Reata Pharmaceuticals Inc (RETA) 2022 Q1 法說會逐字稿

Thank you for standing by, and welcome to the Reata Pharmaceuticals First Quarter 2022 Financial Results and Update on Development Programs Conference Call. 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 the 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 guaranteed of future outcomes. Please also note that any comments made on today's call apply only as of today, May 10, 2022, and may no longer be accurate at the time of any webcast replay or transcript reading. Following the prepared remarks, we will open the call up for questions. (Operator Instructions)

We are joined today by Warren Huff, Reata's Chief Executive Officer; Manmeet Soni, President; Colin Meyer, Chief Innovation Officer; Seemi Khan, Chief Medical Officer; and Dawn Bir, Chief Commercial 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 for our quarterly update. I'll start on Slide 4. As you all know, we're developing omaveloxolone, or omav, a small molecule activator of Nrf2 for the treatment of patients with Friedreich's Ataxia, or FA. We've made significant progress with the program over the last few months. Following the positive results from the MOXIe Part 2 study, we had multiple interactions with the FDA to determine whether there was a path to submission and review of our new drug application, or NDA. This was highlighted by completion of a pre-NDA meeting with the division in the third quarter of 2021.

Following the meeting, we applied for and were granted Fast Track Designation for the program, highlighting the potential of omav to address the serious unmet need for treatment options for patients with this devastating disease. Fast Track Designation provided us with eligibility for rolling submission of our NDA, which we initiated and completed in the first quarter of this year.

Additionally, the FDA recently granted rare pediatric disease designation to omav. Our NDA includes a request for priority review based on the severity of the disease and the lack of approved treatments for patients with FA. If granted, this could result in a Prescription Drug User Fee Act action date, or PDUFA date, in the fourth quarter of this year.

We're working with the FDA while it reviews our NDA this year and if the FDA approves omav for the treatment of patients with FA, we plan to be in a position to launch our first drug early next year.

Finally, we're continuing to complete the regulatory procedures and submissions that are required as a condition to filing a marketing authorization application in Europe. We've secured agreement on our pediatric investigation plan with the Pediatric Committee and we plan to submit an MAA to the European Medicines Agency for omav in the fourth quarter of 2022.

Next slide. Regarding our programs in rare forms of CKD, our priority has been to first work with the division to ensure we are aligned on the trial design for our ongoing Phase III FALCON trial so that we have a clear regulatory path forward for that important program. Based on the issues that the FDA raised during the review of our NDA in Alport syndrome, we submitted a proposed amendment to our protocol for FALCON. We recently completed a Type A meeting to discuss the protocol amendment and to ensure that we're aligned on the trial design with the division.

During the meeting, the division stated that the proposed primary endpoint of eGFR change from baseline at week 108, which is 8 weeks after planned drug discontinuation at week 100, was reasonable because our available data suggests that Bard's acute pharmacodynamic effect on eGFR should be largely resolved. The division also stated that in addition to the primary endpoint, it will be important to demonstrate that the treatment effect accrues over time to support a claim that Bard slows the loss of kidney function in patients with ADPKD, and it provided guidance on an exploratory eGFR slope analysis that would address the question.

Importantly, the agency emphasized that the analysis will be important, but also stated that the results do not need to be statistically significant. They also confirmed that if the FALCON trial is positive, it could support registration of Bard in ADPKD. Seemi Khan will provide additional information about our program in ADPKD later after the call.

With completion of the Type A meeting and alignment on our protocol amendment for FALCON, we'll continue to work with the FDA to confirm our next steps on our Alport syndrome program.

Finally, I'd like to remind you that our strategic collaborator in Japan, Kyowa Kirin, is sponsoring the AYAME trial, a large Phase III clinical trial in patients with diabetic kidney disease. The AYAME trial enrolled over 1,000 patients with stage 3 and 4 diabetic CKD, and the primary endpoint is time to onset of greater than or equal to 30% decline in eGFR or end-stage kidney disease. If the results of this trial are positive, it could provide clinical evidence that improvements in eGFR observed in Bard-treated patients do, in fact, delay progression to kidney failure. Kyowa Kirin expects to complete the last study visit in the second half of this year.

With that, I'd now like to turn the call over to Colin Meyer, who will provide an update on our program with omav in patients with FA, then to Seemi Khan, who'll provide further updates on our program with Bard in patients with ADPKD and our program with RTA 901. Dawn Bir will then discuss our progress in our commercial preparation activities for omav. Lastly, Manmeet Soni will review our financial results for the quarter.

Thank you, Warren. Starting with Slide 7. FA is a relentlessly progressive and debilitating neuromuscular disorder. It is caused by epigenetic silencing of frataxin, which impairs mitochondrial function and is associated with suppression of Nrf2. These effects lead to impaired energy production and neurodegeneration. As the disease progresses, patients with FA become dependent on walkers and in wheelchairs, and they ultimately lose their independence altogether. The median survival for these patients is in the mid-30s.

Despite numerous attempts of developing therapies for FA, prior to MOXIe, none has been successful and there are no approved treatments. FA is inherited recessive form of ataxia which affects approximately 5,000 children and adults in the U.S., with approximately 4,000 patients currently diagnosed.

