Q3 2024 Wave Life Sciences Ltd Earnings Call
Ill now turn the call over to Kate Rausch, Vice President Investor Relations and corporate Affairs. Please go ahead.
Kate Rausch: Thank you operator, good morning, and thank you for joining us to discuss our recent business progress and review with third quarter 2024 financial results.
Kate Rausch: Joining me today with prepared remarks, Dr. Paul Bono, President and Chief Executive Officer, and Marie <unk> Chang Chief Development Officer, and Comorin, Chief Financial Officer. The press release issued this morning is available on the investors section of our website Www Dot wave life Sciences Dot com.
Kate Rausch: Before we begin I would like to remind you that discussions during this conference call will include forward looking statements. These.
Speaker Change: 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 Thanks, Keith Good morning.
Speaker Change: Thank you all for joining us on today's call, it's an exciting time for ways.
Speaker Change: This year, we have executed ahead of plan delivered three positive clinical datasets receive supportive initial feedback from FDA on HD rapidly advanced our obesity program towards the clinic and strengthen our balance sheet to support our maturing and growing pipeline.
Speaker Change: Our best in class RNA platform is consistently translating in the clinic and demonstrating how we can uniquely designed and advance first and best in class RNA medicines, that's re imagining what's possible for patients our achievements have set us up for another potentially transformative year in 2025, as we aim to build on our strong momentum.
Speaker Change: And deliver on key milestones from four clinical programs.
Speaker Change: We are advancing WB and 531 in DMD, and WPS zero zero to 3% and <unk> on their respective paths towards potential accelerated approval of <unk> and <unk> towards multi dose RNA editing data and WVU 007 in obesity toward initiation of dosing in the next clinical cohort.
Speaker Change: As well as advancing our wholly owned pipeline our upcoming milestones offer the potential to unlock our high impact of high value portfolio in both rare and common diseases.
Speaker Change: With ACD in October we delivered a breakthrough in RNA medicine with the first ever clinical demonstration of RNA editing in humans.
Speaker Change: Using our <unk> 006.
Speaker Change: These proof of mechanism data from the ongoing restoration to study in <unk> patients represents a significant milestone for wave and in the development of therapeutic oligonucleotides as a whole.
Speaker Change: We are pleased to observe six nine micro molar of MAA, just two weeks post single dose and impressive durability of effect that we believe could support extended dosing interval.
Speaker Change: These initial data alongside zero-zero sticks that safety profile durability and convenient subcutaneous administration all support a best in class approach to address significant unmet needs for both liver and lung manifestations of ATB and we look forward to delivering multi dose data from restoration to in 2025.
Speaker Change: Our RNA editing approach differs greatly from others in the field. Our chemistry was built from the ground up for our RNA editing gamers. It is novel best in class and supported by deep and broad IP.
Speaker Change: We do not require IV administered lnp's or complex delivery vehicles.
Speaker Change: Our Amer is a compatible with <unk>, enabling convenient subcutaneous.
Speaker Change: Subcutaneous dosing.
Speaker Change: Our RNA editing approach also differs from DNA editing technologies, which rely on hyperactive exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits in adults.
Speaker Change: Proof of mechanism with WV zero-zero sticks is broadly validated our <unk> conjugated RNA editing capability and our recent research day, we unveiled our next Calmac RNA editing programs, which aims to address significant unmet needs in the cardio metabolic space.
Speaker Change: These targets include <unk>, three where we are using an mrna correction approach for those at high risk for a variety of liver diseases as well as two targets that enable best in class LDL C lowering and heterozygous familial hypercholesterolemia patients LDL or which utilizes first in class mrna upregulation.
Speaker Change: And <unk>, which utilizes mrna correction.
Each program is strongly supported by human genetics has well defined patient populations and offers a completely novel treatment approach to collectively address upwards of 10 million patients.
Speaker Change: They also feature readily accessible biomarkers and approaches to assess pharmacodynamics along with established regulatory path.
Speaker Change: We expect to select candidates for all three programs in 2025.
And obesity, we are advancing <unk> 007 are <unk> RNA targeted inhibitor that is a completely novel approach for healthy and sustainable weight loss.
Speaker Change: Enabled by our best in class <unk> RNA technology. We believe this molecule has the potential to unlock the next frontier in obesity treatment and address the $1 million impacted by the disease.
Speaker Change: <unk> have become current standard of care for weight loss, there impacted limited by frequent dosing loss of muscle mass for Tolerability and high discontinuation rates.
Speaker Change: And research day Green shared preclinical data supporting <unk> potential to address these unmet needs across three treatment settings.
Speaker Change: First as a monotherapy, where a single dose delivered weight loss similar to semi blu-tack. These.
Speaker Change: These data showed no loss of muscle mass and a reduction in fat mass favoring visceral fat raw without suppressing food intake.
Second as an add on to <unk> for further improvement of weight loss or to reduce the doses of <unk>.
Speaker Change: In <unk>, we saw a synergistic effect with <unk>, one due to <unk> unique mechanism of action when administered as an add on with <unk>, a single dose of waived inhibiting <unk> double the weight loss observed with <unk> side alone.
Speaker Change: And thirdly, as a maintenance therapy following cessation of <unk> to prevent rebound weight gain weight cycling is known to lead to the return of meta metabolic comorbidities in Dio mice, we showed that inhibiting <unk> SA RNA treatment prevented any significant weight rebound after stopping daily some of Woodside.
Speaker Change: We remain on track to file a cta for <unk> by the end of this year and initiate a clinical trial in the first quarter of next year.
