WVE - Earnings call transcript Q2 2024 | Wave Life Sciences Ltd.

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Operator

Good morning, and welcome to the Wave Life Sciences Second Quarter 2024 Financial Results Conference Call. [Operator Instructions] As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

Kate Rausch

Thank you, operator. you progress us quarter and results. thank our to XXXX and business recent review morning, for today joining discuss financial Good Wave's second

following me Scientific Officer; Yang, Medicine, and Paul call. Moran, Chief and are the Executive Joining Ginnie Erik SVP Anne-Marie Vargeese, Kyle prepared will Ingelsson, Chief Officer. available and Officer; Chief Officer; Development Translational President for Chandra also Chief Dr. Chief Li-Kwai-Cheung, Financial with today Officer; of questions Bolno, be remarks Technology

The website, available of press morning the on is release issued www.wavelifesciences.com. this Investors section our

Before differ factors you no results that uncertainties discussed filings. reason. the will and we to this from to these in materially subject turn press begin, release The differ include I discussions our Paul. call risks to to call would several today that like those described forward-looking could over now in are like to conference for obligation We statements. any update statements to that the are forward-looking SEC could remind cause and revise forward-looking statement in our These actual issued undertake I'd to statements. results during cause any actual or

Paul Bolno

for Good joining Thanks, you on thank morning, Kate. today's call. and us all

and first our made incredible modalities. translation clinic progress platform high-impact of We across continued have both RNA pipeline throughout half advancing demonstrating novel year, the in the the medicines in this of unique our

progress And since trial remarks begin second announced some quarter we've WVE-XXX today of the positive and disease. from we this SELECT-HD A the I'll program made on them. for highlight results the for Huntington's was clinical with

preservation. accelerated and specificity a exquisite serve chemistry to also where wild-type endpoint approval. which a PN stereochemistry of attaining mutant our capabilities our for lowering testament caudate WVE-XXX slowing durable with data, to Huntington a statistically we lowering potential as The correlation clinical significant led enabled between to protein atrophy, announced and proprietary and in potent mutant achieve June, clinical This while best-in-class

all HD is is disease there a Parkinson's devastating in the treatment disease with affecting and compared disease-modifying across are are and disease Alzheimer's and HD therapies no Patients more U.S. to currently limited having options, extremely disease, XXX,XXX stages of patients combined. ALS faced available. than Europe.

designed was knock Huntington of to protein the health preserving is mutant to Huntington selectively healthy while protein, WVE-XXX wild-type neurons. the down critical function and the which

positioned With ever the demonstration addition to the first patients, of presymptomatic population silencing to larger uniquely XXX allele-selective patients. clinical HD in patient in is address symptomatic

results, its to SELECT-HD If our payments. to milestone our our SNPs R&D Takeda package XX-XX shift payment, is including HD commercial potential for Takeda. Wave and we submitted development opt-in Since have and opt-in split. eligible Takeda additional announcing pays a an profit partner, exercised our option and right, programs,

regulators engagement of well Our end decision We team approval. providing clinical a accelerated as on an support Takeda's XXX feedback development an with initiated look by to year. on has regulatory path could update on the the for also update as that forward

With update. option. with a WVE-NXXX, exon-skipping which patients, across we amenable to consistency exon expression skipping, Turning to our provide XX dystrophin next best-in-class data X% looking than our for DMD, achieve clinical meaningful greater would candidate new to expected patients are

there gene gap As dystrophin or there patients. in DMD, paradigm unknown paired well look micro as risks safety a to AAV And need to when urgent mini functional development treatment an remains option we with therapies, the for of deliver at with in associated therapies as benefits and better is current durability. the scientific therapeutic significant

every following unprecedented just skipping study other muscle A doses achieved X Part our we and in concentrations. industry-leading reminder, a week, NXXX administered As of exon

muscle leverage the and recorded tissue top approximately and DMD standard exon-skipping are delivery conjugate for Despite inconsistent care in primarily levels dystrophin approximately patients. concentration than billion the are exon-skipping higher XXx data, of reported DMD therapeutics U.S. the in $X Importantly, technologies sales levels in low year, by last

the XX% approximately [indiscernible] population. of therapeutics For

data totality of would patients. programs would opportunity unlock the our therapeutic us to portfolio up provide representing to of population, address which NXXX the exon-skipping to differentiated with Positive XX% an to enable

aggregation Moving M-AAT mutation to manifestations, candidate liver wild-type WVE-XXX, treating class increase manifestations liver, protein patients reduce aims in for to with in both. RNA and of AATD to the our GalNAc AATD thereby Z-AAT or levels editing, first mutant RNA editing correct circulating protein or lung the causing

