Wave Life Sciences Q4 2024 Earnings Call Transcript

Quartr
Provided by Quartr
March 4, 2025

There are 12 speakers on the call.

Operator

Good morning, and welcome to the Wave Life Sciences Fourth Quarter and Full Year twenty twenty four Earnings Conference Call. At this time, all participants are in a listen only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Raj, Vice President of Investor Relations and Corporate Affairs. Please go ahead.

Speaker 1

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our fourth quarter and full year '20 '20 '4 financial results and recent business highlights, including progress updates for obesity and AATD clinical trials. Joining me today with prepared remarks are Doctor. Paul Volno, President and Chief Executive Officer Doctor. Eric Engelson, Chief Scientific Officer and Kyle Moran, Chief Financial Officer.

Speaker 1

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 statements for any reason.

Speaker 1

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

Speaker 2

Thanks, Kate. Good morning and thank you all for joining us on today's call. Over the past decade, we have been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health and 2024 was an incredibly important year for Wave in realizing this vision. We announced positive data supporting our AATD, GMD and HD clinical programs, derisked an entirely new modality in the clinic with RNA editing and expanded our pipeline with novel high impact programs that have potential to address millions of patients. We have carried this strong momentum into 2025 with the advancement of WVE-seven, our GalNec siRNA for obesity to the clinic and our consistent execution has kept us on track to deliver on key milestones for each program this year.

Speaker 2

I'll start today by discussing the progress we've made advancing WVE-seven for obesity. I'd first like to acknowledge that today, March 4 is World Obesity Day and this year the community is highlighting ways to take action to reduce the burden of obesity and related chronic illnesses. At WAVE, we are engaged with individuals living with obesity as well as clinicians, so we can do our part to combat disease stigma and deliver healthier futures for this community. In these conversations, the opportunity for healthy, sustainable weight loss with our INHIBONEE silencing approach is resonating. Enabled by our best in class siRNA technology, we believe WPE-seven has the potential to lead the next frontier in obesity treatment for more than one billion people living with obesity globally.

Speaker 2

While GLP-1s are rapidly becoming standard of care among weight loss therapeutics, their use is often limited by frequent dosing, loss of muscle mass, poor tolerability and high discontinuation rates. We believe WPE-seven is uniquely positioned to provide a best in class approach that addresses these limitations. It is designed to drive weight reduction through an entirely unique mechanism of action that induces fat burning without impacting muscle mass with doses just once or twice a year. Our preclinical data on seven have not only demonstrated its potential as frontline treatment options, but have shown synergies with GLP-one including as an add on for individuals requiring greater weight loss for who cannot tolerate higher doses of GLP-one. We are also excited about WBE-seven's potential as an off ramp to GLP-one enabling long term healthy weight maintenance with just once or twice yearly dosing.

Speaker 2

This maintenance approach would avoid the weight regain that is common when discontinuing GLP-one and the associated metabolic risk of weight cycling. Dosing is ongoing in our in lite clinical trial of WBE-seven for adults living with obesity and overweight and I'm pleased to say that we have already completed enrollment in the first cohort. We expect to deliver initial data from the trial in the second half of this year, which will include safety, tolerability and biomarkers reflective of healthy weight loss. Turning to alpha-one antitrypsin deficiency and WVE-six, our Galenic RNA Editing Oligonucleotide or AMIR, WVE-six has the potential to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. We do not require IV administered LMPs or complex delivery vehicles like other treatments and developments and our approach vastly differs from DNA editing technologies, which rely on hyperactive exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels.

Speaker 2

Our restoration clinical program started with healthy volunteers and we have now completed all planned cohorts of both single and multi dosing at dose levels higher than those planned for any cohort in the patient study. In our AATD patient study called RESTORATION II, last year we delivered a breakthrough in RNA medicines with the first ever clinical demonstration of RNA editing in humans with WBE006. In our two hundred milligram cohort, we observed mean 6.9 micromolar circulating TEM AAT and 10.8 micromolar of total AAT two weeks post single dose in the first two patients study and observed increases in AAT from baseline as early as day three and as late as day 57, an impressive durability of effect. Six was well tolerated with a favorable safety profile including the completed Restoration one clinical trial of healthy volunteers. Since this announcement, we have seen a surge in enrollment and demand among clinicians and patients to participate in

Speaker 3

the

Speaker 2

study. Multi dosing is underway in the two hundred milligram cohort where patients are receiving WBE-six every other week and our preclinical and clinical data support potential for extended dosing intervals in subsequent cohorts. We have also initiated the second single dose cohort at four hundred milligrams and we believe this higher single dose cohort coupled with the multi dose two hundred milligram cohort will give us meaningful insights into extending the dosing interval. Looking ahead, we will have data from the full first cohort in 2025 including the complete single dose and multi dose portions. We also plan to share data from the four hundred milligram single dose cohort this year.

