Q4 2021 Reata Pharmaceuticals Inc Earnings Call
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Thank you for standing by and welcome to Reata Pharma Keach Coast Conference Cool.
During which the company will discuss fourth quarter and full year 2021 financial results and provide an update when it's Glenn clinical development programs.
An audio recording of today's webcast will be available shortly after the cool in the investors section over at its website at <unk>.
You all have to pharma don't call them.
Before the company proceeds with its remarks. Please note the forward looking statements disclosure on the company's press release.
These are many factors that could cause results to differ from expectations, including those noted in the company's S. E C filing.
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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 comparable GAAP financial measures <unk> earnings release and presentation from today, which again can be found on <unk> website.
Today's statements are not guarantees of future outcomes piece I'll say night that any comments made on today's call apply only as of today February 28 2022.
It may no longer be accurate.
At the time of any webcast replay or transcript rereading.
Following the prepared remarks, we will open up the call 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 reacted Chief Executive Officer, <unk> Soni, President Colin My Chief Innovation Officer, and see Me Khan Chief Medical Officer.
At this time I would like the time to turn the call over to Warren.
Good morning, everyone. We thank you for joining us today.
At Reata, our mission is to develop therapies with novel mechanisms of action and the potential to have a high clinical impact on deadly diseases with few or no available therapies.
This is a challenging mission that involves many risk, but it's also very meaningful.
We announced on Friday that we received a complete response letter from the FDA for a new drug application for our <unk> program in chronic kidney disease caused by Albert syndrome.
This outcome is a significant disappointment for our company as well as the many patients families and investigators who have participated in our development program for <unk> syndrome patients.
In a moment I'll comment on the implications of the CRM for the paradox loan program.
Before I do that I'd like to point out that we're well positioned to recover from this setback and achieve our goal of launching our first commercial product.
We have a strong cash position, our second program Oh man for Friedrichs ataxia at the NDA stage.
Our pipeline of additional development opportunities, including our program and Archie a 901 for diabetic neuropathy entering a phase two proof of concept study with.
With that background I'll start by providing a brief update on AUM as.
I'll start on slide four.
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The old man of NDA submission for Friedrichs ataxia is on track to be completed this quarter and subject to FDA approval were planning for the commercial launch of <unk> early next year.
As you know we had our pre NDA meeting regarding <unk> for the treatment of friedrichs ataxia in the third quarter of last year.
During the fourth quarter of last year, the FDA granted <unk> fast track designation for the treatment of SMA. This makes the AUM have NDA eligible for priority review and rolling submission of the NDA.
The FDA granted our request for a rolling NDA submission with.
We submitted the first NDA modules last month, and we plan to complete our submission next month, while the FDA has not indicated if they'll hold an advisory committee meeting to discuss our NDA. We've initiated preparations for a meeting should they decide to hold one.
We're looking forward to working with the FDA on its review of our NDA for <unk> throughout this year.
S. A is a debilitating degenerative neuromuscular disorder that profoundly affects patients' motor function and in almost all cases shortens their lives.
The disease is relentlessly progressive with no approved treatments. If <unk> is approved we're preparing to be in a position to launch this important drug early next year.
Turning to slide five I'll now turn to our BARDA Ox alone development program and the implications of the cereal.
As you know we've pursued the development of our docs alone for severe forms of chronic kidney disease, because we believe strongly that the drug has the potential to transform the treatment of C. J D.
It has a novel mechanism of action that restores mitochondrial function reduces reactive oxygen species and inflammatory drive this mechanism results in acute increases in estimated glomerular filtration rate or egfr that or the opposite of the acute decline in egfr observed with blood.
Pressure medications that reduce dialysis risk and large clinical outcome studies.
<unk> mechanism of action has been well characterized in hundreds of peer reviewed publications, despite that and largely because of the observed increases in egfr the mechanism of action and clinical profile of our docs alone is controversial among many nephrologist.
As we've discussed in the past drug development in rare forms of CK D is difficult because the disease progresses slowly over many years and the decline in Egfr is real and measurable, but not considered a clinical endpoint.
In addition, there are not enough patients to conduct a true clinical outcomes for time to kidney failure study importantly.
Importantly, the cardio renal division of the F. D. A understands this and has developed alternate endpoints for these diseases.
As all of you know the phase III Cardinal study met all four of its pre specified primary and key secondary endpoints importantly, it met these endpoints in patients with a rare genetic rapidly progressive form of C. G D.
As a result, we believed that the data from the phase III Cardinal study as well as the other studies of our docs alone is C. K D demonstrated a positive benefit risk profile, which would support production on approval.
This was also the position of the many key opinion leaders and patient groups that supported approval of our docs alone.
Nevertheless, we received a negative vote at the AD com and a serial <unk>.
I believe that the committee was not convinced that the improvements in Egfr would translate into a real reduction in the risk of dialysis or kidney transplant.
Without actual outcomes data questions could be raised about on and off treatment Egfr trajectories over time, the off treatment period and changes in clinical chemistry parameters that raised doubts about whether the observed egfr improvements would actually delay dialysis.
Also some expressed concern that there could be a heart failure risk like that observed in beacon, even though we have since implemented risk mitigation procedures in all trials and have observed no imbalances in heart failure other cardiac SAE is or aes or increases in blood pressure since beacon.
