Reata Pharmaceuticals, Inc.

Ladies and gentlemen, thank you for standing by and welcome to the Riata Pharmaceuticals fourth quarter and full year 2020 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 that forward-looking statements disclosed in the company's press release. The company will be making forward-looking statements on today's call, and there are many factors that could cause results to differ from expectations, including those noted in the company's SEC filings. Today's statements are no guarantees of future outcomes. Please also note that any comments made on today's call apply only as of today, March 1st, 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. At that time, we will ask that you please limit yourselves to one question and one follow-up so that we can accommodate as many questions as possible. We are joined today by the company's Chief Executive Officer, Warren Huff, Chief Research and Development Officer, Colin Meyer, Chief Operating and Chief Financial Officer, Manmeet Soni, At this time, I'd like to turn the conference call over to Warren Huff, Chief Executive Officer of REATA.

Thank you. Good morning, everyone, and thank you for joining us today. We have a full agenda of information to share, and I'll begin with our most recent updates, starting on slide four. I'm pleased to report that REATA has submitted its new drug application for rhodoxilone and Alport syndrome. The completion of our NDA follows from the positive phase three year two data we reported just three and a half months ago. This marks a major milestone for our company. It's the first NDA REATA has submitted in its history. More importantly, this NDA marks a major milestone for Outport Syndrome patients who have a devastating disease for which there is no approved therapy. On behalf of everyone at REATA, I extend my deepest thanks to the patients who participated in our clinical trials and also their families. As a serious genetic condition, Alport syndrome can have far-reaching effects on the families who face it. For them, most of all, we're committed to seeing the regulatory process through to completion. As you'll see from our RIADA at a glance slide, we have a number of updates to share today beyond the submitted NDA. Among other topics, we'll highlight the progress of the FALCON study of bardoxelone and autosomal dominant polycystic kidney disease. I'm very pleased with the momentum we see in Falcon enrollment across sites worldwide. Colin will walk through those details. He'll also discuss the Merlin trial of bardoxalone in rapidly progressing forms of CKD. Continuing with recent updates, I want to acknowledge the patient petition that we received from the Friedreich's ataxia community a few weeks ago. More than 74,000 Friedreich's ataxia patients Their families, physicians, researchers, and others came together to express their desire for a regulatory path forward for OMAP. As you know, we issued a response to the petition in which we emphasized our hope to be able to advance OMAP further through the regulatory process pending direction from the FDA. We've requested a Type C meeting to carry the discussion forward. At that meeting, we plan to present additional 72-week data that we believe supports OMAP's potential as a disease-modifying therapy in Friedreich's ataxia. Colin will offer a top-line overview of these data as part of his comments on this call. He'll also offer insights into work underway to develop additional assets in our expanding neurology portfolio. I want to emphasize the strength of our company's position as we move further into 2021. The onset of the COVID-19 pandemic in 2020 imposed significant challenges for Riata at a crucial interval. Our company's mission to develop therapies that can change patients' lives for the better will continue to fuel us on the road ahead. Colin will now discuss updates to our development pipeline.

Thanks, Warren. I'll provide a top line review of progress in our development programs last year. followed by review of updates for a Falcon trial in ADPKD, a Merlin trial in CKD patients at risk of rapid progression, the regulatory status of OMAP and SA, and an update on RTA-901. As we have discussed previously, Alport syndrome is the second most common hereditary form of CKD, which is caused by mutations in collagen that promote inflammation, fibrosis, and loss of kidney function. The misdiagnosis rate has been reported to be as high as 62%, and due to the rapid loss of kidney function, patients have a high likelihood of kidney failure. In the most severe forms of the disease, patients have a 100% lifetime risk of kidney failure, with a median age of kidney failure of 25 years. As shown in the next slide, our NDA contains data from three separate Alport syndrome trials that contain just under 200 unique patients. including the phase two and phase three cardinal studies, as well as the ongoing EGLE open label extension study that is continuing to accumulate data. The EGLE extension study allows patients who complete cardinal to receive open label baroxalone until the drug is commercially available. At this time, we have enrolled 100 patients in the EGLE extension study. Next slide. Unlike most rare disease development programs that contain a relatively small data set, Based on the extensive development history, our NDA contains data from multiple clinical trials in disease states that have enrolled over 3,000 patients, which support our Alport Syndrome NDA. We have shown improvements in kidney function as measured by estimated GFR or eGFR, measured GFR, and creatinine clearance, demonstrating that the changes in eGFR represented as assessed by serum creatinine represents a true change in kidney function. We have shown