U.S. Europe. homozygous Pi*ZZ disease, to address in limited no weekly is today while therapy There patients IV disease. augmentation lung therapies and AATD are XXX,XXX Treatment estimated liver the an for

tool are development and that XXX can irreversible treating could rely SiRNA injury. edits in RNA, bystander By exacerbate DNA-editing disease and silencing the enzymes technologies, market. liver exogenously validated approved lung therapeutics to multiple delivery confined contained GalNAc which collateral result conjugate, that specific hyperactive, in treatments well from is differs XXX and only elegant delivered on a a with editing highly on artificial indels.

of to nanoparticles. enables as high confidence of of a selective translation unlike dosing, GalNAc dose the degree entire to since preclinical convenience and is reliably the as and subcutaneous effective well lipid ease the target delivered clinical sent hepatocyte delivery organ, to

shown neutrophil healthy the enabled achieve XXX editing. and and In this endogenous enzymes ADAR confirmed to MZ levels with functionality potent for protein effectively inhibition MM threshold assay. and our populations and proprietary has studies, both have that preclinical AAT elastase We've durable chemistry recruit exceed

lobular survival, models. Additionally, decreased increases aggregates liver XXX improved hepatocyte preclinical and prevented indicating reduced inflammation, in in mitosis

at initiated of Dosing after our which we and fourth for AATD data designed growing cost meaningfully our our collaboration quarter Wave to in as the teens. of proof is the $XXX are we would milestones candidates, total our there either high not only third sales ongoing percentage transferred would commercialization mRNA deliver but part concept tiered proof with serve in WVE-XXX wholly-owned their derisk data in in of also or this GSK of to pipeline for expect to mechanism RestorAATion-X sole are This and year. editing program, is complete the correct as development quarter and of to of trial diseases. both collaboration, eligible our RestorAATion-X related a up prevalent XXX royalties and in to net and rare GSK double-digit million study. Under responsibilities upregulate

including next on mass and health are and the adults I'll recognized siRNA GalNAc program, being million Europe. is linked inhibiting diseases. public is U.S. give outcomes, Increasingly, risk XXX of many improved to a called it WVE-XXX. an in of fat impacting update Obesity approximately our weight now epidemic is reduction that reduced which health

the frontier are approach by weight to believe novel this treatment we completely and the a impacted by to loss. next we siRNA XXX, millions With technology, advancing potential has Enabled to our unlock address obesity the best-in-class disease. molecule

reduced genetics. receptor of as heterozygous in profile, diabetes INHBE with This carriers of One favorable this can PCSKX obesity. including artery of storage. reduced program loss-of-function odds supported adipocytes, control a on is human obesity type the X target liver think its corresponding the INHBE have cardiometabolic expressed abdominal and fat by which mRNA and coronary disease. is

of gene We of the to INHBE thereby protection transcript, INHBE designed silence recapitulating loss-of-function carriers XXX mutations. the cardiometabolic

tolerability their is for standard weight While and limited loss discontinuation care loss, by GLP-Xs often become have of high impact the mass dosing, of frequent current rates. or muscle

opportunity frontline as following of in X GLP-Xs address doses weight key XXX of combination monotherapy of to improvement to for see areas obesity a a of loss reduce GLP-Xs. We GLP-Xs cessation or therapy with or as with the further maintenance

supporting potent and Preclinically, visceral highly demonstrated siRNA have once we than fat, of a siRNA, intervals year. mass dosing semaglutide to less muscle or of all EDXX durable loss a per effect on also INHBE kilogram, reduction our our milligram twice led in with First, with just an of similar no INHBE fat preferential mass. weight silencing to with and loss X

is GLP-Xs, opportunity As a following opening of distinct exciting silencing the reminder, in induction. an weight combination from INHBE use loss for mechanism

for from results ongoing study the use. New potential this an underscored

and Specifically, throughout semaglutide, in this single loss administered a our duration observed siRNA GalNAc sustained alone was effect doubled with study. the the the dose combination with weight of of when semaglutide INHBE

cessation weight described we INHBE of treatment also our expected As siRNA gain. upon rebound semaglutide previously, with curtailed

