Q2 2021 Reata Pharmaceuticals Inc Earnings Call
Ladies and gentlemen, thank you for standing by and welcome to the Reata Pharmaceuticals second quarter 2021 financial results and update on development programs Conference call.
An audio recording of today's webcast will be available shortly after the call today in the investors section the reata as website at Reata pharma dotcom.
Before the company proceeds with its remarks. Please note that the forward looking statements disclosure on the company's press release.
The company will be making forward looking statements on todays call. There are many factors that could cause results to differ from expectations, including those noted in the company's SEC filings.
On today's conference call non-GAAP financial measures will be used to help investors understand the business performance.
These non-GAAP financial measures are reconciled with comparable GAAP financial measures and reata as earnings release and presentation from today, which can be found on reata as 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 9.2021 and may no longer be accurate at the time of any webcast replay or transcript rereading.
Following the prepared remarks, well open the call for questions.
We ask that you please limit yourself to 1 question and 1 follow up so we can accommodate as many questions as possible.
We are joined today by Reata as Chief Executive Officer Warren Huff.
Research and development Officer, Colin Meyer.
Chief operating and Chief Financial Officer meet Sony.
At this time I would like to turn the conference call over to Warren Huff, Chief Executive Officer of Reata.
Thanks, Good afternoon, everyone and thank you for joining US today, we have several important updates that we'll be sharing with you today first will provide a regulatory update for Alabama law Exelon for Friedrichs ataxia second will provide a regulatory update and a clinical update for production on and rare forms of <unk>.
Katy.
I'll give a brief overview and then hand, the presentation over to Colin for more detail.
We will start with an update on our AUM Avalon zone program in patients with free drinks ataxia on slide 4 as you.
L. A is a rare disease characterized by a progressive loss of motor function with patients often requiring a wheelchair by their mid twenties and having a median survival is 35 years. There are no approved therapies for F N b.
We've reported results from the Moxie part 2 study the baseline controlled study and the delayed start analysis, each of which met their primary endpoint and provide evidence of the effectiveness of <unk> patients with the FAA.
We provided this data to the F D. A and we're pleased to reported in May of this year, we received a communication from the FDA, suggesting that a pre NDA meeting is the most appropriate format for a discussion of the development program.
During the second quarter of this year, we withdrew our request for a type C meeting and request a pre NDA meeting with the FDA. The pre NDA meeting request has been granted and the meeting has been scheduled during the third quarter of this year, we submitted briefing materials for the meeting and we recently received a communication from the division.
Requesting the estimated date of our NDA submission for their planning purposes.
We're pleased with the Fda's continued engagement with us in determining a path forward for the program and pending the outcome. Other pre NDA meeting, we're planning to submit the NDA for <unk> for the treatment of patients with FAA during the first quarter of 2022.
Additionally, as a result of the recent regulatory progress in the second quarter, we re initiated our commercial readiness activities for own math.
Turning to <unk> on slide 5.
As all of you know our new drug application for part of Exelon for the treatment of patients with chronic kidney disease caused by outward syndrome has been accepted for filing and is currently under review by the F. D. A.
In connection with the review of the NDA. The FDA recently completed a bio research monitoring inspection, where we did not receive any observations.
We've recently completed the mid cycle communication review meeting with the F. D. A and we continue to prepare for the Advisory Committee meeting, which has been tentatively scheduled for December the eighth 2021.
The Paducah date for the NDA is February 25.2022.
Additionally, we're pleased to report that in July of this year Cai with Kirin are strategic collaborator and C. J D. In Japan submitted an NDA in Japan to the Ministry of Health Labor and welfare for Paradoxal on for the treatment of patients with CK day caused by airport syndrome based on this submission we've earned a milestone payment and if approved.
Commercial sales K Casey is required to pay us royalties on net sales from paradox alone in its territory.
Next slide.
The purpose of the mid cycle meeting is for the F. D. A to provide us with an update of the status of the NDA review, including any other issues identified the.
The mid cycle communication meeting with the FDA was focused on clinical and statistical review issues, while we've not yet received formal minutes from the FDA in the preliminary agenda for the meeting the FDA identified 4 significant clinical and statistical review issues for us to address.
We discuss these issues with the FDA during the meeting and we believe each is addressable.
D. A invited us to submit clarifying questions and our responses in follow up submissions to the NDA, which of course, we plan to do.
I'll briefly review the issues and our plan responses and then hand, the presentation over to Colin to provide more detail.
Okay.
Importantly, the FTA did not designate any safety issues as significant issues based on its current review the FTA noted during the meeting that it does not currently believe a risk evaluation and mitigation strategies or Rems program is needed for Barack salon throughout the history of the day.
<unk> burdock salon and because of its novel effects on Egfr and other parameters questions have been raised about the safety of long term use of the drug and C. J D patients, we and our partners and collaborators have generated a substantial amount of preclinical data delineating the mechanism of action on BARDA Exelon and we've collected.
The large amount of clinical data, including data in patients treated for 2 to 3 years to address these issues.
We believe this large dataset may be the reason that there were no safety issues listed as significant in the mid cycle communication. The lack of significant safety issues to date is important in evaluating the benefit risk assessment for approval.
With respect to the clinical and statistical issues. We believe each issue raised by the division is addressable first we've always known that the key question regarding the efficacy of BARDA ox alone in Outports syndrome, and other forms of C. J D is 1 of the large improvements in Egfr on.
On treatment will translate into a delay in the need for dialysis or transplant, we would've been very surprised if this issue was not being submitted to the AD com.
