Q3 2019 Earnings Call

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I like to hand, the conference over to your speaker today, any gentle vice president of strategy.

Thank you.

Good morning, welcome to Reatta management's called to discuss the positive results from year, one of the pivotal Cardinal trials Murdoch's alone in patients with CKD caused by Alport syndrome.

Yesterday afternoon, we issued a press release with a summary of these results the press release as well as an 8-K filing with the slide deck being presented this morning can be found on the Investor section of our web site at Reatta pharma Dot com.

This morning, we reported financial results for the third quarter of 19.

The press release as well as our Form 10-Q can also be found on the Investor section of our website had reatta pharma dot com.

Well, let me go remarks today, the Cardinal trial results, but we would be happy to take questions on any aspects of our business, including our third quarter financial results during the Q and a session of today's call.

I'm joined today by our CEO War and have our Chief Medical Officer, calling Meyer and Chief Financial Officer Manmeet Soni.

I'll now turn the call over to warrant.

Thanks Venting good morning, everyone and thank you for joining us.

Yesterday afternoon, we announced positive top line results from the pivotal Cardinal Phase three study a bar docs alone in patients with chronic kidney disease caused by Alport syndrome.

Cardinal was the largest global interventional study ever conducted and Alport syndrome patients.

Alport syndrome is a severe form of CKD and the patients enrolled in the phase three portion of Cardinal we're losing substantial amounts of kidney function when they entered the trial.

After one year in Cardinal patients on placebo lost on average over six milliliters per minute of estimated Gee, how far are clear merrell or filtration rate.

Said another way these patients were rapidly progressing to kidney failure in the need for dialysis or kidney transplant.

By contrast, or Doxil untreated patients experienced a statistically significant improvement in the kidneys estimated glomerular filtration rate or G. fr. While one active drug and their estimate a g. a far was statistically unchanged from baseline after withdrawal of drug.

In effect during the study paradox, one treatment substantially slowed or halted the loss of kidney function that leads to the need for dialysis or kidney transplant in patients with this severe form of CKD and without other treatment options.

On behalf of every one of Reatta I'd like to extend our sincere gratitude to the patients families and caregivers who live with this disease into the Alport syndrome Foundation. The results, we announced yesterday would not have been possible without their efforts and commitment to this program.

[noise] for those of you unfamiliar with Alport syndrome is a hereditary and severe form of chronic kidney disease caused by mutations in jeans that encode for type for college and.

Type for college and comprises approximately 50% of the glomerular basement membrane or GBM. So the kidney the GPM acts as the barrier that separates the blood from the urinary filtrate.

College and mutations in the GBM lead the leakage of a whole blood cells protein and other material into the proximal tubule so the kidney.

This promotes chronic kidney inflammation and a decrease in cellular energy production at least to fibrosis and a progressive loss of kidney function.

Like most other forms of CKD patients with Alport syndrome, commonly take ace inhibitors, and angiotensin receptor blockers, but there are no approved therapies for Alport syndrome.

We believed that there are approximately 30 to 60000 patients with Alport syndrome in the United States at approximately 30 to 64000 patients in the E U five which represent the first commercial markets for products alone that we're targeting.

[noise] Alport syndrome is among the most severe forms of CKD all forms of chronic kidney disease are characterized by a progressive loss in the rate at which kidneys filter blood or G. fr Nephrologist track estimated she a far or EG fr to assess that.

Klein and kidney function and progression of patients kidney disease.

Normal individuals have an EG a far of approximately 120 milliliters per minute when each year far declines to approximately 15 milliliters per minute patience reach kidney failure and required dialysis or kidney transplant to survive.

In the most common forms of CKD caused by diabetes or hypertension patients lose approximately two milliliters per minute on average each year.

If patients are diagnosed after losing approximately one half of their kidney function, which is typical these patients are at risk of kidney failure in approximately 20 to 25 years on average.

By contrast patients in the placebo group or the phase three Cardinal study lost on average approximately six milliliters per minute over one year.

This is three times the rate of loss of more common forms of CKD and at this rate of lost a patient with a baseline each year for 60 would reach kidney failure within approximately seven years.

Patients with the most severe forms of Alport syndrome progressed to the need for dialysis or kidney transplant on average in their mid Twentys.

We thought it would be helpful to provide some additional background on the design and endpoints of studies in chronic kidney disease.

The only drugs approved for common forms of CKD or blood pressure medications, primarily ace inhibitors in angiotensin receptor blockers and SGL T. Two inhibitors.

These are widely used because they slow the rate of EG, a far decline in patients with CKD.

Importantly, these drugs do not stopped the decline in each year for and they certainly did not increase EG fr overtime.

In their Registrational studies, each year far overtime declined in both the active drug and placebo arms of their trials you can see two examples of these studies on the right in there were no trial that angiotensin receptor blocker called loves certain modestly slowed the rate of each year far to climb.

It's difficult to see the difference in the drug versus placebo group on the graph because the treatment effect is so small.

In the credence trial, an S. GLP two inhibitor slowed but did not stop EG a far decline in the treatment group when compared to baseline both the active drug and placebo groups are below baseline and had a negative change in EG fr versus baseline.

These drugs are effective and widely used because they're therapeutic benefit is slowing EG are far decline in comparison to the placebo group.

This translates into a delay in the need for dialysis or a transplant, even though they do not stop the decline of each year for.

[noise] towards Apt and was approved last year in the United States for the treatment of autosomal dominant policies to kidney disease and it is the only approved therapy to slow progression of kidney disease for a rare form of CKD.

