Reata Pharmaceuticals Inc (RETA) 2022 Q2 法說會逐字稿

Thank you for standing by, and welcome to the Reata Pharmaceuticals Second 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 Investor 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 the Reata's earnings release and presentation from today, which again can be found in 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, August 8, 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.

(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 know, we're developing omaveloxolone, or omav, a small molecule Nrf2 activator for the treatment of patients with Friedreich's Ataxia or FA.

FA is a relentlessly progressive and debilitating neuromuscular disorder, which affects approximately 5,000 patients in the United States. There are no approved therapies, and patients typically become dependent on walkers and then wheelchairs in their mid-20s and unfortunately, pass away from the disease in their mid-30s.

Following the announcement of positive data from the MOXIe Part 2 study in October of 2019, we met with the FDA in a Type C meeting, in which the FDA provided us with guidance that it did not have any concerns with the reliability of the modified Friedreich's Ataxia Rating Scale or [MR's] primary endpoint results.

Nevertheless, the FDA was not convinced that the MOXIe Part 2 results could support a single-study approval without additional evidence that lends persuasiveness to the results.

The FDA acknowledged the unmet need of patients with FA, reiterated its commitment to facilitate the development of omav within the constraints of the regulatory standards and emphasized its willingness to consider all available options to meet the regulatory standards. The FDA subsequently requested a Delayed-Start analysis of the data.

During the first quarter of 2021, we submitted the results of the Delayed-Start analysis from a February 2021 data cutoff to the FDA as additional supporting evidence of effectiveness.

And in May 2021, we received a communication from the FDA, stating that after a preliminary review of briefing materials for the Type C meeting, including the Delayed-Start analysis, a pre-NDA meeting would be the most appropriate format for a discussion of the development program for omav in FA.

In the third quarter 2021, we completed our pre-NDA meeting with the FDA. On November 18, 2021, the FDA granted omav Fast Track Designation for the treatment of Friedreich's Ataxia, providing eligibility for FDA programs such as priority review and rolling submission of the NDA.

The FDA granted our request for a rolling submission. And in March 2022, we completed the submission of the NDA. In May 2022, the FDA accepted our NDA for filing and granted priority review designation.

The FDA advised us that it is planning to hold an advisory committee meeting to discuss the application. The PDUFA date is scheduled for November 30, 2022. If approved, we're preparing to launch omav in the U.S. in early 2023.

Next slide. I'd now like to provide some background on the regulatory framework for the omav NDA review. FDA guidance states that a drug's effectiveness must be established by substantial evidence, which generally requires at least 2 adequate and well-controlled clinical trials for a new drug approval.

However, in the context of a rare disease like FA, it's challenging to conduct 2 adequate and well-controlled studies.

The Food and Drug Modernization Act of 1997 or FDAMA (115) as well as FDA guidance provide two alternative pathways to demonstrate substantial evidence of efficacy for drug approval.

Either: one, a single, adequate and well-controlled study that has demonstrated a clinically meaningful and statistically very persuasive effect; or two, a single, adequate and well-controlled clinical trial plus confirmatory evidence.

FDA has regulatory flexibility and may consider a number of factors when determining whether reliance on a single, adequate and well-controlled clinical investigation, plus confirmatory evidence is appropriate. These factors may include the seriousness of the disease, particularly where there is an unmet medical need and the size of the patient population.

In a setting like FA, it's challenging to design and power a single clinical trial with an extremely low p-value that would be considered statistically very persuasive due to the limited number of patients available for clinical research and the relatively slow rate of disease progression in these patients.

As a result, we've been pursuing the second regulatory path of one adequate and well-controlled clinical trial, plus confirmatory evidence.

As summarized on Slide 6, 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.

MOXIe Part 2 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.

We observed improvements relative to placebo in all subsections of the mFARS scale, all major subgroups and all analysis populations. And overall, only 4% of mFARS values were missing, with 9% missing at Week 48 time point.

Sensitivity analyses demonstrate that the missing data do not affect the trial's conclusion. As I mentioned earlier, FDA has not expressed concerns about the reliability of the mFARS primary results from MOXIe Part 2.

Next slide. We recently completed a mid-cycle communication meeting with the FDA. In the preliminary agenda 4 and during the mid-cycle communication meeting, the FDA stated that it has not identified any new significant issues, but it continues to have concerns regarding the strength of efficacy evidence.

The FDA noted 3 specific points of discussion for the meeting, including that MOXIe Part 2 is not exceptionally persuasive and has only weak support from the secondary end points.

