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Reata Pharmaceuticals, Inc. (RETA)
Q3Â 2019 Earnings Call
Nov 12, 2019, 8:00 a.m. ET
Contents:
- Prepared Remarks
- Questions and Answers
- Call Participants
Prepared Remarks:
Operator
Ladies and gentlemen, thank you for standing by and welcome to the Management call to discuss Positive Topline Pivotal Year One CARDINAL Data. At this time, all participants lines are in a listen-only mode. Following the prepared remarks, we will open the call up for questions. We ask that you please limit yourself to one question and one follow-up, so that we can accommodate as many questions as possible. [Operator Instructions] An audio recording of today's webcast will be available shortly after the call today on Reata's website at reatapharma.com in the Investors section.
Before the company proceeds with its remarks, please note the forward-looking statement disclosure and the company's press release, the company will be making forward-looking statements on today's call. There are many factors that could cause results to differ from expectations, including those noted in the company's SEC filings. Today's statements are not guarantees of future outcomes. Please also note that any comments made on today's call speak only as of today, November 12th, 2019 and may no longer be accurate at the time of any webcast replay or transcript rereading.
I would now like to hand the conference over to your speaker today, Vinny Jindal, Vice President of Strategy.
Vineet Jindal -- Vice President of Strategy
Thank you. Good morning and welcome to Reata management's call to discuss the positive results from year one of the pivotal CARDINAL trial of bardoxolone in patients with CKD3 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 Investors section of our website at reatapharma.com. This morning we reported financial results for the third quarter of '19 and the press release as well as our Form 10-Q can also be found on the Investors section of our website at reatapharma.com. We're limiting our remarks today with 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&A session of today's call.
I'm joined today by our CEO, Warren Huff; our Chief Medical Officer, Colin Meyer; and Chief Financial Officer, Manmeet Soni.
I'll now turn the call over to Warren.
Warren Huff -- Founding Chief Executive Officer and President
Thanks, Vinny. Good morning everyone and thank you for joining us. Yesterday afternoon we announced positive topline results from the pivotal CARDINAL Phase III study of bardoxolone in patients with chronic kidney disease caused by Alport syndrome. CARDINAL was the largest global interventional study ever conducted in Alport syndrome patients. Alport syndrome is a severe form of CKD and the patients enrolled in the Phase III portion of CARDINAL were losing substantial amounts of kidney function when they entered the trial. After one year in CARDINAL, the patients on placebo lost on average over 6 milliliters per minute of estimated eGFR or glomerular filtration rate. Said another way, these patients were rapidly progressing the kidney failure and the need for dialysis or a kidney transplant. By contrast, bardoxolone treated patients experienced a statistically significant improvement in the kidneys' estimated glomerular filtration rate or eGFR while on active drug and their estimated GFR was statistically unchanged from baseline after withdrawal drug. In effect, during the study, bardoxolone treatment substantially slowed or halted the loss of kidney function that leads to the need for dialysis or a kidney transplant in patients with this severe form of CKD and without other treatment options.
On behalf of everyone at Reata, I'd like to extend our sincere gratitude to the patients' families and caregivers who live with this disease and to the Alport Syndrome Foundation. The results we announced yesterday would not have been possible without their efforts and commitment to this program.
For those of you who are unfamiliar with Alport syndrome, it is a hereditary and severe form of chronic kidney disease caused by mutations in genes that encode for Type IV collagen. Type IV collagen comprises approximately 50% of the glomerular basement membrane or GBM of the kidney. The GBM acts as the barrier that separates the blood from the urinary filtrate. Collagen mutations in the GBM lead to leakage of whole blood cells, protein and other material into the proximal [Indecipherable] of the kidney. This promotes chronic kidney inflammation and a decrease in cellular energy production that leads 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 believe that there are approximately 30,000 to 60,000 patients with Alport syndrome in the United States and approximately 32,000 to 64,000 patients in the EU-5, which represent the first commercial markets for bardoxolone that we are targeting.
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 kidney's filter blood or GFR. Nephrologist track estimated GFR or eGFR to assess the decline in Kidney Function in progression of patients kidney disease. Normal individuals have an eGFR of approximately 120 milliliters per minute. When eGFR declines to approximately 15 milliliters per minute, patients reach kidney failure and require dialysis or a kidney transplant to survive. In the most common forms of CKD caused by diabetes or hypertension, patients lose approximately 2 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 III CARDINAL Study lost on average approximately 6 milliliters per minute over one year. This is 3 times the rate of loss of more common forms of CKD. And at this rate of loss, a patient with a baseline eGFR of 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 a kidney transplant on average in their mid-20s.
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 are blood pressure medications, primarily ACE inhibitors, an angiotensin receptor blockers and SGLT2 inhibitors. These are widely used because they slow the rate of eGFR decline in patients with CKD. Importantly, these drugs do not stop the decline in eGFR and they certainly do not increase eGFR over-time. In their registrational studies, eGFR over-time declined in both the active drug and placebo arms of their trials. You can see two examples of these studies on the right. In the RENAAL trial, the angiotensin receptor blocker called Losartan modestly slowed the rate of eGFR decline. 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 SGLT2 inhibitor slowed, but did not stop eGFR 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 eGFR versus baseline. These drugs are effective and widely used because their therapeutic benefit is slowing eGFR decline in comparison to the placebo group. This translates into a delay and the need for dialysis or a transplant even though they do not stop the decline in eGFR.
