Q1 2024 Wave Life Sciences Ltd Earnings Call
Operator: Good morning, and welcome to the WAVE Life Sciences first quarter 2024 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 would now like to turn the call over to Kate Rausch, Vice President, Investor Relations, and Corporate Affairs. Please go ahead.
Good morning, and welcome to the wave Life Sciences first quarter 2024 financial results Conference call. At this time all participants are in a listen only mode. As a reminder, this call's being recorded and webcast I would now like to.
Kate Rausch: Thank you. Thank you, Kevin.
I would now turn the call over to Kate Walsh, Vice President Investor Relations and corporate Affairs. Please go ahead.
Kate Rausch: Good morning, and thank you for joining us today to discuss our recent business progress and review WAVE's first quarter 2024 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 the discussions during this conference call will include forward-looking statements.
Kate Walsh: Thank you. Thank you Kevin good morning, and thank you for joining us today to discuss our recent business progress and review with the first quarter of 2024 financial results. Joining me today with prepared remarks are Dr. Paul <unk>, President and Chief Executive Officer, Kyle Moran, Chief Financial <unk> Financial Officer, and Anne Marie and be quite Chang Chief Development Officer.
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Kate Walsh: The press release issued this morning is available on the investors section of our website at Www Dot wave life Sciences dotcom.
Kate Rausch: 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 filing. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul. Thank you.
Kate Walsh: 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.
Kate Walsh: No obligation 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: 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 of our strategy. Next, Anne-Marie will provide an update on our three ongoing clinical trials. And 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.
Paul: Before opening up the call for questions Karl will review, our financials Chandra and Ginny will also be available for questions.
Paul B. Bolno: Chandra and Jenny will also be available for questions. The start of the year has been marked by steady execution for WAVE. First, we've continued to advance our three ongoing clinical trials towards key data updates. This includes our restoration program, which is underway, evaluating WVE006, our RNA editing candidate for patients with AAPD, our potentially registrational Forward 53 clinical trial with WVEN531 for boys with Exxon 53 amenable DMT, and Select HD, our trial evaluating WVE003, a first in class allele selective investigational therapy for patients with HD
Paul: The start of the year has been marked by steady execution per weighted first we've continued to advance our three ongoing clinical trials towards key data updates. This includes our restoration program, which is underway evaluating <unk> 006, our RNA editing candidate for patients with ACD are potentially registrational forward 50.
Paul: Preclinical trial with WB and by three one for boys with exon 53, amenable DMD and select HD our trial evaluating <unk> 003, a first in class allele selective investigational therapy for patients with HD we.
Paul B. Bolno: We also continue to advance our inhibin-E lead clinical candidate for obesity towards CTA filing as early as the end of this year, and we expect to initiate a clinical trial in the first quarter of next year. Last month, we announced meaningful progress in our research collaboration with GSK as they selected their first two programs following achievement of target validation. Before diving deeper into each program, I'll pause to acknowledge an exciting leadership update. As announced this morning, Dr. Eric Ingleson has joined WAVE as Chief Scientific Officer.
Paul: We also continued to advance our inhibitors lead clinical candidate for obesity towards Cta filing as early as the end of this year and expect to initiate a clinical trial in the first quarter of next year.
Paul: Last month, we announced meaningful progress in our research collaboration with GSK as they selected their first two programs following achievement of target validation.
Paul: Before diving deeper into each program a pause to acknowledge an exciting leadership update.
Speaker Change: As announced this morning, Dr. Eric Engel said has joined <unk> as Chief Scientific Officer.
Paul B. Bolno: In this role, he will drive our emerging therapeutic portfolio strategy, including growing our genetics and genomics capability for identifying new high-impact targets and leveraging our best-in-class multimodal platform to continue to advance novel RNA medicine. Dr. Engelson comes to us from GSK, where he most recently held positions of SVP Head of Target Discovery and SVP of Genomic Sciences, leading activities across all therapeutic areas. He was responsible for harnessing the latest methods and technologies in genomics to discover and validate novel drug targets and accelerate the development of next-generation medicine. Prior to GSK, he was professor of medicine at Stanford University and obtained his MD and PhD at Uppsala University. You will have the opportunity to hear directly from Eric in the very near future.
Speaker Change: In this role he will drive our emerging therapeutic portfolio strategy, including growing our genetics and genomics capability for identifying new high impact targets and leveraging our best in class multimodal platform to continue to advance novel RNA medicines Dr.
Speaker Change: Dr. Ingleside comes to us from GSK, where he most recently held positions of SVP head of target discovery and SVP of genomic sciences, leading activities across all therapeutic areas. He was responsible for harnessing the latest methods and technologies in genomics to discover and validate novel drug target and accelerate the development of next generation medicines.
Speaker Change: Prior to GSK.
Speaker Change: As professor of Medicine at Stanford University and obtained at MD Phd at Uppsala University, you will have the opportunity to hear directly from Eric in the very near future.
Paul B. Bolno: Turning to our pipeline in RNA editing, a restoration to clinical trial of WVE006 for alpha 1 antitrypsin deficiency, or AATD, is now underway, and we continue to advance our wholly owned RNA editing pipeline behind it. 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 006 is designed to address the root cause of AADD, to provide a solution to patients with AADD lung disease, or liver disease, or both. Other treatment approaches are often confined to either lung or liver manifestations, not both. The current standard of care treatment, weekly IV augmentation therapy, is limited to treating only lung disease.
Speaker Change: Turning to our pipeline and RNA editing a restoration two clinical trial of <unk> for Alpha one antitrypsin deficiency. Our ACD is now underway, but we continue to advance our wholly owned RNA editing pipeline behind it.
Speaker Change: <unk> is the industry's first ever clinical RNA editing candidate, which aims to correct AED, causing Z mutation to increase circulating levels of wild type protein and reduced mutant <unk> protein aggregation in the liver.
Speaker Change: Oh six is designed to address the root cause of HDD to provide a solution to patients with <unk> lung disease liver disease or both.
Speaker Change: Other treatment approaches are often confined to either lung or liver manifestations not vote. The current standard of care treatment weekly IV augmentation therapy is limited to treating only lung disease.
Paul B. Bolno: SIRNA treatments in development are confined to treating only liver disease and could exacerbate lung injury. 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 the AAT protein with lower functional activity, while the indels have the potential to create loss of function barriers. WVE-006 does not use complex delivery systems such as LMPs.
Speaker Change: <unk> treatments in development are confined to treating only liver disease and could exacerbate lung injury by.
Speaker Change: By targeting RNA <unk> differs from DNA editing technologies that rely on hyperactive exogenously delivered artificial enzymes that can result in an irreversible collateral bystander edits in endo and.
Speaker Change: In fact in preclinical studies the majority of that is observed using DNA base editing whereby vendor edits that yielded isoforms of <unk> protein with lower functional activity, while the <unk> have the potential to create lots of function barriers.
Speaker Change: <unk> does not use complex delivery systems, such as <unk> or fixed contained <unk> conjugate highly specific and elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market.
Paul B. Bolno: O6 contains GalNetConjugate, a highly specific and elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market. GalNeck enables the ease and convenience of subcutaneous dosing, effective and selective delivery to hepatocytes, as well as a high degree of confidence in preclinical to clinical translation since the entire dose is delivered reliably to the target organ. Our proprietary chemistry enables WVE006 to effectively recruit endogenous ADAR enzymes and achieve potent and durable editing in preclinical studies.
Speaker Change: <unk> enables the easy convenient subcutaneous dosing effective and selective delivery had a site as well as a high degree of confidence of preclinical to clinical translation since the entire doses delivered reliably to the target organ.
Speaker Change: Our proprietary chemistry enabled <unk> to effectively recruit endogenous eight our enzymes and achieved potent and durable editing in preclinical studies.
Paul B. Bolno: We've shown AAT protein levels that exceed the thresholds for both MZ and healthy MM populations, and we confirmed the functionality of this protein with the neutrophil elastase acid. Additionally, we saw decreases in lobular inflammation and reduction of liver aggregate.
Speaker Change: We've shown AEP protein levels that exceed the thresholds for both and the unhealthy MF population and we confirm the functionality of this protein with the neutrophil elastase assay.
Speaker Change: Additionally, we saw decreases of <unk> inflammation and reduction of liver aggregates WV easier. There are fixed also prevents increases in mitoses for turnover of accounted site, indicating improved to <unk> survival.