Next slide. Clinical trials in FA are challenging to conduct due to 2 major factors. First, there are a limited number of FA patients who are willing and able to participate in clinical trials. As I just mentioned, there are only approximately 4,000 patients who are diagnosed in the U.S. At the time of MOXIe Part 2, we enrolled patients at all 7 U.S. FA specialty centers who are participating in the natural history study. MOXIe is one of the largest interventional trials completed to date and the only trial to demonstrate a significant effect on a functional endpoint that could support approval.

There are a relatively small number of patients available for future trials with a design similar to MOXIe. Currently, approximately 1,200 patients have volunteered for clinical research and are participating in the natural history study. For MOXIe Part 1 and Part 2, we screened about 1/6 of available patients and enrolled most of them into the trial.

Moving to Slide 9. The second reason that clinical trials in FA are challenging is due to the slow rate of progression of FA. As I just mentioned, patients with FA relentlessly progress. That even though these patients have early mortality, the progression occurs over their lifetime. The time from diagnosis to the death for a typical patient who is diagnosed in their teens and dies in their mid-30s is approximately 20 years. FA researchers have studied progression in a natural history study, and progression over 1 year is clinically meaningful to patients, even though the magnitude of progression over this time is relatively small versus patients' entire disease course.

Because of this, outcome measures have been developed and validated to measure progression over 1 year. The Friedreich's Ataxia Research Alliance, or FARA, worked with the FDA to develop the mFARS scale to accurately track disease progression in FA patients. The scale is composed of 4 subsections: bulbar, upper limb and lower limb coordination and upright stability. As patients lose function, their mFARS score increases towards a maximum score of 99 points. Even though the scale is 100 points, most patients are diagnosed with scores in the 25 to 30 range, and patients die before they reach a score of 100. Therefore, the dynamic range of the scale is approximately 40 to 50 points.

Slide 10 highlights several examples demonstrating the clinical meaningfulness of a single point change in mFARS. Within each of the 4 mFARS sections, every single point matters. In the middle column are some representative assessments, along with what a 1-point worsening can mean to patients. The clinical impact of 1 point for stability or lower limb can mean differences in the ability to stand or walk independently. The clinical impact of a 1-point worsening for bulbar or upper limb sections can mean losing the ability to speak or type, even 0.5 point can matter. A worsening of 0.5 points on speech can be the difference between normal and slurred speech.

Slide 11 shows data from the prospective and ongoing global, multicenter Friedreich’s Ataxia Clinical Outcomes Measures, or FA-COMS, Longitudinal Natural History study. This study is enrolling up to 2,000 patients with FA with quantitative serial data, including mFARS. Patients are being followed annually for up to 25 years. The data on this slide were published in 2016 and assessed data from patients over 5 years. This study evaluated multiple age cohorts. Shown here is the overall cohort as well as the cohort of patients aged 16 to 40, which is the same age range studied in MOXIe Part 2.

While mFARS changed only 1 point in the first year of follow-up in the age-match cohort, over 3 to 5 years, mFARS changed on average about 2 points per year in both cohorts. Although changes in other measures were less apparent in a single year, the changes in mFARS predict [later] worsening in other measures in the study. 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 prespecified primary analysis population or full analysis set included the 82 patients who did not have severe manifestations of the foot deformity, pes cavus, and the primary endpoint was the change from baseline in mFARS scores at week 48.

The analysis methodology we used to analyze the primary endpoint was MMRM. We used 2 covariates, clinical trial site and baseline mFARS. And importantly, all mFARS values at all time points, regardless of whether patients were receiving study drug, were included in the analysis. We did not impute for missing data in the primary analysis. 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 mFARS, compared to placebo after 48 weeks of treatment, with a p-value of 0.014.

As we've discussed previously, we observed improvements in all subsections of the mFARS scale. This change is clinically meaningful in that, on average, 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 1 year progression.

Next slide. This slide shows a forest plot for sensitivity analyses compared to the primary result, which is on the top of the figure. Using a different analysis methodology, ANCOVA, the results were consistent with the primary results. To evaluate the impact of missing data, we conducted 2 analyses using different imputation methodologies. As mentioned earlier, all mFARS data from all time points were used. And overall, only 4% of mFARS values were missing with 9% missing at the week 48 time point.

Treatment-Based Imputation, which assumes that discontinued patients behave like patients in their treatment group; as well as Control-Based Imputation, which assumes that discontinued patients behave like placebo-treated patients, both demonstrated a significant p-value supporting the conclusion of the primary analysis. Additionally, when we look at the pes cavus population alone or the all-randomized population, the treatment effect favors omav. Overall, these sensitivity analyses support the robustness of the primary endpoint results.

