Q2 2022 Reata Pharmaceuticals Inc Earnings Call
Thank you for standing by and welcome to Reata Pharmaceuticals second quarter 2022 financial results and update on development programs Conference Cool.
An audio recording of today's webcast will be available shortly after the cool in the Investor section of <unk> website at Reata pharma dotcom.
Before the company proceeds with its remarks. Please note the forward looking statements disclosure in the company's press release.
Any factors that could cause results to differ from expectations, including those noted in the company's SEC filings.
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 every artist earnings release and presentation from today, which again can be found anybody elses website.
Today's statements are not guarantees of future outcomes. Please also note that any comments made on today's call are probably only as of today August eight 2022 and may no longer be accurate at the time of any webcast replay or transcript rereading.
Following their prepared remarks, we will open the call up for questions. We ask that you. Please limit yourself to one question and one follow up so that we can accommodate as many questions as possible. We are joined today by Warren Huff react as Chief Executive Officer, and meet so neat President Colin Meyer, Chief Innovation Officer, Simi Khan Chief Medical Officer.
And doing that Chief commercial officer at this time I would like to turn the cool I bet to Warren House.
Good morning, everyone. We thank you for joining us today for our quarterly update.
I'll start on slide four.
We're developing <unk>, our own math or small molecule interest two activator for the treatment of patients with friedrichs ataxia or SA.
If there is a relentlessly progressive and debilitating neuromuscular disorder, which affects approximately 5000 patients in the United States.
There are no approved therapies and patients typically become dependent on walkers and then wheelchairs in their mid twenties, and unfortunately pass away from the disease in their mid thirties.
Following the announcement of positive data from the Moxie part two study in October of 2019, we met with the FDA in a type C meeting in which the FDA provided us with guidance.
Did not have any concerns with the reliability of the modified friedrichs ataxia rating scale or <unk> primary endpoint results. Nevertheless, the FDA was not convinced that the moxie part two results could support a single study approval without additional evidence that Linda persuasiveness to the result.
P. A acknowledged the unmet need of patients with FAA reiterated its commitment to facilitate the development of <unk> within the constraints of the regulatory standards and emphasize its willingness to consider all available options to meet the regulatory standards. The FDA subsequently requested a delayed start enel.
As of the data.
During the first quarter of 2021, we submitted the results of the delayed start analysis from our February 2021 data cut off 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.
Pre NDA meeting would be the most appropriate format for a discussion of the development program for <unk> and <unk>.
<unk>.
In the third quarter of 2021, we completed our pre NDA meeting with the FDA on November 18th 2021, the FDA granted <unk> fast track designation for the treatment of friedrichs ataxia, providing eligibility for FDA programs, such as priority review and <unk>.
Submission of the NDA.
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.
The FDA advised us that it is planning to hold an advisory committee meeting to discuss the application.
<unk> date is scheduled for November 30th 2022.
If approved we're preparing to launch <unk> in the U S. In early 2023.
Next slide.
I would now like to provide some background on the regulatory framework for the old map NDA review.
Guidance states that a drug's effectiveness must be established by substantial evidence, which generally requires at least two adequate and well controlled clinical trials for our new drug approval How's.
However, in the context of a rare disease like FAA, it's challenging to conduct two adequate and well controlled studies.
The food and drug modernization act of 1997 or predominant $1 15, as well as FDA guidance provide two alternative pathways to demonstrate substantial evidence of efficacy for drug approval.
One a single adequate and well controlled study that has demonstrated a clinically meaningful and statistically very persuasive effect or to 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 FAA, 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 six 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 the FAA.
We enrolled 103 patients across a wide and representative range of age and disease severity.
Moxie part two met its primary endpoint of change in EM, Fars relative to placebo after 48 weeks of treatment.
Patients treated with <unk> demonstrated a statistically significant placebo corrected two four point improvement in <unk> compared to placebo. After 48 weeks of treatment with a P value of 0.014.
We observed improvements relative to placebo in all sub sections of the M. Four scale, all major subgroups and all analysis populations and.
And overall only 4% of <unk> 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 <unk> primary results from Moxie part too.
Next slide.
We've recently completed a mid cycle communication meeting with the FDA in the preliminary agenda for enduring 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 the efficacy.
The evidence the FDA noted three specific points of discussion for the meeting including that Moxie part two is not exceptionally persuasive and has only week support from the secondary endpoints the significant reduction in the number of patients in the extension phase of Moxie.