Paul B. Bolno: WVE006 also prevents increases in mitoses for turnover of hepatocytes, indicating improved hepatocyte survival. As Anne-Marie will speak to momentarily, we recently received approval for our first CTA for Restoration II and continue to make significant progress in our trial of WVE006 with proof of mechanism data from Restoration II inpatients with AATD expected later this year. Proof of Mechanism for 006 would not only meaningfully de-risk our AETD program but would also serve as proof of concept for our growing pipeline of polio and editing candidates, which are designed to either correct or upregulate mRNA in both rare and prevalent diseases.
Speaker Change: As Anne Marie will speak to momentarily. We recently received approval for our first Cta for restoration to and continue to make significant progress in our trial of <unk> <unk> with proof of mechanism data from restoration two in patients with ATB expected later this year.
Speaker Change: Proof of mechanism for <unk>, six would not only meaningfully derisk, our ACD 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 in both rare and prevalent diseases.
Paul B. Bolno: GSK was early to recognize the potential of our differentiated RNA editing capability and our multimodal platform more broadly. Their leadership in respiratory medicine and development and commercialization makes them an ideal partner for O6, and they continue to bring substantial value to WAVE through their significant investments in deep genetic insight. The collaboration included $525 million in milestones related to 06, of which we received $20 million in the first quarter due to advancements into the clinic.
Speaker Change: GSK was early to recognize the potential of our differentiated RNA editing capability at our multimodal platform more broadly.
Speaker Change: Our leadership in respiratory medicine at development and commercialization makes them an ideal partner for <unk> and they continue to bring substantial value to waive through their significant investment in deep genetic insights.
Speaker Change: The collaboration included $525 million in milestones related to <unk> six of which we received $20 million in the first quarter due to the advancement into the clinic.
Paul B. Bolno: Development and Commercialization Responsibilities Transfer to GSK at their sole cost after we complete our Restoration II study. WAVE is also eligible for double digit tier royalties as a percentage of net sales of 06 up to the high teens.
Speaker Change: Development and commercialization responsibilities transfer to GSK at their sow cost after we complete our restoration to study.
Speaker Change: Wave is also eligible for double digit tiered royalties as a percentage of net sales of <unk> six up to the high teens.
Paul B. Bolno: Additionally, in the discovery part of the collaboration, GSK selected their first two programs to advance following achievement of target validation, marking a transition to the next phase of the research collaboration and triggering a $12 million payment to WAVE. Both of these programs utilize WAVE's next-gen GalNeck siRNA format and are in hepatology. The discovery component of the collaboration encompasses all of WAVE's modalities, including RNA editing, and GSK is eligible to advance up to eight programs in total during the initial research term. For these eight collaboration programs, WAVE is eligible for total potential milestone payments of up to $2.8 billion, as well as royalties on net sales.
Speaker Change: Additionally, in the discovery part of the collaboration GSK selected their first two programs to advance following achievement of target validation marketing a transition to the next phase of the research collaboration and triggering a $12 million payments of ways. Both of these programs utilized wave Nexgen <unk> SA RNA format and earn herpetology did.
Speaker Change: Discovery component of the collaboration encompasses all of waves modalities, including RNA editing and GSK is eligible to advance up to eight programs in total during the initial research term.
Speaker Change: For these eight collaboration programs wave is eligible for total potential milestone payments of up to $2 8 billion as.
Speaker Change: As well as royalties on net sales as a reminder, GSK paid 100% of the costs related to target validation. These partnered programs.
Paul B. Bolno: As a reminder, GSK pays 100% of the costs related to target validation for these partnered programs. The collaboration also expands our wholly owned pipeline as we are able to leverage GSK's genetically validated targets to advance up to three programs for WAVE. Inhibin-E was the first target we selected, and we plan to focus our remaining slots on high-impact targets based on strong clinical genetics, novel biology with measurable biomarkers, and best-in-first-in-class potential. Our HIB&E program aims to be a next-generation obesity therapeutic.
Speaker Change: The collaboration also expands our wholly owned pipeline as we are able to leverage gsk's genetically validated target to advance up to three programs for wave and.
Speaker Change: <unk> was the first target, we selected and we plan to focus our remaining thoughts on high impact targets based on strong clinical genetics novel biology, with measurable Biomarkers and best and first in class potential.
Speaker Change: Our inhibitor program aims to be a next generation obesity therapeutic using galvanic SA RNA silencing, we aimed to recapitulate the protective phenotype.
Paul B. Bolno: Using GalNeck siRNA silencing, we aim to recapitulate the protective phenotype of in tib and E loss-of-function heterozygous carriers who have a favorable cardiometabolic profile, including reduced abdominal obesity, reduced odds of type 2 diabetes, and coronary arteries. Inhibin E mRNA is expressed in the liver with its corresponding receptor on adipocytes, which controls fat storage. Silencing inhibitory E promotes fat burning or lipolysis and decreases fat accumulation. However, while GLP-1s have become the standard of care for weight loss, these treatments come with several limitations, namely frequent dosing, loss of muscle mass, poor tolerability, and high discontinuation rates.
Speaker Change: Any loss of function heterozygous carriers, who have a favorable cardio metabolic profile, including reduced abdominal obesity reduced odds of type two diabetes and coronary artery disease and.
Speaker Change: And if any mrna is expressed in the liver with its corresponding receptor on adequate sites, which controls fat storage silencing inhibitor <unk> promotes fat burning or electrolysis and decrease its fat accumulation.
Speaker Change: While <unk> have become the standard of care for weight loss, the therapies come with several limitations, namely frequent dosing lots of muscle mass poor tolerability and high discontinuation rates with our inhibitor program. We have demonstrated highly potent silencing with an <unk> of less than one milligram per kilogram in the diet induced obesity or <unk>.
Paul B. Bolno: With our Inhibin-E program, we have demonstrated highly potent silencing with an ED50 of less than one milligram per kilogram in the diet-induced obesity or DIO mouse model, and durable silencing following one low single-digit dose, which supports the potential for subcutaneous dosing intervals of every six months or annually. We've also demonstrated weight loss and reductions in fat mass with a preferential effect on visceral fat, with no loss of muscle mass.
Speaker Change: Oh mouse model at.
Speaker Change: And durable silencing following one low single digit dose, which supports the potential for subcutaneous dosing intervals of every six months or annually.
Speaker Change: We've also demonstrated weight Boston reductions in fat mass with a preferential effect on visceral fat with no loss of muscle mass.
Paul B. Bolno: The DIO mouse model has been used with many weight loss therapeutics on the market, including semaglutide, and there is a good precedent for weight loss translation into the clinic. As the Inhibin-E mechanism of action is distinct from GLP-1's, we also see the opportunity to use Inhibin-E siRNA as a frontline or potentially maintenance therapy following GLP-1 weight loss induction. And we now have emerging preclinical data to further support this use. In an ongoing head-to-head study in DIO mice, we observed that the weight loss effect from a single dose of our Ibini siRNA was similar to semaglutat. In addition, treatment with our inhibin-e sRNA upon cessation of semaglutide treatment curtailed expected rebound weight gain.
Speaker Change: Oh mouse model has been used with many weight loss therapeutics in the market, including <unk> and there is a good precedent for weight loss translation into the clinic.
Speaker Change: As the inhibiting mechanism of action is distinct from <unk>. We also see the opportunity to use inhibiting <unk> RNA as a frontline or potentially maintenance therapy. Following <unk> weight loss reduction and we now have emerging preclinical data to further support this use in an ongoing head to head.
Speaker Change: Head study in Dio mice, we observed that the weight loss effect from a single dose of <unk> was similar to <unk> and.
Speaker Change: In addition treatment with our inhibiting S. Irna upon cessation of <unk> treatment curtailed expected rebound weight gain we expect to share new preclinical data from our inherited need program later this year.
Jenny Yang: We expect to share new preclinical data from our Inhibit-Heat program later this year. We remain on track to file our CTA as early as the end of the year and to initiate our clinical trial in the first quarter of 2025. We believe clinical proof of concept can be achieved with just a single dose of our inhibitor E siRNA in a study of healthy overweight volunteers. For DMD and HD, we are on track to deliver clinical data from each of these programs in the coming months.
Speaker Change: We remain on track to file our Cta as early as the end of year and to initiate our clinical trial in the first quarter of 2025, we believe clinical proof of concept can be achieved with just a single dose of our inhibitor ESI RNA in a study of healthy overweight volunteers.
Speaker Change: In DMD and HD, we are on track to deliver clinical data from each of these programs in the coming months.