Turning to Slide 14. The MOXIe extension trial is an ongoing open-label extension trial, evaluating the long-term safety and efficacy of omav in patients with FA. A high percentage of patients who are randomized into MOXIe Part 1 and Part 2 enrolled in the extension. Notably, 97% of patients from the MOXIe Part 2 full analysis set, who completed MOXIe Part 2, were enrolled in the MOXIe extension trial. The discontinuation rate in the extension has been low despite the length of the trial and the operational difficulties experienced during the pandemic. Of the patients from the full analysis set, 88% are still enrolled and being followed in the extension. Importantly, no new safety signals have been identified in the MOXIe extension trial.

Next slide. As a reminder, the purpose of the randomized placebo-controlled MOXIe Part 2 study was to determine if there was a significant treatment effect between the omav and placebo-treated groups. And as discussed, this was demonstrated. The purpose of the delayed start analysis was to determine if this separation observed at the end of MOXIe Part 2 was preserved in the extension once all patients were converted to omav treatment. If patients who were originally randomized to placebo catch up to patients originally randomized to omav, the treatment effect is consistent with a symptomatic benefit. If the patients originally randomized to placebo do not catch up and the difference at the end of the placebo-controlled portion is maintained, the treatment effect is consistent with disease modification and a persistent effect on the course of the disease.

This slide shows a graphical representation of the delayed start analysis. All patients from the full analysis set are shown on the left, and the subset of patients who have completed extension week 120 are shown on the right. In the graph, study weeks 0 to 48, shaded in blue, pertain to MOXIe Part 2 with subsequent study weeks referring to the extension phase. I would like to point out that the timing of the MOXIe extension study coincided with the COVID-19 pandemic. So some mFARS assessments, which required an in-office visit, are missing. As mentioned, 88% of the patients remain in the extension and patients have been returning to in-clinic visits over the past several months.

Understanding the limitations in interpreting open-label extension data, we see that patients originally randomized to omav have continued to show a persistent treatment benefit with minimal to no worsening of the mFARS after 3.5 years of total treatment. Of the 6 time points in extension, all but 1 show separation versus the patients originally randomized to placebo. The data suggests that the extension week 48 time point is an outlier, which was affected by COVID, and this is supported by the separation that was observed at extension week 72 and beyond.

Beyond the missing data at this time point, investigators reported that the already challenging travel that these patients undergo to visit clinical trial sites was even more difficult during the pandemic, and this likely affected their sleep, exercise, eating and other daily activities, which could have affected fatigue levels and other non-neurological aspects of their functioning.

Of note, the same pattern of convergence at extension week 48 is observed in the completers analysis shown on the right. Only a single patient is missing in each group at the extension week 48 visit, and convergence was observed. However, visits beyond extension week 48 show divergence, including extension week 120, which includes all patients. These data further demonstrate that the extension week 48 time point is an outlier.

The completers data also address one other question raised by the full data set on the left. It appears on the graph on the left that the placebo to omav patients may be losing their treatment effect at extension week 120. However, as can be seen in the figure on the right, this is an artifact of this subset of patients who, on average, have longer GAA1 repeat lengths, which is associated with a faster rate of progression. As you can see in the blue-shaded region on the figure on the right, these patients progressed approximately 4 mFARS points over 1 year while they were receiving placebo, from randomization until the day they entered the extension and started receiving omav. However, over the subsequent 2.5 years while receiving omav, these patients only progressed 1 mFARS point on average, which is much lower than would be expected based on their rate of progression before they received omav.

As shown on Slide 16, we have also evaluated the progression of mFARS for omav-treated patients in the extension study by computing annualized mFARS slopes. This calculation of annualized slopes allows all available data through extension week 120 from all FAS patients to estimate the treatment effect over a period of approximately 2.5 years. A total of 257 mFARS assessments contributed to this analysis from 73 patients. And as I mentioned, in the extension, the discontinuation rate has been low at 12%, with only 9 of 73 FAS patients having discontinued.

As you can see in the table on the left, the annualized rates progression in the extension had been 0.27 and 0.45 mFARS points, and the difference between these 2 subgroups is not different suggesting a similar treatment effect. While a placebo-controlled during this phase was not included and formal comparisons cannot be made, the observed rate of progression is much lower than would be anticipated. The same 39 placebo to omav patients progressed 1.42 points in the 52-week period from randomization into MOXIe Part 2 until initiation of treatment in the extension.

Using natural history data as a benchmark, the overall cohort progressed at an average rate of 1.95 points per year and a similar age ratified cohort progressed at an average rate of 1.71 points per year over a 3-year period. These data, in addition to the delayed start analysis, suggests that omav has a durable, persistent effect on the course of FA.

I'll now have Seemi Khan provide an update on our other clinical development programs.

Thank you, Colin. I will provide an update on our progress on CKD and RTA 901 development programs, starting on the next slide. We are evaluating the efficacy and safety of bardoxolone in patients with autosomal dominant polycystic kidney disease, or ADPKD, in FALCON, our Phase III, international, multicenter, randomized, double-blind, placebo-controlled trial. ADPKD is a rare and progressive hereditary form of CKD caused by a genetic defect in the PKD1 and PKD2 genes, leading to the formation of fluid-filled cysts in the kidney and other organs.

