ARWR Arrowhead Pharmaceuticals

Vincent Anzalone VP, IR
Christopher Anzalone CEO, President & Director
James Hamilton SVP, Discovery & Translational Medicine
Kenneth Myszkowski CFO
James Hassard Chief Commercial Officer
Salveen Richter Goldman Sachs Group
Maurice Raycroft Jefferies
Shawn Egan Citigroup
Luca Issi RBC Capital Markets
Esther Rajavelu UBS Investment Bank
Edward Tenthoff Piper Sandler & Co.
Li Watsek Cantor Fitzgerald
Patrick Trucchio H.C. Wainwright & Co.
Mayank Mamtani B. Riley Securities, Inc.
Keay Nakae Chardan Capital Markets
Mani Foroohar SVB Leerink
Call transcript
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Ladies and gentlemen, welcome to the Arrowhead Pharmaceuticals conference call. [Operator Instructions]. I will now hand the conference call over to Vince Anzalone, Vice President of Investor Relations for Arrowhead. Please go ahead, sir.

Vincent Anzalone

Thanks, Aldan. everyone. afternoon, Good joining its for XXXX. to Arrowhead's discuss Thank XXXX us first for fiscal XX, quarter results you today ended December With are us management CEO, today Dr. President and from will quarter; who Christopher of an the Anzalone; Dr. provide overview James Hamilton, Discovery Medicine, for has who in President agreed sub and to Translational graciously Dr. Senior our Vice of Chief the Martin will give who while ill financials. Javier Officer, is San today; and review of Financial out he Ken Myszkowski, our a

Q&A portion will In the addition, be Chief Officer, Hassard, today's James available of our Commercial call. during

Before the efficacy subject like cash comments we statements historical those cause those are plans of any statements. Arrowhead's remind made statements the Section Act statements to to expectations risks These during meaning forward-looking without of include including results with Exchange statements activities. are forward-looking commercialization respect current expected fact, candidates, to XXE Securities XXA Securities the All I other certain of Act begin, than represent uncertainties would statements. that Section XXXX. and projected goals, and limitation you from XXXX our numerous actual regarding of differ drug These management's and expressed expectations the development, around runway statements materially development and today's our and that strategies, to call in within and of contain safety future and could forward-looking of of

said, over CEO the Chris on refer filings, update disclaims statements to to Anzalone, For President Arrowhead reports turn the further our SEC Chris? and Form any call quarterly please XX-K recent these intent our forward-looking on on duty uncertainties, to concerning discussed any undertakes to Form annual today's company. subsequent that and call. details With and like risks the I'd and most of no including of report XX-Q.

Christopher Anzalone

advances The our platform. us create represent in was this Thanks, because value we primary thank value product period positioning for drivers to well respective last us clear and TRiM see us We afternoon, to proprietary substantial our demonstrated shareholders key programs believe as value that today. build We Vince. their in X everyone, throughout we and for XXXX. ways. joining seek candidates you and important to multiple development quarter Good an

First, platform we push RNAi organisms. to and because and relies difficult new on therapeutic is areas innovation. and forward address fundamentally our it diseases, This uncertain

Second, our eventual We we the TRiM the studies platform we amounts and, pipeline these well both. progress for expect commercialization. into goal our areas how later-stage progress either This as generate drive show existing of predictable is would but be works. us, more increasingly measurable drive in clinical regarding toward we large to straightforward in can believe, value data would of

As opportunities of the at calendar alone. we half substantial XXXX, progress year several first with look in fronts, on we both expect the

the middle addressable we bring instance, liver, clinical our year, the of for without For of range the opening ability to could RNAi whole new by have a treatments. concept proof adequate diseases of outside

may a studies program begin also be Takeda during frame, drug candidate we accelerate and have streamline III study market. time to also to We we that to large better clinical expect this ARO-AAT how IIb and to and X about the a idea Phase able Phase may

drugs rapidly a many hepatic what that liver. in earlier-stage to progressively platform We've which our to make by been could other programs. this programs, the do done hope initiatives. to we in develop way new areas seen diverse Let's ability our and concept of tissues our with and builds attractive applying this them upon in prior lower and programs in extra discover liver-targeted program safety begin risk. targeting looking are our have at We profile. predictable, TRiM has reproducible new power Arrowhead's is Each disease an The multiple

to Given expectation experience creation such type could as hepatocyte-targeted highly and expect generally and in new cell APOCX, and future others we HBV, in AAT, be a value a our type ARO-HSD represent this hepatocyte-directed tolerated. substantial event. Lp(a), candidates of Creating programs, clinical also in specifically ANGX potent well

only imagine Now cell but a in single new leveraging new that types. not many with type, cell

think the literally and past, muscle-targeted far? and on data months. made like First we foremost, ability for need to programs, We creation. the the target how new this down lung solid tumors have to said look platform that these we an to to cell in reason expect The about will knock clinic so I bringing target of safety the has of it to progress in into are we first a and so delivery of in program something seen we working TRiM and genes are one our can As XX patients, of recent What have in and be late been pull that this provide over and summer. to success to performs. have have huge prelude we what every idea it's the exciting, we cusp amount toward periods able in now off, value be expect we thousands good liver administered assess new acceptable TRiM profile. would to the believe just for This a we've time type the clinical leverage we bigger. XX a is a could If having

built on platform, While same idea the same distinct. they funnel are the and types tissue structurally are new

start in ongoing months. on by to concerning seen we which and first some are see need of studies seen the or collection the to data program now. then hope we well still still our program. are to expect so early tolerated either safety for for assessing in molecules that exhale we The ARO-HIFX, front to from data that the far, are program, But efficacy but on new before continues. programs. these a at exhale take stage not both is think coming almost our activity first, So We can middle We year lung have and we ARO-ENaC, share first and humans. and have establish for tolerability tumor-targeted focus data targeted not data breath We anything

hope data Regarding ENaC X in patients ARO-ENaC, we healthy and brushing some first levels in knockdown FEVX from also the have X or have volunteers to data preliminary lavage. dose via and bronchial

term course, in focused on informative. be While are, volunteer longer may healthy we the of functional data this more patients, point at improvements

current of number be study, treating will small difficult in on X to changes. the Given drug, only it the active we cohort per discern FEVX patients be may