Jenny Yang: With our potentially registrational Forward 53 clinical trial, WVE-N531, in boys with DMD, our goal is to demonstrate that we can restore endogenous functional, or Becker-like, dystrophin to provide a meaningful clinical benefit for patients amenable to Exxon 53 skin. Significant scientific gaps on the functional benefit of micro- or mini-dystrophin remain, in addition to an unknown safety risk associated with AAV gene therapies, and there is an urgent need to deliver more therapeutic options to patients, especially those which can achieve access to the heart and diaphragm, two areas where we have seen substantial distribution in our preclinical studies, including NHPs.
Speaker Change: With our potentially Registrational forward 53 clinical trial <unk> hundred one in boys with DMD. Our goal is to demonstrate that we can restore endogenous functional or becker like dystrophin to provide a meaningful clinical benefit for patients amenable to exon 53 skipping.
Speaker Change: Significant scientific gaps on the functional benefit of micro or mini dystrophin remain in addition to an unknown safety risk associated with AAV gene therapies, and there is an urgent need to deliver more therapeutic options to patients, especially those which can achieve access to the heart and diaphragm to areas, where we have seen substantial distribution and our <unk>.
Speaker Change: Preclinical studies, including in Hps.
Jenny Yang: Our clinical data for N531, after only three doses every other week, position it as potentially best-in-class. We've demonstrated industry-leading exon skipping of 53%, muscle tissue concentrations of 42,000 nanograms per gram, the first clinical demonstration of uptake in myogenic stem cells, and a half-life that supports the potential for monthly dosing. We continue to make strong progress in our trial and remain on track to deliver 24-week dystrophin protein expression data in the third quarter of this year.
Speaker Change: Our clinical data for <unk> 531, after only three doses every other week positioned it as potentially best in class, we've demonstrated industry, leading exon skipping a 53% muscle tissue concentrations of 42000 nanograms per Gram. The first clinical demonstration of uptake in myogenic stem cells, and a half life, which.
Speaker Change: <unk> supports the potential for monthly dosing.
Speaker Change: We continue to make strong progress in our trial and remain on track to deliver 24 week dystrophin protein expression data in the third quarter of this year.
Jenny Yang: In HD, we continue to advance our first-in-class allele-selective therapeutic, WAVE-003. In a space of extremely high unmet need, as HD patients have no disease-modifying treatments available, there are approximately 30,000 patients in the U.S. with HD and over 200,000 at risk of developing HD. 003 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. 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.
Speaker Change: In HD, we continued to advance our first in class allele selective therapeutic wave.
Speaker Change: There are three.
Speaker Change: In this space of extremely high unmet need as HD patients have no disease modifying treatments available. There are approximately 30000 patients in the U S with HD and over 200000 at risk of developing HD.
Speaker Change: 003 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.
Speaker Change: Having the ability to preserve this important protein is a clear advantage over pants silencing approaches that non selectively lower mutant and wild type protein, especially at HD patients already start with a lower wild type reserve.
Jenny Yang: We've already demonstrated 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, and we're looking to replicate these biomarker data with the first multi-dose data from our SelectHD clinical trial in the second quarter. In addition, we will be looking closely to see if we can differentiate on safety signals seen by the pen silencing approaches, including ventricular enlargement. Now, to discuss the progress we've made on our clinical programs in more detail, I'd like to turn the call over to Anne-Marie. Anne-Marie Thank you, Paul.
Speaker Change: We have already demonstrated successful translation of our compelling preclinical data to the clinic with reduction of mutant Huntington and preservation of wildfire. After a single dose in humans and we're looking to replicate these biomarker data with the first multi dose data from our select HD clinical trial in the second quarter in.
Speaker Change: In addition, we will be looking closely to see if we can differentiate on safety signals seen by the Penn silencing approaches, including ventricular enlargement.
Speaker Change: Now to discuss the progress we've made on our clinical programs in more detail I'd like to turn the call over to Anne Marie <unk>.
Jenny Yang: Thank you, Paul. With our continued execution across modalities and multiple datasets planned for the months ahead, it's certainly an exciting time to be at WAVE. I'll start by covering the progress we've made in RNA editing, where we are advancing our Galnut Conjugated AMR, WAVE-006, in our ongoing restoration clinical program for AATD. As a reminder, our clinical program is comprised of Restoration 1, which is a dose escalation study in healthy volunteers, and Restoration 2, which is a Phase 1b-2a open-label study designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of WAVE-006 in individuals with AATD who have the homozygous PIZZ mutation.
Anne Marie: Paul without continued execution across modalities and multiple data sets for the months ahead. It's certainly an exciting time to be at ways I'll start by covering the progress we've made in RNA editing, where we are advancing a gallon that conjugated hamer Wade zero-zero shakes and our ongoing restoration clinical.
Speaker Change: Graham for AED.
Speaker Change: As a reminder, our clinical program is comprised of restoration, one which is a dose escalation study in healthy volunteers and restoration too which is a phase <unk> open label study designed to evaluate safety Tolerability pharmacodynamics and pharmacokinetics of white sand with euro six and individuals with AA.
Speaker Change: You'll have the homozygous <unk> mutation.
Speaker Change: Mutation.
Jenny Yang: We have rapidly progressed dose escalation in the Restoration 1 trial of healthy volunteers and, consistent with our last update, we've observed safety and pharmacokinetic data translating as expected for a GalNac-conjugated molecule. Just last week, we were pleased to announce that our first CTA for Restoration 2 has been approved, and we expect additional approvals to follow.
Speaker Change: We have rapidly progressed dose escalation in the restoration one trial in healthy volunteers and consistent with our last update we've observed safety and pharmacokinetic data tons racing as expected for a gallon that conjugated molecules.
Speaker Change: Just last week, we were pleased to announce that our first Cta for restoration two has been approved and we expect additional approvals to follow you.
Jenny Yang: Using the data from Healthy Volunteers, we identified a starting dose level for Restoration 2 that's expected to engage target based on preclinical data. Restoration 2 is now underway and includes both single ascending dose and multiple ascending dose portions. And we have the ability to make adjustments to the dose level and frequency as the trial progresses and data emerges. We will be taking multiple assessments of serum MAAT throughout the three dose cohorts, enabling us to quickly detect the potential presence of wild-type healthy MAAT protein in the serum, which would indicate that WAVE006 is successfully editing RNA and represent the achievement of proof of mechanism.
Speaker Change: Using the data from healthy volunteers, we identify the starting dose capsules for restoration Chi that's expected to gauge target based on preclinical data.
Speaker Change: Restoration two is now underway and includes both single ascending dose and multiple ascending dose portion and we have the ability to make adjustments to that.
Speaker Change: This level and frequency as the trial progresses and data matches.
Speaker Change: We will be taking multiple assessments of CRM and.
Speaker Change: Throughout the three dose cohorts, enabling us to quickly detect the potential presence of wild type healthy MAA protein in the salmon, which would indicate that <unk> is successfully editing RNA and represent the achievement of proof of mechanism.
Jenny Yang: We are currently initiating clinical trial sites and remain on track to deliver proof of mechanism data from Restoration 2 in patients with AATD this year, which will be an important step as we work towards completing the study and defining future dose and regimen. Turning to DMD, DERCIN continues in our fully enrolled Open Label Forward 53 trial for boys with exon 53 amenable DMD. This Phase 2 study is evaluating doses of WAVE N531 administered every other week with a primary endpoint of endogenous dystrophin expression, which will be evaluated after 24 and 48 weeks of treatment.
Speaker Change: We are currently initiating clinical trial sites and remain on track to deliver proof of mechanism data from registration two in patients with <unk>. This year, which will be an important step as we work towards completing the study a defining feature dose and regimen.
Speaker Change: Turning to DMD session continues in a fully enrolled open April forward 53 trials voice with exon 53 amenable D&B.
Speaker Change: <unk> II study is evaluating doses of <unk>.
Speaker Change: 531 administered every other week with a primary endpoint of endogenous dystrophin expression, which will be evaluated after 24 and 48 weeks of treatment.
Jenny Yang: The trial will also evaluate digital and functional endpoints, pharmacokinetics, as well as safety and tolerability. For disk-driven protein, we are looking for greater than 5%, which exceeds the level of standard of care, which is approximately 1-5% with approved weekly exon skipping therapies. We know KOLs are very focused on functional dystrophin restoration.
Speaker Change: The trial will also evaluate digital and functional endpoints pharmacokinetics as well as safety and Tolerability.