Each time point makes it challenging to interpret the delay start analysis and three there is a lack of support from Moxie part one is 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 interrupt to 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 <unk> in patients with FAA.
During the meeting we propose to address Fda's concerns in three ways.
To address Fda's first point, we proposed a new propensity matched analysis of Moxie extension data using the largest most robust FAA 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 can.
<unk> population is similar to the treated population.
And standard of care and concomitant treatments are not substantially different we described how FAA meets all of these criteria the.
The FDA acknowledged the approach and agreed to allow us to submit the analysis to the NDA.
Second regarding the interoperability 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 discontinuation. 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 and Moxie part one we.
We noted that based on the small size and short duration of Moxie part one it was not intended to demonstrate definitive efficacy. However, the study did demonstrate dose dependent increases in <unk> target proteins.
And then finally, we discussed an additional NDA amendment containing compelling mechanistic evidence in the setting of Fas well understood disease, pathophysiology, which could also serve as confirmatory evidence data for Moxie part two showed an association between <unk> induced.
In RF to activity and measures of neurologic function with larger increases in interest to target levels associated with larger improvements in <unk> 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 eight.
First we submitted updated data from the long term Moxie extension trial from the March 22 data cutoff to address the interpret ability of the delayed start analysis.
These results demonstrate that the separation and <unk> observed at the end of Moxie part two is maintained through extension week $1 44.
Second we provided the propensity score matched comparison for the progression of <unk> of subjects in the clinical outcome measures and Friedrich <unk> ataxia, or FA Comms natural history study to the patients and our Moxie extension study.
This analysis demonstrated that the rate of progression as measured by <unk> over three years was 55% slower than the moxie extension patients as compared to their matched <unk> patients.
And third we submitted mechanism of action data validating <unk> to the targeted <unk> as a key player in the pathophysiology of FAA. We also submitted clinical biomarker data showing that induction of interest to target proteins and <unk> treated patients and the moxie part two trial.
Was associated with improvements in <unk> 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 Becker will then discuss our recent progress in our commercial preparation activities for <unk> Lastly, mummies Sunny 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 two was preserved in the extension once.
All patients were converted to Omar treatment, if patients who are generally random originally randomized to placebo catch up to patients who were originally randomized to <unk>. The treatment effect is consistent with a symptomatic benefit.
The patients originally randomized to placebo do not catch up.
And the difference at the end of the placebo controlled portion has maintained the treatment effect is consistent with disease modification and a persistent effect on the course of the disease.
Since patients had been returning to the clinic for visits in the past year. The updated data for March contains a meaningful increase in the number of patients with <unk> assessments at later time points and new time points are available for analysis. This is shown by the boxes around the X axis and each of the plants.
Results of the updated analysis are consistent with prior results and showed that patients originally randomized to <unk> has continued to demonstrate a persistent treatment benefit after three years and the extension.
As shown in the graphical plot on the right. The between group difference in empires observed at the end of the placebo controlled Moxie part two period was preserved at six out of seven time points in the Moxie extension.
Additionally, the upper limit of the 90% confidence interval for the difference estimate was less than zero at both extension week 70 to a 120 meeting the formal threshold for demonstrating significant evidence of non inferiority.
[noise] numerically the separation observed at week 48, and Moxie part two was observed at extension week 72 through extension week, $1 44, which represents three 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 FAA natural history study to provide additional clinical evidence in.
And 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 and the Moxie extension provides longer term follow up for disease progression in patients receiving <unk>. However, there is no long term placebo arm for comparison.
The moxie extension data, where compared to natural history external controls using propensity matching provide longer term efficacy data in support of the statistically significant benefit demonstrated by pivotal moxie part too.
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 variables that influence progression and.
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 for the control group versus the treated population.
And compelling evidence of a meaningful change in the progression of the disease between the two groups, we believe that FAA and our data set and meet all of these criteria.
Turning to slide 12, the largest natural history study of that Fay Fay comms constitutes a well established reliable and well documented source of natural history data for FAA for comparison to the Moxie extension results.
<unk> is a global multicenter longitudinal prospective observational study that has enrolled more than 1250 patients.
Clinical outcome measures, including <unk> are assessed annually and patients are followed for up to 25 years in the study.
