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

Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review Wave's second quarter 2024 financial results. Joining me today with prepared remarks are Dr.

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

The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements.

These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings.

We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul..

Thanks, Kate. Good morning, and thank you all for joining us on today's call. We have made incredible progress throughout the first half of this year, both in demonstrating the continued translation of our unique novel platform in the clinic and advancing our high-impact RNA medicines pipeline across modalities.

A highlight of the second quarter was the positive results from the SELECT-HD clinical trial for WVE-003 for Huntington's disease. And I'll begin today with some remarks on this program and progress we've made since we announced them.

The clinical data, which we announced in June, serve as a testament to our best-in-class chemistry capabilities where our proprietary PN and stereochemistry enabled WVE-003 to achieve potent and durable mutant protein lowering while attaining exquisite specificity with wild-type preservation.

This also led to a statistically significant correlation between mutant Huntington lowering and slowing of caudate atrophy, a potential clinical endpoint for accelerated approval. HD is a devastating disease affecting more than 200,000 patients across all stages of disease in the U.S. and Europe.

HD is compared to having Alzheimer's disease, Parkinson's disease and ALS combined. Patients are faced with extremely limited treatment options, and there are no disease-modifying therapies currently available.

WVE-003 was designed to selectively knock down the mutant Huntington protein while preserving the healthy wild-type Huntington protein, which is critical to the health and function of neurons.

With the first ever clinical demonstration of allele-selective silencing in patients, 003 is uniquely positioned to address the larger presymptomatic patient population in addition to symptomatic HD patients. Since announcing our SELECT-HD results, we have submitted our opt-in package to our partner, Takeda.

If Takeda exercised its option right, our HD programs, including potential additional SNPs shift to a 50-50 R&D and profit split. Takeda pays an opt-in payment, and Wave is eligible for development and commercial milestone payments.

Our team has also initiated engagement with regulators on a clinical development path for 003 that could support accelerated approval. We look forward to providing an update on regulatory feedback as well as an update on Takeda's decision by the end of the year. Turning to DMD, our next expected clinical data update.

With WVE-N531, our exon-skipping candidate for patients amenable to exon 53 skipping, we are looking to achieve dystrophin expression greater than 5% with consistency across patients, which would provide a meaningful best-in-class new option.

As we look at the current treatment paradigm and therapies in development for DMD, there remains a significant scientific gap in the functional benefits of micro or mini dystrophin as well as durability.

And when paired with unknown safety risks associated with AAV gene therapies, there is an urgent need to deliver better therapeutic option to patients. As a reminder, in our Part A study of N531 following just 3 doses administered every other week, we achieved industry-leading exon skipping and unprecedented muscle concentrations.

Importantly, the tissue concentration levels are approximately 20x higher than the top levels reported by exon-skipping technologies leverage muscle delivery conjugate in DMD patients.

Despite low and inconsistent dystrophin data, exon-skipping therapeutics are standard of care for DMD and recorded approximately $1 billion in sales last year, primarily in the U.S. For therapeutics [indiscernible] approximately 29% of the population.

Positive data with N531 would unlock the totality of our exon-skipping programs which would enable us to address up to 40% of the population, representing an opportunity to provide differentiated therapeutic portfolio to patients.

Moving to RNA editing, WVE-006, our first in class GalNAc RNA editing candidate for AATD aims to correct the AATD causing mutation to increase circulating levels of wild-type or M-AAT protein and reduce mutant Z-AAT protein aggregation in the liver, thereby treating patients with lung manifestations, liver manifestations or both.

There are an estimated 200,000 homozygous Pi*ZZ patients in the U.S. and Europe. Treatment today is limited to weekly IV augmentation therapy for lung disease, while no therapies address AATD liver disease. SiRNA treatments in development are confined to treating only liver disease and could exacerbate lung injury.

By editing RNA, 006 differs from DNA-editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels.

006 contained a GalNAc conjugate, a highly specific and elegant delivery tool that is well validated with multiple approved silencing therapeutics on the market.

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

In preclinical studies, our proprietary chemistry has enabled 006 to effectively recruit endogenous ADAR enzymes and achieve potent and durable editing. We've shown AAT protein levels that exceed the threshold for both MZ and healthy MM populations and have confirmed this functionality with neutrophil elastase inhibition assay.

