Alnylam Pharmaceuticals (ALNY) 28 Apr 222022 Q1 Earnings call transcript

Good day, and thank you for standing by. Welcome to the Alnylam Pharmaceuticals First Quarter 2022 Earnings Conference Call. At this time, all participants are in a listen-only mode. After the presentation, there will be a question-and-answer session. [Operator Instructions] Please be advised today’s conference may be recorded. like Christine the of Lindenboom, and Communications. now your over Investor I’d Corporate today, host Senior Instructions] to conference hand to Relations [Operator Vice President

unable Relations Lindenboom, today Medical me the Officer; join Garg, Chief a Tanguler, phone to Chief Poulton, President Good Chief Alnylam. Greenstreet, on Senior Financial Yvonne and Vaishnaw, Officer; conflict. I'm Communications at personal Jeff today Christine of morning. President call Officer. Chief Investor due Executive and are Commercial Corporate With Pushkal is Vice the Akshay Tolga Officer; to

conference For the of those of investors.alnylam.com/events. you participating going website, Events our slides via by be section to of the call, accessed can page Investors the accompanying

Harbor for with will and prospects statements expectations, contain future factors, of Securities the file Reform the results under plans and purposes remarks XXXX. update some updates; would remarks provide those the and this upcoming preclinical Tolga by on forward-looking discussed will constitute indicated our from as call recent financials, our of for call our most SEC. Actual and by Private which questions. concerning important will Safe summary call we on context. provide X, quarterly Litigation will today’s During outlined provision a introductory of Alnylam’s those of you on general that Jeff an is the commercial may report to clinical remind Act Slide various including materially a your review progress. in before differ global these Pushkal followed milestones deliver review forward-looking open Yvonne result statements recently our like will I the

any statements. over of and now date. such our turn call We forward-looking disclaim of to the of the obligation Yvonne? not relied representing any With specifically as our this any will that, statements be views update only addition, Yvonne. as upon to In subsequent recording views should represent date I

for joining everyone, you, thank and the today. Christine, Thanks, call

pipeline quarter Alnylam XXXX portfolios. of another progress commercial was of first quarter continued at The and across our

quarter-on-quarter portfolio pipeline of ONPATTRO, combined an therapeutic in revenues on our progress, steady RNAi continued despite we advance. in commercial increase from to expected patients product that First, programs decrease therapy. GIVLAARI OXLUMO, a Alongside observed and our commercial

newly TTR the new from to X to July NDA study HELIOS-A franchise, a of and we with facility. allow XXXX, XX-month related positive new With PDUFA review, for of delay, review the date in a results following vutrisiran. information present is a we April of under for added the earlier Phase secondary announced X packaging vutrisiran months the XX, The the labeling

We studies. also brought that been Phase initiation as clinic ALN-XDH, X the new X And two today, gout the into of Phase initiated. study the with patients with we announced has programs

CNS X, targeting top are from line disorder, RNAi programs a first very in platform. milestone late the our for on a results has expected both XXXX. these Alnylam, Phase entered Additionally, exciting therapeutic, ALN-APP And initial of

three we out, drivers. based for further poised key on growth believe Looking is significant Alnylam

in leader of near-term to global medicines patients. First highly to our is we TTR where become impactful delivering potential aim expansion franchise, the and the differentiated

and best-in-class pipeline find well commercial positions further driven to beyond. drive first Tolga, rare by opportunities performance. delivery, deliver company sustainable a expansion of our platform is product And innovation new growth diseases. a commercializing engine company this on With Tolga? Alnylam of making the let targets, diseases Alnylam and/or the Second, expansion of goals, product our us rare for beyond that, driver medicines results. top developing for transformative while patients me comes extrahepatic around PXxXX call financial which and a We and pipeline and for to diseases candidates now our engine, high-yielding can of third validated into turn all from enhancements, believe our the biotech from a to exceptional genetically over comprised all common ability our our new key prevalent review organic with delivering XXXX for to world,

good everyone. Yvonne, and Thanks, morning,

quarter we as therapy increase three patients increase, stocking reflected spite the and In as benefits. by on of first from compared progress, number The net commercial benefited a X%, with of steady gross decreased non-recurring revenues products our QX of this reported QX variety X%. across XXXX, by QX

QX, January in in the and Additionally, decrease in we saw experience our at some where cases portfolio compliance when Omicron their headwinds did in February, of U.S., peak. were the particularly early COVID a from part patient we across

our We market will encouraged cautiously that into March by have commercial April. our each of products. optimistic that further the the the on recognizing of of extended impact will the have I now that improved COVID for we're in are conditions year, uncertain. minimal performance developed of operations the details balance pandemic that on remains course And provide

X% increase exchange contributed QX, increase three representing revenues QX achieved X% were stocking an on in primarily therapy, following. included commercial and the at markets, driven foreign which global in year-end the the gross on results in in first QX, impact XXXX, modest reported due from up decrease was patients our over primarily unfavorable by worldwide, X% strengthening compliance, negatively over product increase quarter, and patient contributing product therapy in their patient following growth treatment net increase by at to along in January decrease fourth Inventory dynamics, commercial Omicron For patients of X% with in with to demand U.S., compared A decrease ONPATTRO by an across the ONPATTRO end growth. an to the sales quarterly net patients deductions benefits, dollar in cases a in a growth. XXXX a XXXX. a in with despite which all million reported QX representing ONPATTRO, and X% due decrease February of X,XXX in At X% increased $XXX impacted net growth impacted compared In In versus several X,XXX quarter we steady ONPATTRO the QX, patients quarter, increase XX% were products. deductions X% QX, were sales impacted versus an U.S declined to gross which QX on which to non-recurring a in in when international peak. and