have Should focus healthy for leap easier represent in much be should RNAi However, interpret. many is right in Therefore, This a a it would huge indeed a this ARO-ENaC, would for positive, suggest our entire the be but now. different targets lung also ENaC that company would to be could gene have it not may be we this big forward a we diseases. knockdown believe many only We from leveraged our volunteers primary franchise drug may field. event. and against

alpha to and on is Regarding preliminary calendar a short year. the progression-free cell we have some an share able target, the for of good ARO-HIFX, treatment, hope HIFX expression will in metastases assessing something is demonstrated knockdown important. these carcinoma, alpha biopsies and truly be by metastases, too too well-validated HIFX reduction to data renal particularly so form in small cell demonstrating We're HIFX focused period clear suggest in also and and study importantly, be to during potentially we that reduction are we could to solid franchise. observation strong consistent middle alpha have pretreatment we a more think a the a expression could from believe show we'll if that tumor have we taking survival, This of but we it knockdown. evidence we the be drug. Further have

inside designed variety to strategy gene rather a can can cancer wide of to targets specific, a RCC to HIFX of different any be reduction alpha, to would this is variety tumor case delivery not types. of solid solid but show in If it us across of targeting tumors, that suggest address we Our solid product tumors. we enable

forward on to lung, first in gene to increase substantial RNAi expect cell different I believe is company to clinical don't another we a can different X there concept program. could reach end programs. that file that planet our the say we and summer, we the value quarter, fourth with types As the concept a clinical calendar the we across second our CTA point. silence cell X a of expect of represent inflection for muscle-targeted skeletal the could in when a of Later that. type giant have in this a By be expression leap would can proof proof

multiple conducting parallel we're additional studies, these in work we pulmonary. targets continue to While on in tumor and clinical

X least early of I we XXXX. file For and programs pulmonary calendar at to in the number expect development, CTAs latter, us have in a

We on COVID-XX program. our also work continue

and the current RNAi on of as focused within We interrogating a virus potentially other triggers are approach coronaviruses antiviral and number are developing positions targeting well. an different different

While to continues for are the be the various important. suggests our and work next vaccines, about we preparation current the in virus us mutations to excited that coronavirus

results are we possibilities. to up pulmonary may addition, see In formulation now starting on that open early some promising new work important

inhaler nebulized we for opposed for diseases the to a could improve convenience product populations. formulation of been using an Specifically, as more patient That higher-prevalence in some device and a viable would possibility have commercial for evaluating make indications. large

and begin inhaler. then the to COPD, clinical in to to work necessary is which an over treat -- switch out ARO-LungX, formulation program to for with necessary technology plan Our the nebulized to then and development work a to was

to work and therapeutic ultimate our program's patients. decided if And time take shave physicians since a development on is now end, increasingly in it the safety have time actually encouraged may formulation a by convenience and the goal slows form some We overall possibilities. to is We direct this for their inhaler efficacy, CTA path. that off think we more a The forward enables don't the market. the useful to in optimal hold with to are off new

next We quarter, studies. will the over few pending provide ongoing an completion of update a

toward ARO-ANGX presented quarter, positive and our now discuss shift our we programs. and later-stage ARO-AAT, Let's data from to commercialization. Last our progress programs ARO-APOCX

support encouraged and they believe very these We are results of by programs. advancement rapid the

These Phase data after disease. presented liver in Takeda. of of This AASLD we our of biomarkers reductions on in alpha-X Specifically, biopsies only were is and strong Z-AAT production for treatment. the at showing for II multiple data X for us Mutant field from exciting and partner, alpha-X protein ARO-AAT months the improvements the

next We plan expect to a design a data with changes biopsy and data the of also X. XX-month and the some proposing to shortening FDA with NDA. or those the discussing potential goal over We have endpoints, the on month time to study

data ARO-ANGX, Cardiology development. and and of preparing our subsequently multiple at stages plans to their progress, Heart Phase the hosted continued data and now These presented meetings are webinars begin ARO-APOCX on the medical have and Society for the the we I/II European development. and plans including studies to For next of American to future new KOL meetings, discuss Association we

we fact, development review. time and filed getting and IND IIb where for to ARO-ANGX to key intend believe, ARO-AAT, event. lines are already and the proceed regulatory become have FDA clearer. with ARO-ANGX ARO-APOCX a is points and pending an This, a study all In potential Phase path I

execute that For suggested and clarity, drugs we the to There's as have in all advancement direct required each data a clear the programs, X multiple are do. designed they we long increased sight doing as new regulatory continue to the a lines for also line data disease have to therapeutics. products potential for are what With continue to commercial need to of support date generated may soon efficiently. have the time

By Phase the design, have with ARO-AAT and to on Phase intend and the for the then XXXX ARO-APOCX, expect year, we the engage with file healthy preliminary be we to one, first later study; confidence of of open-label pending following: NASH. an from three, patients middle review, suspected and on of data for to potentially volunteers a plan IND ARO-ANGX; about syndrome; studies size NASH report IIb and begin III In FDA track and review, biopsy potentially in Phase X four, chylomicronemia potentially in on half the with a endpoints, level ARO-AAT. dose-finding treatment familial a results of high of a streamlined study study study FDA clinical year, for and in XX-month We following begin ARO-HSD share duration both. of FDA we two, the IIb patients

next depth to the the using there's validation this data we to Silencing looking expect genetic We in need decrease have what of against to this is target HSDXXBXX. effect for a company given would first see not unmet for the in the simply fat. is evaluate of be liver clinical eager steps Therefore, to duration and any data against clearly the so inhibiting are substantial program. these strong disease. NASH, biology and target, HSD The possible we confer expect target, protective modality liver are thought is for we knockdown. But and

to to been has expect of ARO-HSD second and X hepatocyte-targeted one, be number ARO-ENaC, parallel expect the studies. like IIb short questions ARO-APOCX a could ARO-ANGX we on address the We three, studies with drug case in following: In for Phase and the -- will for described. potentially programs label other the the are we we studies year, begin IIb of already a studies for collect our that smaller candidates. XXXX of ARO-HSD; begin the I've answer drug would as for XX-month ARO-HIFX open-label that biopsies and number from in potent run open in candidate Phase both potentially and report our a two, study of ARO-AAT; half and that There

now regular to we readouts Hamilton. So to turn studies over expect the for overview, With Dr. I'd the like James? longer programs are James blinded while these ongoing. that call data