Speaker 2

These data will further inform the therapeutic potential of WVE-six and our pipeline of RNA editing programs. Behind six, we're advancing a wholly owned discovery pipeline addressing both hepatic and extra hepatic targets. We unveiled three of these programs at our research day last year, which collectively provide the potential to address upwards of ten million patients. As the year progresses, we plan on sharing new preclinical data from our hepatic and extrahepatic RNA editing programs with a goal of initiating clinical development of additional programs in 2026. In Duchenne muscular dystrophy, all muscle biopsies have been collected and we are on track to deliver forty eight week data from our FORWARD 53 clinical trial by the end of this month.

Speaker 2

In the interim readout last year, we demonstrated WVE N531's potential to be a best in class therapeutic for up to ten percent of the boys living with DMD amenable to exon 53 skipping. We observed highly consistent mean muscle content adjusted dystrophin of 9%, evidence of improved muscle health, muscle concentrations that support monthly dosing intervals and distribution to myogenic stem cells, the progenitor cells for new myoblast that give rise to new myocytes and ultimately aid in skeletal muscle regeneration. Importantly, we also observed a safe and well tolerated profile. DMD is a devastating disease and there is an urgent need for more effective and safe therapeutic options for patients. We frequently hear from caregivers about the burden of weekly IV dosing and the need for therapies that can distribute to the heart, diaphragm and reach stem cells, which would enhance functional benefit, improve quality of life and ultimately extend survival.

Speaker 2

The upcoming forty eight week data will include dystrophin from muscle biopsies, functional measures, as well as safety and tolerability. We are also on track to deliver feedback from regulators by the end of the month. As a reminder, we have previously shared data from our portfolio of additional exons and pending positive updates on N531. We plan to advance a pipeline of oligonucleotides that addresses up to forty percent of boys living with DMD supported by our best in class muscle delivery. Finally, turning to WVE-three, our first in class allele selective olefinucleotide for the treatment of Huntington's disease.

Speaker 2

HD impacts more than two hundred thousand people in The U. S. And Europe alone and there are no disease modifying therapies available. The disease is devastating sometimes compared to having Alzheimer's, Parkinson's and ALS all at once and is an autosomal dominant genetic disease that impacts multiple generations of family members. For more than ten years, we have been committed to the HD community and to using our platform's exquisite specificity and unique chemistry to pioneer allele selective therapeutics.

Speaker 2

By reducing mutant Huntington at the mRNA and protein level, WVE-three addresses the underlying drivers of neurodegeneration. In addition, by sparing wild type Huntington protein, which is critical to the health of the central nervous system, WVE-three is uniquely positioned to address the full spectrum of HD from the early asymptomatic stage through the onset of symptoms and beyond. It is only through our platform's specificity of stereo chemical control to best in class chemistry that allele selective silencing became possible to patients. Just last week, I attended the annual CHGI conference where our team had the opportunity to share our select HD clinical results and our plan to accelerate development of WVE-three by using caudate atrophy as a primary endpoint, a known imaging marker that is atrophy as a primary endpoint, a known imaging marker that is potentially predictive of clinical outcomes. In addition to our podium and poster presentation, we had dozens of great conversations with HD researchers and advocates and heard enormous enthusiasm for WVE-three and our leadership in allele selective silencing.

Speaker 2

As a reminder, data from our select HD trial showed potent and durable mutant huntingtin reductions of up to 46% and preservation of the wild type Huntington with just three doses of WVE-three. Importantly, there was a statistically significant correlation between allele selective mutant Huntington reduction and slowing of caudate atrophy, marking the first time such a correlation has been observed in Huntington's disease. CAudate is part of the striatum to one of the primary areas where HD manifests in the brain. With atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about two percent to four percent per year, correlations have been shown between CAUT eight loss and clinical outcomes. And at the start of the year, we shared some of our own internal analyses supporting such a correlation.

Speaker 2

Specifically, we looked at natural history datasets including TRACK and PREDICT HD, which showed that an absolute reduction of just one percent in the rate of caudate atrophy is associated with a delay of onset and disability by more than seven point five years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting rate of caudate atrophy as a primary endpoint for an efficient clinical trial. These data along with the full clinical results from SelectHD were both part of our engagement with FDA last year that led to supportive initial feedback. Preparation is ongoing for a global potentially registrational Phase twothree study of WVE-three in adults with SNP3NHD using CAUTAPE as a primary endpoint and we remain on track to submit clinical trial applications including an IND application for this Phase twothree study in the second half of this year. In the interim, we've continued to receive substantial engagement in HD including from potential strategic partners and look forward to sharing more details on trial design and our path forward as the year progresses.

