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spk03: Ladies and gentlemen, thank you for standing by and welcome to the Riata Pharmaceuticals first quarter 2021 financial results and update on development programs conference call. An audio recording of today's webcast will be available shortly after the call today on Riata's website at riatapharma.com in the investor section. Before the company proceeds with its remarks, please note the forward-looking statements disclosure in the company's press release. The company will be making forward-looking statements on today's call. There are many factors that could cause results to differ from expectations, including those noted in the company's SEC filings. On today's conference call, non-GAAP financial measures will be used to help investors understand the business performance. These non-GAAP financial measures are reconciled with comparable GAAP financial measures in RIADA's earnings release and presentation from today, which can be found on RIADA's website. Today's statements are not guarantees of future outcomes. Please also note that any comments made on today's call apply only as of today, May 6, 2021, and may no longer be accurate at the time of any webcast replay or transcript rereading. Following the prepared remarks, we will open the call up for questions. We ask that you limit yourself to one question and one follow-up so that we can accommodate as many questions as possible. We are joined today by RIADA's Chief Executive Officer, Warren Huff, Chief Research and Development Officer, Colin Meyer, Chief Operating and Chief Financial Officer, Manmeet Soni, and Chief Commercial Officer, Don Burr. At this time, I would like to turn the call over to Warren Huff, Chief Executive Officer of RIADA.
spk04: Good morning, everyone, and thank you for joining us today. We have a number of updates that we're excited to share with you this morning. We'll start on slide four. First off, we're pleased with the US Food and Drug Administration's recent decision to accept our filing of our new drug application for Pardoxelone for the treatment of patients with chronic kidney disease caused by Alport syndrome. The FDA will review the application under standard review timeline, and it assigned a PDUFA date for the application of February 25th, 2022. The FDA also advised us that it is planning to hold an advisory committee meeting to discuss the application. We've been actively preparing for this meeting the last several months, and it will be a key focus for our team during the year. With clarity on the review timeline for our NDA, we're continuing our preparations for the commercial launch of Vardoxelone in the United States, subject of course to approval by the FDA. Our core commercial leadership team is already in place, and we're building the organization, infrastructure, systems, and processes necessary for the launch of Vardoxelone in the U.S., These include sales, marketing, market access, patient support, and distribution. We're pleased to have Dawn Burr, our Chief Commercial Officer, join us on this call and look forward to hearing more from her about our commercial launch preparations later in the call. Next slide. Beyond the acceptance of our filing of our NDA for Bardoxelone for Alport Syndrome, we've made significant progress in our Falcon study of Bardoxelone in patients with autosomal dominant polycystic kidney disease Since our last earnings call on March 1st, we've enrolled over 70 patients, and we continue to anticipate completing enrollment at Falcon by the end of the year. Regarding our pivotal neurology program with OMAV in Friedreich's ataxia, we previously reported positive results from the MOXIE pivotal trial, the baseline controlled study, and the delayed start analyses. The FDA recently granted our request for a type C meeting, which is scheduled to occur in this quarter. At that meeting, we plan to present data from the delayed start analyses that we believe supports OMAP's potential as a disease-modifying therapy in FA and discuss next steps for the FA program. With that introduction, I'd like to turn the call over to Colin, who will discuss recent updates to our development pipeline. Don will then provide more detail on our ongoing commercial readiness preparations. Finally, Mammit will review our financial results and provide an operational update.