All become sites or tertiary care centers, specializing NFA and empowers assessments are conducted in a standardized manner by trained neurologist with experienced MFA.
This score for each component of empires is based on measurements of a patient's functional ability using the same standardized set of instructions and similar case report forms and both the phase <unk> study Andrew Remoxy trial.
Investigators, but if they come study meet regularly to review conduct of the study results and study related issues. Additionally.
Additionally, the significant overlap in sites between fee comps Moxie provides a similar testing environment standard of care and standardized instructions for the <unk> assessment.
Lastly, the size of the <unk> database mixed propensity score matching feasible.
Slide.
Patients from Fei comes were matched to moxie extension patients using propensity scores based on five covariance sex baseline age age of onset baseline <unk> score and baseline <unk> score selection of these covariates was selected in Cala.
<unk> with the principal investigator and statistician for <unk> based on clinical relevance. The relevance is prognostic indicators for disease progression and availability in both studies.
The change from baseline in <unk> at year, three for Moxie extension patients compared to the propensity score matched <unk> patients was analyzed as the primary efficacy endpoint using the same mixed model repeated measures or M. M. R. M analysis as we used for the primary analysis from Oxy part two.
<unk>.
All data from all time points were used to estimate the treatment effect.
<unk> populations were analyzed and additional sensitivity analyses were conducted.
For inclusion in each of the study populations patients must have had one baseline <unk> score.
To at least one post baseline <unk> within three years after baseline and three values for all propensity score model covariance.
The MX extension study population included 136 patients with at least one post baseline Empire's assessment irrespective of pest caber status. All of these patients were included in the primary poor population.
The <unk> study population included 598 patients eligible for one to one 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 box extension patients in the match becomes external control groups.
For the 136 patients in each group the median treatment duration was approximately three years as of March 2022.
Slide 15 shows the results of the primary pooled population of 136 patients in the Moxie extension compared to 136 patients in phase <unk> in.
In this population patients in the Bay Comms match set progressed approximately $6 six empowers points by year three.
Whereas patients treated with <unk> and the Moxie extension progressed, only three points, representing a significant minus 361, <unk> point difference with a nominal P value of 0.0001.
This absolute difference translates to a 55% slower rate of progression for Omar treated patients and the moxie extension compared to patients in the phase <unk> study at year three.
Next slide.
In addition to the primary pooled population, we defined two subpopulations the placebo to one map population, which included 95 patients previously randomized to placebo and moxie part two and patients from Moxie part, one who had been off treatment for a minimum of 21 months.
And the old map to Omar population defined as 41 patients previously randomized or mab treatment and moxie part too.
A new propensity score was used to match each of these populations to stay calm study population.
Mcgrath <unk> and baseline characteristics were also highly comparable between box extension patients and unmatched Bacon external control group for the sub populations.
At year three the treatment effect in each of these populations with similar magnitude to the results from the primary pooled population not shown on this slide we conducted additional sensitivity analyses using different matching criteria in all results demonstrated a significant treatment effect.
In summary, while post hoc these analyses provide a robust assessment of the effect of <unk>.
Ongoing extension study.
Whereas the pivotal moxie part two study compared 40 patients randomized to <unk> to <unk> 42 patients randomized to placebo over 48 weeks. The propensity matched analysis includes over three times as many patients who have been treated with Doe map to match <unk> patients for a duration.
That is three times longer than all analysis populations demonstrated a significant slowing of progression for patients treated with <unk>.
Next slide.
In addition.
<unk> to the updated delayed start and propensity matched analysis, we provided additional mechanistic evidence to the division that included an integrated and detailed presentation of the disease pathophysiology of FAA linking for tax inefficiency with Internet two suppression and impair mitochondrial function mechanism.
Of action data showing that <unk> restores interrupt two activity and mitochondrial energy production and preclinical ethane models and FAA patient fibroblast.
And clinical biomarker data demonstrating that induction of an RAF to targets in <unk> patients and the Moxie part two trial was associated with improvements in <unk> scores.
Moving to slide 18, the molecular pathophysiology underlying FAA has been well characterized with many recent publications.
<unk> sits in mitochondrial respiration and ATP production are observed in cells and tissues isolated from patients with FAA for example, maximal mitochondrial respiration and spare mitochondrial respiratory capacity assessed by oxygen consumption rate were lower and fiberglass from.