I believe that if the Nephrologists on the committee had been convinced that part excellent treatment was likely to delay dialysis, we would've received a favorable vote.
For this reason an important event for the <unk> development program will be the result of a yummy a large phase III clinical trial in patients with diabetic kidney disease being conducted by our strategic collaborator in Japan Coyote Kieran.
Kieran has enrolled approximately a thousand stage three and four diabetic kidney disease patients in the Ami study and all of the patients will have a minimum of three years of study drug exposure upon completion of this study.
M. A has as its primary and key secondary endpoints events that are validated to predict the risk of dialysis and transplant, including actual dialysis events and large declines in Egfr of 30, 40 and 53%.
Kyle with Kirin expects to complete the last study visit in the second half of this year.
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 of kidney failure.
Further since it is such a large and long term study it should provide very important information on the safety profile of our docs alone.
It's notable that this study includes a large number of stage four diabetic CK D patients.
With respect to our programs in <unk> syndrome, and ADP Kt, we have requested a type a meeting with the FDA to discuss the Falcon study, we're incorporating changes to that study that we believe address the issues raised by the FDA and the AD com during the review of the outward syndrome NDA.
Further we're reviewing the Fda's comments and the complete response letter and her address assessing next steps for outward syndrome program. We expect to request a follow up meeting to discuss the program. After the type a meeting for ADP J D.
With that update I'll now turn the call over to Collin, who will provide clinical and other regulatory updates on the program NFA as well as an overview of the Ami study then to Doctor Khan, who will provide an update on our program with BARDA ox alone in patients with ADP Kt in our program.
With RTA 901 in diabetic neuropathy.
Finally, my meter will provide an update on our financials and operations.
Yeah.
Thank you morning Collyn.
Okay.
Thanks, Marc starting on slide seven and as Warren mentioned F. A debilitating degenerative neuromuscular disorder that profoundly affects patients' motor function and in almost all cases shortens their lives over time patients become dependent on walkers, and then wheelchairs and they ultimately lose their independence altogether.
Other diseases relentlessly progressive and the median survival for this disease is in the mid Thirty's. There are no approved treatments for FX.
It's a disease of mitochondrial dysfunction caused by mutations in the gene broker taxing it mitochondrial protein that helps us assemble iron sulfur clusters that are necessary for the production of solar energy in the form of ATP.
Researchers have established that interest to the targeted build now is suppressed and FAA.
Patients.
This depression contributes to mitochondrial dysfunction and reduced some of the energy production that is the hallmark of that day.
As far as the most common recessive form of ataxia and based on literature and proprietary research. We believe FAA affects approximately 5000 children and adults in the U S next slide.
The pivotal portion of Moxie was a double blind placebo controlled randomized international study that was one of the largest global interventional studies ever completed NSA, we enrolled 103 patients across a wide and representative range of age and disease severity.
The primary analysis population included the 82 patients who did not have the former even ex the cadence there.
Primary endpoint was the change from baseline in Fars scores at week 48.
The progression of SMA as measured in clinical studies by the modified <unk> ataxia rating scale or in bars, a physician assessed neurological exam.
The ataxia research foundation, or Farah work with the FDA to develop the inspire scale to accurately track disease progression and FAA patients.
This is Gail is composed of four sub sections, including Bull-bar upper limb and lower them coordination and upright stability.
As patients lose function, they're empowered scores increase.
Moxie 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 bars compared to placebo. After 48 weeks of treatment with a P value of 0.014.
Moreover, we observed improvements in all subsections that'd be in par scale and in all major subgroups and analysis populations.
This change is very clinically meaningful and that'd be old map treated patients did not progress during the 48 week treatment period and recover function further the placebo corrected improvement is equal to more than one year progression.
In addition to the changing in bars. Several secondary endpoints were included in Moxie and analyze hierarchically well it was not feasible to power. The trial for these endpoints we observed improvements in those secondary endpoints next slide.
As you know in the second half of 2020, the FDA provided us guidance that although it did not have concerns with the reliability of the <unk> primary endpoint results for Moxie part two it was not convinced that the results from lottery part two as a single study were sufficient to support approval.
To provide additional evidence that persuasiveness. The FDA suggested that we perform and exploratory analysis. The delayed start analysis in the next few slides I will discuss the design of the delayed sort of analysis and results in an updated data cut from August 2021, which was included in our NDA submission.
The intent of the post hoc delayed started analysis.
Valuate, whether old map is a persistent effect on F. A disease course conceptually this analysis evaluates whether the treatment effect that was observed in the placebo controlled moxie part two study is maintained and the Moxie extension study when all patients are receiving Oh man.
Treatment effect is maintained and the box extension study between those originally randomized to old math versus those who have a delayed startup oh mouth, because they were originally randomized to placebo and moxie part too.
And it demonstrates evidence that'd be persistent effect on the course of the disease.
The treatment effect is not maintained the patients would be delayed starts on old math, because they were originally randomized to placebo are able to achieve the same absolute response and catch up to the patients initially randomized to <unk> results are consistent with a symptomatic treatment that does not affect the underlying disease.
Yes.
A total of 70 375 patients without pests caters who completed moxie part two were enrolled in the Moxie extension importantly, the moxie extension is ongoing and we continue to accrue long term safety and efficacy data from this study.
