Q1 2022 Reata Pharmaceuticals Inc Earnings Call
Thank you for standing by and welcome to the Reata Pharmaceuticals first quarter 2022 financial results and update on development programs Conference call.
An audio recording of today's webcast will be available shortly after the call in the Investor section of reactors website, and we ask the farmer don't come.
The company proceeds with its remarks. Please note the forward looking statements disclosure in the company's press release.
There are many factors that could cause results to differ from expectations, including those noted in the company's SEC filings on.
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 react to this earnings release and presentation from today, which again can be found.
We have to its website.
Today's statements are not guaranteed of future outcomes. Please also note that any comments made on today's call apply only as of today May 10, 2022, and may no longer be accurate at the time of any webcast replay or transcript reading.
Following the prepared remarks, we will open the call up for questions. 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 reactors, Chief Executive Officer, non meat Sunny President Colin Meyer, Chief Innovation Officer, <unk>, <unk>, Chief Medical Officer, and Don <unk>.
<unk> commercial officer.
At this time I would like to turn the call over to Warren.
Good morning, everyone. We thank you for joining us today for our quarterly update I'll start on slide four.
You all know we are developing <unk> alone or <unk>, a small molecule activator of interest two for the treatment of patients with <unk> ataxia or FAA, we've made significant progress with the program over the last few months following the positive results from the Moxie part two study we had multi.
People interactions with the FDA to determine whether there was a path to submission and review of our new drug application or.
For NDA. This was highlighted by completion of the pre NDA meeting with the division in the third quarter of 2021. Following the meeting we applied for and were granted fast track designation for the program highlighting the potential of our map to address the serious unmet need for treatment options for.
Patients with this devastating disease fast.
Fast track designation provided us with eligibility for rolling submission of our NDA, which we initiated and completed in the first quarter of this year.
Additionally, the FDA recently granted rare pediatric disease designation to own math. Our NDA includes a request for priority review based on the severity of the disease and the lack of approved treatments for patients with FAA. If granted this could result in a prescription drug user fee Act action date or Paducah.
To date in the fourth quarter of this year, we are working with the FDA, while it reviews, our NDA this year and if the FDA approves our math for the treatment of patients with the FAA, we plan to be in position to launch our first drug early next year.
Finally, we're continuing to complete the regulatory procedures and submissions that are required as a condition to filing a marketing authorization application in Europe . We've secured agreement on our pediatric investigation plan with the pediatric Committee and we plan to submit an MAA to the European Medicines agency for a map in the fourth quarter.
Of 2022.
Next slide.
Regarding our programs in rare forms of CK D. Our priority has been to first work with the division to ensure we are aligned on the trial design for our ongoing phase III Falcon trial. So that we have a clear regulatory path forward for that important program.
Based on the issues that the FDA raised during our review of our NDA in Outports syndrome, we submitted.
Proposed amendment to our protocol for Falcon.
We recently completed a type a meeting to discuss the protocol amendment and to ensure that we're aligned on the trial design with the division.
During the meeting the division stated that the proposed primary endpoint of Egfr change from baseline at week, one and weight, which is eight weeks. After a planned drug discontinuation at week 100 was reasonable because our available data suggests that bard's acute pharmacodynamic effect on egfr should be largely resolved.
<unk>.
The Division also stated that in addition to the primary endpoint it will be important to demonstrate that the treatment effect accrues over time to support a claim that bard slows the loss of kidney function in patients with ADP KD and it provided guidance on an exploratory egfr slope analysis that would address the.
Question <unk>.
Accordingly, the agency emphasized that the analysis will be important but also stated that the results do not need to be statistically significant.
They also confirmed that if the Falcon trial is positive it could support registration of Bard and ADP Katy.
Semicon, we will provide additional information about our program and ADP JD later after the call.
With completion of the type a meeting and alignment on our protocol Amendment for Falcon will continue to work with the FDA to confirm our next steps on our outboard syndrome program.
Finally, I'd like to remind you that our strategic collaborator in Japan, Cai, what Karen is sponsoring the <unk> trial, a large phase III clinical trial in patients with diabetic kidney disease. The Ami trial enrolled over 1000 patients with stage three and four diabetic CK D and the primary endpoint is time to <unk>.
Set of greater than or equal to 30% decline in egfr or in stage kidney disease.
If the results of this trial are positive it could provide clinical evidence that improvements in egfr observed in <unk> treated patients do in fact delay progression to kidney failure Coyote Kirin expects to complete the last study visit in the second half of this year.
With that I'd now like to turn the call over to Colin Meyer, who will provide an update on our program with <unk> in patients with FAA, then to CME Khan, who will provide further updates on our program with Bard and patients with ADP <unk> and our program with RTA 901.
Dawn Bir will then discuss our progress in our commercial preparation activities for own math Lastly, Mommy, Sony will review our financial results for the quarter.
Thank you Juan.
Starting with slide seven.
As a as a relentlessly progressive and debilitating neuromuscular disorder is caused by epigenetics silencing of protection, which impairs mitochondrial function and is associated with suppression of interrupt to these effects Lee to impaired energy production and neuro degeneration.
As the disease progresses patients with FAA become dependent on walkers, and then wheelchairs and they ultimately lose their independence altogether. The median survival for these patients is in the mid thirties <unk>.
Despite numerous attempts to developing therapies for FSA prior to Moxey, none has been successful and there are no approved treatments.