Tolvaptan was approved last year in the United States for the treatment of autosomal dominant polycystic kidney disease and it is the only approved therapy to slow progression of kidney disease for a rare form of CKD. Like blood pressure medications and SGLT2 inhibitors, Tolvaptan only slows and does not stop the decline in eGFR. It was approved because it produced a benefit in estimated GFR versus placebo after treatment for one year and then withdrawal of drug. This is called the off-treatment or retained eGFR and is the same registrational endpoint as our key secondary endpoint in CARDINAL.
In the Tolvaptan registrational study called REPRISE, the change from baseline and retained eGFR for both the Tolvaptan and placebo groups was negative as you can see in the graph on the right. The retained eGFR at the Tolvaptan group declined from baseline by 2.34 milliliters per minute over a year and the retained eGFR of the placebo group declined from baseline by 3.61 milliliters per minute over a year. Tolvaptan was approved based on the 1.27 milliliter per minute improvement in estimated GFR 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 eGFR demonstrating an improvement versus placebo after one year of treatment may support accelerated approval and an improvement versus placebo after two years of treatment may support full approval. This is consistent with the recent approval of Tolvaptan on the basis of a placebo-corrected improvement in retained eGFR. They also provided us with similar guidance during our end of Phase II interactions in ADPKD and the retained eGFR versus placebo is the registrational endpoint of our FALCON study. We were aware that they have provided this guidance to other sponsors, developing drugs for rare forms of CKD.
Following the FDA guidance, the primary endpoint for the Phase III CARDINAL Study is the change in estimated GFR from baseline and compared to placebo, after 48 weeks of treatment in the key secondary endpoint is the change in estimated GFR from baseline and compared to placebo after 48 weeks of treatment and four weeks of drug withdrawal. Obviously, the efficacy analyzes compares the bardoxolone 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 eGFR 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 of treatment in a four-week withdrawal, kidney function would be worsened relative to placebo. However, an improvement in retained eGFR versus placebo strong evidence that the drug has been official has the potential to modify the course of the disease and may delay or prevent the need for dialysis or a kidney transplant.
With that background, I'll hand the call over Colin to discuss the CARDINAL trial results.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
Thanks, Warren. The Phase III 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 and 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 or angiotensin receptor blockers unless these were not indicated or medically indicated. Study subjects were randomized one-to-one to either bardoxolone 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 48 weeks.
At week 100, patients withdrawn from study drug a second time and the last assessment occurs at week 104 after another four-week withdrawal period. As Warren explained, the primary endpoint for the study is the change in eGFR from baseline and compared to placebo after 48 weeks of treatment and the key secondary endpoint is the change in eGFR from baseline and compared to placebo after 48 weeks of treatment and four weeks of drug withdrawal. Both analysis are intention to treat for ITT and include data from our patients. The week 40 analysis uses all available values including those from discontinued patients and the method of analysis is MMRM with no imputation for missing data. The method of analysis for the week 52 endpoint employs ANCOVA methodology that was used in REPRISE trial of Tolvaptan in ADPKD. The week 52 off-treatment analysis includes all available data for patients who completed 48 weeks of treatment, followed by the four-week withdrawal period. If patients discontinue prior to week 48, their 4-week off-treatment value prior to week 52 was used and the ANCOVA model uses a time based co-variance so these data can be included. In this analysis, multiple imputation is used for missing data.
Since the study is ongoing, we are releasing the one-year results under a data access plan submitted to the FDA and designed to preserve the integrity of the second year of 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 III portion of CARDINAL were representative of the broader Alport Syndrome population. Patients were on average in their late 30s and 15% were pediatric. The main baseline eGFR study entry were 63 mil per minute and there was a good distribution of patients across the eligible range of 30 to 90 mil per minute. Patients have low proteinuria on average measured as a urinary albumin-to-creatinine ratio or ACR and just under half had ACR above the macro [Indecipherable] 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 were receiving standard of care ACE inhibitors or ARBs and patients had generally low proteinuria and well control blood pressure. We believe these data demonstrate the patients were receiving exceptional care by their treating physicians and optimize on all available therapies upon study entry.
CARDINAL successfully met its primary endpoint of improvement in eGFR after 48-weeks of treatment compared to placebo. Patients treated with bardoxolone demonstrated a statistically significant placebo-corrected 9.5 mil/min improvement and mean eGFR compared to placebo after 48 weeks of treatment with a p-value of less than 0.0001. Patients treated with bardoxolone had a statistically significant mean improvement in eGFR of 4.7 nok [Phonetic] per minute from baseline while patients treated with placebo had a statistically significant I mean worsening in eGFR of 4.8 nok minute from baseline. We believe these on-treatment results demonstrate a very clinically meaningful treatment effect in a patient population that is rapidly progressing.
For patients on bardoxolone, these data indicate that despite their severe disease, these patients experienced a significant improvement in the kidney function while on active drug. In effect, during the study, bardoxolone treatment substantially slowed or halted the loss of kidney function that leads the need for dialysis or a kidney transplant in patients with this severe form of CKD and without other treatment options. Bardoxolone also met its key secondary endpoint of off-treatment change in eGFR compared to placebo. In the off-treatment analysis, patients treated with bardoxolone demonstrated a statistically significant placebo-corrected 5.1 mil per minute improvement in mean retained eGFR compared to placebo with a p-value of 0.0012. Patients treated with the placebo experienced a statistically significant worsening in mean retained eGFR of 6.1 mil per minute from baseline with a p-value of less than 0.0001. Patients treated with bardoxolone were unchanged from baseline with a slight non-significant reduction in retained eGFR of 0.96 mil per minute with a p-value of 0.45.