The delayed start analysis compares the change from baseline and bars, where patients randomized to placebo drink moxie part two or the placebo to own that group to the change from baseline in bars for patients randomized to Omar very moxie part to the old Man Oh man.
Two time points were used in the analysis. The first time point was at week 48, the final week of the placebo controlled Moxie part two study.
Time point was at week 72, the open label box extension in which all patients received Olga.
In non impurity test was used to evaluate if the difference in bars.
Tween groups observed with their first time point was maintained or non inferior at the second time point analysis methods, including the pre specified.
Non inferiority margin where base merger.
Next slide.
And the August 2021 data cut off.
58 of 73 patients from Moxie part two without educators, who enrolled into a box extension at least 72 weeks of exposure in the market extension in 28 of these patients had at least 120 weeks of exposure in the Moxie extension.
This analysis demonstrated that the difference between groups was maintained specifically between group difference and in bars observe abbvie and the placebo control boxing part two period with preserved at the box extension week 72, and the delayed start period recall that a decrease in <unk>.
Bars shows improvement.
Accordingly, the upper limit of the 90% confidence interval for the different testing that was minus <unk> six.
615 meeting the thresholds for demonstrating significant evidence that the difference was maintained or was non inferior.
Because the treatment effect is maintained between those originally randomized to placebo versus those who originally randomized to own map the delay.
They'd start analysis provides evidence of a persistent effect on the course of the disease.
Slide.
The first year. The Moxie extension study was affected by the COVID-19 pandemic and many visits that were scheduled during that time were conducted remotely.
<unk> exam cannot be conducted remotely and therefore, many patients had missing data during the first several visits but the extension, especially during extension of weeks 24, and 48, therefore and in order to compute an annual rate of progression over the entire extension periods, we conducted a launch it too.
New analysis that incorporates all the available data from a box extension in essence, the analysis computed individual teacher trajectories overtime than estimated the group's average slope.
For reference the fair response or natural history studies published data demonstrate a progression rate of approximately two important points per year.
Over several years of follow up.
This analysis includes many hundreds of patients followed for several years.
Our longitudinal analysis demonstrates a much lower rate of progression for patients treated with him at the.
The two subgroups of patients placebo to AUM and AUM after Oh, Matt sure.
Similar means slopes and empowers with means blokes, a four 5.27 empowers points per year, respectively. There was no significant difference between slopes with a P value of 0.79.
These data suggest that patients treated with Omar progressing at approximately one quarter of the rate of progression as untreated patients who have been followed in the natural history study overall, we believe our data are consistent with a meaningful and persistent effect on the course of the disease.
Regarding safety turning to slide 12, Oh map was generally reported to be well tolerated and reported adverse events were generally mild to moderate in intensity and moxie part to only a small number of patients discontinued due to adverse events in either arm.
The most commonly reported adverse events are shown in the table on the right in this slide.
Increases in immuno transfer races are a pharmacological effect Oh man were associated with statistically significant improvements or reductions into mobility weekend and were not associated with liver injury.
The overall rate of cardiac and vascular adverse events was low and fewer <unk> treated patients reported these aes the.
The overall rate of serious adverse events or <unk> was low.
Next slide.
We believe that the pharmacology of our interim two activators may be applicable to a wide range of other neurological diseases that have a common pathophysiology of mitochondrial dysfunction and neuro inflammation base.
Based on our understanding of the pathophysiology of neurological diseases characterized by mitochondrial dysfunction inflammation and oxidative stress, we believe <unk> may be applicable for diseases, such as progressive Supranuclear palsy.
Amyotrophic lateral sclerosis, or AOS, Parkinson's disease, Frontotemporal dementia, Huntington's disease, Alzheimers disease, and epilepsy consistent with this we've observed compelling activity Oh, Matt and our other two activators in preclinical models of many of these diseases.
Transitioning toward ox loan in our CBD program on slide 15, I'd like to provide a status update on our Asian strategic collaborators ongoing diabetic CD outcomes trial, which is called PMA is being conducted in Japan as Warren mentioned, a Amit is a randomized double.
Blind placebo controlled phase III outcomes trial. The primary endpoint is the time to onset of at least a 30% decline in egfr or kidney failures, including dialysis and transplant.
With an egfr between 15% to 60 ml per minute were enrolled grew between 20 and 79 years old.
He was here and used a similar risk mitigation strategy as we have employed in our recent studies and excluded patients with a history of heart failure or BNP greater than 200 feet per well.
The trial has a minimum treatment duration of three years with an expected median duration of treatment of approximately three and a half years.
For 1000 patients were enrolled the last patient visit is expected to occur in the second half of this year.
If this trial is positive and demonstrates that <unk> reduces kidney failure events without major safety concerns. We believe these data will be very helpful to support our ongoing programs and to convince the nephrology community that the drug can be used safely and will be beneficial over the long term I will now turn.
The call over to see me.
Thank you Colin.
I will start on slide 16 bid by Docs lung program in patients with ADP, TD, which is at Leer and progressive had atrophied.
It can be caused by genetic defect in PD, one or <unk> gene.
Leading to the formation of fluid toothpaste in the kidney and other organs.
The phase III Falcon study is an international multi center randomized double blind placebo control study the efficacy and safety of <unk> in patients with ADP TD randomize one to one.
<unk> active drug or placebo.
Hawkins is enrolling patients age 18 to 70 years.