Speaker Change: Turning to DMD in the third quarter, we delivered interim results from our 453 trial of WB and 531 boys with DMD amenable to exon 53 skipping.
Speaker Change: Supporting and 531 as a potential best in class treatment approach.
Speaker Change: Recall this is a devastating disease and there is an urgent need to deliver safe and more effective therapeutic options to patients. We hear frequently from caregivers about the burden of weekly IV dosing and the need for therapies that can distribute to the heart and diaphragm and reached stem cells, which would enhance functional benefit and ultimately extend survival.
In September we shared 24 week dystrophin data from our 453 trial, which included highly consistent mean muscle content adjusted dystrophin of 9% evidence of improved muscle health muscle concentrations that enabled monthly dosing intervals in a safe and well tolerated profile.
Speaker Change: In light of the recent PMO discontinuation the benefit risk profile for our approach, which relies on novel chemistry to improve tissue and cellular uptake instead of conjugate is even more compelling.
Speaker Change: With upcoming 48 week dystrophin data from forward 53 expected in the first quarter of 2025, we look to build on our interim results as we aim to deliver a much needed therapeutic option for the up to 10% of patients who are amenable to exon 53 skipping.
Speaker Change: Pending positive data and regulatory feedback with <unk> 531, we intend to advance a potentially best in class DMD pipeline of oligonucleotides for up to 40% of boys with DMD.
Finally, turning to <unk> 003, our first in class allele selective oligonucleotide for the treatment of HD.
Speaker Change: In June we shared results of our select HD study that demonstrated potent mutant Huntington silencing of close to 50% and preservation of wild type HGT.
Speaker Change: As a reminder, this unique ability to precisely silence only amusing HGT is enabled by our novel platform and opens up the possibility to treat pre symptomatic patients with HD. In addition to those with symptoms.
Speaker Change: <unk> is a devastating disease affecting more than 200000 patients across all stages of the disease in the U S. In Europe and patients are faced with extremely limited treatment options with no disease modifying therapies currently available.
Speaker Change: With our compelling clinical results, we continue to receive substantial engagement on HD, including from potential strategic partners.
Speaker Change: Additionally, following supportive initial feedback from FDA. We believe there is potential for an accelerated approval path forward for <unk> III using caudate atrophy, and we expect to submit an IND application in the second half of 2025.
Speaker Change: Now I'll turn the call over to <unk> to discuss this update further as well as share some more details on the progress of our clinical trials.
Speaker Change: Thank you Paul.
Speaker Change: I'll continue with wages. There is there are three and more detail on our path ahead.
Speaker Change: A reminder, we shared results from our select H D trial at the end of gene in this study we tested that two milligram dose and typically every eight weeks and we saw excellent translation of our preclinical modeling with potent and durable mutant Huntington reductions of up to 46% plus preservation of wild type Huntington.
Speaker Change: Multi dosing was generally safe and well tolerated for the first time in the H D filled we observed the statistically significant correlation between mutant Huntington reductions and slowing of cordite atrophy and known imaging biomarker that is predictive of clinical outcomes.
Speaker Change: It's notable that this was in the setting of potent allele selective silencing.
Speaker Change: Good day is one of the primary areas, where H D manifest in the brain.
Points of symptom onset and clinical diagnosis HD patients already have a market Brian atrophy, typically haven't lost more than 40% of that court date volume.
Speaker Change: Since last quarter against many years before symptom onset and continues to be laughed at a rate of about 2% to 4% a year. There are clear correlations between cordite loss and clinical outcomes, giving it potential to be an endpoint reasonably likely to predict clinical outcome and support accelerated approval.
Speaker Change: The community and key opinion leaders and hasty filled recognize the urgency for disease modifying therapies in Huntington's disease and are rallying behind ways to enable more efficient trial designs, including the use of biomarkers for accelerated approval.
Speaker Change: Just last month, we were pleased to have Dr. Jeffrey long discussed his what Oncotype volume at our annual research day.
During his presentation Doctor long shed data supporting the correlation between slower rates of quota atrophy predicting significant delays and the loss of function for people living with H D. Smith.
Speaker Change: This predictive relationship between <unk> and clinical outcomes may enable smaller more efficient clinical trials.
Speaker Change: Opens the possibility of early intervention to prevent or delay symptom onset.
Speaker Change: In tons and without two loans walk.
Speaker Change: Work is also being conducted with CACI exco and with the CPAP HD risk consortium that would enable more efficient trial designs.
Speaker Change: Our initial feedback from FDA has been supported the agencies open to a plan for further investigation of Biomarkers, including quota atrophy as an endpoint to evaluate H D. Two question with the potential to predict clinical outcomes.
Speaker Change: The agency recognizes the severity of H D and have indicated they are receptive to and engage with us on a potential pathway for accelerated approval.
Speaker Change: Fda's engagement on this matter is very welcome news for the H D community, who have long advocated for approaches emulating the successful accelerated development of therapies for other life threatening I'm serious nearer degenerative diseases such as ILS.
Speaker Change: With positive data in support of initial feedback from FDA.
Speaker Change: <unk> is now on the Finalization of key aspects of the design and planning for global potentially Registrational phase III <unk> III study, including the submission of an IND application in the second half of 2025.
Speaker Change: Turning to DMD.
Speaker Change: September we announced positive interim data from the ongoing phase III $4 53 study of <unk>, three one which is an exon skipping oligonucleotides being investigated and 11 boys with DMD, who are amenable to exon 53 skipping.