James Hamilton

and year for to I Chris, go clinical to their everyone. ARO-HSD, afternoon, like the designs plan those we ARO-ENaC, and and status. on general have this data ARO-HIFX good Since you, provide Thank through studies update an preliminary would for

with disease a cystic tolerability effects lungs. ARO-ENaC Phase It by infections. airway a First, is ARO-ENaC, safety, caused to RNAi frequent epithelial to transport. Patients pharmacokinetic designed therapeutic dose-escalating is and experience genetic evaluate rare persistent leads our CF. sodium fibrosis by is and the breathing I/II mucociliary difficulty have characterized channel mucus dehydration and reduced the the CF or study mutation lung can CF to I in in of and will inhaled a to that discuss treat up in with ARO-ENaC candidate buildup tolerability XX patients. to X safety, and normal initially and XX an that add intend XX brushing with undergo in patients planned in healthy patients the X up evaluate of to make with BAL, will volunteers changes and the volunteers portion This lavage, We X shortly includes evaluate bronchoalveolar patient efficacy The additional who will was with study CF. healthy each, to protocol the bronchoscopy ENaC design. and knockdown or bronchial lung. the one to XX to cohorts: target

enrolled We results We've volunteer pleased completed as the for and begin the CF and by diseases our small CF the second next in to month, for enrolling an before as well. and with which the all dosing in the finding to patients have relevant expand cohort. initially which at fully considering to This ARO-ENaC now date. single-dose is additional we lung. first ENaC in as are we patient plan drugs expanding TRiM into also of planned be expect is patient the we begin inhibitors dosing cohorts inhibiting of dose pulmonary tolerability the We believe many molecule the cohorts, been limited healthy to particularly pipeline platform this time to been We ENaC cohort, are we toxicity have important safety end

Remember our typically to blood on engagement not ENaC liver-targeted engagement to do will method what we better So bronchial are so do programs. volunteer a cohort, all the secreted, in I of may most a measure In BAL. is target safety the target mentioned, from study? expanded we pharmacologic we expect as First, be importantly, as this in assessing and able we for data able us brushings are and cohorts. are healthy and tolerability signal we This not understanding conducting and activity. give that

lung patients, see study, In The and mucociliary are so lung FEVX would coming currently measuring treat at designed addition, next I'd to RCC. of results. for in a clear X in ARO-HIFX. is a in These of be CF cohorts to the designed RCC total clearly II The carcinoma and will ARO-ENaC of we safety be are cell ARO-HIFX changes Phase each the clinical indications determine index Phase advanced to program we X cell patients clear study least dosing to in first-in-human of this RCC, a clearance is dose-finding clearance of Ib improvements There is or of ARO-HIFX data like patients function. eager LCI. or cell is lot XX out the highlight and in we renal evaluate to with in study patients and dose. functional recommended

We pharmacokinetics based as expression preliminary genes. well post-dose and assessing efficacy alpha HIF-X as also HIF-associated of are on RECIST tumoral and

the dosing multiple fully failed month. study of are enrolled second are cohort we the patients have be which this and in time, therapies. to The pretreated We this expect at heavily lines

data HIFX in program describe of for as Phase the ARO-ENaC, would as delivery is select and looking data we HSDXXBXX a include So non-alcohol-related to II. a positive investigational treatment tolerability knockdown. for supporting disease. ARO-HSD, and this liver potential to studies measurable study target NASH The dose alcohol like alcoholic to liver a There disease. as is further -- for well last first-in-human strong and further to and tumors I'd for to safety result characterize candidate our genetic of suggesting levels phase are also Similar

dose-escalating NASH We well of as or healthy with effects are a study safety, ARO-HSD tolerability, to NASH. and conducting Phase suspected evaluate in volunteers normal, multiple single in I/II as and pharmacokinetics pharmacodynamic the patients

healthy of dose single completed volunteers. have in We the study portion the

portion dose or the We NASH patients. study are currently enrolling and in multiple dosing suspected of NASH the patient

are month. this This After target to not completed the We more patient that and also complete is expect cohort the first is to patient sequentially. cohorts there secreted. cohort patient complete, have X second of enroll enrollment

important this X a that liver mention NASH engagement, target order short is only to of It's only exposure. So assess relative to study biopsies. utilize other later-stage to doses, which, we in studies, involves duration

So improvement, signs are but see optimal rather we level gene the target we don't dose of disease silencing. selecting on substantial expect and regimen to focused achieving

we expect is effective silencing the a target However, express so we would at level know genes, highly platform hepatocyte high of engagement.

In the even would we encouraging in target of inhibition first this there addition, so unexpected. any will are this if to are signs be efficacy, study though see early humans, of we

the of middle but earlier, reports with mentioned be year. to early X order these to readouts around they time. too come, all which we preliminary same expect will programs have exciting of the data It's around we expect this As to an data these know in potential all the coalescing roughly period

intention a would call present Officer. Our a the medical be meeting. an and Myszkowski, Ken report Arrowhead's release line over to fuller data at Financial Chief Ken? press will top in data now set to further then turn highlights appropriate I

Kenneth Myszkowski

Thank good James, you, afternoon, everyone. and

compared on or As million and we the December share of XXX.X the next Takeda December anticipate XX, be deferred projection. milestones be XXXX. remaining the the in based services. over loss the fully approximately would million reported completing grow. the clinical per operating is associated we ended operating both due December shares be during quarter costs license X and discovery upon used million $X.XX achieved to the weighted candidate-specific increase and ended expenses This Revenue quarter for head R&D in was This $X.XX includes outstanding December our R&D or $XX.X today, million our collaboration associated recognized collaboration process a loss quarter to $X.X costs $XX.X payment Janssen XXXX, compared net XXXX, of and Janssen, with to years. in additional a and additive and also to the The Any quarter is the costs. quarter ended XXXX share XX, increased payment recognized key average received be for our milestones net diluted with change of Janssen the due XX, with collaboration was for fiscal XXXX, will the trials ended per XXXX. collaboration agreements activities received trials, due million cash used quarter XX, million million upfront revenue will Net period weighted average shares as December was cash net with XXXX. anticipated periods our the toward increased was with activities to were remaining in to agreements revenue of certain recognition personnel $XX.X $XX.X upfront for ended Revenue clinical Revenue primarily to million performance $XX.X this on of quarter. million during the in in also managing relates signing We fully portion XX, recognized XXXX. count the the from increased of and $XX.X with work with of the for This based discussed. a operating January. December the collaboration increase XX.X compared compensation December million revenue outstanding. The stock Takeda Total the of for manufacturing-related the quarter compares XX, recognition million was diluted is XX, our million December obligations noncash driver for The current $XX.X ended of in continue continues and payments to to quarter million of $XXX portion Takeda. ended the R&D agreement $X.X this as the $XXX the partners of XX, ended

burn We estimate between be to $XXX $XXX and our to cash year million million. full continue

our balance to Turning sheet.