We believe that the 2 year data in the Cardinal trial demonstrate that in the second year of treatment, which we believe is the most predictive of future results BARDA excellent patient's egfr declines from its peak at a rate slower than placebo patients.
This reduced rate of decline is on top of a large absolute placebo corrected improvement in Egfr from 7 to 17 Egfr points, depending on the treatment group.
Based on the progression rate of these patients. This represents 2 to 4 years of delay to kidney failure patients.
Patients on continuous treatment at Goldome <unk> did not have a decline in egfr during this period, suggesting a potential long term delay and kidney failure.
Turning to the second topic, the FDA indicated that it did not appear that a pre specified covariate for treatment duration was used in the primary analysis and this would affect the significance of the results. We clarified in the meeting that the covariate was included in the analysis.
That the exclusion that would've improved the significance of the result and that the primary analysis was performed in accordance with this app.
Turning to the third topic. The FDA conducted a series of post hoc sensitivity analyses to test the significance of the year to key secondary results under a variety of scenarios.
Including using off treatment Egfr values at week, 1 O 4 irrespective of time off drug and excluding all off treatment values collected less than 28 days after the last dose.
[noise] excuse me.
These are post hoc analyses and because outboard syndrome is a rare disease Cardinal had limited power to show effects and sensitivity analyses that might be observed in much larger trials from more prevalent diseases.
The week 1 O 4 analysis effectively included many patients that had been off treatment for a minimum of 88 weeks the less than 28 day analysis excludes nearly 1 half of the trial participants violates randomization principles and results and modeled estimates that meaningfully different from observed week went on for Egfr changes.
Despite these issues the treatment effect and the sensitivity analyses always favorite BARDA exelon.
Okay.
Finally, the FDA raised an issue regarding the effect of Covid, the COVID-19 pandemic on Cardinal.
The FDA acknowledged that COVID-19 did not significantly impact treatment visits data collection or study drug dispensation. They noted that there were significant differences between the patients that finished pre and post COVID-19. The difference between treatment groups pre and post COVID-19 was driven by the enrollment of our <unk>.
A larger number of pediatric patients late in the trial. So that they ended the trial in the post Covid subgroup.
This group had more rapid disease progression and increase the overall rate of progression in the post Covid placebo group.
As I stated earlier, we believe that each of these issues are addressable and the FDA invited us to submit clarifying questions and to address each of the issues on a follow up submissions to the NDA, which of course, we plan to do.
I'll hand, the presentation over to Colin now to provide greater detail on the issues and our planned responses.
Thanks Juan.
On to slide 9 as Warner mentioned, we recently completed the mid cycle communication meeting with the FDA and they identified 4 significant review issues, which were discussed in the meeting.
Accordingly, the FDA did not designate any safety issues are significant issues as is customary with review of all India as the FDA may identify other issues and it may request additional information as it continues to review the NDA the issues. The F D identified where clinical and statistical and include 4 topics.
Acute pharmacodynamic effects versus slowing of decline in kidney function treatment duration as a covariate in week 1 of 4 analysis sensitivity analysis for off treatment analysis window duration and the impact of the COVID-19 pandemic.
We'll provide additional information about each of these issues that were discussed in the next.
Slide Thank you rigor.
Regarding the first topic. The FDA question, whether the observed Egfr increases suggest a slower rate of loss of kidney function in the paradox on group as compared to the placebo group during.
During the mid cycle communication meeting the FDA clarified that his preliminary analysis was computed using 2 distinct chronic egfr slopes a slope in year, 1 based on Egfr data from week 12 to week 48, and a slope in year 2 based on week 64 to week 100 the.
F. P. A noted that the observed changes in Egfr loss and the BARDA, Oxford group starting at week 12 in year..1 after a full manifestation of acute Egfr increase did not suggest a slower rate of loss of kidney function and the placebo group average.
As I'll explain shortly the loss of Egfr from weeks 12 to 48 in year..1 is explained by the loss of Egfr and paradox from patients who discontinued early in the study importantly.
Importantly, the rate of Egfr loss from week 64, after full manifestation of the acute Egfr increase to week 100 in your 2 is lower in the paradox when patients than the placebo patients. The FTA did not comment specifically on the rate of Egfr decline in your 2 of treatment.
As I just mentioned the loss of Egfr observed in patients treated with botox on from week 12 to week 48 in year..1 is explained by the loss of Egfr in patients randomized to burdock Sloan who discontinued treatment in most discontinuation occurred early in the study.
As shown on the figure on the top right of slide 10 patients who discontinued treatment experienced an acute increase in Egfr. There was maximal at week 12 and returned to placebo levels by week 36. This loss of the initial acute egfr effect after discontinuation of drug contributed to the.
Parent Egfr decline during your 1 in the intent to treat analysis.
As shown on the chart on the bottom of Slide 10 data from your 2 of Cardinal should that part oxo untreated patients that we started treatment at week 52 experienced a smaller egfr loss from week 64 to week 100 compared to the patients on placebo.
This was observed in patients in the intent to treat population patients in the Prespecified modified ITT or M. I T. T analysis patients who achieve goal dose in patients who did not achieve condos.
Importantly, patients who remained on boardwalk slow on treatment and maintain their goalposts on average did not progress or patients receiving placebo continued decline.
In addition to the reduced rate of Egfr decline in year 2 for oxo on patients experienced large absolute placebo corrected improvements in Egfr at week 100 across all analysis subgroups based on the historical rate of Egfr loss for these patients this separation would translate.
To a delay in kidney failure of at least 2 to 4 years for those patients who are maintained on their goal dose and did not progress kidney failure could be potentially delayed long term. If they continue to not progress lastly data from eagle demonstrate increases in egfr in patients treated.