XXXX. COVID GIVLAARI, negatively and was reported non-recurring the which key of million dynamics, XX% XX% versus revenues representing in on primarily by patient global XXXX with patient decreased patients QX by from our QX deductions Moving 'XX, achieved driven which growth quarter, an quarterly in to 'XX end At and inventory XXX February; X% new treatment compared commercial demand, first up we reported impacted gross X% negatively negatively stocking compared versus GIVLAARI the to year-end were adds by in the primarily $XX by following net growth representing expansion, quarter, net launch. markets following worldwide, XX% XX% GIVLAARI and U.S., contribution of XX%; to impacted several QX in gross across and which QX, the and due patients included January the the from decrease quarter, in growth were growth. which a impacted reduced increase the compliance, in a 'XX, over with fourth initial with delivered markets, at XX% QX an XXX in international QX by geographic including growth over robust on sales U.K., net commercial to Flat impacted therapy increase QX patient patient In following. the GIVLAARI benefits. In growth despite product

XX%. increase first non-recurring Moving versus representing and an commercial the increase to U.S., now over three the and the demand our XX% were in with quarter treatment compared the quarter, impacted our patient OXLUMO, decreased markets growth the over increase compared global despite demand, to of on with the the a deductions international million quarter. following. early we in increase growth growth. at QX during despite of XX% steady driven up order achieved decrease first part included to therapy, primarily OXLUMO from by gross QX from increase worldwide, A XX% COVID achieved encouraged impacted the versus on performance an X% in well gross emerging In 'XXand which timing reported XXXX. during revenue product benefits, At quarter, XXXX in products, OXLUMO remain than in growth patients several in an as XXX quarterly on XXX following we representing by deductions and we year-end growth were in in revenues of QX ONPATTRO during XX% growth to quarter, OXLUMO due sales quarter, which decreased more 'XX, conclusion, markets. reduction of negatively in patients expected, therapy primarily QX, patient the an offset with QX, the patients the reported $XX end the across net In sales net by in in and the X% by by quarter, in the during by QX, patients, particularly as in challenges as in partner the net

in now approval polyneuropathy our by growth patients TTR With to and disappointed Additionally, we for represent review potential remain to incremental are delay launch for date, I continue will Pushkal? the to recent we this FDA will even the franchise. for XX progress. turn were it U.S., and pipeline that X-month the confident over option TTR R&D that, an July we to product though poised vutrisiran Pushkal, our PDUFA attractive the and opportunity by upon PDUFA new an

Thanks, Tolga, good morning, and everyone.

in clinical are two across you by patisiran efforts on of product indications. Let candidates, a ATTR me we and updating begin amyloidosis, our vutrisiran where advancing number

polyneuropathy ONPATTRO associated in world patisiran markets is around the approved ATTR multiple hereditary While to currently or with amyloidosis. the

this we're APOLLO-B both X track We the of also Phase conducting wild-type To patients. of delivered to year. studies. two the a well line vutrisiran, top we and by remain in the it's report advancing on products to and Stargardt treatment ATTR study, In in cardiomyopathy, amyloidosis, injection, the amyloidosis, We're as subcutaneous are ATTR middle for ATTR this X and in development hereditary conducting which quarterly labeled end, disease. results expanding committed amyloidosis as also to is we're Phase

study which first endpoints In FDA to met The XXXX, which basis under submissions from shows we April amyloidosis polyneuropathy. the Those vutrisiran for and data meeting, patients which AAN months. the HELIOS-A, the review. and positive presented ATTR the EMA, at at the its both currently our study with and form secondary evaluating are X primary is hereditary regulatory results is

a of As review information we the related packaging of added timeline NDA the allow newly facility. ago, secondary FDA announced to a to the review few and has weeks new for extended the labeling

was launch learning our part cGMP an we vutrisiran timeframe facility letter a original upon outcome submitted routine inspection. to recently secondary uncertainty the plan was application, nevertheless of inspection as third-party that NDA, to inspected for amendment as to a we vutrisiran use complete could have labeling and but the packaging Specifically, resulted for with vutrisiran regarding unrelated the response This its it unknown, was the resolution. receiving in

the raised amendment the with the potential no the like at is to regard trials have have resulted a clinical of review this July related date X-month approach there there XX, updated in The not that to efficacy inspection reiterate original specifically safety been been data or the for facility goal allow product, believe that we questions extension, PDUFA to and While were additional requested. issues or no I'd this to vutrisiran, approval. path our a offers to fastest XXXX.

