WAVE Life Sciences Q1 2024 Earnings Call Transcript

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Provided by Quartr
May 9, 2024

Key Takeaways

  • Three clinical trials advancing with key data updates: Restoration 2 proof of mechanism for WVE-006 in AATD this year, 24-week dystrophin data in Q3 for WVE N531 (DMD), and multi-dose HD data in Q2 for WVE-003.
  • INHIBIN E obesity program shows preclinical weight loss comparable to semaglutide, durable silencing supporting potential 6- to 12-month dosing, and is on track for CTA filing by year-end with trial start in Q1 2025.
  • GSK collaboration delivered $20 M milestone for WVE-006’s clinical start and $12 M for two discovery programs, with potential $2.8 B in total milestones plus royalties, all GSK-funded through target validation.
  • Appointed Dr. Eric Engelson as Chief Scientific Officer to lead portfolio strategy and expand genetics/genomics capabilities.
  • Q1 revenue of $12.5 M was flat y/y, R&D and G&A expenses rose, net loss widened to $31.6 M, though $180.9 M in cash supports runway into Q4 2025.
AI Generated. May Contain Errors.
Earnings Conference Call
WAVE Life Sciences Q1 2024
00:00 / 00:00

There are 9 speakers on the call.

Operator

Good morning, and welcome to the Wave Life Sciences First Quarter 20 24 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 turn the call over to Kate Roush, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

Speaker 1

Thank you, Kevin. Good morning, and thank you for joining us today to discuss our recent business progress and review Wade's Q1 2024 financial results. Joining me today with prepared remarks are Doctor. Paul Volnaud, President and Chief Executive Officer Kyle Moran, Chief Financial Officer and Anne Marie Li Kwaicheng, Chief Development Officer. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com.

Speaker 1

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. I'd now like to turn the call over to Paul.

Speaker 2

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 on our strategy. Next Anne Marie will provide an update on our 3 ongoing clinical trials. And before opening up the call for questions, Kyle will review our financials.

Speaker 2

Chandra and Jinhee 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 3 ongoing clinical trials towards key data updates. This includes our restoration program, which is underway evaluating WVE-six, our RNA editing candidate for patients with AATD, our potentially registrational FORWARD-fifty three clinical trial with WVE N531 for boys with exon 53 amenable DMD and Select HD, our trial evaluating WVE-three, a first in class allele selective investigational therapy for patients with HD. We also continue to advance our INHIBON E 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 Q1 of next year.

Speaker 2

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, Doctor. Eric Engelson has joined WAVE as Chief Scientific Officer. 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.

Speaker 2

Doctor. Ingleson 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 medicines. Prior to GSK, he was Professor of Medicine at Stanford University and obtained his MD PhD at Opsela University. You will have the opportunity to hear directly from Eric in the very near future.

Speaker 2

Turning to our pipeline in RNA editing, our restoration to clinical trial of WVE-six for Alpha-one antitrypsin deficiency or AATD is now underway and we continue to advance our wholly owned RNA editing pipeline behind it. WVE-six is the industry's first ever clinical RNA editing candidate, which aims to correct AATD causing Z mutation to increase circulating levels of wild type AAT protein and reduce mutant AAT protein aggregation in the liver. 6 is designed to address the root cause of AATD to provide a solution to patients with AAT lung disease, liver disease or both. Other treatment approaches are often confined to either lung or liver manifestations, not bone. The current standard of care treatment weekly IV augmentation therapy is limited to treating only lung disease.

Speaker 2

SiRNA treatments and development are confined to treating only liver disease and could exacerbate lung injury. By targeting RNA, 6 differs from DNA editing technologies that rely on hyperactive exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels. In fact, in preclinical studies, the majority of edits observed using DNA based editing were bystander edits that yielded isoforms of AAT protein with lower functional activity, while the indels have the potential to create loss of function variance. WVE-six does not use complex delivery systems such as LMPs. 6 contains GalNet conjugate, a highly specific and elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market.

Speaker 2

GalNec enables the ease and convenience of subcutaneous dosing, effective and selective delivery to hepatocytes as well as a high degree of confidence of preclinical to clinical translation since the entire dose is delivered reliably to the target organ. Our proprietary chemistry enables WVE-six to effectively recruit endogenous ADR enzymes and achieve potent and durable editing in preclinical studies. We've shown AAT protein levels that exceed the thresholds for both MZ and healthy populations. We confirm the functionality of this protein with the neutrophil elastase assay. Additionally, we saw decreases of lobular inflammation and reduction of liver aggregates.