Blood pressure medications and SGL T. Two inhibitors told that happened only slows and does not stop the decline in EG a far.

It was approved because it produced a benefit estimated g. a far versus placebo after treatment for one or and then withdrawal of truck.

This is called the off treatment for retained EG fr and is the same registrational endpoint is our key secondary endpoint and Cardinal.

In the told that and Registrational study called reprise.

The change from baseline and retained each year far for both the toll that often and placebo groups was negative as you can see in the graph on the right.

The retain DGF far or the told that Didnt group declined from baseline by 2.34 milliliters per minute over a year.

In the retained each year far the placebo group declined from baseline by 3.61 milliliters per minute over a year. So.

So adapt and was approved based on the 1.27 milliliter per minute improvement in estimated share far compared to placebo, even though both groups were declining from baseline.

The FDA has provided us with written guidance that in patients with CKD caused by Alport syndrome, an analysis of off treatment each year for demonstrating an improvement versus placebo. After one year of treatment may support accelerated approval in an approach.

Movement versus placebo after two years of treatment may support full approval.

This is consistent with their recent approval of told the hapten on the basis of the placebo corrected improvement and retain DGF far. They also provided us with similar guidance during our into phase two interactions in 80, PKD and retained EG fr versus placebo is the registrational endpoint of our Falcon study.

We are aware that they've provided this guidance to other sponsors developing drugs for rare forms of CKD.

Following the FDA guidance the primary endpoint for the phase three Cardinal study is the change in estimated year far from baseline and compared to placebo. After 48 weeks of treatment in the key secondary endpoint is the change in estimated jia far from baseline and compared to placebo after 40.

Weeks of treatment and four weeks of drug withdrawal.

Obviously, the efficacy analyses compare the bar docs loan treated patients to the placebo treated patients. Because this is the best way to determine efficacy of the intervention versus standard of care.

Measuring estimated g. a far after withdrawal of active drug isolates the effect of the drug on the underlying structure of the kidney if the effect of the drug were harmful due to any mechanism known or unknown after one year or treatment and a four week withdrawal kidney function would be worsened relative to placebo.

Though.

However, an improvement in retained each year far versus placebo is strong evidence that the drug is beneficial has the potential to modify the course of the disease and may delay or prevent the need for dialysis or kidney transplant.

With that background I'll hand, the call over to call it to discuss the Cardinal trial results.

Thanks Warren.

The phase three portion of Cardinal is an ongoing randomized double blind placebo controlled international study that enrolled 157 patients at approximately 50 sites in the United States, Europe , Japan, and Australia. The study enrolled patients across a wide range of age kidney function.

Genetic sub types that we believe represents the broad population of patients with Alport syndrome.

Patients were allowed to be on standard of care Ace inhibitors were angiotensin receptor blockers unless these were not indicated or medically contra indicated.

Study subjects were randomized one to one to either box phone or placebo and the total treatment duration is two years patients are initially treated for 48 weeks and then withdrawn from study drug for four weeks. After this withdrawal period patients are restarted on their original treatment assignment and continue on study drug for another four years.

Thanks.

At 100 patients withdrawn from study drug the second time in the last assessment occurs at week 104 after another froch withdraw period.

As warrant explained the primary endpoint for this study is the change in Egypt far from baseline and compared to placebo. After four weeks of treatment and the key secondary endpoint is the change in Egypt far from baseline and compared to placebo. After 48 weeks of treatment and four weeks of drug withdraw.

Both analyses our intention to treat for ITC include data from all patients. The week 40 analysis uses all available values, including those from discontinued patients and the method of analysis is MRM with no imputation for missing data.

The method of analysis for the week 52 endpoint employees and Copa methodology that was used in the Reprised trial of 12, Apt and 80 PKD.

The week 52 off treatment analysis includes all available data for patients who completed 48 weeks of treatment followed by the forward with raw period, if patients discontinued prior two week 48, there are four week off treatment value. Prior two week 52 is used and the KOVA model uses a time based covariance. So these.

Data can be included in this analysis multiple imputation is used for missing data.

Since the study is ongoing we're releasing the one year results Andre data access plan submitted to the FDIC and designed to preserve the integrity of the second your the study. Therefore, we cannot disclose data today that would unblind individual patients to the treatment assignment, we plan to present more in depth data at a medical conference.

Following the conclusion of the study.

Patients in the phase three portion of Cardinal representative of the broader Alport syndrome population patients were on average and their late thirties, and 15% where pediatric the mean baseline Egypt par at study entry was 63 more committed and there was good distribution of patients across the eligible.

Range of 30 to $90 per minute.

Patients have low potent area on average measured as a urinary up undergrounding ratio or a CR and just under half had HCR above the macro and marry a range of 300 milligrams per gram.

Blood pressure was under excellent control and approximately 80% of patients were on standard of care Ace inhibitors or angiotensin receptor blockers importantly, since a high percentage of patients receiving standard of care east inhibitors, or a RBS and patients had generally low proteinuria and well control blood pressure we believe.

These data demonstrate the patients receiving exceptional care by they're treating physicians and optimize on all available therapies upon study entry.

Kartell successfully met its primary endpoint of improvement in each CFR after 48 weeks of treatment compared to placebo.

Patients treated with paradox loan demonstrated a statistically significant placebo corrected 9.5 movement improvement and mean, Egypt far compared to placebo. After four weeks a treatment with a P value of less than 0.0001.

Patients treated with box on had a statistically significant mean improvement in fr of 4.7 Gulf minute from baseline well patients treated with Mark with placebo had a statistically significant mean worsening in each CFR of 4.8 minutes from baseline.