spk01: Thanks, Warren. I'll provide a high-level overview of our Alport syndrome program, and we'll then review the progress of our other development programs. Starting on slide eight, Alport syndrome is a severe hereditary form of CKD, which is caused by mutations in collagen that promote inflammation, fibrosis, and loss of kidney function. Unlike other forms of CKD, which generally progress more slowly and have low rates of actual progression to kidney failure, patients with the most severe forms of Alport syndrome have a 100% lifetime risk of kidney failure. The high risk of kidney failure is due to the very rapid rate of progression observed in Alport syndrome, as shown on this slide. Adult patients with Alpert syndrome progress two to three times more rapidly than patients with more common forms of CKD, such as diabetic, hypertensive, and ADPKD. The rate of progression of Alpert syndrome is very rapid in pediatric patients. Alpert syndrome in pediatric patients progress approximately four times faster than the most common cause of kidney failure in children, KAKET, which is caused by congenital abnormalities of the kidney and urinary tract. Next slide. The clinical meaningfulness of the rate of loss of kidney function is exemplified on this slide, which shows the time to kidney failure based on historical EGFR data from patients enrolled in the Phase III cardinal trial. The data on the left side of this plot are historical data collected over a five-year period before patients entered cardinal, which is noted as year zero on the x-axis. The overall trajectory is shown in gray and the pediatric patients are shown in dark blue. If these same patients followed the same rate of loss in kidney function over subsequent years, you can see that on average the pediatric patients would reach end-stage kidney disease in only five years and all patients in only nine years. This explains why Alpert syndrome patients reach kidney failure at such a young age. Unlike diabetic kidney disease patients, who on average reach kidney failure in their 60s, pediatric Alpert syndrome patients reach kidney failure and need a transplant or dialysis in their 20s. Turning to slide 10, the nephrology community has spent decades studying the impact of kidney failure on quality of life and survival. Patients who are able to obtain a kidney transplant require lifetime immunosuppression and often develop associated complications such as cancer. Patients who cannot obtain a kidney transplant typically spend many hours a week undergoing hemodialysis. Beyond the adverse effects on quality of life, renal replacement therapy greatly increases the risk of infections, cardiovascular disease, and premature death. This slide shows the average decrease in life expectancy by age at kidney failure onset. I have highlighted the ages of 15 through 29 years, since this is the age when the vast majority of patients with the most severe forms of Alpert syndrome develop kidney failure. As you can see, once kidney failure occurs in these patients, they have an average loss of life expectancy of approximately 40 years. these data highlight how important it is to slow the progression of CKD. Next slide. As we discussed on last quarter's call, chronic inflammation is a primary contributor to the progressive loss of kidney function associated with numerous forms of CKD, including Alport syndrome. Pro-inflammatory stimuli have two primary effects, including reversible dynamic effects and irreversible structural effects. Pro-inflammatory mediators can dynamically and reversibly regulate single nephron GFR by modulating the glomerular surface area for filtration, or K sub F. In CKD, inflammation is chronically present, which persistently reduces single nephron GFR and is a key feature of CKD. When inflammation persists over long periods of time, as it does in almost all forms of CKD, it also drives kidney remodeling by activating pro-fibrotic pathways. Over time, these chronic processes result in irreversible fibrosis and ultimately the complete loss of function of individual nephrons. The target of baroxone is Nrf2, a transcription factor with anti-inflammatory and tissue protective effects. which is suppressed in many forms of CKD, including Alpert syndrome. Next slide. We have spent over a decade conducting a large number of preclinical studies to characterize the mechanism of action of Ardoxalone, These effects are now well-documented in the scientific literature and demonstrate that bardoxalone restores single-nephron GFR by increasing the filtration surface area in the kidney, reversing inflammation-mediated constriction. We have shown that this effect is not associated with any changes in afferent or efferent tone, demonstrating that this effect is not associated with increases in intracranial pressure or hyperfiltration. This is a novel mechanism to dynamically regulate GFR, and as I will discuss in the clinical data, this manifests in patients as sustained increases in GFR with baroxaline treatment while patients are taking the drug. Now on slide 13, During our development program, we have spent much effort and time to determine how Vardoxalin regulates the kidney's handling of albumin, the most common protein found in the blood. Albumin is often present in the urine of patients with kidney disease due to defects in the kidney's filtration barrier caused by patients' underlying kidney disease. Albumin is pathogenic and causes damage to the kidney when it's excessively reabsorbed into the kidneys, which induces inflammation and fibrosis. In preclinical models, we have shown that baroxone affects albumin handling via two mechanisms. First, baroxone increases GFR, which increases filtration of albumin. Importantly, this occurs without any evidence of increased permeability or injury to the filtration barrier. Second, as we published in 2012, baroxaline reduces the expression of megalin, the primary receptor that reabsorbs albumin in the proximal tubules of the kidney. This shunts albumin into the urine, reducing its reabsorption and subsequent activation of inflammation within the interstitium of the kidney. In summary, bardoxelone increases filtration of albumin and reduces its uptake, both of which are a pharmacological effect not associated with injury. Next slide. In regard to irreversible disease modifying effects, we have demonstrated that bardoxelone has anti-fibromic effects and improves kidney structure and function in response to many models of CKD, including pressure overload, hyperfiltration, hypertension, high protein, diabetes, and dyslipidemia. As I will discuss in a few slides, this effect on fibrosis in patients is represented by the off-treatment improvements we have observed in our Alport syndrome and diabetic kidney disease trials. Turning to slide 15, the clinical data from our Alport Syndrome Development Program map to each of these observations from our preclinical studies. we have shown that the reversible increases in EGFR, which are due to restoration and filtration surface area in the kidney, are durable for two years versus placebo in the pivotal phase three cardinal study. As discussed on last quarter's call, for patients receiving baroxalone, which is the MITT analysis shown on the slide, separation occurs in the baroxalone relative placebo treated patients in the second year. The rate of loss of kidney function based on the on-treatment changes in the