Q4 2023 Wave Life Sciences Ltd Earnings Call

Operator: Good morning, and welcome to the WAVE Life Sciences fourth quarter and full year 2023 financial results conference call. At this time, all participants are in a listen only mode.

Good morning, and welcome to wave life Sciences fourth quarter and full year 2023 financial results Conference call. At this time all participants are in a listen only mode. 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.

Operator: 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. Good morning, and thank you for joining us today to discuss our recent business progress and review WAVE's fourth quarter and full year 2023 financial results. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer, Kyle Moran, Chief Financial Officer, and Anne-Marie Lee Kwai Chung, Chief Development Officer. The press release issued this morning is available on the investor section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason.

Kate Rausch: Thank you operator, good morning, and thank you for joining us today to discuss our recent business progress and review, we worst quarter and full year 2023 financial results. Joining me today with prepared remarks are Dr. Paul <unk>, President and Chief Executive Officer, Colin Moran, Chief Financial Officer, and Anne Marie will be quite Chang Chief Development Officer.

Kate Rausch: The press release issued this morning and is available on the investors section of our website Www Dot wave life Sciences dotcom.

Kate Rausch: Before we begin I would like to remind you that discussions during this conference call will include forward looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, we undertake no.

Kate Rausch: To update or revise any forward looking statement for any reason I'd now like to turn the call over to Paul.

Paul B. Bolno: I'd now like to turn the call over to Paul. Thanks, Kate. Good morning, and thank you all for joining us on today's call. I will open with comments on our recent progress and continued execution of our strategy. Next, Anne-Marie will provide an update on our three ongoing clinical trials. Before opening up the call for questions, Kyle will review our finances.

Paul: Thanks, Kate good morning, and thank you all for joining us on today's call I'll open with comments on our recent progress and continued execution on our strategy.

Paul: Next Anne Marie will provide an update on our three ongoing clinical trials before opening up the call for questions Kyle will review our financials.

Paul B. Bolno: Chandra and Jenny will also be available. 2023 was a year of execution and tremendous progress for WAVE. Our achievements demonstrate the far-reaching potential of our multimodal platform to reimagine what's possible for human health and pioneer medicine that truly changes people's lives. We are leading the field in multiple areas. We are innovating in obesity with our Inhibin-E program, and today we are announcing that we've accelerated development to initiate our Inhibin-E clinical trial in the first quarter of 2025. We are also leading the field in RNA editing, having brought the first ever RNA editing candidate into human trials last year. In DMD, our novel chemistries have dramatically improved the pharmacology of exon skipping oligonucleotides, translating to best-in-class muscle distribution and skipping with WVE and VY31. In HD, we've pioneered allele selective silencing, another first for the field, and an approach that has the potential to overcome issues experienced by pan silencing approaches. We expect meaningful catalysts throughout this year for all of these programs, setting 2024 up to be a significant year for WAVE.

Paul: <unk> will also be available for questions.

Paul: 2023 was a year of execution and tremendous progress for wave.

Anne Marie: Achievements demonstrate the far reaching potential of our multimodal platform to re imagine what's possible for human health and pioneer Medicine, that's really changed People's lives. We are leading the field in multiple areas. We are innovating in obesity with our hip and knee program and today are announcing that we have accelerated development to initiate our binney click.

Anne Marie: Nicole trial in the first quarter of 2025, we are also leading the field in RNA editing, having brought the first ever RNA editing candidate into human trials last year in.

Anne Marie: In DMD or novel Chemistries have dramatically improved pharmacology of exon skipping oligonucleotide translate into best in class muscle distribution and skipping with WB and by 31.

Anne Marie: In HD, we've pioneered allele selective siloed thing another first for the field and an approach that has the potential to overcome issues experienced by silencing approaches we expect meaningful catalysts throughout this year for all of these programs setting 2024 up to be a significant year for wave.

Paul B. Bolno: I'll start with our ongoing clinical program of WVE006 for Alpha-1 Antitrypsin Deficiency, or AATD. Our restoration clinical program for WVE-006 is well underway, and we have a pipeline of RNA editing programs being advanced behind it. We are pioneering these first-in-class medicines across protein restoration targets such as AATD, as well as mRNA upregulation targets, which I'll discuss further in a moment. WVE006 is the industry's first ever clinical RNA editing candidate, which aims to correct the AATD-causing Z mutation to increase circulating levels of wild-type AAT protein and reduce mutant AAT protein aggregation in the liver. 006 addresses the root cause of AATD to provide a solution to patients with lung disease, liver disease, or both. The current standard of care is weekly IV augmentation therapy and limited to treating lung disease, while siRNA treatments in development are confined to treating liver disease, with the potential to exacerbate lung disease.

Anne Marie: I'll start with our ongoing clinical program of WV Zero-zero six for Alpha one antitrypsin deficiency or <unk>.

Our restoration clinical program for <unk> is well underway and we have a pipeline of RNA editing programs being advanced behind it. We are pioneering these first in class medicines across protein restoration targets, such as <unk> as well as mrna upregulation targets, which I'll discuss further in a moment.

Anne Marie: <unk> is the industry's first ever clinical RNA editing candidates, which aims to correct. The ATV, causing the mutation the increased circulating levels of wild type protein and reduce mutant <unk> protein aggregation in the liver.

Anne Marie: <unk> addresses the root cause of ATB to provide a solution to patients with lung disease liver disease or both.

The current standard of care is weekly IV augmentation therapy, and limited to treating lung disease, while SA RNA treatments in development are confined to treating liver disease with potential to exacerbate luxury.

Paul B. Bolno: By targeting RNA, 006 differs from DNA editing technologies that rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits in indels. In fact, in preclinical studies, the majority of edits observed using DNA-based editing were bystander edits that yielded isoforms of AAP protein with lower functional activity, while indels have the potential to create loss- Our unique, fully chemically modified oligonucleotides are able to effectively recruit endogenous ADAR enzymes.

Anne Marie: By targeting RNA <unk> differs from DNA editing technologies that rely on hyperactive exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and in Dallas in fact in preclinical studies. The majority of edits observed using DNA based Saturday, where bystander edit that yielded ice appointment.

Anne Marie: <unk> protein with lower functional activity, while in does have the potential to create lots of function variance.

Anne Marie: Our unique fully chemically modified oligonucleotides are able to effectively recruit endogenous enzymes.

Paul B. Bolno: O6 has demonstrated potent and durable editing in preclinical studies, resulting in AAT protein levels of up to 30 micromolar, exceeding the thresholds for both MZ and healthy MM populations. Additionally, we confirmed the functionality of this protein with neutrophil elastase inhibition S. Additionally, we saw decreases of lobular inflammation and reduction of liver aggregate. WVE-006 also prevents an increase in mitoses or turnover of hepatocytes indicating improved hepatic survival.

Anne Marie: <unk> has demonstrated potent and durable editing in preclinical studies, resulting in <unk> protein levels up to 30 micro molar exceeding that threshold for both M D and healthy <unk> population and we confirm the functionality of this protein with neutrophil elastase inhibition assay.

Anne Marie: Additionally, we saw decreases of <unk> inflammation and reduction of liver aggregates.

Anne Marie: <unk> also prevents.

Anne Marie: An increase in Mitoses, our turnover at the pad site, indicating improved hepatic survival.

Paul B. Bolno: PO-06 contains a galnet conjugate, which is highly specific and an elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market. When compared to other approaches that rely on lipid nanoparticles and IV delivery, WVE-006 offers the ease and convenience of subcutaneous dosing without sacrificing potency and durability. As Anne-Marie will speak to in further detail shortly, dose escalation is currently ongoing in Healthy Volunteers, and I'm happy to report that safety, tolerability, and PK are translating as expected. We remain on track to deliver proof of mechanism data from restoration to inpatients with AATD later this year.

Anne Marie: Oh six contains a gallon a conjugate which is highly specific and an elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market.

Anne Marie: When compared to other approaches that rely on lipid nanoparticle and IV delivery <unk> offers the ease and convenience of subcutaneous dosing without sacrificing potency and durability.

Anne Marie: As Anne Marie will speak to in further detail shortly dose escalation is currently ongoing in healthy volunteers and I'm happy to report that <unk> safety Tolerability and PK are translating as expected we remain on track to deliver proof of mechanism data for restoration two in patients with ATV later this year.

Paul B. Bolno: Success for 006 would not only meaningfully de-risk our AATD program but would also serve as proof of concept for a growing pipeline of fully-owned editing candidates, which are designed to either correct or up-regulate mRNA. We shared in vivo data for several of these targets across a range of both rare and prevalent diseases last year, and we expect to share new preclinical data on our advancing RNA editing programs during 2024 GSK was early to recognize the potential of RNA editing and our multimodal platform more broadly.

Anne Marie: Success for O six would not only meaningfully derisk, our ATB program, but would also serve as proof of concept for our growing pipeline of wholly owned editing candidates, which are designed to either correct or up regulate mrna.

Anne Marie: We shared in vivo data for several of these targets across a range of both rare and prevalent diseases last year, and we expect to share new preclinical data on our advancing RNA editing programs during 2024.

Anne Marie: GSK was early to recognize the potential of RNA editing at our multimodal platform more broadly.

Paul B. Bolno: Their leadership in respiratory medicine, development, and commercialization makes them an ideal partner for 006, and they continue to bring substantial value to WAVE through their significant investment in deep genetic insight. With the advancement of 006 into the clinic, we achieved the first milestone payment for our collaboration. Additionally, we continue to advance our GSK research collaboration program. For these programs, WAVE is eligible for potential milestone payments of up to $2.8 billion, as well as royalties on that sale. As a reminder, GSK pays 100% of the costs related to target validation for these partner programs.

Anne Marie: Our ship in respiratory medicine development and commercialization makes them an ideal partner for <unk> and they continue to bring substantial value to wave due to their significant investment in deep genetic insights.

