we're still just not sure.
That is kind of the, don't I say the holy grail because it is a heterogeneous condition but it's really the part that everybody kind of knows is there but we just do not have the data or the characterization yet.
Great. Thanks Doctor. Hogan. The next couple of questions come from, Do Kim at BMO. And the first question will be for both Doctor.
Hogan and Doctor. Barrett. Maybe Doctor. Barrett, I'll start with you on this one. When thinking about where or whether just to, initiate treatment with Parsent ahead of an ACE or an ARB, how much will efficacy versus safety versus price weigh in your decisions?
I think that will, that so I think the first thing to say is that, we will need to see the comparative data. We we are not looking at naive patients patients here. We're looking at prevalent patients in the PROTECT study in IgA who who have failed to respond to RAS inhibitors. So so so we're not going to necessarily extrapolate directly from that study to naive patients who will be given who where there may be a choice. I think the first thing to say is this drug will be introduced as an add on therapy, and as we get more used to its experience and perhaps further studies are formed, we will know as a head to head in naive patients at the time of diagnosis which of the two would be the the beneficial, therapy.
My view is sparsentan comes with a maximal ARB included with it for free as it were. So so it may well be that we will be moving relatively quickly from it as an add on therapy when, we fail to get maximal proteinuria reduction to the first therapy of choice. And I think I come from an NHS, which is very different to the health care model in The US, and I think that will very much determine how it is introduced into clinical practice, and that will be the same across the world in terms of health care models. I think the key thing that will drive me will be its safety and efficacy in terms of in terms of what the PROTECT study delivers in IGA. So I'm very excited to to look for and look forward to the proteinuria data and the EGFR data.
I think it's too soon to say where it will fit. I think it will very much begin as an add on therapy to those patients who have failed the fifty percent plus who failed to achieve maximal proteinuria reduction, And I would imagine there will be a drift to this drug being started in RAS naive patients over time, hopefully, with on the basis of a a new study that will look at that specifically.
Thank you, doctor. Doctor Hogan in FSGS.
Yeah. Think I think within this question is really all of the elements that we're looking at to determine how any drug would fit into our clinical paradigm of using it. Right? So does it work? Is it safe?
And and and in The United States, you know, the the difference of of thinking about access to the drug and cost. So certainly, all of these things will be coming into into into effect in our decision making process. That being said, we are coming from a place where we we're not starting a a field where there are other drugs that we could prescribe. There's no approved therapies for FSGS. And so as we have alluded to and as the patients and and members of the video alluded to, you're starting from kind of a very blank slate with regards to what you have to offer to patients.
So I think if the drug is approved, it will have been shown that it was efficacious. As far as safety profile, we'll have to see the DUPLEX data, but the DUET data was very reassuring. And then the price comes in, and that is a complicated issue that is patient specific with regards to insurance, etcetera. But if we know again, for my patients, they come to see me for a second, third opinion usually for, you know, for FSGS, they are, you know, they are identifying themselves as the patient population that is most at need for this type of therapy. And so given the, you know, the you you can get into discussions about the cost of health care in The United States and the burden of CKD and ESRD as I've already been alluded to.
So I think for that reason, I would be very high on using the drug. But obviously, all of these things would be taken into consideration for the individual patient.
Yeah. And, Chris, I just wanted to come in there because we shouldn't underestimate the cost of dialysis, which is the ultimate alternative, which is incredibly expensive. And if it was discovered tomorrow, it would be a high cost therapy that is would like likely not be available to all. We also need to factor in the cost of treating all the complications of chronic kidney disease, the bone disease, the renal anemia, the acidosis, everything else that comes with that. And if you are able, as I showed from the IGA studies, to delay things by at least a decade, then you are met the the health economic exercise to show what you are saving by giving a therapy here and now, I think, would come out very strongly in terms of treating in a preventative way the progressive disease rather than dealing with development of end stage kidney disease because the option the dialysis option is incredibly expensive.
It's expensive in in Europe, and I know it's expensive in The US. And and so that needs to be really thought about very carefully when thinking about the trade off in terms of cost here and now against what the cost will be in the
future. Great. Thank you both. Another one from from Do. Noah, this one is going to you.
How are you seeing patients in DUPLEX able to tolerate eight hundred milligram dose after titration? Do you have any sense for the dose reduction thus far in in the study?