Regarding subgroup analyzes of the off-treatment endpoint, bardoxolone's effect on kidney function was observed across multiple including among males, females, pediatric patients, baseline ACR categories and genetic sub-types. These results suggest that disease progression for patients on bardoxolone was essentially halted during the study even when measured after four weeks of drug withdrawal. Notably this treatment effect is 4 times larger than the treatment effect observed with Tolvaptan in the REPRISE trial, which supported approval of Tolvaptan in ADPKD despite the small difference observed in the trial and the Tolvaptan group losing 2.3 mil per minute from baseline. While the absolute change from baseline for the bardoxolone group was lower than observed in the Phase II 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 mil per minute in the placebo group, which puts them at risk of end-stage kidney disease within a few to several years.
Also, the relative difference between the on and off treatment eGFR values for Bardoxolone treated patients observed in the study was similar to that observed in other bardoxolone CKD studies. In the Phase III portion of CARDINAL the relative difference between the week 48 on treatment values and the week 52 off-treatment values was approximately 6 mil per minute. In the Phase II portion of the trial, the relative difference was also approximately 6 mil per minute. In the BEACON trial, the relative difference was approximately 5 mil per minute. In the BEAM trial, the relative difference was approximately 7 mil per minute.
In terms of the meaningfulness to patients, these data demonstrate that after one year of treatment, bardoxolone was able to on average improve kidney function or patients were receiving drug and after wash-out, their kidney function was not significantly different from baseline. These patients on average did not progress over the course of a year despite the large loss observed in the placebo group. This data indicate that bardoxolone is positively affecting the course of the patients' disease. If they are not progressively losing kidney function, they may never need dialysis.
The main eGFR values with associated P-values are informative, but to better understand the distribution of change, we performed the quartile [Phonetic] analysis for the week 48 and 52 time points. When changes in Kidney Function are assessed by quartile, several key conclusions can be made. In every quartile, at week 48 and week 52, bardoxolone treated patients kidney function was improved relative to the matching placebo quartile. Additionally at week-48 while patients were receiving study drug, approximately 75% of patients receiving bardoxolone did not experience disease progression, while approximately 75 patients receiving placebo lost kidney function. At week 52, the second best performing placebo quartile had an average rate of progression that is comparable to the average rate of progression in other notable forms of CKD including diabetic hypertensive ADPKD. The bottom two placebo quartiles were half a placebo patients progressed at a rate of approximately 12 mil per minute in one year, which is very rapid in result in the need for dialysis or kidney transplant in just a few years.
And patients in the worst performing quartile were the most rapidly progressive disease. Even though Bardoxolone did not increase kidney function, it meaningfully slowed their loss of kidney function. This is evidence that bardoxolone may provide a benefit even in patients who do not have an absolute increase in eGFR and patients with less rapidly progressive disease that is comparable to other forms of CKD, bardoxolone not only appears to hot 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 eGFR after six weeks of treatment and the longer-term changes in on and off treatment eGFR after one year of treatment. In the bardoxolone group, the acute change in eGFR correlated positively and significantly with the change in eGFR at week 48 on treatment and at week 52 after the four-week withdrawal. These data demonstrate that the early increase in eGFR is the positive predictor of eGFR change after one year of treatment on and off-drug. If the early increases were adverse through hyper-filtration or any other [Indecipherable] mechanism they would negatively correlate with change at one year, it won't be associated with significant loss of kidney function in eGFR values that were worse than placebo.
Regarding safety, bardoxolone was generally reported to be well tolerated with the safety profile similar to what we observed in the Phase II portion of the trial. Nine patients in the bardoxolone group and four in the placebo group discontinued due to an adverse event and no single adverse event contributed to more than two discontinuations in either group. Fewer serious adverse events were reported in the bardoxolone ARM with 13% of patients on placebo reporting serious adverse events versus 5% on bardoxolone. No deaths were reported in either ARM. Importantly, no fluid overload or major adverse cardiac events including MI, stroke, heart failure or revascularization were reported in patients treated with bardoxolone. Blood pressure was decreased relative to baseline in the bardoxolone group 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 bardoxolone ARM. The most common adverse events were muscle spasms and increases in aminotransferases, which are common finding in studies of our Nrf2 activators and an expected effect of Nrf2 activation. As evidence that the increases in aminotransferases are a pharmacological effect, acute changes in ALT in bardoxolone treated patients positively and significantly correlated with acute changes in eGFR.
Lastly, albumin area in the bardoxolone ARM was increased at week 48 compared to baseline, but was unchanged when adjusted for eGFR and ACR was unchanged off-treatment at week 52 compared to baseline and relative to placebo. These data demonstrate that the on-treatment increase in urinary protein excretion is due to the increase in eGFR and the week 52 data demonstrate that this effect is not associated with injury. Notably, over the course of the trial, the Data Monitoring Committee met quarterly, reviewing all data on an un-blinded basis and did not note any safety concerns.
With that, I will turn the presentation back over to Warren.
Warren Huff -- Founding Chief Executive Officer and President
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. Importantly, during the study bardoxolone treatment effectively halted the decline in estimated GFR in patients with rapidly progressing disease. Approximately 75% of bardoxolone treated patients had an improvement in their on-treatment eGFR while approximately 75% of placebo-treated patients had worsening eGFR. Importantly, bardoxolone treatment showed a potential benefit even in patients who were progressing most rapidly toward kidney failure.