reductions in inflammatory biomarkers supporting bardoxilin's anti-inflammatory mechanism of action. We have observed sustained improvements in EGFR for up to three years in Alport syndrome patients. Prior to our Alport syndrome trials, we have shown sustained improvements in EGFR for a year and significant improvements in off-treatment EGFR in two prior trials, in the cardinal phase three and a prior diabetic CKD trial. we observed a reduction in the risk of kidney failure outcomes. Next slide. Chronic inflammation is integral to progressive decline of kidney function associated with numerous forms of chronic kidney disease, or CKD, including Alport syndrome. Pro-inflammatory stimuli, such as angiotensin II, increase the production of ROS, resulting in glomerular endothelial dysfunction, pathogenic mesangial cell contraction, and impaired podocyte function. These effects reduce the glomerular surface area for filtration, or case of F, which in turn reduces single nephron GFR. In addition, chronic inflammation drives kidney remodeling by activating NF-kappa-B, TGF-beta, and other profibrotic mediators. Over time, these chronic processes result in the complete loss of function of individual nephrons. InterF2 is a transcription factor with anti-inflammatory and tissue protective effects that is suppressed in many forms of CKD. Genome-wide analyses from kidney biopsies across nine different forms of CKD validate the association between impaired InterF2 activity and reduced kidney function across multiple forms of CKD, including Alport syndrome. Next slide. We have conducted a large number of non-clinical studies to elucidate the mechanism of action of rhodoxilone, which is novel. Our academic collaborators and we have conducted sophisticated imaging experiments in living animals to demonstrate that rhodoxilone acutely increases single-nephron GFR by restoring 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. Lastly, we have demonstrated that rhodoxylin methyl has anti-fibrotic effects and improves kidney structure and function in response to pressure overload and multiple classical animal models of CKD caused by hyperfiltration, hypertension, high protein, diabetes, and dyslipidemia. Next slide. Turning to supportive Alport syndrome-specific clinical data that are contained in the NDA, recall that the Cardinal Phase III study was a randomized, double-blind, placebo-controlled two-year trial. The trial enrolled a broad range of patients with EGFR from 30 to 90 ml per minute and age from 12 to 70 years. The primary endpoints were the on-treatment changes in EGFR at weeks 48 and 100, and the key secondary endpoints were the off-treatment EGFR changes at weeks 52 and 104. We believe the on-treatment changes in EGFR represent the full clinical benefit of Bardoxelone, and the off-treatment changes were included to determine if Bardoxelone's EGFR profile is consistent with disease modification and to rule out harm. As shown on the next slide and previously discussed, Cardinal met its primary endpoints, demonstrating large, clinically meaningful improvements in on-treatment EGFR with significant p-values. It is important to recognize the distinction between the ITT and the MITT populations. The ITT analysis includes all available EGFR values from all patients, even if they discontinued drug. This is a very conservative analysis since it is diluted by patients who discontinued drug and are no longer benefiting from the drug. To understand the treatment effect of bardoxalone while patients are actually receiving drug, we prospectively defined the MITT population, which excludes EGFR values once patients discontinued bardoxalone. In clinical practice, when patients are receiving bardoxalone, the MITT EGFR improvement is likely most representative of the actual clinical benefit. As we discussed during our last call, the MITT EGFR change over time in the second year separated for the bardoxalone patients compared to the placebo patients. As you can see on the next slide, all pre-specified subgroups favored bardoxalone. we observed a treatment effect in pediatric patients, adults, males, females, patients with high and low proteinuria across the EGFR range studied, and all major genetic subtypes, and on top of standard of care ACE inhibitors and . As shown on the following slide and previously discussed, Cardinal also met its key secondary off-treatment endpoints. The persisting significant increase in EGFR following washout observed twice in Cardinal provide evidence that the on-treatment EGFR improvement is consistent with a beneficial and not harmful profile. While we believe the on-treatment effect represents the clinical benefit, the off-treatment improvements demonstrate disease modification. This off-treatment endpoint was previously used to support the approval of Tolbaptin for ADPKD. Next slide. Due to the relatively small size of the cardinal trial, which was conducted in a rare disease population, it was not powered to show a difference in the off-treatment EGFR from year one to year two. Additionally, the patients included in each analysis are slightly different due to dropouts, so these independent endpoints aren't directly comparable. To understand the relationship between the off-treatment change after year one and two, we performed a longitudinal off-treatment EGFR slope analysis. This effectively uses paired values from patients to generate individual slopes. These are then used to estimate the population for each treatment group. As you can see in the figure, the dotted lines represent the off-treatment slopes and shows a 50% slower slope for baroxone. This suggests that baroxone is slowing disease progression by 50%. As I mentioned earlier, Vardoxilin has a novel