<unk> is an inherited recessive formula ataxia, which affects approximately 5000 children and adults in the U S. With approximately 4000 patients currently diagnosed next slide.
Clinical trials in SMA are challenging to conduct due to two major factors first there are limited number of patients who are willing and able to participate in clinical trials.
Just mentioned there are only approximately 4000 patients who are diagnosed in the U S. At the time of Moxie part two we enrolled patients at all seven U S. FAA specialty centers, who were participating in the natural history study.
<unk> is one of the largest interventional trials completed to date and the only trial to demonstrate a significant effect on a functional endpoint that could support approval.
There are a relatively small number of patients available for future trials with a design similar to Moxey. Currently approximately 200 patients have volunteered for clinical research and are participating in the natural history study for Moxie part one and part two we screened about one sixth of available patients enrolled most of them into the trial.
Moving to slide nine.
The second reason that clinical trials and FAA are challenging is due to the slow rate of progression of that day.
As I, just mentioned patience with FAA relentlessly progress that even though these patients have early mortality the progression occurs over their lifetime.
The time from diagnosis to death for a typical patient who is diagnosed in their teens and dyson or mid thirties as approximately 20 years.
The researchers have steady progression any natural history study and progression over one year is clinically meaningful to patients even though the magnitude of progression over this time is relatively small versus patients entire disease course, because of this outcome measures have been developed and validated to measure progression over one year.
The <unk> ataxia research alliance or Farah worked with the FDA to develop the <unk> scale to accurately track disease progression in patients with.
The scale is composed of four subsections, bull-bar upper limb and lower limb coordination and upright stability.
As patients lose function there in par score increases towards a maximum score of 99 points.
Even though the scale is 100 points most patients are diagnosed with scores in the 25 to 30 range and patients die before they reach a score of 100. Therefore, the dynamic range of the scale is approximately 40 to 50 points.
Slide 10 highlights several examples of demonstrating the clinical meaningfulness of a single point change in <unk>.
Within each of the four Empire sections every single point matters in the Middle column are some representative assessments along with what a one point worsening can mean to patients.
The clinical impact of one point for stability or lower them can be differences in the ability to stand or walk independently the clinical impact of the one point worsening for bowl bar or upper limb sections can mean, losing the ability to speak or type even half a point can matter a worsening of five points on speech can.
The difference between normal and slurred speech.
Slide 11 shows data from a prospective and ongoing global multi center <unk> ataxia clinical outcomes measures or Fe comms longitudinal natural history study. This study is enrolling up to 2000 patients with FAA with quantitative serial data, including empires.
Patients are being followed annually for up to 25 years.
The data on this slide were published in 2016 and assess data from patients over five years.
The study evaluated multiple age cohorts shown here is the overall cohort as well as the cohort of patients aged 16 to 40, which is the same age range studied and moxie part too.
While <unk> change only one point in the first year of follow up and the age matched cohort over three to five years in parts change on average about two points per year in both cohorts.
Although changes and other measures were less apparent in a single year. The changes in empires predict later worsening and other measures in this study.
Slide.
The pivotal portion of Moxie was a double blind placebo controlled randomized international study that was one of the largest global interventional studies ever completed in FA.
We enrolled 103 patients across a wide and representative range of age and disease severity.
The pre specified primary analysis population or full analysis that included the 82 patients who did not have severe manifestations of the foot deformity pest gave us and the primary endpoint was the change from baseline in Empire scores at week 48.
The analysis methodology, we use to analyze the primary endpoint was MRM.
We used two covariates clinical trial site and baseline in bars, and importantly, all enforce values at all time points, regardless of whether patients were receiving study drug were included in the analysis, we did not impute from missing data and the primary analysis.
Mark C met its primary endpoint of change in <unk> relative to placebo. After 48 weeks of treatment patients treated with <unk> demonstrated a statistically significant placebo corrected two four point improvement in empires compared to placebo. After 48 weeks of treatment with a P value of zero.
0.014.
As we've discussed previously we observed improvements in all subsections of the Empire scale.
This change is clinically meaningful and that on average <unk> treated patients did not progress during the 48 week treatment period and recovered function.
Further the placebo corrected improvement is equal to more than one year progression.
Next slide.
This slide shows a forest plot for sensitivity analysis compared to the primary result, which is on the top of the figure.
Using a different analysis methodology and cover the results were consistent with the primary results.
To evaluate the impact of missing data, we conducted two analyses using different amputation methodologies as mentioned earlier all in Paris data from all time points were used in overall only 4% of imparts values were missing with 9% missing at the week 48 time point.
Treatment based amputation, which assumes that discontinued patients behave like patients in their treatment group as well as control based computation, which assumes that discontinued patients behave like placebo treated patients both demonstrated a significant P value supporting the conclusion of the primary analysis.
Additionally, what we look at the <unk> population alone worthy all randomized population that treatment effect favors <unk>.
Overall these sensitivity analyses support the robustness of the primary endpoint result.
Turning to slide 14.
Democracy extension trial is an ongoing open label extension trial evaluating the long term safety and efficacy of <unk> in patients with a high percentage of patients who are randomized into moxie part one and part two enrolled in the extension, notably nine.
7% of patients from the Moxie part two full analysis set who completed moxie part two were enrolled in the marks the extension trial.
The discontinuation rate in the extension has been low despite the length of the trial and the operational difficulties experienced during the pandemic.
