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Thank you for standing by and welcome to Reata Pharmaceuticals Conference Call, during which the company will discuss fourth quarter and full year 2021 financial results and provide an update on its clinical development programs. An audio recording of today's webcast will be available shortly after the call in the Investors section of Reata’s website at reatapharma.com. Before the company proceeds with its remarks, please note that forward-looking statements disclosure in the company’s press release. 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 Reata’s earnings release and presentation from today, which again can be found on Reata’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, February 28, 2022, 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 please limit yourself to one question and one follow-up so that we can accommodate as many questions as possible. We are joined today by Warren Huff Reata’s Chief Executive Officer; Manmeet Soni, President; Colin Meyer, Chief Innovation Officer; and Seemi Khan, Chief Medical officer. Chief Research and Development Officer,; Chief Commercial Officer, Dawn Bir; and Chief Operating Officer and Chief Financial Officer,. At this time, I would like to turn the call over to Warren Huff.
Good morning, everyone. We thank you for joining us today. At Reata, our mission is to development therapies with novel mechanism of action and the potential to have high clinical impact on deadly diseases with few or no available therapies. This is a challenging mission that involves many risks, but is also very meaningful. We announced on Friday that we received a Complete Response Letter from the FDA for our New Drug Application for our bardoxolone program in chronic kidney disease caused by Alport syndrome. This outcome is a significant disappointment for our company as well as the many patients, families and investigators who have participated in our development program for bardoxolone and Alport syndrome patients. In a moment, I'll comment on the implications of the CRL for the bardoxolone program. But before I do that, I'd like to point out that we're well positioned to recover from this setback and achieve our goal of launching our first commercial product. We have a strong cash position, a second program, Omav for Friedreich’s ataxia at the NDA stage and a pipeline of additional development opportunities including our program in RTA 901for diabetic neuropathy entering a Phase 2 proof-of-concept study. With that background, I'll start by providing a brief update on Omav. I'll start on Slide 4. The Omav NDA submission for Friedreich’s ataxia is on track to be completed this quarter and subject to FDA approval, we're planning for the commercial launch of Omav early next year. As you know, we had a pre-NDA meeting regarding Omav for the treatment of Friedreich’s ataxia in the third quarter of last year. During the fourth quarter of last year the FDA granted Omav Fast Track Designation for the treatment of FA. This makes the Omav NDA eligible for Priority Review and Rolling Submission of the NDA. The FDA granted our request for a rolling NDA submission. We submitted the first NDA modules last month and we plan to complete our submission next month. While the FDA has not indicated if they will hold an advisory committee meeting to discuss our NDA, we've initiated preparations for a meeting should they decide to hold one. We're looking forward to working with the FDA on its review of our NDA for Omav throughout this year. FA is a debilitating, degenerative neuromuscular disorder that profoundly affects patient's motor function and in almost all cases shortens their lives. The disease is relentlessly progressive with no approved treatments. If Omav is approved, we're preparing to be in a position to launch this important drug early next year. Turning to Slide 5, I'll now turn to our bardoxolone Development Program and the implications of the CRL. As you know, we've pursued the development of bardoxolone for severe forms of chronic kidney disease, because we believe strongly that the drug has the potential to transform the treatment of CKD. It has a novel mechanism of action that restores mitochondrial function, reduces reactive oxygen species, and inflammatory drive. This mechanism results in acute increases in estimated glomerular filtration rate or eGFR, that are the opposite of the acute decline in eGFR, observed with blood pressure medications that reduce dialysis risk in large clinical outcome studies. Bardoxolone's mechanism of action has been well characterized in hundreds of peer reviewed publications. Despite that, and largely because of the observed increases in eGFR, the mechanism of action and clinical profile of bardoxolone is controversial among many nephrologists. As we discussed in the past, drug development in rare forms of CKD is difficult because the disease progresses slowly over many years, and the decline in eGFR is real and measurable, but not considered a clinical endpoint. In addition, there are not enough patients to conduct a true clinical outcomes or time to kidney failure study. Importantly, the Cardiorenal division of the FDA understands this, and has developed alternate endpoints for these diseases. As all of you know, the Phase 3 CARDINAL study met all four of its pre-specified primary and key secondary endpoints. Importantly, it met these endpoints in patients with a rare genetic rapidly progressive form of CKD. As a result, we believed that the data from the Phase 3 CARDINAL study, as well as the other studies of bardoxolone in CKD, demonstrated a positive benefit risk profile which would support bardoxolone approval. This was also the position of the many key opinion leaders and patient groups that supported approval of bardoxolone. Nevertheless, we received a negative vote at the outcome and a CRL. I believe that the committee was not convinced that the improvements in eGFR would translate into a real reduction in the risk of dialysis or kidney transplant. Without actual outcomes data, questions could be raised about on and off treatment, eGFR trajectories over time, the off treatment period, and changes in clinical chemistry parameters that raise doubts about whether the observed eGFR improvements would actually delay dialysis. Also, some expressed concern that there could be a heart failure risk like that observed in BEACON. Even though we've since implemented risk mitigation procedures in all trials, and have observed no imbalances in heart failure, other cardiac SAEs or AEs, or