ADPKD affects both men and women of all racial and ethnic groups and is the leading inheritable cause of kidney failure with an estimated diagnosed population of 140,000 patients in the U.S. As Warren mentioned earlier, we recently met with the FDA in a Type A meeting to discuss the overall ADPKD development program and our proposed protocol amendment. Based on the discussion during the meeting, the FDA is in agreement with the key changes made to the protocol.

As per meeting minutes, the division stated that the proposed primary endpoint of eGFR change from baseline to week 108, which is 8 weeks after the planned drug discontinuation at week 100, is reasonable since the available data suggests that bardoxolone's acute pharmacodynamic effect on eGFR should be largely resolved by that time. The division also agreed with our plan to enroll pediatric patients from age 12 to 17 years.

We are pleased that based on preliminary comments, the FDA confirmed that if the FALCON trial is positive, it could support registration of bardoxolone in the treatment of patients with ADPKD. More than 550 patients of planned 850 patients are currently enrolled in the trial.

Moving to Slide 20, 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 and other 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. In preclinical rodent models, we observed that RTA 901 administered orally once daily rescued existing nerve function, restored thermal and mechanical sensitivity, and improved nerve conductance velocity and mitochondrial function. These effects are dose-dependent, reversible and Hsp70 dependent. We have completed a Phase I study of RTA 901 in healthy volunteers that demonstrated an acceptable safety profile with no safety signals. There were no drug discontinuation or serious adverse events in that study. The pharmacokinetic profile was favorable.

In the first quarter of 2022, we initiated additional Phase I clinical pharmacology studies, including a drug-drug interaction study with RTA 901. Following completion of these Phase I studies, we plan to initiate a randomized, double-blind, placebo-controlled Phase II trial to evaluate the safety and efficacy of RTA 901 in diabetic patients with peripheral neuropathic pain in the fourth quarter of 2022.

With that, I would now like to turn the call over to Dawn to provide an update on our commercial preparation activities.

Thank you, Seemi. Good morning, everyone. I'll continue on Slide 22. The commercial team's full attention is focused on omav launch readiness. Our first responsibility is to intimately know the landscape of the Friedreich's Ataxia market. Knowing the patient community, treating physicians and diagnostic journey is key to understanding the market. Locating our patients and HCPs treating them today, their current mindset, desires for therapy and drivers of adoption are also important as we prepare for Reata's first potential launch.

In Q1, we completed the landscape assessment and our launch strategy development is underway. We've also placed a priority on market preparation through disease education, our patient educational efforts launched over 2 years ago through social and web-based platforms that connect the patient community. In Q1, we finalized our HCP FACT campaign. The goal of HCP disease education is to drive earlier diagnosis, underscore the severity of Friedreich's Ataxia and link HCPs to resources, including diagnostic tools, materials to support patient dialogue about FA and the importance of mFARS as a measure of disease progression.

Continuing on Slide 23. Launch operations is advancing in step with the regulatory process. We've hired our commercial leadership team. Payer engagement was initiated in March to educate payers about FA, the severity of this disease and the need for a treatment. Our trade and distribution model design is complete and partners selected, including a limited specialty pharmacy network and front-end patient access services. Much work is underway and continues in Q2, including the development of our branded launch messaging, materials and tactical launch plan. Our brand name received conditional approval and our internal launch readiness process ensures cross-department alignment and preparation for launch. Sales force sizing and territory alignments will be finalized. The team is poised for a successful launch.

I'll now turn the call over to Manmeet.

Thank you, Dawn, and good morning, everyone. Let me start with our cash balance on Slide 25. As of March 31, we maintained a solid balance sheet with approximately $532 million in cash and cash equivalents. Our cash balance will enable us to fund operations through the end of 2024. With our strong cash balance, we have the ability to focus our efforts on our key strategic priorities, which Warren will cover later in the call.

Moving to expenses. We have taken steps to control our operating expenses. Our non-GAAP G&A expenses for the first quarter of 2022 were $17 million as compared to $21.4 million for the fourth quarter of 2021, representing a significant reduction of 21%. This reduction in the G&A expenses is primarily related to the pause of all commercial spending related to activities for Alport syndrome launch preparation in the United States and the European region.

As we mentioned on the February 28 earnings call, we did a restructuring in early January 2022 of our sales and commercial team to adjust for the delay in the launch of Bard and adjusted the commercial team size appropriately to focus on the preparation for the anticipated omav launch in early 2023.

Our non-GAAP R&D expenses for the first quarter of 2022 were $32.2 million as compared to $35.5 million for the fourth quarter of 2021, representing a reduction of 9% approximately. This reduction in R&D expenses as compared to the last quarter is primarily related to the timing of certain manufacturing activities and R&D-related expenses.

Our non-GAAP operating expenses for the first quarter of 2022 were $49.5 million as compared to $57.3 million for the fourth quarter of 2021, representing a reduction of 14% approximately.

On the operations front, we are actively working on the commercial drug supply for omav for the anticipated commercial launch of FA early next year. With MAA filing for FA in sight, we have also initiated building our European infrastructure and commercial team in preparation for the anticipated launch in Europe.

With that, I will turn the call back over to Warren.