APOLLO XX safety will In the the statistically France. or patisiran and in these on study, parameters and data on secondary slide. improvement by present nutritional attractive if study echocardiographic XX technetium improve suggest well patients vutrisiran as HELIOS-A profile, to significant the overall gait shown an exploratory in this Furthermore, We're also by Patisiran of in these analysis endpoint positive from met addition at in modified impairment that of neuropathy, also NT-proBNP with along neuropathy as year original all amyloidosis We the this presented totality on results relative cardiac measured improvement with endpoints results, as improvement to encouraging improvements and placebo mNIS+X, and all vutrisiran, polyneuropathy. TTR the potentially scintigraphy providing the APOLLO trend life, study. the at Phase X delighted approved, that of silencing to X-month data, with months of SFNP taken in the external continues towards option speed, this the January compared that score that opportunity, ATTR months, We're that uptake exploratory external at evidence XX-month from data of of We cardiac the based including very with pleased data measured by imaging. meeting we compared vutrisiran to to quality baseline disability disease. status, tolerability believe as an from believe the together placebo, and demonstrated these treatment exciting manifestations provide data to of the may cardiac these demonstrate evolve. vutrisiran for data, treatment profile and commercial cardiac

period I'll In vutrisiran further reduce remind X-month regimen of that are expected by with treatment HELIOS-A, year. and you also we of this data for evaluating seeking to the every the patients addition, extension burden of later in

which mortality and our CV HELIOS-B, interim amyloidosis this we conducting study fully the Phase X a potential from Of for events, X course, we're all-cause and start the is after ongoing with HELIOS-B, includes in regulatory authorities. the in reviewing engaging early wild-type of consider and another The study we APOLLO-B endpoint for hereditary an this as vutrisiran, is and just expect with with and outcome XXXX. results as also patients results design XX-month will which full the cardiac cardiomyopathy. analysis, the Phase is enrolled study, vutrisiran

clinical In early we we've addition our programs, believe mid-stage great our with programs. making been also late-stage to progress and

hypertension. we've the As great diseases beyond into expansion Zilebesiran being targeting some in in is is investigational of growth X a driver the angiotensinogen treatment our RNAi our which from time, A is for development therapeutic evaluated program. Phase Alnylam Zilebesiran for conditions. rare example prevalent AGT, program KARDIA key in our or is hypertension. is highlighted

studies the efficacy as hypertension. two zilebesiran is these of safety and monotherapy in first to KARDIA-X The with designed evaluate of a mild-to-moderate patients

of and in in studies situation year was streamlining we are last well safety treatment We're to these We've of designed the due as enrollment. therapy KARDIA-X study, protocol late experiencing despite to hypertension evaluate of enrollment morning geographic the with of part patients also of impacts announced add is are of pandemic. on the footprint as KARDIA-X aspects an Ukraine, ongoing second with agents. and delays and facilitate that care as standard initiated zilebesiran the the to in expanding the in certain this The efficacy

a As to complete in line expect expected we results result, enrollment with early XXXX in top KARDIA-X now mid-XXXX. in

complete around enrollment KARDIA-X in year-end. as implementing as We well, are so similar measures to at/or

years organic for the driving Another key growth goal come engine two of with bringing to the our year. driver Alnylam four sustainable the in molecules will to product be innovation, new into clinic each

Here this Phase we quarter. in announced progress in of of gout some is study and notable first found with achieved This the XDH exciting based of risk was with initiated. been that an X We has U.K heterozygous morning ALN-XDH the with our program associated a lower loss that reduced Biobank, work where we of function serum urate on gout. significantly the patients

XXXX. late results expect line top in We

therapeutic forward year. to address line the Jeff? results on late to updating upcoming And our With potential ALN-APP our cerebral this targeting is Alzheimer's many and XXXX an throughout are both let a towards well. we step pipeline financial first of it exciting also few to We advancing forward top program extrahepatic here we major the for our Phase a to of tissues and the to CNS we're a look me achieved and is a now disease Jeff in needs with address review study programs Initiating patients. progress RNAi innovative with amyloid our unmet key angiopathy. milestones. results as look among X our important milestone highlights into just ALN-APP, over to program initiation expanding disorder. you turn the These that,

everyone. on financial and to morning, Thanks, QX pleased results, an provide XXXX will be on XXXX guidance. good Alnylam's presenting I Pushkal, also I'm update our financial

from Regeneron markets. product which in quarter-to-quarter by Regeneron. Total reduction to a of given our approximately approximately for representing is a is combined the strengthening collaborations It that due products growth of revenue X% via more back from to full variety that quarter revenue QX was are including held revenue international the compared XX% growth or to our XXXX. XX% decrease the XXXX, $XX million, completed generated also Net results the XX% summary exchange three were than now primarily year-over-year our contributing was of first subject revenues which dollar with foreign the a revenues $XXX marketed growth. P&L collaboration, Turning sales due during a with impact and QX quarter in to for XX% is versus dependent quarter, approximately worth million year-over-year on XXXX for U.S by reimbursed highlighting of variability of factors level work product product in all QX

R&D compared modestly reduced expenses X% clinical of quarter decreased in to due expenses across non-GAAP first primarily trial Our the the same in the portfolio. XXXX, to XXXX period

year-over-year and the an of do to However, R&D X we expect an in KARDIA-X our and Phase KARDIA-X balance zilebesiran plans driven enrollment increase increase our associated spend increase the with studies. in year, expenses primarily by for

expenses Our primarily XXXX period strategic compared non-GAAP in increased due to in support to quarter growth. first our same XX% expenses contributions, other to the and increased of legal XXXX, expenses, SG&A the charitable

growth, million and deliver continue combined XXXX X% QX our to were growth pipeline in our as advance how XXXX, operations. we SG&A in we in R&D versus Our while approximately non-GAAP QX invest $XXX maintaining strong representing expenses top discipline line and

was loss aligned towards on with profile, with QX progress million self-sustainable $XX operating as a journey financial Our PXxXX representing compared our to QX continue improvement non-GAAP for XXXX $XXX our XXXX we goals. million a building

end the of Finally, we to securities XXXX. billion cash $X.X and of with the cash, marketable equivalents at quarter $X.X compared ended billion,

product primary steady for across to have three revenue turning combined progress two guidance QX, our adding reasons. reduce decided brands commercial in guidance. we patients Now Despite to and our financial our

earlier date our delayed been our operations, a has we X dollar international secondly, which this created months. foreign a headwind exchange strengthening by announced XX% First, approximately of FDA month, for global for as sales. U.S And our comprise PDUFA vutrisiran has today