increases in blood pressure since BEACON. I believe that if the nephrologist on the committee had been convinced that bardoxolone treatment was likely to delay dialysis, we would have received a favorable vote. For this reason, an important event for the bardoxolone development program will be the results of AYAME, a large Phase 3 clinical trial in patients with diabetic kidney disease being conducted by our strategic collaborator in Japan, Kyowa Kirin. Kirin has enrolled approximately 1000, stage III and IV diabetic kidney disease patients in the AYAME study, and all of the patients were having minimum of three years of study drug exposure upon completion of the study. AYAME has as its primary and key secondary endpoints events that are validated to predict the risk of dialysis and transplant, including actual dialysis events, and large declines in eGFR of 30%, 40% and 53%. Kyowa Kirin expects to complete the last study visit in the second half of this year. If the results of this trial are positive, it could provide clinical evidence that improvements in eGFR observed in bardoxolone treated patients do in fact delay progression to kidney failure. Further, since it is such a large and long-term study, it should provide very important information on the safety profile of bardoxolone. It's notable that the study includes a large number of Stage IV diabetics CKD patients. With respect to our programs in Alport syndrome and ADPKD, we've requested a Type A meeting with the FDA to discuss the FALCON study. We're incorporating changes to that study that we believe address the issues raised by the FDA and the AdCom during the review of the Alport Syndrome NDA. Further, we're reviewing the FDA's comments in the Complete Response Letter, and are addressing next steps for Alport syndrome program. We expect to request a follow-up meeting to discuss the program after the Type A meeting for ADPKD. With that update, I'll now turn the call over to Colin who will provide clinical and other regulatory updates on the program in FA as well as an overview of the AYAME study, then to Dr. Khan, who will provide an update on our program with bardoxolone in patients with ADPKD and our program of with RTA 901 in diabetic neuropathy. Finally, Manmeet will provide an update on our financials and operations.
Thank you, Warren. Starting on Slide 7, and as Warren mentioned, FA is debilitating, degenerative neurological disorder that profoundly affects patient's motor functions and in almost all cases shortens their lives. Over time, patients become dependent on walkers, and then wheelchairs, and they ultimately lose their independence altogether. The disease is relentlessly progressive and the median survival for this disease is in the mid 30s. There are no approved treatments for FA. FA is a disease of mitochondrial dysfunction caused by mutations in the gene frataxin, a mitochondrial protection that helps assemble iron sulfur clusters that are necessary with productions of cellular energy in the form of ATP. FA researchers have established that Nrf2 the target of Omav is suppressed in FA patients. This depression contributes to mitochondrial dysfunction in reduced cellular energy production that is the hallmark of FA. FA is the most common recessive form of ataxia and based on literature and proprietary research, we believe FA affects approximately 5000 children and adults in the U.S. Next slide. The pivotal portion of MOXIe was a double blind, placebo controlled, randomized, international study that was one of the largest global interventional studies ever completed in FA. We enrolled 103 patients across a wide and representative range of age and disease severity. The primary analysis population included the 82 patients who did not have the foot deformity pes cavus and the primary endpoint was the change from baseline and mFARS scores at week 48. The progression of FA is measured in clinical studies by the modified Friedreich's Ataxia Rating Scale or mFARS a physician assessed neurological exam. The Friedreich's Ataxia Research Foundation or FARA work with the FDA to develop the mFARS scale to accurately track disease progression in FA patients. This scale was composed of four subsections, including bulbar, upper limb and lower limb coordination in upright stability. As patients lose function, their mFARS scores increase. MOXIe met its primary endpoint of change in mFARS relative to placebo after 48 weeks of treatment. Patients treated with Omav demonstrated a statistically significant placebo corrected 2.4 point improvement in their mFARS compared to placebo after 48 weeks of treatment with a P value of 0.014. Moreover, we observed improvements in all subsections of the mFARS scale in an all major subgroups and analysis populations. This change is very clinically meaningful in that the Omav treated patients did not progress during the 48-week treatment period and recovered function. Further, the placebo corrected improvement is equal to more than one year of progression. In addition to the change in mFARS, several secondary endpoints were included in MOXIe and analyzed hierarchically. While it was not feasible to power the trial for these endpoints, we observed improvements in those secondary endpoints. Next slide. As you know, in the second half of 2020, the FDA provided us guidance that although it did not have concerns with the reliability of the mFARS primary input results from MOXIe Part 2, it was not convinced that the results from MOXIe Part 2 as a single study were sufficient to support approval. To provide additional evidence of persuasiveness, the FDA suggested that we perform an exploratory analysis, the delayed start analysis. In the next few slides, I will discuss the design of the delayed start analysis, and results from an updated data cut from August 2021, which was included in our NDA submission. The intent of the post hoc delayed start analysis is to evaluate whether Omav has a persistent effect on FA disease course. Conceptually, this analysis evaluates whether the treatment effect that was observed in the placebo controlled MOXIe Part 2 study is maintained in the MOXIe extension study, when all patients are receiving Omav. If the treatment effect is maintained in the MOXIe extension study between those originally randomized to Omav versus those who have a delayed start of Omav because they were originally randomized placebo to MOXIe Part 2, then it demonstrates evidence of a persistent effect on the course of the disease. If the treatment effect is not maintained in the patients who have a delayed start on