Thank you, Manmeet. In closing, we've made good progress in our omav program, including the submission of our NDA to the FDA in preparation for our anticipated MAA filing later this year. If approved, omav will be the first drug available for this severe disease, and we're actively working on commercial preparations to be in a position to launch it early next year.

As Manmeet mentioned, with our strong balance sheet, we'll be focusing on 4 key priorities for the remainder of 2022. Of course, our #1 priority is working with the FDA on their review of our NDA for omav and working towards securing approval of omav for the treatment of patients with FA.

Secondly, with the progress made during the last few months to secure agreement on our pediatric investigation plan, our second priority is to submit an MAA to the European Medicines Agency for omav in the fourth quarter of 2022.

Thirdly, following the completion of the Type A meeting with the FDA, our focus is to continue enrollment in the FALCON study and continue to work with the FDA to find a path forward for the Alport syndrome program. And finally, our fourth priority is to initiate a Phase II study with RTA 901 for patients with DPNP during the fourth quarter of 2022.

That concludes our prepared remarks. We'd like to thank everyone who dialed in. And I'll now turn the call over to the operator for questions.

(Operator Instructions) Our first question today comes from Yigal Nochomovitz from Citigroup.

Colin, I appreciated the comments on the delayed start analysis. I'm wondering if you could just revisit that again because I've been getting a lot of questions lately on this delayed start analysis with people digging into omav. So the way I understand it is, obviously, in MOXIe Part 2, you saw a very nice drug effect, early drop for the omav patients on mFARS and then plateau where there is a very transient placebo effect, and then it shot off on the placebo. So that all looks very, very good. Then you have the off treatment, which again showed a bump-up for the omav patients, which makes sense and placebo continued to rise.

And then you switched the patients from placebo to omav. And from week 0 to week 48 of the extension, what was happening in the trial made perfect sense to me in that you started to see a treatment effect for the patients switched from placebo to omav and you started to see convergence of the 2 cohorts, which, in my mind, is exactly what you want to see in the sense of a drug effect emerging in the patients switched from placebo to omav.

So if you could just help me understand a little bit because you're arguing that rather than that, you want to see a delta to show a preservation of separation between the 2 cohorts. So I'm just -- I'm still a little bit confused as to what the argument is. So if you could help clarify, please.

Sure. And so referring to Slide 15. Once again, the blue-shaded region is MOXIe Part 2. And you're correct, the point of that part of the study was to show a treatment effect or a separation between the groups, which we saw on-treatment as well as off-treatment before patients start on omav. And an important differentiation between a symptomatic treatment and one that actually affects the underlying course of the disease is that if patients -- if the drug has an effect on the underlying disease, you would expect that patients who have been receiving drug for a longer period of time would have a benefit that could not be basically captured by patients who start on that treatment a year later. And so you want to see separation in the extension phase of the trial.

And so I'll first reference on the far right, the completers analysis. But I think one issue that people have had with analyzing the state and interpreting it is simply drawing lines through the figure on the left, on the points. And that really can't be done because it represents different patients at different points in time. And as mentioned on the call, in prepared remarks, there is some missing data primarily in the first 1.5 years in the extension. And so if you look at a completed set of patients on the right, so first, looking at the omav patients, the blue line, they've had minimal progression, those same 11 patients for 3.5 years. And so that's much less progression than you'd expect.

And then if you look at, once again, patients who are initially on placebo, they worsened. And of course, that subset, as I mentioned, worsened about 4 points until they received omav. And you can see that they flattened out and they have a similar trajectory to the omav-treated patients who initially were randomized to omav. And you can see that the curves are roughly parallel. And with the exception of that extension week 48 time point, they are separated. And so that is the profile that you want to see. What you don't want to see is convergence and complete overlap for the patients who received placebo for a year, because that would suggest that catch-up and the drug was not disease-modifying.

And so the reason to present data on the next slide 16 is because it overcomes this issue of missing data, especially in the extension phase. It uses all available data from all patients. And the table on the bottom left is the annualized slopes. And so if -- the best way to analyze the data is to include all data. And if you were simply to plot that out, 0.27 or 0.45 mFARS points per year, that's obviously a low rate of progression versus the 2 comparisons which we have, which are how those same patients behave when they were placebos, they worsened 1.42 points. And then the FA-COMS overall cohort as well as the age-match cohort. And so I think that addresses your question, does it?

Yes. No, that's helpful. I appreciate that. And then just one quick follow-up. So you've gotten, I mean, quite a nice set of accolades from the FDA on fast track, orphan drug and rare pediatric, so quite a long list. I'm just curious if breakthrough is ever something that might also be part of that list. Obviously, you're one of the only companies that's ever shown a success in Friedreich’s Ataxia in Phase III. Clearly, a significant unmet need. It would seem that breakthrough would be something the FDA would want to give serious consideration to.

We don't have breakthrough and a reason for that is it's very late in the game to apply for breakthrough. And the purpose of breakthrough is to allow for basically easy access to the review division on an important development program. And truthfully, our Fast Track Designation was really late in the game, too. And one of the primary reasons for that was to allow us to conduct a rolling submission. And so I think for all those reasons and because we already are in close communication with the FDA, breakthrough was not that helpful to us. We do agree with you though it should be eligible.