With an estimated glomerular filtration rate between 30 to 90 males.
We recently filed a major protocol amendment with the FDA and requested a type a meeting to discuss the overall ADP T D development program as well as the protocol Amendment.
The major changes in the amendment.
<unk>.
Primary end point.
Sample size adjustment to address the endpoint change.
The addition of adolescent patients.
The addition of a sub study for ambulatory blood pressure monitoring.
We have changed the primary end point from the off treatment Egfr change from baseline at week 52, which is four weeks.
After the planned drug discontinuation.
He had one to Egfr change from baseline at week, one theater, eight which is eight weeks after planned drug discontinuation at week hungry.
Additionally, all patients who discontinue early in the study will be requested to return at week, one theater eat.
In order to German teams statistical power.
With these changes in the primary endpoint the sample size has been increased from 550 to 850.
Since the primary endpoint will be assessed at two <unk>.
We have removed the off treatment period between week 48, and 52 at Iran.
We also added an exploratory endpoint of Egfr change.
From baseline at week, one tour, which is 12 weeks after the plan drug discontinuation at the country.
We lowered the age limit from 18 to 12 to allow enrollment of adolescent patients with ADP T D.
Finally, we added a sub study with ambulatory blood pressure monitoring to further evaluate badakhshan impact on blood pressure.
More than 500 patients are currently enrolled in the study.
Yes.
Moving to slide 18, I will discuss our RTA 901 program in diabetic peripheral neuropathic pain or D. P. M P.
<unk> 9001 is a highly potent and selective small molecule C terminal modulator of Hsp 90.
It just be 90 is a molecular chaperone that facilitates the.
Holding and stability of many proteins Aki and 90 to one increases transcription of HSBC 70, and then their molecular chaperone that promotes cell survival and response to stress and effects like Duke unreal function.
Arguing lines it'll one has demonstrated activity in multiple models of diabetic neuropathy. It is.
Has been shown to reduce pain acutely in rat models of painful diabetic neuropathy as well as recovery of.
Lost sensations.
In mouse models of Insensate diabetic neuropathy.
There are approximately 4 million patients with moderate to severe D. P N b in the United States and approximately 2 million patients diagnosed with D. P. N P seek treatment annually.
Despite several approved therapies for DP and be a significant proportion of patients do not continue on standard of care due to tolerability and failure to achieve adequate pain relief and.
Unfortunate.
To 40% of patients remain refractory to available pharmacological treatment.
We have completed a phase one study of 90 to one in healthy volunteers and demonstrated an acceptable safety profile with no safety signals there.
There were no drug discontinuation.
Our serious adverse events.
The pharmacokinetic profile with favorable.
We plan to initiate additional phase one clinical pharmacology study to evaluate the PK and drug drug interaction in the first half of 2022.
Following completion of these phase one studies, we plan to initiate a randomized double blind placebo controlled phase two study in diabetic patients with peripheral neuropathic pain in the second half of 2022.
With that I would like to turn the call over to them and need to provide an update on our operations and financials.
Yes.
Thank you <unk> and good morning, everyone I'll continue on slide 20.
Given our recent progress towards the NDA review and approval of <unk> for the treatment of a fee we have refocused our efforts and initiated preparations for the potential commercial launch in the United States.
We believe F. A affects approximately 5000 children and adults in the United States.
And there are approximately 4000 diagnosed patients in the United States, primarily treated by a variety of specialty physicians and neurologists.
Initially we plan to concentrate our commercial efforts primarily in centers of excellence specialty clinics and key neurology practices.
With this focus we expect that our small and efficient sales force will be adequate to reach the physicians currently treating patients with <unk>.
Okay.
Mid last year, we deployed our national accounts team, which is actively working in the field with the peers.
In the meantime, we continue to invest in disease awareness efforts to educate physicians on the unique disease symptoms that differentiate patients with ethane from patients with similar neurological diseases.
Disease Education efforts are also designed to help physicians recognize patients earlier in their journey and to decrease the time to an accurate diagnosis next slide.
Turning to financials. Please refer to our press release issued earlier today for a summary of our financial results from the fourth quarter of 2021 and the year 2021.
I will focus on three items on today's call.
Our strong cash position as of year end 2021, our plan measures to control our future expenses.
Our updated cash guidance.
With a strong cash position of $590 million at the beginning of 2022 and given that we have no debt on our balance sheet, we have the financial flexibility to continue to pursue our key priorities as we work to deliver on our mission.
Notably under our royalty arrangement with Blackstone there are no payments due to Blackstone until we receive approval for Bard and the United States are the European region.
And important part of our financial flexibility is that we have been able to adjust our expenses very quickly.
As a result of the steps we have taken to control our expenses, we have updated our cash guidance and now expect to extend our cash runway through the end of 'twenty 'twenty four.
As compared to our previous guidance of cash runway through mid 2024.
The actions we have taken include pausing all commercial spend related to launch preparation activities for output syndrome in the United States and the European region.
Reducing our future facing sales and commercial teams at the beginning of this year to adjust for the delay in the launch of paradox alone.
<unk> focus on the commercial team on the preparations for the anticipated <unk> launch in the United States.
Totally pausing capital spend activities for the new headquarters building and initiating efforts to sublease that building at this point, we will not invest the earlier planned $50 million and the capital expenditures.