Bardoxolone was reported to be well tolerated with numerically fewer reported SAEs on bardoxolone versus placebo. We believe that the results from CARDINAL provides significant evidence that bardoxolone 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 to questions.
Questions and Answers:
Operator
Thank you. [Operator Instructions] And our first question comes from Yigal Nochomovitz from Citigroup. Your line is open.
Yigal Nochomovitz -- Citigroup -- Analyst
Hi guys. Thank you very much for taking the questions and congrats on another positive Phase III readout. My question was related to the eGFR trends seen in the trial. Colin, you mentioned that the acute changes in eGFR correlated positively with the change in eGFR weeks 48 and 42 [Phonetic] and however we haven't seen the time profiles yet for eGFR. So given that, could you provide any additional color on the evolution of the treatment effect for Bard from week 0 to week 48 before coming off drug, what was the time to peak effect and how does this compare to the week 48 benefit of 4.7 units. Thank you.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
Yes, Yigal. So the eGFR change over-time was not fully disclosed because it could be un-blinding. Patients on Bardoxolone had a increase in eGFR that manifested early so much what we've seen in other trials and it persisted. The increase at week 48 was substantial. The data reported during the presentation or the ITT analysis that includes patients who discontinued or on low doses of drug when patients who are on their goal dose were included in patients who were discontinued were excluded the treatment effect was even higher. The total slope from baseline to week 40 is positive, clearly divergent from the placebo patients and it's obviously a very meaningful treatment effect considering the placebo patients lost 6 mil per minute in one year.
Warren Huff -- Founding Chief Executive Officer and President
Yeah, I'd just add one thing. This is in part why we provided the quartile analysis because you can compare the change on drug to their matching placebos across the complete range of response and that data clearly shows on and off treatment that the drug treatment improved the effect versus placebos even in the worst performing patients.
Yigal Nochomovitz -- Citigroup -- Analyst
Okay, great. And I think you may have touched on this, Colin. But could you just comment a little bit more detail with respect to the differences in -- any differences in treatment effect for Bard dependent on whether the patients around the 20 versus the 30 milligram dose based on their albumin status?
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
Yes. So I think there's two separate questions, dose and albumin status. And so we haven't disclosed the treatment effect by dose. But in general, patients who are in the higher doses of drug had larger treatment effect. In regards to the albumin status, we saw similar efficacy when you compare drug versus placebo in patients with low versus high albuminuria baseline. And as I mentioned, we also see similar efficacy in adults as well as kids and that's somewhat of a surprising finding because it's well-established that pediatric patients are at high risk of 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 and 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 that how horrible and rapidly progressive Alport syndrome is and our data today are the most robust data ever collected in this patient population.
Yigal Nochomovitz -- Citigroup -- Analyst
Thank you very much.
Operator
Thank you. Our next question comes from Maury Raycroft from Jefferies. Your line is open.
Maury Raycroft -- Jefferies -- Analyst
Hey, everyone. Good morning and congrats on the updated data today. Thanks for taking my question. So you see similarities between data sets comparing retained benefit versus baseline in Phase IIb and then Phase II CARDINAL and then also in the placebo-corrected data in Phase III BEACON and Phase 3 CARDINAL, but you see differences in the final eGFR benefit number in the baseline comparison versus the placebo-corrected comparison. And so I'm just wondering how you guys explain that if you can add more perspective there.
Warren Huff -- Founding Chief Executive Officer and President
Yeah. So that's actually your 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. And so in the Phase II patients within CARDINAL recall that the increase at week 48 was approximately 10 mil per minute and the change post withdrawal was approximately 4 mil per minute or a 6 mil per minute difference and so we saw that difference here in the Phase III portion of CARDINAL. The on Treatment was about 5 and the off-treatment was minus 1 and so it's a 6 point delta. And if you look at the quartile analysis, I think it's instructive because the second quartile in the bardoxolone patients mirrors what we observed in Phase II.
So you can see that the on average bardoxolone treated patients in the second quartile at week 48 were up nine, which is pretty close to the 10 we saw in Phase II, but those patients were up 2.5 post withdraw which is pretty close to the 4 and so we see this relationship across the quartiles here, we saw once again in the Phase 2 CARDINAL trial. We also saw in BEAM and BEACON. The most important of aspect is the rate of progression in placebos that determines the absolute change on and off drug, but the relative change [Indecipherable] similar and once again what regulators care about in treating physicians is the rate of progression either in placebos or natural history and these patients in our Phase III cohort and placebo had significant rapidly progressive loss of kidney function. We have powered the trial to show about a 2.5 mil per minute difference and we saw double of that, a 5 mil per minute difference which as we stated before is 4 times the magnitude seen in the REPRISE trial, a pullback in the support approval. So from our perspective, these data are all internally consistent and when you look in the broader context of our clinical data, it also is consistent, it's just that in this trial, the placebo patients did very poorly, so it dropped down the absolute changes.
Maury Raycroft -- Jefferies -- Analyst
Got it. That's very helpful. And the second question is just based on the decline in GFR you're seeing in the placebo group and the fact that you've got 15% of the population in the study includes pediatric patients. Do you think FDA might ask to change the second year of the study to encourage a crossover to drug earlier?