The significant reduction in the number of patients in the extension phase of MOXIe at each time point makes it challenging to interpret the Delayed-Start analysis. And three, there's a lack of support from MOXIe Part 1 as no dose response relationship was observed.

They also noted with respect to a potential label, they requested additional justification or literature to support the relevance of proposed biomarkers to Nrf2 activation and how that would correlate with the treatment benefit in FA patients.

The FDA did not identify any significant clinical safety issues, and they noted that they are continuing to evaluate the cardiac safety of omav in patients with FA.

During the meeting, we proposed to address FDA's concerns in 3 ways. To address FDA's first point, we proposed a new propensity-matched analysis of MOXIe Extension data using the largest, most robust FA natural history study to provide additional clinical data that could be considered confirmatory evidence.

We noted that in the FDA's draft guidance on substantial evidence of effectiveness that confirmatory evidence could include comparison to reliable, systematically collected and well-documented natural history of patients with the disease, especially when the natural history is well defined.

The external control population is similar to the treated population and standard of care and concomitant treatments are not substantially different. We described how FA meets all of these criteria. The FDA acknowledged the approach and agreed to allow us to submit the analysis to the NDA.

Second, regarding the interpretability of the Delayed-Start analysis, we first noted that the reduction in number of patients was primarily due to missed visits due to the COVID-19 pandemic and not due to study discontinuations.

We then presented updated results of the Delayed-Start analysis using a March 2022 data cutoff, which contain new later time points and increased numbers of patients at later time points than the prior analysis. The FDA acknowledged this data and agreed to allow us to submit the analysis to the NDA.

Third, regarding the lack of a dose response relationship in MOXIe Part 1, we noted that based on the small size and short duration of MOXIe Part 1, it was not intended to demonstrate definitive efficacy. However, the study did demonstrate dose-dependent increases in Nrf2 target proteins.

And then finally, we discussed an additional NDA amendment, containing compelling mechanistic evidence in the setting of FA's well-understood disease pathophysiology, which could also serve as confirmatory evidence.

Data from MOXIe Part 2 showed an association between omav-induced Nrf2 activity and measures of neurologic function, with larger increases in Nrf2 target levels associated with larger improvements in mFARS scores. The FDA agreed to allow us to submit the analysis to the [NDA].

Following the mid-cycle communication meeting, we have subsequently submitted the additional data and analysis to the FDA as NDA updates and amendments, as shown on Slide 8.

First, we submitted updated data from the long-term MOXIe Extension trial from the March '22 data cutoff to address the interpretability of the Delayed-Start analysis. These results demonstrate that the separation in mFARS observed at the end of MOXIe Part 2 is maintained through Extension Week 144.

Second, we provided the propensity score matched comparison for the progression in mFARS of subjects in the clinical outcome measures in Friedreich's Ataxia, or FA-COMS natural history study, to the patients in our MOXIe Extension study. This analysis demonstrated that the rate of progression is measured by mFARS over 3 years was 55% slower in the MOXIe Extension patients as compared to their matched FA-COMS patients.

And third, we submitted mechanism-of-action data, validating Nrf2, the targeted omav, as a key player in the pathophysiology of FA. We also submitted clinical biomarker data, showing that induction of Nrf2 target proteins in omav-treated patients in the MOXIe Part 2 trial was associated with improvements in mFARS scores.

With that, I'd now like to turn the call over to Colin Meyer, who will provide more detail on the results from each of these new submissions. Dawn Bir will then discuss our recent progress in our commercial preparation activities for omav. Lastly, Manmeet Soni will review our financial results for the quarter.

Thank you, Warren. I'll start on Slide 10. As Warren mentioned, we recently submitted an update to the Delayed-Start analysis to the FDA from a data cutoff in March of this year. As a reminder, the purpose of the Delayed-Start analysis is to determine if the 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 are generally originally randomized to placebo, catch up to patients who were 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.

Since patients have been returning to the clinic for visits in the past year, the updated data from March contains a meaningful increase in the number of patients with mFARS assessments at later time points and new time points are available for analysis. This is shown by the boxes around the x-axis in each of the plots.

Results of the updated analysis are consistent with prior results and showed that patients originally randomized to omav have continued to demonstrate a persistent treatment benefit after 3 years in the extension.

As shown in the graphical plot on the right, the between group difference in mFARS observed at the end of the placebo-controlled MOXIe Part 2 period was preserved at 6 out of 7 time points in the MOXIe Extension.

Additionally, the upper limit of the 90% Confidence Interval for the difference estimate was less than 0 at both Extension Weeks, 72 and 120, meeting the formal threshold for demonstrating significant evidence of non-inferiority.