Speaker 2

WVE-six also prevents increases in mitosis 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 2 and continue to make significant progress in our trial of WVE-six with proof of mechanism data from restoration 2 in patients with AATD expected later this year. Proof of mechanism for 6 would not only meaningfully de risk our AATD 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. GSK was early to recognize the potential of our differentiated RNA editing capability at our multimodal platform more broadly. Their leadership in respiratory medicine and development and commercialization makes them an ideal partner for 6 and they continue to bring substantial value to Wave through their significant in deep genetic insights.

Speaker 2

The collaboration included $525,000,000 of milestones related to 6, of which we received $20,000,000 in the Q1 due to the advancement into the clinic. Development and commercialization responsibilities transferred to GSK at their sole cost after we complete our restoration 2 study. WAVE is also eligible for double digit tiered royalties as a percentage of net sales of 6 up to the high teens. 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 $12,000,000 payment to WAVE. Both of these programs utilize WAVE's next gen GalNec siRNA format and are hepatology.

Speaker 2

The discovery component of the collaboration encompasses all of Wave's modalities including RNA editing and GSK is eligible to advance up to 8 programs in total during the initial research term. For these 8 collaboration programs, Wave is eligible for total potential milestone payments of up to $2,800,000,000 as well as royalties on net sales. As a reminder, GSK pays 100% of costs related to target validation of these partnered programs. The collaboration also expands our wholly owned pipeline as we are able to leverage GSK's genetically validated target to advance up to 3 programs for WAVE. INHIB and 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 1st in class potential.

Speaker 2

Our INHIPA program aims to be a next generation obesity therapeutic. Using GalNec siRNA silencing, we aim to recapitulate the protective phenotype of INHIBIN E loss of function heterozygous carriers who have a favorable cardiometabolic profile including reduced abdominal obesity, reduced odds of type 2 diabetes and coronary artery disease. Inhibin E mRNA is expressed in the liver with its corresponding receptor on adipocytes, which controls fat storage. Silencing inhibin E promotes fat burning or lipolysis and decreases fat accumulation. While GLP-1s have become the standard of care for weight loss, these therapies come with several limitations, namely frequent dosing, loss of muscle mass or tolerability and high discontinuation rates.

Speaker 2

With our INHIBBNE program, we have demonstrated highly potent silencing with an ED50 of less than 1 milligram per kilogram in the diet induced obesity or DIO mouse model and durable silencing following 1 low single digit dose, which supports the potential for subcutaneous dosing intervals of every 6 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. 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 inhibiting mechanism of action is distinct from GLP-1s, we also see the opportunity to use inhibiting SI RNA as a frontline or potentially maintenance therapy following GLP-one weight loss induction. And we now have emerging preclinical data to further support this use.

Speaker 2

In an ongoing head to head study in DIO mice, we observed that the weight loss effect from a single dose of our inhibiting siRNA was similar to semaglutide. In addition, treatment with our INHIBANI siRNA upon cessation of semaglutide treatment curtailed expected rebound weight gain. We expect to share new preclinical data from our inherited knee 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 Q1 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.

Speaker 2

In DMD and HD, we are on track to deliver clinical data from each of these programs in the coming months. With our potentially registrational FORWARD 53 clinical trial of 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 exon 53 skipping. Significant scientific gaps on the functional benefit of micro mini dystrophin remain in addition to an unknown safety risk associated with AAV gene therapies. There is an urgent need to deliver more therapeutic options to patients, especially those which can achieve access to the heart and diaphragm, 2 areas where we have seen substantial distribution in our preclinical studies including NHPs. Our clinical data for EN531 after only 3 doses every other week position it as potentially best in class.

Speaker 2

We've demonstrated industry leading exon skipping at 53%, muscle tissue concentrations of 42,000 nanograms per gram, the first clinical demonstration of uptake in myogenic stem cells and a half life which 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 Q3 this year. In HD, we continue to advance our 1st in class allele selective therapeutic wave-three. In this 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.

Speaker 2

With HD and over 200,000 at risk of developing HD. 3 is designed to reduce mutant huntingtin protein, while also sparing healthy wild type huntingtin 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 protein, especially as HD patients already start with a lower wild type reserve. We've already demonstrated 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 and we are looking to replicate these biomarker data with the 1st multi dose data from our Select HD clinical trial in the Q2. In addition, we will be looking closely to see if we can differentiate on safety signals seen by the pan silencing approaches including ventricular enlargement.

Speaker 2

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?

Speaker 3

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 GalNAc conjugated AMR Wave006 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 1b2a open label study designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of Wave 6 in individuals with AATD who have the homozygous PIZZ mutation. We have rapidly progressed dose escalation in the RESTORATION-one 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.