Omav because they are originally randomized placebo, are able to achieve the same absolute response and catch up to the patients initially randomized to Omav, results are consistent with a symptomatic treatment that does not affect the underlying course of the disease. A total of 73 out of 75 patients without pes cavus who completed MOXIe Part 2 were enrolled in the MOXIe extension. Importantly, the MOXIe extension is ongoing, and we continue to accrue long-term safety and efficacy data from the study. The delayed start analysis compares the change from baseline mFARS for patients randomized to placebo during MOXIe Part 2 or the placebo to Omav group to the change from baseline mFARS for patients randomized to Omav in MOXIe Part 2 to Omav to Omav group. Two time points were used in the analysis. The first time point was at week 48, the final week of the placebo controlled MOXIe Part 2 study. The second time point was at week 72 of the open label MOXIe extension in which all patients received Omav. A non-inferiority test was used to evaluate if the difference in mFARS between groups observed at the first time point was maintained or non-inferior at the second time point. Analysis methods, including the pre-specified non-inferiority margin were based on literature. Next slide. In the August 2021 data cut off 58 of 73 patients from MOXIe Part 2 without pes cavus, who enrolled into MOXIe extension had at least 72 weeks of exposure in the MOXIe extension and 28 of these patients had at least 120 weeks of exposure in the MOXIe extension. Results of this analysis demonstrated that the difference between groups was maintained. Specifically, the between group difference in mFARS observed at the end of the placebo controlled MOXIe Part 2 period was preserved at the MOXIe extension week 72 in the delayed start period. Recall that a decrease in mFARS shows improvement. Importantly, the upper limit of the 90% confidence interval for the difference estimate was minus 0.615 meeting the threshold for demonstrating significant evidence that the difference was maintained or was non-inferior, because the treatment effect is maintained between those originally randomized placebo versus those originally randomized Omav. The delayed start analysis provides evidence of a persistent effect on the course of disease. Next slide. The first year of the MOXIe extension study was affected by the COVID-19-pandemic, and many visits that were scheduled during that time were conducted remotely. The mFARS exam cannot be conducted remotely and therefore many patients had missing data during their first several visits of the extension, especially during extension weeks, 24 and 48. Therefore, and in order to compute an annual rate of progression over the entire extension period, we conducted a longitudinal analysis that incorporated all available data from the MOXIe extension. In essence, the analysis computed individual patient trajectories over time, then estimated the group's average slope. For reference, the FARA sponsored natural history studies published data demonstrate a progression rate of approximately two mFARS points per year, over several years of follow up. This analysis includes many hundreds of patients followed for several years. Our longitudinal analysis demonstrates a much lower rate of progression for patients treated with Omav. The two subgroups of patients, placebo to Omav and Omav to Omav, showed similar mean slopes in mFARS with mean slopes of 0.45 and 0.27 mFARS points per year respectively. There was no significant difference between slopes with a P value of 0.79. These data suggests that patients treated with Omav are progressing at approximately one quarter the rate of progression as untreated patients who have been followed in the natural history study. Overall, we believe our data are consistent with a meaningful and persistent effect on the course of the disease. Regarding safety, turning to Slide 12, Omav is generally reported to be well tolerated and reported adverse events which are only mild-to-moderate in intensity, and MOXIe Part 2 only a small number of patients discontinued due to adverse events in either arm. The most commonly reported adverse events are shown in the table on the right of this slide. Increases in aminotransferases are a pharmacological effect of Omav were associated with statistically significant improvements or reductions in total bilirubin, and were not associated with liver injury. The overall rate of cardiac and vascular adverse events was low and fewer Omav treated patients reported these AEs. The overall rate of serious adverse events or SAEs was low. 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 neural inflammation. Based on our understanding of the pathophysiology of neurological diseases, characterized by mitochondrial dysfunction, inflammation and oxidative stress, we believe Omav may be applicable for diseases such as progressive supranuclear palsy, amyotrophic lateral sclerosis, or ALS, Parkinson's disease, frontotemporal dementia, Huntington's disease, Alzheimer's disease and epilepsy. Consistent with this, we've observed compelling activity of Omav and our other Nrf2 activators in preclinical models of many of these diseases. Transitioning to bardoxolone and our CPD programs on Slide 15, I'd like to provide a status update on our Asian strategic collaborators ongoing diabetic CKD outcomes trials, which is called AYAME, this is being conducted in Japan. As Warren mentioned, AYAME is a randomized, double blind, placebo controlled, Phase 3 outcomes trial. The primary endpoint is the time to onset of at least a 30% decline in eGFR, or kidney failure, including dialysis and transplant. Patients with an eGFR between 15 to 16 mL per minute were enrolled, were between 20 and 79 years old. Kyowa Kirin used a similar risk mitigation strategy as we have employed in our recent CKD studies and excluded patients with a history of heart failure, or BNP greater than 200 pg/mL. The trial has a minimum treatment duration of three years, with an expected median duration of treatment of approximately three and a half years. Over 1000 patients were enrolled and the last patient visit is expected to occur in the second half of this year. If this trial was positive and demonstrates that bardoxolone reduces kidney failure events without major safety concerns, we believe these data will be very helpful to support our ongoing programs and to convince the nephrology community that the drug can be used safely and will be beneficial over the long-term. I will now turn the call over to Seemi.