We believe these on treatment results demonstrate a very clinically meaningful treatment effect and a patient population that is rapidly progressing for patients on paradox loan. These studies indicate that despite their severe disease. These patients experienced a significant improvement in the kidney function wall on active drug in effect drawing this.

I'd badakhshan treatment substantially slowed or halted the loss of kidney function that leads to the need for dialysis or kidney transplant and patients with the severe form of CKD and without other treatment options.

Part oxygen also met its key secondary endpoint of off treatment change in each you fr compared to placebo.

In the off treatment analysis patients treated with murdoch's loan demonstrated a statistically significant placebo corrected 5.1 mill permanent improvement in mean retained EG afar compared to placebo with a P value of 0.0012.

Patients treated with the placebo experienced a statistically significant worsening and mean retained Egypt bar of 6.1 don't permanent from baseline with a P value of less than 0.0001.

Patients tree with Barack Sloane were unchanged from baseline with a slight nonsignificant reduction and retained HFR 0.96 month minute with a P value of 0.4 or five.

Regarding subgroup analyses are the off treatment endpoint murdoch's ones effect on kidney function was observed across multiple including among males females pediatric patients baseline STR categories and genetic sub types.

These results suggest that disease progression for patients on paradox loan was essentially halted during the study even when measured after four weeks of drug withdraw notably this treatment effect is four times larger than the treatment effects observed with top apt and the Reprised trial, which supported approval of top apt and.

In 80 PKD. Despite the small difference observed in the trial and the told that in group, losing 2.3 more permanent from baseline.

The absolute change from baseline for the bar Docs phone group was lower than observed in the phase two portion of the trial. This is likely due to rapidly progressive and severe disease. In this patient population. This is highlighted by the large loss of 6.1 no per minute in the placebo group, which puts them at risk in stage can you disease.

Within a few to several years.

Also the relative difference between the on and off treatment EG, if our values per box on treated patients observed in the study was similar to that observed in other parts Roxland CKD studies.

In the phase three portion of Cardinal the relative difference between the week 48 on treatment values and the week 52 off treatment values was approximately six mill permit.

In the phase two portion of the trial. The relative difference was also approximately six mile per minute into Beacon trial. The relative difference was approximately five more permanent into beam trial. The relative difference was approximately seven no permanent.

In terms of the meaningful mr. patients. These data demonstrate that after one year of treatment bird oxen was able to on average improved kidney function or patients were receiving drug and after wash out there kidney function was not significantly different from baseline. These patients on average did not progress over the.

Core severe despite the large loss observed in a placebo group. These data indicate that paradox phone is positively affecting the course of the patients disease. If they are not progressively losing kidney function. They may never need dialysis.

The mean EG, if our values with associated P values are informative, but to better understand the distribution of change we performed a core call analysis for the week 48, and 52 time points when changes in kidney function or assessed by core tile several key conclusions can be made.

In every core tile that week 48 week 52, Murdoch's untreated patients kidney function was improved relative to the matching placebo cortile. Additionally at week 48, while patients were receiving study drug approximately 75% to patients receiving paradox loan did not experience disease progression will approach.

Finally, 75 patients receiving placebo lost kidney function.

At week 50 to the second best performing placebo core tile had an average weighted progression that is comparable to the average rate progression in other notable forms of CKD, including diabetic hypertensive in 80, PKD the bottom to placebo court house or half a placebo patients progress at.

Rate of approximately 12 no per minute in one year, which is very rapid and result in the need for dialysis or kidney transplant in just a few years.

In patients in the worst performing portal with the most rapidly progressive disease, even though put Oxford did not increase kidney function. It meaningfully slowed their loss of kidney function. This is evidenced that murdoch phone may provide a benefit even in patients who do not have an absolute increase in EG fr in patients with.

Less rapidly progressive disease that is comparable to other forms of CKD Murdoch's, where not only appears to halt progression on average, but some patients were able to recover kidney function.

We also conducted a correlation analysis to determine the relationship between the acute changes in June and EG fr. After six weeks of treatment and the longer term changes and on and off treatment fr. After one year of treatment in the paradox loan group the acute change in Egypt for correlated positively.

Okay and significantly with the change in each year far at week 48 on treatment and at week 52. After the four week withdraw.

These data demonstrate that the early increase in Egypt far is a positive predictor of each if our change after one year of treatment on and off drug. If the early increases were adverse to hyper filtration or any other deleterious mechanism. They would negatively correlate with change at one year well be associate.

With significant loss of kidney function in Egypt, our values that were worse than placebo.

Regarding safety Murdoch's loan was generally reported to be well tolerated with the safety profile similar to what we observed in the phase two portion of the trial nine patients in the part Oxon group and four and the placebo group discontinued due to an adverse event and no single adverse event contributed.

To more than two discontinuations in either.

Fewer serious adverse events reported in the box one arm with 13% of patients on placebo reporting serious adverse events versus 5% Murdoch Sloane no deaths were reported in either arm.

Importantly, no fluid overload or major adverse cardiac events, including EMI stroke heart failure Revascularization reported in patients treated with box loan blood pressure. It was decreased relative to baseline and the Murdoch sungroup, but was not significantly different between the two.

Groups, there was an overall low rate of cardiac and vascular adverse events that was numerically lower in the third OCC Sloan arm. The most common adverse events were muscle spasms and increases in immuno transfer races, which are common finding guns and studies over enough to activators and an expected effect of enough to.

Activation as evidence that the increases in immuno Transposes Ari pharmacological effect acute changes in April T. Impart OCC Sloan treated patients positively and significantly correlated with acute changes in EG afar.