Of the patients from the full analysis set 88% are still enrolled and being followed in the extension.
<unk> no new safety signals have been identified and the <unk> extension trial.
Next slide.
As a reminder, the purpose of their randomized placebo controlled moxie part two study was to determine if there was a significant treatment effect between the <unk> and placebo treated groups and as discussed this was demonstrated that.
The purpose of the delayed start analysis was to determine if this separation observed at the end of Moxie part two was preserved in the extension once all patients were converted to Omar treatment.
As patients who were originally randomized to placebo catch up to patients who were originally randomized to <unk>. The treatment effect is consistent with a symptomatic benefit.
If the patients originally randomized to placebo do not catch up and the difference at the end of the placebo controlled portion has maintained the treatment effect is consistent with disease modification and a persistent effect on the course of the disease.
This slide shows a graphical representation of the delayed start analysis all patients from the full analysis set are shown on the left and the subset of patients who have completed extension in week. One 'twenty are shown on the right.
In the grass study weeks zero to 48 shaded in Blue pertain to Moxie part two with subsequent study weeks, referring to the extension phase I would like to point out that the timing of the box extension study coincided with the COVID-19 pandemic. So some empire's assessments, which required an in office. It is.
That are missing.
As mentioned, 88% of the patients remain in the extension and patients happened returning to in clinic visits over the past several months.
Understanding the limitations in interpreting open label extension data, we see that patients originally randomized to <unk> have continued to show a persistent treatment benefit with minimal to no worsening of the <unk> after three and a half years of total treatment.
Of the six time points in the extension all but one show separation versus the patients originally randomized to placebo.
The data suggest that the extension week 48 time point is an outlier, which was affected by Covid and this is supported by the separation that was observed at extension week 72 and beyond.
Beyond the missing data at this time point investigators reported that the already challenging travel that these patients undergo to visit clinical trial sites was even more difficult during the pandemic and this likely affected their sleep exercise eating and other daily activities, which could have affected fatigue level.
<unk> and other non neurological aspects of their functioning.
Of note the same pattern of convergence at extension week 48 is observed in the complete their analysis shown on the right.
Only a single patient is missing in each group at extension and week 48 visit and convergence was observed however visits beyond extension week 48 show divergence, including extension with <unk>, which includes all patients. These data further demonstrate that the extension with 48 time point is an outlier.
The complete risk data also address one other question raised by the full data set on the left.
It appears on the graph on the left that the placebo to <unk> patients may be losing their treatment effect at extension 120.
However, as can be seen in the figure on the right. This is an artifact of this subset of patients who on average have longer GAA, one repeat links which is associated with a faster rate of progression.
As you can see in the Blue shaded region of this figure on the right. These patients progressed approximately four <unk> points over one year, while they were receiving placebo from randomization until the data entered the extension and started receiving <unk>.
However over the subsequent two and a half years, while receiving <unk>. These patients only progressed one important point on average which is much lower than would be expected based on the rate of progression before they receive do math.
As shown on slide 16, we have also evaluated the progression of empires for Omar treated patients in the extension study by computing annualized Empire slopes.
This calculation of annualized slopes allows all available data through extension week, one 'twenty from all Fas patients to estimate the treatment effect over a period of approximately two and a half years.
Total of 257, and <unk> assessments contributed to this analysis from 73 patients and as I mentioned and the extension the discontinuation rate has been low at 12% with only 973 Fas patients having discontinued.
As you can see in the table on the left the annualized rates of progression in the extension have been two 7% for a five <unk> points and the difference between these two subgroups is not different suggesting a similar treatment effect.
While a placebo control during this phase was not included and formal comparisons cannot be made the observed rate of progression is much lower than would be anticipated. The same 39 placebo to <unk> patients progressed 142 points in the 52 week period from randomization into Moxie part too.
Until initiation of treatment in the extension.
Using natural history data as a benchmark the overall cohort progress at an average rate of 195 points per year, and a similar H ratify cohort progressive and the average rate of 171 points per year over a three year period.
These data in addition to the delayed start analysis suggests that <unk> has a durable persistent effect on the course of FY <unk>.
I will now have CME can't provide an update on our other clinical development programs.
Thank you Colin.
I will provide an update on our progress on CEB and Aki and 90 to one development programs starting on the next slide.
We are evaluating the efficacy and safety of <unk> in patients with autosomal dominant polycystic kidney disease at ADP Guidi in Falcon, a phase III International Multicenter randomized double blind placebo controlled trial.
PGD is that rain and progressive regulatory.
Ill CTD caused by a genetic defect in the PK PD, one and <unk> two genes leading to the formation of fluid filled cysts in the kidney and other organs.
<unk> affects both men and women of all racial and ethnic groups and is the leading inhabitable cause of kidney failure than estimated diagnosed population of 140000 patients in the U S.
As Ron mentioned earlier, we recently met with FDA in a type a meeting to discuss the overall ADP JD development program and that proposed protocol Amendment based on the discussion during the meeting the FDA is in agreement with the key changes made to the protocol.
As per meeting minutes, the division stable that the proposed primary endpoint of Egfr change from baseline to week 108, which is eight weeks. After the plan drug discontinuation at the country is reasonable since available data suggests that <unk> loans acute pharmacodynamics.
On Egfr.
Should be largely resolved by that time.
The Division also agreed with our plan to enroll pediatric patients.
Aged 12 to 17 years.