potential and forward R&D our sharing about this look to more at excited very broad Annual obesity of are We program Day. in data the

we in a a Looking siRNA can our of proof a next overweight study in believe CTA early demonstrate trial clinical quarter of of clinical with and ahead, we dose initiate We of year INHBE of concepts remain for as the healthy as volunteers. to just end single year. file a the first XXX track on

areas us patients opportunity vast a therapies high of have millions We ahead of to to deliver in unmet need. differentiated of

additional derisk the in the deliver unlock multiple of We and programs. would are catalysts to year, on poised second which half important

on annual Additionally, including fall, at an we our this pipeline, to our programs. our RNA give wholly-owned editing Day emerging expect R&D update

more over turn I'll Now to the Anne-Marie? programs discuss in our detail, call to Anne-Marie. clinical

Anne-Marie Li-Kwai-Cheung

you, share It's Thank excited and I'll our recent clinical update year certainly on an I'm to and with a results. Paul. clinical begin thus been HD our programs. far, busy

cohort, Our and wild-type excellent reductions preservation we WVE-XXX. to this and XX% SELECT-HD tested and weeks, XX modeling of every clinical milligrams translation doses Huntington where to with intrathecally trial our up tolerability, XX%, Huntington of over silencing of of PK we multiple multi-dose saw Huntington durable dosed X mutant preclinical potent plus safety Huntington. wild-type with designed was In with demonstrate preservation mutant healthy

first Multi-dosing and statistically lowering. of potential such tolerated mutant and allele-selective is caudate cohort predictive mutant the in of known biomarker significant well safe serious between correlation slowing reinforcing that and adverse clinical imaging this demonstration showed a of no generally clinic, outcomes. was was Further, Huntington a reductions events a ever adverse events. benefit This mild-to-moderate also with correlation of atrophy, Huntington the the

all, potential are option We'll sharing have the these to the patient the and knockdown healthy September previously Meeting Disease France. preserves wild-type first Huntington. been Annual a with Network, with at on and the announced that place taking community broader who groups in KOLs Since mutant EHDN, Huntington's most of about European sharing excited the results connecting of Strasbourg, XXth or XXth we be data, Huntington this therapeutic HD

been thing a physicians was and to studies. pressing me HD to placebo-controlled in One patients, There that's need efficient families experienced novel and with conversations clear to long path biomarkers have more for with registration. a challenges my enable large who

atrophy diagnosis, have for marked in are is brain for symptom regulators diagnosis. know the biological the to clinical of primary first XX% of at their onset looking areas of lost Caudate in where clinical we HD approval, brain. one time point the of controls, patients relevance biomarkers disease the accelerated and typically with the having a For At compared than question. manifests caudate more

there where continues years at manifests clear outcomes caudate caudate X% path year, to many it clinical of lost clinical diagnosis correlations rate to between loss of design potential before and a Since X% a approval. to used accelerated giving to and are loss to about the a development be be

month, last including for endpoints Risk the ways use Path engaged more Institute where Critical to meeting outcomes. disease-modifying reasonably disease attended designs, efficient the trial likely we urgency to consortium Huntington's therapies enable in the Critical predict and on and Just of FDA the clinical

joined establishment we Given caudate likely Image atrophy, of pleased announce clinical needed an have to predict as conjunction and atrophy sets Disease the reasonably Huntington Consortium endpoint our data advance Harmonization to on to the and support IXICO are outcomes. working in with CHDI to focus caudate that are we

by accelerated will on approval by feedback. clinical including In now for be The potential regulatory engaged SELECT-HD informed all year-end. we've trial future and regulators tandem, feedback steps development our and is this expect pathway, complete, the

as None opt-in who to sincerely them. Paul to participated sites like would be the addition, package Takeda. SELECT-HD. possible our of submitted In thank mentioned, patients, this would we've research families in and We without