Speaker 3

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. Using the data from healthy volunteers, we identified a starting dose level for restoration 2 that's expected to gauge 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 3 dose cohorts, enabling us to quickly detect the potential presence of wild type healthy MAAT protein in the serum, which would indicate that Wave 6 is successfully editing RNA and represent the achievement of proof of mechanism.

Speaker 3

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. Dosing 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 AVE N531 administered every other week with a primary endpoint of endogenous dystrophin expression, which will be evaluated after 24 48 weeks of treatment. The trial will also evaluate digital and functional endpoints, pharmacokinetics as well as safety and tolerability.

Speaker 3

For this driven protein, we are looking for greater than 5%, which exceeds the level of standard of care, which is approximately 1% to 5% with approved weekly exon skipping therapeutics. 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 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 3

We're also excited by the clinical evidence of myogenic stem cell or satellite cell uptake of WAVN531. This is particularly notable as myogenic stem cells are the progenitor cells for new myelblasts, and we're not aware of any other clinical data for exon skipping or gene therapies that have been able to demonstrate myogenic stem cell uptake. Our preclinical data indicates that WAVN-five thirty one 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, while our boys in our programs are earlier in the disease course and as such have normal baseline parameters, this is something we plan to explore in future studies.

Speaker 3

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 Q3. 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 exon DMD franchise beyond exon 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 our PN chemistry and have demonstrated high levels of skipping and protein restoration in in vitro studies.

Speaker 3

Now moving to Huntington's disease or HD, where we continue to advance Wave003 in our select HD study. Wave003 is our 1st in class allele selective candidate for HD, designed to reduce toxic mutant Huntington protein while preserving the healthy wild type huntingtin protein. Preservation of healthy wild type protein is increasingly becoming an area of focus due to its critical role in neuronal function. 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 wave003 or placebo every 8 weeks.

Speaker 3

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 multi dosing, we are looking for durable mutant HTT knockdown of at least 30% with preservation of the wild type protein. 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 both the pan silencing molecules in transgenic HD mouse models and in HD clinical trials of pan silencing therapeutics such as branoplam, an already administered small molecule, and Tominecen, an IT administered antisense oligo, with additional SAUs of hydrocephalus reported in that program. If wave 3 avoids such ventricular enlargement, it will be an important differentiator and clearly support the benefits of a wild type sparing approach.

Speaker 3

Altogether, these upcoming data will form the basis for decision making for 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 path to bring Wave003 to patients. In the HD community, we've seen growing support for shorter and 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 were founded last year to conduct an unprecedented harmonization analysis of more than 6,000 participant visit MRI images acquired over 2,000 research participants. These markers are sensitive enough to enable highly efficient studies to allow us establish the biological plausibility of the benefit of mutant hunting to knock down with wild type sparing.

Speaker 3

Here we can think of 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 HD data this quarter. With that, I'd like to turn the call to our CFO, Karl Moran to provide an update on our financials.

Speaker 4

Thanks, Anne Marie. We recognized revenue of $12,500,000 in the Q1 of 2024 as compared to $12,900,000 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 to current and prior year quarters. Research and development expenses were $33,400,000 for the Q1 of 2024 as compared to $31,000,000 in the prior year quarter.

Speaker 4

Increased spending for our clinical programs as well as our Inhibiny program was the driver behind this increase. It was slightly offset by the decrease in spending in our discontinued WBE004 program. Our G and A expenses were $13,500,000 in the Q1 of 2024 as compared to $12,200,000 in the prior year quarter. This increase was primarily driven by professional fees and other external expenses. As a result, our net loss $31,600,000 in the Q1 as compared to $27,400,000 in the prior year.

Speaker 4

We ended the Q1 with $180,900,000 in cash and cash equivalents. Subsequent to the end of the quarter, GSK selected their first two programs to advance development candidates following target validation, triggering a $12,000,000 payment to waive, which is not included in our Q1 cash balance. We expect that our current cash and cash equivalents will be sufficient to fund operations since the Q4 of 2025. As a reminder, we do not include any future milestone or opt in payments under our 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.

Speaker 4

Notably, over the past 12 months, we've achieved milestones representing $39,000,000 in non dilutive cash from these collaborations. I'll now turn the call back over to Paul for closing remarks. Thank you, Kyle.

Speaker 2

With INHIM and 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 WBE-six this year and share new preclinical data on our advancing RNA editing programs. Submit a CTA for our Hibbettie siRNA obesity program as early as the end of this year and initiate a clinical trial in the Q1 of 2025, deliver data including dystrophin protein from our potentially registrational FORWARD 53 clinical trial in the 3rd 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 towards building a leading RNA medicines company.