Additionally, 006 decreased lobular inflammation, reduced liver aggregates and prevented increases in mitosis indicating improved hepatocyte survival, in preclinical models. Dosing in our RestorAATion-2 trial initiated in third quarter and we expect to deliver proof of mechanism data in the fourth quarter of this year.

This data would not only meaningfully derisk 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 upregulate mRNA in both rare and prevalent diseases.

WVE-006 is part of our ongoing collaboration with GSK and development and commercialization responsibilities transferred to GSK at their sole cost after we complete our RestorAATion-2 study.

Under the collaboration, there are $525 million in total milestones related to 006 and Wave is eligible for double-digit tiered royalties as a percentage of net sales up to the high teens. I'll next give an update on our GalNAc siRNA inhibiting program, which is now called WVE-007.

Obesity is a public health epidemic impacting approximately 175 million adults in the U.S. and Europe. Increasingly, it is being recognized that reduction of weight and fat mass are linked to improved health outcomes, including reduced risk of many diseases. With 007, we are advancing a completely novel approach to weight loss.

Enabled by our best-in-class siRNA technology, we believe this molecule has the potential to unlock the next frontier to obesity treatment and address millions impacted by the disease. This program is supported by human genetics.

INHBE loss-of-function heterozygous carriers have a favorable cardiometabolic profile, including reduced abdominal obesity and reduced odds of type 2 diabetes and coronary artery disease. One can think of this target as the PCSK9 of obesity. INHBE mRNA is expressed in the liver with its corresponding receptor on adipocytes, which control fat storage.

We designed 007 to silence the INHBE gene transcript, thereby recapitulating the cardiometabolic protection of carriers of INHBE loss-of-function mutations. While GLP-1s have become the current standard of care for weight loss, their impact is often limited by frequent dosing, loss of muscle mass or tolerability and high discontinuation rates.

We see 3 key areas of opportunity to address obesity with 007 as a frontline monotherapy in combination with GLP-1s for further improvement of weight loss or to reduce the doses of GLP-1s or as a maintenance therapy following cessation of GLP-1s.

First, our INHBE siRNA, we have demonstrated highly potent and durable silencing with an ED50 of less than 1 milligram per kilogram, supporting dosing intervals of just once or twice a year.

Preclinically, our INHBE siRNA also led to weight loss similar to semaglutide and reduction in fat mass with a preferential effect on visceral fat, all with no loss of muscle mass. As a reminder, the mechanism of INHBE silencing is distinct from GLP-1s, opening an exciting opportunity for use in combination following weight loss induction.

New results from an ongoing study underscored the potential for this use. Specifically, when administered in combination with semaglutide, a single dose of our INHBE GalNAc siRNA doubled the weight loss observed with semaglutide alone and this effect was sustained throughout the duration of the study.

As we described previously, treatment with our INHBE siRNA upon cessation of semaglutide also curtailed expected rebound weight gain. We are very excited about the broad potential of this program in obesity and look forward to sharing more data at our Annual R&D Day.

Looking ahead, we believe we can demonstrate clinical proof of concepts with just a single dose of our INHBE siRNA in a study of healthy overweight volunteers. We remain on track to file a CTA for 007 as early as the end of year and initiate a clinical trial in the first quarter of next year.

We have a vast opportunity ahead of us to deliver differentiated therapies to millions of patients in areas of high unmet need. We are poised to deliver on multiple important catalysts in the second half of the year, which would unlock and derisk additional programs.

Additionally, at our annual R&D Day this fall, we expect to give an update on our emerging pipeline, including our wholly-owned RNA editing programs. Now to discuss our clinical programs in more detail, I'll turn the call over to Anne-Marie.

Anne-Marie?.

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

Our SELECT-HD clinical trial was designed to demonstrate safety and tolerability, PK and mutant Huntington silencing over 30%, with healthy wild-type Huntington preservation with multiple doses of WVE-003.

In this multi-dose cohort, where we tested 30 milligrams dosed intrathecally every 8 weeks, 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.

Multi-dosing was generally safe and well tolerated with mild-to-moderate adverse events and no serious adverse events. Further, this cohort showed a statistically significant correlation between mutant Huntington reductions and slowing of caudate atrophy, a known imaging biomarker that is predictive of clinical outcomes.