With the new fiberglass from healthy control subjects. Similarly, mitochondrial ETP production and skeletal muscle was lower in patients with SMA that in healthy control subjects or non FTA disease controls.
Also longer GAA, one repeats have been associated with lower maximum mitochondrial ATP production in skeletal muscle from patients with FAA.
A study conducted in 42 patients compare peak vota consumption, which is reflective of mitochondrial function with the <unk> 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 NFA and reduce neurological function in FA patients.
Next slide.
At the cellular level for tax and deficiencies associated with impaired mitochondrial function redox imbalance and iron Dysregulation.
Although the molecular mechanism by which for tax and deficiency suppresses interrupt two has not been fully characterized just regulated in Rev. Two signaling is a common early upstream event that contributes to mitochondrial dysfunction and redox imbalance in patients with FAA.
In fact genetic silent singer for tax and results in suppression of <unk> II.
Multiple publications have now demonstrated that in rough two levels and target gene expression are suppressed in preclinical animal models animal models of the disease.
And in cells from patients with FAA.
As shown on the right of this slide in Rev. Two activity has also been shown to directly regulate myocardial energy production in neurons.
Neurons with genetic silencing of <unk> to have reduced ATP production, Conversely, genetic interrupt to activation due to suppression of its negative regulator keep one leads to increased levels of ATP and neurons. These data establish a clear link between the genetic defect in EF.
Hey, and impair mitochondrial function, which causes Fas clinical symptoms.
We and our academic collaborators has spent several years to demonstrate the relevance of <unk> impacting the underlying pathophysiology of Esa ash.
As shown on slide 20 on the left one map has been shown to restore and Rev. Two levels and FAA patient fibroblast as you can see on the right. This restoration of interrupt too is associated with restoration of modern energy production, which has been shown and FAA disease models and patient samples.
Moving to slide 21, we are also characterized <unk> pharmacodynamic activity in <unk> patients and shown how this relates to clinical activity and moxie part too.
As shown on the left and the dose ranging moxie part one we assessed in Rev. Two targets ferritin and GTT and a standard blood based clinical chemistry panel to determine the dose range associated with optimal pharmacodynamic activity Bay.
Based on the short duration and small number of patients in part one we did not expect to see clear we're definitive improvements in clinical assessments, but we did expect to see clear trends and pharmacodynamic markers, both ferritin and GTT demonstrated dose dependent increases by week four of treatment with Maxim.
<unk> increases observed at 160 to 300 milligrams.
To address Fda's request to show how these PD markers of interest to activation correlate with treatment benefit in <unk> patients as shown on the right. We performed a Churchill analysis of <unk> and in rough to target changes at week 48, and pivotal Moxie part two this.
This analysis shows that ferritin and GTT increases are associated with imports improvements as shown on this plot the patients with the most clinical improvement and largest decrease in <unk> at week 48 as shown on the right. We're also the patients with the largest increases in ferritin and GTT.
Changes in fair Tien and GGG, we're inversely correlated with changes in M Fars to.
To summarize these data provide additional context for the relevance between FAA pathophysiology in rep to induction.
And clinical benefit in patients and we believe these data could also constitute confirmatory evidence.
Next slide.
In summary, Moxie part two provides the primary evidence for our NDA submission and demonstrated a significant improvement in <unk> in patients treated with <unk> compared to patients treated with placebo with a P value of <unk>.
Europe 0.01 for all empowers subsections and major subgroups favored old map with a low amount of missing data.
To supplement the efficacy results of Moxie part two we have provided FDA with multiple submissions of additional evidence supporting the efficacy of our math. These include the delay started analysis with data through March 2022, their propensity matched analysis of patients and moxie extension compared to <unk>.
Patients from becomes.
And mechanistic data showing how old map directly affects the underlying pathophysiology of <unk>.
From a safety perspective, <unk> has been well tolerated with a low incidence of serious adverse events, while cardiovascular disease is common in patients we observed fewer cardiovascular aes no increased simpler pressure and no findings on cereal ecg's or echoes the moxie part too.
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 Don for an update on our commercial preparations.
Thank you Carl and good morning, everyone I'll continue on slide 24.
Our launch preparation continues in step with our regulatory progress as we approach. Our <unk> date of November 30th 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 patient community through advocacy events market research and our patient focused S. A disease education website connect ethane dot com, which supports a variety of patient educational tools and resources.