With Barack so on and cardinal or sustained above baseline in the third year of treatment and beyond.
We believe these analyses demonstrate that and continuously treated patients egfr divergence from placebo overtime and could delay kidney failure.
Next slide.
And the F. D. A is preliminary communication for the meeting the FDA questioned whether we had followed the pre specified analysis model for analyzing week, 1 O 4 off treatment values.
During the meeting we explained and the FDA acknowledged that our analysis was conducted in accordance with and did not deviate from the pre specified SAP, which included treatment duration as a covariate.
All clinical studies using analysis model to compute the treatment effect and P value the NAV.
Alex This model incorporates observe data as well as datasets that are generated from missing data the.
The process of generating datasets from missing data is called the imputation staff and it uses available reference data to produce these datasets.
The statistical analysis plan or SAP for Cardinal pre specified that change from baseline in Egfr for patients treated with Barack slone will be compared to placebo at week, 1 O 4 using an analysis of covariance or on Cobra model.
Both the amputation step Andy analysis model can include covariance or independent variables between patients such as treatment group or baseline characteristics.
During the meeting he discussed how the amputation step was conducted the F. D. A suggested the treatment duration could vary it could have been included in the amputation step. We noted that the SAP did not specify covariance free amputation step and therefore, a treatment duration could vary it was not included in the amputation step of the analysis.
Yes.
We further explained that due to sparse reference data across the full range of treatment durations inclusion of the treatment duration covariate imputation step would've resulted in over 30% of imputed egfr values falling outside the range of observe egfr values.
Many of these values would've been extreme and exceeded biological possibility. For example, the maximum change from baseline in the observed data was an increase of 28 mil per minute, while the maximum changed from baseline and the imputed data would have been nearly 4 times larger with an increase of 105 Mil per.
A minute.
We therefore explained that while additionally, these extreme values would not have affected the overall treatment effect at week, 1 O..4 it would've are artificially more than doubled the standard error and insulated the P value.
Again importantly, during the meeting the FDA acknowledged that the primary analysis was conducted in accordance with and did not deviate from the pre specified SAP.
Turning to slide 12.
And Cardinal we Prespecified a year or 2 off treatment analysis window to include Egfr values obtained at least 14 days after last dose, which is supported by pharmacokinetic and extensive off treatment data demonstrating that the resolution of acute egfr increases occurs by 14 days.
After the last dose.
As shown on the table on the bottom on slide 12, we observed no association between the magnitude of off treatment Egfr values and the post dose period on your 2 these results establish that values collected in the earlier part of the analysis window did not bias or affect the conclusions of the off treatment endpoint.
Output syndrome is a rare disease, which limited the overall size of the trial. The study therefore had limited power to show treatment effects that would be conventional levels of statistical significance and certain sensitivity analyses for more prevalent diseases. Nevertheless, the F. D. A has conducted a series of post hoc sensitive.
The analysis to test the significance of a year or 2 key secondary results under a variety of scenarios, including using off treatment Egfr values at week, 1 or 4 irrespective of time off drug.
Approximately 1 half or 12 out of 26 of discontinuation.
For patients treated with Barack Sloan occurred within the first 16 weeks of treatment in these patients were therefore off treatment for a minimum of 88 weeks at the time of day or week 104 assessment.
When patients discontinue blocks alone, they're egfr trajectory was similar to placebo patients, including these patients that had discontinued for a long period of time inherently dilutes the treatment effect in this sensitivity analysis. Despite this the treatment effect and the analysis favored Barack Sloan, even when including these patients in the week 1 of them.
For analysis.
Furthermore, based on the precedent established on the reprise study of top Acton for the treatment of patients with ADP J D. We powered cardinal to assess the off treatment effect of Barack flown by including Egfr values collected at least 14 days after the last dose rather than powering the trial to include Egfr values 104.
2 weeks after randomization for all patients, including those who discontinued treatment early.
2 of the Fda's other sensitivity analyses only included values collected at least 28 days after the last dose.
These analyses excluded nearly 1 half the trial participants and violated randomization principles, which resulted in modeled estimates that meaningfully differed from observed week 140, GFR changes. However, the treatment effect in these analyses favorite paradox 1.
We perform sensitivity analyses similar to those performed by the FDA that included more available off treatment Egfr data by using a cutoff of at least 21 days. After the last dose the results for these new analyses were similar to the primary week, 1 O 4 analyses and we provided to the FDA as a follow up to this meeting.
Moving to slide 13, as COVID-19 emerged as a pandemic with serious public health implications. During the first quarter of 2020, we took steps to protect the health and safety of patients and health care workers involved in the ongoing Cardinal trial, while also maintaining the conduct of our studies in accordance with <unk>.
<unk> provided by the FDA and the EMA <unk> due.
Due to the timing of study conduct 31% of your 2 week 1 O..4 assessments were conducted pre COVID-19 or before March 1.2020, and 69% of week..1 of 4 assessments were conducted after the start the global pandemic.
In our mid cycle communication meeting, we were pleased that the FDA acknowledged that the COVID-19 did not significantly impact treatment visits data collection or study drug dispensation.
However, the FDA noted that there appeared to be differences for the week 1 O 4 endpoint when analyzed according to data collected in patients pre COVID-19 versus post COVID-19 with the study's findings driven by the post Covid subgroup.
The difference between treatment groups pre and post Covid was driven by the inclusion of a larger number of pediatric patients in the post COVID-19 subgroup.
