Thanks, Warren.
Turning to Slide X.
the review Warren identified mentioned, FDA, completed were significant recently we meeting. mid-cycle in and communication issues, As with which four they the the meeting discussed
did issues. issues Importantly, not FDA designate significant as safety the any
and information of four FDA kidney COVID-XX will analysis, I As information NDA. request is in in function, duration the these slowing identified continues include slide. of each issues, impact discussed Week issues treatment of may acute next the for and and as were and pandemic. covariate customary clinical XXX it a topics: all duration issues pharmacodynamic other with about Thank provide the window may review to additional sensitivity FDA the off-treatment were that the statistical review versus NDAs, in you. identify as decline analysis The of a effects it analysis the additional
question topic, first eGFR loss a bardoxolone placebo whether the the function compared FDA to the of group. suggest in observed kidney the group the slower rate of increases Regarding as
observed from Year FDA using and eGFR placebo Week Week Week at in X group. data that computed of mid-cycle Week starting rate preliminary acute function XXX. kidney distinct The eGFR did suggest communication changes manifestation of slopes. based FDA XX in the a its the increase the not bardoxolone on analysis XX on that XX loss was Year loss Year based in the clarified the the slope of group Week two in full to to in X XX meeting, eGFR During EGFR noted A slope X a slower in after chronic
from Weeks Year X eGFR to loss eGFR in of As of study. the I’ll loss XX XX patients explain by the in shortly, who the bardoxolone is explained in early discontinued
the Importantly, of did than Year Week on The decline the of full the to the of Year not rate X in bardoxolone placebo rate after FDA XXX eGFR of from specifically treatment. XX increase Week eGFR acute X patients is loss lower in patients. comment manifestation in the eGFR
As early with by I patients eGFR discontinued in to bardoxolone most eGFR of in study. XX from explained Week patients bardoxolone in the is Year discontinuations treated in who mentioned, and occurred randomized just treatment, loss XX of observed the loss the Week X to
Week on to acute in placebo Year at eGFR an drug after eGFR XX acute Week This As to was XX. the initial of loss the in effect contributed patients the of the during treat X analysis. intent in by eGFR that decline figure of treatment who to discontinuation experienced levels XX, apparent returned and the top increase discontinued maximal right Slide shown
patients This who achieved the not patients loss observed in XX the did patients on on XX the population, analysis, the that who and in bardoxolone-treated Dose. Slide smaller data shown to to to Goal XXX patients eGFR pre-specified CARDINAL mITT show Goal a from X Year treatment Week bottom As experienced at compared Week achieve chart intent placebo. Dose, in the patients that was XX, modified treat restarted of of in patients or Week ITT from
treatment remained their on on continued while maintained bardoxolone not did to placebo and Dose patients average decline. progress patients who receiving Importantly, Goal
sub eGFR delay in decline placebo-corrected In patients these failure patients, eGFR translate four XXX Based all separation large, the experienced two analysis least Week to years. kidney in groups. at a across X, of eGFR absolute of rate for historical addition to on of bardoxolone the would to this loss reduced rate improvements at Year in
they For continue potentially those Goal maintained patients their if not who failure did Dose to are progress, progress. on and long-term not could delayed kidney be
eGFR patients, in and baseline time of diverges above failure. these kidney CARDINAL treatment third beyond. increases continuously treated patients from with the believe that We data sustained Lastly, in demonstrate delay in and placebo from are EAGLE treated over analyses demonstrate bardoxolone year in could eGFR in
for In followed we the Next FDA the whether pre-specified had Week analyzing slide. the FDA’s model off-treatment preliminary values. analysis the for communication meeting, XXX questioned
and treatment explained model analysis an treatment clinical analysis for the effect is using of of covariates, model generated we as such model. the analysis data Covariance analysis was datasets statistical from conducted treated process observed in well patients, for and and model the plan variables compute with with bardoxolone not produce included Analysis meeting, reference All missing it to datasets be CARDINAL studies the patients the deviate use duration The FDA Both independent the for compared group for ANCOVA to SAP and that that p-value. During include covariate. a data, generating at or the change and as incorporates can imputation The acknowledged that would to missing in data. are XXX placebo called or did baseline The between which datasets. imputation step pre-specified eGFR SAP, as from or accordance uses Week as available baseline or step, pre-specified data an these characteristics. treatment analysis our
a covariates step duration imputation not we of in The the was the imputation We would covariate step eGFR outside step of data observed how of would covariate the Many that extreme the analysis. range therefore, treatment durations, due over imputed further reference the imputation step and, not the duration sparse falling the resulted have biological duration these did was explained During in covariate been and FDA XX% included SAP of inclusion discussed step. values to could have range suggested meeting, We noted in full treatment the included been specify that imputation the values. across for plausibility. have the of values the eGFR imputation in treatment exceeded of the treatment conducted.