The next question today comes from Madhu Kumar from Goldman Sachs.

Yes. So kind of following up on kind of the commentary related to the delayed start analysis in Yigal's question. Do you expect to provide additional data updates from the MOXIe of the label extension trial? I guess kind of more granular, would you expect the FDA to want to see more updates from that open-label extension through the review process?

Yes. This is Warren Huff. The data that we're showing here is the data that was submitted with the NDA. Of course, the patients are continuing, and so they're accruing additional data over time. We've let the agency know that there is additional data if they want to see it and they basically said that if they want to see the additional data, they'll let us know.

(technical difficulty) piece. Did they suggest kind of a time line for those kind of requests? Would that be at the acceptance of a filing? Would they kind of disclose towards major amendments? Like how should we think about that in terms of the regulatory review process?

This is Colin. And so as part of our NDA submission and review process, we have a 120-day safety update, which we're obligated to provide. And the focus of that update is on safety. And so as Warren said, we let them know that we have updated data that is part of that 120-day safety update, but falls more on the efficacy side. And so it's really up to the review division to determine if they want to see additional efficacy data. And so we don't know, and it just depends upon their view. They may or may not ask for that additional efficacy data.

Right. That will just be driven by the timing of their review of the NDA.

Okay. Great. I guess one last question is, are there any -- I mean obviously kind of in the light of how Neurology 1 has viewed kind of statistical analysis. Have there been any questions about like the statistical analysis you all have performed so far on MOXIe or the MOXIe of the label extension that kind of like think about in terms of kind of review process for Neurology 1?

So we're obviously aware of recent interactions they've had with other sponsors, and we cannot disclose the specifics of any back and forth we may have had with them. But one reason to highlight some of the data in this presentation, including on Slide 13, is to show that we did meet the prospectively defined prespecified primary analysis. We have a relatively low amount of missing data, once again, 4% overall, 9% at week 48. And no matter how you handle imputation, the p-value remains significant and all sections of mFARS, all analysis populations favor omav. And then in the extension, obviously, I highlighted that despite some missing data due to COVID, we've had a low discontinuation rate.

And so without directly answering your question, I'll note that some of the issues that this division has raised with other sponsors appears less relevant to our program.

The next question today comes from Annabel Samimy from Stifel.

This is [Stacey] calling in for Annabel. I guess for omav, investors are clearly skittish about FDA's CNS division right now, given all the controversies over aduhelm and reversal around programs that were allowed to file on limited data, but then FDA reversing course. So what gets you comfortable that omav will be -- we'll see a different outcome from these programs aside from the fact that they are in different indications? And then also whether the 22 patients in the delayed start will provide sufficient evidence in conjunction with the FDA's unpredictability? And how you were handling the missing patient data?

Okay. Well, this is Warren Huff and I'll start. Every program is unique. And our program with omav in patients with Friedreich’s Ataxia is quite different from the other programs that you mentioned that have recently been reviewed by the division at CNS Neuro One. So there's a couple of key distinctions. Number one, just the disease itself, Friedreich's Ataxia, it's one of the worst neuromuscular diseases in terms of life-shortening effects. I would argue that it's much worse than the other things seen in these patients, past in their 30s, very young, and they're struck by the disease on average at age 10 or 12 years old.

There's no approved therapy for it. There's been close cooperation of the patient group and the key opinion leaders with the FDA on development of the mFARS endpoint. FDA had meaningful input on that endpoint. They also suggested and the patient group followed their advice to develop data in a longitudinal study, which provides a good data set on the progression rate of the disease. And so for those reasons, it's different, I think, from some of the other things that they reviewed.

I'd also just say our basic data set, as Colin explained, is just very straightforward. We believe we cleanly hit the primary endpoint. FDA has indicated multiple times in writing that the mFARS endpoint is an approvable endpoint. And so we don't believe there's real controversy over that. So I'd just say on balance that, again, every program is different. We think that the data support -- should support approval and hope that the FDA will see it the same way.

Colin, do you want to address the question on the delayed start?

Sure. And so FDA requested a delayed start analysis to allow us to further interrogate the extension data. And so what we've disclosed publicly is much less than what we've provided FDA. Obviously, in our NDA, FDA has every data point from the extension. The primary analysis for the delayed start was extension week 72, but we've performed the analysis on all time points. And you mentioned 22 patients in the delayed start. And I think you're referencing the completers on the right of Slide 15, we conducted the delayed start analysis on the full analysis set and so the figure on the left.

Once again, there's a limitation and not there's some missing data. And that's why I think there's 2 additional pieces of data that help us, one of which is the patients who've been on drug the longest, and so showing that their rate of progression is much lower than would be expected. The other is all data in the extension. And so as I mentioned during our formal presentation, there's 257 mFARS assessments from 73 patients, and so the same patients who were in the primary analysis that of MOXIe Part 2. And when we use all their data across the entire extension and compute the rate of progression, it's less than half mFARS point, when the benchmarks show a rate that's approximately 2 to 3x (inaudible).