Numerically, the separation observed at Week 48 in MOXIe Part 2 was observed at Extension Week 72 through Extension Week 144, which represents 3 years of treatment in the extension.

To assess the treatment effect more formally in the extension, we recently performed a new propensity-matched analysis of the MOXIe Extension data to the largest, most robust FA natural history study to provide additional clinical evidence.

In the FDA's draft guidance on substantial evidence of effectiveness, the FDA has stated that confirmatory evidence could include comparison to reliable, systematically collected and well-documented natural history of patients with the disease.

Accruing data in the MOXIe Extension provides longer-term follow-up for disease progression in patients receiving omav, However, there is no long-term placebo arm for comparison.

The MOXIe Extension data were compared to natural history external controls using propensity matching to provide longer-term efficacy data in support of the statistically significant benefit demonstrated by pivotal MOXIe Part 2.

In this slide, we highlight criteria cited by FDA that are important when comparing clinical results from a treated population with an external natural history control group.

These include a well-defined understanding of the disease progression and variable [site] influence progression, an objective outcome measurement that is not subject to significant investigator biases, a well-documented database of natural history information on a group of patients that closely resembles the treated population, no substantial difference in the standard of care or available therapies with the control group versus the treated population and compelling evidence of a meaningful change in the progression of the disease between the 2 groups. We believe that FA and our data set meet all of these criteria.

Turning to Slide 12. The largest natural history study of FA, FA-COMS constitutes a well-established, reliable and well-documented source of natural history data for FA for comparison to the MOXIe Extension results.

FA-COMS is a global, multicenter, longitudinal prospective observational study that has enrolled more than 1,250 patients. Clinical outcome measures, including mFARS, are assessed annually, and patients are followed for up to 25 years in the study.

All FA-COMS sites are tertiary care centers, specializing in FA. And all mFARS assessments are conducted in a standardized manner by trained neurologists with experience in FA.

The score for each component of mFARS is based on measurements of a patient's functional ability using the same standardized set of instructions and similar case report forms in both the FA-COMS study and/or MOXIe trial. Investigators of the FA-COMS study meet regularly to review conduct of the study, results and study-related issues.

Additionally, the significant overlap in sites between FA-COMS and MOXIe provides a similar testing environment, standard of care, and standardized instructions for the mFARS assessment. Lastly, the size of the FA-COMS database makes propensity score matching feasible.

Next slide. Patients from FA-COMS were matched to MOXIe Extension patients using propensity scores based on 5 covariates, sex, baseline age, age of FA onset, baseline mFARS score and baseline gait score.

Selection of these covariates was selected in collaboration with the principal investigator and statistician for FA-COMS, based on clinical relevance, the relevance as prognostic indicators for disease progression and availability in those studies.

The change from baseline in mFARS at Year 3 from MOXIe Extension patients compared to the propensity score-matched FA-COMS patients was analyzed as the primary efficacy endpoint, using the same mixed model repeated measures, or MMRM, analysis as we used for the primary analysis for MOXIe Part 2.

All data from all time points were used to estimate the treatment effect. Three populations were analyzed and additional sensitivity analyses were conducted.

For inclusion in each of the study populations, patients must have had: one, baseline mFARS score; two, at least one post-baseline mFARS within 3 years after baseline; and three, values for all propensity score [model] covariates.

The MOXIe Extension study population included 136 patients with at least one post-baseline mFARS assessment, irrespective of pes cavus status. All of these patients were included in the primary pooled population. The FA-COMS study population included 598 patients eligible for 1:1 matching with the MOXIe Extension population for a total of 136 patients in each group.

Next slide. Demographics and baseline characteristics were highly comparable between MOXIe Extension patients and the matched FA-COMS external control groups. For the 136 patients in each group, the mean treatment duration was approximately 3 years as of March 2022.

Slide 15 shows the results of the primary pool population of 136 patients in the MOXIe Extension compared to 136 patients in FA-COMS. In this population, patients in the FA-COMS matched set progressed approximately 6.6 mFARS points by Year 3, whereas patients treated with omav in the MOXIe Extension progressed only 3 points, representing a significant minus 3.61 mFARS point difference, with a nominal p-value of 0.0001.

This absolute difference translates to a 55% slower way of progression for omav-treated patients in the MOXIe Extension compared to patients in the FA-COMS study at Year 3.

Next slide. In addition to the primary pool population, we defined 2 subpopulations, the placebo-to-omav population, which included 95 patients, previously randomized placebo in MOXIe Part 2 and patients from MOXIe Part 1, who had been off treatment for a minimum of 21 months, and the omav-to-omav population, defined as 41 patients, previously randomized to omav treatment in MOXIe Part 2.