our at XX, Our investments September in $XXX.X and XXXX. at to decrease is primarily for due $XXX investments XX, cash million totaled cash cash used operating with December and compared million activities. The XXXX,

XXXX, in payment investments million. collection our total the -- our $XXX current January of and upfront $XXX the approximately cash cash With million

brief million. overview, back XX, to XXX.X shares common December I With turn at outstanding the now will Our Chris. XXXX, call were that

Christopher Anzalone

Ken. Thanks,

us of have in front lot We year. a this

ARO-HSD, ARO-APOCX, from We the expect waves ARO-HIFX, throughout and of clinical ARO-ENaC, ARO-AAT. year readouts ARO-ANGX data

program. potentially on development ARO-AAT to streamlining accelerating and the expect gain We clarity

ARO-HSD, ARO-ENaC initiate ARO-HIFX. and and to for ARO-ANGX possibly expect and Phase for multiple studies We ARO-APOCX IIb

and patients. We Phase III ARO-APOCX study to initiate also expect for a FCS

We candidate those expect cell targeting muscle. Arrowhead end this clinical and types, at of year, least new to first least the clinical our I skeletal programs X targeting file including for XX the by CTAs to year, different of programs feel about value going Arrowhead about It wholly-owned. is we're indeed for in all We growth. pieces could seems creation. are be great potential today, where what amount substantial accomplish and like is This scalable forward. X can X have a and at And expect sustainable the of confident we place

a disciplined capital-efficient strong and which balance use have move to of in We sheet rapidly us are allows in cash, our forward manner. a

substantial eligible be from Janssen will Takeda are the and also eligible for on continue if partner are We advance. programs to And as for we of products any the in of nondilutive our commercialized, royalties payments capital ultimately form milestone sales. Amgen,

for validated platform diseases is the have therapeutic technology TRiM, increasingly throughout mechanism a can of and powerful body. RNAi believe in TRiM We we be that verge an showing on the potentially

And rapidly are adequate and right differentiated options. drug the norms pipeline always not culture large are follower, of and addressing to we combination, call like the Thanks fast treated. us or This first-in-class the open a a unwavering all your for a be make without is molecules; have products. have development. joining questions. efficient me-too faster I These again better, candidates gives than powerful We would and way of treatment in to diseases challenging the to a in growing our it field. numerous Arrowhead team opportunity of us diseases lastly, product the to Operator? place now finds incremental innovative difference today. others in the and way more


[Operator Instructions].

line from from Sachs. Our Richter Salveen first comes question of Goldman the

Salveen Richter

of could that you preclinically to on translate? with the saw you the on you ENaC man? us one that what gives here you the or HIF-X want help And the what program, knockdown regard see and just in confidence to optimism understand So translation threshold kind program, then could

Christopher Anzalone

much. Salveen, thanks very

and out So evidence, genetic let patients. so me of the a true matter ENaC able safely, one is a There's mucociliary with clearance types of good That's that here. of possibility create that these evidence on the question. good do But has knocking and there's helping therapeutic tricky in are that start can we to fact ENaC. pioneers been no experimental the

So humans we could idea say analysis, do heterozygotes, hard in best the what see if a think. heterozygote look you be at The ENaC to benefit, sort is of got, essentially helpful. knockdown we've clinical I it's suppose, knockouts genetic

so still percent it knockdown, of feels we sort bogey are a reach us alpha, a now, But that an we between helpful. one. if the helpful. feels And lot where as could awful of the learn. we XX-or-so billiards, see green say can and something like we pocket, so lot in they There's respect to to to have XX% also with like HIF-X right be could hard is knockdown that's in

you a do been oncology. We models, have done we've always is trick able as as in as translation much animal as know, we -- but have could to with

see so benefit. you next over would so I we here, call really been waiting a good up The see looking see how We have clinical knockdown think the so to of are. that how to we'll the where about don't we confident knockdown. we're next have And against couple animal need win much a months. and stack months, see reasonable feel us, to seeing that see bit forward knockdown. similar few we'll good. XX% we We we'll to a that -- over to But arbitrary, That's just feels but see we're or and idea a the data data


line from from question Maury the next Our of Raycroft Jefferies. comes

Maurice Raycroft

So I mentioned Chris, to think can't remarks. the you It on but, sounds I check do wanted end readouts. of you predict prepared order like I quick of timing your just in a the XQ for the Phase X readouts by

checking just end a of possible guidance is softer update come and could in is it the XQ? So Or for XQ? if

Christopher Anzalone

the of and studies, nothing so second end finished It's be going is the quarter. for ongoing to are these shooting then. we're No, -- by

be we'll data. an make so to an we we'll And the we'll kicker interpretable if hand, see what really see have and we us. and in That's interpretable if -- have for see we can going

I end our think by hit quarter, goal. can second we that that's the the of that

Maurice Raycroft

Got it.


end data So the of That's report quarter the you'll the then? the second by goal?

Christopher Anzalone

Yes, just top yes. going to of a subset data. line. It'll it's Again, be be

mentioned we remarks, prepared data appropriate in our at fuller set is as James As meetings. -- the to medical goal show here a

show goal it the taste or forward. we'll a is So to whether -- our not then appears you are working, give more to drugs you it will going disclose and here

Maurice Raycroft

it. Got

XX do Okay. And there? plan idea the And data, have reporting can and with then doses an of you you you subjects how additional many will subjects ENaC the range dose for on the clarify be? enrolling, planning that on what you're

Christopher Anzalone

So if to unpack going because going can't how don't be that. just I I let's tell reporting to don't on -- you patients we're know. many we're see I

talking the are? As those hope we'll to my midstream, I some that the the want data sort of respect brushing to I second maybe volunteers about is patient bronchial population. lavage, in think have With address but we'll this first from and dose do the doses and said, you what the healthy be cohort and James,

James Hamilton

Yes, sure.

the safety that with so dose, favorable, either us on highest is previous up actually dose It's knockdown us or to BAL. cohort, of to what profile bronchial healthy give the best dose cohorts. brushings we select the -- since and we'll go chance and cohorts will the based been highest the that in in the has likely So see showing volunteer

Maurice Raycroft


have the many already HIF-X say you question Fair maybe sense and just like? look baseline And you can of levels expression give patients, biopsies HIF-X Okay. quick what for enough. a how last

Christopher Anzalone

to seen any Those patched, haven't are data are data we going and yet. -- haven't the so So we yet. be seen these

we've talk Although had so about James, do to want you biopsies many how far?