We are pleased that based on preliminary comments the FDA confirm that is the Falcon trial is positive it could support registration of <unk> in the treatment of patients make ADP candy.
More than 550 patients.
Glenn 850 patients.
Currently enrolled in the trial.
Moving to slide 20, I wanted to discuss.
And mind you the program.
Betty peripheral neuropathy or <unk>.
I do remind you to one is a highly potent and selective small molecule C terminal modulator of HSV 90.
It just been 90 is a molecular chaperone that facilitates the holding and stability of many proteins Aki.
<unk> 90 to one increases transcription of HSBC 70, and then the molecular chevron that promote cell survival.
Response to stress and affects mitochondrial function.
<unk> 90 to one has demonstrated activity in multiple models of diabetic neuropathy.
In preclinical Jordan models.
We observed that RV and 901 administered orally once daily rescued existing nerve function.
Terminal and mechanical sensitivity and improve nerve conductance velocity and mitochondrial function.
FX had a dose dependent reversible and HST 70 dependent.
We have completed a phase one study of IV lines, one in healthy volunteers that demonstrated an acceptable safety profile with no safety signals.
There were no drug discontinuation or serious adverse events in that study.
The pharmacokinetic profile was favorable.
In the first quarter of 2020 to be initiated additional phase one clinical pharmacology studies, including a drug drug interaction study with <unk>.
Your line Jade one appalling.
Following completion of these phase one studies, we plan to initiate a randomized double blind placebo controlled phase II trial to evaluate the safety and efficacy of <unk>, one in diabetic patients with peripheral neuropathic pain.
In the fourth quarter of 2022.
With that.
I would now like to turn the call over to Don to provide an update on our commercial preparation activities.
Thank you Simeon good morning, everyone I'll continue on slide 22, the commercial team's full attention is focused on <unk> launch readiness. Our first responsibility is to intimately know the landscape of the friedrichs ataxia market.
Knowing the patient community trading positions and diagnostic journey is key to understanding the market locating our patients in hcp's treating them today. They are current mindset desires for therapy and drivers of adoption are also important as we prepare free audits first potential launch.
In Q1, we completed the landscape assessment and our launch strategy development is underway.
We've also placed a priority on market preparation through disease education, our patient educational efforts launched over two years ago through social and web based platforms that connect the patient community.
In Q1, we finalized our HCP stacked campaign the goal of HCP disease education is to drive earlier diagnosis underscore the severity of friedrichs ataxia and link hcp's to resources, including diagnostic tools and materials to support patient dialogue about FAA and the imports.
<unk> is a measure of disease progression.
Continuing on slide 23.
Launch operations is advancing in step with the regulatory process, we hired our commercial leadership team payer engagement was initiated in March to educate payers about the severity of this disease and the need for a treatment or trade and distribution model design is complete and partners selected <unk>.
<unk>, a limited specialty pharmacy network and front end patient access services.
Much work is underway and continues in Q2, including the development of our branded launch messaging materials and tactical launch plan. Our brand name received conditional approval and our internal launch readiness process ensures cross department alignment in preparation for launch.
Sales force sizing and territory alignments will be finalized the team is poised for a successful launch I'll now turn the call over to Mandy.
Thank you Don and good morning, everyone. Let me start with our cash balance on slide five.
As of March 31, we maintained a solid balance sheet with approximately $532 million in cash and cash equivalents.
Our cash balance will enable us to fund operations through the end of 2024.
With our strong cash balance we have the ability to focus our efforts on our key strategic priorities, which Walter will cover later in the call.
Okay.
Moving to expenses, we have taken steps to control our operating expenses.
Our non-GAAP G&A expenses for the fourth quarter of 2022 was $70 million as compared to $21 4 million.
For the fourth quarter of 2021.
Representing a significant reduction of 21%.
This reduction in the G&A expenses is primarily related to default of all commercial spending related to activities for output syndrome launch preparation in the United States and the European region.
Yes.
As we mentioned on the February 28 earnings call. We did a restructuring in early January 2022 of our sales and commercial screen to adjust for the delay in the launch of <unk> and adjusted the commercial team size appropriately to focus on the preparation for the anticipated <unk> launch in early 2023.
Our non-GAAP .
R&D expenses for the fourth quarter of $40 two were $42 2 million as compared to $45 5 million for the fourth quarter of 2021, representing a reduction of 9% approximately.
This reduction in R&D expenses as compared to the last quarter is primarily due to the timing of certain manufacturing activities and R&D related expenses.
Our non-GAAP operating expenses for the fourth quarter of $2000 or.
Were $49 5 million as compared with $57 3 million for the fourth quarter of 2021, representing a reduction of 14% approximately.
On the operations front, we are actively working on the commercial drug supply for <unk> for the anticipated commercial launch of.
Early next year.
With MAA filing for FAA insight, we have also initiated building our European infrastructure and commercial team in preparation for the anticipated launch in Europe with that I'll turn the call back over to Walter.
Thank you ma'am meat.
In closing we've made good progress in our <unk> program, including the submission of our NDA to the FDA and preparation for our anticipated MAA filing later this year if approved <unk> will be the first drug available for this severe disease and we're actively working on commercial preparations.
To be in a position to launch it early next year.
As Matt mentioned with our strong balance sheet will be focusing on four key priorities for the remainder of 2022 of.
Of course, our number one priority is working with the FDA on their review of our NDA for <unk> and working towards securing approval of <unk> for the treatment of patients with FAA.