Speaker Change: But this chicken protein, we are looking for greater than 5%, which exceeds the level of standard of care, which is approximately 1% to 5% with a proof weekly exon skipping therapy six.
Speaker Change: We know Kols are very focused on functional dystrophin restoration also extended dosing intervals beyond the current weekly infusions would be very meaningful to patients and families and ultimately we think monthly dosing could be an option within 531.
Jenny Yang: Also, extended dosing intervals beyond the current weekly infusions would be very meaningful to patients and families, and ultimately, we think monthly dosing could be an option with N531. Our compelling preclinical data supports our excitement for this program and its potential to be transformative for patients. Specifically, in Part A of our clinical trial, WAVE N531 demonstrated industry-leading mean 53% exon skipping, which was driven by muscle tissue concentrations of 42 micrograms per gram, which is far above what other exon skipping companies have reported.
Speaker Change: Our compelling preclinical data supports our excitement for this program and its potential to be transformative for patients.
Speaker Change: Specific team Pate of all clinical trials wave and <unk> III, one demonstrated industry, leading 53% exon skipping, which was driven by muscle tissue concentrations at 40, 10 micrograms per Gram, which is far above the exon skipping companies have reported.
Jenny Yang: We're also excited by the clinical evidence of myogenic stem cell or satellite cell uptake of WAVE N531. This is particularly notable, as myogenic stem cells are the progenitor cells for new myoblasts, and we're not aware of any other clinical data for exon skippers or gene therapies that have been able to demonstrate myogenic stem cell uptake.
Speaker Change: So excited by the clinical evidence of myogenic stem cell fashion lifestyle uptake of wave and five free one.
Speaker Change: This is particularly notable as monogenic stem cells are the progenitor cell phone you might block and we're not aware of any other clinical data for exon skip <unk> gene therapies that have been able to demonstrate myogenic stem cell uptake.
Jenny Yang: Our preclinical data indicates that WAVE N531 concentrations in the heart and diaphragm exceed that of skeletal muscle, which could speak to the promise of addressing what remains a huge unmet need in DMD, impacting respiratory and cardiac involvement. In our Forward 53 study, we are monitoring cardiac and respiratory markers. However, boys in our programs are earlier in the disease course and, as such, have normal baseline parameters.
Speaker Change: Our preclinical data indicates that <unk> III, one concentrations in hot and diaphragm exceed the skeletal muscle, which could speak to the promise of addressing what remains a huge unmet need in DMD impacting respiratory and cardiac involvement.
Speaker Change: And a $4 53 study we are monitoring cardiac for research markets, how well the boys in our programs around even the disease course, and as such have normal baseline promises. This is something we plan to explore the future studies.
Jenny Yang: This is something we plan to explore in future studies. We look forward to the opportunity to build on this compelling data set as we plan to deliver potentially registrational 24-week district fin expression data in the third quarter. If positive, these data would support our plans to file for accelerated approval in the U.S. and would accelerate our clinical development plans to build a multi-Exxon DMD franchise beyond Exxon 53. 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 RPM chemistry and have demonstrated high levels of skipping and protein restoration in in vitro studies.
Speaker Change: We look forward to the opportunity to build on this compelling data set as we plan to deliver potentially Registrational 24 week dystrophin expression data in the third quarter.
Speaker Change: If positive these data, which supports our plans to file for accelerated approval in the U S and would accelerate our clinical development plans to build a multi exxon DMD 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 op <unk> chemistry and have demonstrated high levels of skipping M protein restoration in in vitro studies.
Jenny Yang: Now moving to Huntington's disease or HD, where we continue to advance WAVE 003 in our Select HD study. WAVE-003 is our first-in-class allele-selective candidate for HD, designed to reduce toxic mutant Huntington protein while preserving the healthy wild-type Huntington protein. Preservation of healthy wild-type protein is increasingly becoming an area of focus due to its critical role in neuronal function.
Speaker Change: Now moving to Huntington's disease will H D. While we continue to advance <unk> in our CLEC type <unk> study waves.
Speaker Change: <unk> three is our first in class allele selective candidate to HD designed to reduce toxic mutant Huntington protein, while preserving the healthy wild type Huntington protein.
Speaker Change: Preservation of healthy Wild type protein is increasingly becoming an area of focus due to his critical role in your radar function.
Jenny Yang: New preclinical data in adult mice continue to demonstrate the need for a cautious approach in pan-silencing studies, as complete loss of Huntington in mice has been associated with progressive subcortical calcification and neurodegeneration. In the multi-dose portion of our ongoing select HD studies, patients have been receiving WAVE 003 or placebo every eight weeks. We remain on track to report data from this multi-dose cohort with extended follow-up, along with single-dose data, in the second quarter. With multidose therapy, we are looking for durable mutant HTD knockdown of at least 30% with preservation of the wild-type protein.
Speaker Change: New preclinical data in adult life continued to demonstrate the need for a cautious approach and Panasonic two studies as complete loss of Huntington and Mike has been associated with progressive Subcortical pacification and neuro degeneration.
Speaker Change: In the multi dose portion of our ongoing select tasty studies.
Speaker Change: Patients have been receiving <unk> three or placebo every eight weeks.
Speaker Change: We remain on track to report data from this multi dose cohorts with extended follow up along with single dose data in the second quarter.
Speaker Change: With multi dosing we are looking for durable <unk> knockdown of at least 30% with preservation of the wild type protein.
Jenny Yang: We will also be looking at safety and tolerability, including brain imaging. In particular, we will be monitoring for signs of ventricular enlargement, which have been identified by the pan-silencing molecules in transgenic HD mouse models and in HD clinical trials of pan-silencing therapeutics such as Braniplam, an orally administered small molecule, and Tominercin, an IT-administered antisense oligo, with If WAVE-003 avoids such ventricular enlargement, it will be an important differentiator and clearly support the benefit of a wild-type sparing approach.
Speaker Change: We will also be looking at safety and Tolerability, including Brian imaging.
Speaker Change: In particular, we will be monitoring for signs of intraocular enlargement, which have been identified by the <unk> molecules and transgenic HD Massimo dose and then HD clinical trials of <unk> financing therapeutics, such as Broadcom normally administered small molecule termination and itchy administered <unk> with additional assay.
Speaker Change: Use of Hydrocephalus reported in that program.
Speaker Change: If we proceed with your three of which such ventricular enlargement. It will be an important differentiator and clearly support the benefits of a wild type styling approach.
Kyle B. Moran: Altogether, these upcoming data will form the basis for decision making for the advancement of our program, including supporting an opt-in package for Takeda. We are actively planning for the next steps that, pending positive data, would enable efficient and accelerated paths to bring WAVE 003 to patients. In the HD community, we've seen growing support for shorter, more efficient development paths to registration and novel biomarkers such as imaging. Specifically, the use of MRI imaging for caudate volume loss has recently been shown to correlate well with clinical outcomes in work conducted by Ixico on behalf of the Huntington's Disease Image Harmonization Consortium, which was founded last year to conduct an unprecedented harmonization analysis on more than 6,000 participant visit MRI images acquired by more than 2,000 research participants.
Speaker Change: Together these upcoming data will form the basis for decision, making for advancement of our program, including scorching an option package for Takeda.
Speaker Change: We are actively planning for the next steps that pending positive data would enable efficient an accelerated path to bring <unk> to patients.
Speaker Change: H D community wishing growing support for sure more efficient development path to registration and novel Biomarkers such as imaging.
Speaker Change: Specifically the use of MRI imaging for Colgate funding has recently been shown to correlate well with clinical outcomes.
Speaker Change: <unk> conducted by Exco on behalf of the Huntington's disease image Harmonization consortium, which are found in last year to conduction and unprecedented harmonization analysis of more than 6000 participants visit MRI images acquired Chief research participants.
Kyle B. Moran: These markers are sensitive enough to enable highly efficient studies to allow us to establish the biological plausibility of the benefit of mutant Huntington's knockdown with wild-type sparing. Here we can link up confirmatory studies more in the range of 80 patient treatment arms. We've seen examples of imaging biomarkers used for accelerated approval in therapeutic areas such as multiple sclerosis. We look forward to delivering our HCD data this quarter. With that, I'd like to turn the call over to our CFO, Kyle Moran, to provide an update on our finances.
Speaker Change: These markets are sensitive enough to enable highly efficient studies to allow us to establish the biological plausibility of the benefit of mutant Huntington knockdown with wild type sparing.
Speaker Change: Okay. We can link a confirmatory study is more in the range of 80 patient treatment arms. We've seen examples of imaging biomarkers used for accelerated approval in therapeutic areas such as multiple sclerosis.