This group had more rapidly progressive disease enrolled later in the trial and therefore had weak 1 for assessments conducted during the post Covid period importantly.
Importantly, although differences were observed for the pre and post Covid results. The point estimate for the change from baseline in Egfr at week..1 of 4 is similar across both periods for botox on treated patients next slide.
During the mid cycle communication meeting the FDA did not communicate significant issues about any safety topics. Prior safety topics that we have disclosed and discussed on previous calls we're not mentioned in writing or during the mid cycle communication review meeting. Additionally, no new safety signals have.
But on the identified and the ongoing Eagle extension study.
Based on its current review the FDA stated that it does not believe a risk evaluation and mitigation safety program or rems will be needed for blocks 1.
Yeah.
Moving onto our other programs in C. J D. On slide 16, we're also evaluating the safety and efficacy of Barack phone for the treatment of patients with ADP J D. The most common hereditary form a C. J D. The phase III Falcon trial Falcon has a similar trial design to the Cardinal trial interest enrolling patients with stage 2 to 3 <unk>.
D across approximately 100 sites globally.
We recently had a type b meeting with the FDA regarding the ADP J D development program, we have not received minutes from the meeting yet however, based on the discussion of the meeting we are considering amendments to the Falcon protocol.
Based on our experience during the Cardinal trial and Albert syndrome patients, we requested the ftes input regarding the feasibility of using year, 1 data to support early submission and accelerated approval, we acknowledged with the FDA that like her experience in Cardinal the timing of clinical study milestones at year 1.
1 and the required regulatory interactions prior to an initial submission may not allow sufficient time as previously noted by the FDA to submit the initial application before year 2 data are available.
Thus, while the study uses inefficient just study design that is intended to support an early submission its ability to support an early NDA may not be possible.
In response to an inquiry the FDA indicated that it is unlikely that the results from their first day of the trial would support an application for accelerated approval.
As such the F D. A recommended against on blinding the trial after the first year and conducting the proposed you want analysis.
The FDA instead encourage us to specify the year 2 off treatment analysis as the primary endpoint, we plan to modify the protocol. So that the primary endpoint will be the year or 2 off treatment analysis, and we will not on blind the trial until after its completion.
Our current SAP specifies that patients who did not receive at least 1 dose of study drug and the second year will be considered missing in the week, 1 or 4 analysis. The FDA recommended also evaluating the key efficacy endpoint using egfr values obtained at specified time points for example, 104.
Exact randomization, regardless of whether a patient discontinued study treatment at an earlier time point.
This is similar to 1 of the sensitivity analysis conducted by the FDA during the review of our output syndrome NDA.
We will be incorporating the FTC's feedback and submitting the revised for the FDA to review.
We want to be sure that we power Falcon for the new F. D. A comment on discontinued patients as a result, we may or may not need to increase the sample size from the current target of 550 patients.
More than 370 patients are currently enrolled in the study.
We continue to expect to enroll 550 patients in Falcon by the end of 2021. However, if we decide to increase the target enrollment we will provide updated guidance on our enrollment timeline.
Yes.
Moving to slide 17, Merlin is a double blind placebo controlled phase II trial in patients at risk of rapidly progressing C. J D. Due to multiple etiologies, including common and rare forms of CK D. Such as diabetic C. J D Hypertensive C J D Iga nephropathy.
J S and others. The primary endpoint of Merlin is the change in Egfr from baseline to week 12, we have completed enrollment in the Merlin trial and expect to have top line data in the fourth quarter of 2021.
If the results of this study are positive we would potentially proceed to a larger phase III trial with similar eligibility criteria patients at risk for rapid progression experienced a significant risk of progressing to end stage kidney disease in a population with high unmet need across multiple forms with C. J D.
With that I would like to turn the presentation over to meet provide a financial and operational update.
Thanks, Colin and good afternoon, everyone.
Please refer to our press release issued earlier today for a summary of our financial results for the second quarter of 2021.
Let me start with our cash balance on slide 19.
As of June 30th we maintained a solid balance sheet with approximately $755.7 million in cash and cash equivalents.
As you will note, we used approximately $22 million in cash during the quarter as compared to $45 million in the first quarter of this year.
Although our non-GAAP operating expenses increased by approximately $8 million during the second quarter as compared to the first quarter of this year. The reduction in cash used is explained by the receipt of $23 million tax reform related to cares Act during the second quarter.
In keeping with our current guidance, we expect our cash balance to fund our operations through mid 2024.
Moving to expenses, our research and development expenses for the quarter were $40.1 million as compared to $36.8 million for the second quarter of 2020.
Our non-GAAP R&D expenses were $34.8 million for the second quarter of 2021 as compared to $29.3 million for the same period of the year prior.
Higher R&D expenses were primarily due to increased spend related to ongoing clinical study expenses related to clinical programs and medical affairs activities for botox loans to support disease awareness and education activities.
General and administrative expenses for the quarter were $22 million compared to $16.6 million for the second quarter of 2020.
Our non-GAAP G&A expenses were $40 million for the second quarter of 2021 as compared to $9.3 million for the same period of the year prior.
Higher G&A expenses were primarily due to increased spend related to commercial readiness activities and hiring personnel to support growth and other activities.
Our GAAP net loss for the second quarter of 2021 was $72.7 million or $2 per share on both basic and diluted EPS.
As compared to a net loss of $67.6 million or $2 <unk> per share on both basic and diluted business for the same period of the prior year.
Our non-GAAP net loss for the second quarter of 2021 was 48 point.
Our $48 million on a dollar per liter.