Secondly, with the progress made during the last few months to secure agreement on our pediatric investigation plan. Our second priority is to submit an MAA to the European medicines agency for <unk> in the fourth quarter of 2022.
Thirdly, following the completion of the type a meeting with the FDA.
Our focus is to continue enrollment in the Falcon study and continue to work with the FDA to find a path forward for the output syndrome program.
And finally, our fourth priority is to initiate a phase II study with RTA 901 for patients with <unk> during the fourth quarter of 2022.
That concludes our prepared remarks, we'd like to thank everyone, who dialed in and I'll now turn the call over to the operator for questions.
Thank you.
Ladies and gentlemen at this time, we will begin the question and answer session.
If you would like to ask a question. Please press star followed by one on your telephone keypad. If for any reason you may like to remove that question. Please press star followed by two again to ask a question star followed by one.
As a reminder, if you are using a speaker phone. Please remember to pick up your handset before asking your question. Please keep your question to one question and one follow up.
Our first question today comes from Yigal <unk> from Citigroup. Please go ahead. Your line is now open.
Hi, Warren Colin nominate and team. Thank you so much for taking the question Alan I appreciated the comments on the delayed start analysis I'm wondering if you could just revisit that again.
I've been getting a lot of questions lately on the latest analysis and people are digging into on that.
So the way I understand it is obviously multi part too you saw very nice drug effect early drop.
Patients on <unk>, and then plateau, whereas.
Transient placebo effect and then it showed up on the placebo. So that all looks very very good and then you had the off treatment, which again showed a bump up for for the on that patients which makes sense.
Placebo continued to rise.
And then you switch the patients from placebo on that front.
Zero to week 48 of the extension.
What was happening in the trial made perfect sense to me and that you started to see a treatment effect for the patient switched from placebo to own that and you start to see convergence of the two cohorts, which in my mind.
Exactly what you want to see it in the sense of the.
A drug effect emerging in the patients switched switched from placebo to own that.
So if you could just help me understand a little bit because you're arguing that rather than that you want to see a delta.
So preservation of separation between the two cohorts.
So I'm just I'm still a little a little bit confused as to what the argument is so if you could help clarify please thank you.
Sure and so referring to slide 15.
Once again, the Blue shaded region is moxie part two and you are correct to point out that part of the study was to show a treatment effect or separation between the groups, which we saw on treatment as well as off treatment before patients start on <unk>.
And an important differentiation between a symptomatic treatment and one that actually affects the underlying course of disease is that if patients if the drug has an effect.
On the underlying disease, you would expect that patients who had been receiving drug for a longer period of time would have a benefit that cannot be basically captured by patients who start on that treatment a year later and so you want to see saturation in the extension phase of the trial and so I'll first reference on the <unk>.
Right the complete analysis, but I think one issue.
That people have had with analyzing the state and in tripping. It is simply drawing lines through the figure on the left on the points and that really cant be done because it represents different patients at different points in time.
I mentioned on the call.
Prepared remarks, there is some missing data primarily in that first year and a half.
And the extension and so if you look at our completed set of patients on the right. So first looking at the <unk> patients in the Blue line, they've had minimal progression those same 11 patients for three and a half years and so that's much less progression then you would expect.
And then if you look at once again patients were initially on placebo they worsened and of course that subset as I mentioned worst in about four points until they received a map and you can see that they flattened out and they have a similar trajectory to the <unk> treated patients who initially randomized to <unk> and you can see that the curves are roughly parallel.
No.
With the exception of that extension and week 48 time point.
Separated and so that is the profile that you want to see what you don't want to see is convergence and complete overlap for the patients who received placebo for a year because that would suggest would suggest that catch up and the drug was not disease modifying.
And so the reason to present data on the next slide.
<unk> is because it overcomes this issue of missing data.
Actually in the extension phase it uses all available data from all patients and the table on the bottom left is the annualized slopes and so if the best way to analyze the data has to include all data and if you were simply to plot that out to 745 <unk> points per year, It's obviously a.
A low rate of progression versus for two comparisons, which we have which are how those same patients behave when they were placebos they were one or two points.
Then the comps overall cohort as well as the <unk> cohort and so.
Think that addresses your question does it.
No no not that.
Helpful. I appreciate that thank you.
And then just one quick follow up so you've gotten quite.
Quite a quite a nice set of accolades from the FDA on.
Sorry, the doggy bargains.
On fast track orphan drug and rare pediatric.
So quite a long list I'm just curious.
<unk> ever something that might also be part of that list.
Obviously, one of the only companies that has ever shown a success and we need to take tax it in phase III.
Clearly significant unmet need it would seem that breakthrough would be something the FDA would want to give serious consideration to.
Thanks.
We don't have breakthrough.
A reason for that is it's very late in the game to apply for breakthrough and the purpose of breakthrough is to allow for basically easy access to the review division.
On an important development program.
And truthfully, our fast track designation was really late in the game to in one of the primary reasons for that was to allow us to conduct a rolling submission.
And so I think for all those reasons and because we already are in close communication with the FDA breakthrough.
Was not that helpful to us.
Okay got it thank you.
We do agree with you, though it should be eligible.
Got it thank you.
Thank you.
The next question today comes from Matthew Kumar from Goldman Sachs. Matthew. Please go ahead. Your line is now open.