second year is reduced by approximately one-third. Consistent with the separation in year two of cardinal phase three, in the ongoing EGLE extension study, we have shown that these increases are sustained for a total of three years. This duration of sustained EGFR increase is meaningful since, as I mentioned a few slides ago, on average, these patients would reach kidney failure in five to nine years. We have also demonstrated a persisting increase after withdrawal in EGFR versus placebo after year one and year two in the phase three cardinal trial. And we believe this increase is due to the anti-fibrotic effects of our oxalone and is consistent with the disease modifying profile. These off-treatment improvements also validate that the large durable on-treatment increases in EGFR are beneficial. When we analyzed the off-treatment data using a longitudinal analysis to compute off-treatment slopes, as opposed to calculating changes at discrete time points, we have demonstrated that there is a reduction in progression by approximately 50% in the bardoxelone-treated patients compared to placebo-treated patients. The data from the cardinal trial are also supported by data from the beam and beacon diabetic CKD trials that also demonstrated significant on and off treatment improvements in EGFR relative to placebo. Overall, the clinical profile of Ardoxelone is well characterized, and the on and off treatment differences in EGFR observed in the pivotal phase three cardinal trial demonstrate a meaningful benefit in patients with one of the most rapidly progressive forms of CKD. Next slide. Our Alpert Syndrome Development Program has demonstrated an acceptable safety profile. Adverse events were mild to moderate, generally occurred within the first 12 weeks, were reversible with treatment discontinuation, and were not life-threatening. We identified no safety findings in Bartoxelan patients who discontinued and received, on average, 33 weeks of treatment. By the end of the two-year study, these patients had kidney function that was similar to placebo-treated patients, demonstrating that these patients did not experience any adverse kidney findings. Fewer serious adverse events were observed in redox-treated patients. We mitigated against the risk of fluid retention. No new safety signals have been identified in the ongoing extension study. Overall, our Alport syndrome data are consistent with a comprehensive safety database of over 3,000 patients. In summary, we believe our data demonstrate that Bredoxone targets the underlying pathophysiology of Alport syndrome, and our clinical safety and efficacy data support an acceptable and positive benefit-risk profile for Bredoxone for the treatment of Alport syndrome. We'll now discuss our other CKD development programs on slide 18. As you know, we are also developing baroxone for the treatment of patients with ADPKD, the most common hereditary form of CKD, with approximately 140,000 diagnosed patients in the U.S. Despite standard of care, a high percentage of patients ultimately progress to kidney failure. Similar to the Cardinal trial, the Phase III Falcon trial is two years in total duration, and the key primary and secondary endpoints are at the end of the first and second years of treatment. We plan to enroll approximately 550 patients from sites in the US, Europe, Australia, and Japan. Currently, more than 290 patients have been enrolled in Falcon, and we expect to complete enrollment by the end of this year. As shown on slide 19, In the first quarter of 2021, we initiated MERLIN, a double-blind, placebo-controlled Phase II trial evaluating the safety and efficacy of ratoxelone in patients at risk of rapidly progressing CKD due to multiple etiologies, including common and rare forms of CKD, such as diabetic CKD, hypertensive CKD, IgA nephropathy, FSGS, and others. The primary endpoint of Merlin is the change in EGFR from baseline to week 12. We plan to enroll approximately 70 patients aged 18 to 70 with EGFR between 20 to 60 ml per minute and with one of several risk factors for rapid progression. We anticipate complete enrollment by the end of the second quarter of 2021. If the results of the study are positive, we would potentially proceed to a larger phase three trial with similar eligibility criteria. Patients at risk for rapid progression experience a significant risk of progressing to end-stage kidney disease in a population with high unmet need across multiple forms of CKD. Now, turning to slide 22 with our neurology programs, I will provide an update on our program with omaviloxelone, or omav, and Friedreich's ataxia. FA is a rare disease characterized by progressive loss of motor function, with patients typically requiring a wheelchair by their mid-20s and a median survival of 35 years. There are no approved therapies for FA. On our last call, we highlighted the results from the delayed start analyses where we compared patients initially randomized to placebo and OMAP to each other in the extension. We believe these analyses demonstrate that OMAP's profile is consistent with disease modification. We requested, and the FDA granted, a Type C meeting to discuss the delayed SART analyses, as well as the overall data from our MOXIE study and the overall development program. The meeting is scheduled for the second quarter of 2021. Next slide. We believe that the pharmacology of our Nrf2 activators may be applicable to a wide range of other neurological diseases that have a common pathophysiology of mitochondrial dysfunction and neuroinflammation. OMAD and analogs have shown activity in numerous non-clinical models, as well as patient biopsy samples, and we believe that pharmacology is applicable to a broad set of neurological diseases, including other movement disorders, such as PSP, Parkinson's disease, and Huntington's disease, as well as diseases that affect neuromuscular function and memory. Finally, on slide 25, our earlier stage pipeline includes RTA901, a highly potent and selective oral small molecule C-terminal modulator of HSP90. HSP90 is a molecular chaperone that facilitates the folding and stability of many proteins. RT-901 increases transcription of HSB-70, another molecular chaperone that promotes cell survival in response to stress and affects mitochondrial function. RT-901 has demonstrated activity in multiple models of diabetic neuropathy. It has been shown to reduce pain acutely in models of painful diabetic neuropathy, as well as recovery of lost sensation in models of insensate diabetic neuropathy. Of the approximately 4 million U.S. patients with moderate or severe diabetic peripheral neuropathic pain, approximately half of those treated do not achieve an adequate pain reduction with available therapies. We have completed Phase I SAD and MAD studies in healthy volunteers and have demonstrated an acceptable safety profile with no safety signals, drug discontinuations, or SAEs while achieving appropriate safety margins. In the second quarter of 2021, we are planning to initiate clinical pharmacology studies to support the launch of a Phase II study in the fourth quarter of this year in patients with diabetic peripheral neuropathic pain. This study will be a randomized, placebo-controlled, dose-ranging study using a standardized pain scale. I will now turn the call over to Dawn Burr, our Chief Commercial Officer, to provide an update on our commercial readiness for doxilone.