James Hamilton

sure. Yes,

I won't then and viability of II pre-dose we cohort patients and So of now staining the those we cohort post-dose X X all start the know we've in of until completed about patients. pre- the And in slides. biopsies

of how those completed. how So to biopsies many many yet, we'll able we know don't analyze, be but have been that that's


line from Our next question comes from Citi. the Shawn

Shawn Egan

then to in the update? Is I they the just more patients? the -- on volunteers? healthy new update comprehensive you it Thank there provided as able Is update. muscle one to you actually see have provide how safety there skeletal And for many details any patients on follow-up Are program. the Just well? you

Christopher Anzalone

up little bit. broke you a there Sorry,

between been the So that with question? -- treated that how volunteers Is have healthy patients you're so far and asking patients? many was ENaC

Shawn Egan

safety everything include? the today patients update that that How Just so good far. gave looks did you many

James Hamilton

healthy the in all four study. first true. the volunteers patients Sure. all in That X That's includes the

Christopher Anzalone

volunteers to you And many healthy go into how want that is?

James Hamilton

Yes, sure.

So XX total for of per additional a then BAL studies. that's that volunteers, XX we'll healthy cohort, add and X the

Shawn Egan

it compound And it antisense at great. muscle, point? is for strategic gating of it an for then skeletal the seems Or this being area that for there it's program? RNAi more about Great, after? Are optimization area that oligo. for you're steps like Is active the and going indication

Christopher Anzalone

you -- right the first now. Once takes to of and you and once the just have like, get we're through belt it time in a on sort GLP that For the one, got insights, now. conveyor we're just nomination there's just talks

that steps, process we so and file we've the feel complete are that sometime candidates. are the got We in on comfortable need feel IND-enabling that summer. comfortable that right in we CTA to now. And we drug track to just We


of Capital. from question Luca line Issi the Our RBC next from comes

Luca Issi

the all on progress. Congrats one Maybe on Terrific. AAT. AX

I you're PKs. us during SEQUOIA for achieve whether know expand biomarkers looking the to are a think picture. sense that to that a you just mentioned of is Can hoping pursuing? to meeting. one. FDA then of of bit on here? what HIF-X that some success optionality the goals that you the the and And on agenda this meeting? that's further alpha, second for little So meeting? primarily worth bogey some Can is give I really focus upcoming And and what's that you the streamline molecule this more trial bigger the is dose the maybe you trial understand escalation, at But are key on a you're what what on key a

Christopher Anzalone


able XX-month because So first the into go really collect learned haven't than We're we paired data the earlier want change we think points. to and too with Certainly, we then we expected. yet. we've may an study, effect discussions I the change AAT, biopsy the FDA We started pretty that data. collecting FDA some have want how much can't and a the will is with see much substantial to length because we we to discussion that go still open about be to end what of

treating the at recall, required years. can at so more planning we'll for we maybe also be we point, X were appear does endpoints. see As on on some patients shorten and least we you That to first not may if this then But study. want agree appropriate to

kind far we I drug the next focus and you, been second, as another regard there, safety HIF-X But we've can are and an feel development targeting Those There program, several well-validated been alpha, now advised. If FDA our this sort HIF-X on also first we've -- discussions, drug to get pretty we'll looks going months batched, -- is our tolerability, range, feels franchise. tumor haven't hit know, got for in data you that we're as is drug, to be say. If if what we ARO-HIFX, that. good and what on and good But think only percent about target. mean, what those then have the just just biopsies for knockdown. hard of knockdown it not focused good. and right solid we consistent and primary alpha, gets. the a a back that's knockdown, over does it's we since it have of the to got so yet. idea And franchise. are X like the we'll then With knockdown. of we things: has quite we but mentioned course, seen just getting other that, I focused we tell us knockdown we acceptable; we're -- really to is and see let here And really for have are XX-or-so in So think good you there's that the

can this place again, we then there's for HIF-X a knock as drug. in so alpha with we of we cancer If long see tumors, a And targets. solid knockdown, And can think down that we we knock we other show whole generally, as us think, reasonable host can a lot of upside.

fill of with going after, ourselves, go there's maybe to to want blank, targets so against we're number maybe in a others, in And the partnership various that tumors.

interesting, we're waiting really where we're the So races. positive, if really off just for data a spot data. right then look exciting And those in to now, I we're think


next line UBS. Esther comes the from Rajavelu Our question from of

Esther Rajavelu

I have APOCX couple on one then a AAT. on and

I said start And the the what that So of today comments with I than Phase initiating you're to with regards you the a patients, And past registrational But potential. II talked -- III you recent II Phase that in had past, patients noticed to believe levels you've patients your Phase still suggest Am then those too seem in FCS. about hypertriglyceridemia X that's XXX. excluding trial and severe with II reading it? trial, trial in to Phase going the trials I severe with greater who you're going that into a strong in the the in with pancreatitis. FCS? are sort Or much the

two That questions that? is why So there. in

Christopher Anzalone


you So are to with reading yes, into respect much FCS, that. too

medical ARO-APOCX over patients, speed hand and think it's just we James. -- as file ahead I'll drug patients. still this for as but and that a follow study, going are to that intention IND We full first so going full then for The up say quickly be to timing of and is with APOCX plan respect to APOCX, to a unmet that on there. We those a can pivotal pivotal study We our need. speed it -- is to With for is plans really we on are for we things, those population. a our an ahead forward think that important strong it of in couple move I'll

X are Phase so XXX. it's above patients regulatory studies, And going pretty We know, severe underserved market. So think kind large there, clear, it's be population. in we fat as with patients reasonably of to is We IIb as a view think right? our that we hypertriglyceridemia, pathway the you and the a those market, grossly think,

So it's really focused on. one that we're

We those and more require outcome between III XXX to have don't we're an a that, that need the XXX. going want in optionality. is to Phase also do look at, patients we the elevated Now study, that retain I probably that, we know we unmet triglycerides, that but comprehensive want to Phase think say also would think study, so study. medical IIb an who

case in going And patient we're population. Phase so that that into future, want want right study to the we to do to IIb in just now expand

I'll anyway, hand to James. it that, with over So

James Hamilton

APOCX, is Sure. question right? excluding was in pancreatitis with the The about patients that

Esther Rajavelu

Yes, that's right.