So as you know, we continue to be blinded, to the data. We can see the patients who are able to get through that titration period to the highest doses, but we don't know which arm the patients are on. So, and we won't know that full data set until, you know, the first quarter of next year. So we don't, I will say in general, we feel confident in terms of patients able to get to the higher doses. And on that aggregated number, it does feel like the titration's working.
But, you know, we'll need to do a more fulsome analysis of patients staying on that dose and what they are between groups. But again, we feel confident based on what we're seeing so far.
Thanks, Noah. And a follow-up maybe for Peter, and this is from Laura Chico at Wedbush. Thanks, Laura. How should we think about the payer mix differences for sparsentan in FSGS versus IgA?
Yes. I assume, Laura, your question is about the payer mix in The U. S. And as I showed in my part of the presentation, in particular IgA nephropathy but also primary FSGS in generally a younger patient population. So when I think about the payer mix and what we're seeing in our research is that about 50 to 60% are commercial coverage, about 25 to 30% is Medicare, I would say about 15% Medicaid and then 5% is others.
Great. Thanks, Peter. And a follow-up from Lisa Bayko at Evercore. And this one is directed towards Doctor. Barrett.
Data for the FSGS study, the DUPLEX study are expected in the first quarter in February, followed by IgA and PROTECT in the third quarter. Do you have any read through from the data in FSGS to IgA in terms of how you're thinking about it? A similar question for Eric.
The diseases are different. The fundamental processes they're affecting in the glomerulus are the same. I wouldn't I would I would not bet my own money on relating the proteinuria reduction seen in FSGS to IgA. I think you will see proteinuria reduction in both, and I'm confident, to be honest, that both of these drugs will prove to be effective, but I wouldn't want to make any direct extrapolation. If you see, for instance, 35, 40% reduction in proteinuria or more in FSGS, I would suggest that that is very encouraging for the IgA, but I wouldn't like to say whether you'll see more or less in IgA nephropathy.
I I just I can think the diseases are different and the patient populations are different. What I've said before is that I think FSGS is a more challenging disease to study. And from an IgA nephropathy perspective, that gives me great confidence that we're going to see an effect in IgA nephropathy because you've already hit a target in the DUET study with a more challenging disease like FSGS. And so that from an IgA perspective, that fills me the confidence that you've seen the effectiveness that you have seen in FSGS. And and I would and I think that from an IgA perspective, I'm feeling very happy that endothelin receptor antagonism is going to offer me another option for my patients.
So I'm gonna agree with doctor Barrett. I think, you know, it certainly would help in building confidence if we see positive results next quarter from DUPLEX, that it certainly would build confidence. But it doesn't guarantee success. These are different trials, different patient populations, and I think the inverse is true as well. If we see something come out of DUPLEX that isn't as positive, that doesn't necessarily mean a direct read through for IGAM because, again, they're different populations, different trials.
The good news is we're not going to have to wait that long. We're going to see results from both of these quarter, and we're going to see, or, next year. We're going to see quarter one and quarter three both of these results. So, the waiting game will not have to be too long.
Great. Thank you both. A follow-up from Laura Chico Laura, thanks again. Doctor.
Hogan, what is the minimum degree of proteinuria improvement you would deem clinically meaningful in the FSGS population?
That's a very good question. You know, I think that what we've seen over time is certainly that the reduction of proteinuria to the levels of the complete response or complete remission, and then initially the partial remission and then the FSGS partial remission endpoint we know are important kind of landmarks. But I think that there's other data, particularly published recently by John Trusz and others that has looked at it more as a continuous reduction of proteinuria on a continuous variable perspective that the lower the reduction in proteinuria, the better. But really any reduction in proteinuria does improve kidney outcomes from the reference range of no reduction in proteinuria. So clinically, what's meaningful is any reduction in proteinuria.
I think that the statistics may support that the lower you go, the better on a percentage basis, and that by reaching those those landmarks of complete response or partial response or, you know, FSGS partial response endpoint that you may demonstrate this, you know, significance in that way as well. So I think from a clinical perspective, that would be my answer is that really any reduction is meaningful, and the statistics of some recent studies tend to support that. Although certainly, we would be trying to push down clinically as low as you can go. And that's why I think you start to think about the complete remission data and how strong that is with regards to patients, you know, kidney survival in the long term, that that would be the ultimate goal and again, the reason to consider additional therapies.