spk02: Thank you, Colin. Good morning, everyone. I'll start on slide 27. It's an exciting time as Riata prepares for our very first potential launch and the commercialization of bardoxalone for the treatment of Alport syndrome, a rare and deadly kidney disease with no approved therapy. With the acceptance of filing of our NDA and PDUFA date of February 25, 2022, our timeline is clear. We've taken concerted steps to ensure launch readiness by Q1 2022 and have hired commercial leadership and their direct reports to support each commercial function. We've also been actively preparing the market through disease education efforts designed to create a favorable environment to support bardoxalone adoption at launch. Our disease awareness campaign launched over a year ago and reaches nephrologists through website, digital, social, print, and broadcast platforms. The objective of the campaign is to provide education on accurate diagnosis and disease severity and highlight the urgency to recognize and treat Alport syndrome. Patient access to therapy at launch is also a key priority. The market access team has designed a distribution program to support product availability at approval. Ongoing payer and pricing research help us understand the reimbursement landscape and identify payer educational needs related to Alport syndrome. as payer education is critical to facilitating patient access at approval. Next slide. Alport syndrome represents a significant launch and near-term commercial opportunity for RIADA. Knowing where patients are and who is treating them today is important to launch planning. Currently diagnosed Alport syndrome patients and the physicians treating them have been located through ICD-10 claims data. Through this data, we believe there are approximately 14,000 projected diagnosed Alport syndrome patients in the United States, with the majority being treated by a nephrologist. Claims data also indicates that there are approximately 4,500 nephrologists with diagnosed patients in their practice. This list can further be refined by volume of patients, allowing us to target our launch planning efforts on the right audience treating patients today. We've also identified key market influencers. These adult and pediatric nephrologists have a broad-reaching presence and are recognized by their peers for their expertise in the diagnosis and the management of Alport syndrome. Continued disease education efforts, genetic testing programs, and the introduction of a specific therapeutic option for Alport syndrome may help to increase awareness and recognition of the disease. Turning to slide 29. With the fundamentals in place, we are now prepared to grow and advance our commercial launch strategy. We've hired a seasoned commercial leadership team with a combined 150 years of biotech and product launch experience at successful companies, including Pharmacyclics, Genentech, Alexion, Shire, and Biomarin. Each has assembled strong teams to support all key commercial functions, including marketing, sales, commercial operations, and market access. In Q1, we finalized the planning for our product distribution platform that will leverage a tightly controlled specialty pharmacy network and front-end patient hub. Commercial drug packaging has been designed. Customer targeting is complete. As launch preparation accelerates, several key events will take place in the coming months, including the deployment of our market access directors. This team will be charged with educating top regional and national payers about Alport syndrome burden of disease, They will share pivotal cardinal data with pharmacy directors and seek coverage and reimbursement of Bardox alone upon approval. Additionally, we will finalize our patient access programs and design services to support reimbursement of out-of-pocket patient costs and bolster patient adherence to therapy. Branded launch development will gain momentum, and we will prepare to onboard, train, and deploy our first sales force, a small focus team of nephrology specialists. We are moving forward quickly from a very strong foundation. I'll now turn the call over to Mammeet to provide a summary of our financials for the quarter.