Speaker 2

With that, I'll now turn the call over to Eric to share more detail on ATIPEDE and provide an update on our emerging pipeline. Thank you, Paul, and thank you to everyone joining us on the call today.

Speaker 4

As some of you may know, I spent the first part of my career as a physician scientist focusing on obesity and adocortiometabolic diseases, last as a professor of medicine at Stanford, then five years at GSK as Head of Human Genetics, Genomic Science and later target discovery across all therapeutic areas before joining WAID last spring. For all of these reasons, I'm incredibly excited to talk about our INUVNE program, our obesity program with strong support from Jumunetics. The benefit of such support should not be underestimated as therapeutic targets supported by Gym Genetics are on average associated with a two to four times higher probability of success in drug development when compared to targets without any genetic evidence. INIBINI is a gene predominantly expressed in liver that produced the heptokin active INE. Active knee is accretive from liver and binds its receptor apt seven in adipose tissue.

Speaker 4

In light of omnipresence of energy dense food, liver and the b and e mRNA is upregulated resulting in higher circulating active knee levels due to maladaptive response and this promotes fat storage and an increase of abdominal obesity. We chose the targeted ligand in the BINI for several reasons. First, using our best in class oligonucleotide chemistry to turn off protein production directly at the upstream source is the most efficient way to down regulate activity of this ligand receptor pair. And second, Gallonac conjugates allow for a highly specific and efficient targeting to liver cells. In Ebene silencing leads to lower active knee levels resulting in higher adipose like policies, thereby decreased abdominal obesity, ultimately leading to healthy weight loss and an improved cardiometabolic profile.

Speaker 4

Several large human genetics studies have found that carriers of heterozygous loss of function variance in the NIBINI gene have favorable metabolic profiles, including reduced abdominal obesity and visceral fat, serum triglycerides, APO B, fasting glucose, HVA1C and decreases in several measures of liver disease, specifically ALT, corrected T1, an MRI measure of liver inflammation and fibrosis and lower nonalcoholic fatty liver disease activity score. Importantly, these carriers also have reduced risk of type two diabetes and coronary heart disease. So essentially, the outcome study has already been done using Nature's experiment, which also supports the therapeutic threshold of fifty percent silencing of inhibinib RNA. In addition to genetic studies and our convincing preclinical data, recent internal work has demonstrated a strong correlation of circulating active knee levels with BMI in blood samples from healthy individuals, providing an additional confirmation of the importance of this mechanism in driving obesity in humans. As we've seen over the past several years, there have been incredible efforts to develop new therapies in the obesity space, which treat the underlying causes of disease and subsequently drive meaningful outcomes for people living with obesity.

Speaker 4

It's important to step back and examine the approach for ourinibnibnibnib Galenic SRNA within the broader context of current treatments such as GLP-one agonists and other therapies in development. Although transformational for obesity medicine, GLP-one drugs are associated with many disadvantages as already mentioned by Paul. Drugs are associated with many disadvantages as already mentioned by Paul. Several of these concerns have been highlighted recently, including a draft guidance from FDA earlier this year on developing therapies for weight reduction, which emphasized the agency's focus on establishing study standards that focus on sustained fat loss as opposed to pound by pound weight loss, which also involves shrinking muscle mass. WVE-seven leverages an orthogonal approach from GLP-one, focusing on peripheral action directly on fat tissue rather than a centrally acting appetite regulation.

Speaker 4

Not only does this mean that we sidestep disadvantages GLP-one, but it also opens up opportunities to position our therapy in relation to centrally acting drugs as an alternative, addition or as an off ramp, three use cases supported by preclinical data that we presented at our Research Day last fall. Our first in human study of WVE-seven is called INLIGHT. This study is designed to test safety, tolerability, pharmacokinetics, biomarkers for target engagement, auto weight and composition and other measures of metabolic health. The single ascending dose portion of the trial in adults living with overweight or obesity is underway and as Paul shared earlier, the first cohort is already fully enrolled. We're very excited by the progress we've made bringing this unique and transformative approach into the clinic and look forward to sharing data from the trial in the second half of this year.

Speaker 4

Now turning to our emerging pipeline of RNA editing programs. We're continuing to advance WVE-six in the Phase 1b2a restoration two study in patients with AATD who have the homozygous BICD mutation. Our initial proof of mechanism data demonstrated impressive potency and durability of effect with WVE-six. Our expected data later this year will assess the ability of six to restore healthy mAAT protein levels with multiple doses as well as at higher dose levels. These data will also provide valuable learnings for our broader RNA editing pipeline, which we continue to advance towards the clinic.