Most importantly, given that these actions now extend our cash runway through the end of 2024, we have no need to raise capital in the near term.
This increase in cash runway guidance, not only demonstrates our financial discipline and ability to quickly re prioritize our spend.
It also allows us to focus our efforts toward three strategic priorities as I will detail.
The first is preparing for Omar regulatory and commercial success.
The second is completing the Falcon study under the amended protocol and resurrecting that the output syndrome program.
Port is initiating our phase II study for the RTA 901 for <unk> in the second half of this year.
Moving to expenses R&D expenses for the ear were $156 million as compared to 159 $1 million for the same period of the ear products.
R&D expenses decreased slightly primarily due to the timing of manufacturing activities.
G&A expenses for the year were $99 million as compared to $75 1 million for the ear products.
Higher G&A expenses were primarily due to increased spending related to commercial readiness activities and personnel costs to support growth in our development activities.
Our GAAP net loss for 2021 was 297, four and $4 million as compared to a net loss of $247 8 million for the prior year.
Our non-GAAP net loss for 2021 was $193 $9 million as compared to a non-GAAP net loss of $158 $3 million for the year prior.
The increases in GAAP and non-GAAP non-GAAP net loss, primarily driven by commercial launch readiness activities.
With that I will turn the call back over to Warren.
Thank you Amy.
In closing, we're well positioned to recover from the setback in our output syndrome program.
And achieve our goal of launching our first commercial product.
We're on track to complete the submission of the NDA for <unk> for the treatment of FAA. This quarter, if approved <unk> will be the first drug available to treat this severe disease and we're actively working on commercial preparations to be in a position to launch them have early next year.
We believe that the results of Kiowa Karen's Ami study will be an important milestone for the paradox alone development program. It will provide efficacy and safety data from a large long term offense trial of the drug at.
At the same time, we're working with the FDA and assessing next steps on our output syndrome program in the U S. And also continue to enroll patients in the Falcon study in patients with ADP JV.
Additionally, we're looking forward to initiating a phase II study of RTA 901 in patients with diabetic neuropathy later this year.
As we continue to pursue these efforts we're doing so with a strong cash position, providing us with the necessary financial flexibility in this environment.
Above all we remain committed to our goal of developing and commercializing novel Therapeutics for the treatment of patients with severe life threatening diseases.
So that concludes our prepared remarks, we'd like to thank everyone, who dialed in and I will now turn the call over to the operator for questions.
Ladies and gentlemen at this time well begin the question and answer session. Please press star followed by one to ask a question.
If you change your mind, you can press Star T D.
Please keep your questions to one question and one follow up.
The first question comes from Eagle No come of it from Citigroup you go. Please go ahead.
Hi, Great I warn and team. Thank you very much for taking the questions. So obviously you mentioned I am a numerous times in your remarks and as you highlighted in the slides. The primary endpoint is a composite of time to a greater than 30% decrease in egfr from baseline or time to our ESR D. And then <unk> also has a secondary.
Endpoint, which is exclusive lead time to ESR D.
So my question is would hitting on the primary be enough to show positive evidence of disease modification or do you believe you really need that secondary endpoint to work, which isolates times ESR D and assuming these endpoints it would that be enough in your view to resubmit The airport NDA and has FDA expressed any interest.
Thus far in seeing this outcome data.
Yeah.
Sure.
I'll take that I'll take that question and I'll start with the.
Last part of it first no we havent discussed the design or what the implications of a llama it would be with the FDA.
Sure.
Plan to do that I think at a minimum when that data comes in.
To take the first part of the question.
It's in the eyes of the older I think that there that study is so large and so long they are going to be a large number of hard dialysis events as well as large large declines at that 30%, 40% and 53%.
And Egfr and so I think if the safety profile was clean.
And if there is a meaningful reduction ideally a significant reduction in the heart dialysis events that is going to be extremely persuasive.
I also think that.
If we saw a proportional increases in the heart dialysis events.
To the large declines in GFR that is going to be very persuasive because it provides significant evidence that the egfr trajectories observe what the drug over time actually.
Translate into a reduced risk of dialysis events.
Okay. Thanks, very much and just a quick follow up on I am a so the last patient visit.
Half of the year. So should we expect that the topline data are also going to show up in the second half of this year.
Okay.
No you have to look to karen's guidance on.
On when they plan to release the data.
The U S for them.
Just a month ago.
The current guidance is currently that they they would have last patient coming in second half of this year. They have not guided currently havent got it they have not guided release.
Yes.
Okay, and then if I could just ask one quick question on that day. So if the FAA does request an AD com what do you believe would be the key issues and questions that FDA would bring to the table, but obviously, having said that it's hard to envision what they would want to discuss given the bar is very low and.
And you have positive phase III data following as you know a very long history of disappointment and developing as a drugs.
Yes, no agree it.
I think it's a really straightforward.
Set of issues for the agency and I really don't know exactly what they would bring.
The panel or mostly general neurologist, so I assume there would be some discussion of the clinical meaningfulness of the changeover time.
And I think it's.
And I think that is very easy to demonstrate.
The data suggest that there is a significant shortening.
A reduction in the rate of progression in these patients which is because of the really great work done by by Farrah The patient organization is well understood.
So other than that I really don't know what the discussion would be about I guess potentially.
Potentially you would have to discuss the safety issues associated with it.
But.
Those seem very manageable.