spk00: Thanks, Warren, Colin, and Don, and good morning, everyone. Please refer to our press release issued earlier today for a summary of our financial results for the first quarter of 2021. I will be covering three topics, our cash position, our Q1 financial results, and our operational readiness. Let me start with our cash balance on slide 31. As of March end, we maintained a solid balance sheet with approximately $777.6 million in cash and cash equivalents. In keeping with our current guidance, we expect our cash balance to fund our operations through mid 2024. Moving to expenses, our R&D expenses for the quarter were $34.9 million compared to $47.7 million for the first quarter of 2020. Lower R&D expenses were primarily due to a net decrease in spend related to completed preclinical and clinical studies and manufacturing activities offset by increased regulatory expenses for our NDA submission. G&A expenses for the quarter were $20.7 million compared to $20.8 million for the first quarter of 2020. G&A expenses were consistent with the prior year spent. Our GAAP net loss for the first quarter of 2021 was $67.5 million or $1.86 per share on both basic and diluted basis as compared to a net loss of $48.9 million or $1.47 per share on both basic and diluted basis for the same period of the prior year. Our non-GAAP net loss for the first quarter of 2021 was $41.9 million or $1.16 per share on both a basic and diluted basis. as compared to a non-GAAP net loss of $29.6 million or 89 cents per share on both a basic and diluted basis for the same period of the year prior. The increase in GAAP and non-GAAP net loss is primarily driven by the recognition of tax benefits related to CARES Act, totaling $22.2 million that we recognized in the first quarter of 2020, offset by a decrease in R&D expenses discussed earlier. Moving to non-GAAP measures on slide 32, our non-GAAP R&D expenses were $28.1 million for the first quarter of 2021 as compared to $36.7 million for the same period of the year prior. Our non-GAAP G&A expenses were $12.8 million for the first quarter of 2021 as compared to $13 million for the same period of the year prior. To summarize, our non-GAAP operating expenses were $41.2 million during the first quarter of 2021 with multiple programs reflecting the potential of our pipeline and key regulatory and commercial launch readiness activities. Next slide. We are making the necessary investments to ensure the strong and successful commercial launch of BAROQ's loan early next year pending FDA review and approval. From an operations and manufacturing standpoint, RYADA's current and planned inventories of investigational product and potential commercial product is adequate to meet our 2021 and planned 2022 demands. We are actively engaged in key CMC development, registration, and validation activities across the Bar Oxalum program to ensure commercial availability post-approval and beyond. We continue to invest in and expand our medical affairs team to increase disease awareness and education in the nephrology community for Alpert syndrome. Beyond our Alpert syndrome program, the infrastructure and capabilities that we are building support our long-term goal of becoming a commercial global entity, providing a platform to support multiple additional indications and new product launches over the next several years and beyond. With that, I will turn the call back over to Warren.
spk04: Thank you, Mammeet. As our presentation today indicates, we're making significant progress across our broadening set of programs. Turning to slide 35, we've now fulfilled a major regulatory milestone for Bardoxelone and Alport syndrome. We remain focused on working with the FDA during their review of our NDA, preparing for an FDA Advisory Committee meeting, and continuing our preparations for a commercial launch next year pending FDA approval. Additionally, we remain on track to file our MAA for marketing authorization in the European Union in the fourth quarter of this year. Additionally, we're looking forward to the planned Japan new drug application submission by our partner in Japan, Kiowa Kirin, for bardoxelone for the treatment of CKD caused by Alport syndrome in the middle of this year. Finally, we remain dedicated to advancing OMAV in FA and look forward to updating you on the next steps for this program following our Type C meeting later this year. That concludes our prepared remarks, and we'd like to thank everyone who dialed in. I'll now turn the call over to the operator for questions.
spk03: We will now begin the question and answer session. To ask a question, you may press star then 1 on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw from the question queue, please press star, then two. Please keep your questions to one question and one follow-up. The first question is from Miguel Nochemovitz of Citi Group. Please go ahead.
spk11: Hi, Warren and team. Good morning, and congrats on the NDA acceptance for Alport Central, and thanks for taking the questions. So you mentioned, Warren, in the prepared remarks that you've been actively preparing for the ADCOM over the past several months. So could you discuss what you believe will be the key issues you expect to be raised by the advisory committee regarding the rhodoxylone clinical program in Alport and how you are preparing to address these issues? Thank you.
spk04: Yes, sure, Nicole. Thanks for that. Yes, I think that we've been, as I mentioned, in active preparation. you know, with first-class outside help and review and, of course, have gotten, you know, good review of the data and program by many outside key opinion leaders as well as the advisors that I mentioned. I think the issues that we anticipate are basically just the known issues around our program. You know, bardoxaline is a, you know, new molecular entity with, you know, a novel mechanism of action It has, you know, a very different mechanism than the agents that have previously been approved in the CKD space, like blood pressure medications and the SGLT2 inhibitors. It directly treats the inflammatory processes. We see nice improvements in GFR that have not been observed frequently. Obviously, the effect of those was a key feature of the design of the clinical program, the off-treatment key secondary analysis. I think that those issues will be kind of the key issues that will be explored in the review process and at the adcom.