Speaker Change: The interim analysis was conducted after 24 weeks of 10 milligram per kilogram dosing every two weeks.
Speaker Change: We are pleased to observe that way than 531 was safe and well tolerated treatment related adverse events were mild in intensity and there were no serious adverse events or study discontinuation.
There were also no oligonucleotide costs relate to safety events.
Speaker Change: As a reminder, <unk> does not leverage muscle delivery conjugates.
Speaker Change: Such patients are not at risk for conjugate related events such as Hypomagnesaemia.
Speaker Change: Additionally, we observe mean muscle content adjusted dystrophin expression of 9% as measured by Western blot.
Speaker Change: Importantly, dystrophin expression was also highly consistent with 89% of ambulant boys, having levels exceeding 5% of normal.
Speaker Change: The dystrophin expression was quantified from to watch at homes consistent with those observed in Becker muscular dystrophy patients, who despite milder disease.
Speaker Change: We also observe mean exon skipping a 57% mean muscle concentrations of 41000 nanograms per gram.
Speaker Change: <unk> warehouse and phase III, one in my sight, Upi and remarkably in myogenic stem cells.
Speaker Change: <unk> remains the only DMD therapies take that has been changed to distribute to myogenic stem cells, which are the progenitor cells. When you my boss that give rise to new mine sites and ultimately a skeletal muscle regeneration.
Speaker Change: <unk> ahead, we expect to deliver data from the final time point of the study after 48 weeks of treatment in the first quarter of 2025.
Speaker Change: These data will include additional safety dystrophin quantification as well as analysis of functional assessments through a year of treatment.
Speaker Change: Also expect feedback from the FDA on the pathway for accelerated approval in the first quarter of 2025.
Speaker Change: I would like to continue to express our deepest gratitude to the boys families and study staff who are participating in this study.
Speaker Change: Turning to wave there was ever a six in October we announced positive proof of mechanism data from the ongoing phase <unk> restoration two study in patients with <unk>, who have the homozygous <unk> mutation as.
Speaker Change: As you May recall, our restoration clinical program consists of two parts.
Speaker Change: Restoration, one in healthy volunteers and restoration too and homozygous easy patients.
Speaker Change: A proof of mechanism results, meaning confirmation of editing included data from the first two patients in cohort one of registration to two each day 57, following that single dose as well as top line safety data observed across the restoration, one and two studies.
Speaker Change: We disclosed that we had seen a safe and tolerable profile for wave servicing mistakes all adverse events were mild to moderate with no serious adverse events and no discontinuation there were no imbalances between treatment and placebo groups, we were especially encouraged by the safety profile. We've seen in restoration, one as we've escalated to multi dosing and the final co.
Speaker Change: <unk> of healthy volunteers at dose levels greater than those time for any co hosted the patient study.
Speaker Change: I'm on the first two patients to reach day 50, Stefan in cohort one circulating wall type MAA protein reached a mean of $6 nine month Cremona at day 15, representing more than 60% of total AAP.
Speaker Change: Remember these easy patients did not make any healthy protein so seeing rapid and durable MAA levels was remarkable.
Speaker Change: Additionally, our goal is to induce at least 50% editing to convert patients from the homozygous easy to the heterozygous MZ phenotype. So the fact that we are already at 60% is very encouraging.
Speaker Change: Main total <unk> increased to $10 eight might Cremona at the two week time point in the first dose level meeting the level that has been the basis of regulatory approval for <unk>.
Speaker Change: Mentation therapies. Additionally increases in total <unk> from baseline and MAA T levels were observed Italia say, three and three day 57, meaning almost two months post single dose.
Speaker Change: Early data suggest potential for monthly or longer dosing.
Speaker Change: Actually based on our preclinical data and clinical data with Pan chemistry, we expect even more protein to be restored with multi dosing.
The restoration to trial is ongoing and we expect to share multi dose data from the study in 2025 with that I'd like to turn the call over to our CFO calm around to provide an update on our financials call.
Calm Around: Thanks, Anne Marie our revenue for the third quarter of 2024 decrease from the prior year quarter.
Calm Around: As a reminder, the prior year revenue was higher due to one time events in our Takeda collaboration including the recognition of the remaining deferred revenue related to the terminated <unk> program as well as revenue related to the development milestone achieved for the HD program.
Calm Around: In addition to these one time events the year over year decrease included a noncash reductions are cumulative revenue under our GSK collaboration to reflect an adjustment to the amortization of the upfront payment in accordance with revenue recognition standards.
Calm Around: Research and development expenses were $41 2 million for the third quarter of 2024.
Compared to $31 6 million in the prior year quarter.
Calm Around: This increase was primarily driven by spending for our <unk> inhibitor program, along with our <unk> HD in DMD programs.
Calm Around: Our G&A expenses were $15 million for the third quarter of 2024 as compared to $13 $1 million in the prior year quarter.
Calm Around: As a result, our net loss was $61 $8 billion for the third quarter as compared to net income of $7 3 million for the prior year quarter.
Calm Around: We ended the third quarter with $310 $9 million in cash and cash equivalents.
Calm Around: Which includes approximately $187 $5 million of proceeds from our Upsized offering in September.
On October one the green shoe option from the offering was fully exercised and we received an additional $28 $2 million.
Calm Around: We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027.
Calm Around: It is important to note the potential future milestone and other payments to waive under our GSK collaboration and not included in our cash runway.
Speaker Change: That I will turn the call back over to Paul for closing remarks.