Speaker 2

With that, I'll turn over the call to the operator for Q and A. Operator?

Operator

Thank Our first question comes from Salim Syed with Mizuho. Your line is open.

Speaker 5

Great. Congrats on the progress guys and thanks for the questions. Paul, a few from me if I can. For Doctor. Ingleson, 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 making to join WAVE?

Speaker 5

So that's question number 1. Question number 2 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 you're prioritizing that? And the third like can you do anything in advance of actually getting the data there to expand into other exons quickly? And then the last one just on Huntington's. Can you just help us, is it May or June, just given we're in the Q2?

Speaker 5

And do you guys have access to the any blinded safety data or the ventricular enlargement data? Thank you.

Speaker 2

Thanks, Salim. Why don't we work from back to front? 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, I'm and we are not in the possession of any data on the readout.

Speaker 2

So that's about as much as I can say about HD, but we're in the quarter and we are on track for delivering that data. Appreciate the question on DMD. As you know, we have done extensive work across other exons. We have now across the 4 additional exons that expand that population, shown as good if not better dystrophin protein from these other exons. And the work's underway internally to assure that following and we have gated following the dystrophin data readout that we'll be poised to advance and actually accelerate those other exons.

Speaker 2

Acceleration comes in 2 paths. 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 having identified sites with patients. 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 that can confirmatory study for N591 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 for the other axon.

Speaker 2

So doing both the umbrella registration to bring multiple programs forward, but also rapidly identifying those for the expediency to assure that we have patients for those other studies. And that data looks extraordinarily promising for patients who have not been on 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 has been engaged in the collaboration for a very long time at GSK. He was involved from the early time of initiation of the collaboration.

Speaker 2

And that really came from his role of SVP of genomic medicine at GSK. So we think about a lot of what we've been saying on calls for a while now of thinking about how to translate big genetic insights into medicine, 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 with the most recent update of 2 programs transitioning. So we're well underway in that collaboration. I think it's safe to say that Eric brings 1, a robust understanding of our capabilities then.

Speaker 2

But 2 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, 1, with Inhib and E. And Eric, coming before GSK was professor of medicine at Stanford with a particular focus in metabolic disease including obesity. So it 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 medicines. 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 5

Okay. Got it. Super. Thanks, Paul.

Operator

One moment for our next question. Our next question comes from June Lee with Truist. Your line is open.

Speaker 6

Great. Congrats on the great addition to the team. Looking forward to talking to them in the future. Regarding alpha-one antitrypsin program, are you able to share what you saw in the restoration 1 that triggered the advancement to restoration 2? Were there any specific bogeys that you are looking to hit in healthy volunteers before you advance to the patients?

Speaker 6

And 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 2

Thanks, June. And appreciate the congrats on Eric and we will definitely be connecting him with all of you in the coming weeks. Excitingly on the transition for AATD from restoration 1 to 2, as we said at the very beginning, the design of restoration 1 really accomplished 2 important features to transition to restoration 2 and that's namely safety, which continues to progress well. And secondly, PK transition. As you know from our preclinical model, we've established in the SERPINA1 model the ability to see substantial levels of protein.

Speaker 2

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 a human equivalent dose of less than a milligram per kilogram, it's 1.75 per 1. 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 targets and then continuing to build both dose and dose frequency to be the drivers for the restoration 2. To your last question on thinking about what success look like in restoration 2 for GSK, the key for us there is to establish in this study the dose and dose frequency with which to bring forward and obviously a potentially registrational study. So as we think about this design, there's a combination of not just looking at protein levels, but really looking at protein levels too.

Speaker 2

And I think this is important as we think about the expansion beyond alpha-one antitrypsin to our other GalNec conjugated RNA editing programs, establishing that translation from prediction from animal models to humans, which for GalNec in the siRNA space is pretty well established. So I think it will do 2 things. 1, for AATD establishing its dose, 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.

Speaker 2

But importantly, and I think this is critical for WAVE with as we shared earlier, we have 4 other GELNET conjugated tumors that we've generated data on. What we want to establish is the paradigm for preclinical clinical translation and this study is poised to do that.

Speaker 6

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 mouse model, as you mentioned. Is there something that you can expect at a medical conference or would it be something that you would share during a subsequent earnings call? Thank you.

Speaker 2

Thank you and thank you for recognizing that. So before we had done a lot of comparable work, so it's nice to have an ongoing head to head study with GLP-one. So we are comfortable on weight loss similar to sema. 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.

Speaker 2

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 6

All right. Looking forward. Thank you.

Speaker 2

Thank you, Duke.