A new propensity score was used to match each of these populations to the FA-COMS study population.

Demographics and baseline characteristics were also highly comparable between MOXIe Extension patients and a matched FA-COMS external control group for the subpopulations. At Year 3, the treatment effect in each of these populations was similar magnitude to the results from the primary pooled population.

Not shown on this slide, we conducted additional sensitivity analyses using different matching criteria, and all results demonstrated a significant treatment effect. In summary, while post hoc, these analyses provide a robust assessment of the effect of omav in the ongoing Extension study.

Whereas the pivotal MOXIe Part 2 study compared 40 patients, randomized to omav, to 42 patients, randomized placebo, over 48 weeks, the propensity-matched analysis includes over 3x as many patients who have been treated with omav to match FA-COMS patients for a duration that is 3x longer.

And all analysis populations demonstrated a significant slowing of progression for patients treated with omav.

Next slide. In addition to the updated Delayed-Start and propensity-matched analyses, we provided additional mechanistic evidence to the division that included an integrated and detailed presentation of the disease pathophysiology of FA, linking frataxin deficiency with Nrf2 suppression in impaired mitochondrial function.

Mechanism-of-action data is showing that omav restores Nrf2 activity in mitochondrial energy production in preclinical FA models and FA patient fibroblast and clinical biomarker data demonstrating that induction of Nrf2 targets in omav-treated patients in the MOXIe Part 2 trial was associated with improvements in mFARS scores.

Moving to Slide 18. The molecular pathophysiology underlying FA has been well characterized with many recent publications. Deficits in mitochondrial respiration and ATP production are observed in cells and tissues isolated from patients with FA.

For example, maximal mitochondrial respiration and spare mitochondrial respiratory capacity, assessed by oxygen consumption rate, were lower in fibroblast from patients with FA than in fibroblasts from healthy control subjects.

Similarly, mitochondrial [ATP] production in skeletal muscle was lower in patients with FA than in healthy control subjects or non-FA disease controls. Also, longer GAA1 repeats have been associated with lower maximum mitochondrial ATP production in skeletal muscle from patients with FA.

A study conducted in 42 patients compared peak VO2 consumption, which is reflective of mitochondrial function, with the Friedreich's Ataxia Rating Scale score and found that reduced mitochondrial function correlated with reduced neurological function.

Taken together, these data demonstrate a clear link between reduced mitochondrial function in FA and reduced neurological function in FA patients.

Next slide. At the cellular level, frataxin deficiencies are associated with impaired mitochondrial function, redox imbalance and iron disregulation.

Although the molecular mechanism, by which frataxin deficiency suppresses Nrf2, has not been fully characterized, disregulated Nrf2 signaling is a common early upstream event that contributes to mitochondrial dysfunction and redox imbalance in patients with FA.

In fact, genetic-silent [singa] frataxin results in suppression of Nrf2. Multiple publications have now demonstrated that Nrf2 levels and target gene expression are suppressed in preclinical animal models -- [meant] animal models of the disease and in cells from patients with FA.

As shown on the right of this slide, Nrf2 activity has also been shown to directly regulate mitochondrial energy production in neurons. Neurons with genetic silencing of Nrf2 have reduced ATP production. Conversely, genetic Nrf2 activation due to suppression of its negative regulator Keap1, leads to increased levels of ATP in neurons.

These data establish a clear link between the genetic defect in FA and impaired mitochondrial function, which causes FA's clinical symptoms. We and our academic collaborators have spent several years to demonstrate the relevance of omav to impacting the underlying pathophysiology of FA.

As shown on Slide 20 on the left, omav has been shown to restore Nrf2 levels in FA patient fibroblast. As you can see on the right, this restoration of Nrf2 is associated with restoration of mitochondrial energy production, which has been shown in FA disease models and patient samples.

Moving to Slide 21. We have also characterized omav's pharmacodynamic activity in FA patients and shown how this relates to clinical activity in MOXIe Part 2.

As shown on the left, in the dose-ranging MOXIe Part 1, we assessed Nrf2 targets, ferritin and GGT, in a standard blood-based clinical chemistry panel to determine the dose range associated with optimal pharmacodynamic activity.

Based on the short duration in small number of patients in Part 1, we did not expect to see clear or definitive improvements in clinical assessments, but we did expect to see clear trends in pharmacodynamic markers. Both ferritin and GGT demonstrated dose-dependent increases by Week 4 of treatment, with maximal increases observed at 160 to 300 milligrams.

To address FDA's request to show how these PD markers of Nrf2 activation correlate with treatment benefit in FA patients, as shown on the right, we performed a tertile analysis of mFARS and Nrf2 target changes at Week 48 in pivotal MOXIe Part 2.