James Hamilton


the in for actually of kind study. hypertriglyceridemic the We don't active either pancreatitis of patients with the the of hypertriglycerides and XX IIb greater So severe Phase studies an we patients with than pancreatitis or weeks. middle road, those exclude either do any XXX within exclusion last have

from sequelae. want don't the may anyone had pancreatitis suffering recently study just in still we be So who associated has and

some endpoints of looking at severe pancreatitis that. the and like in So things actually rates study, hypertriglyceridemic we have

don't we those patients. exclude So

Esther Rajavelu

Got it.

the them. include within they've last XX only had it it's you're weeks So or to going so not that

James Hamilton

first their dose. to prior Right,

had -- patients recently very pancreatitis. have So excluding don't we just who

Esther Rajavelu


need on the read-through in for the have for readout be and can frame XXXX. what And then for you readouts a scenarios of AAT, us And you that Okay. XX-month few some could sounds trial? fibrosis seem have confidence, III you the your response It prior registration. in Phase X-point a like question, that to for more reduction Chris, you that not in to may

you rate how fibrosis? shown is polymer it that that you So tying are a it? link between reduction other mean about thinking I for studies to and and reduction are maybe that polymer -- going have

Christopher Anzalone

a think with the don't to that get FDA. But yes, don't accumulation the Z speak liver our disease. I much too clear is out nutshell, I want I the in that Again, this it's on want because alpha-X Yes. what protein ahead discussions of causes of to

clear it's day. think as I

an approval show rare a make to we you -- NASH, least at endpoint reduction endpoint can that for I endpoint don't that -- not if this approval might fibrosis. that's that in think be think endpoint an for mean that could an kind we should a disease. of don't we approval be of so we And argument that, or have shouldn't an part we that composite

dependent of the resolution frankly, wasn't It SEQUOIA either. worsening scale looking histologic and fibrosis in study fibrosis. -- -- a of be will improvement it rating So was upon wasn't without

hope clear increasingly good well biology the these be bit we a that that as marker. on could -- again, we and a think move we Our is folks, reducing can is that that the because burden simply


the question comes from of Ted Sandler. line next from Tenthoff Our Piper

Edward Tenthoff

Kind topics mean I little here. changing going bit, Great. a on of so much

AAT. You have partnering a lot success and B hepatitis guys assets, with obviously of had both

be grow kind company? up? what when is someone's look in broader partnerable of do might at going going be you combos, these Give As Liver asset? When the are something -- that Like, you're what we to respect different similarly? core kind Arrowhead be sense a with for cardiovascular what are oncology you how a of be on looking think forward, and future. to us to that is to in targeted disease, a is going you going assets,

Christopher Anzalone

we focusing Yes. such. question on of grow change Thanks, dynamic because will, a are Ted. That's a and great it's question, as of we capable what and course,

future specific area. you We Ted, there as company, We, even in ourselves just broadly. saw was that too seeing a we value never thought to to thought focused on technology too powerful, know, only create we're million quite much $XX was followed what you time, this that a company focus some and therapeutic were a Here's narrowly. we as when we for us the

And last push the cell most of looking so other the now this technology done that, to just you've decade, awful types. seen an again we're that. over cusp work on of into lot of we've and And

So then it the question. to gets

an what with that pulmonary now, lot, we do a least said We've in to That, make cardiovascular virtually a lot going I like We partners keep us. look As got to talked the last of Okay, to areas. what areas synergy physicians. not those we're this of can about be and focus sense types at right past, do on. embarrassment we guarantee the and for those lot X in-house we awful on? will Those offer we've of of you. the to riches

in ARO-HIFX enable is really It to as that build be. build will infrastructure be term that certain oncology? look, is other oncology quite I marketing in blow we In and see to data franchises, am good hard. other that would positive My some out to infrastructure a up good areas hope we we us well. near could that though, start sales As Will bring partner the in we broad-based It that working have point, be mean won't with at it some deep oncology a prioritize point, out be We're generate certainly help some data expertise own would us at to that wholly-owned makes some we'd targets We such. to and to for that company -- yet. want offerings, with franchise. first. there doesn't our but us. But not some probably sense open


the Our of Young comes Cantor. from from next Alethia question line

Li Watsek

for Alethia. on Li is this Yes,

interest targets? companies So just what other with other looks the the be wondering to if about similar thinking targets HIF-X program successful, you oncology? you of might then are in NASH And how

Christopher Anzalone


and we the do then targets fit... was So other oncology question how

Li Watsek


Christopher Anzalone

with other the fit was then we do we're And strategies? how Is other going? that NASH Okay. one where

Li Watsek


Christopher Anzalone

tell targets. Yes, oncology Okay. much on the have to you don't I

with We are other targets. some working

disclosed We anything -- programs. internal are do there, have haven't we we some but

it's partner As the other of with But have at year some I I time the we if mentioned ago, second in a would this a data, right that just this positive would we oncology is. at know point. to or don't I when some don't bring know next the year to or time. partner. do least to we do like part extent to like

hard. offer It With is don't have thinking to boy, right genetic much I respect does about compelling that, bit And on protective NASH. data be of so silver if like should other a HSD, NASH knock We now. a the targets you it mean NASH, to for doesn't a seem we're against have to that bullet. effect down that It is HSD. can

combination In frankly, to probably to going be a right that that approach. no HBV fact, populations. patient more NASH the I And it's is like what combination different idea for would a expect in different it's have combination is. going be I

HSD could layer sort because least compounds. said right then could patient alcoholic even the haven't to different of these there that really tell hepatitis yet. diseases. how top that for can a it. number see data backbone early were in of But were seen I be idea It's exciting a other it's data variety a of The as us HSD think genetic that's we also as you for for help of we're too of now at We've we we they nice the that think as well. like again, any past on some ARO-HSD learning and We probably populations, and NASH.

at I us And point so we're now anything foresee right populations, future. doing could in in that those the while into some not getting patient

we of about sort thinking a right non-answer sorry, but NASH that's answer, So that's are now. how


line from comes Trucchio question Our Patrick next of the H.C. from Wainwright.