Anne Marie: With the advancement into the clinic of Olympics, we achieved the first milestone payment for our collaboration.

Anne Marie: Additionally, we continued to advance our GSK research collaboration programs for these programs wave is eligible for potential milestone payments of up to $2 8 billion.

Anne Marie: As well as royalties on net sales.

Anne Marie: As a reminder, GSK pays 100% of the costs related to target validation of these partnered programs.

Paul B. Bolno: This collaboration is also expanding WAVE's pipeline, as we are able to leverage GSK's genetically validated targets to advance fully-owned WAVE programs. Inhibin-E was the first target that we selected, and we have the opportunity to advance two additional programs. As with Inhibin E, we are focused on high-impact targets that are based on strong clinical genetics, novel biology, meaningful, measurable biomarkers, and with first or best-in-class potential.

Anne Marie: This collaboration is also expanding waves pipeline as we are able to leverage gsk's genetically validated targets to advanced wholly owned waste programs.

Inhibiting <unk> was the first target would that be selected and we have the opportunity to advance two additional programs.

Anne Marie: As with inhibitor <unk>, we are focused on high impact targets that are based on strong clinical genetics novel biology, with meaningful measurable biomarkers and with first or best in class potential.

Paul B. Bolno: Moving on to inhibin E, we are rapidly advancing this program for the treatment of obesity and are excited to announce today that we have selected our lead clinical candidate well ahead of our prior expectations. This accomplishment clearly demonstrates the speed and translational power of our siRNA capability. Our candidate is a GalNeck siRNA that utilizes WAVE's next-generation siRNA format and is designed to silence the inhibiting gene through RNA-knots.

Anne Marie: Moving onto inhibit E.

Anne Marie: We are rapidly advancing this program for the treatment of obesity and are excited to announce today that we have selected our lead clinical candidate well ahead of our prior expectations.

Anne Marie: His accomplishment clearly demonstrates the speed and translational power of our <unk> capability.

Anne Marie: Our candidate has a <unk> that utilizes waves next generation SA RNA format and is designed to silence the binney gene through RNA knockdown.

Paul B. Bolno: His approach would induce weight loss, preserve muscle, and restore and maintain a healthy metabolic profile. There is strong human genetic evidence supporting this target. Inhibin-E loss-of-function heterozygous carriers identified in large genetic databases have a favorable cardiometabolic profile, including reduced abdominal obesity and reduced odds of type 2 diabetes and coronary arteries. Our program is designed to recapitulate this protective phenotype, which would fill a large unmet need in obesity. Currently, there are more than 174 million people in the U.S. and Europe alone with obesity and other metabolic disorders.

His approach would induce weightloss preserved muscle and restore and maintain a healthy metabolic profile.

Anne Marie: There is strong human genetic evidence supporting this target and.

Anne Marie: Inhibiting <unk> loss of function heterozygous carriers identified in large genetic databases have a favorable cardio metabolic profile, including reduced abdominal obesity and reduce AD the type two diabetes and coronary artery disease.

Anne Marie: Our program is designed to recapitulate, this protective phenotype, which would fill a large unmet need in obesity.

Anne Marie: Currently there are more than 174 million people in the U S and Europe alone with obesity and other metabolic disorders.

Paul B. Bolno: While GLP-1s are rapidly becoming the standard of care for weight loss, these therapies come with several limitations, namely loss of muscle mass, poor tolerability, and discontinuation rates as high as 68 percent. Our Inhibin-E program has the potential to provide an optimal therapeutic approach for obesity without the limitations of GLP-1s, as well as to work complementary with this GLP-1 class. We presented the industry's first in vivo data supporting preclinical proof of concept for this target. With our first-generation siRNA format, we showed that silencing inhibition in the DIO mouse model led to significantly lower body weight and a substantial reduction of visceral fat as compared to control.

Anne Marie: While G O P ones are rapidly becoming the standard of care for weight loss. These therapies come with several limitation, namely Boston muscle mass poor tolerability and discontinuation rates as high as 68%.

Anne Marie: Our inhibitor program has the potential to provide an optimal therapeutic approach for obesity without the limitations of <unk> ones as well as to where complementary with the <unk> one class.

Anne Marie: At our R&D day last year we.

Anne Marie: We presented the industry's first in vivo data supporting preclinical proof of concept for this target.

Anne Marie: With our first generation <unk> in a format, we showed that silencing in hip and knee in the DIR mouse model led to significantly lower body weight, a substantial reduction of visceral fat as compared to control. We also shared data on our next generation SA RNA formats, which led to significantly more potent and durable knockdown in preclinical study.

Paul B. Bolno: We also shared data on our next-generation siRNA format, which led to significantly more potent and durable knockdown in preclinical studies. Today, we are announcing the selection of our lead clinical candidate, which utilizes this next-generation siRNA format. Our Inhibin-E program demonstrated highly potent silencing with an ED50 of less than one milligram per kilogram in the DIO mouse model.

Anne Marie: Yes.

Anne Marie: Today, we are announcing the selection of our lead clinical candidate, which utilizes the next generation SA RNA format.

Anne Marie: <unk> inhibitors program demonstrated highly potent silencing with an EDI 50 of less than one milligram per kilogram and that the Io mouse model and durable silencing follow one low single digit dose, which supports the potential for subcutaneous dosing intervals of every six months or annually.

Paul B. Bolno: And durable silencing follows one low single-digit dose, which supports the potential for subcutaneous dosing intervals of every six months or annually. We also observed weight loss and reductions in fat mass with a preferential effect on visceral fat. And importantly, these reductions in fat and visceral fat came with no loss of muscle mass.

Anne Marie: We also observed weight loss and reduction in fat mass with a preferential effect on visceral fat and importantly, these reductions in fat and visceral fat came with no loss of muscle mass. These.

Paul B. Bolno: These data reinforce the potential both for inducing healthy weight loss as well as the potential for long-term maintenance. Compared with the current standard of care, GLP-1s, which require weekly dosing, a therapeutic agent that is dosed once or twice a year and induces fat loss with muscle sparing, would transform the treatment paradigm for obesity. As the Inhibin E mechanism of action is distinct from GLP-1s, there is an opportunity to use Inhibin E siRNA both in combination, as well as to transition patients off of GLP-1s to maintain weight loss.

Anne Marie: These data reinforce the potential both for inducing healthy weight loss as well as the potential for long term maintenance use.

Anne Marie: Compared with current standard of care G O P ones, which require weekly dosing a therapeutic agent that is dosed once or twice a year and induces fat loss with muscle spirit would transform the treatment paradigm for obesity.

Anne Marie: As the inhibiting mechanism of action is distinct from GOP. One there is an opportunity to use and have been E. <unk> both in combination as well as to transition patients off of GOP, one to maintain weight loss.

Paul B. Bolno: With the selection of our candidate, we now expect to submit a CTA for this program as early as the end of 2024 and expect to initiate our clinical trial in the first quarter of 2025. We believe clinical proof of concept can be achieved with a single dose of inhibin E siRNA due to its potency and long duration of effect. We expect to share more preclinical data on our inhibin E program later this year. Turning to DMD and HD, we are on track to deliver clinical data for both programs this year. In DMV, we are advancing our potentially registrational Forward 53 clinical trial of WVEN531 in boys with DMV. Our goal in Forward 53 is to demonstrate that we can deliver endogenous functional or Becker-like dystrophin and thus provide a meaningful clinical benefit for patients amenable to exon 53 skipping. There remain significant scientific gaps on the functional benefit of micro or mini-districts.

Anne Marie: With the selection of our candidate we now expect to submit a Cta for this program as early as the end of 2024 and expect to initiate our clinical trial in the first quarter of 2025.

Anne Marie: We believe clinical proof of concept can be achieved with a single dose of inhibitor ESI RNA due to its potency and long duration of effect, we expect to share more preclinical data on our inhibitor program later this year.

Anne Marie: Turning to DMD and HD, we are on track to deliver clinical data from both programs this year.

Anne Marie: In DMD, we are advancing our potentially registrational forward 53 clinical trial of <unk> and 531 in boys with DMD.

Anne Marie: Our goal and $4 53 is to demonstrate that we can deliver endogenous functional or becker like dystrophin, and thus provide a meaningful clinical benefit for patients amenable to exon 53 skipping.

Anne Marie: There remains significant scientific gaps on the functional benefit of micro or mini dystrophin.

Paul B. Bolno: There is an urgent need to deliver more therapeutic options to patients, including achieving better access to the heart and diaphragm, two areas where we have seen substantial distribution in our preclinical studies, including NHPs. Clinical data thus far for N531 positions it as potentially best-in-class, including industry-leading exon skipping of 53%, muscle tissue concentrations of 42,000 nanograms per gram, and a half-life that supports We are also the first to show evidence of uptake in myogenic stem cells, which Anne-Marie will discuss further.

Anne Marie: As an urgent need to deliver more therapeutic options to patients, including achieving better access to heart, a diaphragm shoe areas, where we have seen substantial distribution in our preclinical studies, including in Hps.

Anne Marie: Clinical data, thus far for and 531 positions it as potentially best in class, including industry, leading exon skipping a 53% muscle tissue concentrations of 42000 nanograms per gram and a half life that supports the potential for monthly dosing.

Anne Marie: We are also the first to show evidence of uptake in myogenic stem cells, which Anne Marie will discuss further.

Paul B. Bolno: We remain on track to deliver 24-week Distress and Protein Expression data in the third quarter of this year. In HD, we are advancing WVE-003, our first-in-class allele-selective therapeutics. OO3 is designed to reduce mutant Huntington protein while also sparing healthy wild-type Huntington protein, which is critical to the health and function of neurons.

Anne Marie: We remain on track to deliver 24 week dystrophin protein expression data in the third quarter of this year.

Anne Marie: And HD, we are advancing <unk>, our first in class allele selective therapeutic.

Anne Marie: <unk> three is designed to reduce mutant Huntington protein, while also sparing healthy wild type Huntington protein, which is critical to the health and function of neurons.