During the second quarter, we launched our HCP focused disease education website. Thank S. Dot com focused on S. A recognition diagnosis and genetic testing and disease progression management and severity underscoring the urgency of the need for treatment. We also dip.
Played a digital marketing campaign to drive traffic to the website that Leverages banner advertisement search engine marketing and an email campaign all tailored to reach physicians currently treating <unk> ataxia patients do.
During the first month of active digital promotion to thank Kathy Dotcom website thought over 3300 visitors with more than 65% being hcp's from our identified list of U S physicians treating assay, indicating accuracy in our targeting efforts at a high level of inter.
Just in treating this disease.
We also advanced key operational projects to prepare for the launch of <unk> alone and initiated Payor 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 health care providers.
Complete the benefits investigation process and compliant Lee offer programs to alleviate the burden of out of pocket cost. It also includes a limited specialty pharmacy distribution channel designed specifically to support the needs of our rare disease product launch.
Furthermore, we've initiated the sizing and design of our first in neurology focused sales force 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 <unk>, who will provide our Q2 financial update.
Thank you dawn and good morning, everyone.
We released our financial and filed our 10-Q earlier this morning.
I would like to highlight a few financial items for this quarter.
Our strong cash position.
Instancy and 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 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 fourth 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.
Under the QR code enactment.
As a result, we will not recognize any deferred revenue subsequent to the second quarter of 2022 until future milestone or collaboration revenues that aren't.
On the operations front, we continue to progress on the commercial drug supply for <unk> for the anticipated commercial launch early next year.
With that I will turn the call back over to Warren.
Thank you Mimi.
In closing we've made substantial progress in our own map program, including the acceptance of our NDA during the quarter and submission of additional information and analysis to the FDA, which we believe strengthens the body of evidence demonstrating the effectiveness for <unk>.
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 <unk> 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.
<unk>, 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.
Thank you ladies and gentlemen at this time, we will begin the question and answer session. If you would like to ask a question today. Please press star followed by one no telephone keypad.
To withdraw your question. Please press star followed by case. Please keep your questions to one question and one follow up.
Our first question today comes from Tiago, and you'll come up at all sticky great. Tycho. Please go ahead. Your line is open.
Hi, Thanks, Warren and team just first one operational question, which I think a lot of people are wondering about have you received a date yet for the AD com and if so can you disclose that now thank you.
Yeah. Thanks Yigal.
Have a date for the outcome, 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 F. D. A commentary regarding the concerns on the strength of the efficacy evidenced.
So when the FDA made this comment where they're concerned specifically on the lower point O. One four P value for the primary analysis population for non pest Cabot's 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 it was a higher Plano three four and include.
Did that patents canvas and in the mid cycle was there any preliminary discussion that a label might focus on non pest catalyst.
How are you all this is colin and so the we believe the comment about the strength of the efficacy evidence was based.
Based upon the primary results, which is the 82 patients that contribute to that between the difference of $2 four with a P value of 0.01 for.
The FDA has not raised a concern about patients.
With pest gave us 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 that P value is typically lower.
And so FDA.
Old Us recently and as we said on this call today that this this is not a new issue.
The strength of the evidence that has been the concern is typically the concern for for rare disease trials with a single study and so we've been engaged with FDA in a dialogue 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.
As we disclosed on this call and in the Q They had specific discussion points and.
And we engaged in a dialogue so that we could address those concerns by providing additional submissions and so kind of 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 too.
Okay, and then just one quick follow up on delayed start 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 that particular detailing the data are not raised at the mid cycle and did they.
Provide any initial thoughts on your updated March 'twenty, two data cut where you have much better sampling at the more distal time points. Thank you.
Yes, there wasn't any there wasn't 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 studied dropouts. So just.
Just to be clear about it this was during COVID-19, and so patients had to have in Fars assessments done in clinic.
Of course, most of the clinics were closed during this period and so.
Patients Couldnt come back in so they were missing values and particularly at that week 48, and 72 time point.
What is the impact of the pandemic waned.
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.
We asked to submit it and they said, yes, absolutely submitted.
And one other point to make just to follow up on Warren's comments is that.
Because of the COVID-19 pandemic hit and because there are fewer patients I think that 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 <unk>.
<unk> that the dropout rate has been low and so recall that moxie part two was completed about two and a half years ago and so at this point in time or patients are have been in the extension for at least approximately two and a half years.