Okay. Thank you.
Mhm.
The next question comes from Charles Duncan of Cantor Fitzgerald Charles Please go ahead.
Yes. Good morning, Thanks for taking the question.
Warren and team.
Yeah, and persisting through a challenging time.
Had a couple of questions on <unk> I guess I'm wondering if you could characterize your perspectives and the interaction with the agency.
An old man versus say Bard at this at this point in the process I know, you're probably not going to provide details, but what do you think about the interactions with the agency thus far on <unk> and its history of clinical development, then I had a follow up on some of their data.
Sure Charles.
Obviously, when we first interacted.
With this division.
The FDA around.
The positive results from Moxie part too.
Initially took the position that.
We needed to provide additional analyses.
That would provide additional support for the use of that study for a single study approval and so we engaged in a dialogue with them.
All throughout last year, providing different analyses and as Colin pointed out they suggested in that context that we due to the delayed start analysis that he's that he summarized and as you know the background is that we submitted that and requested a type C meeting to discuss it with them.
And after reviewing the data they came back to us and told US that it was more appropriate for us to.
To withdraw our type C meeting request and request a pre NDA meeting.
And they also asked us to focus.
The questions for the pre NDA meeting on what we needed to know to get the NDA filed a traditional pre NDA meeting so.
We took that as they believe that the delayed start analysis provided the additional support to allow us.
To submit the NDA.
And then in the pre NDA meeting.
They really focused their comments.
On.
The.
Type of approval on the content of the NDA.
And he was very much a straightforward pre NDA meeting.
They also.
<unk>.
They they also gave us dispensation.
On.
A number of.
Content requirements for the NDA because of the severity of the disease they allowed us to submit certain.
Clinical pharmacology studies in preclinical studies post approval.
So it was a very had a very cooperative tone.
They did ask us if we were going to submit for accelerated or full approval.
We kind of.
We said we thought the data supported full they said that would be a review issue and so.
That was a those are the main topics of discussion.
During the pre NDA meeting they also.
<unk> told us that.
Sort of invited us to submit for fast track, which we did.
Following the meeting.
They also invited us to request rolling submission.
Which we did they granted the fast track they granted the rolling submission.
And so.
That's where that's really where we are I think that the additional analysis that we provided.
As well as I think other external factors.
Open the door for the NDA filing for us.
Okay. That's helpful. Appreciate the color notes its difficult question to answer regarding slide 12 and the.
Adverse events I wanted to ask you. If you got any of them would suggest that you construct a rems program, particularly the a L. T increases if you think that that would be necessary and are you prepared to do that and then with regard to the old man from launch I assume that.
Youre going to talk more about pre commercial build.
Once the NDA is filed and accepted for review.
Yes, let me would you take the last.
Sure. So hey, Charles this is Matt meet Ah, Yes, we have as we as I mentioned in my prepared remarks, we have refocused our priority.
Towards Omar launch and as you know we already had commercial sales team marketing per diem, which were higher than last year and they are now focused towards home App launched so that all is already working along with our disease awareness efforts.
The sizing.
<unk> targets all of that book has already initiated and it's well underway.
I'll take the first question, particularly with respect to the transaminase is.
We think the trans Ams Naas as well that there's a very strong evidence that those are.
Purely effect of induction of those enzymes.
We have observed no highs law cases.
Our other meaningful evidence of actual hepatic injury.
With <unk> or with <unk>.
And so I think also think that the.
The transaminase as are clinically manageable they have a very specific.
Profile.
Of an acute increase.
Debt levels off.
Without associated increases in bilirubin.
So.
We would propose careful management of them an observation in the label, but don't think of Rems would be required for that.
Okay. Thanks for taking my questions and I'll hop back in the queue.
Yeah.
The next question comes from Maury Raycroft Jefferies Maury. Please go ahead.
Hi, good morning, and thanks for taking my questions.
And a follow up on <unk> I guess to complete the NDA submission by end of first quarter can you specify what items are remaining at this point for the NDA and say, where you're at with CMC and manufacturing of commercial product at this point.
Yes, thanks for the question Maury.
Yes, we've submitted both the non clinical and clinical modules.
Together.
Last month and the remaining <unk>.
Section is the CMC.
Frankly, when we were delayed with the submission.
CMC activities.
They got behind.
They're hard to speed up quickly, but yes. So it's the it's the last module that will go in and we're on track to have that completed in March.
Got it okay.
Also just.
We can't say much because it's related to kirin, but just wondering if you can provide some additional color on why the JP MBA requested Karen to get three year or longer data in there.
Hi, Ami study.
Yes, I'm not going to speak for them I'm going to just speculate, but I guess I'm, assuming because that base.
Basically answers the fundamental question.
About <unk>.
The the theoretical concern has been that the acute increases.
In egfr or pressure mediated.
And we've provided a substantial amount and care and it provided a substantial amount of evidence.
That the increases are not pressure mediated there the restoration of single Nephron GFR.
Normal functioning of the the individual nephron.
But there is this because of that I think the history of development and the understanding of blood pressure medications.
There have been a.
Concern, but if there were damage to manifest.
Certainly it would manifest in.
Three years of treatment.
And so I suspect that the.
<unk> wanted to see.
We're truly long term data to definitively I believe definitively answer that question.
Got it okay.