Paul B. Bolno: Having the ability to preserve this important protein is a clear advantage over pan-silencing approaches that non-selectively lower mutant and wild-type proteins, especially as HD patients already start with a lower wild-type reserve. We have demonstrated the successful translation of our compelling preclinical data to the clinic with reduction of mutant huntingtin and preservation of wild-type after a single dose in humans. We anticipate building on this data with the first multi-dose data from our SELECT-HG clinical trial, which is on track for the second quarter. And so, with an HIV and AIDS program advancing towards the clinic, data readouts from DMD and NHD expected in the coming quarters, and RNA editing proof of mechanism data for AATV expected this year, 2024 will be a breakout year for WAVE. Now, to discuss the progress that we've made on our clinical programs and our expectations for data this year, I'd like to turn the call over to Anne-Marie. Anne-Marie.

Having the ability to preserve this important protein is a clear advantage over pen silencing approaches that non selectively lower mutant and wild type protein, especially as HD patients already start with a lower wild type reserve.

Anne Marie: We have demonstrated the successful translation of our compelling preclinical data to the clinic with reduction of mutant Huntington and preservation of Wild type after a single dose in humans, we anticipate building on this data with the first multi dose data from our select HD clinical trial, which is on track for the second quarter.

Anne Marie: And so with inhibitor <unk> program advancing towards the clinic data Readouts from DMD and HD expected in the coming quarters and RNA editing proof of mechanism data for ATB expected. This year 2024 will be a breakout year for Wade.

Speaker Change: <unk> discussed the progress that we've made on our clinical programs at our expectations for data this year I'd like to turn the call over to Anne Marie and Murray. Thanks.

Eun Kyung Yang: Thank you, Paul. 2024 should certainly be an exciting year for WAVE, and I look forward to the many milestones we have on the horizon. I'll start with WAVE-006, Galnut Conjugated AMR, or RNA Editing Oligonucleotide for AATD. We're advancing WAVE-006 in our ongoing Restoration Clinical Program. The program is comprised of two interconnected portions, Restoration I for healthy volunteers and Restoration II in AATD for patients who have the homozygous PIZV mutation. In addition to generating safety and PK data, Restoration One is designed to rapidly establish a dose level and regimen that's expected to engage targets. In restoration 2, we will be taking multiple assessments of serum MAAT through the low, medium, and high dose cohorts, which will enable us to quickly detect the potential presence of wild-type healthy MAAT protein in serum, representing achievement of proof of mechanism. Remember, these easy patients have never made MAAT proteins, so the presence of any MAAT would demonstrate that WAVE-006 is successfully editing RNA. We are progressing well in Restoration 1. Dose escalation is ongoing.

Anne Marie: Hey, Paul 20 transfer should certainly be an exciting year for waste and I look forward to the many milestones we have on the horizon.

Anne Marie: Start with weight zero, six all gone that conjugated <unk> RNA editing oligonucleotides for TD.

Anne Marie: We are advancing wages or is there a fix in our ongoing restoration clinical program.

Anne Marie: <unk> is comprised of two interconnected portions restoration, one healthy volunteers and restoration to NIH.

Anne Marie: The patients who have homozygous TICC mutation.

Anne Marie: In addition to generating key safety and PK data restoration, one is designed to rapidly establish a dose level and regimen, that's expected to engage target.

Anne Marie: Administration change, we will be taking multiple assessments of CRM.

Anne Marie: Trade day, low medium and high dose cohorts, which will enable us to quickly the taxes, hence your presence of wall type healthy MAA protein and Sharon.

Anne Marie: Presenting from achievement of preferred mechanism.

Anne Marie: Remember these days the patients have never made MAA to proteins presence of any NII would demonstrate that <unk> six is <unk>.

Anne Marie: Yesterday at the Shanghai market.

Anne Marie: We are progressing well in restoration one dose escalation is ongoing pharmacokinetic data is as expected and blinding blinded safety data has been encouraging we're.

Eun Kyung Yang: Pharmacokinetic data is as expected, and blinded safety data has been encouraged. We're on track to initiate the Restoration 2 study and deliver proof of mechanism data from Restoration 2 in patients with AATD this year. Turning to DMD, this week, our team attended the 2024 MDA Clinical and Scientific Conference, where we showed posters on our clinical data from Part A, including the first evidence of myogenic stem cell or satellite cell uptake. Myogenic stem cells are the progenitor cells for new myoblasts, and we're not aware of any other clinical data for excellence skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake.

Anne Marie: We're on track to initiate the restoration to study and deliver proof of mechanism data from registration Chilean patients with FCA.

Anne Marie: <unk>.

Anne Marie: Turning to DMD. This week our team attended the 2020 for MDA clinical <unk> Scientific conference, while we should have posters on our clinical data from pace, including the first evidence of myogenic stem cell or satellite cell uptake.

Anne Marie: Myogenic stem cells of the progenitor cell Sydney, Myobloc and were not aware of any other clinical data for exon skippers with gene therapy, but have been able to demonstrate myogenic stem cell uptake.

Eun Kyung Yang: The DMD community is excited about these data and what they may mean for their boys. Our post also highlighted our industry-leading mean 53% exon skipping, which was driven by muscle tissue concentrations of 42 micrograms per gram, or 42,000 nanograms per gram, which is thousands fold above what other exon skipping companies have reported. These data give us confidence in achieving best-in-class dystrophin protein expression in our ongoing, potentially registrational, Phase 2 clinical trial, Forward 53. BORD53 is an open-label trial that is currently evaluating 10 MycNickic doses of N531 administered every other week. The trial is powered to evaluate functional endogenous dystrophin expression after 24 and 48 weeks of treatment, which will be the trial's primary endpoint. The trial will also evaluate digital and functional endpoints, pharmacokinetics, and safety and tolerability. All three are fully enrolled with 11 boys, and dosing continues.

Anne Marie: The DMD community is excited about these data on what they may mean for Pep boys.

Anne Marie: Post has also highlighted our industry, leading mean, 53% exon skipping, which was driven by muscle tissue concentrations of 42 micrograms per gram ore 42000, nanograms per Gram, which is thousands pounds above all other exon skipping companies have reported.

Anne Marie: These data give us confidence in achieving best in class dystrophin protein expression in our ongoing potentially registrational phase III clinical trial forward 63.

Anne Marie: 463 is an open label trial, which is currently evaluating 10 million doses of <unk> one administered every other week.

Anne Marie: The trial is powered to evaluate functional endogenous dystrophin expression. After 24 unfortunate eight weeks of treatment, which will be the trials primary endpoint.

Anne Marie: The trial will also evaluate digital and functional endpoints pharmacokinetics and safety and Tolerability.

Speaker Change: Well it's.

Speaker Change: It is fully enrolled with 11 boys and dosing continues.

Eun Kyung Yang: We remain on track to deliver potentially registrational 24-week dystrophin expression data in the third quarter, which, if positive, would support our plans to file for accelerated approval in the US. These data would also accelerate our clinical development plans to build a wholly owned multi-Exxon DMD franchise beyond Exxon 53. As you may recall, we generated data on compounds that would together address up to 40% of the DMD population, all of which utilize RPN chemistry and have demonstrated high levels of skipping and protein restoration in in vivo studies. Moving now to HD, WAVE 003 is our first-in-class allele-selective candidate for Huntington's disease or HD. We believe WAVE-003 offers an optimal treatment approach for HD as it aims to reduce the toxic mucin Huntington protein while preserving the healthy wild-type Huntington protein, which is increasingly becoming an area of focus due to its critical role in neuronal function. Recently, a new manuscript by Dr. Jeff Carroll shared new preclinical data demonstrating that complete loss of Huntington in mice is associated with progressive subcortical calcification and neurodegeneration, which underlines the need for a cautious approach in pan-silencing studies.

Speaker Change: We remain on track to deliver potentially Registrational 24 week dystrophin expression data in the third quarter, which if positive would support our plans to file for accelerated approval in the U S.

Speaker Change: These data, but also accelerate our clinical development plans to build a wholly owned multi Exxon bnb franchise beyond exon 53.

Speaker Change: As you May recall, we've generated data on compounds that would together address up to 40% of the DMD population all of which utilize our pan chemistry and have demonstrated high levels of skipping and protein restoration and in vivo studies.

Speaker Change: Moving now to H D wave <unk> three is our first in class allele selective candidates huntington's disease or H D.

Speaker Change: We believe waves over to Richard.

Speaker Change: <unk> offers an optimal treatment approach for H D. At the aims to reduce the toxic mutant Huntington protein, while preserving the healthy wall type Huntington protein, which is increasingly becoming an area of focus due to its critical role in urinal function.

Speaker Change: Recently, a new manuscript by Dr. Jeffs, Taro Shat, we presented preclinical data demonstrating that complete loss of Huntington and mice is associated with progressive Subcortical pacification and neuro degeneration.

Speaker Change: Which underlines the need for a cautious approach in Perm financing studies.

Eun Kyung Yang: Just last week, we attended the annual CHDI HG Therapeutics Conference, and we heard first-hand from KOLs about their enthusiasm for WAVE-003 and its first-in-class allele-selective design. Another key theme was the growing support for shorter, more efficient development paths to registration, specifically those predicated on MRI imaging, for example, called 8-volume loss. Imaging biomarkers such as these correlate well with clinical outcomes and are sensitive enough to enable highly efficient studies to allow us to establish the biological plausibility of the benefit of mutant hunting to knockdown with wild-type sparing.

Speaker Change: Just last week, we attended the annual CACI H T Therapeutics conference and we had firsthand from Kols about their enthusiasm for <unk> and its fast and cost allele selective design.

Speaker Change: Another key theme was the growing support short term more efficient development path to registration specifically that is predicated on MRI imaging for example, Colgate on Vietnam.