This analysis shows that ferritin and GGT increases are associated with mFARS improvements. As shown on this plot that patients with the most clinical improvement and [largest] decrease in mFARS at Week 48, as shown on the right, were also the patients with the largest increases in ferritin and GGT. Changes in ferritin and GGT were inversely correlated with changes in mFARS.

To summarize, these data provide additional context for the relevance between FA pathophysiology, Nrf2 induction and clinical benefit in FA patients. And we believe these data could also constitute confirmatory evidence.

Next slide. In summary, MOXIe Part 2 provides the primary evidence for our NDA submission and demonstrated a significant improvement in mFARS in patients treated with omav compared to patients treated with placebo, with a p-value of 0.014. All mFARS subsections and major subgroups favored omav with a low amount of missing data.

To supplement the efficacy results of MOXIe Part 2, we have provided FDA with multiple submissions of additional evidence, supporting the efficacy of omav.

These include the Delayed-Start analysis with data through March 2022, the propensity-match analysis of patients in MOXIe Extension compared to match patients from FA-COMS and mechanistic data showing how omav directly affects the underlying pathophysiology of FA.

From a safety perspective, omav has been well tolerated, with a low incidence of serious adverse events. While cardiovascular disease is common in FA patients, we observed fewer cardiovascular AEs, no increases in blood pressure and no findings on serial ECGs or ECHOs in MOXIe Part 2.

Further, we have not identified any new safety findings in the ongoing Extension study. We plan to discuss all of these pieces of evidence in our upcoming advisory committee meeting.

With that, I'll turn the call over to Dawn for an update on our commercial preparations.

Thank you, Colin. Good morning, everyone. I'll continue on Slide 24. Our launch preparation continues in step with our regulatory progress. As we approach our PDUFA date of November 30, we are making every effort to ensure that the market is aware of this devastating disease with no approved treatment and that operationally, we are prepared to commercially launch in early 2023.

For years, we've engaged with the FA patient community through advocacy events, market research and our patient-focused FA disease education website, connectfa.com, which supports a variety of patient educational tools and resources.

During the second quarter, we launched our HCP-focused disease education website, thinkfa.com, focused on FA recognition, diagnosis and genetic testing and disease progression, management and severity, underscoring the urgency of the need for treatment.

We also deployed a digital marketing campaign to drive traffic to the website that leverages banner advertisement, search engine marketing and an e-mail campaign, all tailored to reach physicians currently treating Friedreich's Ataxia patients.

During the first month of active digital promotion, the thinkfa.com website saw over 3,300 visitors, with more than 65% being HCPs from our identified list of U.S. physicians treating FA, indicating accuracy in our targeting efforts and a high level of interest in treating this disease.

We've also advanced key operational projects to prepare for the launch of omaveloxolone and initiated payer engagement supporting patient access and reimbursement.

The Reata Reach patient access program will include front-end patient services, designed to intake new patient start orders from healthcare providers, complete the benefits investigation process and compliantly offer programs to alleviate the burden of out-of-pocket costs.

It also includes a limited specialty pharmacy distribution channel, designed specifically to support the needs of a rare-disease product launch.

Furthermore, we've initiated the sizing and design of our first neurology-focused salesforce. We plan to initiate the hiring of the sales team in Q4 with regulatory success. Thank you.

I'll now turn the call over to Manmeet, who will provide our Q2 financial update.

Thank you, Dawn, and good morning, everyone. We released our financials and filed our 10-Q earlier this morning. I would like to highlight a few financial items for this quarter, our strong cash position, consistency in our operating expenses as compared to the prior quarter and collaboration deferred revenue.

Let me start with our cash balance on Slide 26. As of June 30, we maintained a solid balance sheet with approximately [$401] million in cash, cash equivalents and marketable debt securities. Based on our current plan, our cash balance will enable us to fund operations through the end of 2024.

Moving to expenses. Both our GAAP and non-GAAP operating expenses remained consistent as compared to the first quarter of 2022. Lastly, as of the end of the second quarter of 2022, we have recognized all of the deferred revenues related to milestones achieved earlier under the .

As a result, we will not recognize any deferred revenue subsequent to the second quarter of 2022 until future milestone or collaboration revenues are earned. On the operations front, we continue to progress on the commercial drug supply for omav for the anticipated commercial launch of FA early next year.

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

Thank you, Manmeet. In closing, we've made substantial progress in our omav program, including the acceptance of our NDA during the quarter and submission of additional information and analysis to the FDA, which we believe strengthened the body of evidence, demonstrating the effectiveness for omav in FA.