Lastly, albumin area in the Badakhshan arm was increased at week 48, compared to baseline, but was unchanged when adjusted for each year far.

And HCR was unchanged off treatment, a week 52 compared to baseline and relative to placebo.

These data demonstrate that the on treatment increase and urinary protein excretion is due to the increase in EG are far and the week 52 data demonstrate that this effect is not associated with injury.

Notably over the course the trial the data monitoring committee met quarterly reviewing all data on an unblinded basis and did not note any safety concerns with that I'll turn the presentation back over to warn.

In summary, Cardinal met its primary endpoint with a highly significant P value. It also met its precedented Registrational key secondary endpoint with a highly significant P value.

Excuse me.

Importantly, during the study part oxygen treatment effectively halted the decline in estimated she fr in patients with rapidly progressing disease, approximately 75% of our docs loan treated patients had an improvement in there on treatment EG fr, while approximately 75% a placebo treated patients had worsening each year.

More importantly, our doxil in treatment showed a potential benefit even in patients who were progressing most rapidly towards kidney failure.

Badakhshan was reported to be well tolerated with numerically fewer reported as a ease on paradox loan versus placebo.

We believe that the results from Cardinal provide significant evidence that burden excellent produces a clinically meaningful benefit to patients with Alport syndrome, and we believe that has the potential to become the first FDA approved therapy for this disease.

We plan to work closely with the Alport syndrome Foundation, and the National Kidney Foundation to communicate with the patient community and we're planning to meet with the FDA and other regulatory agency soon to discuss the appropriate next regulatory steps.

In parallel we will accelerate the launch preparations that began over a year ago and we now plan to extend these activities to include the territories outside of the United States that we recently reacquired.

Operator, I'd now like to open the call two questions.

Thanks.

Ladies and gentlemen, if you have a question at this time. Please press the star followed by the number one key on your Touchtone telephone. If your question has been answered.

So from the Q Please press the pound.

Once again to ask a question. Please press star and then one now.

And our first question comes from.

Some of it from Citigroup Your line is open.

Hi, guys. Thank you very much for taking my questions and congrats on another positive basically read out.

My question was related to the.

Trends seen in the trial column, you mentioned at the acute changes in Egypt correlated positively with the change in Egypt five weeks 40 842 on the however, we haven't seen the time profiles for for each year far so given that could you provide any additional color on the evolution of the treatment effect for barred from weeks zero 48, four coming off drug.

What was the time to peak effect and how did this compared to the week 48 benefit of 4.7 unit.

Yes, you call. So the easier for change overtime was not fully disclose because it could be unblinding.

Patients on box on had a.

Increasing each you have far that manifested early somewhat what we've seen and other trials.

In it persisted.

The increase at week 48 with substantial the data reported here in the presentation are the ITC analysis that includes patients who discontinued or on low doses of drug when patients who were on their goal dose were included in patients who were discontinued were excluded the treatment effect was even higher.

Total slope from baseline through inquiry is positive clearly divergent here from the placebo patients when it's obviously, a very meaningful treatment effect, considering the placebo patients lost six more permanent in one year I just I just at one thing. This is in part why we provided the Cortile analysis, because you can compare the change.

On drug to their matching placebo is across the complete range of response and that data clearly shows on and off treatment.

That the drug treatment improve the effect versus placebos, even in the worst performing patients.

Okay. Great. Thank you may have touched on this column, but could you just comment in a little bit more detail with respect to the differences and any differences in treatment effect for bard dependent on whether the patients around the 20 versus the 30 milligram dose based on their health status.

Yes, so I think this two separate questions dose and up Im curious status and so.

We havent disclosed the treatment effect by by dose, but in general patients who on the higher doses of drug or how do you have archer treatment effect.

In regards to the albumin or any status now we saw similar efficacy.

When you compare drug versus placebo in patients with low versus high up marry up baseline and as I mentioned, we also see similar efficacy and adults as well as kids and that somewhat of a surprising finding because it is well established that pediatric patients are at high risk are progressing.

At a very young age adults progress later, but within our trial the rate of progression was actually similar it was also similar between males and females in the treatment effect with similar versus placebo in these subgroups and so I think that's one reason why the placebo patients did so poorly it's under appreciated in the literature and among.

Nephrology community at how for one rapidly progressive Alport syndrome as in our data today are the most robust data ever collected in this patient population.

Thank you very much.

Thank you. Our next question comes from Maury Raycroft from Jefferies. Your line is open.

Hey, everyone. Good morning, and congrats on the update updated data today.

Thanks for taking my question so.

You see similarities between datasets comparing retain benefit versus baseline base you beam in phase two Cardinal and then also in the placebo corrected data in phase three beacon in phase three Cardinal RBC differences in the final fr benefit number.

In the baseline comparison versus the placebo corrected comparison, and so I'm just wondering how to how you guys explain that.

If you can add more perspective there.

Yes. So that's that's actually the first statement isn't exactly correct and so we do see a similar relative change between the on treatment and off treatment effect across all of our trials that we've conducted on so in the phase two patients within Cardinal recall that the increase at week four.

Create was approximately 10 not for a minute and the change post withdrawal was approximately 4 million minute or a six more permanent difference.

And so we saw that difference here in the phase three.

Portion of Cardinal.

The on treatment was about five and the off people was minus one and so it's a six point Delta and if you look at the core call analysis, I think it's instructive because the second core tile.

In the box on patients mirrors, what we observed in phase II. So you can see that the on average products untreated patients in the second quartile weak 48 were up nine which is pretty close to the 10, we saw in phase two but those patients were up 2.5 post withdraw which is pretty close to the for and so we see this really.