Patrick Trucchio

follow-up I on have programs. a cardiometabolic the

would what wondering would looking you're be Secondly, to expected? open-label you ARO-ANGX? anticipate? enrolling anticipate And when I'm in studies and studies would smaller with patients you And in the how how So the studies many these data from answer many studies? questions ARO-APOCX these

Christopher Anzalone

Yes. Thanks. I'm up. that picked glad you

studies those X Phase course I think and the APOCX a study APOCX III it's IIb an in for We've one lot. important point. for We've about talked talked the in Phase past of ARO-ANGX, about the FCS Phase for IIb and patients.

for studies. now are these to just questions some starting other smaller explore We

a But probably we be point, yet. We more have what those of our mean. set those that are bit, call, handful going those then. set There's haven't this by assume exploring next things. and that talk I set can on so a to these motion conference at those I we'll about

frame we of but long, Phase And look, during be was to to many is because One they're exposure. questions answer here these IIb say not be this goal going going a to Our are can blinded. twofold. as time studies year as

going we a advantage into we the be do that answer that And that move some to as and to questions. frame study that. are there's -- those we time so might a well can't pivotal other to until finished, -- can't looking that time of so take we just time We're

process. label, be on shorter are some these or longer still to the on in ones of think so Many some of these studies. to while going are of them I chance open and a these us be it them can report gives studies --

us about these so. that yet about seeing. or still next But expect have and those specifics really you couple over set can't months we'll what I tranches allows talk give to it I so that. because continue the tell And sort to we're in we're of of you the on

Patrick Trucchio

few follow-ups. then programs on just And lung it. Got a the

on First of those of a asked delayed on a drove And RNAi FDA is the specifically protocol changes? had to for? that ARO-ENaC, need for driver something ARO-COV, Is because the competing a work then what hamster what decision Or changes? been more the model. program conduct in

trials EUA U.S. how antibody, do you new -- And some variants? view as the the positioning use the of to resistance but monoclonal they with these compared which I'm resistance? So could authorization this emerging this expect for the avoid wondering RNAi XXXX. variants things new impacting extent begin human in if secondly, for and to should how more then are what to are to triggers progressing program program in have emergency we RNAi have several authorizations And ARO-COV appear issues antiviral

Christopher Anzalone

of lot a There's Okay. there. questions

and measure frankly, us. So The see I have in a by with for important Because bronchial weren't volunteers. in yet. ENaC. bronchial an the want now developed were in we remarks, in required really order patients. we start sure included -- measure to It see this in first lavage ready and Since look driven really That's we going we're can entirely at knockdown let's look to as to changes at because, desire to the healthy volunteers. protocol brushing by wasn't to and the We healthy mentioned go, assay is a in assay wasn't so protocol knockdown have this our be didn't we to It prepared small study anybody. it. then,

just well FEVX how it's it a difficult changes likely measure gives patients it's working pulmonary And and well be better how us in X going so this to to this and it's is that in so epithelial given cohort drug delivering cells. is to on because see small, a too

change the folks. was protocol including for those that and in the So rationale

able to hard the in we Now to fast models, and it's to we not control animal do COVID part we've -- are move been wanted studies. just the large to as COVID, models been because animal get don't -- animal with on these to as COVID, slots respect has

CROs we work So that in can our we as have with. other areas we've of not we been fast variety been or do can own we where have got studies larger as a

of So We're because it's it, lagged that. a still excited course. of bit about

that is mentioned antivirals, are You our a point, all program, that has has at going variants new belief our here the It it this people certainly reinforced That -- virus does is not just not right? real the mutate to that for talking possible there RNAi-mediated some role around affected is about. vaccines. but

And so our coronaviruses. goal not only broad-based here that, also make potentially antiviral work a but to future current this could against coronavirus, was

thought for is so just And this again, kind way underlines therapeutic. of sort out it our we it out. playing play might the And need the of

HBV, with about than going good that be multiple a shown in one probably single triggers. we've is better to HBV. this And point a but trigger was be triggers way playing antivirals. would good we're it at your is The know multiple As the for pretty we same it reason is view we

will is to coronaviruses different remember, you mutation, triggers. a variety wide against out for of has guard the across coverage That is our you As but the reason HBV genotypes. broader as be are there. well reason One other may here that case compound two to give


B. of line Mamtani from comes Securities. Our Mayank from question next the Riley

Mayank Mamtani

and productive even Congrats on XXXX, you. XXXX like seems for a a busier it ahead

from comment antisense, target at you on there follow-up that? can engagement? that quick or this -- ENaC. point PD from So anything you've a on anything an on a on learned standpoint anything alternative gives confidence you Is And a approach,

Christopher Anzalone

It's question. antisense good we've data to for seen. interpret a that's that us the Yes, hard

it. been bad been news but the at news way there's look no So us, no there's for we either, good there

unfortunately. know a And anxious over like. our like. see have of of sure. for And data heck data more and what lot to look to couple We'll wait no, next that's a so those what going We're the see course, of to we're, months, look

Mayank Mamtani

we duration proteins. on HSD if there for the to again Okay. I program? follow-up program. just -- from read-through biopsy all, a And AAT the then anything, any at it's got from biopsy the learned understand Is different the quick we And X-month

-- We internally are different of as about complicated read-through types about you NASH about the knockdown Any program? think disease. think talking you guys

Christopher Anzalone

that I learned are proteins there's in these that don't all different. is read-through. know programs these we've What all

different. triggers to and so are And -- all are knockdown, and be going Depending and the duration the protein depth different. upon trigger the

and will experience Lp(a) that our confident knockdown ANGX of we good, HBV And that ARO-HSD with in so and to because apply deep see AAT that particular are and anything durable others. we we we and with HSD. don't and in know learned But APOCX AAT can I and

I adept is are -- think really looking just We integration at We're success here of narrow. knockdown. pretty

of in As study. we don't very short We this alleviation not really it. expect mentioned, disease we're for looking

a Phase a to And we pick us that knockdown is about And expect in that into learn a there's may then -- take But deep get dose biomarker, at so disease this And how choose progression. there we're don't -- biopsy just point. trying the and unfortunately, a dose. -- a know IIb looking at way we're and since idea circulating is. of that since larger that the only to and would we'll anything take see to durable we give some don't about to study