We continue to prepare for the upcoming advisory committee meeting and the opportunity to discuss our application with the committee later this year. If approved, omav will be the first drug available for the severe disease. And we're actively working on commercial preparations to be in a position to launch it early next year. 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 of Citigroup.

Just first one operational question, which I think a lot of people are wondering about. Have you received a date yet for the omav AdCom? And if so, can you disclose that now?

Yes. Thanks, Yigal. We have a date for the AdCom, but we're actually not able to disclose it. We're prevented from disclosing it until the FDA makes the public disclosure. There is a tentative date.

Okay. Got it. And then I just wanted to drill down a little bit more on the FDA commentary regarding the concerns on the strength of the efficacy evidence.

So when the FDA made this comment, were there concerns specifically on the lower 0.014 p-value for the primary analysis population for non-pes cavus or was this comment about the strength of the evidence, more about the comment on the all randomized population, where the p-value, as you know, was a higher 0.034 and included the pes cavus?

And in the mid-cycle, was there any preliminary discussion that a label might focus on non-pes cavus?

Yigal, this is Colin. And so the -- we believe the comment about the strength of the efficacy evidence was based upon the primary results, which is the 82 patients that contribute to the between group, difference of 2.4 with a p-value of 0.014. The FDA has not raised a concern about patients with pes cavus.

I think, importantly, as Warren discussed earlier, in the context of a single-study approval, typically for a single study to support approval without any other evidence, the p-value is typically lower. And so FDA told us recently and as we said on this call today, that this is not a new issue. And so the strength of the evidence has been the concern.

It's typically the concern for rare disease trials with a single study. And so we've been engaged with FDA in a dialogue and really since we met with them a couple of years ago to provide additional evidence of persuasiveness. And so the recent mid-cycle meeting communication, they restated that concern.

As we disclosed on this call and in the Q, they had specific discussion points. And we engaged in a dialogue so that we could address those concerns by providing additional submissions. And so in conclusion, we've simply been going down the path of a single-study approval with confirmatory evidence, and FDA has not said that they've had specific concerns about MOXIe Part 2.

Okay. And then just one quick follow-up on delayed starts. So it sounds like the FDA was more focused on the lower sampling from the Delayed-Start at the outer time points, as you had noted.

Was there any commentary on the convergence of the curves at Week 48 or was that particular detail on the data not raised at the mid-cycle? And did they provide any initial thoughts on your updated March '22 data cut, where you have much better sampling at the more distilled time points?

Yes, there was a specific discussion of the convergence at Week 48 of the extension. We did get a question earlier about that, which we addressed. So it was just the general statement that there was a reduced in -- and we -- I'm not sure they were clear that, that reduced in were not study dropouts.

So just to be clear about it, this was during COVID-19 and so patients had to have mFARS assessments done in clinic. And of course, most of the clinics were close during this period. And so patients couldn't come back in, so there were missing values, particularly at that Week 48 and 72 time point.

But as the impact of the pandemic waned, those patients stayed in the study, they came back to the clinic. And so the data filled in at the later time points, and so we showed them that data, and they acknowledged it. And we asked to submit it, and they said, "Yes. Absolutely. Submit it."

And one other point to make, just to follow-up on Warren's comments, is that because the COVID-19 pandemic hit and because there were fewer patients, I think, that wasn't initially clearly recognized by the division. And so they had wondered if the low [win] could be due to dropouts.

And so in addition to clarifying that patients have restarted coming to the clinic, we also clarified that the dropout rate has been low. And so recall that MOXIe Part 2 was completed about 2.5 years ago.

And so at this point in time, all patients are -- have been in the extension for at least approximately 2.5 years. And 86% of the patients, who enrolled in the extension, still remain. So there's been a very low dropout rate over 3 years, including during the pandemic.

[Really] a good accumulation of additional data at the later time points.

Our next question comes from Madhu Kumar of Goldman Sachs.

So on this point around the reduction number of patients. So I mean, I feel like the updated data does speak to that pretty interestingly. I guess the question is, is there any way to show kind of the overlap of patients over time and show that like patients who were missing specifically, it's a Week 48 and Week 72 came back specifically in Weeks 96 to 144?

The best way that we've addressed that is by conducting the analysis of those 2 subgroups in determining the rates of progression, and we've demonstrated that the slopes are basically the same. And so the p-value is greater than 0.5 and there's no difference.

And so that includes all patients that estimates longitudinally the treatment effect over time, and it shows that they're progressing at the same rate. And so that's really the best way to address it.

We have conducted other sensitivity analyses similar to what you described and have provided those in our updated report to the FDA.