And 86% of the patients who enrolled in the extension still remain and so there has been a very low dropout rate over three years, including during the pandemic and a good accumulation of additional data at the later time points.
Great. Thanks, so much.
Thank you. Our next question comes from Matthew came out of Goldman Sachs. Please go ahead. Your line is open.
Hey, guys. Thanks for taking our questions. So on this point around the reduction number of patients. So 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 showed that.
Patients who were missing specifically, it's a week 48, and <unk> 72 came back specifically in weeks 96 to $1 44.
The best way that we've addressed that is by conducting an analysis of those two subgroups and 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 is no difference in 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.
I guess on the first question around a week suburban or secondary endpoints is there any kind of further analysis of the secondary endpoints that can provide you can interpret from employers.
I think it's important to note that Fda's view as we had disclosed new over two years ago. So there was no support.
From the secondaries and they've actually changed their language, just saying that there is now a week support and so we believe that the data that we've provided have allowed them to see that they are at least is some.
Quote weak support and recall.
That ADL nominally favoured.
<unk> for the P value of 0.04 with online questions favoring <unk>.
First secondary Pgi C.
It was trended and was close to significant was actually not only significant in the all randomized population see GIC favorite or math and.
The rest of them the majority of <unk> and so there was a consistency.
Generally in the secondaries, which we believe is the reason why FDA download cities big support.
Alright, thanks very much.
Yeah.
Thank you and the next question goes to Charles Duncan of Cantor Fitzgerald. Charles. Please go ahead. Your line is open.
Yes, good morning, Thanks, Warren and team very 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 producer push or would it be considered a major amendment and then also wonder.
<unk>.
Whether or not you could provide a little more color to an earlier question in terms of an AD com date could that be a Q3 or Q4 events.
Okay.
Okay.
Okay I'll take the.
I'll take your first.
Question Charles.
They have not indicated that there would be a <unk> 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.
Back to the <unk> date.
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 AD comm date.
They provided us with a tentative date for our own trap, but we're simply prevented.
Under the FDA rules from disclosing the date until.
Until they.
Make the data public themselves.
As you know probably from looking at.
At other projects, it's normally six to eight weeks before the <unk> date.
Yes.
Sense.
Second question is relative to the three pieces of information and lot of work being done here against some that can I ask you. What do you think FDA will find most compelling.
But if you had to choose.
Your top dataset that you find most compelling which would it be would it be the delayed start or the propensity match where are the additional.
Additional mechanistic information.
Well, starting with the starting with the clinical data.
I think both the delayed start analysis as well as the propensity matched analysis are extremely important in my opinion compelling.
The address slightly different questions. So the propensity matched analysis.
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.
And done at many of the same sites that participated in the clinical trial.
We are rigorously match the patients and it provides a.
Dataset of an additional 136 patients over almost three years.
With multiple sensitivity analyses showing consistently.
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 set 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.
Good.
The delayed start analysis addresses a separate question.
Which is during the controlled portion of the study was the course of the disease modified that awards. In addition to the clinical benefit observed at week 48 did it impact of progression and there's now a large amount of data.
We have 120, and 144 weeks and the extension showing that that difference at the end of one 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 provide some of the best evidence for modification of the course of the disease and so I think it's very important as well.
Finally, the mechanism of action data is a clear basis for providing confirmatory support.
Under phenomenal 115, and because of all of the work basic work done around the impact of <unk> in the disease that is a very strong rationale for confirmatory evidence as well.
Very good last quick question relative to the AD comm 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 Satcom investigator group.
It's unclear and we don't have.
And understanding of who will be on the panel.
And so we'll have to see from those numbers will be.
Okay.
Thanks for the added color, but I mean, one to make to make one just slide slide five point, though many of the Fei comms investigators were investigators in the site and that actually lends credibility to the matching analysis, because obviously the clinical practices the same.
Got it.
Thanks Juan.
Okay.
Thank you. Our next question comes from Annabel <unk> of Stifel. Annabel. Please go ahead. Your line is open.
Oh, hi, Thanks for taking my question. So you didn't really touch on that as much but you did mention.
Is that the FDA I'm, sorry viewing of cardiac safety issues.
So can you remind me what cardiac safety concerns they wouldn't have it doesn't appear to be evidence that you provided.