Great. Thanks, Doctor. Hogan. And we've got time for, one or two more. The next question comes from, let's see here.
Let's go to back to Lisa at Evercore. Bill, a question for you. The treatment landscape or the landscape for development programs in HCU, how do you compare TBT058 to any of the other programs that are out there?
Well, I think that there's not a lot of work underway in this area, so happy to be working on the most advanced program. The TBT-fifty eight is the leading. It's the only one that's in the clinic dosing patients right now as far as we can tell. There's a program from AGLIA that's unfortunately, they began their study right as COVID reared its head, and I think that they've had great challenges getting started as the whole world of clinical development has felt the impacts of that. There have been other programs in development in the industrial world, in the biotech world that have begun and ended in the past couple of years, and everything beyond that is predominantly in academic labs.
Labs. So there's not a tremendous amount of competing programs to guide off of.
Thanks, Bill. And then the last question for this session, I know we've got quite a few more in here. So I will follow-up with all of you individually and make sure we get responses for him that we didn't cover off. But for Doctor. Barrett, can you talk a little bit more about the strengths and weaknesses behind the predictive treatment effect based off of on ESTD ESTD based off the Kaplan Meier curve that you presented in your presentation.
This one's coming from Maury Raycroft, Jefferies.
Yeah. So so I presented two sets of data. The first from the kidney health initiative, which looked at the relationship of proteinuria reduction, early proteinuria reduction, and that's relationship to long term kidney protection. And that essentially has used the patient level data from every patient involved in any randomized controlled trial in IgA nephropathy ever that had both early proteinuria data and long term kidney outcome data. So that data is highly robust.
It was used by the KHI group, which is the combination of the FDA and the ASN and was the basis for our white paper supporting an early reduction in proteinuria as a reasonably likely surrogate for long term kidney protection effects and and really accelerated drug development programs by giving the opportunity for an accelerated approval based on an early change in proteinuria. What we did with the data that I have in my own registry, which is a very large registry in Leicester of IgA patients, is we looked retrospectively at what the outcomes were in my cohort who we don't immunosuppress, but we do treat with maximal tolerated RAS inhibitors. And so what we did was we took those patients who were maximally treated with supportive care, and we looked at those who had still more than one gram of proteinuria over over twenty four hours after ninety days of maximal supportive care. And the Kaplan Meier curve there, the for the Lester data showed what happened to those patients over time. We then projected, I did projected what an effect would be of a 30% reduction in proteinuria on the outcomes of that cohort using the data from the KHI working group.
And that was the second curve on the Kaplan Meier graph showing that we were able to shift and delay the progression of kidney disease in the vast number of IgA patients with, a reduction or an extension of over a decade to the time point that patients, that fifty percent of patients met that endpoint, which was for the purpose of this study end stage kidney disease or a GFR of less than 15 mils per minute. And so what that meant was from the time of the start of the study, the time they hit the GFR of 15 or developed endostation kidney disease moved out to twenty four years, which is a con considerable length of time during which we have the opportunity to intervene, as I've said, with therapies that could potentially improve outcome for those patients. So what it what it translated to was that changing the hazard ratio through to what it would actually mean for a patient population, giving them a longer period off dialysis because traditionally, we would be considering dialysis or a kidney transplant when patients hit a GFR below 15 mils per minute. So so that was what, in real terms, it would mean for my population of patients with IgA.
And, of course, that's based on a thirty percent reduction, but it could be a high degree of proteinuria reduction. We could see proteinuria reduction of that magnitude, adding in additional agents could increase that proteinuria reduction even more, and the curve would then move further and further and further away and mean patients had more and more time away away from hitting that target of a GFR of less than 15.
Great. Thank you very much for that comprehensive overview, Doctor. Barrett. This concludes our inaugural Research and Development Day. Thank you all so much for spending a few hours with us and going into, a lot of great detail that I hope will provide some great insights as we move forward throughout the balance of the year and into next year.
I want to specifically and especially thank Doctor. Hogan and Doctor. Baird for joining us and providing their excellent insights. And, we look forward to sharing more with you as we move through into an exciting twenty twenty one. Thank you all very much and look forward to speaking again soon.