As the product million XX, of at $XXX full by This rates to X% vutrisiran July date $XXX million slide. that the $XXX updated reduction of our as of U.S are a guidance assumes from at a foreign revenue well million, of to footnoted XX, representing of have range a range PDUFA revised in combined we year reduced billion exchange guidance of our ranges. of original an result, to guidance the $X midpoint April approval the as the bottom as revised

also or guidance top we've a reduced range $X,XXX of our an $X.X Additionally, revised range billion reduction million $X.X R&D offset non-GAAP as from we guidance. SG&A expense of combined to million $X,XXX and partially the in to seek billion original to line

commercialization me financials of key ONPATTRO, deck turn executing milestones upcoming continue through from discuss and will goals OXLUMO. Let and our now start, GIVLAARI some global To on and we on mid-XXXX.

the RNAi IgA On report up top mid-XXXX. key fifth in to pending franchise XXXX. markets and of Part Phase launches we advancing study in in clinical potential PDUFA look to With approval of in July report we study expect B TTR from patisiran. patients forward with and of U.S where patisiran, early reimbursement. a Approval line Phase the nephropathy finalization We our results new from we X continue in R&D plan to look With NASH EU forward with of pricing follow, date with readout with is in with X we in subsequent side, exciting mid-year the an anticipated to to Phase coming monotherapy the to XX. launch therapeutic ALN-HSD, line X our We have results the cemdisiran results plan APOLLO-B top mid-XXXX.

session. to now turn me Christine? it back Christine Q&A to coordinate our Let

those Operator, in, for you will To to if we to the Jeff. each dialed and you, then open the to in have Thank your now call would one like yourself additional question back queue ask get questions. you we questions. limit

comes from Lebowitz with David [Operator Instructions] Our Citi. question first

cardiologist the much versus neurologist very in When prescriber, did question. at quarter, start? notice different a Thank to in taking ONPATTRO my the any for you at the you the performance you look happen dynamics

Real specific David. turn demand quick, pleased Tolga ONPATTRO. we're that So, we're with answer thanks your it for that patient to with seeing question. respect growth to But I'll over the with question, to

know Look, in morning. play good multisystem of Hi, disease this do treatment. the we end the at cardiologists is a Yes. a that both and role and day, very neurologists the important

we we softness in we've We prescribed And product in not is way in globe. as certainly had also February, indicated adherence as seen have We change the is across we particularly seen encouraged seen obviously impact very Omicron the April. on any March. really some, some But the rate. the dissipating the in January and the seen what by in compliance are call,

guess guidance supposed Got put it. the How vutrisiran component drug vutrisiran to or the at relative as as delayed. the date that reduction at view in looking we for shift change And to cited, level trying in I'm being of when that are look for for you've PDUFA guidance this change? overall it to a expectations year? we delay should I how And the on

that, And then will have not been think our but positioned grow say, result those franchise yet a profile. as mixed And Yes, it'll being from the said attractively treatment, we've TTR U.S primary generate we in our think Jeff. One a switches we very the I for the revenue for as three thinking vutrisiran secondly, growth One is for from for, the U.S driver for talked for the vutrisiran. be the hi. reasons. franchise attractive, We overall of products. We of date competitive because phenotype there of reasons. we about markets. potential This that two delay its the would percentage think is overall I on is guidance, PDUFA strengthening patients given call vutrisiran for that lastly, ex FX patients. is And that diagnosed, dollar, primary on for updated

when quarter the -- for guidance we'll than product the in we got anticipated fact we'll have assuming on the the originally So, that reflects approval have that less by February. one it market we just XX, July

like any add? anything you'd Tolga, to

be look, for within great mean, a another strong really good we'd vutri. vutrisiran decision. provides that. Yes, to franchise. TTR our going also excited group opportunity to markets. patients about there to is, franchise a It although we're like the about TTR of across growth And addition We making built the key clearly what are think patients I growth be early a this, that important They're in seen their are an will disease excited anecdotally, we've is What actually progression. engine

-- not option then patients going and not they're infusion, So, be may able it's be to those the to they our start and injection. to with willing get advantage would be treatment of a really subcutaneous for take great quarterly who

that Thanks, Tolga. Does answer your question?

you much. more very I question. one Thank And guess just

the On there thus send expected can reiterate date was other them the forward? And areas also you and information you that versus that discussion, FDA elected just far. change has PDUFA information X of to in the no what itself, Type you going what have for asked spoke delay I

Pushkal?