Speaker Change: Imaging biomarker, such as these correlate well with clinical outcomes and defense to FNF to enable highly efficient studies to allow us to establish the biological plausibility of the benefit of mutant Huntington knockdown with wild type styrene.

Eun Kyung Yang: We were excited by the energy in the HD community and discussions around how they can advocate for accelerated registrational paths if a sponsor demonstrates support. Our ongoing SelectHD study is evaluating WAVE003 in 24 HD patients that have received doses of 30mg of 003 versus placebo every 8 weeks. We are on track to report data from this multi-dose cohort with extended follow-up, along with all single-dose data, in the second quarter. With multi-dosing, we're looking to replicate the promising single-dose data showing durable mutant Huntington's knockdown of at least 20% with preservation of wild-type protein.

Speaker Change: We were excited by the energy and the H D community and discussions around how they can advocate for accelerated Registrational path is a sponsor demonstrates supporting data.

Speaker Change: Our ongoing select tasty study is evaluating <unk> in <unk> H D patients that have received doses of 30 milligrams of <unk> versus placebo at every eight week.

Speaker Change: We are on track to report data from this multi dose cohorts with extended follow up along with all single dose data in the second quarter.

Speaker Change: With multi dosing window going to replicate the promising single dose data showing durable mutant Huntington knockdown of at least 20% with preservation of wild type protein.

Eun Kyung Yang: These data will form the basis of decision-making for the advancement of this program, including supporting an opt-in package for these applications. We're actively planning the next steps that, pending positive data, would enable an efficient and accelerated path to bring WAVE 003 to patients. And with that, I'd like to turn the call over to our CFO, Kyle Moran, to provide an update on our finances. Thanks, Anne-Marie. Our net loss was $16.3 million and $57.5 million for the fourth quarter and full year 2023 periods, respectively.

Speaker Change: These data will form the basis is decision, making for advancement of this program, including supporting an option for you.

Yes.

Speaker Change: We're actively planning the next steps that pending positive data would enable an efficient an accelerated path to bring <unk> 003 patients.

Speaker Change: With that I'd like to turn the call to our CFO <unk> to provide an update on our financials.

CFO: Thanks Anne Marie.

CFO: Our net loss was $16 3 million and $57 5 million for the fourth quarter and full year 2023 periods respectively.

Kyle B. Moran: Our net loss significantly improved over the prior year periods, primarily due to the substantial revenue earned from our collaboration partners. During the fourth quarter, we recognized revenue of $18.9 million under our collaboration with GSK, which became effective in January 2023. We also recognize revenue of $10.1 million in the fourth quarter of 2023 under our collaboration with Takeda, as compared to $1.2 million in the prior year quarter. Research and development expenses were $34.1 million in the fourth quarter of 2023, as compared to $31.1 million for the prior year quarter. This increase was primarily driven by increased external expenses related to our DMD and AATD programs, as well as increases in compensation-related costs. These increases were partially offset by decreased spend on our discontinued C9 program. Our G&A expenses were $13.7 million, essentially flat compared to the prior year quarter.

CFO: Our net loss significantly improved over the prior year periods, primarily due to the substantial revenue earned from our collaboration partners.

CFO: During the fourth quarter, we recognized revenue of $18 $9 million under our collaboration with GSK, which became effective in January 2023.

CFO: We also recognized revenue of $10 1 million in the fourth quarter of 2023 under our collaboration with Takeda as compared to $1 2 million in the prior year quarter.

CFO: Research and development expenses were $34 1 million in the fourth quarter of 2023 as compared to $31 1 million for the prior year quarter.

CFO: This increase was primarily driven by increased external expenses related to our DMD and ATB programs as well as increases in compensation.

CFO: <unk> related costs.

CFO: These increases were partially offset by the decreased spend on our discontinued <unk> program.

CFO: Our G&A expenses were $13 7 million.

CFO: Essentially flat compared to the prior year quarter.

Kyle B. Moran: We ended the fourth quarter with $200.4 million in cash and cash equivalents. Subsequent to year-end, we also received $20 million in a milestone payment for GSK and $14 million in net proceeds from the full exercise of the Green Shoe Option for our December 2023 financing. We expect that our current cash and cash equivalents will be sufficient to fund operations into the fourth quarter of 2025. As a reminder, we do not include any future milestones or opt-in payments under our GSK or TCATA collaboration in our cash runway, but we do have the potential to receive meaningful near-term milestone payments this year and beyond. I'll now turn the call back over to Paul for his closing remarks. Thank you, Kyle.

CFO: We ended the fourth quarter with $204 million in cash and cash equivalents subsea.

CFO: Subsequent to year end, we also received $20 million and a milestone payment for GSK and $14 million in net proceeds from the full exercise of the green shoe option prior to December 2023 refinancing.

CFO: We expect that our current cash and cash equivalents will be sufficient to fund operations into the fourth quarter of 2025.

CFO: As a reminder, we do not include any future milestones are opt in payments under our GSK Takeda collaboration and our cash runway, but we do have the potential to receive meaningful near term milestone payments in this year and beyond.

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

Paul B. Bolno: As we look to the remainder of 2024, we are at a truly exciting inflection point, with the opportunity to further validate our best-in-class platform in the clinic and unlock the broad potential of our pipeline. This year, we're on track to deliver three important clinical data readouts, as well as advance our Inhibin-E program into the clinic. In summary, we plan to deliver the first ever clinical proof of mechanism data for RNA editing with WVE-006 this year and share new preclinical data on our advancing RNA editing program.

Paul: Thank you Kyle as we look to the remainder of 2024, we are at a truly exciting inflection point with the opportunity to further validate our best in class platform in the clinic and unlock the broad potential of our pipeline.

Paul: This year, we're on track to deliver three important clinical data readouts as well as advance our inhibitor program towards the clinic and in summary, we plan to deliver the first ever clinical proof of mechanism data for RNA editing with <unk> this year and share new preclinical data on our advancing RNA editing programs.

Operator: Submit a CTA for our Inhibin-E siRNA obesity program as early as the fourth quarter, and initiate a clinical trial in the first quarter of 2025. Deliver data, including dystrophin protein, from our potentially registrational 453 clinical trial in the third quarter. And deliver HD data from the multidose select HD trial with extended follow-up, along with all single dose data, in the second quarter. We look forward to sharing our progress with you along the way, as we reimagine what's possible for patients and continue on our journey to building a leading RNA medicines company. And with that, I'll turn the call over to the operator for Q&A. Thank you. Ladies and gentlemen, if you have a question or comment at this time, please press star 11 on your telephone. If your question has been answered and you wish to remove yourself from the queue, please press star 11 again.

Paul: Submit a cta for our inhibitor SA RNA obesity program as early as the fourth quarter and initiate a clinical trial in the first quarter of 2025.

Paul: Deliver data, including dystrophin protein from a potentially registrational forward 53 clinical trial in the third quarter and deliver HD data from the multi dose select HD trial with extended follow up along with all single dose data in the second quarter.

Paul: We look forward to sharing our progress with you along the way as we re imagine what's possible for patients and continue on our journey to building, a leading RNA medicines company and with that I'll turn the call over to the operator for Q&A operator. Thank.

Speaker Change: Thank you ladies and gentlemen, if you have a question or comment at this time. Please press star one on your telephone. If your question has been answered you were seeing with yourself from the queue. Please press star one again, we will pause for a moment, while we compile our Q&A roster.

Operator: We'll pause for a moment while we compile our Q&A roster. Our first question comes from Steve Seedhouse with Raymond James. Your line is open. Hi, good morning. This is Timur Ivanov on behalf of Steve.

Speaker Change: Our first question comes from Steve <unk> with Raymond James Your line is open.

Speaker Change: Hi, Good morning, this is <unk> for Steve.

Timur Ivanov: So we have a couple of questions for your AATD, your RNA editing. I think you mentioned you will be disclosing serum MAAT. So what level of MAAT are you targeting eventually, since one of your competitors expects the target to achieve healthy levels eventually? Is that something you're looking at right now?

Speaker Change: So we have a couple of questions for your eight Atg RNA editing I think you mentioned you will be disclosing.

Speaker Change: Hum.

Steve: So what level.

Speaker Change: Are you targeting eventually.

Speaker Change: Since one of your competitors expects to target to achieve eventually healthy levels is that something.

Eun Kyung Yang: Or, you know, what is your expectation for the MAAT level? Thank you. Emery, would you like to start, and then I'll...

Speaker Change: Youre looking at right now or.

Speaker Change: What is your expectation for the MAA ETE level. Thank you.

Speaker Change: And when would you like to start and then ill.

Paul B. Bolno: So I think the important point to recognize is that we're not delivering exogenous AAT replacement therapy; we're restoring wild-type healthy MAAT through RNA editing, and demonstration that that MAAT is functional is really the key. We're already in the ballpark of 11. We know that MZ patients have a lower normal limit of 11, with a very low risk of clinical outcomes. And with the editing and restoration of the MAAT, we believe that patients will be able to respond in like a healthy patient. I think just kind of stepping back as well, and as Anne-Marie said, the threshold that came out of 11 micromolar because that was the lower limit of the heterozygous patient, obviously, the target of where you can get the correction.

Speaker Change: So I think the important point to recognize that we're not delivering exogenous AIG replacement therapy.

Speaker Change: Mr and wall type healthy NIH through RNA editing and demonstration.

Speaker Change: MAA is functional is really the case we've.

Speaker Change: We are already in the ballpark of 11, we note that Mg patients have a lower normal limit of 11 with very low risk of clinical outcomes and with the Shanghai restoring of.

We believe that patients will be able to respond in healthy patients.

Speaker Change: I think just kind of stepping back as well.

Speaker Change: And then where is the threshold that came out of 11 micro molar because that was below the limit of the heterozygous patient obviously the target of where you can get with correction I think if we think about the range that we've already seen in preclinical studies as we said earlier on the call. We're already achieving ranges that are both not only within the heterozygous, but also the healthy and so I think we need to refresh.