Paul Bono: Thank you Kyle it's been an incredible year for wave and as we just shared with you. We expect our positive momentum to continue through the achievement of multiple near term milestones across the portfolio.
Paul Bono: I would like to thank all of our colleagues who are working persistently to unlock the broad potential of RNA medicines. Additionally, I would like to express our deepest gratitude to the patients and families participating in our studies and all who inspire us of ways and with that I'll turn the call over to the operator for Q&A operator.
Speaker Change: We will now open the call to Q&A, ladies and gentlemen, if you have a question or comment at this time. Please press star one on your telephone. If your question has been answered you were seeing with yourself from the queue. Please press star wouldn't want again, we will pause for a moment, while we compile the Q&A roster.
Okay.
Speaker Change: Our first question comes from Steve <unk> of Raymond James Your line is open.
Speaker Change: Good morning. Thank you congrats on all the recent progress.
Speaker Change: Firstly on the <unk> program can you just review any key efficacy assessments that youre evaluating both lung and liver and the multi dose cohorts.
Speaker Change: And I think that you would plan specifically on sharing with the next update and then second on that program.
Speaker Change: Do you anticipate being able to assess circulating levels of the protein around times of infection or illness or vaccination just to assess.
Phase response of the protein.
Speaker Change: I will address the second question then Murray do you want to address the first but in terms of as youre, bringing up challenges.
Murray: There is no planned approach to study that is part of a global study obviously you follow what happens in patients experiencing so there is an opportunity over a longer period of time, if theres events like patients experience respiratory viruses or other to correlate those clinical signs and symptoms back to circulating levels, but it's not a <unk>.
Speaker Change: Land prospective I guess as you're referring to it's a challenge protocol MMA do you want to take the first question around that the endpoints, yes restoration to it's a study that's focused on safety Tolerability pharmacodynamics and pharmacokinetics. So its not focused on efficacy outcomes in the long run labor and recall this is.
Speaker Change: J F. K program then they have plans of course to do studies that would explore that.
Speaker Change: Okay. So the I mean, the patients were assessed for things like fiber scan I think a baseline rate to two.
Speaker Change: Enrolled him just to meet eligibility, but I guess youre not assessing.
Speaker Change: Something like fiber scan.
Nora Sri: Nora Sri endpoints in the study such as that but this is a study that's really focused on safety Tolerability PK and PD.
Speaker Change: Okay, so to that point.
Nora Sri: They are being captured as <unk>.
Nora Sri: <unk> for the <unk>.
<unk> points out the primary endpoint of the study which is safety biomarkers.
Nora Sri: Understood.
And Huntington then just last question for me.
You mentioned.
The interest you're receiving from strategic partners I think theres, a lot of interest and just sort of how that.
Speaker Change: Would play out so could you comment on I guess with just the anticipated total cost of the phase three program that you.
Speaker Change: Our conceptualizing right now and just what partnerships ship structures in terms of costs and economics are you open to or looking for with that program. Okay.
Speaker Change: Yes, no great question and as Andrew alluded to we're in the planning phases of that design in the study and obviously that has an impact of costs. So as we established final patient numbers I think.
Speaker Change: Of interest there is usually two things that are required in order to.
To get a transaction done and one is owning the asset and so we own the asset which is a good first step and then secondly, a clinical regulatory path and I think with today's update and having that I think those are two both very positive features in terms of driving our strategic partnerships I think as we are engaged in these discussions I think there is.
Speaker Change: Different frameworks than we had let's say years ago. When we established the Takeda partnership where the opportunity was looking down at 800 patient multi year generation HD like study, where there was a more desire to have somebody really step in the totality of the expenses I think as we do this and do this analysis and continue on.
Speaker Change: Engagement with strategic collaborators I think it does open up more opportunities to think about geographies in terms of other ways of partnering as well as financial partnerships.
Speaker Change: Debt decreased the cost for us to accelerate the asset, but I think what's ultimately encouraging as it starts with having a clear clinical development pathway and I think as we shared at research day I think caught it atrophy is becoming a really compelling biomarker going forward. So we will keep people updated but obviously the most important thing is advancing the program.
Speaker Change: Okay.
Speaker Change: Thanks, so much.
Speaker Change: One moment for our next question.
Speaker Change: Yeah.
Speaker Change: Okay.
Speaker Change: Our next question comes from Joon Lee with <unk> Securities. Your line is open.
Speaker Change: Hey, congrats on the progress and thanks for taking our questions.
Looking down the road for me, how can you envision a registration trial to differentiate from any of the knee.
Speaker Change: <unk> <unk> from <unk> from a labeling perspective, specifically at obesity week literally shared post hoc analysis of surmount, one which showed about a 11% lean body mass loss.
Speaker Change: How concerning is that from an ABL standpoint, and is that something the FDA may be noticing as a potential safety concerns. Thank you.
Speaker Change: Yeah. Thank you Jim for the question I think as we think about that last piece I'll, let lily answer the questions related to the <unk> regulatory discussions, but I think as we think forward about the profile that emerged for our inhibitor program as we shared preclinical across three different model types.
Speaker Change: What we see is remarkably consistent.
Speaker Change: There is weight loss, that's similar to <unk> and I think what's important there is really thinking about what do we mean by weight loss and we really mean fat loss. So we're seeing substantial reductions in visceral fat that are correlating to that reduction in weight and so I think to your point.
Speaker Change: I think as we think about the study and as we've shared one key component besides measuring abdominal current besides measuring body weight through Dexter and others looking at seeing what we saw pre clinically translate hopefully to humans, which is that consistent retention of muscle mass. If you remember that slide we shared at research day, we actually saw an increase in <unk>.