Yeah. Thanks for taking our questions. So kind of following up on the commentary related to the delayed start analysis.
Next question do you expect to provide additional data.
Updates from the Moc sealed the label extension trial, I guess kind of more Granularly would you expect the FDA to want it seemed more updates from that open label extension through the review process.
Yes. This is <unk>.
More than half the data that we're showing here is the data that was submitted with the NDA.
Of course, the patients are continuing and so they're accruing additional data over time, we've let the agency know that there is additional data if they want to see it and they basically said that if they want to see the additional data they'll let us know.
Piece on the day to get kind of a timeline for those kinds of requests that would be at the acceptance of the filing would they kind of disclose towards major amendments like actually thinking about that in terms of the regulatory review process.
Yes. This is Colin and so as part of our NDA submission and review process and we have 120 day safety update which we're obligated to provide and the focus of that update is on safety and so as Warren said, we let them know that we have updated data that is part of that 120 day safety update but falls more on the efficacy side.
And so it's really up to the review division to determine if they want to see additional efficacy data and so we don't know and it just depends upon their review they may or may not ask for that additional efficacy data right that will just be driven by the timing of their review of the NDA.
Okay great.
One last question is are there any obviously kind of in the light of head neurology one has viewed.
As you would kind of statistical analyses have there been any questions about like the statistical analysis Youll have performed so far.
<unk>, our democracy open label extension, the kind of like think about in terms of kind of review process from neurology one.
So we're obviously aware of recent interactions <unk> had with other sponsors and we cannot disclose the specifics of any back and forth. We may have had with them, but one reason to highlight some of the data in this presentation.
On slide 13 is to show that.
Did.
Did meet the prospectively defined Prespecified primary analysis.
We have a relatively low amount of missing data once again, 4% overall, 9% at week 48, and no matter, how you handle imputation the P value remains significant.
And Youre all sections of <unk> analysis populations favour <unk>.
And then in the extension, obviously I highlighted that despite some missing data due to Covid, we've had a low discontinuation rate and so without directly answering your question I'll note that some of the issues that this division has raised with other sponsors.
Appears less relevant to our program.
Okay, great. Thank you so much everybody.
Thank you.
The next question today comes from Annabel <unk> from Stifel. Annabel. Please go ahead. Your line is now open.
Hi, This is stacy calling in for Annabel, Thanks for taking our question I.
I guess for Allomap investors are clearly skittish about Fda's DNS Division right now given all the controversies over agile Ham and reversal of around programs that were allowed to file on limited data, but then FCA reversing course, so what gets you comfortable that <unk> will be we will see a different outcome from these programs aside from the fact.
They are in different indications and then also whether the 22 patients and the delayed start will provide sufficient evidence in conjunction with the Fda's and predictability and how you are handling the missing patient data.
Okay. Well. This is this is Warren Huff and I'll I'll start.
Every every program is unique.
Our program with <unk> in patients with frequency of taxi is.
Quite different from the other.
Other programs that you mentioned that were recently been reviewed by the division CNS neuro one.
There's a couple of key distinctions number one just the disease itself friedrichs ataxia is.
It's one of the worst.
Neuromuscular diseases in terms of life shortening effects.
I would have I would argue that it's it's much worse than the other things seeing these patients.
Pass and they're in their thirties.
Very young and they are struck by the disease on average at age 10 or 12 years old.
There is no approved therapy for it.
Theres been close cooperation of the patient group.
And the key opinion leaders.
With the FDA on development of the <unk> endpoint.
FDA had meaningful input.
On that endpoint.
They also suggested in the patient group followed their advice to develop data and.
Longitudinal study, which.
Provides.
A good data set on the progression rate of the disease.
And.
So for those reasons, it's different I think from some of the other things that they've reviewed I'd also just say our basic dataset. Colin explained is just very straightforward.
We believe we cleanly hit the primary endpoint.
FDA has.
Indicated multiple times in writing that the <unk> endpoint is an approvable endpoint.
And so we don't believe there is real controversy over that.
So I'd just say on balance that again every every every program is different.
We think that the data support should support approval.
And hope that the FDA will see it the same way, calling you want to address the question on the delayed start.
Sure and so FDA requested a delayed start analysis.
To allow us to further interrogate the extension data.
And so what we've disclosed publicly is much less than what we provided FDA obviously in our NDA FDA has every data point from the extension.
Primary analysis for the delayed start with extension week 72, but we performed the analysis on all time points.
You mentioned 22 patients and the delayed start in.
I think youre referencing the complete or is on the right of slide 15.
<unk> conducted the.
<unk> analysis on the full analysis set so the figure on the left.
Once again, there is a limitation and that Theres, some missing data and that's why I think there's two additional pieces of data that help us one of which is the patients who have been on drug the longest and so showing that their rate of progression is much lower than would be expected.
The other is all data in the extension and so as I mentioned.
During our formal presentation.
There is 257 Empire's assessments from 73 patients and so the same patients who were in the primary analysis set of Moxie part two and when we use all of their data across the entire extension and compute the rate of progression and its less than half a point.
When the benchmark show.
A rate that is approximately two to three times.
So that gives us comfort and be brief that heavily.
In the NDA.
And so I think that is the best way to tackle the missing data.
Due to Covid does allow us for a much more robust characterization of the data.
Thank you so much.
Yeah.
Thank you.
The next question today comes from Maury Raycroft from Jefferies. Please go ahead. Your line is now open.