This was also the first ever demonstration of such a correlation in the clinic, reinforcing the potential benefit of allele-selective mutant Huntington lowering.

Since sharing this data, we have been connecting with KOLs and patient groups who are excited about the mutant Huntington knockdown and most of all, the first potential therapeutic option that preserves healthy wild-type Huntington.

We'll be sharing these previously announced results with a broader HD community at the Annual Meeting of the European Huntington's Disease Network, or EHDN, taking place on the 12th to 14th September in Strasbourg, France.

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

For accelerated approval, we know regulators are looking for biomarkers with biological relevance for the disease in question. Caudate is one of the primary areas where HD manifests in the brain.

At the point of clinical diagnosis, patients have a marked brain atrophy compared to controls, typically having lost more than 40% of their caudate at the time of first symptom onset and clinical diagnosis.

Since loss of caudate manifests many years before diagnosis and continues to be lost at a rate of about 2% to 4% a year, where there are clear correlations between caudate loss and clinical outcomes giving it the potential to be used to design a clinical development path to accelerated approval.

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

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

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

We would like to sincerely thank the patients, families and sites who participated in SELECT-HD. None of this research would be possible without them. Turning to DMD, we are advancing our open-label FORWARD-53 trial of WVE-N531 for boys with exon 53 amenable DMD. We are on track to deliver a 24-week dystrophin data later this quarter.

The preclinical and clinical data we've observed thus far with WVE-N531 bolster our confidence and excitement to deliver potential transformative new therapeutic option for patients.

In part A of our clinical trial, N531 demonstrated industry-leading mean 53% exon skipping, which was driven by muscle tissue concentrations of 42,000 nanograms per gram which is far above what other exon-skipping companies have reported. Also in Part A, we observed clinical evidence of myogenic stem cell or satellite cell uptake of N531.

This is particularly notable as myogenic stem cells are the progenitor cells for new myoblasts, and we are not aware of any other clinical data for exon skippers or gene therapy that have been able to demonstrate myogenic stem cell uptake.

Preclinically, we've shown N531 concentrations in the heart and diaphragm exceed that of skeletal muscle, which could speak to the promise of addressing what remains a huge unmet need in DMD, respiratory and cardiac function.

As a reminder, in addition to having a safe and tolerable profile, we are focused on what we believe will be the key for success for next-generation exon skippers. Firstly, of course, is increasing the quantity of dystrophin available to provide a better light dystrophin profile of greater than 5%, which would exceed the current standard of care.

Secondly, delivering high-quality functional dystrophin through exon skipping. Dystrophin produced through exon skipping includes important regions that are absent from mini or microdystrophin. Lastly, consistency of response. We know prior therapies have provided highly variable and inadequate response at the patient level.

Despite there being approved therapies in the market, when we speak to KOLs and patients, we hear a need for more and better treatment options -- about the treatment options available.

Coupled with extending dosing in tools to once or twice a month, N531 could provide meaningful benefit to patients and their families currently needing weekly infusion. We are well poised to provide a meaningful new therapeutic option for the treatment of DMD.

If positive, dystrophin data would support our plans to file for accelerated approval of N531 in the U.S. and would accelerate our clinical development plans to build a multi-exon DMD franchise beyond exon 53. We've generated data on compounds that would all together address up to 40% of the DMD patients.

And importantly, these programs continue to demonstrate skipping and protein restoration in preclinical studies that's on a par with or exceeds N531. With WVE-006, we are rapidly advancing our RestorAATion clinical program for AATD, the first RNA editing program in the clinic.

This clinical program is comprised of RestorAATion-1, a dose escalation study in healthy volunteers, and RestorAATion-2, a Phase Ib/IIa open-label study with single and multiple ascending dose portions that's designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of 006 in patients with AATD who have the homozygous Pi*ZZ mutation.

RestorAATion-1 continues to dose escalate and pharmacokinetic data are translating as expected for a GalNAc-conjugated oligonucleotide. Utilizing our pharmacokinetic data from healthy volunteers as well as our robust preclinical data, we identified the dose level expected to engage target.