Speaker 4

Last year, we shared preclinical data on three of our programs leveraging RNA editing, which are wholly owned and build on our learnings from WVE-six. All three programs are strongly supported by human genetics and offer novel ways to treat diseases in areas of high unmet needs. These programs also feature readily accessible biomarkers and approaches to assess pharmacodynamics along with established regulatory path. As with WVE-six, they leverage Gallonac conjugation proficient delivery to liver. Our PLN3 program aims to correct the PMPLA3I148M variant to revert homozygous carriers with liver disease to the heterozygous state, which we expect will dramatically decrease steatosis and fibrosis in I-148m driven liver disease.

Speaker 4

This program includes a large genetically defined population of 9,000,000 people in The U. S. And Europe that are not served by PLMT3 silencing or by other therapies in development. Together, our LDLR and APOB programs comprise a comprehensive package designed to substantially lower LDL cholesterol among people with familial hypercholesterolemia or SH. Both programs apply RNA editing technology aiming to up regulate LDLR and to correct the dominant APOB mutation respectively.

Speaker 4

Fewer than fifty percent of people living with heterozygous FH reached their treatment goals with current options including statins and PCSK9 inhibitors and our early data indicates that LDL RF regulation and APOB correction can result in over ninety percent of these individuals reaching the treatment call. This initial disease indication of FH includes one million people in The U. S. And Europe. Additionally, our LDL RAP regulation approach has massive upside expansion opportunities to people with statin intolerance or prior cardiovascular disease with poorly controlled LDL cholesterol, two groups that comprise over 30,000,000 people in The U.

Speaker 4

S. And Europe combined. We anticipate sharing new preclinical data from hepatic as well as hexahepatic programs this year, and we expect to initiate clinical development on multiple RNA editing programs in 2026. With that, I'd like to turn the call over to Kyle to provide an update on our financials. Kyle?

Speaker 5

Thanks, Eric. Our revenue for fourth quarter and full year 2024 was $83,700,000 and $108,300,000 respectively, compared to $29,100,000 and $113,300,000 in the prior year quarter and year. The quarter over quarter increase was driven primarily by the recognition of the remainder of the revenue under our Takeda collaboration. Research and development expenses were $44,600,000 in the fourth quarter of twenty twenty four as compared to $34,100,000 in the same period in 2023. Research and development expenses for the full year were $159,700,000 in 2024 as compared to $130,000,000 in 2023.

Speaker 5

This increase was primarily driven by spending for our Inhibiny program along with our AATV and DMD programs. Our G and A expenses were $16,100,000 for the fourth quarter of twenty twenty four as compared to $13,700,000 in the prior year quarter and $59,000,000 for the full year of 2024 as compared to $51,300,000 in 2023. Our net income was $29,000,000 for the fourth quarter of twenty twenty four as compared to a net loss of $16,300,000 in the prior year quarter. Net loss for the full year was $96,700,000 for 2024 as compared to $57,500,000 in 2023. We ended the year with $302,100,000 in cash and cash equivalents compared to $200,400,000 as of 12/31/2023.

Speaker 5

The increase in cash year over year is primarily due to our financing proceeds and the receipt of milestone payments and research funding from GSK. We expect that our current cash and cash equivalents will be sufficient to fund operations into 2027. It's important to note the potential future milestones and other payments waived under our GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Speaker 2

Thank you, Kyle. We are off to an incredible start in 2025 and are looking forward to multiple value accretive inflection points ahead with expected milestones across all four of our clinical programs and data from our growing RNA editing pipeline. With that, I'll turn it over to the operator for Q and A. Operator?

Operator

Thank Our first question coming from the line of Ron Feiner with JPMorgan. Your line is now open.

Speaker 3

Hi guys, this is Ron on for Eric. We were hoping to ask about Wave six. If you can give us a little bit more information on the level of protein we should expect at baseline at the readout? I know that at the top line, the news that you put out earlier, baseline was zero. But kind of looking at other clinical trials such as augment patient therapy, the baseline is slow to 6% for the total and about half of that for the functional.

Speaker 3

So just kind of trying to get level set on that. Thanks.

Speaker 2

Yes. Thank you. I mean, if you remember the baseline was below the lower limit of detection on the assay. But I think stepping back as we look forward, we're highly encouraged that at the starting point of a single dose, the lowest single dose of two hundred, we saw what would be therapeutically relevant levels of not just total AAT. So that was the 10.8 of nearly 11 micromolar.

Speaker 2

But I think the most important thing for people to follow as we continue to generate our data as others generate data is to really be tracking the M protein levels across studies. That M protein level is important because that is definitively zero. So ZZ patients who are entering these studies don't make any MAAT protein. And so if we continue to track MAAT protein levels and safe to imagine that over 60% of the protein we saw at the M level was sorry, the total level was M protein, that's highly indicative of the mechanism of editing. So it's the best way to benchmark across programs in terms of the impact of the therapeutics having on editing efficiencies and protein generation and what should we follow to be consistent.