Our share on both a basic and diluted basis as compared to a non-GAAP net loss of $40.9 million on a $1.23 per share on bolt on basic and diluted basis for the same period of the year prior.
The increase on GAAP and non-GAAP net loss is primarily driven.
By increased clinical study activities commercial launch readiness activities and increased personnel cost to support the growth of our development activities compared to the same period after you get price.
Moving to slide 20, which is a reconciliation of GAAP to non-GAAP financial measures non-GAAP R&D non-GAAP G&A expenses and non-GAAP operating expenses excuse stock based compensation expense, while non-GAAP net loss also exclude other income and expense items.
To summarize our non-GAAP operating expenses were $49.1 million during the second quarter of 2021, reflecting investment in clinical on the clinical and regulatory.
<unk> activities on commercial launch readiness activities for our pipeline.
We are actively preparing for the launch of our off on for the treatment of output syndrome, and recently initiated launch readiness efforts for hormel black flow and predicts ataxia.
That also on the call back over to Warren.
Thanks, Matt My.
As our presentation today indicates we're making significant progress across a broadening set of programs. We remain focused on working with the FDA during their review of our NDA from <unk> for the treatment of patients with outboard syndrome.
And continued to make steady progress in our other programs in C. J D.
On the back of our recent interaction with the FDA in the mid cycle communication meeting, we're preparing for an AD com tentatively scheduled for December the eighth 2021, and at Paducah date of February 25.2022.
In addition, we remain on track to file our MAA for marketing authorization in the European Union in the fourth quarter of this year.
Lastly, we remain dedicated to advancing own math NFA and look forward to updating you on the next steps for this program following our pre NDA meeting later this quarter as we prepare to submit the NDA by the first quarter of 2022.
That concludes our prepared remarks, and we'd like to thank everyone, who dialed in I will now turn the call over to the operator for questions.
Ladies and gentlemen at this time well begin the question and answer session.
To ask a question you May press Star and then 1 using a touch tone telephone.
All your questions you May press star 2 if.
If you are using a speaker phone we do ask you. Please pick up the handset before pressing the numbers to ensure the best sound quality.
We also ask that you please limit yourself to 1 question and 1 follow up.
At this time on pause momentarily to assemble the roster.
Our first question today comes from Google.
Nacho move it from Citi. Please go ahead with your question.
Hi, great I warn and calling on team. Thank you very much for taking the question as well I really appreciate all the detail on the Cardinal review issues are the force significant clinical and statistical review issues. So regarding those those 4 issues is there more analysis work that you need to do or is what you've shown us today in the slides essentially.
How do you intend to answer the Fda's questions and can you confirm that you will not need to conduct any additional clinical work to respond to these 4 issues.
Sure. Thanks Yigal this is Warren.
Yeah, what we've tried to be very detailed and transparent.
In the presentation of the issues and what you see here is our main approach to addressing each 1 of the 4 topics that they raised will be preparing additional analyses to help support.
Each 1 other questions and to present.
Our position back to the FDA in a very.
Clear linear fashion, but we do not anticipate having to produce any additional clinical data to respond to any other questions.
Okay great.
And then just 1 on on 1 of them.
Could you elaborate a little bit more as far as what you believe to be the key issues that you expect the FDA will will raise at the pre NDA meeting.
This is colin.
<unk> clearly had been in a dialogue with the division.
You know for the passenger so about the.
Interpretation of the efficacy data and so.
For the for the pre NDA meeting its primarily me discuss the mechanics of submission of the NDA and so we do not anticipate there to be on any meaningful discussion of interpretation of clinical efficacy or safety data and so it's more about the submission standards on how we construct our integrated summaries of safety and efficacy.
<unk> of you know the list of studies that need to be included in various non clinical CMC and from other quality topics and so on.
We've actually already received an information request for them that was a routine request. So they can understand which patients will be on what datasets.
And I think you may recall, we commented before that when they ask us to withdraw the type C meeting and submit for the request from the pre NDA meeting they told us to redirect our briefing materials to the topics that would typically be covered in the pre NDA meeting.
Great. Thank you.
Yeah.
Our next question comes from solving.
Richter from Goldman Sachs. Please go ahead with your question.
Hi, Thank you so much for taking our questions. This is sonya on for solving.
Just 2 questions from us on the first on them.
Okay. What is the risk that the FDA requires either on additional trial or the likelihood of conditional approval.
The 3 pre NDA meeting.
So the purpose of the Penn gaming interest to discuss the package for the NDA.
And Preston determined if there'll be any additional trials required in that in the post marketing setting.
FDA had previously signaled that we needed additional evidence to support an NDA submission for marketing authorization and so we believe that the data that we provided them on a baseline a controlled study as well as.
The other datasets.
Have allowed us to overcome that hurdle and so.
We do not believe at this point that there will be another free marketing trial needed, but we'll determine at the meeting if a post marketing trial may be needed.
Thank you on just 1 quick follow up on you mentioned that there will be some additional analyses for.
The issues that came up with Cardinal.
When we get to see if there's additional analyses on it.
Potentially.
And we showed here today on our earnings call. We are working on from obviously additional wants to supplement the ones that we disclosed today.
1 other I think aspect of the dialog with that on a few occasions. The FDA asked about data and we clarify that it was within the NDA and so part of what we'll be communicating to them, it's where the actual content can be found.
Thank you so much.
Our next question comes from Carter Gould from Barclays. Please go ahead with your question.
Great. Good afternoon, I'll Echo the earlier comments. Thank you for the level of disclosure Tonight, I guess, just first to start off around the sensitivity analysis.
Treatment window.