In the third quarter of 2024, we commenced dosing in AATD patients in the first single dose cohort in RestorAATion-2. Throughout dose cohorts, we will be taking multiple assessments to measure the potential presence of wild-type healthy M-AAT protein in the serum. As a reminder, ZZ patients do not produce any M-AAT protein.

So detection of M-AAT protein would be the first ever clinical demonstration of RNA editing in humans. The trial is progressing, and we expect to announce a proof of mechanism in the fourth quarter of 2024.

Beyond that, we have the flexibility to adjust both dose level and frequency in RestorAATion-2 as we look ahead to delivering a medicine that can bring AATD ZZ patients to a healthier MZ phenotype with total serum AAT protein levels above the anticipated therapeutic threshold of 11 micromolar.

With that, I'd like to turn our call to our CFO, Kyle Moran, to provide an update on our financials..

Thanks, Anne-Marie. We recognized collaboration revenue of $19.7 million in the second quarter of 2024 as compared to $22.1 million in the prior year quarter. This slight decrease in revenue reflects typical variations in recognition of collaboration revenue.

Research and development expenses were $40.4 million in the second quarter of 2024 as compared to $33.3 million in the prior year quarter. This increase was primarily driven by spending in our INHBE program along with AATD and DMD programs and early-stage pipeline initiatives.

Our G&A expenses were $14.3 million for the second quarter of 2024 as compared to $12.3 million in the prior year quarter. As a result, our net loss was $32.9 million for the second quarter as compared to $21.1 million in the prior year quarter. We ended the second quarter with $154 million in cash and cash equivalents.

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

It is important to note that we do not include any future milestones 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. I'll now turn the call back over to Paul for closing remarks..

Thank you, Kyle. It is an incredibly exciting time for Wave as we are poised to sustainably translate new human genetic insights into breakthrough medicines. With ongoing validation of our platform and several important program milestones ahead, our confidence and conviction in the promise of our pipeline has never been stronger.

In this half of 2024, we expect to provide updates across each of our clinical programs, including dystrophin data this quarter as well as advance our obesity program into clinical development with the submission of the CTA.

We are also planning an R&D day this fall to share new preclinical data on our wholly-owned portfolio, including our WVE-007 INHBE program. We look forward to keeping you updated on our progress along the way.

In closing, I would like to thank our teams that are working tirelessly to advance our programs, deliver our clinical results and are preparing to initiate new clinical studies. Additionally, I would like to express our deepest gratitude to the patients and families participating in our studies and all who inspire us at Wave.

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

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

Congrats on the progress and looking forward to a lot of data readouts in the next 5 months. Glad to hear that you have submitted the opt-in package to Takeda with decision by year-end.

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

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

Great. And on DMD, just looking at the approved antisense oligos in DMD, about 42% exon skipping for the 53 from Viltepso lead to around 4.8% dystrophin. So would you say the bar for N531 is around 5%.

Is there some internal bar for efficacy you'd like to see in the forthcoming data?.

Yes. Thank you for the question, Joon. I mean as we think about dystrophin expression and our guidance to 5% or more, right, greater than 5%, I think we look at this as the 42% you were citing from Viltepso was after 6 months of dosing. So what's encouraging to us is the 53% that we were seeing after 3 doses at 6 weeks.

So again, getting the machinery of dystrophin production going earlier with a protein that has a high rated stability. I think if we think about that conversion where you said that 42% to 4.8%, it's also important as we looked at those data sets from the clinic out of 6 months that really that 4.8% was being driven by 2 outliers.

So as Anne-Marie mentioned, the consistency of response, which we saw early is something we'll be looking for in this study. And if you remove those outliers, it is actually somewhere around 3%, just slightly above 3% dystrophin.

So again, the production that we see of high quality, high quantity, so greater than 5% and consistency we think will drive a differentiated profile.

I do think as Anne-Marie -- getting back to your first question, I was reflecting on a lot of the work that's happening over the course of this year in clinical surrogate endpoints, both through the HD Risk Consortium work that's being done to evaluate the CHD Track-HD data.

And I do think it is highly encouraging, the work that's being done on caudate imaging. I don't know Anne-Marie, if there's any additional insights you want to reflect on back on the first question..