spk11: Okay, got it. And just one quick follow-up. Do you have any thoughts on why the FDA opted for standard, not priority review, given the severity of Alport syndrome and the lack of any approved therapies to treat Alport?
spk04: Well, I think it's the same answer. It's that the, you know, Bardoxylin is a new molecular entity. Again, it has a novel mechanism. It's unlike other agents that have been approved. And so it presents, you know, novel review issues that I think they wanted to give themselves plenty of time, you know, to review. I'd also just note that, you know, they have deferred the PDUFA dates on two other programs, you know, in review recently.
spk11: Got it. Thank you.
spk03: The next question is from Carter Gold of Barclays. Please go ahead.
spk05: Good morning and congrats on the FDA acceptance. I guess coming back to the sort of OMAP type C meeting, can you just discuss at a high level sort of the range of potential scenarios coming out of that meeting as you think about it and how you anticipate communicating feedback from that meeting? Could that be something delivered inter-quarter or are we going to have to wait until the 2Q call for that? Thank you.
spk04: Colin, would you like to address that?
spk01: Sure. And so we've provided guidance since last year that FDA has requested additional evidence of persuasiveness before they're willing to accept an NDA. And so we've been working collaboratively with at the division to try to provide additional analyses that we hope will influence their view on our development program. We need to have the meeting with them in the second quarter, this quarter, and we will be prepared to release the findings of that when it's clear to us and we'll provide guidance on what the next steps will be with the development program.
spk03: The next question is from Mari Raycroft of Jefferies. Please go ahead.
spk07: Hi, everyone. Good morning. Congrats on the progress, and thanks for taking my questions. Just to follow up on the Friedrichsthataxia question, I guess just checking if you have any additional clarity on EMA's views on your Friedrichsthataxia data, and is there a path forward in the EU that could be independent of the second pivotal?
spk01: We're in the process of seeking guidance from the EMA, and we'll incorporate that into the development program. And so at this point, we have no additional comments on what they may require of us. Got it.
spk07: Okay. And then for the Kirin Phase 3 study in diabetics, CKD in Japan, data aren't expected until first half of 22. Just checking if there is any possibility for FDA to request blinded data from that study or potentially from the Falcon ADPKD study to augment their L-PORB review, or could Rihanna potentially submit some blinded data from either of those studies to help with the review?
spk01: Yeah, so Maury, those studies are ongoing, and we view it as highly unlikely that they will request any data from those two ongoing trials that, by the way, are overseen by an independent data safety monitoring board. And so our NDA filing for Alpert syndrome, it doesn't just include the approximately 200 patients that we've treated with baroxone who have Alport syndrome. It includes a data set of 2,500 people who have been exposed to baroxone with hundreds of other placebo-treated patients. And so in our view, it's a very large data set for FDA, especially for such a rare disease. We believe the safety profile is very well characterized, and as I've discussed earlier, This call and the past couple calls in the Alport syndrome program, the adverse event profiles, very similar to what we've seen in prior trials. The frequency of serious adverse events was actually cut in half in the paroxysmal group relative to placebo. There were no signals for fluid retention that we observed in a trial in 2012. In Alport syndrome trial or any trial since then that have enrolled over 600 and exposed 600 people to paroxysmal, From our perspective, the safety data is very well described. One last point is that we've been able to characterize the specific adverse events of interest that we've seen. For most of them, we have peer-reviewed publications that we believe describe the underlying mechanism of action in pharmacology. Clearly, all this is very well detailed in the NDA that we submitted. It's our view that the safety profile is very well characterized.
spk07: Great. It's all helpful perspective. Thanks for taking my questions.
spk03: The next question is from Annabelle Samimi of Stiefel. Please go ahead.
spk09: Good morning, everyone. This is Nick Rubino on for Annabelle. Our congratulations as well, and thanks for taking our questions. I think we, along with most you know, everyone else as well, expect the topic of hyperfiltration to be front and center at the adcom. What can you provide to the FDA to get them comfortable with the EGFR increases? Can you demonstrate that the EGFR increases are due to increases in glomerular surface area rather than forced filtration? And are there other factors that you're using to demonstrate lack of damage?