Paul B. Bolno: I think if we think about the range that we've already seen in preclinical studies, as we said earlier on the call, we're already achieving ranges that are both not only within the heterozygous, but also within the healthy. And so I think we need to reframe how the RNA editing, and we should say the editing field, thinks about protein levels versus, let's say, exogenous protein. So, if you imagine exogenous protein, the concept of more and more was really born from that, because you're putting an exogenous protein in, it's being depleted, and you're trying to stay at a threshold that will protect you.

Speaker Change: How.

Speaker Change: RNA editing and we should say the editing field thinks about protein levels versus let's say exogenous proteins. So imagine exogenous proteins.

Speaker Change: The concept of more and more of it was really born from that because youre, putting an exogenous protein in it is being depleted and youre trying to stay at a threshold level of protection. We're.

Paul B. Bolno: If we're doing editing and already achieving the correction of the transcript at levels that would be equivalent to heterozygous patients or potentially healthy patients, then you've established a threshold for, so 11 micromolar would establish, at a lower limit, a threshold of protection that's equivalent to these heterozygous patients, with the knowledge that you've corrected the underlying genetics, or you've corrected the transcript, so that when these patients And so there's a different dynamic at play in editing correction than when one thinks about protein replacement. So I think there is still a lower limit of 11 micromolar.

Speaker Change: We're doing editing and already achieving the correction of the transcript that level that would be equivalent to heterozygous patients and potentially helping patients.

Speaker Change: Then you've established a threshold for so 11 micro molar are established at a lower limit would establish a threshold of protection that's equivalent with these heterozygous patient with the knowledge that you corrected the underlying genetics or use it correctly. The transcript so that when these patients do need more protein, they're able to produce more wild type protein and so is it different.

Speaker Change: Dynamic at play and editing correction level.

Speaker Change: One thinks about booking replacement. So I think there is still a lower limit of 11 micro molar our preclinical data as well as the top of that as I said.

Paul B. Bolno: Our preclinical data has well surpassed that. As I said, it got to threshold levels in even healthy patients. But I think we need to shift from a more-is-more concept within editing once you've achieved those threshold levels, and then really, it is about how to keep patients and save patients on these therapies. But we will be measuring both total AAT proteins and, as Anne-Marie said on the call, being able to look at MAAT to look at that percentage of edited proteins. Okay, thank you very much for that.

Speaker Change: Got the threshold level that we had healthy patients, but I think we need to shift from a more as more concept with an editing once you've achieved the threshold level and then really it is about how to keep patients safe patient public therapies, but we will be measuring both total AAC protein and as <unk> said on the call being able to look at and to look at that.

Speaker Change: <unk> edited protein.

Speaker Change: Okay. Thank you very much for that and we also have a question about the progress.

Paul B. Bolno: And we also have a question about the progress of the clinical study itself, just in terms of what dose levels you have completed in the Healthy Volunteers, and what dose do you actually need to complete before you can start dosing patients. And have you started screening AATD patients already? So, as you know, the Restoration I and Restoration II studies are interconnected, and in Restoration I, in healthy volunteers, we're progressing through the dosing as expected, with the aim of starting Restoration II at a therapeutically relevant level, and we're on track to do that, with data from restoration to for proof of mechanism expected. I think what's important to add to that, as Anne-Marie said on the call earlier, I mean, when you bring a new modality into the clinic, how is PK translated? And I think, as we said on prior calls and discussions, that a key driver of that dose selection is going to be based on modeling. And I think what's encouraging is that modeling is sustainable in that healthy volunteer setting. So I think we're on track to deliver that. Okay, great. Thank you very much.

Speaker Change: The clinical study itself.

Speaker Change: Just in terms of what dose.

Speaker Change: <unk> have you completed in healthy volunteers and what dose do you actually need to complete before you can start dosing patients.

Speaker Change: Have you started screening.

Speaker Change: TD patients already.

Speaker Change: Okay.

Speaker Change: So im sure.

Speaker Change: Sorry, Paul.

Speaker Change: As you know the restoration, one and restoration two studies are interconnected and in restoration one in.

Speaker Change: In the healthy volunteers.

Speaker Change: Progressing through the dosing is expected with the aim of stock King restoration shoe therapy, PTT relevant level and we're on track to do that.

Speaker Change: With data from restoration to a proof of mechanism expected this year.

Speaker Change: I think what's important and to add to that as <unk> said on the call earlier I mean, it's important when you bring in new modality into the clinic, how teekay translate it and I think as we said on prior calls and discussions that a key driver of that dose selection is going to be based on modeling and I think what's encouraging is that modeling as David in that.

Speaker Change: The volunteer study. So I think we are on track to deliver that.

Speaker Change: Okay, great. Thank you very much.

Operator: One moment for our next question. Our next question comes from Salim Syed on Mizzou Hill. Your line is open.

Speaker Change: One moment for our next question.

Speaker Change: Our next question comes from Selim side with Mizuho. Your line is open.

Salim Qader Syed: Hey, good morning, guys. Congratulations on the progress and enjoy the new website, Paul. I guess on inhiBINI, Paul. I know you're not going to give us the full clinical trial design, but perhaps can you just guide us how you're sort of thinking about the initial trial design size? Would you be willing to use an active comparator, just given how quickly the space is moving?

Selim: Hey, good morning, guys congrats on the progress.

Selim: And join the new website Paul.

Selim: I guess on inhibiting.

Selim: Paul.

Selim: You can't you're not going to give us the full clinical trial design, but perhaps could you just guide us how youre sort of thinking about the initial trial design.

Paul: Would you be willing to use an active comparator just given how quickly this space is moving.

Paul B. Bolno: And just sort of where your intentions are in terms of treatment, in the treatment landscape, where do you really see this inhiBINI product getting plotted? Thank you. Thank you, and thanks for noticing that the updated web design hopefully makes it easier to access information for all our constituents.

Speaker Change: And just sort of.

Speaker Change: Where are your intentions are in terms of treatment in the treatment landscape, where do you really see.

Inhibiting <unk>.

Speaker Change: Getting slotted thank you.

Speaker Change: Thank you and thanks for noticing the updated web design.

Speaker Change: Hopefully it makes it easier to access information for all our constituents.

Paul B. Bolno: As it relates to that, and I'm glad we're talking about clinical trial designs for inhibiny, and there will be a lot more to come on that as we move throughout this year. I think the other update to your point on the evolving landscape and how inhibitory silencers relate to other therapeutics. I think we've got a lot of opportunities throughout 2024 to continue to provide updates on thinking about these synergies. As it relates to the initial trial design, I think this is one of the advantages we have with a very potent and durable program. As we were saying, we think we're beyond potential twice-yearly dosing into thinking about annual. Let's just think creatively about designing healthy volunteer studies because we do have biomarkers, not just biomarkers of target engagement, but because inhibition in some of the genetic studies has shown that actually these patients have lower levels of trachealyzerides and LDL, they have higher HDL, there are a whole bunch of other biomarkers we wish to study.

Speaker Change: As it relates to that and I'm glad we're talking about clinical trial designs for <unk> inhibitor and there will be a lot more to come on that as we move throughout this year I think the other updates to your point on the evolving landscape and how do inhibiting silence errors related to other therapeutics I think we've got a lot of opportunities throughout 2020 forward to continue to provide us.

Speaker Change: Based on thinking about the synergies as it relates to the initial trial design I think this is one of the advantages we have with a very potent and durable program. As we were saying we think we're beyond potential twice a year dosing into thinking about annual lets us think creatively about designing healthy volunteer studies, because we do have biomarkers not just biomarkers of target engagement.

Speaker Change: But because it had been in some of the genetic studies that show that after these patients have lower levels of triglycerides and LDL. They are higher HDL. There are a whole bunch of other biomarkers with which the study. So I think as we think about running an overweight healthy volunteer study it provides ample opportunity for us to build a profile.

Paul B. Bolno: So, I think as we think about running an overweight healthy volunteer study, it provides ample opportunity for us to build a profile, not just to establish dose and safety, but also to look at pharmacodynamic effects across these biomarkers. And then think about that, to your point, on how do we want to sequence that in on the treated population? So, I think the initial study, we don't have to think about, you know, is this a run-in on whether it's GLPs or other therapies? I think the advantage we have in the healthy overweight volunteer study would be a clean population with which to exhibit the effects.

Speaker Change: Not just to establish dose and safety, but also to look at pharmacodynamic effects across the Biomarkers and then think about that to your point on how do we want to sequence that in on the treated population. So I think the initial study we don't have to think about is this a run it on whether it's <unk> or other therapies I think the advantage we have in the healthy over.

Speaker Change: Volunteer study would be a clean population with with which to exhibit the effects that then would set us up to the ability to think about how we use this either in combination or sequence that patients could transition off of <unk> ones. As we think about subsequent clinical studies, but I think.

Paul B. Bolno: But it would set us up for the ability to think about how we use this either in combination or sequenced as patients could transition off of GLP1 as we think about subsequent clinical studies. But I think, first and foremost, we're just very excited to see the speed with which we can translate our RNA platform from a target that we introduced last year into the clinic. And I think it just speaks not only to the discovery capability we have in RNAi but also to the synergy we have with having our own internal manufacturing capability, where when we see an important, high-impact program, we can rapidly translate that into the clinic. So I think more will come on that over the course of the year. Great. Thanks, Paul.

Speaker Change: First and foremost.

Speaker Change: We're just very.

Speaker Change: Excited to see the speed with which we can translate our RNA platform from a target that we introduced last year into the clinic and I think it just speaks not only to the discovery capability. We have in RNA, but also get a synergy we have with having our own internal manufacturing capability, where when we see an important high impact program we could.

Speaker Change: Rapidly translate that into the clinic.

Speaker Change: I think more to come on that over the course of the year.

Speaker Change: Great. Thanks, Paul.