Warren Huff -- Founding Chief Executive Officer and President
It is notable that we had a significant number of kids in this trial and kids on placebo did poorly, adults on placebo did poorly. FDA had previously requested that this be a two-year trial and so we'll obviously have to have discussions with regulators to determine if there would be any change to the design.
Maury Raycroft -- Jefferies -- Analyst
Got it. Thank you and congrats again.
Warren Huff -- Founding Chief Executive Officer and President
Thanks.
Operator
Thank you. Our next question comes from Joseph Schwartz from SVB Leerink. Your line is open.
Joseph Schwartz -- SVB Leerink -- Analyst
Great. Thanks very much and congrats again. We heard from physicians who have experience using bardoxolone at ASN that patients feel 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 in that sort of data?
Warren Huff -- Founding Chief Executive Officer and President
We collected one quality [Phonetic] of life instrument in the trial and today we did not disclose the data and what we previously stated and what you heard is that patients often report that they are feeling better and doing better. In kidney trials, the precedent endpoint is change in eGFR specifically for rare forms of 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 comparison simply be made to placebo and so we think that they will consider those data, the most important and relevant and the decision is whether or not to approve bardoxolone.
Joseph Schwartz -- SVB Leerink -- Analyst
Okay, that makes sense. And then can you describe the shape of the albuminuria occur for patients on bardoxolone and how closely does what you saw in Phase 3 mirror what you saw in Phase II and where did the average level of proteinuria end up relative to baseline?
Warren Huff -- Founding Chief Executive Officer and President
Yeah. So it's qualitatively, similar to what we've seen in the Phase II portion of CARDINAL and in other trials in patients who have pre-existing proteinuria. Once again if patients already have damage to their filtration barrier and so if you can just visualize it, if it has holes that can 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 GFR, there was no increase versus placebo. That's important because it indicates that the increase was due to the change in GFR and if there wasn't some additional increase, that could suggest damage and that was further exemplified by the week 52 off-treatment data and so without even correcting for eGFR, the change from baseline in bardoxolone treated patients at week 52 was no different in the change from baseline in the placebo patients.
We actually just published a paper in Kidney International. I think it came online a few weeks ago. Kidney International is one of the most prestigious and rigorous kidney journals the acceptance rate is about 6% these days. In the paper that we published includes many notable global KOLs and it 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 we've hypothesized for some time and there has been some confusion in the nephrology community about the mechanism of action for the in-acute increase in GFR. We believe that we've done the definitive preclinical experiment to demonstrate that the mechanism is associated with an increase in surface area and surface area is often constricted in many forms of chronic kidney disease. We are also able to rule out hyperfiltration. Hyperfiltration 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 was not observed, just like in our CARDINAL Phase 3 trial increase in blood pressure was not observed. The only way to increase blood pressure locally within the kidney is to relatively vasodilate 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 hyperfiltration. And so that effectively rules out hyperfiltration as a mechanism and there should no longer be any questions.
In those experiments, the investigator also measured permeability to albumin to determine if bardoxolone could somehow increased permeability, which potentially would suggest injury to the kidney. In normal animals, there was no increase in [Indecipherable] of albumin in response to the bardoxolone analog. In animals that had diabetes, that did have increased permeability at baseline, the analog also did not increase permeability and so there is no evidence that this increase [Indecipherable] and it's expected based upon the fact that these patients already had a week of glomerulus and once again the off-treatment data showing that proteinuria returns toward baseline and it's no different than placebo is evidenced that it is not harmful, but truthfully regulators care much more about the off-treatment retained eGFR because that is the ultimate evidence if any drug is harmful or hurtful.
Yes, this if bardoxolone was harmful after one year of treatment, eGFR in the bardoxolone treated patients will be worse than placebo or be worse than the 6 mil per minute of last seen in the placebo group. But as we mentioned, it was no different statistically then baseline and was separated by 5 mil per minute and so that's the best evidence that the drug is beneficial to the kidney.
Joseph Schwartz -- SVB Leerink -- Analyst
Very helpful. Congrats again.
Warren Huff -- Founding Chief Executive Officer and President
Thank you.
Operator
Thank you. Our next question comes from Adam Walsh from Stifel. Your line is open.
Adam Walsh -- Stifel -- Analyst
Well, hi, guys. Let me add my congratulations and good morning to you. Just a couple of questions here on the albuminuria adjusting for eGFR. I'm curious if you discussed that with FDA are they -- did they have a similar understanding of the way you look at albuminuria 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 is it possible you can talk about the SAEs that we're seeing in Bard and also these are really small numbers, but there is slightly more of Bard patients within AE that might get permanent treatment discontinuation. If you could comment there as well, that would be great. Thank you.
Warren Huff -- Founding Chief Executive Officer and President
Sure. And so I think the first thing is with regulators and specifically FDA albuminuria has not come up, they actually do not care about changes in albuminuria, they care about changes in estimated GFR. In our interactions with them face-to-face and in written comments to us, they wanted to see change in eGFR because once again proteinuria can be pharmacodynamically changed independent of effects on the kidney and there are a few extremely large cardiovascular trials that show that proteinuria goes in the opposite direction of kidney function and these trials were much larger than the nephrology trials that were mentioned. And so in the on-target trial that was conducted several years ago [Indecipherable] reduced proteinuria versus the single intervention, but eGFR in clinical outcomes were actually worsened and so -- and that's -- yeah ESKD events and that was a 25,000 patient trial.