spk01: Yes. So we obviously, as I've talked about on many calls over the past few years, we've spent literally over a decade to characterize the novel profile of bardoxelone. And so from a preclinical perspective, we've conducted a few studies, including working with one of the top labs in the world, Professor Kashihara in Japan. who's the president of the Japanese Society of Nephrology, and using sophisticated imaging techniques in living animals, he's shown that baroxalone increases single nephron GFR without increasing pressure in the kidney, and the increase in GFR is due to an increase in infiltration surface area, which is constricted in many forms of CKD. And so those data have been presented publicly. We have other peer-viewed manuscripts that support these findings. We've demonstrated in other models of hyperfiltration specifically that bardoxone and analogs are protective And so from our perspective, we've thoroughly characterized the specific mechanism of action in relevant animal models. And there's actually no controversy about what the drug is doing. I think clinically it's important to note that you can never prove mechanism in people. And since the FDA acknowledges that, They've required a trial design that, in their view, would allow them to determine if the mechanism of action of baroxalone is beneficial or harmful, independent of mechanism. And that's why they gave us the two-year trial design for both Alpert syndrome as well as for ADPKD. Recall, this is the same endpoint, the off-treatment endpoint, that served as a basis for approval for colvaptin for ADPKD. And so in FDA's view and the view of the National Kidney Foundation's working group with FDA and EMA, in settings where there's an acute effect of a drug that either increases or decreases GFR, the way to appropriately assess for any disease-modifying activity is to withdraw the drug, which we've done twice in the Alpert syndrome trial, and both times have demonstrated a persisting increase in GFR versus placebo, which not only rules out harm, but it validates that the on-treatment changes are beneficial. And recall that they're sustained for two years versus placebo and three years in the ongoing extension study. The one known profile of hyperfiltration is with amlodipine, a specific type of calcium channel blocker, that in a study called ASK resulted in a very small transient increase in GFR that peaked at month six and was lost after that. And so the profile is very different. We observed sustained large increases for three years. And once again, the purpose of the off-treatment endpoint was to address this very question. And so, once again, I think clinically this is well described. Yes, hyperfiltration may come up, but we think we have, you know, literally spent years to address this question, both mechanistically and clinically.
spk09: Great. That was an awesome review. Thank you. And that actually kind of leads into my follow-up. In terms of how much of the three-year data from EGLE are you going to be able to discuss with the FDA by the time of the adjunct?
spk01: So we have publicly disclosed data obviously from the EGLE trial through three years and that's phase two patients. We have many patients from phase two but also the phase three trial who are still being followed in the EGLE trial. All of the data that we had, the data cut use for the NDA were included in the NDA itself. And so, you know, publicly we will disclose, you know, data as it matures, but FDA has access to all those data, and we think that it provides additional support beyond, you know, the primary cardinal data.
spk09: Great. Thank you very much.
spk03: The next question is from Brian Scorny of Baird. Please go ahead.
spk08: Hey, good morning, guys. Thanks for taking the question. First one on Bardoxalone. As part of your partnership with Karen, I'm just wondering if you will be able to submit any of the safety data to the FDA during the course of the review of Bardoxalone for IOMI. Obviously, there's a lot of information on that. In fact, I'm just not sure what the partnership sharing privileges are and if the FDA would have access to that.
spk04: No, I mean, under the Arranges, we'll have access to the data when the trial's completed, but it's an ongoing, you know, blinded study. So we wouldn't anticipate, you know, being able to use that data, you know, during the current review of the Alport syndrome, you know, NDA.
spk08: Got it. And then on the Type C meeting for OMav, do you know currently who's going to be in attendance there and I know that that Farah has the petition out to the FDA. And we're just wondering if you know if Farah has a meeting with FDA. I know other examples where senior leadership hold meetings with advocacy groups around new drug applications outside of the sponsor.
spk04: No, we actually don't know actually who will, you know, be in attendance. You know, at the Type C meeting we make requests, but you really never know until you actually attend the meeting. And we're not privy to or aware of what the FARA's activities are with respect to their interactions with the FDA. Great.
spk08: Thank you.
spk03: The next question is from Charles Duncan of Cantor Fitzgerald. Please go ahead.
spk10: Good morning, everyone. Warren and team, congrats on the progress and the acceptance. Also, clearly, certainly Colin seems ready for an ADCOM presentation. I had a quick question on the OMAD program. I guess I'm wondering if there's a possibility For another pivotal study, I think you kind of outlined that in or point to that on slide 35. But would the next steps be another pivotal study in Friedreich's ataxia? Or could you see moving to another potential indication or moving on to a different candidate? What do you anticipate for the neurology program going forward?
spk04: I think we're committed to pursuing the approval of OMAP for Friedreich's ataxia. Despite the fact that we have not yet been able to submit an NDA and we may have to do another study, we have a very well done pivotal study, the largest one that's been done in FA patients with a clearly positive result. It will be a disappointment if we have to repeat or add to that, but we're prepared to do it and we feel like there will be high enthusiasm for the study and that we could execute it in a very efficient way with relatively low risk since we already have one positive pivotal study in hand. So we very much believe that the pharmacology is applicable to a broad set you know, of neurodegenerative diseases, as Colin outlined earlier. But, you know, we have business to finish in FA first.