Nation ship across the courthouse here, we saw once again in the phase two Cardinal trial, we also saw and beaman beacon the most important.

Aspect is the rate of progression and placebos that determines the absolute change on and off drug, but the relative change in scepter similar and once again, what regulators care about and treating physicians is the rate of progression either in placebos or natural history and these patients in our.

Phase three cohort and placebo had significant rapidly progressive loss of kidney function. We have powered the trial to show about a two and a half muffin that difference than we saw double about a five more permanent difference, which as we stated before is four times the magnitude scene in the reprise trial a pullback in the.

Supported approval so from our perspective. These data are all internally consistent and when you look the broader context of preclinical data.

It also is consistent it's just that in this trial the placebo patients did very poorly sort drugged down the absolute changes.

Got it kind of that's very helpful and the second question is just based on the decline in Gfsr, you're seeing in the placebo group and the fact that you've got 15%. The population in study includes pediatric patients do you think FDIC might ask to change the second year. The study to encourage a crossover to drug earlier.

It is notable that we had a significant number of kids in this trial and.

Kids on placebo did poorly adults simple seem to poorly.

Ft. A have had previously requested that the speak to your trial and so we'll obviously have to have discussions with regulators to determine if there would be any change to the design.

Got it thank you and congrats again.

Thanks.

Thank you.

Next question comes from Joseph Schwartz from Leerink.

Your line is open.

Great. Thanks, very much and congrats again.

We heard from physicians, who have experience using paradox alone at San that patient steel better when they're taking the drug.

So could you talk about what quality of life measurements, you're performing in the study how interested are regulators.

That sort of data.

We collected one quality of life instrument and the trial in today, we do not disclose the data and what we previously stated in what you heard us that patients often report that they're feeling better and doing better.

In kidney trials, the precedented endpoint.

No change in Egypt, far specifically for where forms of could kidney disease. It's the retained benefit versus placebo and so we were given this design by FDA, specifically requested the off treatment analysis to support approval and the comparisons we may be made to placebo and so we think that they will consider those data.

Most important and relevant in the decision is whether or not to approve an excellent.

Okay that makes sense.

Then can you describe the shape of the albumin area curve for patients on paradox alone and how closely does what you saw in phase three mirror, what you saw on phase two and where did the average level of proteinuria end up relative to baseline.

Yes, so its qualitatively similar to what we've seen in the phase two portion of Cardinal and and other trials in patients who have preexisting.

Proteinuria, what's going to patients already have damage to their filtration barrier and so if you can just visualize it. So if it has holes that conns leak out protein. If you increase filtration through any mechanism proteinuria will go up and so we did see that as I mentioned.

And it was stable after the initial increase and importantly, when you correct for GE Fr. There was no increase versus placebo that's important because it indicates that the increase was due to the change in Jia far and that there wasn't some additional increase that could suggest damage.

And that was further.

Further exemplified by the week 52 off treatment data and so without even correcting for each year far the change from baseline in bought often treated patients that week 52 with no different from the change from baseline in the placebo patients. We actually just published a paper and can international I think it came online a few weeks.

Joe Kennedy International is one of the most prestigious and rigorous can you journals. The acceptance rate is about 6%. These days.

In the paper that we published includes many notable global care wells that highlights this methodology and demonstrates a similar effect to what we observed in our Beacon trial I think the last thing I'd like to mention is that mechanistically.

Weve hypothesize for some time and there's been some confusion in the nephrology community about the mechanism of action for the acute increase in CFR.

We believe that we've done the definitive preclinical experiments to demonstrate that the mechanism is associated with an increase in surface area and surface area is often constricted.

Many forms of chronic kidney disease.

Also able to rule out hybrid filtration hybrid filtration within the kidney can only be caused by two factors. One is increased blood pressure, that's transmitted to the kidney and in those preclinical experiments increased blood pressure. It was not observed just like in our Cardinal phase three trial increase in blood pressure was not up.

Sure.

The only way to increase blood pressure locally within the kidney is two relatively phase so dilate the blood vessel going into the filtration apparatus and that did not occur the blood vessel going in and out were directly measured and there was no evidence of hyper filtration and so that effectively rules out hyper full trade.

As a mechanism and there should no longer be any questions.

In those experiments the investigator also measured permeability to albumin determine if barack Sloane could somehow increased permeability, which potentially would suggest injury to the kidney and normal animals. There was no increase in sieving of albumin in response to depart from analog.

In animals that had diabetes that did have increased permeability at baseline.

The analog also did not increase permeability and so there's no evidence that this increase is due a cheerios and its expected based upon the fact these patients already had equal meritless and once again the off treatment data showing that proteinuria returns towards baseline and it's no different than placebo is.

Evidence that it's not harmful, but truthfully regulators care and much more about the off treatment retain EG fr because that is the ultimate evidence.

Any drug is harmful or hurtful, yes. This if murdoch's loan was harmful after one year of treatment UGI apart in the bird often treated patients will be worse than placebo or be worse than the six more permanent of last seen in placebo group, but as we mentioned it was no different statistically.

Then baseline and was separated by five no per minute and so that's the best evidence that the drug is beneficial to the kidney.

Very helpful. Congrats again.

Thank you.

Thank you. Our next question comes from Adam Walsh from Stifel. Your line is open.

Hi, guys, let me add my congratulations and good morning to you.

Just a couple of questions here on the albumin urea adjusting for each of our Im curious if you discussed that would that be a are they do they have a similar understanding of the way you you look at albumin area.