DMD, we of exon for are XX with open-label Turning FORWARD-XX amenable our WVE-NXXX to boys DMD. trial advancing

data track option The to on this transformative clinical dystrophin for thus quarter. our are XX-week new to excitement confidence and and observed preclinical We data later patients. therapeutic WVE-NXXX deliver we've bolster far with potential a deliver

gram This other concentrations of have our exon stem aware skippers we what any exon are and which trial, exon-skipping NXXX. driven of as nanograms by of to clinical industry-leading demonstrated uptake is per muscle for cells myogenic of companies clinical stem data A cell Also above the not have uptake. evidence observed myoblasts, far which in XX,XXX part clinical cell tissue satellite was XX% mean reported. progenitor therapy NXXX Part stem In that cells been A, gene new notable myogenic particularly myogenic are for able demonstrate of or we is other or cell skipping,

the promise need respiratory of that in which in cardiac diaphragm speak could exceed function. Preclinically, what addressing unmet we've the a of shown heart NXXX huge skeletal and and concentrations DMD, to muscle, remains

believe a on safe reminder, the a what in focused success profile, key exon we for are be having to for skippers. we and tolerable next-generation addition As will

provide course, of dystrophin greater X%, the is light dystrophin which of current standard quantity than increasing the of care. exceed profile a would Firstly, available to of better

exon dystrophin Secondly, through includes important are skipping mini functional or skipping. Dystrophin delivering absent through high-quality regions produced from microdystrophin. that exon

NXXX treatment and about Coupled a twice once or families available. Lastly, dosing needing provided options with therapies benefit better -- Despite patient response patients in patients, their provide level. in highly therapies when a consistency have being treatment of at we We infusion. to prior more tools and the options the and approved hear response. month, currently extending know KOLs the we to weekly speak to and inadequate there need for market, variable could meaningful

to meaningful for option the data our plans our well new therapeutic would U.S. support franchise DMD. a provide multi-exon the to and If in are approval of development DMD dystrophin for beyond to file plans poised XX. build a exon positive, accelerate of would We NXXX treatment accelerated clinical

DMD would compounds or in of generated together on a up XX% to continue demonstrate importantly, NXXX. the these that skipping and with programs par address And all restoration that's patients. We've on protein data studies exceeds preclinical to

patients are clinic. healthy AATD, advancing of is clinical study for rapidly in RestorAATion-X, With a RestorAATion WVE-XXX, RestorAATion-X, we program RNA clinical ascending designed in editing program the and our evaluate escalation program that's comprised to dose study homozygous open-label dose the in AATD pharmacokinetics pharmacodynamics tolerability, volunteers, first This the Pi*ZZ with portions multiple Ib/IIa and the XXX safety, single who and with Phase mutation. have of a

data escalate expected dose pharmacokinetic translating for to are GalNAc-conjugated as continues RestorAATion-X oligonucleotide. a and

in data be quarter data, the volunteers AATD cohorts, to Utilizing dose we third well of pharmacokinetic dosing of engage as in Throughout identified patients XXXX, serum. measure RestorAATion-X. we target. our M-AAT the in healthy will in robust the level as expected to first our presence potential from single protein the In dose assessments dose multiple preclinical we healthy cohort wild-type the taking commenced

As patients M-AAT do a not any protein. ZZ reminder, produce

clinical The of the of fourth ever demonstration to detection humans. XXXX. would of protein M-AAT we RNA be progressing, is a So mechanism proof expect announce first quarter of trial editing and the in in

of to to levels serum provide Kyle with flexibility we ZZ our as micromolar. With turn Beyond frequency AATD dose that like to financials. total that, our healthier we AAT delivering CFO, can to to protein both RestorAATion-X medicine update above a our the level MZ have anticipated a that, Moran, call threshold patients on bring and XX therapeutic the adjust to in look I'd ahead phenotype an

Kyle Moran

recognition in in compared of Anne-Marie. $XX.X of quarter. revenue in million in second million Thanks, recognized as year the XXXX collaboration quarter variations slight to $XX.X decrease reflects typical This revenue. the of We prior collaboration revenue

to driven compared DMD along of our Research in early-stage initiatives. quarter. as was increase XXXX prior primarily This million were by the $XX.X program INHBE expenses spending in and million and $XX.X with and the AATD quarter year second pipeline development programs in

of Our in second quarter. for G&A expenses million to the $XX.X XXXX as the prior million were $XX.X year compared quarter

cash a As equivalents. compared our second quarter prior We $XXX second quarter. $XX.X million was million ended in net loss for and quarter with $XX.X the to result, million year the the in as cash

be our any the or this near-term receive beyond. sufficient opt-in have of or payments milestone but under fourth We do to cash collaboration year we not meaningful runway, It cash fund is and Takeda payments important our cash expect potential the GSK that that future in milestones do to note XXXX. equivalents we our quarter into current and to will operations include