Speaker Change: In that study and about 5% so the idea of being able to see healthy sustainable weight loss driven off the bat.
Speaker Change: Really does open up the opportunity to think about a label build as we move forward in the first step of that is the clinical trial, which is on track to start in the first quarter of next year.
Speaker Change: Great looking forward. Thank you.
Speaker Change: One moment for our next question.
Speaker Change: Our next question comes from Eric Joseph with Jpmorgan. Your line is open.
Speaker Change: Hi, guys. This is a run on for this morning can you guys elaborate a little bit about when you guys. I mean, when you say revenue supportive.
Speaker Change: Have they requested additional data are they looking at other surrogate biomarkers.
Speaker Change: And then can you maybe say a bit.
Speaker Change: The NDA submission is so far out in the second half of 'twenty five.
Speaker Change: Yes, let <unk> start with the question and then ill follow up Emory join start with the first question sure.
Speaker Change: Would be two potential outcomes from an interaction with FDA, one where they say they don't agree and another where they indicate that opening engaged to develop new biomarkers and I think what's great is the that is what we have from FDA. They really recognize the seriousness of this disease and the support is something that needs to be accelerated approval pathways for H D.
And they are open to us to collecting biomarker such as Colgate.
To measure H D progression and potentially predictive of clinical outcome.
Speaker Change: That leaves us in a great spot I mean, as I mentioned earlier in select HD, we saw a correlation between the mutant Huntington knockdown I'm slowing of Cuda atrophy and as Jeff loan presented in our research day just recently.
Speaker Change: Extensive natural history data that establishes this relationship between slowing of quota atrophy and predicting significant delays in the west, meaning a function and because Colgate is the stage of the disease changes early and reliably.
Speaker Change: Laos us to drive these smaller and more efficient studies have really taken together, we're in a really great position to advance the program and the <unk>.
<unk> is now underway for the potentially global Registrational phase III <unk> III study.
Speaker Change: And finalization of the key.
Speaker Change: Study design aspects now of course, we will be working to advance that.
Speaker Change: Appropriate stage and that includes finding the IMD won't be more specific about when but next year is when you'll get some updates from us on this program.
Speaker Change: I think just to follow up on your that your question and timing to Emory point Theres planning timing, but also because it is a potentially registrational study would also mean CMC and manufacturing work to support that not just into the clinical trial, but also to make sure that their support on the outcome on the other side of the trial that the impacted CMT.
Speaker Change: <unk> would be able to support that central registration on the other side. So I think that's why guidance is into the second half to assure everything planned and done to meet that timeline I think <unk>. Other point I mean, we are really at this convergence where over the course of this year in particular the work that's been done by external researchers on court that's now.
Speaker Change: <unk> published is providing that information.
Speaker Change: The FDA had been looking for looking for correlations between caudate atrophy and clinical outcome measurements and so I think the work that's being done by <unk> by Jeff long and others continues to provide those information that are that are supportive I think your other question on biomarkers.
Speaker Change: Beyond that I do think we will continue to explore mutant protein reduction in specificity. There was a lot of interest on those two biomarkers affirming that we were seeing Huntington reduction using Huntington reduction in the absence of wildfire and I think thats, an important correlation and lastly, and interestingly enough. There was no discussion around NFL it.
Speaker Change: So I think it's encouraging and we will continue to stay engaged with the agency as the program progresses.
Speaker Change: But yes. Thank you for the question.
Speaker Change: Thank you I guess.
Speaker Change: Just on PMT.
Speaker Change: What stage are the other DMD candidates for the other exons and.
Speaker Change: Or do you think about timing for it is there.
Speaker Change: Yes, I think the steps for DMD as we as we've shared before are that we do have the pn exon skippers.
Speaker Change: Synthesize and tested and we've seen dystrophin levels.
Speaker Change: As high or higher than what we saw with Empire 31, So again encouraging around the other Exxon I think our feedback is really to provide additional guidance pending regulatory feedback and the 48 week data from <unk> 31 in the first quarter, so more to come on the DMD programs.
Speaker Change: Thank you so much.
Speaker Change: Thank you.
Speaker Change: Question.
Speaker Change: Yeah.
Speaker Change: Our next question comes from Selim said with Mizuho. Your line is open.
Speaker Change: Hey, guys. Thanks for the color today.
Speaker Change: Last one for me just on the Huntington's piece here.
Speaker Change: So I guess as Youre thinking about trying to design the phase two three study it sounds like you don't have full.
Speaker Change: Agreement from the FDA that.
Speaker Change: Caught it attributes can be used as an endpoint.
Speaker Change: For full potential.
Speaker Change: Approval.
Speaker Change: Do you get the sense that.
Speaker Change: The FDA doesn't even want to approach this topic of like getting to a full agreement.
Speaker Change: On using it prior to the design or is there a scenario here, where they come to that agreement prior to you actually finalizing the details here.
Speaker Change: And then just sort of related to the design as well.
Speaker Change: Or are you sort of factoring in the pre symptomatic.
Speaker Change: The population is that something that you would add on at a later point or do.
Speaker Change: Do you think thats going to be part of the initial.
Speaker Change: Design. Thank you.
Yes, I think just to go back to Emory outline I mean, I do think there were two scenarios and one is kind of I think where youre alluding to and that's not the scenario, where the FDA disagrees with the use of the biomarker.
Speaker Change: Our clinical service, so I think we find ourselves in the position.