In your discussions with them that's number one and then number two on the safety side.

Colin I know you said that we might not get individual patient level data today, but it.

Is it possible you can talk about the CE that were seen in Bart and also there.

Now these are really small numbers, but they're slightly more bard patients within a he led the permanent treatment discontinuation. If you could comment there's while that'd be great. Thank you.

Sure and so I think first thing is with regulators and specifically FDA.

Album, and area has not come up they actually do not care about changes in albumin area.

They care about changes in estimated CFR in our interactions with them face to face and written.

Comments to us they wanted to see change in EG fr because once again proteinuria can be pharmacodynamically changed independent of effects on the kidney.

And there are a few extremely large cardiovascular trials that showed that proteinuria goes and the opposite direction of kidney function and these trials were much larger than the nephrology trials that weren't mention and so in the on target trial. There was conducted several years ago.

Dual dual Ras blockade.

Reduced proteinuria versus the single intervention, but each year far in clinical outcomes were actually worsened and so yes, yes, kt events and that was a 25000 patient trial in the accomplished trial in Ace inhibitor plus.

Plus mode opinion.

Actually worsened proteinuria then the other group.

But kidney function and renal events were actually improved and so there is actually plenty of conflicting evidence in the literature.

Proteinuria does not necessarily translate directly to improvements in kidney function and that's why in this setting of agents that may reduce proteinuria within nephrology. After the requires for full approval that they show in Egypt far benefit because.

I see our may or may not reflect actual improvements in kidney function and once again, that's why FDIC and we did not have discussions about album and area and the focus was on actual kidney function. The in the again to retain DGF our endpoint is definitive.

In terms of whether the intervention will either harm.

Or protect the kidney.

In regards to safety.

Right.

And that's why they ticket for approval.

Got in regards to the serious adverse events.

Once again at 10 on placebo for on box, so meaningfully lower in the Murdoch's loan group.

And they were sporadic ins of one so we cannot disclose it.

There was nothing concerning to the data monitoring committee as I stated and importantly, no deaths no fluid overload events no CHF events, Noah Myers no stroke. So no evidence of any adverse cardiovascular effects in the bird oxygen group and even less severe adverse events. So.

On assay, both cardiac and vascular reduced in the bird Doxil, Andrew and once again no no no change in blood pressure.

As far as adverse events.

No. We commented on that on the most common we can't disclose the specific distribution because it may on line, but it's similar to what we saw in phase two cardinal.

And those that contributed to discontinuation were few the difference with only five and as I mentioned.

Individual adverse events accounted for no more than two discontinuations and so for instance, despite the muscle spasms that I've mentioned.

A maximum of two patients discontinued from that the Tolerability.

That that we've reported we believe is quite good nitration design that we have is able to effectively.

So with any individual patient who may have a tolerability issue.

Great. Thanks, so much.

You're welcome.

Thank you and our next question comes from Brian Skorney from Baird. Your line is open.

Hi, Thank you for taking your questions. This is Jack down dialing in for Brian .

Just two quick questions from us.

First I was hoping you could dive a little bit more deeply into the two different statistical plans that were used to 48 and 52 week analyses and.

Provide some additional color as to how many patients specifically were evaluated at each pit.

Time point and then my second question just real quickly.

With respect to presenting the results are we ready to read out the full results of the two year trial or would you present, one your results and medical conference prior to completing the study.

Thank you.

Sure. So I'll start with your second question and we will wait to present the full results until the trial has completed.

Much of the data that we would like to present at a medical conference would unblind here for instance, the.

As a serious adverse events would be necessary to disclose but the ins of one generally and that would unblind individual patients and investigators.

We had to submit a data access plan to F.D.A. to detail, how we would maintain the integrity the second or the trial.

While it's ongoing and because of that.

We'll have to wait to disclose the detailed data until future medical meeting as far as your first question and so yes, we had two different.

Methods of analysis.

Method of analysis for for the weak 48 on treatment is im RM.

That uses all patients and so it's an end of 157, which is all patients randomized.

When patients have missing values. The model is able to appropriately handle it in model. The population. There is no imputation from missing data. So what that means is no individual value. No is basically added into the model such as last observation carry forward or any other methodology.

And before the week 52 off treatment analysis. It also included a 157 patients obviously, that's the most important analysis. That's the analysis that FDA will used to determine if they believed the drug is efficacious. We use the same methodology that was used in the Sucre.

Trial with 12, apt and so to reprise trial.

Statistical analysis plan is publicly available.

And we used almost identical methodology.

One of the reasons, why we decided to use that methodology and change from when we started is because that is the methodology that FDA did accept and we were unaware that methodology and when we initially met with after FDA back in 2016 benefit to that methodology is it allows every single patient.

To be included and so for patients who completed the 48 week treatment period and had an off treatment value. Those patients were included for patients who were discontinued.

And had an off treatment value before that we could do to period. Those values were also included in the analysis and as I mentioned, there was a time based covariance to appropriately adjust and then for patients who discontinued early.

It had no argument value those patients had multiple amputation.

Effectively added value and so it's a full 157 patients. So there's there's no missing data.

Incomplete data I should say.

Awesome. Thank you so much sorry, I just have one more quick follow up.

With regard to the baseline fr.

Are you seeing that patients with higher baseline HFR progressing more rapidly or less rapidly as compared to patients with lower base signage. If our we'd seen some interesting literature that might suggest higher EG five patients with alport syndrome might actually progress more rapidly.

But I was wondering if you guys could provide any comment on that thank you again for the questions and congrats on the results.