Hey, good morning, everyone. This is zane on for Maury. Thank you for taking our questions.
I also had a question on the delayed Scott NLS.
Can you elaborate on why the placebo patients in the extension portion did not see the large improvement like you see in the market.
So there is an improvement in the extension I think the first point to make is that the reference point should be.
<unk> at the beginning of the trial, so if you're referring to slide 15, it should be.
The week 52 time points and so you can see there is not that much progression on the left side and on the right, which is the same patients over time.
When sandoz patients progressed four points before they received AUM of over one year and then over the next two and a half years. They progressed only only one point and once again a limitation on the data on.
On the left.
As factors there is some missing data. So it is not the same patients over time and so the annualized data once again in the table on slide 16. The left shows that the rate of progression is low.
And it's not different from each other and if you're referring to the improvement that <unk> seen within the first.
12 to 24 weeks.
There is a slight improvement as you can see in the figure on the left extension week 24 as well as.
The figure on the right, but over a long period of time, we see.
A very slow rate of progression.
Got it.
And then for the review process is Omar is an analog of Baird.
Do you think FDA will rely on any data from that discussion is from production in any way or with any views be completely independent.
It's unclear.
<unk> is a distinct chemical entity.
While it has a.
Similar mechanism of action induces interact to that has different PK and PD properties, obviously different dose different.
CNS penetration.
And most of the issues with production related to <unk>.
<unk> syndrome, where the trial design the off treatment periods separation over time and that.
Those issues are not relevant to moxie and FAA patients and Furthermore, I'll highlight that from a safety perspective, despite the background cardiomyopathy, there's been no evidence of any.
Increase in risk from a cardiac perspective with moxie and so.
There are no imbalances in adverse events.
Say, he's no elevation of blood pressure, it's actually slightly down.
<unk>.
But with our math, we conducted cereal ecg's because arrhythmias are common backup.
Back on <unk> in this patient population.
And there are no findings.
Lastly, we conducted echos and.
Moxie part two when there were no findings and so potentially FDA could look to block sone.
But when we review them all.
The data there does not appear to be.
Much relevance.
Got it thank you.
Thank you.
The next question today comes from Charley more from Beth Johnny. Please go ahead. Your line is now open.
Alright.
Thanks for taking the question. This is Charlie on for Brian <unk>.
I just wanted to ask about our docs loan in an hour.
Ports.
And if you spoken with the FDA.
What will be needed for resubmission.
As well as specifically have you discuss Yummies study.
If that would be the data from that would be acceptable as it pertains to our courts, considering it's in a different indication in Japanese patients.
Sure. This is this is Warren Huff I'll take that question.
As I mentioned in the remarks.
Our our first priority was to make sure that we had alignment with the agency in our ongoing Falcon study in patients with ADP Katy.
So we have requested a type a meeting we hit submitted a detailed protocol amendment that we felt addressed the issues that were raised in the airport syndrome Ad com.
And we did reach alignment with them.
We recently completed the type of interaction receive the minutes.
And we did.
To get alignment with them.
On modifications to Falcon.
That would allow us if positive to support NDA approval.
And as I mentioned the key one is that we move the primary endpoint of week one O eight.
They indicated that that would be acceptable based on the available data on a resolution of the effects.
And then of course, there were other changes made to accommodate the protocol changes.
For example in the analysis plans.
As I said this was the most important thing that went from my standpoint went well.
Preserves the integrity of that trial and the ability to move forward with an approval and 80 Kt, we havent requested a meeting.
Yet.
From the division to discuss the path forward and output syndrome. As I said, we just completed the interactions for PK PD, we obviously will be doing that and we will report the results of those interactions after we have them with.
With respect to the <unk> trial and this is just our view we haven't reviewed the design of the trial or its implications with the FDA yet.
But because the trial is such a large long term study.
With.
Event endpoints.
That had been shown to be very predictive of your risk.
In stage kidney disease.
That the data will be an important addition to the data on <unk>. The central question with <unk> has always been do the improvements in estimated GFR that are consistently observed across multiple types of TKD will does translate.
Into.
Production in the risk of kidney failure.
Just based on the size and duration of the trial, they're going to have a large number of hard dialysis events.
In addition, they setup endpoints that were multiple thresholds of Egfr decline, 30%, 40% and 52% I believe.
That are well validated to predict the risk of kidney failure. So even though it is a Japanese study.
In diabetic kidney disease, I think that because you observe the same improvements in GFR.
Based on the same mechanism of action, it's not specific to any single form of <unk> I think it will be very persuasive in convincing the nephrology community.
And regulatory agencies.
All of the long term effects of treatment with Bard.
On their risk of kidney failure I'd also add it's also will provide additional safety data.
Since the patients that are being treated in that study.
<unk> diabetic kidney disease.
That was the at risk population in the Beacon trial and so it will also provide an additional large body of safety information on long term use of <unk>.
Great. Thank you so much for the answer.
Sure.
Thank you.
The next question today comes from Joseph Schwartz from STP Linnik. Joseph. Please go ahead. Your line is now open.
Sure.
Alright, Thank you very much.
Thank you.
I prepared really well all.
Awesome.
Mitch regulatory steps.
We received some feedback thank a lot.
<unk>.
Okay. Thank you set for US a lot of the similar stage and yet there were some.
Pretty major surprises. So I was wondering if there's anything that you think is fundamentally different year.
Or if youre doing anything.