Thank you, Colin. I will start on Slide 16 with bardoxolone program in patients with ADPKD, which is a rare and progressive hereditary form of CKD passed by genetic defect in PKD1 or PKD2 gene, leading to the formation of fluid filled cyst in the kidney and other organs. The Phase 3 FALCON study is an international multicenter, randomized, double blind, placebo control, studying the efficacy and safety of bardoxolone in patients with ADPKD randomized one-to-one to active drug or placebo. FALCON is enrolling patients aged 18 to 70 years with an estimated glomerular filtration rate between 30 to 90 mL. We recently filed a major protocol amendment with the FDA and requested a Type A meeting to discuss the overall ADPKD Development Program, as well as the protocol amendment. The major changes in the amendment included the primary endpoint, sample size adjustment to address the endpoint change, the addition of adolescent patients, and the addition of a sub study for ambulatory blood pressure monitoring. We have changed the primary endpoint from the off treatment eGFR change from baseline at week 52, which is four weeks after the planned drug discontinuation in year one to EGFR change from baseline at week 108, which is eight weeks after planned drug discontinuation at week 100. Additionally, all patients who discontinue early in the study will be requested to return at week 108. In order to maintain statistical power with these changes in the primary endpoint, the sample size has been increased from 550 to 850. Since the primary endpoint will be assessed at year two, we have removed the off treatment period between week 48 and week 52 at year one. We also added an exploratory endpoint of eGFR change from baseline at week 112, which is 12 weeks after the planned drug discontinuation at week 100. We lowered the age limit from 18 to 12, to allow enrollment of adolescent patients with ADPKD. Finally, we added a sub study with ambulatory blood pressure monitoring to further evaluate bardoxolone's impact on blood pressure. More than 500 patients are currently enrolled in the study. Moving to Slide 18, I will discuss our RTA 901 program in diabetic peripheral neuropathic pain or DPNP. RTA 901 is a highly potent and selective small molecule, C-terminal modulator of HSP90. HSP90 is a molecular chaperone that facilitates the folding and stability of many proteins. RTA 901 increases transcription of HSP70, another molecular chaperone that promotes cell survival in response to stress and affects mitochondrial function. RTA 901 has demonstrated activity in multiple models of diabetic neuropathy. It has been shown to reduce pain acutely in rat models of painful diabetic neuropathy, as well as recovery of lost sensations in mouse models of insensate diabetic neuropathy. There are approximately 4 million patients with moderate to severe DPNP in the United States, and approximately 2 million patients diagnosed with DPNP seek treatment annually. Despite several approved therapies for DPNP, a significant proportion of patients do not continue on standard of care due to tolerability and failure to achieve adequate pain relief. Unfortunately about 40% of patients remain refractory to available pharmacological treatment. We have completed a Phase 1 study of 901 in healthy volunteers and demonstrated an acceptable safety profile with no safety signals. There were no drug discontinuations or serious adverse events. The pharmacokinetic profile was favorable. We plan to initiate additional Phase 1 clinical pharmacology study to evaluate the PK and drug-drug interaction in the first half of 2022. Following completion of these Phase 1 studies we plan to initiate a randomized, double blind, placebo controlled Phase 2 study in diabetic patients with peripheral neuropathic pain in the second half of 2022. With that, I would like to turn the call over to Manmeet to provide an update on our operations and financials.
Thank you, Dr. Khan, and good morning, everyone. I'll continue on Slide 20. Given our recent progress toward the NDA review, and approval of Omav for the treatment of FA, we have refocused our efforts and initiated preparations for the potential commercial launch in the United States. We believe FA affects approximately 5000 children and adults in the United States and there are approximately 4000 diagnosed patients in the United States, primarily treated by a variety of specialty physicians and neurologists. Initially, we plan to concentrate our commercial efforts primarily in centers of excellence, specialty clinics, and key neurology practices. Because of this focus, we expect that a small and efficient sales force to be adequate to reach the physicians currently treating patients with FA. Mid last year, we deployed our national accounts team, which is actively working in the field with the payers. In the meantime, we continue to invest in disease awareness efforts to educate physicians on the unique disease symptoms that differentiate patients with FA from patients with similar neurological diseases. Disease education efforts are also designed to help physicians recognize patients earlier in their journey, and to decrease the time to an accurate FA diagnosis. Next slide. Turning to financials, please refer to our press release issued earlier today for a summary of our financial results from the fourth quarter of 2021 and the year 2021. I will focus on three items on today's call; our strong cash position as of year-end 2021, our planned measures to control our future expenses our updated cash guidance. With a strong cash position of $590 million at the beginning of 2022 and given that we have no debt on our balance sheet, we have the financial flexibility to continue to pursue our key priorities as we work to deliver on our mission. Notably, under our royalty arrangement with Blackstone, there are no payments due to Blackstone until we receive approval for bard in the United States or the European region. An important part of our financial flexibility is that we have been able to adjust our expenses very quickly. As a result of the steps we have taken to control our expenses, we have updated our cash guidance, and now expect to extend a cash runway through the end of 2024, as compared to our previous guidance of cash runway through mid 2024. The actions we have taken include pausing all commercial spend related to launch preparation activities