observed therefore increase the doubled data the maximum FDA primary would Again, p-value. it standard would the been larger, not in the the example, nearly of Week that, data error have pre-specified from For was analysis was the of these in have increase the in addition with change inflated meeting, affected change of baseline maximum imputed while would overall SAP. an artificially four-times baseline and the XXX extreme at acknowledged We from the values accordance more explained conducted XX than and have treatment effect mL/min, XXX, the an while the did that importantly, from during with not deviate mL/min.
is the to dose. we Slide occurs XX least analysis Year and days pharmacokinetic increases XX. the eGFR include to Turning eGFR last the demonstrating extensive after data CARDINAL, pre-specified off-treatment at off-treatment by of last the obtained acute X window after which by days in XX dose, that supported values resolution
under bardoxolone trajectory for that in their for patients of by only all the of discontinued dose, had dilutes the XXX Two effect for patients powering eGFR the including Slide analysis at CARDINAL bias significance eGFR period first certain of that one-half discontinuations a and not did levels limited bardoxolone Year or the study, scenarios, statistical off-treatment the we within early. analysis. assessment. of disease, of Alport including analysis powered between Year treated of magnitude favored rather Week the included part we patients. X bardoxolone analysis XX values Including eGFR size bardoxolone, the effects these in eGFR of These test other the after values XX of time, discontinue the the values of excluded patients even including a of Week eGFR the the Week using and key tolvaptan effect to dose on modeled has hoc similar in treatment of with off-treatment endpoint. the analyses values series XX Approximately values a changes. Furthermore, establish and significance collected include of nearly These inherently ADPKD, trial randomization Despite in with secondary when of the the the including the discontinued XX one-half more last than at study limited a show trial or of for syndrome conclusions table to had after in weeks off-treatment to a participants after based XXX bottom their meet rare variety off-treatment XXX is was irrespective time-off those observed As the prevalent that results resulted patients earlier off-treatment on meaningfully eGFR least effect the the of When trial. observed of REPRISE this, the the the overall XXX the weeks to power of from effect treatment, which established to at weeks therefore, for for XX values post the assess the analysis in long shown that Nevertheless, the time there for collected conventional analyses XX, The treatment in that days treatment precedent window association period estimates differed sensitivity treatment FDA’s FDA treatment X. principles, in randomization the patients placebo no of at which collected at days these sensitivity occurred were minimum drug. results a post sensitivity Week violated XXX least diseases. patients, of in XX last sensitivity these dose. the analysis. conducted patients
the data of these a analyses more that to by bardoxolone. eGFR the cutoff these The to similar using meeting. and were the days primary to similar analyses performed last at available included FDA performed Week a those by treatment as to follow-up we FDA the after least results dose. new this sensitivity However, XX provided favored XXX effect for We off-treatment analyses analyses in the
XX% Due implications CARDINAL XXXX, COVID-XX with Moving health patients conduct also safety in our of of guidance protect were the the while not conduct, Week the and FDA XXX Slide and visits, ongoing that significantly drug involved pandemic. first XX% assessments March the EMA. timing healthcare we or were study communication two before to the did a dispensation. start workers the XXXX data conducted and health COVID-XX pandemic of accordance global maintaining and of X, the quarter with XXX collection serious of pre-COVID meeting, of the as or pleased steps your conducted XX, public assessments to mid-cycle as Week In emerged treatment in were by during FDA we that impact acknowledged the the to our studies took trial, provided study after the
there number appeared to that treatment The However, conducted the by according post-COVID trial, larger to period. the the was post-COVID later be difference with of pediatric assessments patients Week patients group by COVID pre had for driven study’s post-COVID had data groups during progressive collected subgroup. of enrolled the differences the Week inclusion XXX post-COVID the driven XXX disease findings FDA and noted endpoint between and post This analyzed therefore. in when versus the a in pre-COVID subgroup. rapidly more the in