mechanism of action, and sustained increases in EGFR have not been observed in CKD studies with any other intervention. The one intervention that has been shown to increase EGFR, amlodipine, does so by increasing pressure, causing hyperfiltration. In the African American study of kidney disease, also known as PASC, the initial EGFR increase was small and transient. The increase in EGFR was only four mil per minute and peaked at six months of treatment. After this time, EGFR declined quickly and more rapidly than was observed in the other treatment groups. We performed a quartile analysis by EGFR change at week 12 in Cardinal to determine what happens to the patients who have the largest acute changes in EGFR after two years of treatment. As you can see in the table, the quartile with the largest EGFR change had a very large increase in EGFR of 27 mil per minute at week 12. And after two years of treatment, these patients had the largest on and off treatment changes at weeks 100 and 104 relative to all other bardoxelone placebo quartiles. Conversely, the bardoxelone patients who had the smallest acute changes at week 12 had the smallest improvements at the end of two years. These data are very important since they demonstrate that acute increases in EGFR are not associated with accelerated progression of kidney disease long-term and are opposite the pattern of hyperfiltration. Turning to slide 19, as we've discussed previously, the largest improvements in EGFR across all pre-specified subgroups were observed in the pediatric patients. These patients have the most severe mutations and progress at the fastest rate. The improvements in EGFR at least 100 and 104 were large, clinically meaningful, and even statistically significant within the subgroup. Notably, in most forms of CKD, two years of treatment may represent only 10% or less of patients remaining dialysis-free time, since it often takes decades for patients to progress to kidney failure. However, in these patients, with very rapid progression, the two-year duration of treatment represents approximately 30% of these patients' remaining dialysis free time. Next slide. We've previously shown the proteinuria data measured as the urinary albumin to creatinine ratio, or UACR, across all patients. Initial increases were observed in the bardoxone group that were mathematically accounted for by the change in EGFR. which would be expected to increase UACR. Importantly, UACR did not worsen over time, and the values returned to placebo levels during the two off-treatment periods. In the overall population, which was primarily adults, there was only a slight worsening in UACR in the placebo patients, despite the large losses of EGFR. The pediatric UACR data are shown on this slide. and demonstrate a meaningful worsening of UACR in the placebo patients over the two-year duration of the trial. These patients had a doubling of UACR, whereas the bardoxilin-treated pediatric patients had no change from baseline. By week 104, UACR levels in the bardoxilin-treated pediatric patients were reduced when compared to the placebo pediatric patients. We believe the pediatric data highlight the overall data set and provide evidence that rhodoxone has a clinically meaningful and disease-modifying profile. Moving on to other topics, on slide 21, those unfamiliar with rhodoxone's profile sometimes ask if it is consistent with hyperfiltration. As shown on this slide and now extensively studied in non-clinical and clinical studies, the profile is opposite of hyperfiltration. Hyperfiltration is caused by increases in pressure within the kidney that cause damage, including increased permeability to albumin and worsening of fibrosis. We have shown that varoxilin acutely increases GFR by increasing glomerular surface area without affecting intraclomerular pressure or permeability to albumin. In the gold standard model of hyperfiltration, the 5-6 nephrectomy, we observed preservation of kidney function and reduced fibrosis. As mentioned a few minutes ago, the clinical EGFR profile of hyperfiltration clinically is associated with transient, small increases in EGFR, followed by accelerated decline of EGFR after six months of treatment. Off-treatment EGFR changes are worse than placebo, and hyperfiltration increases kidney failure composite events. Bardoxone's EGFR profile is associated with large, sustained increases in EGFR for at least three years, persistent improvements in off-treatment EGFR, and a reduction of kidney failure composite events. The UACR profile of hyperfiltration is associated with initial increases in UACR that are out of proportion to changes in EGFR and continue over time. Off-treatment values are higher than placebo due to loss of glomerular integrity. Baroxone's profile demonstrates an initial increase that is accounted for by increases in EGFR. plateaus after the initial increase and returns to baseline within four weeks of stopping drug. Therefore, the profile of Arnoxolone is novel and differentiated from hyperfiltration. We believe we have fully addressed this issue and there is no evidence that supports that Arnoxolone's mechanism of action is due to hyperfiltration. Next slide. Clinically, we have observed increases in ALT and AST. which is associated with reductions in total bilirubin or improvement in liver function. While ALT and AST are used clinically as biomarkers of liver toxicity, as seen on the left part of the slide, they are expressed in numerous tissues other than the liver, including fat tissue, the kidney, muscle, the brain, lungs, and others. They have an important role in energy metabolism and glutathione synthesis, which are fundamental processes associated with Nrf2 activation. Genetic suppression of Nrf2 