for Alport syndrome in the United States and the European region, reducing our field facing sales and commercial teams at the beginning of this year to adjust for the delay in the launch of bardoxolone and to instead focus on the commercial team on the preparations for the anticipated Omav launch in the United States. Totally pausing capital spend activities for the new headquarters building and initiating efforts to sublease that building, at this point, we will not invest the earlier planned $50 million in the capital expenditures. Most importantly, given that these actions now extend our cash runway through the end of 2024 we have no need to raise capital in the near term. This increase in cash runway guidance not only demonstrates our financial discipline and ability to quickly reprioritize our spend but also allows us to focus our efforts toward three strategic priorities as I will detail. The first is preparing for Omav regulatory and commercial success. The second is completing the FALCON study under the amended protocol and resurrecting the the Alport Syndrome program. Third, is initiating our Phase 2 study for the RTA 901 for DPNP in the second half of this year. Moving to expenses, our R&D expenses for the year were $156 million as compared $159.1 million for the same period of the year prior. R&D expenses decreased slightly primarily due to the timing of manufacturing activities. G&A expenses for the year were $99 million as compared to $75.1 million for the year prior. Higher G&A expenses were primarily due to increased spending related to commercial readiness activities and personnel costs to support growth in our development activities. Our GAAP net loss for 2021 was $297.4 million as compared to a net loss of $247.8 million for the prior year. Our non-GAAP net loss for 2021 was $193.9 million as compared to a non-GAAP net loss of $158.3 million for the year prior. The increases in GAAP and non-GAAP net loss are primarily driven by commercial launch readiness activities. With that, I will turn the call back over to Warren.
Thank you, Manmeet. In closing, we're well positioned to recover from the setback in our Alport syndrome program and achieve our goal of launching our first commercial product. We're on track to complete the submission of the NDA for Omav for the treatment of FA this quarter. If approved, Omav will be the first drug available to treat this severe disease and we’re actively working on commercial preparations to be in a position to launch Omav early next year. We believe that the results of Kyowa Kirin’s AYAME study will be an important milestone for the bardoxolone development program. It will provide efficacy and safety data from a large, long-term events trial of the drug. At the same time, we're working with the FDA and assessing next steps on our Alport syndrome program in the U.S. and also continue to enroll patients in the FALCON study and patients with ADPKD. Additionally, we're looking forward to initiating a Phase 2 study of RTA 901 in patients with diabetic nephropathy later this year. As we continue to pursue these efforts, we’re doing so with a strong cash position providing us with the necessary financial flexibility in this environment. Above all, we remain committed to our goal of developing and commercializing novel therapeutics for the treatment of patients with severe life-threatening diseases. So that concludes our prepared remarks. We'd like to thank everyone who dialled in and I'll now turn the call over to the operator for questions.
Ladies and gentlemen at this time we will begin and question-and-answer session. [Operator Instructions] The first question comes from Yigal Nochomovitz from Citigroup. Yigal, please go ahead.
Hi great. Hi Warren and team, thank you very much for taking the questions. So obviously you mentioned AYAME numerous times in your remarks and as you highlighted in the slide, the primary endpoint is a composite of time to a greater than 30% decrease in eGFR from baseline or time to ESRD, and then AYAME also has a secondary endpoint which is exclusively time to ESRD. So, my question is, would hitting on the primary be enough to show positive evidence of disease modification or do you believe you really need that secondary endpoint to work, which isolates time to ESRD, and assuming these endpoints hit, would that be enough in your view to resubmit the Alport NDA? And has FDA expressed any interest thus far in seeing this AYAME outcome data? Thank you.
Sure, I'll take that question and I’ll start with the last part of it first. No, we haven't discussed the design or what the implications of AYAME would be with the FDA. I will plan to do that I think at a minimum when that data comes in. To take the first part of the question, it's in the eyes of the beholder, I think that that study is so large and so long, there are going to be a large number of hard dialysis events as well as large, large declines at that 30% 40% and 53% in eGFR. And so I think if the safety profile was clean and if there is a meaningful reduction, ideally a significant reduction in the heart dialysis events that is going to be extremely persuasive. I also think that if we saw a proportional increases in the heart dialysis events to the large declines in eGFR, that is going to be very persuasive because it provides significant evidence that the eGFR trajectories observed with the drug over time, actually translate into a reduced risk of dialysis events.
Okay thanks very much and just a quick follow up on AYAME. So, the last patient visits is the second half of the year, so should we expect that the top line data are also going to show up in the second half of this year?
No, you have to look to Kirin’s guidance on when they plan to release the data. Manmeet do you...?
Yes Warren. This is Manmeet Yigal. Yes, their current guidance is currently that they would have last patient coming in the second half of this year. They've not guided currently. They have not guided.
Okay and then if I could just ask one quick question on FA. So, if the FA does request an AdCom what do you believe would be the key issues and questions that FDA would bring to the table? But obviously having said that, it's hard to envision what they would want to discuss given the bar is very low and you have positive Phase 3 data following as you know a very long history of disappointment in developing FA drugs?