It seems like Theres been some bit of evolution and sort of how FDA is addressing this or their stance on that so.
I guess it would be helpful to get some additional color on in your view how that how that position has evolved or is this just a reflection of the level of discontinuation you saw early in the study and I guess my my brief follow on I Didnt hear any comments on the call, but in the Q there in the Q there was some commentary around.
CMC for Botox alone and there'd be some some commentary on forthcoming if you could put any kind of color around that and your level of confidence that you are all set on the manufacturing side. Thank you.
Yeah. So this is more on I'll start and Paul and feel free to.
To supplement this.
The FDA has been what's been very consistent and the our port.
Review.
With respect to the window period, we had specified in the protocol on the analysis of window that.
It was 14% to 35 days and in the year 1 O 4 data there the distribution of values was primarily between day 21 out to around day 35, and beyond we actually opened on the the 35 day because of the pandemic.
To pick up any values that came in late because of rescheduled visits and that kind of thing.
But they are early on express some sensitivity about whether the values taken prior to day 28 could bias the results and we've shown we demonstrated that if you look at the observed results. This is the data that set forth in the presentation you simply see no relationship.
Between the off treatment period beyond day, 14, you know and the magnitude of the results. If they were biased you would expect them to be high.
On the left and lower on the right and that's clearly not the case Nevertheless.
Nevertheless, they continue to explore that issue in there in their sensitivity analyses.
And I think you ask your second question was about seen our CMC yeah. So in the in addition to the the the written comments that we got and the you know in the discussion in the meeting was all around the clinical and statistical topics.
They did let us know in the meeting that we would be receiving comments on CMC. They did not indicate what they were.
And I think they I also believe they indicated that we would not be receiving any non clinical comments. So we haven't seen those yet so.
So I'm not in a position to comment on that.
Thank you.
Our next question comes from Maury Raycroft from Jefferies. Please go ahead with your question.
Hi, Thanks for taking my questions just on.
A follow up on the post hoc operating and sensitivity analyses that FDA did can you talk more about preliminary revenue receptivity that FDA had to your rebuttal findings that help reconcile their findings or did FDA seem pretty sad and viewing their method as the standard over the best way to assess the data.
So the purpose of the mid cycle communication meeting is for them to communicate any issues they've identified to us.
So that we can provide additional data for them to review, an NDA and so there.
There was more clarification during the call we did have some discussion.
But we will be providing additional data as part of the NDA to address this and we believe all these issues are addressed by data analyses that we currently have.
I just I'd just add that these these were all sensitivity analyses. This is just this is what the FDA does to probe the robustness of your data they're going to run the data in many different forms.
As they draw their conclusions about how persuasive. It is so it's not surprising that they did these analyses and it's not surprising some of them are not going to be significant but in all of them as I said the treatment effect favors paradox loans. So it's not like it favors placebo and goes the other way when you start spicy.
Spicing up the data as we discussed you can lose significance because it can be much lower but.
But importantly, Mike and subgroup analysis of.
The data favorite part oxo on.
Got it that's helpful perspective, and also sort of following up on an earlier question. All of these different for stat issues you guys provide an overview on how youre going to address each of them.
But if there's an area where FDA is not satisfied you've got a lot of data outside of the outboard phase III, including the chronic kidney disease studies, where you've got off treatment data out to 8 weeks and so I'm wondering if if that could be leveraged as a possibility where your thoughts are there.
Yeah. Some of our responses will definitely include data from the other clinical trials outside of airports and from syndrome and absolutely no question about it.
Got it okay. Thanks for taking my questions.
Yes.
Our next question comes from Annabel <unk> from Stifel. Please go ahead with your question.
Hi, Thanks for taking my question I'm, sorry, if I can on belabored. This point again, but with the sensitivity analysis that.
On the SBA debt given that you know as he said clearly from a statistical perspective discontinuation.
You know cost from dilution there are violations of randomization from 1.
You know just.
That in conjunction with the fact that ADP J D. It looks like Youre looking at E off treatment is that an indication that they don't think that 4 weeks of treatment of sufficient share.
On the.
This treatment effect.
I'm extremely GFR increases that you saw during the treatment period.
So that's my first question.
Yes, I think that's really 2 in ones will address the first 1 I think that.
F D a.
It's on.
We're unclear if they completed obviously their entire review of the clinical data.
And in regards to the patients who discontinued as we showed here and as we provided FDA during our meeting will provide and follow up those patients behaved like placebos. After they go off study drug and so 1 of the sensitivity analysis that we conducted includes basically the diluted patients.
And once again it shows that Theres, a smaller treatment effect, but it's still favors box alone.
But regarding your question about the off treatment duration and so we've had multiple discussions with this division.
To demonstrate and to discuss that 28 days is sufficient to wash out the treatment effect and there hasnt been agreement about this in the prior discussions.
And we have a lot of data to support this we've done extensive exposure response modeling across many of our trials showing that there's a linear effect with egfr in plasma concentration without lag that basically supports the extensive clinical data and that the effects are resolved within 14 days.
1 aspect of the data.
That we identified and discussed the meeting demonstrates from 2 short term studies of approximately 100 patients.
Who had their first off treatment value collected 28 days after the last dose that there's complete resolution and so the change from baseline for those patients.
Minus 0.7 with a P value of <unk> 9.1 showing complete resolution median change was 0.0 FDA noted.
That they had not completely reviewed that data and so that already has been 1 follow up that we provided to them, but we have data showing that patients do not reach their maximal effect within 14 days of reaching their final dose. There is a data set of 177 patients.