So given that this is an analog of <unk> and there was an issue that came up there before and you had very precise A&P exclusion criteria here in this study.
Do you have a sense of what the FDA is monitoring.
And then if I could just get a follow up now.
Obviously, you provided a lot of mechanistic validation I guess my question was was this provided in the original package further mechanistic validation because it for some time when you can understand for some time.
Disease pathway here in house, and they have a lot to Ted.
Address that.
Part of the pathway.
So.
Well explanation there why you need so much additional MRI 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.
To enroll as long as they had mild to moderate FAA 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 abroad SM Q search to look at any potential signals of arrhythmia is and we saw none.
And once again blood pressure was unchanged and there were no findings on a slow ecg's <unk>. So at this point.
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 to the M away. The reason why we have provided additional data.
As in the context of their comment about.
Efficacy and so we walk through three different submissions that we've made any one of them could constitute confirmatory evidence and could be sufficient to support approval and.
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 interim two theres now numerous publications demonstrating that <unk> has suppressed NSA.
But importantly, we've been able to show that in our clinical trial that induction of interact two is associated with clinical benefit.
So that's a very strong mechanistic link.
That is.
As a as a newer finding that has since been submitted to FDA.
Great. Thank you.
Thank you. Our next question goes to Maury Raycroft of Jefferies. Maury. Please go ahead. Your line is open.
Hi, good morning, and thanks for taking my questions.
I was going to ask one on the natural history data.
You mentioned that the patient baseline characteristics match up well on the Baidu five different points can you talk about how the patients Matt job by GAA, one are repeats baseline protection levels or FAA activities of daily living.
Yes, so broadly based.
Baseline characteristics and demographics are similar and most of them numerically or.
Almost the same the one difference.
Actually biased against the drug is GAA, one repeat linked and so it's a little bit longer numerically in the <unk> treated patients versus the extension and so if.
If that were to affect the results that 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 analysis, but other than that one difference there theyre very similar.
Got it Okay, and then for the biomarker data can you remind what the relationship is between GGP and Barrington Biomarkers that you have data out in the slides and the biomarker protection and can you provide any commentary on whether FDA has preference for specific biomarkers are assays for mechanism.
<unk>.
So fda's guidance is that the.
Underlying pathophysiology has to be well understood.
So there's a.
A couple of decades worth of.
Research and literature, demonstrating that the positive mutation NFA is due to reduction in for tax and activity for 96% of patients they have less pretax in.
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.
It is not well understood for tax and deficiency is associated with suppression of <unk> and.
So as I said on the call if you simply take.
Sorry, RNA against for Taxane and cells administered to reduce pretax and that results in suppression of interest to directly.
So in rough too.
As you recall is a transcription factor that controls the production of many target genes in <unk> and <unk> are two of them and so we have shown in numerous publications that.
<unk> can dose dependent <unk> increased production of GTT and ferritin and the benefit of using those two 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 interrupt to activation, we see increases earlier as I said after treatment and it was pretty much maximal by week four.
As I showed in moxie part to the changes at week 48, we're 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 for tax efficiency interrupt two suppression underlying pathophysiology and now our drug's ability to restore <unk> to <unk>.
How would that be associated with clinical benefit.
Got it okay. Thank you very much.
Thank you. Our next question comes from Joe Schwartz of SBB Securities. Zhu. Please go ahead. Your line is open.
Hi, Alan This is will on for Joe. Thank you for taking our questions today.
One for US recently, you have seen senior members of the leadership team at the Neurology Division at the FDA have some differing opinions of several high profile reviews.
Are you sensing that there are some wide differences in opinion regarding Omar do you have any insight into how many people are in favor of us it's more critical.
Matt.
Any insight here would be helpful. Thank you.
Yes, I don't think.
We have no visibility into the internal discussions with the FDA.
So we couldnt comment we could really have no view.
<unk>.
What differences in view there might be.
Inside the review team or their senior people at the FDA.
Okay.
If if any.
And I will say that in our in our meetings, we have had a wide range of participants and they have been very open and transparent with us.
Warren said because of that transparency and we've been able to address any concerns coming from any part of the review team or senior members to supplement the NDA.
Okay. Thank you.
Thank you 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 COVID-19 only at his wife website at reata found that dot com in the investors section. Thank you very much for your participation.
Patient you may now disconnect.
Yeah.
Sure.
Okay.
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