Yes, I know, I agree. I think it's a really straightforward set of issues for the agency and I really just don't know exactly what they would bring. The panel are mostly general neurologists, so I assume there would be some discussion of the clinical meaningfulness of the change over time and I think that is very easy to demonstrate. The data suggests that there is a significant shortening or reduction in the rate of progression in these patients which is because of the really great work done by FARA, the patient organization, is well understood. So other than that, I really don't know what the discussion would be about. I guess potentially would have to discuss the safety issues associated with it, but those seem very manageable.
Okay, thank you.
The next question comes from Charles Duncan at Cantor Fitzgerald. Charles, please go ahead.
Yes, good morning. Thanks for taking the question, Warren and team, yes and persisting through a challenging time. I had a couple of questions on Omav. I guess I'm wondering if you could characterize your perspectives and the interaction with the agency on Omav versus say bard at this point in the process. I know you're probably not going to provide details, but what do you think about the interactions with the agency thus far on Omav and its history of clinical development? Then I had a follow up on some of the data.
Sure, Charles. Obviously, when we first interacted with this division of the FDA around the positive results from MOXIe Part 2, they initially took the position that we needed to provide additional analyses that would provide additional support for the use of that study for a single study approval, and so we engaged in a dialogue with them all throughout last year providing different analyses. And as Colin pointed out, they suggested in that context that we do the delay-start analysis that he summarized. And as you know, the background is that we submitted that and requested a Type C meeting to discuss it with them and after reviewing the data, they came back to us and told us that it was more appropriate for us to withdraw our Type C meeting request and request a pre-NDA meeting, and they also asked us to focus the questions for the pre-NDA meeting on what we needed to know to get the NDA filed, a traditional pre-NDA meeting. So, we took that as they believe that the delayed-start analysis provided the additional support to allow us to submit the NDA. And then in the pre-NDA meeting, they really focused their comments on the type of approval, on the content of the NDA, and it was very much a straightforward pre-NDA meeting. They also -- they also gave us dispensation on a number of content requirements for the NDA because of the severity of the disease. They allowed us to submit certain clinical pharmacology studies and preclinical studies post approval. So it was a very -- had a very cooperative tone. They did ask us if we were going to submit for accelerated or full approval. We’ve kind of basically said we thought that data supported full. They said that would be a review issue and so that was -- those are the main topics of discussion during the pre-NDA meeting. They also told us that sort of invited us to submit for fast track, which we did following the meeting. They also invited us to request rolling submission, which we did. They granted the fast track. They granted the rolling submission and so that's really where we are. I think that the additional analysis that we provided as well as, I think, other external factors opened the door for the NDA filing for us.
Okay, that's helpful. I appreciate the color. I know it's a difficult question to answer. Regarding Slide 12 and the adverse events, I wanted to ask you if you thought any of them would suggest that you construct a REMS program, particularly the ALT increases, if you think that, that would be necessary and are you prepared to do that? And then with regard to the Omav launch, I assume that you're going to talk more about pre-commercial build once the NDA is filed and accepted for review?
Yes. Manmeet, would you take that -- first?
Sure. So hey Charles, this is Manmeet. Yes, we have, as we -- as I mentioned in my prepared remarks, we have refocused our priority towards Omav launch and as we already had commercial sales team, marketing payer team which were hired last year, and they are now focused towards Omav launch. So that all is already working along with our disease awareness if it's sizing initial targets, all that work has already initiated, and it's well underway.
I'll take the first question, particularly with respect to the transaminases. We think the transaminases, well that there's a very strong evidence that those are purely effect of induction of those enzymes. We have observed no high law cases or other meaningful evidence of actual hepatic injury with Omav or with bardoxolone, and so I think -- also think that the transaminases are clinically manageable. They have a very specific profile of an acute increase that levels off without associated increases in bilirubin. And so we would propose careful management of them and observation in the label, but I don't think REMS would be recorded for that.
Okay, thanks for taking my question. I'll get back in the queue.
The next question comes from Maury Raycroft at Jefferies. Maury, please go ahead.
Hi, good morning and thanks for taking my questions. I'll add a follow-up on Omav. I guess to complete the NDA submission by end of first quarter, can you specify what items are remaining at this point for the NDA, and say where you're at with CMC and manufacturing of commercial product at this point?
Yes, thanks for the question, Maury. Yes, we've submitted both the nonclinical and clinical modules together last month and the remaining section is the CMC. Frankly, when we were delayed with the submission, CMC activities, they got behind, and they're hard to speed up quickly. But yes, so it's the last module that will go in and we're on track to have that completed in March.
Got it. Okay, and also just you probably can't say much because it's related to Kirin, but just wondering if you can provide some additional color on why the JPMDA requested Kirin to get three year or longer data in the AYAME study?
Yes, I'm not going to speak for them. I'm going to just speculate, but I'm assuming because that basically answers the fundamental question about bardoxolone. The theoretical concern has been that the acute increases in eGFR are pressure-mediated, and we've provided a substantial amount and Kirin and have provided a substantial amount of evidence that the increases are not pressure-mediated, that they're the restoration of single-nephron GFR, normal functioning of the individual nephrons. But there's this, because of, I think, the history of development and the understanding of blood pressure medications, there have been a concern. But if there were damage to manifest, you certainly, it would manifest in that three years of treatment. And so, I suspect that the PMDA wanted to see truly the long-term data to definitively, I believe, definitively answer that question.