Speaker 2

I say that because while historically we've tracked as an industry total AAT levels in the field of IV protein replacement. In editing and correction, one of the things that we saw pre clinically was that with time you see a reduction of aggregate. So if you have alpha one antitrypsin protein aggregates breaking up, they also go into serum. And so you can have changes in levels of serum total protein over time that's coming from a variety of sources, those that are directly related to the editing and those related to C protein coming out through the aggregate. So the most consistent way to follow editing efficiency is m protein because it's zero in these ZZ patients.

Speaker 3

Great. Thanks. And maybe just one more on seven. When you're doing Bexa scanning, do we expect the pattern of lean muscle mass change or its proportional or absolute to mirror that of the weight loss? And how often are you going to do DEXA scanning compared to weight measurements?

Speaker 2

Yes. So we haven't broken out when the DEXA scans are coming in those intervals. But I think to your point, the importance of adding DEXA scan is to really replicate we saw in preclinical models, which is that weight loss that we saw, definitive weight loss was coming off of fat. So, with all fat loss with no change in muscle mass in the preclinical experiments across multiple systems where we run that single dose combination and on the withdraw study. So, we have multiple examples of preserving muscle sparing with fat lowering.

Speaker 2

And to your point using DXA scanning as part of that study will enable us to use that as one of the biomarkers that we can evaluate in healthy, sustainable weight loss in the clinic, in this study.

Speaker 3

And then just maybe one short one. What signal from the DXA scan would be indicative of a healthier weight loss versus a pattern with GLP-1s? Thanks.

Speaker 2

Yes. We have not shared that. What I can share is we'll have multiple opportunities to DXA scans across the study to give a dynamic range with which we can show that.

Speaker 3

Great. Thank you so much guys.

Operator

Thank you. And our next question coming from the line of Salim Singh with Mizuho Group. Your line is now open.

Speaker 6

Great. Good morning, guys. Thanks for the questions. Paul, maybe just a few from us on DMD since we're getting that readout pretty soon here. The can you just confirm for us, are the discussions being had with the forty eight week data, the discussions with regulators being had with the forty eight week data or is it just the twenty four week?

Speaker 6

And can you perhaps just as we get closer here bookend the scenarios that we should be considering coming out on this readout? And then just two quick clarifications here. Just remind us where if how much PMO switchers, if that's even a consideration in this current data set? And then also just as you're kind of considering with the current data that you have in hand, just your pharmacoeconomic work, how you're preliminary thinking about pricing here?

Speaker 4

Thank you.

Speaker 2

Yes. No, thank you for the questions. And as you pointed out, this is around the process of the data. So one, what's been consistent was that the agency is being engaged around our twenty four week data, the data we had shared previously. Obviously, we'll continue to have these data as we move forward, but the data was from the existing datasets that we have.

Speaker 2

And as I mentioned, we anticipate having that feedback in line with the data from the forty eight week study. So that'll we'll be able to give an update both on the regulatory interactions as well as the data from the study. As it relates to and sorry, Selene, there were a couple there, so I want to make sure we hit each one of those. As we think about the variety of scenarios coming out of this, I mean, I think one of the things that we've seen is the most consistent highest level of dystrophin that's been seen before, the nine percent. And so if we think about that consistency and that magnitude, I think we're going to learn a lot about what a subsequent six months thing on the same dosing regimen is going to do to dystrophin kinetics.

Speaker 2

So I think there's the opportunity to understand what happens with stabilization and blood selling of dystrophin or frankly increasing in dystrophin. So we're going to be able to assess that over the additional six months of dosing. I think the other thing that's going to be important with further dosing is we already saw at the initial study was improvement in muscle repair, right? We saw reductions in CKs, we saw muscle improved health improvement, getting to those regenerative stem cells. So a whole variety of features of improvement in muscle health.

Speaker 2

And what's going to be important to us as well is we will also be assessing that muscle architecture over the subsequent six months. So again, more opportunities to look at the impact of improvement in muscle health, muscle repair. And then lastly and importantly, being able to assess clinical measurements. So while not powered for statistically significant clinical outcome measurements, it's still a relatively small study. I think we do expect to observe trends.

Speaker 2

And so being able to look at 95% stride velocity, being able to look at time to rise and other sensitive markers will give us that opportunity to assess the translation of that improvement in dystrophin to muscle health and muscle integrity ultimately to the impact on clinical measurements. We

Speaker 4

have done

Speaker 2

a number of early discussions and do see a substantial opportunity in PMO switchers, both in our engagement with clinicians and patients. We also know that a substantial portion of the exon 53 patients are not on therapy. So there's an opportunity not just to switch those who are currently on therapies to a less frequent regimen with potential higher dystrophin and opportunities there without a change in safety risk benefit profile. So we see that as a very important opportunity on switching, but we do know that there's a large opportunity on patients who are not on existing therapies. And at this stage, we haven't yet to comment on our pharmacoeconomic analyses and pricing funds.