back now I'll over for closing to the turn remarks. Paul call

Paul Bolno

and as of new Kyle. Wave our advance promise dystrophin our as our XXXX, into you, Thank ongoing the of of conviction confidence program never submission well we updates including an this ahead, milestones to half validation CTA. clinical development across as several stronger. of genetic for program the clinical With It are of this is and incredibly our into translate our poised in we with time the provide exciting expect In pipeline sustainably breakthrough programs, data insights quarter obesity has important to each medicines. been human platform

this R&D wholly-owned also our program. preclinical on to are data fall We keeping way. portfolio, to planning our progress an new day you WVE-XXX on the INHBE look updated forward share including along our We

our our to thank our results to clinical like would tirelessly clinical I advance studies. working deliver are and initiate preparing closing, In that are to programs, new teams

and at families our in to I deepest studies all to and gratitude participating the us express who like Additionally, our would inspire Wave. patients

And to over the it turn I'll Q&A. with operator that, for

Operator

our Instructions] of will question first Lee. the [Operator line And Joon come from

Joon Lee

progress opt-in the and on Glad next have with the forward Congrats to months. package hear data decision X Takeda a that lot readouts in of you looking year-end. by to the submitted to

regulators, the the between the those far of what is Regarding possibility And Takeda a conversations conversations? a imaging I follow-up. so Or it is have has biomarker? as been and And feedback involved you with quick FDA? [indiscernible] using on the in just

Paul Bolno

Thank you, interactions. involved point don't Joon. specific interactions Obviously, Takeda But we is time. our regulatory yes, in in on comment

Joon Lee

the Great. dystrophin. from antisense for about to And Viltepso XX% around the lead DMD, in approved XX exon just at DMD, skipping oligos on looking X.X%

is you'd the like So around would for X%. to you say bar bar data? the some in Is see internal forthcoming NXXX for there efficacy

Paul Bolno

right, I as you think look about were you to Yes. Joon. expression Viltepso citing this I question, or we for guidance X% dosing. we X from at our was as greater XX% X%, months more, think the Thank dystrophin the and mean of after than

doses that XX% the weeks. we were at is us after to X encouraging X what's So seeing

a with of the a protein dystrophin production rated that stability. getting machinery going high has earlier again, So

it's X that X.X%, think important to the X.X% where you by X we out outliers. as conversion we of that said about being data was driven those I months think really sets from that XX% looked at also that clinic if

Anne-Marie it saw for is actually as which early this if So of outliers, mentioned, X% somewhere response, those you be And just study. we the looking in around above dystrophin. is something consistency we'll X%, slightly remove

So greater quantity, think high and see we than differentiated production high X% of a we so profile. again, that will quality, drive consistency the

over done Anne-Marie as I that's Track-HD reflect the question, the endpoints, work was on Consortium it the Risk year insights the the this think on I a back CHD your of on first imaging. know through don't to first getting that's do back both work question. being you I to of to evaluate course want HD highly data. on the caudate reflecting lot encouraging, think clinical in happening done if surrogate -- And any do that's additional is there's I being Anne-Marie, work

Anne-Marie Li-Kwai-Cheung

Yes.

in with more is in of endpoints predict intent the with FDA engaged in the think and I HD the meeting people mentioned as they're I Consortium had, and general reasonably clinical to in particular. trying efficient to to also outcome. highly therapies aligned recent bring absolutely HD ways the Risk community supporting And likely with we find

why atrophy reasonably think that into providing really placing caudate set And the clinical consortium, necessary and a that's as important start to predict an consortium it's to endpoint establish I outcome. the will that be to imaging likely we've entered the data

So very it's all encouraging.

Joon Lee

looking fall. I'm R&D to forward in the Great. event the

Operator

Salim with the Syed of will that come And Mizuho. from line

Salim Syed

little this get to Paul, that I follow Takeda up the on year. wanted to bit Congrats we're going progress. a on the stuff

event quarterly the to time it be you linked? And format, Are things for just Street, it other just X or going what we words, the supposed we that then for for event? is another is happens? this also clarify you clarify and the us, as is Takeda feedback going the could as anticipating these event we're -- some if X Or as call? to can you expect get us, -- quarterly the are to going feedback are In decision X So get disclosure you regulatory the to just events? are going to to that next X are the wait

given that a you're to considering could the in third related wait And from that, would a you given company, quarter and now then finance Takeda financing you just occur? feedback just just at be would runway XQ potentially to on event the Or willing for as the DMD 'XX? your be to is DMD body regulatory lastly, XQ is event,