Speaker Change: We look forward to delivering all hey, Vijay to this quarter with that I'd like to turn the call to our CFO Collin <unk> to provide an update on our financials.
Kyle B. Moran: We recognized revenue of $12.5 million in the first quarter of 2024, as compared to $12.9 million in the prior year quarter. This slight decrease was a result of lower revenue from our Takeda collaboration. Revenue from the GSK collaboration was relatively consistent in the current and prior year quarter. However, research and development expenses were $33.4 million for the first quarter of 2024, as compared to $31 million in the prior year quarter. Increased spending for our clinical programs, as well as our inhibitory program, was the driver behind this increase and was slightly offset by the decrease in spending in our discontinued WBE004 program. Our G&A expenses were $13.5 million in the first quarter of 2024, as compared to $12.2 million in the prior year quarter. This increase was primarily driven by professional fees and other external expenses.
Collin: Thanks Emory.
Collin: We recognized revenue of $12 $5 million in the first quarter of 2024 as compared to $12 9 million in the prior year quarter.
Collin: This slight decrease was a result of lower revenue from our Takeda collaboration.
Paul B. Bolno: As a result, our net loss was $31.6 million in the first quarter as compared to $27.4 million in the prior year. We ended the first quarter with $180.9 million in cash equivalents. Subsequent to the end of the quarter, GSK selected its first two programs to advance to development candidates following target validation, triggering a $12 million payment to WAVE, which is not included in our Q1 cash balance. We expect that our current cash and cash equivalents will be sufficient to fund operations through the fourth quarter of 2025.
Collin: Order Gsk's selected their first two programs too advanced development candidates following target target validation.
Collin: Triggering a 12 million dollar payment wave, which is not included in our queue one cash balance.
Collin: We expect that current cash and cash equivalents will be sufficient to fund operations since the fourth quarter of 2025.
Paul B. Bolno: As a reminder, we do not include any future milestone or opt-in payments under a GSK or Takeda collaboration in our cash runway, but we do have the potential to receive meaningful near-term milestone payments this year and beyond. Notably, over the past 12 months, we've achieved milestones representing $39 million in non-dilutive cash from these collaborations. I'll now turn the call back over to Paul. Closing remarks.
Collin: As a reminder, we did not include any future milestone are often payments under our D. S K or Takeda collaboration in our cash runway, but we do have the potential to receive meaningful near term milestone payments this year and beyond.
Collin: Notably over the past 12 months to achieve milestones representing $39 million and non dilutive cash from these collaboration.
Collin: I'll now turn the call back over to Paul closing remarks.
Operator: With Inhibin-E rapidly advancing toward the clinic and meaningful data updates for all three of our clinical programs expected this year, we are well positioned to deliver program and platform value. Positive clinical data would validate our best-in-class editing, splicing, and silencing capabilities and would serve to unlock our robust preclinical pipeline. Taking a look at our upcoming milestones, 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 within him any rapidly advancing toward the clinic and meaningful data updates for all three of our clinical program is expected. This year, we are well positioned to deliver program and the platform value positive clinical data would validate our best in class editing spicing and violence and capabilities.
Collin: Served to unlock a robust preclinical pipeline.
Collin: Taking a look at our upcoming milestones we plan to deliver the first ever clinical proofing mechanism data for RNA editing with W. V. E 006, this year and so your new preclinical data on our advancing RNA editing programs.
Operator: Submit a CTA for our inhibiting siRNA obesity program as early as the end of this year and initiate a clinical trial in the first quarter of 2025, deliver data including dystrophin protein from our 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. 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 toward building a leading RNA medicines company. With that, I'll turn it over to the operator for Q&A. Operator. Thank you, ladies and gentlemen. If you have a question or comment at this time, please feel free to ask.
Collin: Submit a C T a for our inhibited S. Irna obesity program as early as the end of this year and initiate a clinical trial in the first quarter of 2025 <unk>.
Collin: Delivered data, including dystrophin protein from our potentially Registrational forward 53 clinical trial in the third quarter.
Collin: And deliver H D data from the multi dose elect HD trial would extended follow up along with all single dose data in the second quarter.
Speaker Change: We look forward to sharing our progress with you along the way as we re imagined what's possible for patients and continue on our journey towards building, a leading RNA medicines company with that I'll turn it over to the call to the operator for Q&A operator, Thank you ladies and gentlemen, if you have a question or a communist. This time. Please press star one on your telephone. If your question has been answered you wish to move yourself.
Operator: 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. We'll pause for a moment while we compile our Q&A list. Our first question comes from Salim Syed from Mizzou. Your line is open.
Operator: From the queue. Please press star one on one again will pass for a moment, while we compile or to you in a roster.
Collin: Mmm.
Speaker Change: Our first question comes from southern side with Mister <unk>. Your line is open.
Salim Qader Syed: Great. Congratulations on the progress, guys, and thanks for the questions. Paul, a few from me, if I can.
Southern Side: Great. Congrats on the progress guys Uhm and thanks for the questions. Paul a few from me if I can for Doctor Engulfs and can you just remind us given all the prior relationship with Jesus Payne what data did he have access to that perhaps wasn't in the public domain.
Paul B. Bolno: For Dr. Engelson, can you just remind us, given all the prior relationship with GSK, what data did he have access to that perhaps wasn't in the public domain that he could have potentially used in his decision to join WAVE? So, that's question number one. Question number two on DMD, if you could just remind us if there's any, just given, I don't know, I don't think you guys have access, even though it's open label, but is there anything you can do in terms of patient identification or site prep or other exons of interest? How are you prioritizing that?
Speaker Change: That he could've potentially used in his decision making to join wave. So that's question number one.
Speaker Change: Question number two on on D. M. D. If you could just remind us if there's any just give them I don't know I don't think you guys have access even though it's open label, but is there anything you can do in terms of patient identification our site prep or other.
Speaker Change: Other other exxon's of interest how you're prioritizing that uhm.
Paul B. Bolno: Can you do anything in advance of actually getting the data there to expand it to other exons quickly? And then the last one, just on Huntington's, can you just help us out? Is it May or June, given we're in the... second quarter, and do you guys have access to any blinded safety data or the ventricular enlargement data?
Speaker Change: And the third like can you do anything in advance of actually getting the data.
Speaker Change: There to.
Speaker Change: To expand it to other exxon's quickly and then the last one just on on Huntington's can you just help us if it is it may or June just given we're in the.
Speaker Change: Second quarter, and and do you guys have access to the any blinded safety data or or they've been truculent enlargement data. Thank you.
Paul B. Bolno: Thanks Salim. Why don't we work from back to front?
Speaker Change: Thankfully why don't we work from back to front, so I think pretty quickly on the on the last one I can't provide any other information other than will have data this quarter I can say at this point.
Paul B. Bolno: So I think pretty quickly on the last one; I can't provide any other information other than we'll have data this quarter. I can say at this point that I am, and we are not in possession of any data on the readout. That's about as much as I can say about HD, but we're in the quarter, and we are on track to deliver that data.
Speaker Change: And we are not in the possession of any data on the read out so.
Speaker Change: That's about as much as I can say about each day, but we are in the quarter and we are on track for delivering that data.
Paul B. Bolno: I appreciate the question on DMD. As you know, we have done extensive work on other exons. We have now across the four additional exons that expand that population shown to be good, if not better, dystrophin proteins than those other exons. And the work's underway internally to assure that following, and we have dated, following the dystrophin data readout, that we'll be poised to advance and actually accelerate those other exons. Acceleration comes in two paths.
Speaker Change: Appreciate the question on D. M. D. As you know we have done extensive work across other iphones, we have now across for the for additional iphones that expand that population shown as good if not better dystrophin protein from these other exxon and the work underway internally to assure that following and we have dated.
Speaker Change: Following the dystrophin data read out that will be boys too advanced and it actually accelerate those other accents acceleration comes in two cats, one as you pointed out we've identified in as you're well aware, we can work with leading experts at our various sites, including additional sites and hasn't been able.
Paul B. Bolno: 1, as you pointed out, we've identified, and as you're well aware, we can work with leading experts at our various sites, including additional sites, and have been able to start identifying sites that have patients and their proportion of patients with the other exons. And I think that's definitely helpful work to be able to bring forward these other programs extraordinarily rapidly, since it's not only the sites but also having identified sites with patients.
Speaker Change: To start identifying.