Speaker 6

Okay, perfect. Super helpful. Thanks so much.

Speaker 2

Thank you.

Operator

Thank you. And our next question coming from the line of June Lee with Drew Securities. Your line is now open.

Speaker 7

Hey, congrats on the progress and thanks for taking our questions. Correct me if I'm wrong, but our understanding is that pending outcome of the meeting PTC is having with the FDA in second quarter, there is a chance that Huntington lowering may be deemed an adequate surrogate endpoint, reasonably likely to predict clinical outcome. If that is the case, would you still proceed with the MRI as a primary endpoint? And I have a quick follow-up.

Speaker 2

Yes. And I think it's an important if, but yes, I think if they were to demonstrate data along clinical measurements correlating with mutant Huntington and the FDA, we're willing to accept that data as a clinical surrogate biomarker for Huntington's disease, meaning that mutant huntingtin lowering could be associated as a reasonably likely to predict clinical benefit and the FDA were to make that an endpoint, then we're in a position to file off of our earlier data. We have a placebo controlled data with the highest I'd say the most substantial lowering of mutant huntingtin that's been seen to date at forty six percent lowering and on top of mutant huntingtin lowering spares wild type, which we know is an important indicator to clinicians, patients, but also to the agency itself. So we would deem that existing data set substantial to file and view the subsequent studies we run as confirmatory and make those changes. So if that changes at a regulatory endpoint, it's beneficial for the field and for us in particular.

Speaker 7

Great. And then you mentioned Huntington prevalence of more than two hundred thousand in The U. S. And Europe alone, which is higher than the fifty thousand to 60,000 historically cited by other companies. What changed?

Speaker 7

And what kind of data are you looking at that tells you that the opportunity here might be much bigger than previously thought?

Speaker 2

I think historically as numbers get cited in early datasets, they tend to oftentimes reflect the symptomatic HD. So patients who move to the diagnosis clinically on HD. And I think again, one of the main advantages of why we see allele specific silencing is so critical in the disease treatment paradigm for Huntington's disease is that ability to move into that early setting. And if we think about the work that was done over the last year by the Huntington's research community in restaging Huntington's disease, we used to have a designation between pre manifest and manifest as kind of a bifurcation. What's really been done in that restaging is realizing that Huntington's disease starts well before the onset of symptoms and that you can have substantial changes in caudate on measurement on MRI before the onset of symptoms occur where a patient would have historically been diagnosed with Huntington's disease.

Speaker 2

So as we take that opportunity to say, if you have an allele specific therapy, meaning you can treat earlier in the disease setting, knock out the bad protein well before you get, neurodegeneration and preserve wild type proteins, so you don't exacerbate the onset of disease. The real opportunity in Huntington is to move early in the disease setting to genetic diagnosis. And I think one of the things we'll all learn, in the HD community is as more therapies continue to come forward and genetic testing continues to increase, the propensity and incidence of Huntington's may be well under predicted based on the current diagnostic criteria.

Speaker 7

Great. Thank you. Great. Thank you.

Operator

Thank you. Our next question coming from the line of Joe Swartz with Leerink Partners. Your line is now open.

Speaker 8

Great. Thanks very much.

Operator

I was

Speaker 8

wondering how should we think about how the effect of WBE06 could look after multiple doses of two hundred milligrams? Can you share any general insights that you have from your preclinical healthy volunteer or modeling works that we can appreciate how the kinetics might evolve from the strong single dose data you reported last year?

Speaker 2

Yes. I mean, it's data not only that we have from six, but with PN chemistry across multiple formats, what we've seen is every time we've gone from single doses to multi doses, we've seen higher intercellular retention of drug translating to improvements in efficiency. So as we said, and thank you for acknowledging with the early data from the single dose, we see already a substantial uptake of the protein production. And we expect with multiple doses for that not just to be sustained, but actually to be increased. And so the opportunity also exists and this is important as we think about the future dosing regimens for the study is that we've seen consistently with multi dosing also extension and durability, meaning drugs stays in.

Speaker 2

So it's not just drug into the cell, it's retention, meaning decreasing drug out and therefore improving that potency and durability quotient. So we're going to learn two things from the two hundred milligram multi dose is one is what continues to happen on the protein dynamics, but importantly, we're also going to see what happens with that durability. It's why this four hundred next milligram cohort is important because imagine we already saw the two hundred milligram cohort, which is therapeutically relevant levels of MAAT protein, that next window that we'll get on the dose response between two to four will be really important. And that data, so that amplitude data, and we've said this before, the amplitude data between the single doses and what happens with the multi dose will continue to refine our modeling as we think about the prediction of the multi dose frequency in Cohort two and then ultimately what the design of Cohort three is that would lead to a potentially registration settlement.