spk10: Yeah, that suggests another question to me that I'll take offline regarding strategy. But I did have one question for perhaps Don or Colin regarding the total addressable market When you think about ADPKD in patients that have high percent or probability of progression and then those patients included in the Merlin study, can you give us a sense of the total percentage or total amount of patients that you could see being able to treat with bardoxalone if it demonstrates the clinical activity that it's shown in Alport syndrome?
spk01: Chas, are you specifically referring to the Merlin patient population or ADPKD only?
spk10: Well, it's kind of both. ADPKD for those patients who have high probability of progression, but also Merlin, if you could group those or you want to split them up.
spk01: Okay. We don't have estimates right now, but we think the number is obviously much larger than just the Alpert syndrome in the PKD population. I think what's different about our approach than other approaches recently is that there's been several trials conducted with agents that affect pressure within the kidney, SGLT2 inhibitors that complement ACE inhibitors and ARBs. They treat the underlying cardiovascular disease. It's typically systemic. that affects the kidney and promotes progression. We're targeting intrinsic kidney disease using the MERLIN trial, and so trying to exclude out the patients that have cardiovascular disease and identify those that still have rapidly progressive disease despite all available therapies. And so we're not willing right now to comment on that opportunity, but I think it's broad.
spk10: But you see this being able to provide a target product profile that may ultimately be, if not disease-modifying, certainly a delay to kidney progression.
spk01: Yes, for patients who are at risk, and this ties into our thesis for Alpert syndrome, and as I discussed here, and I think it's been lost a little bit, that Alpert syndrome is extremely rapidly progressive, and so the first few slides that I presented, I think people have thought that, okay, Alpert syndrome progresses a few multiple minutes faster, but it's still kidney failures far off in the future, but for Alpert syndrome patients, it's five to nine years on average, and you see the the figure, the plot. And so we're targeting patients like that who likely have some inherited or acquired disorder and are at risk for progression to kidney failure, you know, not just in their lifetime, but in the near term.
spk04: Yeah, and not just in the near term, but in the near term for relatively young patients.
spk00: Excellent. Thanks for taking the time. And that's the whole concept. I think that's the whole concept for Merlin, right, where we are only – concentrating on the risk of rapid progression in those multiple etiologies, right, of CKD.
spk10: Appreciate that, Tyler, and me. Thank you.
spk03: As a reminder, if you have a question, please press star, then 1. The next question is from Joseph Schwartz of SVB Lyric. Please go ahead.
spk06: Hi, thanks and best wishes heading into a couple of very important FDA meetings soon. I was actually hoping to ask on both of them for BARD and OMAV. First on BARD, the FDA seems to be making life difficult for many sponsors lately by taking issue with things that seem to be taken for granted in the past. So how confident are you that you're on the same page with the division reviewing Vardox alone and that you've followed their guidance to a T because this increasingly seems like it will be required to bring any new drugs to market nowadays?
spk01: Joe, so I think that we've been transparent with our discussions with the agency, dating back to our pre-IND meeting with Alport Syndrome, which we had in 2016. They gave us the design for the Alport Syndrome trial, which we've executed. They gave us the same design for the Falcon trial, and as I mentioned previously, it's the same endpoint that serves as a basis for approval for colbaptin. And so from our perspective, the design is what they told us to do. We've executed it. We don't believe there's any discrepancies between what they told us to do and what we've executed. From an analysis perspective, we defined a statistical analysis plan. Of course, we had filed it with FDA, being transparent in the way that we analyzed the data. So I think that we've done all that we can do to transparently conduct and analyze the trial and provide the data to FDA. And I think it's distinct from other, so I don't think that any of the recent issues that you may be alluding to are relevant to us. Okay.
spk06: Yeah, that's helpful. Thanks. I mean, I recall that you refined the STAT plan. That seemed to be good, proactive work, so hopefully that will help. Now, just on OMAV, I was curious how much of your upcoming Type C meeting will focus on the delayed start analyses that you have now versus establish what's required for the next pivotal trial for OMAV, and what is the purpose of discussing the former if the latter is already expected to be required?
spk01: We're gonna discuss the overall set of data that we've generated. And so what's new are the delayed start analyses. And it's important because we believe the data demonstrate disease-modifying activity. And if FDA agrees with that interpretation, that would put them in a position where they will view the development program differently. And so we're hopeful that, once again, upon review of all the data, that we'll have a successful meeting. And once again, we'll provide guidance about the outcome once it occurs. But it's not just about the laser analysis. It's about the overall development program and data generated to date.
spk06: Great. That's helpful. Thanks for taking my questions. You're welcome.
spk03: Thank you. And I'm showing no further questions in the queue at this time. Ladies and gentlemen, thanks for your participation on today's conference. As a reminder, an audio recording of the call will be available shortly after the conference call on Riata's website at riatapharma.com in the investor section. Thank you very much for your participation. You may now disconnect.
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