Mayank Mamtani

clarify, X-month duration months? or to And biopsy, right, XX

James Hamilton

do get XX X two dose. biopsy is post-dose after post-dose day and the These last different time we is so is other And XXX. Yes, other the at patients One the points. doses. at day

better we to get duration. a them So stagger of idea

Mayank Mamtani

in you context -- have my keeping partners think and should Also, about J&J, burn opportunities as Takeda. obviously for final some flows, your How we And of and question cash Amgen coming there? near-term... in, Great. rate think the Okay. you some on about

James Hamilton

I here. think lost might you have we

Mayank. quiet, very You're

Mayank Mamtani

now? Can Can me hear me now? you you hear

Christopher Anzalone

back. you're Yes,

ahead. go So

Mayank Mamtani


cash final flows. on So was question

about you like should about of out might XXXX for As about think little and bit programs expense Again, burn a pushed being in the different getting the XXXX? we and AAT partnered milestones think think stage partner out. the of rate? APOCX J&J, think we obviously the some commercial should Takeda, about your and Amgen from be how How context

Christopher Anzalone

and that between we We've afford that's think we burn of million time. during to reiterated to on of have XXXX. possible. chance and and that of certain, We But guidance million because, B, a year. worst it A, case don't I that that we got so $XXX any this was you payments tell again, any even expect fiscal today can't it's give Well, milestone And But is cash it. -- I trigger do any uncertain; okay. $XXX can't if in others plenty some that. That's we triggering I think get until it's we

And burn. year next feel then comfortable to milestone right to absorb I We that of have quite of have can that plenty again, kind access cash payments. now additional we

good our look, balance additional all sheet about X right about And feel to our partnerships. good capital now. between I feel access so I


question from next of Keay comes the Nakae Chardan. line Our from

Keay Nakae

with your now a Chris, to to than levels thesis higher your you believe intervals? low too that dose you achieve dose XX% working and on needed? if is HIF, the knockdown prove right if Do current on higher that go an should be respect to disease, could effect based that have knockdown could

Christopher Anzalone

in be the a so highest we knockdown This get as traditional We'll fact, seen then to signs we that high what like more. we're we knock see. not giving. from see we can we dose response what not cancer Yes. we've respect those and far, we if, where At helpful least until trial, see It'll dose can't We looks escalate sick it's down. -- at don't is XX% toxicities. as the we see really dose those no right, living people

that as we're in knockdown point, possible and still that like to be long And we're as issue. it so more evidence certainly think safety said, I have neither happy seeing get ENaC not got to knockdown HIF-X we alpha there's And seen escalate. your we had. XX% DLTs, to that sure, far is we've in nor And we so a


Leerink. comes question SVB from of from line Our Foroohar next Mani the

Mani Foroohar

your or knockdown a was -- reasonably prepared benefit is to readout, many need it's I from up isn't Like B, the which et the move an that see How FEV you that's in see quickly A, either you very necessarily and data Maury you in uninterpretable a benefit data in want to the do healthy was sets dose how others. deepen comments base -- relationship Vertex, Around substantial ENaC or the while dose do choose interpret to higher? this. set, your possible unclear it profiles between cetera, as that normal I follow actually from that forward you on seen doesn't seeing early one you on and Bio, volunteers. set efficacy? Translate knockdown to think Should target touched so mentioned data that who effective;

Christopher Anzalone


-- So to until I we I a the but of the into look, so that play look, we those is changes, saw disease the we're in guess X we FEVX there's that can't to. would we this this data. a hard lot at go it's that franchise want drug discern see -- ourselves broad be, think certainly news. way don't got good worried good working But answer said game we patients, areas. we other think We've can is if knockdown point. got it can a We've we to We that that

let's treat is look, large some not with because a now CF, number in more so a very X And patients cohort.

FEVX patients. start we XX we one. or if if see can get so see change an Let's to to That's

is study Second is, it's a look, pretty -- well. this as short

knockdown. -- way we to happy be changes. to we'd getting FEVX in dosing good so And to Maybe manifest we're more the a start say see those assume need to just bit in of

longer plenty can least them that's at is bit treat have lost some To if cannot I see well more treat as all that we a this good the or really contrary, if think some And not suggests to we year we we've an patients something powerful. time we of FEVX but knockdown. changes. register to got see them that FEVX longer change, as monitor So see

Mani Foroohar

Great. helpful. that's

James Hamilton

the be will dose of X the have cohorts middle year lower we'll The cohorts.

the dose patients to CF go. we top So have in still

James Hassard

shouldn't would talking matter be theoretically it like but ends the of about this, end. also a you're baseline genotype a that small And what background patients. is therapy, the or is make the When this small It difference. characteristics may

is a get think safe. And delivery, So we here the get down, knocked point that I then functional that's we're win. we and main

Christopher Anzalone

what able focus to want That's on. be Right. we to

the ultimately course, to at want important. are tolerability of on couple we drug that at are Let's those off forward. over of the patients we'll both really quarters, -- next going look, when FEVX, the we're we're of because of this focused course, looking and, is and what those: be going the But data of look and are knockdown drug. If to safety races, positive, continue we the to

Mani Foroohar

to you might a a sort have evidence, or parse correlation a expected there XXXX going this to there's out maybe the some unclear show Obviously, out guys, and to of say, reasonably as to later-stage kind alcoholic Are companies over in correlative of early And pivotal trial? studies we data. commented really been That's causation of issue? positive, couple that see be really at see, other datasets biomarkers the also is to to in knockdown you as that then on of benefit there hopping that and clinical of that steatohepatitis. need helpful. a What NASH, longer-term terms there in is okay, tracking? if from would nonalcoholic early potential HSD parse positive, both genetic it's Are and benefit datasets you're

James Hamilton

I one. function so mean sure. studies and been the ALT target individuals one easy for Yes, to to stage biomarker that loss those is mutation in beyond. out ALTs, have read to tend that's this lower -- correlative and that early and that for I'll the easy that's of an take us

imaging lot other a terms not there's else a of in that, from or blood biomarker standpoint tests. Beyond whole

to Phase you're think looking pharmacologic at then of and I studies proof biopsy effect show benefit. IIb


does conclude the like of Anzalone back Thank to to question-and-answer This session hand further today's I'd program program. for you. the any remarks. Chris

Christopher Anzalone

to today. us a It's joining for you we'll you, with next to quarter. and talk everyone, been speak pleasure Thanks,


and you, This the program. gentlemen, does participation ladies Thank conference. in conclude for your today's

Good now may You disconnect. day.