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

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

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

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

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

So could you just clarify for us, is this -- are you anticipating that the feedback we're going to get to the Street, is it going to be 1 event or 2 events? In other words, are we supposed to expect the regulatory feedback as 1 event and the Takeda decision as another event? Are these 2 things linked? And then also just what is the disclosure format, if you can just clarify for us, are we going to get that some time as it happens? Or are you going to wait for the quarterly -- the next quarterly call? And then just lastly, just related to that, as you're considering financing the company, just given DMD is a third quarter event and the feedback from the regulatory body in Takeda could be potentially a 4Q event, would you wait for that to occur? Or would you be willing to finance on DMD given your runway is now at 4Q '25?.

Thank you, Salim. And I'll take these in reverse order. So as it relates to when and where potential financings occur. Again, besides just the Takeda opt-in, there's also continued milestones through the GSK collaboration, which we announced even in the first quarter.

We received a $12 million payment for work that was happening under the research collaboration. So we do anticipate some big milestones through 2024 and 2025. As it relates to your first question in terms of disclosure, it's important to think about these as 2 independent events.

The Takeda opt-in decision is not predicated on regulatory feedback, it is based on the data from the prior study. So as we said on the call, the submission of the package was driven off of the data that met the threshold for us to submit that package.

Now those 2 pieces that are happening simultaneously towards the end of the year, there are interactions of what's happening across both of those, the regulatory feedback and the ongoing discussion with Takeda. So we do view those as while the 2 separate distinct opportunities to provide feedback.

Obviously, any time we cross the material threshold and an opt-in decision that shifts the nature of the program into not just a cash infusion, but also importantly, a shift in the HD program to a 50-50 profit split and a 50-50 R&D split is material. And so those updates would happen as they occur.

Again, the time line for these takes us to by the end of the year. So these 2 events pretty introduce distinctly as 2 separate events..

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

Great. This is Lisa on for Luca.

First on the Takeda opt-in, just wondering, should Takeda ultimately choose not to opt in, just wondering what are your options for the program if that happens? And secondly, on INHBE, given the target can potentially reduce fat and maintain muscle, wondering if you are thinking about any ways to assess muscle preservation in the clinic? Any color there would be helpful..

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

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

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

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

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

As it relates to the profile for INHBE, which we're incredibly excited about, given where we think it differentiates itself from the existing standard of care and obesity, to your point on both fat loss and being able to spare muscle.

And the fact that we can design not just what we saw the DIO mouse model, but a clinical study in healthy overweight volunteers to recapitulate that phenotype. Yes, we'll be embedding in the study the opportunity to look at both fat and muscle.

I don't know, Erik, if you want to add anything additionally or Anne-Marie in terms of the clinical trial design that we plan to..

Not really. Again, we as Paul said we see in the human genetic data, we see muscle sparing. We see profound effects on the fat distribution, and we replicate that in our preclinical studies. We haven't shared yet the design of the first clinical study.

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

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

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

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

This is Nick on for Steve.

Just wanted to clarify for the RestorAATion-2 update in Q4, do you plan to show changes in AAT protein concentration? Or do you plan to only show the proportion of corrected M-AAT versus Z-AAT? And as a quick follow-up, will the initial readout include data from the multi-ascending dose cohorts or only single-ascending dose cohorts?.

Yes. So the initial proof of mechanism data is not tied to either a single or multi-dose threshold, that's tied to exactly the first part of your question of profile. And so we'll be evaluating and assessing as part of that total protein, M protein in combination.

And the key driver of that is, to your point, to really be able to assess for the first time in humans, the principle of RNA editing. And therefore, the translation from what we've seen in the SERPINA1 model and how that's translating now into humans. But we will be assessing both M-AAT protein and total..

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

This is Lili on for Joe.

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

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

We do think in going forward, as we've shared before, that we do think there's the possibility to image that within 12 to 18 months. Obviously, the design of that study has to be agreed to with regulators.

But the benefit of this is that there are the ability with imaging to see that over reasonably short periods of time with much smaller patient population than what has been done before in HD with large clinical outcome studies.

Anne-Marie, I think do you want to reflect on the caudate atrophy and some of the imaging data coming?.