Speaker 8

Okay. Thanks. And then for WV007, how long will patients be treated by the time you share data this year? Do you hope to match the total weight loss effect of GLP-one therapy at a similar time point recognizing these would be cross trial comparisons of course? Or should we focus on the amount of non lean body mass changes given this is a different mechanism?

Speaker 2

Absolutely. So we haven't provided the cutoff point yet. We'll continue to run the study and we'll provide data from the study. But it's fair to say as you think about the data from the single dose and thinking about the impressive durability of the opportunity of six month to twelve month durability, the single dose data is real reflective of what you'd expect to see with long term treatment. Pre clinically, we saw weight loss similar to the GLP-1s and semaglutide.

Speaker 2

So I think the opportunity exists to follow weight. I think what's going to be really important, as you brought up is really to delineate this concept of weight loss in a very broad stroke category of muscle and fat to really be able to break that down into fat loss. And I think that's what we want to see in the upcoming study is those changes in body composition in addition to biomarker data. So I think the totality of that data to distinguish it from GLP-one. So not just I think where we are currently is every medicine is put up against the same because it's very much similar classes and what's that impact to overarching weight loss at the expense of muscle with the properties that are very similar.

Speaker 2

I think the full opportunity in this initial dataset is really distinguish this unique category of medicines from that GLP-one where we're not doing essentially chemical starvation, we're driving a metabolic shift in phenotype. And so we believe that these data will be supportive in addressing that thesis and being able to demonstrate the difference of INHIVEN E as an independent mechanism for healthy sustainable weight loss.

Speaker 8

Thanks for the insights.

Speaker 2

Thank you.

Operator

Thank you. Our next question coming from the line of Roger Tsong with Jefferies. Your line is now open.

Speaker 9

Great. Thanks for the question. So a couple of questions from us. So the first one is for the ATD. I think Paul you mentioned you're expecting the higher dose on the multi dose and the higher dose may be able to increase the m protein production correction in the total protein production.

Speaker 9

So my question is, do we know the coloration between the m protein level and the total protein level versus the liver and the lung function given so far we only have the replacement therapy, but we have some other genetic medicine try to increase the level and it'll be higher than what you have seen in the stat two hundred milligram dose? Thank you.

Speaker 2

Yes. I mean, it's a wonderful question going back to just the basis for RNA editing. And if we think about the basis that drove how 11 micromolar, which we all kind of cite and, you know, has been subsequently, there's been discussions around with IV protein replacement where that level is setting. We have to kind of remember how we got to that level. So your question about what's required for lung and liver protection.

Speaker 2

And so if we do think about the heterozygous phenotype, that 50% level of correction, so the nadir of that was about 11 micromolar. If you look at the kind of lower limits of that heterozygous population, that was the benchmark for setting that level of total protein. And it was really set off a dynamic range of essentially people who are walking around with one copy of a healthy alpha one antitrypsin protein and the other within this folded copy, which isn't necessarily an apples to apples when you imagine when you're adding on protein on top of that to set a level with replacement, those patients still have a reserve of being able to make 50% M protein in production. But when we take this back to what we're doing in the field of editing, the thesis was really could we restore that heterozygous population back where we know that by doing that, that we could actually have them rely on the human clinical data that shows that those heterozygous patients have protection of lung function and liver function. What was encouraging too, when we think about the benefit of RNA editing is by editing in the promoter region, we're really restoring that functional activity back to these patients.

Speaker 2

So we do need to think about RNA editing as a different category than how we think about protein replacement because we're really restoring that function back to these patients. So we went back to our clinical data and if you think about what we've already seen at 11 micromolar of total protein and over 60% of that being M protein, we've essentially recapitulated what you'd expect to see in that heterozygous patient. We're encouraged to see what happens over time with repeat dosing and where the levels of protein can go also M protein, but also looking at the durability. But again, it's going to be great to see what happens as we increase that total level of protein and what that level of correction can continue to be. So I think the key for us still remains that if you follow the translation of turning these patients again, you have no baseline level of m protein and be able to correct them back to a heterozygous phenotype, looking at m protein will enable us to be able to understand how well we can correct that as a field in humans and we're highly encouraged by our initial clinical data.

Speaker 9

Thank you. Maybe just a quick one for DMD, understanding you're talking with the FDA and then for the potential regulatory path. So understanding you try also maybe be able to do some umbrella kind of a registrational trial. Would that be the topic we will get the update this quarter or there will be coming a little bit later? Thank you.