Paul Bolno

take in these order. Thank you, reverse Salim. And I'll

the So under also the besides that first occur. just as million there's GSK received collaboration. We continued happening work and $XX payment for was which through milestones the research financings to relates Takeda potential collaboration, announced where we it when the in Again, a quarter. opt-in, even

through big So and XXXX we do some XXXX. anticipate milestones

predicated data question it X As as to of based from disclosure, Takeda is not independent feedback, important it these study. The terms is in think relates decision opt-in your prior to on first it's events. regulatory the about the on

we said us of the that package. that So off driven met on the was submission submit of to data for the package as the the call, threshold

with Now across those end ongoing interactions those, happening the X pieces what's that of are happening regulatory of are simultaneously discussion there feedback the and year, the both the Takeda. towards of

the So a opportunities but the the those Obviously, provide in nature separate XX-XX split shift HD cross material an that a R&D we material. program we just as the do importantly, is any cash shifts the XX-XX also and a distinct X to and program into decision feedback. a of threshold profit view opt-in not infusion, time to while split

happen those so us to And these by the Again, the end for line the occur. as time would they year. takes updates of

events. pretty events separate X as X introduce these distinctly So

Operator

the come Issi from of will line that Luca with RBC. And

Lisa Walter

Lisa Great. This on is for Luca.

that wondering, Takeda in, to First not if Takeda options program the opt-in, the are for just should your on what wondering opt happens? just choose ultimately

thinking about Any secondly, clinic? And muscle INHBE, target be you the wondering ways preservation can fat reduce any maintain in there color on and assess the would given to are if potentially muscle, helpful.

Paul Bolno

you, Sure. Lisa. Thank

makes question, decision. in, first waiting mean, that the for opt your we're decision obviously, for not Takeda not I So to if

having asking whether on sets, is planning had So or Takeda from whether which interested not in one data in on of the or opting disclosure, these and is of we'd and benefits inbound questions we've be strategics not interest conversations. other data a full

Obviously, time, Takeda data, given these were have publicly partner, is disclosed, are relative But a the with we the at allowed that HD space and we're same to are sets wonderful discussions the engaged accelerated in with regulators ourselves these be them. alignment and position to that to with others data to around to this has continue we best path a going put go supportive and to registration assure should to aligned patients. the that this to program path

had we've want addition, folks potentially fund the decisions. to from Takeda who to the In asset also discussions step in in financially

in So best forward with us a making put there we aligns are assure put parallel path registration. we if ongoing accelerated in with to program patients treatment that's the for that Takeda, a on FDA sure discussions the the light is disease-modifying the to that

relates design given INHBE, incredibly it where can muscle. and care just what study DIO fat it and we're we loss but that itself the about, to the obesity, both recapitulate phenotype. from excited the saw volunteers in think the existing which As clinical we standard your that mouse profile fact of to overweight we And spare point being differentiates not a healthy for able on model, to to

be embedding plan design clinical muscle. at to I anything add if Anne-Marie study to the trial and in know, we want Erik, that fat you the don't the Yes, of or terms to. additionally opportunity both look we'll in

Erik Ingelsson

on our effects Not studies. distribution, and we human the sparing. that genetic see really. as in profound replicate the preclinical we said muscle data, Paul fat see we Again, in We see we

but first and study. of It will overweight measure yet will be we the the the muscle, of clinical design that yet. shared in measures we and volunteers haven't different fat distribution haven't shared We details of healthy

Paul Bolno

spaces for as enough, aren't I are to very at interestingly that know test. there go the SomaSignal that, tests DEXA, looking aware, that MRI, into determine we new that's we just ways whether who are mean those of good,

filing in of trial. of the more to closer So on but we'd get embed beginning there us differentiate program, we that the clinical give regulatory obviously the for really the clinical distinguish the updates trial. ways are [indiscernible] and the as and to profile

Operator

And of line that Raymond Seedhouse one is the James. Steven with from

Nicholas Econom

This is Steve. Nick for on

for the QX, AAT do to the Z-AAT? show corrected proportion Just do of in Or show versus only plan plan you wanted to in clarify update concentration? RestorAATion-X protein changes to you M-AAT

dose quick data the as And include only the a single-ascending from will cohorts cohorts? dose multi-ascending or initial readout follow-up,

Paul Bolno

Yes.