Operator: One moment for our next question. Our next question comes from Joon Lee with Truist. Your line is open. Thanks for the updates and for taking our questions. On the inhibin E program in obesity, can you elaborate a bit on the nature of the inhibin E mutation in the general population that confers protection against obesity? I understand that they are heterozygotes, but how penetrant are the heterozygote phenotypes, and what are some potential genetic modifiers of the phenotype that could cause them?

Speaker Change: One moment for our next question.

Speaker Change: Our next question comes from Joon Lee with <unk>. Your line is open.

Joon So Lee: Okay. Thanks for the update and for taking our questions on the inhibiting E program in obesity can you elaborate a bit on the nature of being hip and knee mutation in the general population that confer protection against obesity I understand that they are <unk>, but how penetrated are the headwinds.

Joon So Lee: <unk> and what are some potential genetic modifiers, a phenotype that could complicate your clinical assessments and I have a quick follow up.

Joon So Lee: And I have a quick follow-up Yeah, I mean, as we look at loss of function, protective loss of function variance, I think it's always, They are few and far between to find, and when you find them, you learn a lot of interesting things on the other side of them. So, I think the notion of us being able to find out what happens in patients who are heterozygous. So, I think your question is, rather than looking at it, like, let's say, a toxic gain of function that we need to knock down and correct, the opportunity here to see what is it about this population that is protective. So, I think the penetrance is probably, like, less than 0.1 percent.

Speaker Change: Yes, I mean, I think as we look at lots of pumps protective loss of function variance I think it's always.

Speaker Change: There are few and far between defined and when you find them you heard a lot of interesting things on the other side to them. So I think the notion of us being able to find what happens in patients who are heterozygous. So I think your question is rather than looking at it like let's say a toxic gain of function that we need to knock down and correct. The.

Speaker Change: <unk> here to see what is it about this population that is protected so I think the penetrant is probably less than 1% and this is because we probably as a species evolved actually for fat storage in another direction. When we go back to clinical genetics and see that actually this loss of function confers reduction of abdominal.

Paul B. Bolno: And this is because we probably, as a species, evolved for fat storage in another direction. When we go back to clinical genetics and see that, actually, this loss of function confers a reduction in abdominal obesity, a reduction in key measurements of bad cholesterol, so triglycerides, LDL, and an improvement in good cholesterol, HDL. And then, importantly, as we think about kind of the byproducts of both of those, and I think that's what's unique about the human clinical genetic experience in the UK Biobank, as you follow these patients out, is that you see this reduced odds rate of cardiovascular disease and type 2 diabetes. So, it's a really protective loss of function. The question in all of these always comes out in our minds to your point of, you know, what happens if you were to induce that into something you need from birth? Is this a correlative mutation, in which case you just happen to see it, or do you need it from birth, you know, or is it inducible? And so when we really thought back, and this is why the data last year was so important, to have the first data That's what we were excited about, right?

Speaker Change: The reduction in key measurements of bad cholesterol triglycerides, LDL improvements and good cholesterol HDL and then importantly, as we think about kind of the byproducts of both of those and I think that's what's unique about the human clinical Tonight experienced in the UK biobank as you follow these patients out.

Speaker Change: See this reduced that rate of cardiovascular disease and type two diabetes. So it's a really a protective loss of function the.

Speaker Change: The question in all of these always comes out in our minds to your point of what happens if you were to induce them with somebody you need for Bert is is this a correlate of mutation which case. It just you just happened to see it or do you need it from birth or is it inducible and so when we really thought back and this is why the data last year was so important to have.

Speaker Change: The first date of really looking at the in vivo induction of a loss of function and to see that translation of whether or not that would confer the same phenotype. That's what we're excited about that data. We shared last year showed for the first time that there was inducible Sylvia induced greater than 50% silencing, which we did you could see that correlate with backlog.

Paul B. Bolno: That data we shared last year showed for the first time that it was inducible. So if you induced greater than 50% silencing, which we did, you could see that correlate with fat loss and, you know, I say weight loss, but really we should be focusing on it was fat loss without muscle depletion, equivalent to semaglutide. And so I think that was really the first important notion that, you know, as we think about population genetics, that we found a target that had the ability to be induced, so you didn't need it from birth, it didn't correlate, it delivered the phenotype. And so as we continue to follow this and continue to run experiments now, we are seeing that it's an inducible phenotype.

Speaker Change: And I'd say weight loss, but really we should be focusing a lot. It was back loss without muscle depletion.

Speaker Change: Equivalent December good side, and so I think that was really the first important notion that as we think about the population genetics that we found at target that had the ability to be induced so you didn't need it from birth.

Speaker Change: It didn't correlate it delivered.

Speaker Change: Phenotype and so as we continue to follow this will continue to run experiments now we are seeing that fits an inducible phenotype and I think the best example of this was within the backlog caused that it came at the expense of visceral fat White back when we can measure that highly specifically and so collectively we need to continue to run. These studies of Biomarkers and then.

Paul B. Bolno: And I think the best example of this was within the fat loss concept; it came at the expense of visceral fat, white fat, and we can measure that highly specifically. And so collectively, we need to continue to run these studies and biomarkers and then run, I think, the human experiment to really see whether we can continue to see these changes move forward. That's really helpful, Paul. Thank you. And, you know, with regard to the assessment, would it be as simple as weighing them?

Speaker Change: I think the human experiment to really see can we continue to see these changes to move forward.

Speaker Change: That's really helpful. Paul Thank you.

Speaker Change: Yes.

Speaker Change: <unk> took the assessment would it be as simple as weighing them or is it more complicated given the beneficial impact potentially on muscle mass.

Joon So Lee: Or is it more complicated given the beneficial impact potentially on muscle? Curious about your thoughts on how you're going to capture the overall effect. So I think the opportunity, and just to make sure I'm being accredited, how do we see the benefit of fat loss in the clinic as opposed to, you know, corresponding with weight loss? So make sure I get. Yeah, you know, I mean, you know, GLP-1 is pretty straightforward. You just weigh them, and then weight loss is the end point. In your drug, you lose weight from fat. At the same time, you don't lose muscle mass.

Speaker Change: I was curious your thoughts on how you're going to capture the overall clinical benefit.

Speaker Change: So I think the opportunity just to make sure I appreciate Brexit how do we see the benefit of fat loss in the clinic as opposed to.

Speaker Change: Corresponding with weight loss, so to make sure I get.

Speaker Change: Yes, I mean.

Speaker Change: <unk> one is pretty straightforward you just wait and then wait losses endpoint and you ignore drug you lose weight from the SaaS at the same time, you don't lose muscle muscle mass so.

Speaker Change: How do you capture that benefit would you have to do a functional test or is it just waned.

Paul B. Bolno: So, you know, how do you capture that benefit? Would you like to do a functional test? want to, As we think about going into the clinic, you're right, we're also going to measure weight because that is an important feature, but we can do hip-to-weight ratio. If we think about the phenotype of loss of protective loss of function, those humans, I don't want to call them patients, those humans in the population that have this loss of function have a low hip-to-weight ratio and BMI.

Speaker Change: In reality I mean, the beauty of the the preclinical models as we have dissected that out right. We can see reduction in weight and we can measure that that was the key.

Speaker Change: Moving this program forward right. So we are seeing weight loss coming at fat loss and re measure muscle lean muscle mass and that's why we showed actually reflect that knowing lots of lean muscle mass, which I think is an important determinant as.

Speaker Change: As we think about going into the clinic, you're right. We're also going to measure weight because that is an important feature but we can do hip to weight ratio. We think about the phenotype of loss of protective loss of function. Those those humans that aren't calling patients those humans in the population that have this loss of function have low hip to weight ratio and BMI. So we can.

Paul B. Bolno: So we can take measurements that correlate with that reduction of abdominal fat and reduction in weight and demonstrate that. There are also opportunities, as well, in the clinic for imaging to be able to specifically look at abdominal and visceral fat. So there are measurable biomarkers to really distinguish this program from other classes of obesity products that really speak to on-target mechanisms. Thank you.

Speaker Change: We can take measurements that correlate with that reduction of abdominal fat.

Speaker Change: Reduction in weight and demonstrate that there is also opportunities as well in the clinic for imaging to be able to specifically look at abdominal and visceral fat. So there are measurable biomarkers to really distinguish this program from other classes of obesity product that really speak to on target mechanisms.

Speaker Change: Thank you and looking forward to the progress there.

Operator: One moment for our next question. Our next question comes from Joseph Schwartz with Learning Partners. Hi, thanks very much. I was wondering a couple things about inhibE. Can you first talk about the key characteristics that you were able to achieve that encouraged you to elect your inhibE lead clinical candidate ahead of expectations? What were you aiming for? How did it come together quicker than you planned?

Thank you.

Speaker Change: One moment for our next question.

Speaker Change: Okay.

Speaker Change: Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.

Joseph Patrick Schwartz: Alright, Thanks, very much I was wondering a couple of things on it maybe can you first talk about the key characteristics, which you were able to achieve that encouraged you to elect Youre <unk> lead clinical candidate ahead of expectations, what where you're aiming for.

Joseph Patrick Schwartz: And what work remains to be done before you can move on to humans? Yeah, no, thanks for the question, Joe. So, I mean, the key characteristics were obviously started with the program last year, which we'd already established, which is weight loss similar to other obesity products in the class. And importantly, and to June's last question, demonstration of differentiation to that, you know, on target, meaning this mechanism of loss of function wasn't just weight loss at the expense of muscle, so it wasn't induced anorexia, it was actually targeted loss of fat. And so we were able to demonstrate that consistently as part of the biology of the program.

Joseph Patrick Schwartz: It come together quicker than you planned and what work remains to be done before you can move into humans.

Speaker Change: Yeah no. Thanks for the question Joe. So you mean, the key characteristics were obviously started with the program last year, which we had already established which is weight loss similar to other obesity products in the class and importantly to June's last question demonstration of differentiation to that on target meeting this mechanism of off a bunch of.