Speaker Change: Sites that have patients and their proportion of patients with the other excellence and I think that's definitely helpful work to be able to bring forward. These other programs extraordinarily rapidly since it's not really.
Speaker Change: The site, but having identified sites with patients.
Paul B. Bolno: We are poised to also, as we think about the development plan, not just think about how to quickly bring them into the clinic, but actually reimagine an umbrella study that has, at its core, the confirmatory study for N531, if that data is positive. So, bringing that to a potential full approval, but also thinking about that study with a common placebo arm as the basis for the umbrella study for the other exons. So, doing both the umbrella registration to bring multiple programs forward but also rapidly identifying those for expediency to assure that we have patients for those other studies.
Speaker Change: We are poised to also as we think about the development plan not just think about how to quickly bring them into the clinic, but actually re imagine an umbrella study that has at its core that couldn't confirmatory study for and by three one if that date is positive so bringing that to a potential full approval uhm, but also.
Speaker Change: Thinking about that study, where they come in placebo arm as the basis for the umbrella for the other accent. So doing both that umbrella registration to bring multiple programs forward, but also I rapidly identifying notes for the expediency Jewish sure that'd be have patience for those other studies and that data looks extraordinarily promising for patients who have not.
Paul B. Bolno: And that data looks extraordinarily promising for patients who have not been in other studies and are available for the other exons that we want to explore. As to your first question, we are excited to work with Eric. Eric's been engaged in the collaboration for a very long time at GSK. He was involved from the early time of initiating the collaboration.
Speaker Change: I've been on other studies and are available for the other exxon's that uhm, we want to explore.
Speaker Change: As to your first question Uhm, we are excited to work with with Uhm, Eric inherits been engaged in the collaboration for a very long time at G. S. K. He was involved from the early time of the initiation of the collaboration and it really came from his role of S. B P of genomic medicine at G. S. K. So we think about a lot of what we've been saying.
Paul B. Bolno: And it really came from his role as SVP of genomic medicine at GSK. So we think about a lot of what we've been saying on calls for a while now about thinking about how to translate big genetic insights into medicine and GSK's investment in 23andMe, UK Biobank, and really building out a robust genetic medicine target discovery organization. And thinking about how WAVE played a role in translating those genetic insights into medicines, which is the most recent update of two programs transitioning.
Speaker Change: <unk> calls for awhile now thinking about how to translate big genetic insight into medicine Gsk's investment in 23 in the UK Biobank and really building at a robust genetic medicine target discovery organization and thinking about how the way it played a role in translating those genetic and.
Speaker Change: Sites into medicines with the most recent update up two programs transitioning so we're well underway and that collaboration I think it's safe to say that Eric bring one or about the understanding of our capability said, but to US. We're excited to have Eric inside wave to be a real partner with our team as we think about that X.
Paul B. Bolno: So we're well underway in that collaboration, and I think it's safe to say that Eric brings, you know, one, a robust understanding of our capability set. But two, is we're excited to have Eric inside WAVE to be a real partner with our team as we think about the expertise we've built in RNA editing and upregulation and correction, in siRNA and silencing and splicing, and are really poised to translate those insights, one, with inhibin-E. And Eric, you know, coming before GSK was professor of medicine at Stanford with a particular focus on metabolic diseases,
Speaker Change: <unk>, we built in RNA editing and Upregulation and correction in S irna, and balancing and slicing and are really poised to translate those insights one within him and he and Eric coming before G. S. K was professor medicine, tampered with a particular focus and metabolic diseases, including the visa so brings a lot of <unk>.
Paul B. Bolno: So he brings a lot of expertise to where we currently are, but importantly, I think, really brings the lens of helping us continue to build a sustainable portfolio of high-impact medicine. So I think he brings both what he's seen inside GSK, but we're really excited for him to work with us on the targets that we've seen and identified that are unique and high-impact, and to help us rapidly translate those medicines into the clinic.
Speaker Change: Experts teeth, and where we currently are but importantly, I think really brings the lens of helping us continue to build a sustainable portfolio of AIPAC medicine, So I think.
Speaker Change: It brings both of them before he has seen in five G. S. K uhm, but we're really excited for him to work with us on the targets that we've seen and identified that are unique in high impact and to help us rapidly translate those <unk>.
Speaker Change: Ended up.
Speaker Change: <unk>.
Operator: Okay, got it. Super. Thanks, Paul. One moment for our next question.
Speaker Change: Okay got it Super Thanks, Paul.
Speaker Change: One moment for next thank you.
Joon So Lee: Our next question comes from Joon Lee with Truist. Your line is open.
Speaker Change: Our next question comes from Julie with Trust Your line is open.
Paul B. Bolno: Great. Congratulations on the great addition to the team. Looking forward to talking to him in the future.
Julie: Alright, congrats on the Great addition to the team looking forward to talking to them in the future regarding Alpha one Antitrypsin program are you sure. What you saw in the restoration one that triggered the Max advancement to respiration too were there any specific bogeys that you were looking to head and healthy volunteers.
Joon So Lee: Regarding the Alpha 1 antitrypsin program, are you able to share what you saw in Restoration 1 that triggered the advancement to Restoration 2? Were there any specific bogeymen that you were looking to hit in healthy volunteers before you advanced to patients? For the forthcoming Restoration 2, what would be considered a success and good enough for GSK to take it forward? And I have a quick follow-up.
Speaker Change: For you attached to the patients and for the.
Speaker Change: <unk> coming restoration to what might be considered a success and didn't ask for a chest K two ticket Ford and I have a quick follow up.
Paul B. Bolno: Thanks, June, and appreciate it. So congratulations to Eric, and we will definitely be connecting him with all of you in the coming weeks.
Speaker Change: Thanks to you and and I appreciate it.
Speaker Change: The congrats on on Eric and we will definitely be connecting him with all of you in the coming weeks Uhm Excitingly on the transition for a T V from restoration wanted to as we said at the very beginning the design of restoration, one really accomplish too important features to transition to restoration too and that's namely safe.
Paul B. Bolno: Excitingly, on the transition for AAPD from Restoration I to II, as we said at the very beginning, the design of Restoration I really accomplished two important features to transition to Restoration II, and that is namely safety, which continues to progress well, and secondly, PK transition. As you know from our preclinical model, we've established in the SERPIN-A1 model the ability to see substantial levels of protein, so we can characterize that in the preclinical model. Just for a basis, in the mouse preclinical model, those doses that we were seeing substantial levels of protein are human-equivalent doses of less than a milligram per kilogram, which is 1.75 to 1.
Speaker Change: <unk>, which continues to progress well and secondly, P. K translation as you know from our preclinical model, we've established in the surf and a one model the ability to see substantial levels of protein. So we can characterize that in the preclinical model just for a basis in the mouth preclinical model those doses that we were.
Speaker Change: Seeing substantial levels of protein or human equivalent dose of less than one milligram per kilogram.
Speaker Change: 751, so if we think about that a lot of our modeling went into establishing that first dose as we said to be a dog that we would anticipate engaging target and then continuing to build both dos and don'ts frequency to the the drivers for the restoration to to your last question I'm thinking about what success look like and Rusty.
Paul B. Bolno: So if we think about that, a lot of our modeling went into establishing that first dose, as we said, to be a dose that we would anticipate engaging the target, and then continuing to build both dose and dose frequency to be the drivers for Restoration II. To your last question about thinking about, you know, what success looked like in Restoration II for GSK, the key for us there is to establish in this study the dose and dose frequency with which to proceed in, obviously, a potentially registrational study.
Speaker Change: <unk> two four G. S. K the key for US there is two established in this study the dos and don'ts frequency with which to bring forward and obviously or potentially registrational site. So as we think about this design.
Paul B. Bolno: So, as we think about this design, you know, there's a combination of not just looking at protein levels but really looking at protein levels too, and I think this is important as we think about the expansion beyond alpha-1 antitrypsin to our other galnet-conjugated RNA editing programs, establishing that translation from prediction from animal models to humans, which for galnet in the siRNA space is pretty well established. So I think I'll do two things.
Speaker Change: <unk> <unk> a combination of not just looking at protein levels, but really looking at protein level too and I think this is important as we think about the expansion beyond alpha one antitrypsin to our other gal that conjugated RNA editing programs, establishing that translation from prediction from animal models to humans, which for gallon that can.
Speaker Change: Yes, Irna space is pretty well established so I think it will do two things one for a T D. Establishing the Joseph frequency with which to move forward I will say this is not an option agreement G. S. Can you have the license of this transition does that is if there's a pause there, but importantly, and I think this is critical for wave with his we'd shared earlier we have <unk>.