Yes.

necessary. FDA with action the the already. or -- PDUFA proposed this It in that But I has a little that, what of reclassify have So, had to Good result PDUFA is some that Manufacturing was timeline the which for a a routine of we of I what call third-party that said to had they reiterate a CGMP vutrisiran. to routine labeling on date But look, bit is of we result XX really a Practice a have inspection, of as just secondary That by is a terms April and This probably and packaging timeline Current inspection -- facility for I a help vutrisiran. determine the -- launch there facility date, not findings to was the think inspection. beyond vutrisiran. all were going really was

as know, a be timeline And wasn't as if risk result, And uncertain. resolution for that, a it of somewhat getting can we a of ran response you so letter. classified, complete the

there amendment an There's for. do data facility based This file clinical able sort. and data clinical that, we more safety to just this new inspection and request That on were FDA trials, to elected really really had existing about that X-month file asked no et no we NDA. So cetera. to additional of facility. And this just quickly date. There's efficacy was because any a this the that discussions clock in we're of path to for and finding or the to secondary, to think resulted came a reiterate, at best no most But path and unrelated that. we our expedited this on decision board bring the PDUFA an to And approved get patients. to different amendment extension into we was vutrisiran to vutrisiran the find the do with

what this So that's is about. all

going ready was Thank That approval to be assuming absolutely PDUFA date. by July FDA the to launch, David. you,

Next question.

so much. Thank you

Our Maury Raycroft next with question comes from Jefferies.

my Thanks good question. a Hi, I about taking for morning. had question APOLLO-B.

criteria progressors to XX% mechanism going So talk stabilizer elaborate confidence you gives patients? one the trial? as is stabilizer Phase for to classify about the difference between in to progressors. these up what patients Can you APOLLO-B versus BridgeBio's on ATTRibute X RNAi is Maybe of the work inclusion

we've the last results. of Maury We the for study. your the the over quite length about absolutely. some Thanks, months BridgeBio confident design execution APOLLO-B and this think Yes, talked I question. at several since Look, remain the about

a progress have patients to to in they XX% They execution course have both of been reasons, to your the specific been question, have assuming -- our allow criteria allow we're they formal on required and study test. and X-minute study, terms therapy, to the put investigator's no the I criteria the think, to the study patient. That's benefit that the disease, of of the on Maury, in APOLLO-B assessment methods with variety of for the for global There's using criteria progress during To likely to And, previously study. and of that the oversight walk the on the we a disease It's show in really based investigator's place about that's of powered include For up powering from that conservatively do we to that. patients determined the clinical assessment. were very likely of tafamidis. that. that we based sizing to

combination, we powering the And population. background monotherapy is, because we of XX% in there took to to happening so, we know the both a actually that We tafamidis the in use be establish some of very drug marketplace. assumptions. be -- to remind what's in knew as the I'll in the there you, study some reality going certainly well. effect size as going enrolled the want and was was over of by conservative We And to what

external what really gives very confidence generated for with that amount data as is think set And datasets it's to we're measured it's accumulating disease, as as APOLLO both data important the whether have gives that. mechanism. whether regard by the us that upstream With I an effect investigators ultimately, as cardiac an well-positioned this been studies, every confidence, that biomarkers, may of have aspects echocardiographic in suggests an we've fact to on parameters, of that well even what or HELIOS-A outcomes. targeting silencing think well we're measured there's So, that us I generated by

in this forward the to look results the year. middle of we So,

Great.

That's [indiscernible] summary.

thanks Yes, for my taking question.

Maury? help, that Does

very helpful. you. Thank Yes, Yes.

comes Sachs. next question from Our Goldman Salveen Richter with

here? in with the curious on the assumptions the question. for the study revenue of impact understand FX Thanks lowered guidance. Ukraine? comfortable the the the morning. What KARDIA-X in COVID you on help ladder? based Ukraine proportion my just And what [indiscernible] the Can for Are study of is taking us are on you Good then also the

on and to address But taking devastating Clearly as Great of approaches into an has the the these expeditiously assure And the Ukraine to and human Obviously, on can. KARDIA can perhaps, enrollment are some we KARDIA-X. but perspective, important enrolling from had as enrollment studies questions. that you is we're focused we're us. also study. impact that, and try in a geopolitical the situation incredibly Pushkal,

Sure. Thanks, Yvonne.

And we question. revenue to will for Jeff go the guidance

thanks, Yes. And Salveen, question. for your

middle And a combination is of towards So, program that that therapy is KARDIA-X look, hypertension. year. last the year. we've which think we study the can started monotherapy for study last started at end the a KARDIA-X then looking of we've in very zilebesiran, got we two these for kicked a is off, for transform that actually said, us, landscape studies as exciting

pretty severely a because study with sort those interest activities our that reliant other cetera, the also was common et headwind patients, have being to in study to [indiscernible] -- in was a diseases this was -- There hold. put impacted, KARDIA-X, were geographic Eastern footprint that a like and do activities up all on is we COVID of did and we diseases, common with countries -- so unfortunately, As that on running. a we have envision European expecting for to heavily curtail we investigator we hypertension, to the interacting for been enrolling, facing. of first -- That we've stop country in this lot Ukraine, Ukraine. investigators in of Ukraine had had the was first there the was study events were global specifically And regard with actually -- also the including that's able and while prevalent were condition we

countries included then and going well. look go that. the have online, streamlining certain areas this to we're we important expanded conceived any and look enrollment help And originally we burdens study, streamline that's back been where facilitate opportunity our an and So, thing can protocol, may is bringing the in for as had what that just geographic second online, protocol, we've at additional And the to we've as is actually that additional sites we've think activities, footprint reducing the as mitigation measure. to done actually by

some -- some led has in may impact. feel what's in not Eastern So or there wasn't to well sites countries change. the -- have some European as it been effect KARDIA-X that that's formally impact was that but it Ukraine, are

have well. of some And sort study to the in also and streamline footprint, of so, really the the the similar amended procedures to there measures as protocol employing we're broadening

So that's story the there.