similar the from estimate periods in change observed for the treated for XXX Week and point post-COVID across were for at the results, baseline both is bardoxolone differences patients. although Importantly, pre eGFR
slide. Next
that communication issues During in during previous on were safety FDA topics meeting. mid-cycle safety mentioned communicate topics. have Prior calls writing the not disclosed review discussed significant any did the mid-cycle communication not and the meeting, or we about
study. it risk identified current will safety in review, Additionally, its ongoing FDA the for be that safety bardoxolone. and a been believe new EAGLE mitigation on extension does evaluation or no stated program needed not signals Based the REMS have
globally. the Slide Phase the on X evaluating Moving bardoxolone and the programs B Stage of ADPKD, a form We enrolling patients approximately to to XX, has CKD design with most efficacy X meeting FDA patients had with the our development also with CKD, ADPKD trial trial program. treatment for regarding trial. other Type the of CARDINAL CKD is on to in X common hereditary safety a similar of FALCON across FALCON recently the XXX the sites we’re
minutes We from have not meeting yet. the received
ability previously study data allow initial the data may the Thus, support application we CARDINAL, NDA efficient inquiry, our are that from protocol. an FALCON FDA unlikely FDA the of based design However, of would study in the the trial we’re time required not noted an submit available. syndrome is response to and feasibility for to the X the accelerated using during study experience indicated regulatory early Year considering application sufficient and initial as the support FDA’s that to interactions patients, our X on not early its input Year support first the Based prior to FDA may clinical to it intended to submission meeting, milestones the trial year CARDINAL is approval. uses discussion approval. an Alport amendments our the the X requested support of like by be regarding while that submission accelerated on acknowledged at with an We that the early Year an possible. of timing the before the in to experience In submission, the results
first We the encourage its and so point. be conducting recommended until after after FDA against X the the proposed analysis. X off-treatment modify such, year the completion. not Year instead to unblinding we endpoint end plan trial analysis us to as FDA primary Year will and Year X primary The the the As the the the unblind a that analysis protocol will off-treatment trial specify
receive do The who NDA. in key endpoint patients evaluating this values dose eGFR missing be similar at an one SAP of This regardless a is weeks during specified earlier the not discontinued efficacy recommended at Week study drug FDA review XXX considered using time of will time syndrome the also current obtained year whether conducted Our the second to one XXX analysis. the study FDA of Alport analysis least treatment randomization, points, that sensitivity at specifies in by example, after over for point. patient
feedback and FALCON the the to that FDA patients. for on We new be revised submitting sure FDA incorporating the review. We want to we discontinued for comment SAP power will the be FDA’s
a the size result, of increase sample current study. XXX enrolled from the to are need As target patients. we than not may the or XXX More patients in may currently
We continue to XXX by in the expect patients of enroll XXXX. to FALCON end
provide our target However, if increase we to timeline. on decide enrollment enrollment, updated guidance we the will
Moving to Slide XX, hypertensive CKD common The and MERLIN as including Week is primary a double-blind, risk placebo-controlled forms from to and Phase CKD, others. X in XX. multiple a rapidly of CKD, diabetic MERLIN etiologies, IgA rare eGFR is trial baseline of to endpoint of in patients progressing at nephropathy, such CKD, change due FSGS,
trial CKD. trial progressing quarter the data stage proceed like criteria. for to of X update. of with Patients results larger rapid to with at would progression need unmet multiple have provide that, of a completed XXXX. can in this population a the in experience expect have enrollment to disease Phase I risk significant financial of and similar and potentially the Manmeet presentation forms high a kidney a eligibility turn end would We If to across operational With over risk are are fourth the to positive, top-line MERLIN study we