Particularly different in order to.
Great.
Any major.
Rises.
Yes.
<unk>.
All of the.
Decisions that have been coming out of the agency, particularly with the vision that we've been hearing.
Even on this call. Thank.
Thank you.
Yes, Thanks, Joe.
Alex This is Warren I'll address that yes, I think there are there are several key differences obviously in.
The.
Regulatory profile.
Omar for Friedrichs ataxia versus our program in outboard syndrome or <unk>.
First I would say that the mechanism of action.
In this disease is just not controversial.
Friedrichs ataxia is well understood to be a genetic mitochondrial disease.
The target our target <unk> two was identified in the key research was done by the FAA research community they approached us.
Because we had the molecular tools.
To activate the target it's known that <unk> two is suppressed.
In the presence of the for tax and silencing.
That is believed to.
B, a key mechanism through which might have conrail.
Function is severely impaired in the patients the relationship between mitochondrial respiration ATP production in neurologic function is well understood. There is really well done clinical studies showing high correlation between whole body.
<unk> of respiration and.
And neurologic function, so just across the board.
<unk>.
The.
The relevance of the target.
The nature of the disease is well understood.
And it's just not controversial.
Number one number two the endpoint the primary endpoint.
In the Friedrichs ataxia studies.
Or just not controversial either it's a neurologic exam.
That measures essentially clinical function.
FDA has said that it's either an intermediate clinical endpoint or a clinical end point, depending upon there.
Your kind of view of the data overall, the totality of the data.
But it's clearly measuring patients ability to do things like stand.
Walk.
You move their arms and hands, it's not like GFR, where it's a laboratory in point then you have got to extrapolate out to a clinical end point right. It is a direct measure of neurologic function in the patients over time and I would add because of the great work that the patient group.
And the researchers have done that rate of progression and the fact that it's relentless.
And it doesn't really reverse as had been well characterized.
And then I could tell them you want to add to it yes. So I think those are two excellent points and there are a few others as well.
So beyond the mechanism and the endpoints.
Clinical profile of <unk> is not controversial and so obviously recovering some function.
And then slowing progression is what would be expected with a drug that is efficacious, whereas I think we all know increasing kidney function with barack slow and has been controversial.
There is other elements of the clinical profile of our oximetry controversial such as increases in proteinuria and there is no similar finding this controversial with <unk>. Another one is that obviously <unk> had the legacy safety finding from the Beacon trial, we don't have that and I spoke to that just.
Just a few minutes ago with Omar there is no similar finding.
And then another important aspect is that while there are no approved drugs for output syndrome.
Nephrologists believe that Ace inhibitors, and <unk> have some treatment effect, even though it hasnt been clearly demonstrated there is a belief that there is at least some utility and those agents, whereas with FAA. There are no available therapies that have any impact on progression now.
I would say lastly, there was there was controversy in the KOL community.
<unk>.
And there was a vocal minority of that thought that to the drug.
It should not be used.
We are unaware of any such controversy within the FAA community.
Mentioned in the call. We included all of the FAA Kols at the time in our clinical study in the U S and several globally.
And I think the reason why theres less controversial because our data our incorruptible it's consistent.
The mechanism is well validated so I think there's many reasons why this program.
Is different than <unk>.
Thank you good luck.
Thank you.
Next question is a follow up question from me down a chunk of it from Citi. Please go ahead. Your line is open.
Hi, warrant and Colin Thank you very much for the follow up.
Look at Slide 13, again, it just raises another question.
What's your plan with respect to the breadth of the label.
Obviously, you have some pest cabinets patients enrolled.
Enrolled although the P value was not significant as the plan to apply for a broad label for both the non <unk> tablets as well as the Penny tablets are you planning to focus on the non partnered cabinets.
Yes.
We would focus on a label that includes patients with and without <unk> and I think there is an important differentiation.
As well regarding our <unk> population and so recall that we.
On a post hoc basis noted from Moxie part, one which was a small dose ranging placebo controlled study that patients that had severe pest gave us.
We're less likely to show a treatment effect.
And so <unk> has higher foot and obviously if patients have.
An abnormality thats non neurological in this case skeletal we would think that that could interfere with the ability to detect a treatment effect with <unk> and so for moxie part two we prospectively.
Find the <unk> population and really it was just patients with severe <unk> and so <unk> any.
Hi arch.
And for the study.
Used a flashlight test, where basically patients stood up and if they're arch was so high that you could see light underneath the foot from a flashlight, we defined that is <unk>, but in reality, it's severe <unk>, we took X rays of all patients.
And from our understanding patients who are in the.
The non <unk> population many of them likely had some manifestation of pest gave us and Youre right. We did not show significance in the <unk> population, but we would not expect to show significance with 10 and 10 patients.
But the point estimate favored.
In the all randomized population, which included those patients.
There was a significant treatment effect, Furthermore, and as I mentioned.
The full analysis set we saw improvements in all sections on the <unk>. So that includes bowl bar, which is speaking in swallowing.
As well as upper limb coordination and so those factors are where sections are unaffected by any.
Hi arch in their foot and so for all those reasons, we think that the drug should get a broad label and include patients with <unk> and that will obviously be part of our discussions with them.
Okay. Thanks that makes sense, thanks a lot.
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 call on <unk> website, and we ask that pharma dot com in the investors section.
You very much for your participation you may now disconnect.
Okay.
Thanks.
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