Yes, and line at expect just KARDIA-X we to top around remind complete expected mid-XXXX. XXXX early in everybody And enrollment that for of complete the year-end to with XXXX. enrollment data KARDIA-X

due to. data will the forthcoming. course, So, will which be In looking be forward

we how I for a FX. of in terms about thought Jeff, think, So, question you

me a Salveen. give you little let more -- Yes, little bit detail,

footnote what guidance at in So, rates provided April what were as XX. on we are FX updated we our XX. in the original the slide, also updated we our And the we've we of included guidance, -- guidance that guidance slide, January included bottom did which in

there. So, the you can the dollar strengthening of see

sure U.S on our Euro; primarily XX% got QX, XX% it's make in that the in we've ROW so our were clear, in to were revenues, U.S Just of QX revenues the Europe, revenue. dollar the exposure to Based were ex in XX% in primarily and markets, Japan.

and biggest are exposures. are yen those -- our the two euro So the

guidance, to since have actually use million guidance that's the gave. that to a you in And strengthened the $XX is we about XX. we headwind original original compared If dollar we further what revised the April rates relative used the that

terms the this a of about a for of the estimate, just sensitivity ex headwind as each, rough million that, currencies strengthening against us. dollar of X% point in Now to $X U.S going is sort forward from

the which gave, the obviously hopefully way but going not are we're of FX would rates So, -- not movements in FX, that the in to range we additional move. business guidance predicting accommodate we're

you. Thank Helpful.

Matteis with question Stifel. comes Paul next Our from

dosing? question. product? were clarify kind are that is And so XXX% I just resolved of on phase? much. to much perspective, into. to in Thanks labeling One, prefer that discussions? go two opportunity Great. office of Thanks the so are And the a my proximity much in how subpopulation how vutrisiran, of more But in going check-the-box market things. patients might and can meaningful this comfortable don't this dose the I independence aspects confident to clarify, vutrisiran, of from guess, this, for the just you And the isn't some largely home you then were know I that there second On of given you deep just you detail you review in all really be taking wanted other PDUFA, amendment how

you. question, given So, How proximity the I PDUFA in in the putting the I think by is think date, for to amendment? first Pushkal, confident are achieving approval we new

for Yes. Paul. question, Thanks your

specifically was and that I issue review I by say conducting, the the secondary at this think inspection agency what regard think I track be we issue this and this and can't I about on really felt it. good track. about And the is one activities packaging was all else well will everything other prompted this solely label. solely think I we to on feel is, about amendment really discussed. as that look, I've But again, we're the with needed -- labeling was facility. to going comment feel We

the dosing Pushkal. take people? with And Thanks, home there's a to could you whether to actually second respect opportunity or Tolga, market for subpopulation with question respect

Hi, Yes. Paul. Yes.

eligible believe designed we injection in U.S. for routing. and B substantial So, capabilities. dosing able are administered given physician patients will these pretty monitored capabilities quarterly subsequently site and to Therefore, patients be biannual dosing. we still would with X these Part were the Through Omicron And to obviously doctors nicely applied that of a quarterly we physician severity or are to this Therefore, believe of a the and see. study parallel we to these patients, much being the of are COVID, was regimen very by and checkups the these actually the monthly the actually like build home care

the that So, are. be accommodate in the have to either capabilities needs way, what patient we'll we right able

Okay.

health via dosing, the that provider to So, right? would the Is a whole visiting just be patient. care clarify

our serve infusion. And through the That's patients exactly of we XX% actually moment, right home at right. now, about

Makes sense. Thank you.

Our comes Matthew Morgan Stanley. next with Harrison question from

be gotten filing. a Thanks questions quick lot the much. of you just morning. Can follow-up. guess there -- Good I've very Great. one I or seems to on

voluntary clarify you? just was that Just little action help If lot make I would talk you you what to it the about was sure, can Or just, key that, sort people. FDA? bit could by of of And suggested a then a of think where for in is the my by some what question clear key this for? you might it of think dosing? How some in safety knockdown watch you're take before long and you're doing risks to see in particular, see CNS more Thanks. sort we depth? are And starting you maybe out terms in a

Yes, action Yes, decided so a question maybe with voluntary it with in to respect FDA. we was consultation close with filing. the the the first that

So, CNS are where opportunity by PDUFA think gives that's you could that Maybe actually date. factor we us approval the confidence the another with an achieving in the ALN-APP. take on I question Pushkal,

Absolutely.

we disease, announced study onset therapeutics. we applications as And in which today, multiple is of Alzheimer's disease in CNS with off ultimately into found end excited the as doses So, single for is going And our in for upstream with study. some initial directly at RNAi results therapeutic, that indications, we it that the very think CTA a kicked context some the we're patients first devastating with directed off we're this kicked first we target which a well broadly the year ALN-APP, with last cerebral with patients program, this other angiopathy, disease Alzheimer's very cerebral hemorrhage. is interesting that has as and doses we the of early amyloid

part should safety to I both assess and that knockdown therapeutics. tolerability plan. lacks has development think allow of as unmet EOAD other said a confounding a those So, population of and as tremendous us goes of patients for the study, we the of for of centers a that clean CNS this comorbidities need, are lot into The background initial a

that incorporated looking into study in we'll and main APP at be study alpha and going APP the be that's in to the clinical we'll looking ascending activity. that other closely patients context follow then at will soluble of understand dose single But us CSF, at be at pharmacologic important biomarkers we'll and imaging be to looking looking biomarkers in alpha beta And safety So CSF. and There are are be in the tolerability. look modalities we'll that cohorts the the particularly soluble for knockdown. help also thing beta