In the accomplished trial, an ACE inhibitor plus mode opinion actually worsened proteinuria than the other group, but kidney function and renal events were actually improved and so there's actually plenty of conflicting evidence in the literature that proteinuria does not necessarily translate directly to improvements in kidney function and that's why in the setting of agents that may reduce proteinuria, within nephrology, FDA requires for full approval that they show an eGFR benefit because ACR may or may not reflect actual improvements in kidney function and once again that's why FDA and we did not have discussions about albuminuria and the focus was on actual kidney function.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
And at the end again the retained eGFR endpoint is definitive in terms of whether the intervention will either harm or protect the kidney.
Warren Huff -- Founding Chief Executive Officer and President
In regards to the safety -- go ahead.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
And that's why they take it for approval.
Warren Huff -- Founding Chief Executive Officer and President
In regards to the serious adverse events, once again 10 on placebo, four on bardoxolone, so meaningfully lower in the bardoxolone group and they were sporadic in [Indecipherable] 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, no MIs, no stroke. So no evidence of any adverse cardiovascular effect in the bardoxolone group and even less severe adverse events. So non-SAE, both cardiac and vascular were reduced in the bardoxolone group and once again no change in blood pressure.
As far as adverse events, we commented on the [Indecipherable], we can't disclose the specific distribution because it may unblind, but it's similar to what we saw in Phase 2 CARDINAL and those that contributed to discontinuation were few, the difference was only five. And as I mentioned, individual adverse events accounted for no more than two discontinuations. And so for instance, despite the muscle spasms I mentioned, a maximum of two patients discontinued from that. The tolerability that we've reported we believe is quite good and the titration design that we have is able to effectively deal with any individual patient who may have a tolerability issue.
Adam Walsh -- Stifel -- Analyst
Great, thanks so much.
Warren Huff -- Founding Chief Executive Officer and President
You're welcome.
Operator
Thank you. And our next question comes from Brian Skorney from Baird. Your line is open.
Jack Allen -- Robert W. Baird -- Analyst
Hi, thank you for taking our questions. This is Jack Allen donning-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 for the 48 and 52 week analysis and provide some additional color as to how many patients specifically were evaluated at each time point?
And then my second question is just real quickly, with respect to presenting the results will you wait to read-out the full results of the two-year trial or would you present the one-year results on medical conference prior to completing the study? Thank you.
Warren Huff -- Founding Chief Executive Officer and President
Sure. So I'll start with your second question. We will wait to present the full results until the trial is completed. Much of the data that we would like to present at a medical conference would unblind. For instance, the asset serious adverse events would be necessary to disclose, but there are ins of one generally and that would unblind individual patients and investigators. We had to submit the data access plan to FDA to detail how we would maintain the integrity of the [Indecipherable] the trial while it's ongoing and because of that we'll have to wait to disclose the detailed data until a future medical meeting.
As far as your first question. And so, yes, we had two different methods of analysis. The method of analysis for the week 48 on treatment is MMRM 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 and model the population. There is no imputation for missing data. So what that means is no individual value is basically added into the model such as last observation carried 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 were use to determine if they believe the drug is efficacious, we use the same methodology that was used in the Otsuka trial with that Tolvaptan so the REPRISE trial, their 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 where we started is because that is the methodology that FDA did accept and we were unaware of that methodology when we initially met with FDA back in 2016. A benefit to that methodology is it allows every single patient to be included. And so for patients who completed a 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 the week 52 period, those values were also included in the analysis. And as I mentioned, there was a time-based co-variance to appropriately adjust. And then for patients who discontinued early and had no off-treatment value, those patients had multiple imputation to the effectively add a value and so it's a full 157 patients. So there is no missing data or no incomplete data I should say.
Jack Allen -- Robert W. Baird -- Analyst
Awesome. Thank you so much. And then, sorry, I just have one more quick follow-up. With regard to the baseline eGFR, are you seeing that patients with higher baseline eGFR are progressing more rapidly or less rapidly as compared to patients with lower baseline eGFR. We'd seen some interesting literature that might suggest higher eGFR patients with Alport Syndrome might actually progress more rapidly, but I was wondering if you guys could provide any comments on that. Thank you again for the questions and congrats on the results.
Warren Huff -- Founding Chief Executive Officer and President
Thanks. So, yes. And so of patients with higher eGFRs can progress more rapidly. And I think that's highlighted by the pediatric patients and so their normal is typically a little bit higher than adults and even though their baseline eGFR was slightly higher than the adults, they probably lost more kidney function from a percentage basis than the adults and those patients progress the kids doing earlier in life and so then that may also contribute to the larger loss in the placebos than we initially expected. But overall, we believe the losses due to the fact that patients across the spectrum, kids, adult, males, females loss kidney function at a rapid rate.
Jack Allen -- Robert W. Baird -- Analyst
Awesome. Thank you so much.
Warren Huff -- Founding Chief Executive Officer and President
Thank you.
Operator
Thank You. And our next question comes from Charles Duncan from Cantor Fitzgerald. Your line is open.
Charles Duncan -- Cantor Fitzgerald -- Analyst
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 [Indecipherable] lots of good clinical questions have been answered. With regard to regulatory strategy, could we assume that you'd be meeting with the agency perhaps to enable an NDA by roughly mid-20 and then with regard to international or MAA filing, what kind of time-frame would you anticipate for that and is there any additional clinical work you need to enable there?