Yes. Happy to. So there are -- it's one way in which we're very lucky in the HD environment is that there's some -- a lot of natural history data available that's being collected prospectively by the community.

And that includes databases called Track and Predict-HD, and this means there are rich data sets available that would allow us to establish the predictive relationship between caudate change and clinical outcomes. And then one of the first things that you need to establish an endpoint that's reasonably likely to predict a clinical outcome.

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

So that's the first part of it. The second part of it is that you have to show that your drug is able to have an impact on caudate atrophy. And obviously, in our SELECT-HD study, we've already seen the first signs of that. So I think taken together, this is a strong package. We're excited to be engaging with regulators on this package..

Just to follow up. I mean, I think the profile is extraordinarily important.

Initially, as Anne-Marie said, showing a high impact on the target, addressing questions that have been involved with agency around wild-type sparing, so knocking down the target substantially, showing that we preserve wild type, showing that the concentration and the knockdown of protein correlates with caudate atrophy.

And then as Anne-Marie said, now having the imaging tools available to assess that relative to clinical outcome measurement, I think really sets up a dynamic for the first time, I think, for the HD community with disease modification to engage in this conversation around the potential accelerated registration pathway..

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

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

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

No. It's a wonderful question, and we put a lot of time into the modeling work going into -- from the SERPINA1 study to our nonhuman primate studies to our humans.

And I think that's really where we're able to take advantage of and I think benefit GalNac conjugation and the translative pharmacology that we've seen in the liver surface area between mouse, nonhuman primates and humans.

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

I think what's exciting as we think about the field of RNA editing and particularly RestorAATion-1 is even in the healthy volunteers while you don't get TD assessment, that PK is translating very nicely.

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

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

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

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

So at your optimal dose, is crossing the 11 micromolar range enough? Do you need to get to an MM phenotype? How are you guys thinking about the product profile?.

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

So really as 3 really important ingredients for a chronic therapy.

As you mentioned, 11 micromolar is a threshold that we think about the conversion of ZZ patients to an MV patient, and that's really one of the features of editing, that really reflects while we're talking there about micromolar, about a fold improvement over baseline, and we saw that as a sevenfold improvement from where patients started -- from where Mike started to where we got them to.

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

So our preclinical data really demonstrated the fact that the full editing -- and that's really 1 of the best ways to look at it going forward because while you always see where that micromolar threshold is, it's that really ability to turn and push that threshold above where those patients are. So we're going to get a sense of that.

Obviously, the proof of mechanism is the first step on that journey. But through the study, both single, multiple cohorts, that's where we're going to be able to continue to establish what that upper limit looks like.

But again, as you pointed out, our preclinical data supports that we can surpass an 11 micromolar threshold, which gives us a lot of confidence given the totality of the profile that this really could be a best-in-class therapeutic and first-in-class for RNA editing for the treatment of alpha-1 antitrypsin deficiency..

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

We recently conducted a Carewell call discussing the data that's been generated in the Huntington space? Can you PTC, UniQure and Roche and -- regarding the safety signal of hydrocephalus seen with Tominersen and AMT-130, there are sort of 2 petting or maybe complementary theories.

One is hydrocephalus due to defective cilia due to nonspecific knockdown of wild-type Huntington leading to defective CSF flow. And the other is what you described as pseudoatrophy due to reduced inflammation within the caudate and the ganglia -- basal ganglia driving that sort of pseudoatrophy and having concerns of hydrocephalus.

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

Yes. No. I mean I think those are dualing theories that have been out there since the tominersen experience. And I think they spoke to why we looked at imaging at the point where we did. And the key driver was the [indiscernible]. So sure, we weren't seeing hydrocephalus.

So I think it was really important to note that we didn't see hydrocephalus on the study. I think, to the point on that theory, and I think it was one that was prevailing, was the cilia that are responsible for the movement of CSF flow are structurally comprised of healthy Huntington protein.

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

So the ability to demonstrate that, the ability then to be able to assess whether or not the absence of hydrocephalus and some of those other signals were there. Again, we didn't see that. I think they're highly encouraging. So it was really a fundamental driver both in what we saw in the existing study and we drove forward.

I don't know, Anne-Marie, if there's anything you want to add to that..

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

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

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

This concludes today's program. Thank you all for participating. You may now disconnect..