is associated with lower tissue expression and serum activity of ALT, whereas genetic activation of Nrf2 generally increases ALT production and activity. We have shown in cells from multiple tissues, including the liver, muscle, colon, macrophages, and kidney, that baroxone increases production of ALT and AST, demonstrating that these increases are due to pharmacological increases in production. and not injury. Next slide. The clinical profile of ALT, AST, and bilirubin is consistent with data we have published from our prior trials in diabetic CKD. ALT and AST levels peak approximately two weeks after patients reach their goal dose. Levels then trend down to a new steady state, likely as a new equilibrium is reached. And during the off-treatment periods, the levels return to baseline and placebo levels. Across our entire development program and clinical trials conducted to date, we have not observed any cases of Heye's Law, which is associated with large increases in total bilirubin and impaired liver function. Instead, we have observed reductions in total bilirubin or improvements in liver function. In Cardinal, we conservatively implemented stopping criteria in accordance with FDA guidance, and a total of six patients met these criteria. Notably, none of these patients had any evidence of liver injury. We have relaxed these criteria in our ongoing Falcon trial to further reduce these discontinuations. The draft proposed Alport syndrome label provides guidance for monitoring and management that we believe will minimize discontinuations due to these increases. Next slide. Regarding changes in body weight, we have previously shown in non-clinical models that this effect is due to metabolic reprogramming resulting in utilization of stored fuels in the form of fat, increased energy production, and reduced weight due to fat loss. We have shown in four prior trials that changes in EGFR are not due to changes in creatinine production or excretion, demonstrating that weight loss is not due to muscle loss. We have also shown that weight loss is dependent on baseline BMI. In the cardinal trial, there was no correlation between weight and EGFR change. Further, in the pre-specified subgroups of BMI lower than or higher than 30, the EGFR change was almost identical despite the large difference in weight loss of 1.9 versus 7.1 kilograms. In summary, EGFR increases with baroxone are not due to weight or muscle loss and reflect true increases in GFR. Next slide. In conclusion, our Alport syndrome program has been conducted in a rare, severe form of CKD with no approved therapies. Our phase three cardinal trial hit its primary and key secondary endpoints, demonstrated disease-modifying activity and an acceptable safety profile, and is supported by a large safety database of over 3,000 patients. We are pleased to have submitted our first NDA, And we believe that if approved, baroxone may be the first therapy to preserve KD function with disease-modifying effects in patients with Alport syndrome. Next slide. Turning to our ADPKD development program, ADPKD is the second, I'm sorry, is the most common hereditary form of CKD with approximately 140,000 diagnosed patients in the U.S. Despite standard of care, including blood pressure control and one approved drug, patients still lose kidney function at a fast rate. Because of this, a high percentage of patients ultimately progress to kidney failure. Our phase three Falcon trial is currently enrolling patients. Enrollment was paused last year due to COVID, and we've been able to resume enrollment at most sites. Currently, over 220 patients have been enrolled, and we're planning to increase the sample size of Falcon to 550 patients from 300. primarily to account for the increased variability in the second year of the cardinal trial so that we can maintain the same statistical powering assumptions. We are not changing the estimated treatment effect dropout estimate or any other parameters, and this change will make the trial similar in size to other ADPKD trials. Similar to the cardinal trial, the trial is two years in total duration, and the key endpoints are at the end of the first and second year of treatment. Even with the sample size increase, we expect enrollment to be complete by the end of 2021. Turning to slide 30, we recently initiated MERLIN, a double-blind, placebo-controlled phase two trial evaluating the safety and efficacy of rhodoxone 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, IgE nephropathy, FSGS, and others. We plan to enroll approximately 70 patients aged 18 to 70 with EGFR between 20 to 60 ml per minute, and one of several risk factors for progression. The primary endpoint of Merlin is a change in EGFR from baseline to week 12. Enrollment began in February last month, and they are expected in the second half of this year. If results of this study are positive, our plan would be to potentially proceed to a larger Phase Z trial in this population of patients at high risk for progression to kidney failure. Now let's move to our program in Friedreich's ataxia. FA is a rare disease characterized by progressive loss of motor function with a median survival of 35 years. There are an estimated 5,000 patients in the U.S. out of 4,000 diagnosed, and these patients have no approved therapies. On our last call, I stated that we submitted a baseline controlled study to FDA in response to their request for additional analyses to increase the persuasiveness of the MOXIE Part 2 data. After their internal review, they stated that these analyses did not strengthen the results, and they recommended an initial analysis. We have named these analyses the Delayed Start Analysis. and it compares patients initially randomized to placebo