I think thatm I'd just add, I think 1,000 patients with -- they'll have an average exposure of about 3.5 years because it took them about a year to enroll the study. And so, I think the requirement is that every patient has at least three years of exposure.
Got it. Okay, thanks for taking my questions.
Sure.
The next question comes from Annabel Samimy of Stifel. Annabel, please go ahead.
Sorry. Sorry, I was on mute, but thank you for taking my question. So as it relates to the bardoxolone CRL, I guess I noticed that a number of the issues that FDA brought in ways to resolve them were specifically related to Alport syndrome. So I'm just wondering, do you think that AYAME could answer a number of these questions? And separately, in any of the other studies that you're conducting specifically Warren, you that any of these studies can address those specific requirements that they're requesting in Alport syndrome patients? And I guess the second question I have with the ADPKD trial, I guess now that you've taken away the 48-week eGFR review, can you just maybe remind us what the initial intent of the interim look was then, was it to potentially get accelerated review or was there something else that you were trying to accomplish and now that is not there, what are you taking away with the lack of that review at the 48-week time point? Thank you.
Sure, yes. Years ago, back in 2016, when the FDA proposed the design for the CARDINAL study, they suggested that we have a 1-year off treatment that could potentially support accelerated approval based on the data. And then the idea was to continue the study on a blinded basis to the investigators, patients and people involved in the conduct to collect the second year of data, which would support full approval. We were the first company, I think, to conduct that design. And when we completed the year one data, by the time we could assemble that data, make our regulatory submissions for meeting requests and have a meeting, we were well into the second year of the study, and it became clear that we were going to have the second year data during the review. And it's my belief that, that impacted their willingness to take the year one data, we were so close to having the year two data. So in the pre-NDA meeting that we had, we agreed to just submit with the year two data. After that interaction with respect to essentially the same issue for the FALCON study, and so I forgot the exact interaction, but we submitted a description of the timing to the division and basically said we're going to have the same issue for PKD. And they said, yes, we're not likely to take or won't take the year one data and so that led to our conclusion to just eliminate the off-treatment during the year one.
Okay, got it. Yes?
And in respect to, with respect to the first question, they didn't say specifically in the CRL, they specifically asked for another eGFR or clinical endpoint study in Alport syndrome, but in their briefing book, in their conclusions, they stated that one deficiency of the application was that we did not have positive data in another form of CKD. And so I think that probably leaves open the discussion. If we did have that, we would obviously go back to the FDA and request to resubmit the Alport syndrome NDA with the supplemental data. And I think particularly if AYAME was unequivocally positive, we would want to have that discussion with them.
Okay. If I could just drill down on that, I think they did ask specifically for some quality-of-life measurements for Alport specifically. So do you think you can pull any of that from MERLIN or is there anything else that you can pull that would provide them with that data?
Yes what's interesting about that is that we had a significant effect in the PGIC, which is a measure, patient-focused measure of the PGIC. Colin, can you comment on that?
The patient global impression of change is used in many different types of trials, not just kidney trials, where patients report overall and if they're doing better, worse or unchanged, and that was a pre-specified secondary endpoint in our trial and actually that's met significance at year two. And so we believe those data are supportive and as Warren said, we would want to take this data back with other data to try to address their concerns.
I think the comment that they put in the CRL, that I think the comment that they put on an endpoint that captures how patients is just the boilerplate description of a clinical endpoint from its regulatory language. So I think that the implications of that was they were still agreeing to take an eGFR-based endpoint or a hard clinical endpoint.
Okay, great. Thank you so much. Can you just remind us when we're going to see the MERLIN data?
It's already – yes, Annabel, this is Manmeet. It's already there in our 10-K filing, which we submitted this morning it was already there, and we had already submitted that data to the FDA.
Yes. Colin, do you want to describe it?
Sure. The MERLIN trial was enrolled approximately 80 patients randomized evenly to bardoxolone with placebo, across many of the epidemiologies, the most common type was with diabetic patients, also enrolled patients with hypertensive CKD, ADPKD for those who do qualify for FALCON and others. Importantly, we used the same titration design that was used in the Alport syndrome trial, CARDINAL as well as the ongoing Falcon trial ADPKD. And from an entity perspective, we showed a significant increase across all those patients with the phenotype of patients who actually demonstrated or are at risk of rapid progression. From an additional data perspective, we included through our treatment eGFR assessments at multiple time points. And so after three, seven, 14, 21, 28 and 35 days, and consistent with what we've seen in our other trials, we see resolution of the acute eGFR effect within approximately 21 days. And so the data suggests that somewhere between 14 and 21, and so there's no longer a significant effect versus placebo at day 14, but there's still some slight numerical reduction by day 21. Importantly, the between group difference between drug and placebo at days 21, 20 and 35 is the same. And so that continues to support our case that the drug does in fact lose its acute effects on eGFR within the time frame that we've originally hypothesized.
Okay, great. Thank you.
The next question comes from Brian Skorney at Baird. Brian, please go ahead.