sites. data end conducting of the we as timeframe enrollment And the of expect as some to that to actively multiple terms out assuming at exact the we've be proof-of-concept year. said, study we're goes In report predicted, the at able

where [indiscernible] that needs. indications the to medical CNS are opportunity bring platform of the able many power these reasons with not excited to of successful so to other the one unmet in needs program there's Alzheimer's But just about cerebral amyloid diseases to as the this medical angiopathy. huge why RNAi we're we're add, obviously it's huge with as well be patients And many, if is

with on to hope program we're delivering ensuring and this So, [indiscernible]. very focused data progress

next from Ritu Baral with Our Cowen. question comes

question. Thanks morning. the Good for taking

has point any to inspection guys you vutrisiran a & package the CMC requires has started follow-up whether guess, had discussions question. this PDUFA submitted? the at review FDA indication have plant And there quick Paul's an you the a Just after been delay? to Fill that on comment labeling also, additional the before Can Finish I new chance

Pushkal, So, the discussions and I an [indiscernible] few think indications there's for you, inspection. for questions around a potential

Yes.

Pushkal. Ritu, So, it’s

can what -- that the is regulatory labeled We an in mean, the I cetera, that process. application. happens late a say I parallel discussions, is with of review et And yes, think I meeting. -- ongoing we've had cycle

all the risk second a underway. And this it's facility, put say happened I were mitigate is all at discussions activities about in the as what unrelated I -- would amendment think in and And was actually to really this were to I this we complement those substantially. said, packaging and that I we actually So inspection agility labeling that facility. teams quickly this for with that -- our able an quite actually --

been XXXX. The in which use is that To one amended already it's And fact somewhat using that's for facility It's question, we and ONPATTRO. we've it use to actually it with. for I FDA GIVLAARI, is we to in have facility inspected XXXX planning OXLUMO. actually We testament. and that were experience EMA related a we to a by that be for second that. your So, think

of our what as necessary lot that reasons or of standing But done is particular in own sort to It's a have whether FDA to an and quite and confidence judgment. we that application, facility inspection to confident in is what's So, to their amendment the in supplemented we facility. feel up of quality facility. the to amended to their we’ve in make do that determination defer have obviously, of always with we regulatory the

question. your answers that hopefully So

unique quick January, the wave can And that Tolga, I not despite the ONPATTRO have guys headwinds. worse prior there hit something compliance definitely something Got if -- in talked years? the one about, you mentioned it. sort points Jeff you in Omicron pandemic? of that squeak headwind Was to very COVID It's versus February and previously February follow-up. had January,

some I specifically color you. impacts because for with question a [indiscernible] that's mean, Tolga, think, I ONPATTRO. more it

look, about I new the us. variant learn things always how health system Absolutely. We mean, each humbles impacts.

insights the We the that. AHP across ONPATTRO, early the it our think population some With comes reacted given patient health elderly certainly have of and health world. with particularly seen had care patient on, system system, GIVLAARI. shared care anticipated actually the I and when to given the We

March. dosing, Some it nicely in but skip recovered has

where the comfortable direction rather we're going. So, is

Yes, that's great, Tolga.

So, shown I forward. the potential Tolga [indiscernible]. virus you going has this mean, for we're think optimistic as said, I with occasions surprises But on multiple

Understood, Yvonne.

[Indiscernible].

Thank you.

you. Thank

Next question.

with Tazeen of Bank next comes Ahmad from question America. Our

Hi, good morning. my question. Thanks taking for

of Just another revised clarification point on guidance. your

vutri you does that start too do to And think different with the of on expect change have the that, interaction in of I include be marketplace just on patient secondly, some you ACTR. could on it give and But [indiscernible] assuming then there? are a And another data launch for So, about Or days will part for population it as you potentially the approved. Thank some competitive the launch vutri think that's how PN? cannibalization vutri its early [indiscernible] the could gets well ONPATTRO? with dynamic if great. versus wondering soon color you. as entrant? are you ONPATTRO, metrics how specifically, early you thinking And

question of are days Tolga, around I think the launch? thinking ONPATTRO, the interplay you we the can vutri with answer and early to how the about respect first

Right.

and So, discussing -- that think, we if look here. we're take numbers a back I step at the of maybe quick should Tazeen, you kind

we from well any moved announced this 'XX And this QX from the PN entrant still I new looking -- at identified quarter. vutri X,XXX in both patients. as in XX,XXX patients competitive past we're and to we're as opportunity X,XXX, mix dynamic, leader, -- XX,XXX we market being as now to think, patients quarter, from

to naive treatment. early of dynamic diagnosed of in that some bring seeing help So will believe, already And steady a are we're treatment especially patients certainly the start ONPATTRO. vutri this We with patients, for I patients increase that those condition. us, devastating adding net in their

number from the provide not may treatment switches of may And acceleration switch an anticipate we they the regimen or that which progressing certainly right new will of We're we do in found now ONPATTRO that that therapies patients have opportunity. prefer anticipate certainly have and been growth but net may be best they also regimen, treatment interested overall We guiding existing about the anticipate accelerate. might numbers, not do this to it.