Yes. On the -- I guess, on the first question around the weeks [that form] the secondary endpoints, is there any kind of further analysis of the secondary endpoints that can provide that is kind of separate from mFARS?

I think it's important to note that FDA's view as we had disclosed over 2 years ago that there was no support from the secondaries. And they've actually changed their language to saying that there's now a weak support. And so we believe that the data that we've provided have allowed them to see that there at least is some "weak support".

And recall that ADL nominally favored omav for the p-value of 0.04, with all 9 questions favoring omav. The first secondary PGIC was trended and was close to significant -- was actually nominally significant in the all-randomized population. CGIC favored omav, and the rest of them, the majority favored omav.

And so there was a consistency, generally, in the secondaries, which we believe is the reason why FDA now knows that there's peak support.

And the next question goes to Charles Duncan of Cantor Fitzgerald.

Thanks, Warren and team, for a thorough analysis. Good luck with this one, but I do appreciate all the work that you've done. I guess I'm wondering if you sense that the additional information submitted could result in a PDUFA push? Or would it be considered a major amendment?

And then, also wondering whether or not you could provide a little more color to an earlier question in terms of an AdCom date. Could that be a Q3 or a Q4 event?

Okay. I'll take your first question, Charles. They have not indicated that there would be a PDUFA date extension. We -- they invited us to submit the amended data to the NDA. They encouraged us to get it in quickly because as you know, FDA, particularly in rare deadly diseases like this, like the respect of the PDUFA date.

And so they are -- of course, can make a decision at any time to extend it, but they haven't given us any indication of that yet at this point.

With respect to the AdCom date, they've provided us with a tentative date for our own prep, but we're simply prevented under the FDA rules from disclosing the date until they make the date public themselves. But as you know, probably from looking at other projects, it's normally 6 to 8 weeks before the PDUFA date.

Makes sense. Second question is relative to the 3 pieces of information and a lot of work being done here. I guess I'm not going to ask you what you think FDA will find most compelling. But if you had to choose your top data set that you find most compelling, which would it be, would it be the Delayed-Start or the propensity-match or the additional mechanistic information. Why?

Well, starting with the clinical data, I think both the Delayed-Start analysis as well as the propensity-matched analysis are extremely important and, in my opinion, compelling. They address slightly different questions.

So the propensity-matched analysis is -- we have the benefit of a very well-done perspective, long-term natural history study in a disease, where there's been no intervening therapy and done at many of the same sites that participated in the clinical trial.

We rigorously match the patients, and it provides a data set of an additional 136 patients over almost 3 years, with multiple sensitivity analyses showing consistently a greater than 50% reduction in the rate of progression. So it basically approaches the standards for a controlled study.

And I want to make clear, under the guidance documents, it only has to be -- provide evidence of the natural course of the disease. The standard is not that it has to equal that for a second controlled study. And so I think it's extremely strong data, indicating the long-term effects in the extension continue and that the rate of progression has slowed.

The Delayed-Start analysis addresses a separate question, which is during the controlled portion of the study, was the course of the disease modified?

In other words, in addition to the clinical benefit observed at Week 48, did it impact the progression? And there's now a large amount of data out at 120 and 144 weeks in the extension, showing that, that difference at the end of 1 year is maintained.

And if you look at the FDA's preliminary guidance, for example, in the Alzheimer's disease space, it's very clear that a randomized start design like this provides some of the best evidence for modification of the course of the disease. And so I think it's very important as well.

And finally, the mechanism-of-action data is a clear basis for providing confirmatory support under FDAMA (115). And because of all of the work -- basic work done around the impact of Nrf2 in the disease, that's a very strong rationale for confirmatory evidence as well.

Very good. Last quick question relative to the AdCom composition, so the panel in terms of the added members of the neurology panel. Would you anticipate that any of those folks would come from the FA-COMS investigator group?

It's unclear, and we don't have an understanding of who will be on the panel. And so we'll have to see who those members will be.

I mean, to make one just [side] point though, many of the FA-COMS investigators were investigators in the site. And that actually lends credibility to the matching analysis because, obviously, the clinical practice is the same.

Our next question comes from Annabel Samimy of Stifel.

So you didn't really touch on this much, but you did mention that the FDA is still reviewing the cardiac safety issues. So can you remind me what cardiac safety concerns they would have? It doesn't appear from the evidence that you provided that you have any.

So given that this is an analog of bardoxolone. There was an issue that came up there before and you had very precise [CNP] exclusion criteria here in the study, do you have a sense of what the FDA is monitoring?