And so that gives us comfort and we briefed that heavily in the NDA. And so I think that is the best way to tackle the missing data due to COVID, this allows for a much more robust characterization of the data.

The next question today comes from Maury Raycroft from Jefferies.

This is [Farzin] on for Maury. I also had a question on the delayed start analysis. Can you elaborate on why the placebo patients in the extension portion do not see the large improvement like you see in the MOXIe Part 2?

So there is an improvement in the extension. I think the first point to make is that the reference point should be not baseline at the beginning of the trial. So if you're referring to Slide 15, it should be the week 52 time point. And so you can see there's not that much progression on the left side. On the right, which is the same patients over time, once those patients progressed 4 points before they received omav over 1 year, then over the next 2.5 years, they progressed only 1 point. And once again, a limitation on the data on the left, is that there's some missing data. So it's not the same patients over time.

And so the annualized data once again in the table on Slide 16, on the left, showed that the rate of progression is low and it's not different from each other. And if you're referring to the improvement that's seen within the first 12 to 24 weeks, there is a slight improvement, as you can see in the figure on the left, extension week 24 as well as the figure on the right. But over a long period of time, we see a very slow rate of progression.

Got it. And then for the review process, since omav is an analog of bard, do you think FDA will rely on any data from the AdCom discussions from bardoxolone in any way? Or will the reviews be completely independent?

It's unclear. Omav is a distinct chemical entity. While it has a similar mechanism of action, induces Nrf2, that has different PK and PD properties, obviously, different dose, different CNS penetration. And most of the issues with bardoxolone related to Alport syndrome, where the trial design, the off-treatment period, separation over time, and that -- those issues are not relevant to MOXIe in FA patients. And furthermore, I'll highlight that from a safety perspective, despite the background cardiomyopathy, there's been no evidence of any increase in risk from a cardiac perspective with MOXIe.

And so there are no imbalances and adverse events, SAEs. No elevation of blood pressure, it's actually slightly down with omav. We conducted serial ECGs because arrhythmias are common background finding in this patient population, and there are no findings. Then lastly, we conducted serial echos in MOXIe Part 2, and there were no findings. And so potentially, FDA could look to bardoxolone. But when we review all the data, there does not appear to be much relevance.

The next question today comes from [Charlie Mall] from Baird.

This is Charlie on for Brian Skorney. I just wanted to ask about bardoxolone in Alport and if you've spoken with the FDA about what will be needed for resubmission. As well as specifically, have you discussed the AYAME study, and if that would be -- the data from that would be acceptable as it pertains to Alport's considering it's in a different indication in Japanese patients?

Sure. This is Warren Huff. I'll take that question. As I mentioned in the remarks, our first priority was to make sure that we had alignment with the agency in our ongoing FALCON study in patients with ADPKD. And so we requested a Type A meeting. We had submitted a detailed protocol amendment that we felt addressed the issues that were raised in the Alport syndrome AdCom. And we did reach alignment with them. We recently completed the Type A interaction, received the minutes. And we did get alignment with them on modifications to FALCON that would allow it, if positive, to support NDA approval.

And as I mentioned, the key one is that we moved the primary endpoint to week 108, they indicated that that would be acceptable based on the available data on resolution of the effects. And then, of course, there were other changes made to accommodate the protocol changes, for example, in the analysis plans.

As I said, this was the most important thing that went -- from my standpoint, went well, preserves the integrity of that trial and the ability to move forward with an approval in ADPKD. We haven't requested a meeting yet from the division to discuss the path forward in Alport syndrome. As I said, we just completed the interactions for PKD. We obviously will be doing that, and we'll report the results of those interactions after we have them.

With respect to the AYAME trial, and this is just our view, we haven't reviewed the design of the AYAME trial or its implications with the FDA yet. But because the trial is such a large long-term study with events endpoints that have been shown to be very predictive of your risk of end-stage kidney disease, I think that the data will be an important addition to the data on bardoxolone. The central question with bardoxolone has always been due to the improvements in estimated GFR that are consistently observed across multiple types of CKD, will those translate into a reduction in the risk of kidney failure?

Just based on the size and duration of the AYAME trial, they're going to have a large number of hard dialysis events. In addition, they set up endpoints that were multiple thresholds of eGFR decline, 30%, 40% and 52%, I believe, that are well validated to predict the risk of kidney failure. So even though it is a Japanese study in diabetic kidney disease, I think that because you observe the same improvements in GFR based on the same mechanism of action that's not specific to any single form of CKD, I think it will be very persuasive in convincing the nephrology community and regulatory agencies of the long-term effects of treatment with Bard on the risk of kidney failure.

I'd also add, it also will provide additional safety data since the patients that are being treated in that study have diabetic kidney disease that was the at-risk population in the BEACON trial. And so it will also provide an additional large body of safety information on long-term use of bardoxolone.

The next question today comes from Joseph Schwartz from SVB Leerink.