and OMAP to each other in the extension. We believe this analysis is intended to determine if OMAP's profile is consistent with disease modification. FDA stated that the potential for these analyses to sufficiently strengthen the study results was questionable due to the small number of patients available for analysis. Next slide. The results of the delayed start analyses are shown on the next slide. We compared the rate of change in mFARS in the extension for the patients initially randomized to OMAP versus those originally randomized to placebo. We conduct the analysis using two populations. First, we used all available data in the extension to compute annualized rates of mFARS change, and 73 out of 82 where 89% of patients who enrolled in MOXIE Part 2 contributed to this analysis. Notably, this is higher than the 14 Part 2 patients who contributed to the baseline control study. Second, we analyzed patients who completed one and a half years in the extension, which includes a total of 20 patients. Eleven of these patients have received OMAP for a total of two and a half years. As can be seen in the figure on the left, which includes data from all extension patients, Once patients entered the extension, those initially randomized to OMAP progressed at a very slow rate of approximately 0.5 mFARS points per year after another 1.5 years of follow-up. Patients initially randomized to placebo progressed about 1.5 points from their initial baseline of MOXIE Part 2 to baseline extension, also progressed at a rate of approximately 0.5 mFARS points per year in the extension. which is slower than the prior rate of progression. In the extension, the slopes are generally parallel and there's no significant difference between them. Most important, patients initially randomized to placebo did not catch up with the patients who were initially randomized to OMAP. If OMAP only provided symptomatic treatment, they would be able to achieve the same treatment response relative to their initial baseline. However, patients who initially received OMAD have been able to maintain better absolute MPHAR scores, demonstrating that the first year of treatment, Emoxy Part 2, provided a treatment benefit. This is the hallmark of disease-modifying activity. The analysis on the right, which includes all patients who have completed one and a half years in extension, shows similar findings. The data at each time point contains the same patients, with the exception of week 100, which has some missing values due to site closures related to COVID-19. In this completer subset, the 11 patients who have received two and a half years of treatment have, on average, not progressed. The patients initially randomized to placebo who progressed while receiving placebo have also, on average, not progressed during the one and a half years on OMAP during the extension. Consistent with the analysis that includes all patients, the patients originally randomized to placebo did not catch up with those initially randomized to OMAD, which demonstrates a disease-modifying profile. Next slide. From a regulatory perspective, we have requested a Type C meeting with the FDA to discuss the delayed start analyses and the development program. Pending discussions with FDA and EMA, we plan to initiate a second pivotal trial of OMAD in the second half of 2021 to support approval. Turning to slide 37, we believe the MOXIE results provide proof of concept for the use of OMAD in other neurological diseases that have a common pathophysiology of mitochondrial dysfunction and neuroinflammation. OMAD and analogs have shown activity in numerous nonclinical models, as well as patient biopsy samples, and we believe the 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 other diseases that affect neuromuscular function and memory. Now on slide 39, our earlier stage pipeline includes RTA901, which is wholly owned by RIATA. RTA901 is a highly potent selective oral small molecule C-terminal modulator of HSP90. HSP90 is a molecular chaperone that facilitates the folding and stability of many proteins critical for cellular viability. Hsp90 also regulates the expression of Hsp70, another molecular chacrone that promotes cell survival in response to stress and affects mitochondrial function. Intermenal Hsp90 inhibitors previously developed as anti-cancer agents increase Hsp70 expression, but also inhibit client protein folding, which results in cytotoxicity. In contrast, RTA-901 increases transcription of HSP-70 without inhibiting client protein folding, resulting in robust cytoprotection in the absence of cellular toxicity. This biology is distinct from our Interactive Activator program, but has many parallels. Next slide. RTA-901 has demonstrated activity in multiple models of diabetic neuropathy. It has been shown to reduce pain acutely in models of painful diabetic neuropathy. Most notably, RTA-901 treatment results in recovery of lost sensation in models of insensate diabetic neuropathy, which is a novel and differentiated profile from other agents that have targeted diabetic neuropathy. Next slide. 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 one SAD and MAD studies in healthy volunteers that demonstrated an acceptable safety profile with no safety signals, drug discontinuations, or SAEs while achieving appropriate safety margins. In the second quarter of this year, we're planning to initiate two additional clinical pharmacology studies to support the launch of the phase two study in the fourth quarter of this year. This study will be a randomized, placebo-controlled, dose-ranging study using a standardized pain scale. I'll now turn the call over to Manish to provide a summary of our financials for the fourth quarter and full year of 2020.