Warren Huff -- Founding Chief Executive Officer and President
So our plan with all of our lead programs including our Friedreich's Ataxia program where we also have positive data is to meet with regulators as soon as possible and so we do not comment on ongoing regulatory interactions, but we will provide commentary after our initial meetings and it would be our plan to expeditiously meet with them and if positive, proceed with filing the NDA as quickly as we can. From an international perspective, obviously we just reacquired the rights From AbbVie for both of our drugs and so we're currently developing this strategy. It was their responsibility to interact with regulators externally or globally. We were allowed by AbbVie to conduct the trial in their territories and so we will also be planning to meet with those regulators. And then KKC or Kyowa Kirin company, our Japanese and Asian partner with bardoxolone has already obviously had ongoing interactions with the PMDA and those will continue.
Charles Duncan -- Cantor Fitzgerald -- Analyst
Okay. And then Colin, with regard to other uses of bardoxolone in terms of rare kidney diseases, say ADPKD, do you have any thoughts regarding obviously in fact that's pretty impressive here, predictive value for say FALCON or anything along those lines can you help us understand how to think through that.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
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 in FALCON, not only because of that but because the sample size for FALCON, it was approximately 2 times the size of CARDINAL where we had an extremely low p-value in the on-treatment as well as the key secondary off-treatment regulatory endpoint. Our view is that in the FALCON trial, those patients likely won't have disease as it's rapidly progressive as we saw in CARDINAL. And so once again, I would refer to our quartile analysis and based upon the approval of Tolvaptan and based upon the REPRISE trial for patients not on Tolvaptan, they progress at a rate of about 3.4 mil per minute. It's about or 3.6, it's about 2.4 in patients on Tolvaptan and so our best estimate is that the rate of loss will be somewhere around 3 mil per minute off treatment in our FALCON trial and you can see in the quartile that had approximately that loss the placebos there was 5 mil per minute treatment difference in quartile two. And so we would expect that these data would translate broadly and once again, the main determinant of the absolute treatment effect is really progression, but we would expect a similar relative change across all of our trials.
Charles Duncan -- Cantor Fitzgerald -- Analyst
Then if I could ask just one operational follow-up up and that is regarding commercial strategy, maybe bring Manmeet or Warren. Could you anticipate increased visibility on commercial strategy over the course of 2020 and can you provide any color on how we might measure that over the course of next year or so?
Manmeet S. Soni -- Chief Financial Officer and Executive Vice President
Sure. So we believe like Bard presents an extremely exciting commercial opportunity. And based on the data, which we have shown you we believe if Bart is approved by regulators that will be the first approved treatment options for patients with Alport syndrome in the United States and then followed by Europe and around the world. And as we have said earlier, right, this is a great opportunity right. In the US, we have approximately we estimate around prevalence of 30,000 to 60,000 patients in the US and approximately 32,000 and 64,000 in the EU-5, which will be the first countries where we plan to commercially launch. And also we have claims data on AAS [Phonetic] which we believe are approximately 11,000 diagnosed 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 aspects of these rare diseases. They have been engaging with the KOLs for the last couple of years to understand this disease and the insights which we have gained are very helpful for engagement of advocacy for education and clearly aid the speed and accuracy of diagnosis, as we have seen very often in the rare diseases and available treatment option speeds formation of multi-disciplinary teams and centers of excellence and that's what we expect will happen over here.
We have an exceptional medical sales team including field based MSL's liaisons that are focused on medical education and disease awareness in North America and in Europe. We are already working to expand our MSL team in the coming weeks to increase the focus and penetration to Tier 1 and Tier 2 beyond the KOLs, which we have a decent coverage and disease awareness campaigns have already been launched, to design, to educate physicians about Alport syndrome. Genetic testing program has been initiated to improve the accuracy and timely diagnosis in the United States. We also have our 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 staff would be hired based on [Indecipherable] PDUFA date at the timelines, but we are already working on the patient hub-centric 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 completed our field force sizing and structure is complete for sales and [Indecipherable] team. So we feel very comfortable with our commercial readiness based on the state we are right now.
Warren, anything to add?
Warren Huff -- Founding Chief Executive Officer and President
I'm just going to say I think we're very comfortable with where we are. But based on the results we will obviously be accelerating our activities really across the board.
Charles Duncan -- Cantor Fitzgerald -- Analyst
And that's helpful added color. Congrats on the results and going to be a busy year for you. Thanks.
Warren Huff -- Founding Chief Executive Officer and President
Yeah. Thanks.
Operator
Thank you. [Operator Instructions] And our next question comes from Matt Kaplan from Ladenburg Thalmann. Your line is open.
Matthew Kaplan -- Ladenburg Thalmann -- Analyst
Hey guys, good morning and congrats on the results. Just wondered if you can give us a sense in terms of -- with related to safety, the dose titration and I guess the average dose patients were able to achieve in the study and I guess reasons why they weren't able to perhaps -- why patients weren't able to dose titrate higher?
Warren Huff -- Founding Chief Executive Officer and President
Sure. So we haven't commented specifically on the numbers at a given dose, but most patients were able to reach their goal dose. What we've typically seen in our prior trials is approximately two-thirds of patients can reach the goal dose. Occasionally, a patient can't because of real or perceived tolerability issues and muscle spasms is a good example. That was one of the most commonly reported adverse events in the Phase III cohort. But as I mentioned earlier, no more than two patients discontinue for any single adverse events, so clearly those do not preclude continuation on bardoxolone.