It seems like you've prepared really well for (inaudible) next regulatory steps and received some good feedback. And I think a lot of that, as you said, a lot of the same things that you said for bardoxolone at a similar stage and yet there were some pretty major surprises. So I was wondering if there's anything that you think is fundamentally different here and/or if you're doing anything particularly different in order to avoid any major surprises and hope you buck the trend of all of the negative decisions that have been coming out of the agency, particularly this division, as we've been during even on this call.

Yes. Thanks, Joe. I'll -- this is Warren. I'll address that. Yes, I think there are several key differences, obviously, in the regulatory profile of omav for Friedreich's Ataxia versus our program in Alport syndrome of bardoxolone. First, I would say that the mechanism of action in this disease is just not controversial. Friedreich's Ataxia is well understood to be a genetic mitochondrial disease. The target -- our target, Nrf2 was identified and the key research was done by the FA research community. They approached us because we had the molecular tools to activate the target. It's known that Nrf2 is suppressed in the presence of the frataxin silencing that is believed to be a key mechanism through which mitochondrial function is severely impaired in the patients.

The relationship between mitochondrial respiration, ATP production and neurologic function is well understood. There's really well-done clinical studies showing high correlation between whole body respiration and neurologic function. So just across the board, the relevance of the target and the nature of the disease is well understood and it's just not controversial, number one.

Number two. The endpoint, the primary endpoint in the Friedreich's Ataxia studies, are just not controversial either. It's a neurologic exam that measures essentially clinical function. FDA has said that it's either an intermediate clinical endpoint or a clinical endpoint, depending upon their kind of view of the data overall, the totality of the data.

But it's clearly measuring patients' ability to do things like stand, walk, move their arms and hands. It's not like GFR where it's a laboratory endpoint, then you've got to extrapolate out to a clinical endpoint, right? It is a direct measure of neurologic function in the patients over time. And I'd add because of the great work that the patient group and the researchers have done, that rate of progression and the fact that it's relentless and doesn't really reverse is -- have been well characterized. Yes. And then Colin, you want to add to that?

Yes. So I think those are 2 excellent points. And there are a few others as well. And so beyond the mechanism and the endpoints, the clinical profile of omav is not controversial. And so obviously, recovering some function and then slowing progression is what would be expected with a drug that is efficacious, whereas I think we all know increasing kidney function with bardoxolone has been controversial. There's other elements of the clinical profile with bardoxolone that are controversial, such as increases in proteinuria, and there's no similar finding this controversial with omav.

Another one is that, obviously, bardoxolone had the legacy safety finding from the BEACON trial. We don't have that, and I spoke to that just a few minutes ago. With omav, there is no similar finding. And then another important aspect is that while there are no approved drugs for Alport syndrome, nephrologists believe that ACE inhibitors and ARBs have some treatment effect. Even though it hasn't been clearly demonstrated, there is a belief that there is at least some utility in those agents, whereas with FA, there are no available therapies that have any impact on progression.

I would say lastly, there was controversy in the KOL community about bardoxolone. And there was a vocal minority that thought that the drug should not be used. However, we're unaware of any such controversy within the FA community. As I mentioned on the call, we included all the FA KOLs at the time in our clinical study in the U.S. and several globally. And I think the reason why there's less controversy is because our data are interpretable, it's consistent and the mechanism is well validated. So I think there's many reasons why this program is different than bardoxolone.

The next question is a follow-up question from Yigal Nochomovitz from Citi.

I looked at Slide 13 again, it just raised another question. What's your plan with respect to the breadth of the label? I mean, obviously, you have some pes cavus patients here enrolled, although the p-value is not significant. Is the plan to apply for a broad label for both the non-pes cavus as well as the pes cavus? Or are you planning to focus on the non-pes cavus?

Yes. We would focus on a label that includes patients with and without pes cavus. And I think there's an important differentiation as well regarding our pes cavus population. And so recall that we, on a post hoc basis, noted from MOXIe Part 1, which was a small dose-ranging placebo-controlled study, that patients that had severe pes cavus were less likely to show a treatment effect. And so pes cavus is high-arch foot. And obviously, if patients have an abnormality that's non-neurological, in this case, skeletal, we would think that that could interfere with the ability to detect a treatment effect with omav.

And so for MOXIe Part 2, we prospectively define the pes cavus population, and really it was the patients with severe pes cavus. And so pes cavus is any high arch. And for the study, we used a flashlight test where basically patients stood up. And if their arch was so high that you could see light underneath the foot from a flashlight, we define that as pes cavus. But in reality, it's severe pes cavus. We took x-rays of all patients. And from our understanding, patients who are in the non-pes cavus population, many of them likely had some manifestation of pes cavus. And you're right, we did not show significance in the pes cavus population, but we would not expect to show significance with 10 in 10 patients. But the point estimate favored omav in the all-randomized population, which included those patients there was a significant treatment effect.

Furthermore, as I mentioned, in the full analysis set, we saw improvements in all sections on the mFARS. So that includes bulbar, which is speaking and swallowing, as well as upper limb coordination. And so that's -- those factors are -- receptions are unaffected by any high arch in their foot. And so for all those reasons, we think that the drug should get a broad label that includes patients with pes cavus, and that will obviously be part of our discussions with them.

And 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.