Think that I'll, just add I think a thousand patients with their they'll have an average exposure of about three and a half years, because it took them about a year to enroll the study and so I think the requirement is that the is that every patient has at least three years of exposure.
Sure.
Got it okay. Thanks for taking my questions.
Sure.
The next question comes from Annabel <unk> Stifel on about please go ahead.
Oh, sorry, sorry, I was on mute, but thank you for taking my question.
So as it relates to the paradox on Sierra.
I guess I noticed that a number of.
The issues that FDA brought in ways to resolve them were specifically related to all parts.
Syndrome.
So I'm just wondering do you think that could answer a number of these questions and separately in any of the other studies that you're conducting specifically, Brian do you think that any of these studies can address the specific requirements that they are requesting and alto <unk> syndrome patients.
The second question I have.
With the ADP <unk> trial, I guess now that you've taken away.
<unk> 48.
<unk> Egfr review can you just maybe.
Remind us what the English one test at the interim look was then was that.
Potentially get accelerated review.
Or was there something else that you were trying to accomplish and now that it's not there.
What are you taking.
Taking away with the lack of that review at the 48 week time point.
Thank you.
Sure, Yes years ago back in 2016.
When the FDA proposed design for the Cardinal study.
They they suggested that we have the one year off treatment.
It could potentially support accelerated approval based on the data.
And then the idea was to continue the study on a blinded basis.
The investigators patients and people involved in the conduct to collect the second year of data, which would support full it which would support full approval.
We were the first company I think too.
To conduct that design.
And when we completed the year one data by the time, we could assemble that data make our regulatory submissions for meeting request and have a meeting we were well in to the second year of the study and it became clear that.
We were going to have the second year data during the review.
And it's my belief that that impacted their willingness to take the year. One data we were so close to having the ear to data. So in the pre NDA meeting that we had we agree to just submit with the year to data.
After that interaction.
With respect to that is essentially the same issue for the Falcon study.
And so I forget the exact interaction, but we submitted the description of the timing.
To the division and basically said, we're going to have the same issue for PK PD and they said, yes, we are not likely to take or won't take the year one data.
And so that led to our conclusion to just eliminate the off treatment during the year one.
Okay got it and with respect with regards to various parties with respect to that.
With respect to the first question.
They had they didn't say specifically in the CRM. They specifically asked for another egfr or clinical endpoint study in <unk> syndrome, but in their briefing book in their conclusions. They stated that one deficiency of the application was that we did not have.
Positive data in another form of CK D.
So I think that probably leaves open the discussion if we did have that we would obviously go back to the FDA and.
Requests to resubmit the output syndrome, NDA with a supplement of data and I think particularly if a llama.
What's was unequivocally positive we would want to have that discussion with them.
Okay.
If I could just drill down on that I think they did ask specifically for some quality of life.
Measurements for our parts specifically so do you think you can pull any of that from Maryland or is there anything else that you can pull that would provide them with that data.
Yes, what's interesting about that is that.
We had a significant effect.
In the Pgi C.
Which is a measure.
Patient focused measure of the TGI seek Colin can you comment on that.
And the patient global impression of change is used in many different types of trials not just can you trials, where patients report all get there.
Doing better worse or unchanged and that was a pre specified.
Secondary endpoint in our trial actually.
Inefficient.
At year, two and so we believe those data are supportive and as Warren said, we'd want to take this data back with with other data to try to address their concerns.
I think the comment that they put in the CRM.
I think the comment that they put on an endpoint that captures how patients. It's just the the boiler plate description of a clinical endpoint.
It's regulatory.
Language.
So I think the implications of that was they would still agreeing to take an egfr based endpoint or a hard clinical endpoints.
Okay, great. Thank you so much and can you just remind us when we're going to see the Merlin data.
Yeah.
Alrighty.
We it's holiday Yeah, Hey, Annabel this is Matt it's already there in our 10-K filing which be.
700. This morning, it was already there and we had already submitted that data to the FDA Colin do you want to describe it.
Yeah.
Sure. The Merlin trial was enrolled approximately 80 patients randomized evenly two blocks Loma placebo across many of the etiologies are the most common type was diabetic patients.
Also enrolled patients with hypertension, TKD ADP JV for those who can qualify for Falcon and.
And others importantly, we use the same titration design that was used in the outboard Senegal, Cardinal as well as ongoing Falcon trial in ADP Katy.
From an efficacy perspective.
We showed a significant increase across all of those patients with the phenotype of patients who actually demonstrated or are at risk of rapid progression.
From a <unk>.
Additional data perspective, we included zero off treatment Egfr assessments.
Multiple time points and so after three 714, 21, 28, and 35 days and consistent with what we've seen in our other trials, we see resolution of the acute egfr effect within approximately 21 days and so the data suggests that <unk>.
Between 14, and 21, and so there's no longer a significant effect versus placebo at day 14, but theres still some slight numerical reduction by day 21 importantly that between difference between drug and placebo at day 21, $2035 is the same and so that.
To support our case that the drug does in fact.
Lucid acute effects on egfr within the timeframe that we have.
Hypothesized.
Okay, great. Thank you.
Yeah.
The next question comes from Brian <unk> at Bad Brian . Please go ahead.
Hey, good morning, Thanks for taking my questions a couple on the Merlin data.
I know that you gave that the day 14 off treatment to be $3, seven ml and characterize 21 28 and 35.