Matthew Kaplan -- Ladenburg Thalmann -- Analyst
And I guess once patients achieve the goal dose, do you typically see any dose down titration or was that allowed in study?
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
Typically what we see is that, if there are any tolerability issues, they occur within the first six to 12 weeks. And so in our MOXIe call about a month ago, we highlighted the adverse events that were more frequent and the OMAP treated patients were typically more come in the first 12 weeks, but those imbalances typically went away for a much smaller after that and so it's similar for bardoxolone. We have not done that analysis yet, but in our prior trials, we see a similar pattern. And so in the adjustment that's needed occurs when the patients are coming into the clinic frequently and typically once they get to approximately week 12, they are at a good steady state at whatever dose they are on.
Matthew Kaplan -- Ladenburg Thalmann -- Analyst
Great. Thanks Colin for that detail.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
You are welcome.
Operator
Thank you. Our next question comes from Brian Skorney from Baird. Your line is open.
Jack Allen -- Robert W. Baird -- Analyst
Hi, sorry, this is Jack again on for Brian. Just one more quick follow up. I know you're not going to disclose the specific eGFR benefits earlier in the trial, but you mentioned they might be similar in magnitude to what we've seen in the Phase II. Can you provide any color as to whether double digit benefits or who is kind of the smaller closer to BEACON type benefits in 12 weeks, anything to that regard. Thank you so much.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
Yeah, we're not going to comment specifically on what the change was over-time except to say that there was a very meaningful increase that once again on-treatment was meaningfully above baseline with a positive slope versus baseline on-treatment.
Jack Allen -- Robert W. Baird -- Analyst
Awesome. Thank you again for taking my question.
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
No problem.
Operator
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 Warren Huff for any closing remarks.
Warren Huff -- Founding Chief Executive Officer and President
Thank you. In closing, I'd like to briefly review the developments at Reata over the last few weeks. On October the 10th, we announced that we reacquired certain development and commercialization rights to develop bardoxolone, omaveloxolone and our other Nrf2 activator programs. This provides us with the opportunity to control the development and launch of our products in Europe and around the world with our partner Kyowa Kirin. On October the 11th, we announced the presentation of several important studies at ASN including the work from the lab of Dr. [Indecipherable], which we mentioned earlier, which demonstrated the precise mechanism of GFR improvements listed by activation of Nrf2. Of course on October the 14th, we announced positive data from the MOXIe study of omav in patients with Friedreich's Ataxia. MOXIe was the largest global interventional study ever conducted in FA, it was the first to demonstrate a statistically significant improvement in neurologic function in patients with FA. We believe that OMAP has the potential to become the first FDA approved therapy for Friedreich's Ataxia. And of course, yesterday we announced the positive data from the CARDINAL Study of Bard in Patients With Alport syndrome.
These development position us to achieve our long-standing goal of becoming a fully integrated global pharmaceutical company, marketing drugs with novel biology in the potential for high clinical impact on severe diseases with no approved therapies. We are working to build a franchise in treating severe forms of chronic kidney disease in addition to Alport syndrome, we've generated positive proof of concept data for bardoxolone in four other rare forms of CKD. The improvement in kidney function observed at a 12 weeks in patients With autosomal dominant polycystic kidney disease and our PHOENIX trial was similar to the improvement observed at 12 weeks in our Phase II study of Patients With Alport syndrome. This similarity and the significant unmet need in ADPKD prompted us to initiate the FALCON study in May of this year. It has a design that's similar to CARDINAL with identical treatment schedules and endpoints for accelerated and full approval and is conservatively powered.
We've observed similar significant improvements in eGFR in our PHOENIX study in patients with IgA nephropathy, CKD caused by Type 1 diabetes and FSGS. The consistent improvements we observed across types of CKD that originate from very different causes reinforces our view that bardoxolone addresses a common final pathway of progression in CKD and strengthens our view that significant growth opportunities exist for it in rare forms of CKD. We're planning to pursue the development of bardoxolone 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 700,000 patients in the United States. We're also planning to expand our work in neurologic disease based on the MOXIe results. We believe that the MOXIe results provide proof of concept that improvements in mitochondrial function from omaveloxolone treatment may provide a therapeutic benefit in a number of other neurodegenerative diseases.
2019 has been a remarkable year for Reata. It goes without saying that we remain grateful to the patients, their families, the caregivers, the investigators, and the study staff who participated in CARDINAL, MOXIe and our other clinical studies and of course we're grateful for the efforts of our dedicated employees at Reata. We want to thank all of 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.
Operator
Thank you. An audio recording will be available shortly after this conference call on Reata's website at reatapharma.com in the Investors section. [Operator Closing Remarks]
Duration: 66 minutes
Call participants:
Vineet Jindal -- Vice President of Strategy
Warren Huff -- Founding Chief Executive Officer and President
Colin Meyer -- Chief Medical Officer and Executive Vice President, Product Development
Manmeet S. Soni -- Chief Financial Officer and Executive Vice President
Yigal Nochomovitz -- Citigroup -- Analyst
Maury Raycroft -- Jefferies -- Analyst
Joseph Schwartz -- SVB Leerink -- Analyst
Adam Walsh -- Stifel -- Analyst
Jack Allen -- Robert W. Baird -- Analyst
Charles Duncan -- Cantor Fitzgerald -- Analyst
Matthew Kaplan -- Ladenburg Thalmann -- Analyst