of So not the that's tied profile. part the your question either threshold, a to initial proof of mechanism to single data is tied multi-dose of exactly first or

in and be assessing part And so point, protein, is, able to of how model in seen protein we therefore, we'll And assess RNA we've will from editing. in translation of principle what the time of translating assessing And that combination. the to the key both really SERPINAX protein total humans, the M total. and the be driver M-AAT as into for that's first evaluating your be now humans. But and that to

Operator

Partners. come And that Schwartz Leerink will from the line with of Joseph

Lili Nsongo

you're us the give generated on And the more just tell proposed if to support into you And likely can you a us some design reasonably data predict be include what as could changes this will that's if so little far wondering to been was you insight might analogies? interim Lili needed see meaningful caudate atrophy might and expecting? benefit? biomarker How of biomarker? for to is soon study I This in kind establish that Joe. what

Paul Bolno

large So thank MRI of the both to there on time, assess with is over then on Anne-Marie, coming And sets off and you to that looking the at data start, Track-HD I'll for the to caudate. that emerging over engaged question. I'll changes data we're it can Anne-Marie lot of and turn consortium a speak and but

has time the much some with that the Anne-Marie, regulators. that what be caudate in and than to want But with that patient large the this design the the to reflect study with possibility over imaging of XX been benefit do outcome that data imaging within going smaller is clinical before done think short to coming? HD think you with in there that to ability the to forward, are image of We agreed do as we've shared we XX months. Obviously, see periods has of before, to atrophy reasonably population do on studies. of think I there's

Anne-Marie Li-Kwai-Cheung

to. Happy Yes.

HD So that's way we're and it's very data -- called the available and this means allow to then available change of an outcome. natural between databases need that history there that's to establish us that one clinical first lot caudate which predict are collected lucky Track sets there in -- that there's the in is includes clinical relationship some likely of being a Predict-HD, the establish by you data community. And environment prospectively and are endpoint a would the And things reasonably rich that predictive outcomes. to one

that So the regulatory the in by atrophy and this them for a standard Consortium, submission we show they would required can value scans and mentioned, Image the caudate and harmonized made run the that that's the predictive that between so outcome. Huntington's we Disease way available the consortium that FDA CHDI a meet IXICO Harmonization

So it. that's of the first part

that it signs an already And that. of to part the of second drug on to seen caudate able we've The impact have study, first you SELECT-HD that show have is is your in atrophy. our obviously,

engaging taken think this strong a with on regulators So excited be is package. together, We're I this to package.

Paul Bolno

this to the as atrophy. that community think dynamic down knockdown Anne-Marie time, up potential I imaging been we target, available Anne-Marie profile said, mean, for think sparing, tools addressing that registration clinical a Just with Initially, the disease is showing target the HD type, caudate the I first said, wild-type outcome with to questions to accelerated I with follow for think, impact and measurement, have showing having involved correlates engage knocking the pathway. the agency protein extraordinarily relative substantially, sets really conversation that high now in the a And of up. assess concentration around that so on as around the modification to wild I important. showing preserve the then

Operator

will the Wells Fauth that And of Fargo. come line from Tiago with

Tiago Fauth

I had one just on the AATD.

Just into the of and if wondering models finding mostly questions those from your animal dose of can translatability discuss you the expectations in studies about humans, of some mutations the approach. of there's animal more the models novelty

would details that to gives dose at likely actually you're So humans? appreciated. taking a that on are therapeutic levels what you relevant in those forward be More range confidence be

Paul Bolno

to we're of I our time the really GalNac benefit nonhuman that think study lot modeling a primates and put surface pharmacology nonhuman take primate area translative into seen our in we to the conjugation work between SERPINAX to and the and the humans. humans. into studies and we've question, advantage mouse, wonderful a of going that's liver where It's able think -- No. And from I

So as is, well-established think modeling in exposures, drug about think very at that as to going, say we're species, where think is we look in PK and I pathway those we there again, about we concentrations pharmacology. able a of

of exciting get RNA I is as in think volunteers healthy think you and particularly translating field about assessment, don't editing while even nicely. very the PK RestorAATion-X TD the what's we is that

the modeling think PK I of modeling we've can on where again, TD the that got lot So [indiscernible] but confidence to to a across translate primates species, that early us nonhuman preclinical in humans. gives mouse

to back that's us I we dose as that think about and the this but also so piece frequency. is have finding, set of cohorts, data proof up And we for PD mechanism critical the multiple then prediction. just we which now give it relate to dose not in the assess affirm why say really ability of is is will modeling us why