Speaker Change: As much as you can expect when you bring an entirely new biomarker forward is that they are open to that biomarker in the totality of data right. So we've got to generate the data. We've got the plan. The plan is focused on chordate atrophy as being that driver along with other clinical Biomarkers as we said and we'll stay engaged with the agency.
As that progresses. So I do think there was a scenario as we painted at the beginning for the quarter fourth quarter feedback, which would be that the FDA is not aligned around that as a use of chordate atrophy for this study. So I think we're not in that position. So that's highly encouraging as again, we bring an entirely new clinical biomarker forward.
Speaker Change: For the potential accelerated approval.
Speaker Change: I think if we think about the patients as youre talking about for the stage I think the staging system and I think Thats also.
Speaker Change: Really important as we think about caught it as clinical surrogate endpoint a lot of the staging system for HD has now shifted so that incorporates for encompasses caught it which is as we think about the stage one patients.
Speaker Change: These patients have changes in cotton atrophy on imaging, but arent, yet symptomatic and so the ability to build those clinical patients and earlier, where you can leverage those clinical biomarkers are important I don't know if you want to comment on the stage of patients that we would be exploring in the study.
Speaker Change: Yes.
Speaker Change: Timing to exclude patients at the earliest stages of new staging system that has been more recently set forth by the experts in the area based on the extensive natural history data and these early stages with the today's quote I is already changing before the first clinical.
Speaker Change: Symptoms appear.
Speaker Change: So it would be certainly our intention to study eylea phases patients earlier in the disease course, where you really have an opportunity to intervene and because of the selective allele selective approach we have.
Speaker Change: Adequate benefit risk to do that kind of experiment so yes.
Speaker Change: That would be our intention.
Speaker Change: Okay.
Speaker Change: Just a follow up.
Speaker Change: So we don't have like full certainty that cutting atrophy can be used for et cetera.
Speaker Change: I presume here at the base case thinking here.
Speaker Change: We'll need to have an extended trial here or at least potential to two points of where you could file on the accelerated one where you would actually have to run it all the way to get total.
Speaker Change: To us that's functional capacity.
Speaker Change: The right way to think about it.
I think yes <unk>, yes.
Speaker Change: That is the right way to think about it so the way that these kinds of interactions with FDA is not going to give you full agreement without the actual data in hand.
What they've given us is really I think encouraging feedback on that commitments for accelerated approval. They are understanding of the seriousness of the disease and that support for us collecting quarter atrophy as a biomarker has the potential to predict clinical outcome.
Speaker Change: I think this is really the best outcome, we could hope for at this stage, we're really encouraged by it and with the huge opportunity that H D.
Speaker Change: And the fact that we can do the small and efficient study to show the slowing of quota atrophy, which predicts the slowing of clinical outcomes were really in a great shape not study once completed would form the basis of the accelerated approval and then I'd say no cases with accelerated approval, we would need an ongoing.
Speaker Change: <unk> study, which would read out later and which support the concessions here for the appraisal. So this one study that we're proposing is the study that would.
Speaker Change: Two registration and we consider that still.
Speaker Change: Very much something that is achievable to support the first HD appraisal to slow disease progression.
Speaker Change: Okay got it thank you so much.
Speaker Change: One moment for our next question.
Speaker Change: Yeah.
Speaker Change: Okay.
Speaker Change: Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open.
Speaker Change: Hey, guys. This is Jamie on for Joe.
Speaker Change: A few questions about RNA editing, we're trying to put the data that you've reported so far the context with the design.
Speaker Change: A restoration to whereas he might go with multiple doses.
Speaker Change: Reported that 80 protein and protein with 60% of the total is it fair to say that mrna editing is numerically lower than that and there's potential for it to increase and what it also be fair to say that you're still near the bottom of adult care. Since that was the first Joe I think you said that registration to Hao.
Speaker Change: 200 milligram single dose.
To like seven multiple doses is that correct and could you give me some context into how much higher you might be able to dose okay. Thank you.
Speaker Change: Yes, no. Thank you for the questions.
Speaker Change: Getting to the first one on the editing efficiency Youre right with the low end of the dose curve meeting the lowest and single dose at the lowest dose.
Speaker Change: You see 60% of the protein being M protein.
Speaker Change: That's.
Speaker Change: A surrogate for looking at what's happening at the cellular level right. So we're already achieving nearly what would be 60% edited protein in circulation.
Speaker Change: The opportunity we have with continued repeat dosing based on what we've seen in the preclinical models and what we've seen clinically with other pn oligonucleotides is exactly that as you give repeat doses. This is still at the same low dose level. We would continue to expect to see that increase right that was more.
Poser you could say.
Speaker Change: It's more protein you could capture more pilot sites and you can also rescue more either side, so where we saw again pre clinically we would expect it's reasonably see translate in humans with the repeat dosing.
The next part of your question, we also see which is the opportunity to extend dosing so by going up higher and as Emory shared we're already dosing through the healthy volunteer study well beyond that which is in the restoration two patient studies. So we have ample opportunity to continue to explore dose increases if you remember the 200 milligram.
Speaker Change: Starting dose is the dose lower than in <unk>.
Speaker Change: And in a world. So we've got the ability to go higher I think we will explore another dose cohort that will give us a sense of a dose response between those two but the other opportunity I think we have which is exciting for alpha one antitrypsin again being a substitute gallon that therapy with this level of efficiency.
Speaker Change: And the ability to push out the dosing intervals. So not just thinking about where do you see the amplitude increase and get that peak editing, but also being able to see the fact that we think we can get a lot less frequently so.