Paul B. Bolno: One, for AATD, establishing the dose and dose frequency with which to move forward. I will say, this is not an opt-in agreement. GSK has a license, so this transition is not as if there's a pause there. But importantly, and this is critical for WAVE, as we shared earlier, we have four other galnet-conjugated aimers that we've generated data on. What we want to establish is the paradigm for preclinical to clinical translation, and this study is poised to do that.
Speaker Change: Or other gallon unconjugated gamers that we've generated data on what we wanted to establish it as the paradigm for preclinical the clinical translation and this study is poised to do that.
Joon So Lee: Great, looking forward to the update there. And regarding the additional preclinical data, the head-to-head trial against, not trial, study against semaglutide in a mouse model, as you mentioned, is this something that we can expect at a medical conference, or would it be something that you would share during a subsequent earnings call? Thank you.
Speaker Change: Great and can afford it.
Speaker Change: The update there and have regarding the additional preclinical data <unk> <unk> <unk> child study against <unk> tied in mass model. As you mentioned is there something that you can expect in a medical conference or would it be something that you would share during a subsequent earnings call. Thank you.
Paul B. Bolno: Thank you and thank you for recognizing that. So, you know, before we did a lot of comparable work, so it's nice to have an ongoing head-to-head study with GLP-1. So, we are comfortable with weight loss and leucema. That's an important update. And additionally, and I think we've talked a lot about what we see as one of the advantages as part of a maintenance therapy regimen, which is this question of prior basal mechanism. We were surmising that you could blunt that rebound weight gain. Obviously, now we have data to demonstrate that we're seeing that. This is an ongoing study, and we do plan to share data, as you said, at upcoming meetings later this year.
Speaker Change: Thank you and thank you for for recognizing that so you know before we had done a lot of comparable work. So it's nice to have an ongoing head to head study with G. O P. One so we are comfortable on weight loss and what it's Emma that's an important update and additionally, and I think we've talked a lot about what we see is one of the advantages as part of a maintenance therapy red.
Speaker Change: <unk>, which is the question of prior.
Speaker Change: Prior based on mechanism, we were surmises that you could blunt that rebound weight gain obviously now we have data to demonstrate that we're seeing that this is an ongoing study and we do plan to share data as you said at upcoming meetings later this year.
Operator: All right, I'm looking forward to it. Thank you.
Speaker Change: Alright looking for it thank you.
Speaker Change: Thank you too.
Steven James Seedhouse: Sorry, one moment for our next question. Our next question comes from Steve Seedhouse with Raymond James. Your line is open.
Speaker Change: Sorry, one moment for next question.
Speaker Change: Our next question comes from Steve Sweet House with Raymond James Your line is open.
Nick: Hi, thank you. This is Nick on behalf of Steve.
Speaker Change: Hi. Thank you. This is Nick on for Steve from the clinical trials <unk> country for restoration to it looks like the eligibility criteria involved.
Nick: Pontification of lung disease by Spirometry and liver disease by five Oh scam.
Nick: From the clinicaltrials.gov entry for Restoration 2, it looks like the eligibility criteria involve some quantification of lung disease by spirometry and liver disease by fibroscan. We were just wondering if you plan to measure those changes from baseline and FEV and liver stiffness throughout the duration of Restoration 2, and if so, do you plan to share those data in your first update?
Nick: Just wondering if you plan to measure those changes from baseline <unk> throughout the duration restoration too and if so do you coin sure those dating your first update.
Jenny Yang: Thanks, Nick. Emery, would you like to take that question? Sure.
Speaker Change: <unk> <unk> would you like to take that question.
Jenny Yang: Sure, yes, we will be measuring these kinds of outcomes in the study, but for the duration of the study and the fact that these patients actually have very limited disease enrolment, you wouldn't expect to see much change over the course of the study.
Speaker Change: <unk>, yes, we will be measuring these kinds of 10 <unk>.
Speaker Change: Out comes in the study that for the duration of the study and the fact that these patients actually have that Ain't Medicaid enrollment you wouldn't expect to see much change over the course of the study.
Nick: Okay, thank you. And just as a quick follow-up, just thinking about the non-human primate PK results for N531 that were shared at MDA, you have exposures reaching about 60 microgram per gram, it looks like, at the equivalent human dose in cardiac tissues. Can you comment on the implications of cardiotoxicity with your PN chemistry? And secondarily, does this exposure profile make you inclined to pursue development in cardiovascular diseases? Thank
Speaker Change: Okay. Thank you and just as a quick follow up just thinking about the nonhuman primate P. K results four and 531 that were sure to M. D. A you've exposures, reaching about 60 microgram per gram. It looks so I get the equipment equivalent human dose and cardiac tissues can you comment on the implications of cardio toxicity with Ya.
Speaker Change: And chemistry.
Speaker Change: Secondarily does this exposure profile make you're inclined to pursue development and cardiovascular diseases. Thank you.
Paul B. Bolno: Yes, and one, I appreciate the question. So we've done exposure. Obviously, we've done a substantial amount of work in PN chemistry in multiple areas, whether that's in CNS and systemic. Obviously, safety has allowed us to continue to progress, and we don't see the PN molecule. The PN itself is a neutral charge causing cardiovascular disease.
Speaker Change: Yes, and one I appreciate the question. So we've done exposure, obviously, we've done substantial amount of work in T. N chemistry in multiple areas, whether that's been CNS stomach, obviously safety. It allowed us to continue to progress and we don't see <unk> itself is a neutral charge.
Paul B. Bolno: But it does, as you point out, give us good exposure, and in this case, putting functional protein restoration in those potential tissues. So we do see that as a substantial advantage in DMD, where we know, particularly in the later stages, cardiomyopathy becomes an issue. So again, restoring dystrophin protein, functional dystrophin protein, not micro or mini dystrophin protein early, is an important component. So as you saw, with 53% of the skip transcript in the skeletal muscle, that gives us a high degree of confidence based on the preclinical data that we're seeing substantially more, not just in the heart but also in the diaphragm.
Speaker Change: Causing cardiovascular disease, but it does as you point out give us good exposure and in this case, putting functional protein restoration in.
Speaker Change: In those potential tissues. So we do see that as a substantial advantage and D. M D, where we know, particularly in the later stages cardiomyopathy becomes an issue. So again, restoring dystrophin protein functional dystrophin protein that micro or mini dystrophin protein early is is an important component. So.
Speaker Change: And you saw with 53% skipped transcript in skeletal muscle that gives us a high degree of confidence based on the preclinical data than receiving substantially more not just been heart, but also a diet breath.
Paul B. Bolno: Interesting question, as you pointed out, as we think about other applications. So when we do think about, particularly in the area of editing and upregulation, there are opportunities for us to be thinking about these other target tissues for a variety of treatments. So we look at this data as early support for, obviously, the DMD and splicing, but the opportunity and, you know, with Eric coming on board, bringing his experience, we are thinking more broadly about what potential tissues would be in play and how we think about the diseases in those areas.
Speaker Change: Interesting question as you pointed out as we think about other application. So when we do think about particularly in the area of editing and Upregulation. There are opportunities for us to be thinking about these other target tissues for a variety of treatment. So we look at this data is early supporting obviously the D.
Speaker Change: M D and splicing, but the opportunity and with Eric coming on board, bringing his experience we are thinking more broadly about what potential tissues would be in play and how would we think about the diseases in those areas.
Paul B. Bolno: Paul, can I just add, I just wanted to confirm that we've never seen any data in TOCS that would indicate there's a cardiac TOCS issue, so these... Concentrations in the heart are all upside for us. OK, thank you.
Speaker Change: Hello can I say I just want you to confirm I have not seen any and <unk> that would indicate that as a cardiac <unk> face.
Speaker Change: Concentrations in <unk> pull up side fries.
Speaker Change: Okay. Thank you.
Operator: One moment for our next question. Our next question comes from Ananda Ghosh with HC Wainwright. Your line is open.
Speaker Change: One moment for our next question.
Speaker Change: Our next question comes from a <unk> H C. Wainwright your line is open.
Ananda Ghosh: Thanks for the update. I have two questions about the Inibin program. You know, the first question is, there was a report in the PNAS, I think, original and published, which mentioned that Inibin Beta E is linked to energy expenditure and improved insulin resistance. So, are there data that kind of show that you guys tested these aspects in your animal model? And the second question is, how much innovation might be required to see a translation? And like, how are you thinking about dosing decay, et cetera, as you think about developing the program? Thanks. Yeah.