Speaker Change: It wasn't just weight loss at the expense of muscle. So it wasn't an <unk> was actually targeted loss of fat and so we were able to demonstrate that consistently as part of the biology of the program.

Paul B. Bolno: I think the driver, as we thought about selecting the candidate, was really driven around dose and dose frequency. So recognizing that this is a large indication, those two things, as we've learned from other products like Inclistirin, are important to be seeing, as we said, low single-digit doses, so very, you know, being able to use a low amount of drug. Galvisate and Galnet conjugated siRNA helps with that

Speaker Change: I think the driver as we thought about selecting the candidate was really driven around dose and dose frequency. So recognizing that this is a large indication of those two things as we've learned from other products like <unk> are important to be seeing as we said low single digit dose, so very being able to use a low amount of drug <unk>.

Speaker Change: Conjugated <unk> helps with that and importantly to durability. We wanted a product that had a profile of at most twice a year dosing and potentially less frequent picking annually those achievements through what helped us identify a lock in on our candidate what's still to be done as the IND, enabling studies those are underway in terms of what.

Paul B. Bolno: And importantly, too, durability. We wanted a product that had a profile of, at most, twice-yearly dosing and, potentially, less frequent taking annually. Those achievements were what helped us identify a lock on our candidate. What's still to be done are the IND enabling studies. Those efforts are underway. In terms of what has enabled us to accelerate this, I think there are really two fundamental parameters. One is with the resources; as we said last year in the funding, it was really about accelerating the time to candidate year. We could run experiments in parallel to make sure that they were moving forward, coupled that with, you know, I think, which is really nice is the translation of the sRNA template. So with sRNA, we were able to move that template rapidly and see that benefit.

Speaker Change: Enabled us to accelerate this I think there are really two fundamental parameters wanted with the resources as we said last year and the financing is it really about accelerating the time to candidate here, we could run experiments in parallel to make sure.

Speaker Change: Because they were moving forward coupled that with.

Speaker Change: Think which is really nice is the translation of the SA RNA template. So with <unk>, we were able to move that template rapidly and to see that benefit the second feature which enabled us to truly accelerate it was having in house manufacturing, meaning we didn't have to go out to a CMO to start trying to find a slot to make material not just for <unk>.

Paul B. Bolno: The second feature which enabled us to truly accelerate it was having in-house manufacturing, meaning we didn't have to go out to a CMO to start trying to find a slot to make material not just for our preclinical studies and toxicology studies but to get ready for the clinic. So by having in-house manufacturing, we could deliver the data preclinically, high-end enabling study material, and importantly, make our clinical trial material so that we can be best positioned to rapidly move to the clinic. So I think the convergence of all of the things that we have been working on in WAVE over the last decade has really allowed us to rapidly translate the insights from last year on the impingement target into a potential medicine that we'll bring into the clinic in early 2025.

Speaker Change: Preclinical studies and toxicology studies, but getting ready for the clinic, so by having in house manufacturing, we could deliver the data pre clinically IND, enabling.

Speaker Change: <unk> study material and importantly, make our clinical trial materials. So that we would get that would be best positioned to rapidly move to put it. So I think the convergence of all of the things that we have been working on in wave over the last decade, we're really able to allow us to rapidly translate the insights from last year on the <unk> target into a potential medicine that will bring into the clinic.

In early 'twenty.

Paul B. Bolno: Okay, that's helpful. Thank you, Paul. And then, given there are so many different animal models for obesity, I was wondering which one or ones should we focus on that best demonstrate the potential for a differentiated clinical profile of WVE-06 relative to the wide array of incretins in development? And which ones tend to translate the best both for weight loss effects as well as the metabolic.

Speaker Change: Okay. That's helpful. Thank you Paul and then given there are so many different animal models for obesity I was wondering which one or one should we focus on that best demonstrate the potential for a differentiated clinical profile of <unk>.

Speaker Change: <unk> six relative to the wide array of <unk> in development, and which ones tend to translate the best both for weight loss effects as well as the metabolic.

Paul B. Bolno: Central Metabolic Center. Yeah, I think we've chosen to focus on the diet-induced obesity mouse model because, you know, there are other models of being overweight that require how you're fed and making sure that you could as best possible recapitulate what's seen in humans. I think these models, as we've seen, and we've shared data before, are highly correlative. We can benchmark them against existing GLP1s and the performance of those in weight loss. But I think what's also important in these models is that they do allow us to do what we've done, which is distinguish fat loss from weight loss, being able to do lean muscle mass measurements to show that you don't lose muscle mass at the expense of weight loss. So really, fat loss as a concept of what healthy weight loss is.

Speaker Change: Central metabolic benefits.

Speaker Change: Yes, I think.

Speaker Change: We have chosen to focus on the diet induced obesity mouse model in that there is other models are being overweight that require how your fed and making sure that you could as best possible chilly whats seen in humans I think these models as we've seen and we share data before.

Speaker Change: Our highly correlated we can benchmark that against existing <unk> ones in the performance of those in weight loss, but I think what's also important. These models is it does allow us to do what we've done which is discern fat loss from weight loss being able to do lean muscle mass measurements to show that you don't lose muscle mass at the expense of weight loss, so really fat loss.

Speaker Change: As that concept of healthy weight losses.

Paul B. Bolno: And so the model just lets us do a lot in terms of measuring the biomarker, et cetera, to be able to best plan for dose, dose frequency, and moving to the funnel. Thank you. One moment for our next question. Our next question comes from Luca Issi with RBC Capital. Your line is open.

Speaker Change: So the model that lets us do a lot in terms of measuring the biomarker et cetera to be able to best plan for dose dose frequency at the Lincoln tunnel.

Speaker Change: Thank you.

Speaker Change: One moment for our next question.

Speaker Change: Our next question comes from Lucas Lee with RBC Capital. Your line is open.

Luca Issi: Oh, great. Thanks so much for taking my question and congrats on the progress. Maybe two quick ones here.

Lucas Lee: Great. Thanks, so much for taking my question and congrats on progress maybe two quick one here maybe on Huntington could you just remind us the mechanics of the Takeda opt in rights here would.

Paul B. Bolno: Maybe on Huntington, can you just remind us the mechanics of the Takeda opt-in right here and what you think they need to see in Q2 in order to exercise that option? Again, any comment there would be much appreciated. And then maybe on GLYP1, if I captured it correctly, you mentioned that this continuation rate for GLYP1 can be as high as 68%. That seems a little bit higher number versus what we'd be hearing from doctors. So just wondering if you can expand on where the number comes from and maybe give your opinion on why that matters and implications for your program. Thanks so much. Yeah, no, absolutely not.

Lucas Lee: Would you see that you need to see in Q2 in order to exercise that option again any color there much appreciate it.

Lucas Lee: And then maybe on <unk> wondering if a capture it correctly you mentioned the discontinuation rates were flipped one could be as high as 68% guidance seems a little bit higher number versus what you would be hearing from docs. I was just wondering if you could expand on where that number comes from and maybe bigger picture why that matters and implications for your program. Thanks, So much yes.

Paul B. Bolno: So starting with the HD program, obviously, as Anne-Marie pointed out, the key for us is delivering key biomarker data demonstrating that we can achieve, like we thought, it's important to remember, in the single dose data, a 35% reduction versus placebo. So we've seen knockdown of the mutant protein. We've seen that we did that in a way that was wild type sparing.

Lucas Lee: No absolutely so starting with the HD program.

Lucas Lee: Obviously as <unk> pointed out the key for US is delivering key biomarker data demonstrating that we can achieve like we thought and it's important to remember in the single dose data at 35% reduction versus placebo. So we've seen knocked out of the <unk> protein. We have seen that we did that in a way that was wild type sparing. So that was the early clinical data.

Paul B. Bolno: So that was the early clinical data at a single dose. I think what we've also subsequently and importantly received from Takeda, as we reported in the fourth quarter, was the $7 million milestone payment on achieving distribution studies showing that we could actually target at therapeutically relevant concentrations the drug in the right region of the brain that should be targeted for HD. So, as we put these data together, the key for us is to deliver the multi-dose data demonstrating that package now. And that's the package that's required to be submitted to Takeda. I think we're focused on doing what's best for the program. We're generating that data. We'll be working with them collaboratively. And just a reminder, so when that package gets submitted, it's at our discretion to submit the package. Takeda then has an evaluation period with which to decide to opt-in, but opt-in comes with a payment.

Lucas Lee: Uh huh.

Lucas Lee: A single dose I think what we've also subsequently and importantly receive from Takeda as we reported in the fourth quarter was $7 million milestone payment on achieving distribution study showing that.

Lucas Lee: We could actually target at therapeutically relevant concentrations of drug in the right region of the brain that should be targeted for HD. So as we put these data together the key for US is to deliver now the multi dose data demonstrating that package and that's the package that's required to be submitted to Takeda.

Lucas Lee: I think we're focused on doing what's best for the program were generating that data will be working with them collaboratively and just to remember the reminder, so what that package gets submitted at our discretion to submit the package. Takeda then has an evaluation period with which to decide to opt in opt incomes with a payment.

Paul B. Bolno: That would be a substantial payment to support our contributions to the clinic, and it then switches over to a 50-50 R&D profit split with additional milestone payments along the progress of the program. So I think step one for us is to deliver data that we think, you know, whether it's DECADA. We want to deliver a package that we believe is the right package with which this program should move forward or not.

Lucas Lee: That would be a substantial payment bonds supporting.

Lucas Lee: Our contributions to the clinic and had bench with switches over to a $50 50, R&D split profit split with additional milestone payments along the progress of the program. So I think step one for US is to deliver data that we think whether it's takeda.

Lucas Lee: We aim to deliver a package that we believe is the right package with witches program should go forward or not and so I do think about this coming dataset at.