Operator

Duke. Sorry, one moment for our next question. Our next question comes from Steve Seedhouse with Raymond James. Your line is open.

Speaker 7

Hi, thank you. This is Nick on for Steve. From the clinicaltrials dot goventry for restoration 2, it looks like the eligibility criteria involves 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 FEV and liver stiffness throughout the duration of restoration too? And if so, do you plan to share those data in your first update?

Speaker 2

Thanks, Nick. Anne Marie, would you like to take that question?

Speaker 3

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 enrollment, you wouldn't expect to see much change over the course of the study.

Speaker 7

Okay. Thank you. And just as a quick follow-up, just thinking about the non human primate PK results for N5 31 that were shared at MDA, you have exposures reaching about 60 microgram per gram, it looks like at the equivalent human dose and 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?

Speaker 7

Thank you.

Speaker 2

Yes. And one appreciate the question. So we've done exposure. Obviously, we've done 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 PM molecule.

Speaker 2

PM itself is a neutral charge causing cardiovascular disease. 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% 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 heart but also in diaphragm.

Speaker 2

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 up regulation, 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 supporting obviously the DMD 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 we think about the diseases in those areas.

Speaker 3

Paul, can I just add, I just wanted to confirm, we've never seen any data in tox that would indicate there's a cardiac tox issue? So these concentrations in the heart are all upside for us.

Speaker 7

Okay. Thank you.

Operator

One moment for our next question. Our next question comes from Ananda Ghosh with H. C. Wainwright. Your line is open.

Speaker 8

Hi, Paul. Thanks for the update. I have two questions on the Inhibin program. The first question is, there was a report in P and S, I think, Regeneron published, which mentioned that maybe beta E is linked to energy expenditure and improved insulin resistance. So are there data that kind of that you guys tested these aspects in your animal model?

Speaker 8

And the second question is how much of innovation might be required to see translation? And like how are you thinking about dosing PK, etcetera, as you think about developing a program? Thanks. Yes.

Speaker 2

No, it's a great question. Thank you. I'll take the last one first. If we think about demonstration of loss of function driving disease in publications. These are heterozygous carriers of 50%.

Speaker 2

There's been data suggesting like at even 40% or lower you see improvement. We've then surpassed that. So we had our R and D day where we provided the update on both the target and our first generation, so it's a while ago construct, not even a candidate. We had already surpassed 50% silencing and demonstrated that that had a meaningful full effect on phenotypes. So we surpassed that.

Speaker 2

We continue to do that as we ED50 of less than a milligram per kilogram. That looks improved 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 format. So we see better potency against best in class siRNA and we see better durability, which is an important feature in us than the current best in class siRNA. 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.

Speaker 2

So we think that that sets ourselves up very nicely. To your point on improved insulin resistance, I mean that has translated in humans where there's improvement in an outcome benefit in type 2 diabetes. That's been seen in both the Regeneron publication on the UK Biobank data in Alnylam. So we do know that looking at the human data set for Hibbett A that there is this advantage in improving type 2 diabetes as a function of improved insulin resistance. We've not currently looked at that.

Speaker 2

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 and as a fat loss. And I think you bring up an important point. We need to look at obesity as a public health challenge, one that has cardiovascular implications and an immunity Humans that have a reduction of inhibinete 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 Vapbox.

Speaker 2

Okay. Thanks. Thanks very much. Thank you.

Operator

One moment for our last question. We'll take our last question from Joseph Schwartz with Leerink Partners. Your line is open.

Speaker 3

Hi, everyone. Jenny on for Joe. We were just wondering if you could give us any insight into GSK's process for choosing their 2 recent programs. Did they see any data? And how are they defining target validation?

Speaker 2

Thank you. I mean, there's not a lot I can share unfortunately around what's under their temp, but I can walk through process and I think that would be helpful. So if you imagine they have invested in these genetic activities that's given them targets. And so we think about inhibiti as a good surrogate. Targets that have strong genetic differentiation and potential, we can say based on the selection, these were in hepatology.

Speaker 2

As we said publicly, we've got targets across therapeutic areas beyond hepatic and across modalities. But in these cases, there's we generate programs that validate that target, that target biologically. And when that target achieved the threshold that we prove that concept, right, we've demonstrated that by impacting that target, we're recapitulating some biology that 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 8 opportunities that they have. And so all I can say is we've met that validation criteria on that translation.

Speaker 2

And the key now is really thinking about these as therapeutics that drive towards the clinic. So if we think about therapeutic engage, 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 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 at Wave.

Operator

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 2

Thank you, operator. 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.

Operator

Ladies and gentlemen, that concludes today's presentation. You may now disconnect and have a wonderful day.

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