Speaker Change: Starting with the first cohort we've always said that first cohort is going to give us a lot of information handset multi dose is going to give us a sense of potency and activity and we will be able to do extended follow up to get the durability and then make the adjustments and the subsequent cohorts around not just dose dosing intervals.
And I guess, one more follow up on that.
Speaker Change: Yes.
Speaker Change: As we're playing away around with.
Dosing do you think you can go higher than in Q3, and I think that's like 280 milligrams I'm just just for context.
Speaker Change: Absolutely I mean as I was just referring to we're starting at 200 and we have ample.
Speaker Change: Ample headroom well above that across three cohorts and as you saw the multiple cohorts with which we've been dosing on the healthy volunteer side. So we have ample room to expand.
Speaker Change: Expand dose beyond where we're starting.
So short answer is yes, we can go higher than <unk>.
Speaker Change: Thank you.
Speaker Change: One moment for our next question.
Speaker Change: Yeah.
Speaker Change: Our next question comes from Lucas Lee with RBC Capital. Your line is open.
Speaker Change: Oh, great. Thanks, so much for taking my question Congrats on all the progress.
Speaker Change: Two quick one one circling back on Huntington. This would be 100% clear here are you considering running a pivotal trial solo or is finding a partner gating the start that pivotal.
Speaker Change: Let me call there much appreciate it and then on Alpha one you mentioned that the IV is suboptimal. So Q3 I'll agree with in terms of convenience for the patients, but how youre thinking about editing efficiency looks like at least pre clinically maybe ivy can drive higher Ids efficiency for sub Q. So wondering how you're thinking about that trade off.
Thanks, so much.
Speaker Change: Yes, I'll take the second and then we'll definitely come back to the first but as it relates to editing efficiency I think we've seen high degrees of editing efficiencies in our preclinical models I think sometimes there isn't.
Speaker Change: I don't know apples to pears comparison around the editing efficiencies based on some of the preclinical models that are really important which is if you think about the editing efficiencies in transgenic wave of data is probably the most translatable, meaning that when you have a gallon next sub acute conjugate in the preclinical models the trans gene within these models express.
Speaker Change: The protein across both the hepatocytes and the other cells in the liver. So if you're using an LNP intravenously in a preclinical model you can have a different amount of editing efficiency or presumed editing efficiency in those models that may artificially amplify that response that wouldn't translate to humans.
Speaker Change: Contrary as if you have a and maybe it's why we saw a surprising more in the early part of our study, but if you're using a gallon a conjugate. The preclinical models you would underrepresent, what youre thinking about seeing because you'd only be getting to a subset of those cells in the liver to be able to drive your editing efficiency. So ultimately I think the most important thing.
Speaker Change: To look at M protein across the field in the clinic and Thats, the best way to assess percentages of editing efficiency in a clinically relevant way, but I think the data both pre clinically and now clinically really demonstrate that sub two gallon that going down that getting to the target tissue of interest and our high degree of editing efficiency that we've seen in our preclinical.
And clinically I think will be consistent and again, that's at the lowest dose and single. So I think we've got a lot more to go from here to really think about what the maximum potential is for alpha one antitrypsin.
Speaker Change: As it relates to your question on partnering I think it's one we spend a lot of time, reflecting on.
In the announcement with Takeda not opting in we've received as we said on prior calls inbound interest in that program.
Speaker Change: I think where we're at when compensation has always pick up is around clarity on our clinical development path. So I think we are engaged in those discussions as we said both on the program, but in a way that's going to optimize the program and optimize it for wave in waves shareholders. So we do think about that but the most important pieces.
Speaker Change: Regulatory clarity and direction to have a program that's going to be high impact for patients, who don't have other opportunities and to assure that the program moves forward and so we'll continue those discussions as we continued to advance the program.
Speaker Change: Got it thanks, so much one moment for our next question.
Speaker Change: Okay.
Speaker Change: Our next question comes from Catherine Novack with Jones trading your line is open.
Speaker Change: Hi, good.
Morning, guys I just wanted to touch on the DMD program for a minute you mentioned that youre going to discuss accelerated approval with the FDA.
Speaker Change: Yes.
Speaker Change: Any unknowns regarding the accelerated approval pathway with regard to.
Speaker Change: Exxon therapies and exon skipping therapies in dystrophin and then how can we think about how much weight. We can give functional outcomes at 48 weeks with some of the DMD drugs failing confirmatory studies do you get a sense of after you start to look more at clinical outcomes or is accelerated approval still primarily just looking at skeletal muscle dystrophy.
Speaker Change: Thanks.
Speaker Change: No absolutely and again, thank you for the questions as we think about DMD, which is different than that we have regulatory approval based on existing paradigm based on a clinical surrogate biomarker of which is dystrophin.
Speaker Change: There is no reason to believe that changes even in the recent feedback we've heard from peer companies in this space that are discontinued programs. They werent driven on an FCA interaction on dystrophin, but rather safety. So I think as we think about the opportunity that was there prior.
Speaker Change: <unk> continues to exist as a safe.
Speaker Change: Production of Dystrophin still has a path forward I think what we added to that and as we've said before when we shared this data earlier this quarter.
Speaker Change: What was important to us beyond the mean dystrophin number and Thats really been the focus I think of the field. This presentation of mean dystrophin is really thinking about the consistent expression of dystrophin and I think if we think about all of this being predicated off of Becker Theres broad distribution and a becker patients and so I think the notion that we need to see levels of.