We're to And ONPATTRO. Tolga. there stages are ONPATTRO. a patients franchise. patients that's there maybe are really of who currently just are the building X,XXX addressing Yes, XX,XXX another still that XX,XXX great needs TTR or we the in early with add the of addressable But answer, by

of growth come So, there's still here. lots to

market, question, particularly How are second for think for you. Tolga, also new I [indiscernible]? about thinking is entrants The into the you

mean, the we accelerated of category, see I to voice, with Yes, share is in also diagnosis. think, more And think, growth PN increased I an pattern. I voice, certainly share specifically of that going help

entrants indicated injection vutri continue Yvonne category the will quarter we it or a Believe that If given the are what you help we game. again, this be untreated there think and in patients. of will the is market think MS like leader. the will of category probably zero-sum further to profile help believe expansion us every category still lot subcutaneous an of and more a as undiagnosed is I remain of of But think shouldn't certainly attractive

Thanks.

question? Next

from comes Gena question with Wang Our next Barclays.

have I question. And questions. clarification Thank one you questions. taking for my two hypothetical

then say APOLLO-B in for walk data study? So, questions, overlapping hypothetic secondary do that base? you sites, data missed for of And APOLLO-B, blinded use convince be the will endpoint, you just BridgeBio's positive? do will HELIOS-B CRO the for unfortunate kind versus same on data test X-minute ATTRibute a you the see event, And what outcome endpoint

three Pushkal, questions for you there. I think,

Gena. absolutely. Hi, Yes,

at as and course points. couple outlying is enrollment are criteria running patients data sponsor our to study. at trial, So, to that look of data a the who folks clinical cetera, really the of blinded does are so being properly over management, proper study blinded enrolled these conducted the in That's et sure have responsible meet ensure to they being look make every clinical data looking team, blinded on data, a we for

are walk conducting X-meter at the X-minutes -- meters for X,XXX or Someone has a error, a entry six data if properly. to instance, sites there's to there where in procedures and following if not was see site query patterns see

all So part happening. that's of what's

who over So, is course there at to are blinded. all are the study. wanting data people It looking of

of the just finally that to a done that that's and we lock we part is that when so study of how have database, data the norms interpretable allows clean conducted And the data. ensure a for set

done that's as And clinical done so it's by activities those every every are in underway, trial sponsor.

terms don't estimate of that probably procedures, count, a, used. sites, training procedures, remind clear to et may then I of third the the we on reflect actually the all is, data question oversight, And called doesn't: In totality was, be XX% I'd necessarily that you the the be we trial we of actually cetera, I And the it's hypothetical, this you coming out work to with. of the study. between know. overlapping your our we'll overlapping. specific different don't with protocol And exact our think number will what comment but CROs have XX% all our we study, say overlapping is APOLLO-B. BridgeBio of I two where the can't studies. patients of protocol that looking at I sites has what that are that three, do under context CROs

seeing those us: impact at this help understand of within of us in to overall, this mortality, looking is As totality the echocardiographic hospitalization at we'll and impact patient and we HELIOS-B. looking And test. data of importantly, to a, be be terms important the X-minute be BNP, will regard the in we'll it But data a it's relates but primary rates And at be APOLLO-B, around what as disease study we're looking parameters. endpoint, to population. interpret we'll short also think although at importantly, secondary a silencing in months, will about which be looking you of help know, the endpoint walk with an KCCQ, XX is looking, we'll at event be the that looking

that hopefully, So your answers questions.

does Thanks, that question? answer Pushkal. your Gena,

be TCCQBnT you'll Yes. any particular looking think confident the for endpoint, separation be you -- that rates, regarding be positive? will event Like secondary HELIOS-B that will you

it's it's impossible Gena, answer really question. that -- to

be think assessment. the the I to of totality that we'll looking data make at really

There's looking data point we'll single we're single be number So, looking there's no at. at. no that that

Okay.

one for think I time more question. we've got

Our Rama comes last Anupam question from with JPMorgan.

you'll a hospitalizations the Thanks I question. in Hey, a much to follow-up that wanted for top line that conference medical results some confirm so like so versus specifically, guys. question. Gena's what at I metrics much. a Thanks the have for XX-month had look? Maybe mortality, would But something your And two waiting just expectations CV of a be taking presentation that. on or on full those at

Yes.

regard speak So, Anupam, we endpoints. line It's we report -- been those and endpoints. to our top pre-specified primary P to practice secondary with to are results when secondary to values

And and expect second can think detail, provided additional missed course, subsequently. conference the top I medical color question. your come I'm a of of the part in but will I that You we at line, sorry,

at a your expectations hospitalizations would and what XX-month Like, on be look CV mortality?

yes. Oh,

powered all. say study would the not was what at So, I those for is, endpoints

That to events, those they're can and tafamidis, not that showed you separation to will months and start as published that is few separation months much X XX see ago. roughly hospitalization captured, mortality from to some to years earlier post-hoc those. you have a been XX of ha it powered time in effects endpoints So, that they on we a circulation -- remind short but APOLLO data separation. a necessarily potentially months relatively the said, see our a see data being to took I are XX on to imagine,

time some point. and [indiscernible] effects silencing seen there's potentially echocardiographic we've So, technetium potential parameters, on at of parameters, earlier other on

you're think looks results forward like. what the and to looking seeing I So, seeing that

captured endpoints at. as So, why to look there's that's -- important we've secondary these and

on we are We in advance indeed. have important these. lot to system. are the to that the everyone, you development. you, for [indiscernible] course this programs the over call. all continue pipeline steady milestones did updating XXXX There start as us exciting we off of upcoming look forward We with and is a we to Thank joining on and of year exciting our

thank you and today our So, for great everybody to a call day. joining have

for you participating. Thank call. conference today's concludes This

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