Debt, we have that support that in our modeling shows that the offset once again is similar we have a dataset of over 650 patients with over 1000 data points demonstrating resolution.
First within 14 days.
So once we can discuss this multiple times, we discussed at our end of phase 2 meeting for PK D day.
They noted in the review of the NDA debt in a Japanese study there is a small subset of 19 BARDA oxo on patients.
Who received England clearance that had resolution of their acute increase in GFR as assessed by measured GFR relative to baseline on placebo within 4 weeks, but in that subset Egfr did not appear to have been resolved and we think this is due likely to the effects on infusion.
Fluids during the England clearance procedure, which once again demonstrated resolution effects and so they raised that issue and they asked about whether or not we could include an additional off treatment.
The time point for Falcon, which we agreed to do.
Okay, and if I could just ask you said you had a lot of data and is there anything from eagle that you'll be able to provide additional support for them.
The timing that you have now.
Not for off treatment, but I think as you probably noted in the first.
Issue that they raise they are looking at all data that would support that paradox phone has an effect on irreversible disease progression. This can come from the off treatment analysis from within the Cardinal trial as well as longer term on treatment data and that's why they asked about the slopes of the.
On treatment changes and so the Eagle data can supplement that analysis, because as we've discussed the slope in your 1 is affected by discontinued patients and then from the blocks from treated patients in all various subgroups. They progressed at a slow rate in the second year and that continues basically to be maintained that treatment effect about baseline in the eagle and so we think all of it.
It's helpful to basically address this question. Yeah. This is this is Warren Huff. If you were asking if there's a way to provide further data along the way if we needed it we actually because of the comments that they have made.
And all in all of our newly initiated trials. We've started collecting weekly off treatment data. So for example, our Maryland study collects weekly off treatment data and if we needed it that data could be used to further buttress our position here.
Great. Thank you so much.
Our next question comes from Brian <unk> from Baird. Please go ahead with your question.
Hey, good afternoon, Thanks for taking my question.
Was hoping maybe you could just kind of to some extent give us.
How do we think about these 4 issues that were raised in terms of.
How meaningful do you consider them to be when we go on to the AD com.
Decision by the FDA it seems like some of them maybe 3 of them are just areas where there.
Some except on just the post hoc on sensitivity analysis, turning up loss of significance like like Covid not a.
A little bit the impact it would have a kind of it seems like an obvious unexplainable issue.
Where they may be just looking for a defense nonetheless, but on the on the first 1 on the acute PD effects versus the slowing of decline in kidney function I guess it just seems like a concern on that has repeatedly been raised over the years was addressed by you previously, especially in sort of the.
Media data release, and I would have expected to be a meaningful part of the NDA.
Discussion in the submission. So I guess the question here is why is the FDA asking a question that seems.
Right.
Has it been previously well addressed can you give any insight into that.
Sure. This is Warren I'll start and I said this in the opening comments I really am not at all surprised that they would want to serve up the question of whether the acute increases in GFR gonna delay dialysis to an AD com. These are you know.
BARDA Exelon has a highly novel mechanism of action. These improvements have never been observed before.
And so it really doesn't surprise me at all on we'd expected this and welcomed it you know this is to me a not a bad question to be served up they could have completely disregarded the on treatment effects and only looked at the off treatment effects I think that their question acknowledges that if you're.
Slowing their rate of progression.
With the on treatment benefits, that's a clinical benefit that could support their efficacy determination.
And I think that the answer to the question that they put.
Is is very cool.
To us it's very clear, let me just say that the the design of the trial is a little complex because it collects the off treatment values at both year, 1 and year 2.
And this really precludes a classic chronic slope analysis.
Because you just don't have continuous treatment.
And they actually recognize that when we asked them how they did the analysis. They stated that they actually did 2 separate slopes 1 from year, 1 and 1 free here too that in itself violates the findings of the NK F F D. A.
Working group, which basically said that you need 2 to 3 years of chronic slope data to compute a slope. So I think everybody looking at struggles a little bit with like what's the appropriate way to do the analysis, but I think it's just it's just very clear that the year 1 change rate of change the loss of <unk> <unk>.
<unk> in year, 1 just doesn't predict year, 2 or the future years, we have that data, it's empirical and the year..2 data is really we believe is very compelling and that the you know the patients, particularly the patients on continuous treatment just decline at a much lower rate.
At a lower rate than the placebo patients and the patients on gold does don't decline at all.
It's just it's just fairly obvious and that's on top of a large placebo corrected improvement and I think it's difficult to make the case that this is not likely to delay dialysis. Colin do you want to comment and I think that Brian mentioned, a couple of other things.
I think the tone has changed and the type of question, we're getting from the agency about this is different than.
Dan before as you know we've talked on these calls as well as with each day and analysts individually about the mechanism of action by docs on questions about hyper filtration proteinuria.
Other safety topics on those did not make the list and so on this question that I asked.
As you know purely a clinical question about efficacy and I said, well if this only reversible, whereas irreversible component to the increase in Egfr, it's not about how do we know this is on hyper filtration.
So I think the tone is different and as Warren said, we were fully expecting that this would be the main question we're at outcome.
And then if I could just ask real quick I Didnt hear you mentioned pretty spot on the specification of covariates for the mutation stop on being an update to Falcon.
Any plans to do that or is it sort of the issue that you said about imputing figures falling so far outside of the range reported.
Reasonably be expected to be observed.
It makes it sort of a moot point.
Probably makes it a moot point, but I think that's 1 thing that was a relatively.
Minor point in the discussion and so we'll obviously provide an updated analysis play on Falcon to FDA to address their primary comments to our flash them. If they agree and if not we can have further dialogue with them.