Speaker Change: Let me help all thanks for the update I have two questions Sunday are you needing program. You know the first question is what was the reporting the PNA is I pink original unpublished, which mentioned that maybe beta he's linked to energy expenditure unimproved insulin resistance. So at the data that kind of you know that you guys <unk>.
Speaker Change: These aspects did you want any of the model and the second question is how much of innovation might be required to see translation and like how are you thinking about <unk> <unk>.
Speaker Change: The program.
Paul B. Bolno: Yeah, no, a great question. Thank you. I'll take the last one first.
Speaker Change: Yeah, No I take great question. Thank you I'll take the the last one first if we think about demonstration of loss of function driving disease and obligations. These are heterozygous carriers. So 50 per cent there'd been data, suggesting like it even 40 per cent of our lower you see.
Speaker Change: <unk>, we've Denver surpassed that so we had our R&D day, where we provided the update on both the target and our first generation. This awhile ago <unk>, even the candidate Uhm, we had already surpassed 50 per cent silencing and demonstrated that that had a meaningful effect on phenotypes. So we surpassed that continued to do.
Paul B. Bolno: If we think about the demonstration of loss of function driving disease in publications, these are heterozygous carriers, so 50%. But there's been data suggesting that at even 40% or lower, you see improvements. So we surpassed that, we continue to do that, as we said, with our clinical candidate now, we're at an ED50 of less than a milligram per kilogram. That looks better over what the existing siRNAs are currently in the market. So we've got better potency, which is consistent with our NAR paper where we published on our siRNA formats, where we see better potency against best-in-class siRNA, and we see better durability, which is an important feature in that sense compared to the current best-in-class siRNA.
Speaker Change: That'd be sent with our clinical candidate now where an immediate 50 of less than a milligram per kilogram uhm, that's looks improved over what the existing F. Irna as are currently in the market. So we got better policy, which is consistent with our <unk>, our paper, where we published on our S. Irna format to receive better potency against best in class S. Irna.
Speaker Change: I would think better durability, which is an important feature that status. The current best in class at the irony. So we put those features together based on our candidate and data we have substantial knockdown that achieves what's been seen in humans and a durability profile now that not only looks to the potential for twice a year, but once a year uhm. So we think that <unk>.
Paul B. Bolno: So we put those features together based on our candidate and data; we have substantial knockdown that achieves what's been seen in humans, and a durability profile now that not only looks at the potential for twice a year but once a year. So we think that that sets us up very nicely. To your point on improved insulin resistance, I mean, that has translated in humans where there's an improvement in outcome benefit in type 2 diabetes.
Speaker Change: <unk> set ourselves up very nicely uhm to your point on improved insulin resistance I mean that that has translated inhumans, where there is an improvement in an outcome benefit and type two diabetes. That's been seen in both the regeneron publication on the UK Biobank data Island. So we do know that looking at the human data set for Ebony.
Paul B. Bolno: That's been seen in both the Regeneron publication on the UK Biobank data and Elm Island. So we do know that looking at the human data set for inhibin-A, there is this advantage in improving type 2 diabetes as a function of improved insulin resistance. But we have not currently looked at that.
Speaker Change: There is this advantage and improving uhm type two diabetes is a function of improve insulin resistance. We've not currently looked at that we'd been bulking measurement betterment that relate to weight fat and muscle, but obviously as we continue to build the preclinical package take we have multiple opportunity to really think well beyond obese.
Paul B. Bolno: We've been focused on measurements that relate to weight, fat, and muscle. But obviously, as we continue to build the preclinical package, I think we have multiple opportunities to really think well beyond obesity as fat loss. And I think you bring up an important point.
Speaker Change: <unk> <unk> <unk>.
Speaker Change: Lost and I think you bring up an important point, we need to look at obesity as a public health challenge one that it has cardiovascular implications and an ebony human so you'll have a reduction of inhibiting have low triglycerides low L. D. L. I H D L and they have this improvement.
Ananda Ghosh: We need to look at obesity as a public health challenge, one that has cardiovascular implications. Humans that have a reduction in inhibiny have low triglycerides, low LDL, high HDL, and they have this improvement in insulin resistance. So as we think about the totality of actually treating a substantial population with metabolic syndrome, I think the opportunity for this program extends well beyond just fat loss.
Speaker Change: So as we think about the totality of actually treating a substantial population with metabolic syndrome I think the opportunity for this program extends well beyond just that off.
Operator: Okay. Thanks. Thanks very much. Thank you.
Speaker Change: Okay, Thanks that sounds.
Speaker Change: Thank you.
Joseph Patrick Schwartz: One moment for our last question. We'll take our last question from Joseph Schwartz with Learning Partners. Your line is open. Hi. Everyone's Jenny on for Joe.
Speaker Change: One moment for our last question.
Speaker Change: Okay.
Speaker Change: We'll take our last question from Joseph Schwarzer Lyric partners. Your line is often.
Speaker Change: Hi.
Joseph Patrick Schwartz: <unk>. They were just wondering if you could give us any.
Speaker Change: Alright, and to <unk> process for choosing I can reset.
Speaker Change: Did they see the data in holiday Friday target validation.
Paul B. Bolno: Thank you. I mean, there's not a lot I can share, unfortunately, around, you know, what's under their tent, but I can walk you through the process, and I think that would be helpful. So, if you imagine that they have invested in these genetic activities, that's given them targets, and so if we think about inhibin E as a good surrogate, you know, targets that have strong genetic differentiation and potential, we can say, based on the selection, these were in hepatology.
Speaker Change: Thank you I mean, there's not a lot I can ship unfortunately around under.
Speaker Change: Under their attempt, but just I can walk through process and that I think that would be helpful. So have you imagined. They they have invested in this genetic activities, that's given them targets and so if we think about and hip any as a good surrogate.
Speaker Change: Targets that have strong genetic differentiation and potential we can say based on the selection. These were in herpetology. So we said publicly we've got targets across therapeutic areas beyond.
Paul B. Bolno: As we said publicly, we've got targets across therapeutic areas beyond hepatic and across modalities. But in these cases, there are, we generate programs that validate that target, that target biologically. And when that target's achieved a threshold where we've proved that concept, right, we've demonstrated that by impacting that target, we're recapitulating some biology, that triggers, at their discretion, the ability to move that program into their pipeline. So that triggers the program nomination that takes away from those eight opportunities that they have.
Speaker Change: <unk> across modalities, but in in these cases, there's we generate programs at validate that target that target biologically and when that targets achieved a threshold that we prove that concept right we've demonstrated that impacting.
Speaker Change: Impacting that target where recapitulated some biology.
Speaker Change: That triggers at their discretion the ability to move that program into they're pregnant so that triggers.
Speaker Change: The program domination that takes away from those eight opportunities that they have and so all I can say is we met that validation criteria on that translation and the key now is really thinking about visa therapeutics that drive towards the clinic. So we think about you know therapeutic and get you know this is a cross modality we're doing.
Paul B. Bolno: And so all I can say is that we've met the validation criteria for that translation. And the key now is really thinking about these as therapeutics that drive us towards the clinic. So, if we think about, you know, therapeutic engagement, you know, this is across modalities, we're doing this work, and so there's a lot of ongoing work that I think, holistically, we really benefit from. So, if you think about, you know, why we did this part of the collaboration, there's a lot of research and discovery efforts that we're doing across these various targets that are informing us in our strategy as we think about the pipeline creation that we.
Speaker Change: This work and so there's a lot of ongoing work that I think holistically, we really benefit from so if you think about why we did this part of the collaboration there's a lot of research and discovery effort that we're doing a cross these barriers targets that are informing us in our strategy as we think about the pipeline creation at <unk>.
Paul B. Bolno: Thank you. I'm not showing any further questions at this time. I'd like to turn the call back over to Paul for any closing remarks.
Speaker Change: Thank you I'm not showing any further questions start much turn the call back over to Paul for any closing remarks.
Paul: Thank you for it.
Paul B. Bolno: Thank you all for joining the call this morning. We're excited to see many of you in New York at the RBC conference next week, and we look forward to keeping you all updated on our progress. Have a great day.
Paul: Thank you all for joining the call. This morning, we're excited to see many of you in New York at the RBC comforts next week and we look forward to keeping you all updated on our progress have a great day, ladies and gentlemen does conclude today's presentation. You may now disconnect and have a wonderful day.
Operator: Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day.
Paul: Mmm Mmm [music].
Paul: [music].
Paul: [music].
Operator: [music].