Hey, good morning everyone. Thanks for taking my questions. A couple on the MERLIN data. I know that you gave the day 14 of treatment to be 3.7 mL and have characterized 21, 28 and 35 as unchanged. Can you give the actual values for day 21, 28 and 35 off treatment? And then also in the 10-K, when you said that the FDA didn't accept this data as a major amendment, did they look at the data at all or they just refused even to accept it to begin with? And then on FALCON, just wondering on the change in protocol for the off-treatment period to be removed following year one, studies have been going on for about 2.5 years. So I'd imagine there's probably a couple of 100 patients who may have stopped treatment for four weeks for year one. How are they accounted for in the final statistical analysis for week 108? Thanks.
I'll start, again, I'll start with the last question, and Colin and then I'll hand it over to you to comment on MERLIN. In FALCON, the -- our proposed design for the statistical analysis plan would be to take patients that did not have a week 108 because they finished the study prior to the amendment and used their 104 in the analysis. We'll be asking the FDA to comment on that and in the Type A meeting with a request. And the question -- there was a question about the MERLIN values. Colin, do you want to comment on those?
Yes. We see a slight separation at days 21, 28 and 35. That's around a couple of more [indiscernible], which is consistent with what we've seen in all of our trials of over three months in duration where we start to see some persistent effect on kidney function consistent with disease modifications. And so a similar difference was seen in our Kyowa Kirin's Phase 2 TSUBAKI trial. And so from our perspective, once again, it shows that the acute effect is resolved and that there is the beginning of some disease-modifying effect. And then, Brian, as far as to the FDA look at our information from MERLIN and considered from mature amendment will, we were unsure if they reviewed as we provided as it was certainly late in the review and so they obviously did not consider it as a major amendment and therefore they stuck to additional PDUFA date. And so those data, from our perspective, I think will be helpful in future discussions to and discuss the sufficiency of the off-treatment periods.
Great, thank you.
The next question comes from Joe Schwartz at SVB Leerink. Joe, please go ahead.
Hi all, this is Will on for Joe. Thank you for taking my questions today. So one for us, since this is the first call that's been hosted since the AdCom, it'd be great to hear some of your thoughts on the points that the agency raised during that meeting. And then in terms of what the FDA wants to see, it kind of sounded rather straightforward when the company laid out the company's interpretation of this. However, during the AdCom it sounded much different. So any additional thoughts here on the AdCom and that those discussions would be appreciated. And then I have one quick follow-up.
Yes. I really, this is Warren, I'll address that question. I think that the briefing book that we got, immediately prior to FDA's briefing book, really focused most of its discussion on their PK model, on the time for resolution for the off-treatment value and that there was actually very little discussion of that issue at the AdCom. Lisa Thompson during the AdCom introduced a question immediately after our presentation and before the general discussion, regarding the separation, lack of separation and the off-treatment values over time and so that was introduced basically at the AdCom in the afternoon. So it wasn't really addressed in their briefing document or our briefing document. And so, I assume that was a concern of theirs, the trajectory over time. But honestly, I think most of the discussion was about just the concern of the long-term effects of the acute eGFR improvements. And that's why I said in the opening remarks; I think if the nephrologists were convinced that it was going to delay dialysis, I think we would have gotten a positive vote. And that's why I believe that the Kyowa Kirin study has the potential to provide very important information that could have a very meaningful impact on the view of the bardoxolone mechanism and clinical profile among nephrologists. And I think that would have potentially affected the outcome.
Okay, great. That's helpful, thank you. And then could you just briefly remind us of the regulatory status for Bard in AS in the European markets?
It's -- we're under review, and we're in that active phase receiving questions and responding now.
Thank you.
[Operator Instructions] The next question comes from Matt Kaplan at Ladenburg. Matt, please go ahead.
Hi, good morning and thanks for taking the questions. Just wanted to followup in terms of the protocol amendment for FALCON. I guess, first, when do you think you'll have a buy-in from the FDA in terms of the protocol amendments that you're recommending? And then given the discussion at the AdCom in terms of the off-treatment period, can you talk a little bit about the off-treatment period that you're going to be incorporating, I guess, at week 108, in the context of how long that off-treatment period should be, and to address FDA's questions previously?
Sure. I'll actually take these. We've requested a Type A meeting.
Recently?
Yes, so recently. So we're obviously hoping that's a 30-day clock for those and so we're hoping to have meaningful feedback within 30 days or so. With respect to the off-treatment period, we moved the primary endpoint to week 108, which we believe is consistent with the PK/PD analysis of the division. But that's obviously one of the questions, like do they want it longer? And we're also incorporating a 12-week point of collection if we need to extend that. And so again, we think the 108 is consistent with their PK/PD analysis, but we're specifically asking them.
Great, and then I guess lastly, given the increase in sample size to 850, when do you anticipate a potential readout from FALCON?
I think we're not really ready to provide any guidance on that until we get some feedback from the FDA.
Sounds good. All right, thanks for taking the questions.
Sure.
Thank you. I'm showing no further questions in the queue. Again, thanks for your participation on today's conference call. As a reminder, an audio recording of the call will be available shortly after the call on Reata's website at reatapharma.com in the Investors section. Thank you very much for your participation. You may now disconnect.