Great. Thank you.
Our next question comes from Charles Duncan from Cantor Fitzgerald. Please go ahead with your question.
Yes, Hi, Warren and team thanks for all the information on the call.
Lots of questions on BARDA actual on so I ask 1 on on lab.
In terms of the upcoming FDA meeting with the agency I guess could we anticipate that like today's comments you would be able to provide some information before the minutes or should we assume that you'll wait till have minutes or should we just assume that you're going to go.
Go forward with an NDA filing in first quarter.
Normally we like.
Like most sponsors want to wait for the minutes on.
Unless we're in a position like we are now where you really need to make disclosures before youre going to receive them. So normally we would wait.
Unless we're compelled for some other reason.
The reason to disclose them.
Okay and then.
It seemed in the press release that FDA asked for a date.
For a submission in and I guess I'm wondering is that I'd tell you. It's on to me and I'm just kind of wondering what your what your thinking is for the agency asking you for when you would submit.
Well I think it's consistent with the fact that they ask us to.
To request, a pre NDA meeting and they ask us to ask the questions that we needed to ask typical for a pre NDA meeting, which basically means questions that you need to have answered to submit your NDA. So very mechanical meeting a bed datasets and that kind of thing.
So that's all consistent with that they you know that they think theyre going to give us a path to filing correct and they are doing resource planning likely so they can allocate the optional reviewers to the NDA right.
Okay. Good and last question is I know lots of people who've done lots of work around BARDA and its value, but on all NAV and its value I guess I'm wondering if there are any key inputs on pharmacokinetic value that you would point us to provide perspective on <unk>.
Not asking for pricing of course here, but just kind of what is the key.
Call it clinical value that you see on map is providing.
Sure Charles So I think that the data that we've provided to the agency and disclosed publicly demonstrates not only that the drug is disease modifying but also it can help meaningfully result in slower.
A slowing down of disease progression in some patients actually recover function and it's consistent across the all all subtypes are all sections of the Empire scored and its associated with improvements in how patients report that they're feeling and doing and so we think it's a pretty meaningful dataset and theres not 1 app.
Back to you that's driving the results and so we hope that.
That would suggest the drug would have broad.
Activity.
On improvements for these patients.
Very helpful. Collyn last question is would you anticipate filing for a broad or narrow indication based on some phenotypic observation.
Oh man.
Our plan would be to provide a draft label to F. D. A debt that is broad of mirrors eligibility criteria from our trial, which were quite broad.
Okay very good helpful. Thanks.
Okay.
Our next question comes from.
Joe Schwartz from SVP Leerink. Please go ahead with your question.
Great Hi, guys. This is will on for Joe and thanks for taking our question today.
1 for us.
And we can go back and get a little bit of historical perspective or context on reaching agreement with the FDA for their return Egfr benefit.
Does this needs to be demonstrated in a context of anything or is this merely just hitting that 2.5 bar I any contact therapy, great. Thank you.
Well they requested that we include this analysis in the trial.
In a pre IND meeting, which was 2016.
And as you know that same analysis supported approval of 12, apt on which with a much smaller placebo corrected difference.
And so in our view you know they wanted to see a difference that was statistically significant.
And they didn't have a specific.
Delta that they wanted to see although they mentioned debt.
It should be greater than 1 mile from it at the time, but they backtracked on that in the context of our peak of the interaction they take less.
Yes, so they would take less than 1 if the trial is adequately powered.
Great. Thank you.
Once again, if he would like to ask a question. Please press star and then 1.
Our next question comes from Matt Kaplan from Ladenburg Thalmann. Please go ahead with your question.
Hi, Good afternoon, guys, just going back to our docks on I guess as you're preparing for the AD comm meeting in December.
With the 4 issues.
Identified by the FDA are there any other issues that you're preparing to.
For at that meeting that could derail the ad com.
Being successful.
We prepared for numerous potential issues those that have been raised previously are those that they could raise across many different topics, including efficacy on safety.
What's important to acknowledge with this mid cycle review meeting is that you know 1 purpose is so that they can communicate issues to us so that we can address them.
Other assist that both sides can be aware of the issues. So that they can be thoroughly briefed before the outcome and so.
We'll be prepared for additional issues, but at this time, but these are the issues that on the FDA identified as quote significant and so as we discussed on the call today.
Sure.
A few of these are what we believe are straightforward clarifications and interpretation of GFR over time. Once again is something that we are prepared to do and thats extensively briefed on in the NDA will be on that.
Not only the AD comm briefing books, but on a presentation.
Okay. That's helpful and then just with with them on the locks alone.
Uh huh.
What are your plans following the FAA NDA submission.
First quarter to continue to develop the product in other indications.
Yeah. So we've talked for some time about the applicability of AUM app to many other settings of neurological diseases, including other movement disorders.
Progressive Supranuclear palsy.
AOS Huntington's disease certain types of dementia as well as other neurodegenerative diseases and of course the feature that the drug is primarily of faxes mitochondrial dysfunction, which we believe is in.
Inherent to a wide variety of settings, and so with the recent breakthrough with division for FAA, We're now actively planning internally to initiate.
New studies in follow on indications in the future and we will be discussing that more in detail on on future calls.
Thanks for taking the question guys.
Yeah.
Yes.
And thank you and I'm showing no further questions in the queue at this time.
Ladies and gentlemen, thank you for your participation on today's conference as a reminder, an audio recording of the call will be available. Shortly after the conference call on Reata as website at Reata farm on Dot com in the investors section.
Thank you very much for your participation you may now disconnect.