Paul B. Bolno: So I do think about this coming data set as an important decision point for the program. This will decide whether or not the program does have the data with which to support moving forward. As it relates to your question on the discontinuation rate, there was a, and again, as you said, there's reported, you know, how do physicians and various surveys report out, this was based on an analysis, so a claims database following how many patients are staying on it. And so with a prime Therapeutic Analysis with a claims database, looking at patients staying on. So these things are always points in time.

Lucas Lee: An important decision for the program. So this will decide whether or not the program does have the data with which to support moving forward or not.

As it relates to your question on the discontinuation rate there.

Lucas Lee: And again there is as you said there is reported to physicians in various surveys report out this was based on an analysis.

Lucas Lee: Claims database following how many patients are staying on it and so with the Prime Therapeutics analysis with claims database looking at patient Bangor. So these things are always point in time people use them in different ways and report different ways, but this was.

Paul B. Bolno: People use them in different ways and report different ways, but this was a; we tend less to use surveys and look at the published numbers. This is based on a published analysis. That's very helpful. I think it's important. I mean, I think that's the fundamental question, whether it's 68 or 70, as some people say, I think the ultimate question is, why are people dropping off of a medicine that, you know, has the effects that it doesn't have? So I think we think about this often as shifting the narrative from what's weight loss versus what's healthy, sustainable fat loss. And so the opportunity we have in front of us is to utilize human clinical genetics to induce a phenotype that is about healthy weight loss independently. Or, more importantly, as it was pointed out earlier, one of the questions is thinking about how this will be used in common practice. And I think the real opportunity in front of all of us is People will use GLP-1 for induction weight loss, and I think the key is how to move people and migrate them from GLP-1 to chronic therapy where they increase their risk by staying on it of complications and sarcopenia.

Lucas Lee: We can let figures surveys and look at the published numbers that is based on our published analysis.

Speaker Change: Got it that's very helpful. I think is important and I think I mean.

Speaker Change: That's the fundamental question, whether it's 68 70 as some people say I.

Speaker Change: I think the ultimate question is why are people dropping off a medicine that has the effects that it doesn't so I think we think about this oftentimes is shifting the narrative from what's weight loss versus what's healthy sustainable fat loss and so the opportunity we have in front of us is to utilize human clinical genetics to induce athene.

Speaker Change: That is about healthy weight loss independently or most importantly, as it was pointed out I think earlier in one of the questions is thinking about how these will be used in common practice and I think where the real opportunity in front of all of us is.

Speaker Change: People will use <unk> for induction weight loss and I think the key is how to move people and migrate people from <unk> as a chronic therapy, where they increase their risk by staying on it of complications in soccer taenia. So ultimately, saying after that induction phase how can you have sustainable maintenance backlogs and a.

Paul B. Bolno: So ultimately, saying after that induction phase, how can you have sustainable maintenance fat loss in a way that's a once or twice a year sub-q injection and provides all of these continued cardiovascular benefits and diabetes risk benefits that have been seen in the UK Biobank clinical data? So I think that's why that data is important for us, to see that there's a substantial opportunity, not just from the front end, but really from the capabilities to transition patients to this therapy. I got it.

A way that once or twice a year sub Q injection and provides all of this continued cardiovascular benefits in diabetes risk benefits that have been seen in the UK biobank clinical data. So I think thats why that data is important for us is being able to see that there is a substantial opportunity not just from the front end.

Speaker Change: But really on this capability to transition patients to this therapy.

Speaker Change: Okay.

Paul B. Bolno: Thanks. One moment for our next question. Our next question comes from Ananda Ghosh with AC Rainwright. Your line is open.

Speaker Change: Got it thanks, so much.

Speaker Change: One moment for our next question.

Speaker Change: Okay.

Speaker Change: Our next question comes from Ananda grocery the AC rain right. Your line is open.

Ananda Ghosh: Yeah, hi, thank you. I will focus on the DMD program and was just wondering, you know, given the DMD landscape and the new data coming out from SRP 5051 or DIME 251, how do you see your DMD program differing from the current developments in the landscape? Thank you.

Ananda: Yeah, Hi, thank you.

Ananda: I will focus on the BMT program.

Ananda: Just wondering given the dnb landscape on the new data coming out from a therapy, probably brutal high volatile.

Ananda: One how do you see European D program differentiate.

Ananda grocery: From from the current developments in the landscape. Thank you.

Paul B. Bolno: I mean, and obviously, this was something we focused on at the very beginning of our journey in DMD, which was we needed to see several things to bring this program forward into the clinic, to begin with. And I think to your point on differentiation, first and foremost is the production of a functional DistroPin, Becker-like DistroPin as the core driver. So that's important, right? That was one, an important construct. Two, we wanted to see high levels of muscle concentration, meaning high levels of muscle concentration that then become productive, meaning they get to the right compartment of the cell. That's what we see with the highest level of exon skipping at 53% skip transfer.

Speaker Change: Yes, Great question I mean, obviously this is something we focused on at the very beginning of our journey and DMT, which was we needed to see several things to bring this program forward into the clinic to begin with and I think to your point on differentiation first and foremost is the production of functional <unk>.

Ananda grocery: Ben Becker like dystrophin as the core drivers. So that's important right that that was one and important construct too.

Ananda grocery: We wanted to see high levels of muscle concentration meeting high levels of muscle concentration that then become productive when we get to the right compartment of the cell. That's what we see with the highest level of exon skipping at 53% skip transfer.

Paul B. Bolno: I think that combination, coupled with, you know, the data that we're going to have in Q3, which will be the 24-week data, where we can now have it over the same time as the commercial products within the 53 landscape, will give us a benchmark of that translation, meaning strong functional dystrophin-like numbers that would support moving forward in potential registration. I think all of that also comes with another point of differentiation, which is not just the number of dystrophins but where dystrophin comes from. So what we've seen is both in the double knockout mouse, we saw it in the X mouse, we saw it in our non-human primate distribution, higher levels of the drug in the heart and the diaphragm over skeletal muscle.

Ananda grocery: Think that combination coupled with the data that we're going to have in Q3, which will be the 24 week data, where we can now have over at the same time.

Ananda grocery: Commercial products with 53 landscape will give us a benchmark of that translation meetings.

Ananda grocery: <unk> functional dystrophin like numbers that would support moving forward potential registration.

Ananda grocery: All of that also comes with another point of differentiation, which is not just on the number of dystrophin, but where dystrophin comes from so what we've seen is both in the double knockout mouse, we saw it in the X valves, we saw that our non human primate distributions is higher levels of skip.

Ananda grocery: And the heart when the diaphragm over skeletal muscle.

Paul B. Bolno: So I think if we think about the progress with these boys, one of the key features that we focus on is respiratory and cardiac function. So the ability to get into tissues with exposures that help these boys is a key point of differentiation. I think if we think about early development too, so the young boys into maturation, there is also this ability to get into the regenerative cells. So the update that we are sharing at NDA, which is really the ability to get into the satellite cells, the stem cells, and muscles that are regenerating. Also, gives us a lot in improving the regenerative potential of muscles. So when we think about that capability, where we're distributing it to, in addition to the high productivity of dystrophin, we do think that there are a lot of points of differentiation.

Ananda grocery: I think as we think about the progress with these boys one of the key features that we focus on it respiratory and cardiac function. So the ability to get into tissues with exposures that helped the boys and the key point of differentiation I think as we think about the early development to the young boys and cell maturation.

Ananda grocery: There is also this ability to get into the regenerative cells. So the update that we are sharing NBA, which is really the ability to get into the satellite cells the stem.

Ananda grocery: Stem cells and muscle that will be generated also gives us a lot in improving the regenerative potential muscles. So when we think about that capability, where we are distributing to in addition to high productivity of district, and we do think that there is a lot of points of differentiation.

Paul B. Bolno: Let alone just dosing frequency. So within Exxon 53, the current products are dosed on a weekly IV infusion. As we shared from our original data with the 25-day half-life, we do expect this to be a monthly dosed product. The benefit of that muscle exposure is, so as we shared, thousands of fold higher than what's been seen before. We think that not conjugating gives us the differentiation as it relates to what's been seen with some of the other conjugate programs in terms of hypomagnesemia, hypokalemia, some of the other concerns.

Let alone just dosing frequency so within exon 53, the current products or don't start out weekly IV infusion as we shared from our original data with a 25 day half life, we do expect it to be a monthly dose product the benefit of that muscle exposure. So as we shared.

Ananda grocery: Thousands of folds higher than what's been seen before we think that without a conjugate also gives us the differentiation as it relates to what's been seen with some of the other conjugate program in terms of Hypomagnesaemia Heiko.

Paul B. Bolno: So I think we can differentiate on a whole, a whole number of features, whether it's convenience, tolerability, and efficacy in the right region. I think we're in a really good position so long as, and I think that's the last key question answered in Q3, as we see that translated dystrophin, and we are poised with a fully enrolled study to deliver those dystrophins. Thank you very much. And I'm not showing any further requests at this time. I'd like to turn the call back over to Dr. Paul Bolno for any closing remarks. Thank you all for joining the call this morning. We believe 2024 is going to be an exciting year for WAVE, and we look forward to keeping you all updated on our progress. Have a great day. Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day. Help check out my channel by subscribing to my channel.

Ananda grocery: Other concerns so I think we can differentiate on a whole a whole number of features whether it's convene.

Ananda grocery: Convenience tolerability.

Efficacy in the right regions I think we're in a.

Ananda grocery: And a really good position so long as and I think that's the last key answered question in Q3, as we see that translate the dystrophin and we are poised with a fully enrolled study to deliver those district the numbers.

Speaker Change: Got it thank you very helpful.

Speaker Change: And I'm not showing any further questions at this time I would like to turn the call back over to Dr. Paul Barlow for any closing remarks.

Speaker Change: Thank you all for joining the call. This morning, we believe 2024 is going to be an exciting year for wave and we look forward to keeping you all updated on our progress have a great day.

Speaker Change: Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.

Speaker Change: [music].

Speaker Change: Okay.

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