And then, if I could just do a follow-up now. Obviously, you've provided a lot of mechanistic validation. I guess my question was, wasn't this provided in the original package, further mechanistic validation?

Because we've been saying for some time, we've understood for some time that the disease pathway here and how omaveloxolone could address that Nrf2 part of the pathway. So just a little explanation there of why you needed so much additional MOA data.

Sure. So first, in regards to the cardiac safety, they did not provide any specifics about any concerns. As you know, these patients often have cardiovascular disease. In our trial, we allow patients in to enroll, as long as they had mild to moderate FA cardiomyopathy. Arrhythmias are common because of that. And importantly, as I said, we've extensively characterized the cardiac safety.

There were fewer cardiac adverse events in these patients. We did a broad SMQ search to look at any potential signals for arhythmias. And we saw none. And once again, blood pressure was unchanged, and there were no findings on ECGs and ECHOs.

And so at this point, where -- we don't know if they have any specific concerns, and we provided, obviously, all of our underlying data to them.

In regards to the MOA, the reason why we provided additional data is in the context of their comment about efficacy. And so we walk through 3 different submissions that we've made. Any one of them could constitute confirmatory evidence and could be sufficient to support approval. And so we wanted to provide a robust data set to FDA.

One thing that we've been exploring more recently and that's emerged in the past year, it's not only the role of Nrf2, there's now numerous publications demonstrating that Nrf2 is suppressed in FA.

But importantly, we've been able to show that in our clinical trial, that induction of Nrf2 is associated with clinical benefit. And so that's a very strong mechanistic link that is a newer finding, that has since been submitted to FDA.

Our next question goes to Maury Raycroft of Jefferies.

I was going to ask one on the natural history data. You mentioned that the patient baseline characteristics match up well on the 5 different points. Can you talk about how the patients match up by GAA1, repeat baseline frataxin levels or FA activities of daily living?

Yes. And so broadly, the baseline characteristics and demographics are similar. Most of them, numerically, are almost the same. The one difference that's actually biased against the drug, is GAA1 repeat link. And so it's a little bit longer, numerically, in the omav-treated patients versus the extension.

And so if that were to affect the results, it would make the treatment effect smaller. But regardless, we saw, obviously, a greater than 50-plus percent reduction in the rate of progression across all of our analyses. But other than that one difference, they're very similar.

Got it. Okay. And then for the biomarker data, can you remind what the relationship is between GGT and ferritin biomarkers that you have data on in the slides and the biomarker frataxin? And can you provide any commentary on whether FDA has preference for specific biomarkers or assays for mechanism of action?

So FDA's guidance is that the underlying pathophysiology has to be well understood. And so there's a couple of decades worth of research and literature demonstrating that the causative mutation in FA is due to reduction in frataxin activity for 96% of patients. They have less frataxin for the other 4%. They have point mutations. And so that's well understood.

What has emerged in the past few years is that through some mechanism, that is not well understood. Frataxin deficiency is associated with suppression of Nrf2. And so as I said on the call, if you simply take siRNA against frataxin in cells and administer it to reduce frataxin, that results in suppression of Nrf2 directly.

So Nrf2, as you recall, is a transcription factor that controls the production of many target genes, and GGT and ferritin are 2 of them. And so we've shown in numerous publications that omav can dose dependently increase production of GGT and ferritin. And the benefit of using those 2 clinically is that those parameters are found on your standard clinical chemistry panel.

And so we can, at basically every time point when we draw blood, assess them to look for Nrf2 activation. We see increases earlier, as I said, after treatment, it was pretty much maximum by Week 4. And as I showed in MOXIe Part 2, the changes at Week 48 were associated with clinical benefit in patients.

And so I think the whole story has emerged over the past few years. And now there's a very strong link between frataxin [deficiency], Nrf2 suppression, underlying pathophysiology and now our drug's ability to restore Nrf2 and have that be associated with clinical benefit.

Our next question comes from Joe Schwartz of SVB Securities.

This is Will on for Joe. So one for us. Recently, we have seen senior members of the leadership team of the neurology division at the FDA have some different opinions over several high-profile reviews.

So are you sensing that there are some wide differences in opinion regarding omav? And do you have any insight into how many people are in favor versus more critical of omav? Any insight here would be helpful.

Yes. I don't think -- we have no visibility into the internal discussions of the FDA. And so we couldn't comment. We could really have no view of what differences in view there might be inside the review team or the senior people at the FDA, if any.

And I will say that in our meetings, we have had a wide range of participants, and they have been very open and transparent with us. As Warren said, because of that transparency, we've been able to address any concerns coming from any part of the review team or senior members to supplement the NDA.

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.