Unchanged she'd give the actual values for day, 21, 28, and <unk> 35 off treatment and then also in the 10-K when you say that the FDA didn't accept this data as a major amendment did they look at the data at all or are they just refuse given to accept that to begin with and then on Falcon just wondering on the.
The change in protocol for the off treatment period to be removed. Following your one study has been going on for about two and a half years. So I would imagine there's probably a couple of hundred patients who may have stopped treatment.
Four weeks for year, one how are they accounted for in the final statistical analysis for week, one Oh, hey, thanks.
I'll start off again I'll start with the last question, Paul and then I'll hand, it over to you to comment.
On Merlin and Falcon the.
Our proposed design for the statistical analysis plan would be to take patients that did not have a weak one away because they finished the study prior to the amendment and use their 104 in the analysis will.
We will be asking the FDA to two.
To comment on that and in the type a meeting request.
And the question there was a question about the Merlin values, Colin do you want to comment on those.
Yes, we see a slight separation.
Days 21, 28, and <unk> 35. This round of couple of milk per minute, which is consistent with what we've seen in all of our trials, but over three months in duration, where we start to see some persistent effect on kidney function consistent with disease modification and so a similar difference was seen in our.
Kyowa Kirin phase II <unk> trial.
And so from our perspective once again it shows that the acute effect is resolved and that there is the beginning of some disease modifying effect.
And then Brian as far as noted after you look at our information from Berlin and considered formation bent metal.
We're unsure if they.
Review that we provided as it was fairly late in the review.
And so they obviously did not.
<unk> as a major amendment and therefore, the structure additional proliferate and so those data from our perspective, I think will be helpful. In future discussions to discuss the sufficiency of the optima periods.
Alright, thank you.
The next question comes from Jared Shaw SVP Leerink J.
Please go ahead.
Hi, all this is will on for Joe. Thank you for taking our questions today.
So one for us since the first call that's been host since the AD com it'd be great to hear some of your thoughts on the points that the agency raised during that meeting and then in terms of what the FDA wanted to see it kind of sounded rather straightforward when the company laid out the company's interpretation of this.
During the AD comm it sounded much different so any additional thoughts here on the AD com and those discussions would be appreciated and then I have one quick follow up.
Yeah I really.
This is Warren I'll address that question.
I think that that the briefing book.
That the that we got immediately prior to Fda's briefing book really focused most of its discussion.
On their PK model.
On the time for resolution.
For the off treatment value.
And but there was actually very little discussion.
That issue at the AD com.
Aliza Thompson during the AD Comm introduced a question immediately after our presentation.
And before the general discussion.
Regarding the separation lack of separation in the off treatment values over time.
And so that was introduced basically at the AD com in the afternoon.
So it wasn't wasn't really addressed in their briefing document our briefing document.
And so I assume that was a concern of theirs that trajectory over time.
But honestly I think most of the discussion was about just the concern of the long term effects.
Now of the acute egfr improvements.
And that's why I said in the opening remarks, I think if the Nephrologists. We're convinced that it was going to delay dialysis I think we would've gotten a positive vote.
And that's why I believe that the Kailua Kieren study.
It has the potential to provide.
Very important information that could have a meaningful impact on the view of the BARDA excellent mechanism and clinical profile, among nephrologist and I think that would potentially affect the outcome.
Okay. Great. That's helpful. Thank you and then could you just briefly remind us that the regulatory status for Bard and E S and theyre in the European.
Markets.
It's that we're under review and we're in the active phase receiving questions and responding now.
Thank you.
Okay.
As a reminder, please press star followed by one to ask a question. If you change your mind you can press Star T D.
Please keep your questions to one question and one follow up.
The next question comes from Matt Kaplan Ladenburg. Please go ahead.
Hi, good morning, and thanks for taking my questions.
Just wanted to follow up in terms of the protocol Amendment for Falcon.
I guess first when do you think you'll have.
Ryan from the FDA in terms of the.
Protocol amendments that Youre recommending and then and then given the discussion at the AD com in terms of the off treatment period can you talk a little bit about the off treatment periods that you are going to be incorporating I guess that at week went away.
And in the context of.
How long that auction period should be.
And to address Fda's questions previously.
Sure I'll actually take these where we've requested a type a meeting. So recently, yes recently, so we're obviously, hoping there's a 30 day clock for those and so we're hoping to have meaningful feedback.
Within the within 30 days or so with respect to the off treatment period, we move the primary endpoint to week, one O eight which we believe is consistent with the PK PD analysis.
Of the division.
But that's obviously one of the questions like do they do they want it longer.
And we're also incorporating.
A 12 week point of collection.
If we need to if we need to extend that and so again, we think the 100 <unk> consistent with their PK PD analysis, but.
But we are specifically asking them.
Great and then I guess lastly, given the increase in sample size to $8 50.
When do you when do you anticipate a potential readout from from Falcon.
We're not really ready to provide any guidance on that until we get some feedback from the FDA.
Sounds good alright, thanks for taking the questions.
Sure.
Thank you I'm showing no further questions in the key again, thanks for your participation participation on today's conference call. As a reminder, in or do you have a recording of the call will be available. Shortly after the call on <unk> web site, and we ought to pharma dot com in the investors section.
Thank you very much for your participation you may now disconnect.
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Yes.
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