Thanks, So, yes, and so patients with higher Jia, Fars can't progress more rapidly and I think thats highlighted by the pediatric patients and so their normal it's typically a little bit higher than adults and even though the their baseline HFR was slightly higher than the adults. They probably a lot lost more kidney function from.

Percentage basis than the adults and those patients progress the kids to earlier in life on so that May also contributed to the larger loss and the placebos than we initially expected, but overall, but we believe the losses due to the fact that patients across the spectrum.

Kids adult smells females.

Last kidney function at a rapid rate.

Awesome. Thank you so much.

Yeah.

Thanks.

Our next question comes from Charles Duncan from Cantor Fitzgerald. Your line is open.

Hi, Hi, guys Warren and team congrats to really interesting data.

And rigorous program. Thanks for taking my questions I had just a couple of.

Questions more operational because lots of good clinical questions, but with regard to regulatory stranded sheet could we assume that you'd be meeting with agency perhaps.

To enable the 98 by roughly.

And then with regard to international ran a final what kind of timeframe would you anticipate for that and is there any additional clinical work handy to enable them.

So our our plan you know with you know with with all of our lead programs, including our for you. It's a taxi program, where we also have positive data is to meet with regulators as soon as possible and so we do not comment on ongoing between interactions.

We will provide commentary on after our initial meetings and it would be our plan to expeditiously expeditiously meet with them.

Positive precede we're following the India as quickly as we can.

International perspective, obviously, we just we acquired the rights from Abbey.

For both of our drugs and so we're currently developing the strategy it was their responsibility.

To interact with regulators externally.

Or globally, we were allowed by Abbvie to conduct the trial and their territories and so we will also be planning to meet with those regulators and then K K C or Q acquiring company, our Japanese and Asian partner with box loan has already obviously had ongoing interactions with the PMTA and those will continue.

Okay, and then Cohen with regard to.

Other uses of our docs loan.

In terms of rare kidney diseases say 80 PKD.

You have any thoughts regarding you know, obviously effect size pretty impressive tier predictive value for sayeed falcon or or anything along those lines can you can you help us understand how to think through that.

Yes, and so we were extremely pleased by the Cardinal data in part because the patients were so rapidly progressive yet there was such a meaningful treatment effect and so this increases our confidence and falcon not only because that but because the sample size for Falcon and it was approximately two times the size of key.

Cardinal where we had an extremely low P value and the on treatment as well as the key secondary off treatment regulatory endpoint. Our view is that in the Falcon trial those patients likely wont have disease that is rapidly progressive as we saw.

And Cardinal and so once again I would refer to our core Kyle analyses based upon the approval of top Afton and based upon the reprise trial for patients not on pullback than they progress at a rate of about 3.4 mile per minute, it's about or 2.6, it's about 2.4 and patients onto of apt and and so our best estimate is that.

The rate of loss will be somewhere around three more permit off treatment in our Falcon trial.

And you can see end quarter, how that had approximately that loss the placebos.

There was five small for minutes, you know treatment differences cortile too.

So we would expect that these data would translate broadly and once again.

The main determinant of the absolute.

You can affect this way to progression, but we would expect a similar relative change across all of our trials.

Then if I could ask just one operational final follow up and that is regarding commercial strategy, maybe bring and need in our or Warren could you anticipate increased visibility on commercial strategy over the course of 2020 and can you provide any any color on.

How we might measure that over the course in next year's.

Sure.

So we believe like Bart presents an extremely exciting commercial opportunity and based on the data, which we have shown you. We believe this bought as approved by the glitters, but it will be the fullest approved treatment options for patients with all purposes.

Syndrome, and the United States, and then followed by.

Europe and along the lines.

And as we've said earlier right.

This is.

Up.

Great opportunity that in the U.S., we have approximately we estimate that on prevalence of 30 to 60000 patients in the us at approximately 32000 to 64000 in that you five which will be or the flows countries, where we plan to commercially launch.

So and also be hop.

Claims data on yes, which we believe approximately 11000 diagnose patients in the United States, which we believe is a decent opportunity and we have been very committed to succeeding commercially and understand the unique the unique aspects of this rare diseases. They had been engaging with the care wells for the last couple of years to understands this disease and.

The insights, which we have gained are very helpful for engagement and advocacy for education, and clearly eight the speed and accuracy of.

Most of the as you have seen.

Very often in the rare diseases and of label treatment option speed spot mission of multi disciplinary themes and centers of excellence and that's what we expect will happen over here, we have an exceptional medical sales team and cute and get a few based and muscle sizes that are focused on medical education and disease awareness.

North America and in Europe that already working to expand out MSL team and the coming weeks to increase the focus and penetration to tier one tier two beyond the kill switch.

Have a decent coverage and disease awareness campaigns have already been launched two design to educate physicians about alport syndrome.

Genetic testing program has been initiated to improve the accuracy and timely diagnosis into United States.

We also have a core commercial organization in place with the leadership team, which includes marketing commercial operations market access and sales capabilities, obviously sales reps and the other stop would be higher based on you know, but do funded at the timelines, but we are.

We're already working on the patient hub centered model, which is under development to support the label utilization and ease of access to make sure. We can manage the compliance and adherence over there.

We have preliminary computed on a few for sizing and structure does compete for sales and existing so we feel very comfortable with our commercial readiness based on the state right now get done anything glad I'm just going to say I think we're very comfortable with where we are but based on the results will obviously be.

Accelerating act our activities really across the board.

That's helpful added color congrats on the results and can be a busy year free.

Thanks, Thanks, Sir.