And us think does give are of that translation. so the GalNac advantage we seeing we that the having in do predictability

Tiago Fauth

on just actual be there's expectations Got perceived the bar landscape. quick it. Because there. competitive to the given Perhaps what's one AATD again, mix follow-up from investors

thinking need So How at guys product micromolar profile? optimal phenotype? to XX you your Do about is crossing an the MM range to get dose, enough? the you are

Paul Bolno

I that -- conjugation, dosing, subcu point, and meaning the we and GalNAc a about lot and see the of and the we mean enter spend time clinic across durable to obviously, profile question, high an therapeutic, frequent advantage as why last editing. thinking the entire Yes. and of we great potent

as really So ingredients chronic for X important therapy. really a

threshold features one As you micromolar a patient, we to baseline, while to and reflects over where that that's really editing, the saw where them the to. an about a of patients ZZ sevenfold talking mentioned, MV XX and of as started is -- conversion there we really we're improvement think started that got about that a micromolar, Mike we improvement patients from from where about fold of

MM surpassing phenotype. -- even the healthy an us MV took that of threshold into That threshold

that always push patients to fact really ways full and editing while So above our X look of those that's really it's threshold -- best ability to that that threshold the it turn the micromolar where the and see going you demonstrated where data preclinical is, really at forward because that are.

that So be cohorts, we're this the we're of multiple of surpass to you what given preclinical where RNA antitrypsin looks alpha-X that's upper going micromolar limit which of can Obviously, going first-in-class But to as But single, to data lot a for that a of that. for first the that totality step both that a like. journey. the pointed supports therapeutic be through could able sense out, get really to continue the again, us threshold, of and treatment proof is we XX gives editing an best-in-class on establish profile the study, mechanism deficiency. the our confidence

Operator

Truist. from And Joon that Lee will be a with question follow-up

Joon Lee

having sort a the Can leading described space? recently CSF and of UniQure defective hydrocephalus to to complementary and with theories. generated to to signal of the cilia pseudoatrophy concerns knockdown you AMT-XXX, you are and And seen within is and safety that's X Tominersen there basal wild-type reduced -- One nonspecific driving ganglia due is ganglia Roche Huntington hydrocephalus other the flow. conducted caudate as the We due and sort Carewell call of pseudoatrophy maybe or hydrocephalus. the PTC, in been of the petting inflammation data -- discussing of defective that Huntington due what regarding

the evidence versus your these whatnot other? evidence Would and have your theories on in you of your to what -- preclinical hear what sort love support models to and one thoughts

Paul Bolno

think theories think tominersen No. I we mean key since those why where the are been And there Yes. imaging I they out was point at experience. did. And the driver that have I the looked [indiscernible]. at the dualing spoke we to

seeing weren't hydrocephalus. we sure, So

didn't was study. the So that really it hydrocephalus we I on see important to note think

it of theory, are on movement the protein. think the to cilia that healthy the comprised and CSF point structurally think, I of I are Huntington was one flow was that responsible for that prevailing, was

to potent think of a go the back and point Huntington's the the mutant of space, of a early into wasn't we so it on driver, to type. tominersen, disease suppression dose, reflect when goes the starting And really it and really durable lower was this to sparing to I make wild protein, more of more decided so version was while underlying biology

demonstrate or and other hydrocephalus the whether So those Again, see absence of to be of were the ability signals didn't then assess some there. not ability we to able to the that, that.

I encouraging. they're highly think

there's know, So saw study driver the it was both drove that. to forward. if in I really don't fundamental a existing to anything we in you want Anne-Marie, add what and we

Anne-Marie Li-Kwai-Cheung

that a and And that a reported think flow age are a burden. in benefit lower they they've and also because also they risk functional. slower Tominersen known better group it's CSF younger generations got disease young less that targeting age becomes with

that might the around cilia. So point theory also towards

Operator

remarks. with questions Thank you. Dr. Paul Bolno turn I'm like the the to over now would closing to I showing at no any this back in further queue time. call

Paul Bolno

on enjoy forward hope you of Have keeping you time you for look all this our joining Thank Wonderful. remainder we morning. our to to progress. great the a summer, some and your day. updated call We take

Operator

Thank program. for today's all participating. concludes This you

disconnect. now may You

Wave Life Sciences (WVE) 8 Aug 242024 Q2 Earnings call transcript