Speaker Change: Becker consistently across the patients is going to be better predictive of running confirmatory studies that are.
Speaker Change: That's predicted to have clinical outcome measurements. So I think there is no change to the regulatory paradigm I think what will be important to us as we assess these data is it'll be the first opportunity now with a year of dosing. So really look at the strike, 95% strive velocity other measurements to start seeing corroborating data that's associated with district, and I think all of that would be important.
Speaker Change: In decision, making going forward not from a regulatory context, I think regulatory context remains that dystrophin as a clinical surrogate endpoint and we would design the study as such.
Speaker Change: Okay, Great. That's helpful. And then just one last one on the H D. Partnership you kind of mentioned that you think regulatory alignment as needed but is there a chance that future partners would want to be involved in regulatory discussions given the importance of getting a novel surrogate endpoint approved.
Speaker Change: Yes, I mean, I think as we said there's going to be ample opportunities throughout the trial and then importantly on the other side of this study with data for regulatory interactions I think that clarity is as Anne Marie pointed out if there was no alignment on openness to move.
Speaker Change: Move forward and that the only clinical trial to advance would be a clinical outcome study. One that's really designed to do that where you can pull as biomarkers for it but the design of the study would be much like other studies that had been run in the past that were really powered and run in large numbers to see a clinical benefit I think that would have been a different decision tree for.
Speaker Change: Wave and partners. So I think the clarity that we could run smaller focused studies similar to what Jeff long shared at the meeting similar to Emory has been sharing we're now powering for kratos changes in up to two years, you're talking about 100, Jamba sharing 130 to 150 patients that looks like a very different design and thats important to have that.
Clarity and trial design as we are engaged in these discussions because it does impact how we think about the cost of those studies in time for those studies and Brett. So I think with that now on the other side of this planning I think makes these conversations a lot smoother.
Speaker Change: Got it that's helpful. Thanks, guys.
Speaker Change: One moment for our next question.
Speaker Change: Yeah.
Speaker Change: Our last question comes from Madison, El Saudi with B Riley Your line is open.
Speaker Change: Hey, guys. Congrats on the progress. Thank you for taking my question.
Are you able to talk to the schedule of GSK milestone payments as part of the Orange edit collaboration.
Including what's related to the initial human proof of concept data.
Speaker Change: And then wondering of different forms.
The cadence of how you may look to reveal mad data through 2025.
Speaker Change: Then secondly.
Speaker Change: Regarding the FDA Huntington discussion.
Speaker Change: Local collecting biomarker data so could you clarify.
Speaker Change: Would that be from the current select.
Speaker Change: Patients at a longer.
Follow up past a point when one would expect to see functional separation.
Speaker Change: Thanks.
Speaker Change: Thank you. So first question, we cant disclose the GSK milestone breakdown.
Speaker Change: But as we said.
Have milestones in 2024, and we expect to continue with milestones with GSK as we look to 2025 and beyond.
Speaker Change: For the <unk> study clarity in 2025, we have said and we typically proof of mechanism for ACD as we've always said, whether the anomaly was structured to look at engagement predicated off of protein.
Speaker Change: What's important on the MA as I think we go back to how we would usually share data, which is the totality of data from a cohort. So you get multiple patients multiple doses multiple time points are much more comprehensive data set as we would usually sharing data announcement and then Doug.
Speaker Change: Data are historically shared in our press release and our call. So we'd be able to provide an update on that I think your last question in terms of the HD biomarkers those are going to be part of that discussion with the agency was predicated on this study that could be potentially registrational and not on select HD. So is emery said on the call.
Speaker Change: I'll collect HD.
Speaker Change: While we had this regulatory interaction so we're not collecting further biomarkers from that study.
Speaker Change: For this decision I don't know Maria if you wanted to add anything to that last point, Yeah. I would just add the study. We're planning is going to be powered to show a statistically significant slowing of quota atrophy not powered to show.
Speaker Change: Clinical outcomes I play that will show up in since your point, it's really a study of quota atrophy and other biomarkers that would enable an accelerated approval.
Speaker Change: Got it that's helpful and then if I could squeeze in one more.
Speaker Change: So it sounds like the regulatory clarity alignment certainly key to kind of bringing a strategic board just wondering if to the extent you can mention what is kind of the next topic.
Speaker Change: Regulatory comes up that you guys are focused on it and they're procuring a partner is necessary.
Speaker Change: Two initiating dosing and second half thanks.
Speaker Change: Yes, I think our plans right now are to focus on designing the study design moving forward in that study recognizing that before we get there. We've got a number of important inflections to deliver an inhibitor <unk> getting into the clinic and dosing in the first quarter at the multi dose data as we think about alpha one antitrypsin.
And then the 48 week DMD data so a lot of activity coming and then being able to continue that transition. So we have ample time as we discussed with strategic collaborators both financial strategic collaborators as well as <unk>.
Speaker Change: Strategic large corporate so we've got a lot of discussion happening prior to beginning to dose our first patient in a potentially registrational study in the first step is getting the regulatory submission and so I think we've got a lot of time to be able to do that in a lot of options on the table as we move towards that.
Speaker Change: Got it helpful. Thanks, guys.
Speaker Change: I'll now turn the call back over to Dr. Paul Baldwin for any remarks.
Speaker Change: Yeah.
Speaker Change: Thank you for joining our call. This morning, we are looking forward to seeing you at the upcoming investor conferences, and keeping you updated on our progress have a great day, ladies and gentlemen. This does conclude today's presentation. You may now disconnect and have a wonderful day.