And again, ladies and gentlemen ask a question. Please press Star then one now.

And our next question comes from that Kaplan from Ladenburg Thalmann. Your line is open.

Hey, guys. Good morning, and congrats on the results just wanted if you can give us.

A sense in terms of with related safety.

The.

Titration and the I guess, the average dose patients were able to.

Achieved in the study and and I guess reasons, why they weren't able to perhaps why patients weren't able to Joe's titrate higher.

Sure. So we haven't commented specifically on the numbers that are given dose, but most patients were able to reduce reach their goal dose what weve typically seen in a prior trials is approximately two thirds of patients can reach the goal dose occasionally patient can't because of.

Real or perceived tolerability issues in muscle spasms is a good example.

That was one of the most commonly reported adverse events in the phase three cohort.

But as I mentioned earlier no more than you know.

Two patients discontinued for any single adverse event, so clearly those to not preclude continuation on murdoch's loan.

And I guess once patients achieved the gold is.

You typically see any.

It was down titration or was that allowed study.

Typically what we see is that if there any tolerability issues they occur within the first six to 12 weeks.

And so in our.

Moxy call about.

A month ago, we highlighted that adverse events that were more frequent and the OMAP treated patients.

Particularly more common the first 12 weeks, but those imbalances typically went away for a much smaller after that and so it's similar.

For OXXO, we have not done that analysis, yet button or prior trials, we see similar pattern and so any adjustment that's needed occurs when the patients are coming in clinic frequently and typically once they get to approximately 12, there at a good steady state.

At whatever dose thereon.

Great. Thanks Collyn.

Yes.

Our next question comes from Brian Skorney from Baird. Your line is open.

Hi, So this is Jack again on for Brian .

Just one more quick follow up.

No you.

Not going to disclose the specific Egypt far benefits earlier in the trial, but you mentioned they might be.

Similar to magnitude to what we've seen in the phase two.

Could you provide any color as to whether a double digit benefits or who is out of a smaller closer to beacon type benefit 12 weeks.

In that regard thank you so much.

Yeah, we're not going to comment specifically on what the change was overtime, except to say that there was a very meaningful increase.

That once again on treatment no was meaningfully above baseline it with a positive slope versus baseline on treatment.

Awesome. Thank you again for taking my question.

Thank you and that does conclude the question and answer session for today's conference I'd now like to turn the conference back over to warrant for any closing remarks.

Thank you.

In closing I'd like to briefly review the developments that re out over the last few weeks on October the 10th we announced that we reacquired certain development and commercialization rights to develop paradox alone OMA Avelox alone and our other internet to activator programs. This provides us with the opportunity to control the development of the launch of our products in Europe .

At around the world with our partner Cai We're Karen.

On October the 11th we announced the presentation of several important studies it ASEAN.

Including the work from the lab of dust, Dr., Kashiwahara, which we mentioned earlier, which demonstrated the precise mechanism of Jeff our improvements elucidated elicited by activation of in RF too.

Of course on October the 14th we announced positive data from the Moxy study of old math and patients with friedrichs attacks here Moxy was the largest global interventional study ever conducted an essay and was the first to demonstrate a statistically significant improvement in neurologic function in patients with ebay we believed.

Oh man has the potential to become the first FDA approved therapy for friedrichs attacks here and of course yesterday, we announced a positive data from the Cardinal study of BARDA in patients with Alport syndrome.

These develops position us to achieve our long standing goal of becoming a fully integrated global pharmaceutical company marketing drugs with novel Biology, and the potential for high clinical impact on severe diseases with no approved therapies.

We're working to build a franchise in treating severe forms of chronic kidney disease. In addition to Alport syndrome, we generated positive proof of concept data for murdoch's alone in for other rare forms of CKD.

The improvement in kidney function observed at 12 weeks in patients with autosomal dominant Paul assisted kidney disease in our Phoenix trial was similar to the improvement observed at 12 weeks.

Our phase two study of patients with Alport syndrome, the similarity in a significant unmet need and 80 PKD prompted us to initiate the Falcon study in May of this year. It has a design that similar to cardinal with identical treatment schedules and endpoints for accelerated and full approval and as conservatively powered we.

I've observed similar significant improvements in EG fr in our Phoenix study in patients with Ita nephropathy CKD caused by type one diabetes and SSG us the consistent improvements we observed across types of CKD that originate from very different causes reinforces our view.

Paradox loan addresses a common final pathway of progression in CKD and strengthens our view that significant growth opportunities exists for it and rare forms of CKD.

We're planning to pursue the development of our docs loan for the treatment of each of these additional rare forms of CKD collectively the programs in rare CKD address many of the most severe forms of CKD and a total population that we estimate to be approximately 700000 patients in the United States.

We're also planning to expand our work in neurologic disease based on the Moxy results. We believe that the Moxy results provide proof of concept that improvements in mitochondrial function from Omega locks on treatment may provide a therapeutic benefit in a number of other neurodegenerative diseases.

2019, it's been a remarkable excuse me has been a remarkable year for reatta. It goes without saying that we remain grateful to the patients their families. The caregivers the investigators in the study staff, who participated in Cardinal Moxy and our other clinical studies and of course, we're grateful for the.

What's our dedicated employees at Reatta.

We want to take all you for your commitment to our company over the years and we look forward to updating you on our continued progress in the coming weeks and months.

Thank you and not every audio recording will be available. Shortly after this conference call on Reorders web site at Reatta pharma dotcom and the Investor section.

Ladies and gentlemen, this now concludes today's conference call. Thank you for participating you may now disconnect and have wonderful day.

Yes.