Speaker 2

No, thank you. I mean, as we said, the discussion encompass the data from the or initial interim data from the twenty four weeks. But importantly, as we also said, it's about what's next for the program in terms of accelerated registration and confirmatory study design. So we're able to provide in totality an update as part of these datasets on next steps for the program.

Speaker 9

Thank you.

Operator

Thank you. Thank you. And our next question coming from the line of Luca Easi with RBC Capital Markets. Your line is now open.

Speaker 10

Oh, great. Thanks so much for taking our question. This is Lisa on for Luca. Just wondering, how should we think about dosing for RNA editing versus DNA editing versus siRNA? So it looks like your second dose for A1ET is already at four hundred milligrams versus, we know, Intellia is using an eight times lower dose in their pivotal study in HAE at about fifty milligrams and Amylem is approved for TTR at a dose sixteen times lower at twenty five milligrams.

Speaker 10

Appreciate that these are totally different mechanisms of action, but how should we think about total drug exposure here for ADAR? Is there any risk on the safety side with going to such high doses? Thanks so much.

Speaker 2

Yes. I mean, I think one of the things you have to look at is the two hundred milligram is lower than Inclisiran. So I think sometimes we have to think about the calculations of doses of mgs per kg and what that is total drug delivered versus the absolute dose. So we're giving these at absolute doses, not dose one per kilogram per patient. Importantly, this is the first time anybody has been exploring ADAR editing to understand the kinetics of the enzyme.

Speaker 2

So what we do realize is the opportunity you have when you bring a whole new mechanism and modality forward and are frankly leading that for the field is the real opportunity to be able to explore the ranges of what's possible. And so ultimately what's important is dose, but dose to establish an efficacy threshold, but also a durability threshold. I mean, if we could be dosing this monthly, quarterly, less frequently, we're going to understand that. So there are nuances always across different enzymatic systems. We understand as a field what happens with, siRNAs.

Speaker 2

Although it's important to note in siRNAs we're seeing things that are incredibly different than what's been seen with alnylam before. I mean, we showed a 30 fold improvement in AGO2 loading over alnylam, which isn't just translating to better potency, it's translating to radically different durability, the prospects for highly infrequent dosing. And so that's important to be able to think about the nuances of how does chemistry add to not just a potency quotient, but a durability quotient. I think the opportunity we also have for ATD specifically is to really understand the upper bound. I mean, our initial dose let us get to therapeutic levels within a heterozygous patient population.

Speaker 2

We're going to understand where one could go even beyond that. And so I think that opportunity of really being able to explore dose is important. I think the other thing to note is we've gone higher than all anticipated doses even above the third cohort in the healthy volunteer study. So from a safety perspective, not just preclinical safety, but human clinical safety, we have substantial single and multi dose human safety data that does let us continue to explore the upper bounds of editing. And I think that's going to be important as we set the paradigm for what's going to what is good editing going to look like.

Speaker 2

And so I think ultimately dose is less important in the absence of what it's doing. And I think we're going to understand a lot between the two and four, but also importantly what the repeat dosing at two hundred does. So I think it's going to be exciting time for the field as we look across modalities and mechanisms that what levels of RNA protein editing and correction are going to be possible.

Speaker 10

Got it. Thanks so much Paul.

Speaker 2

Absolutely. Thank you.

Operator

Thank you. And our next question coming from the line of Catherine Novak with Jones Trading. Your line is now open.

Speaker 11

Hi, good morning and thanks for taking my questions. I just wonder if you can give any more details about the multiple dose cohorts in AATD. How many patients are you anticipating granularity as to when in 2025 we should expect this? And then in conjunction with that thoughts on the MAAT threshold, understanding that Z protein is not functional, so we're not really looking at total AAT, do you think consider the twenty micromolar MAAT to be the threshold for success? Thanks.

Speaker 2

Yes. So I think stepping back, each cohort as we said is eight patients with repeat dosing. So we've been very clear with what the number of patients are going to be. So that'll be the totality of that data set and they'll have seven dose. So these patients are going to get a substantial amount of medicine repeated, which is going to let us in a really nice way look at that translation from single to multi dose and we'll have that total data set from the single and the multi with which we can look at the dynamic effects of protein production.

Speaker 2

To your point, which is interesting is if we remember back to what the established threshold is for the therapeutic activity of a heterozygous patient. So assume eleven micromole is in nadir, 50% of that is M and the other part is Z. We're already at 60% edited M protein looking at that total. So to your point, we're still the measure. So I don't want anybody I wasn't sure if there's something to interpret it.

Speaker 2

We're still going to show total protein as we do the study. So we'll be able to look at that relative ratio between total protein and then specifically M protein. The reason we highlight in protein is it is critical because the m protein is only again produced based on the medicine's ability to edit the transcript. And so it gives them most insight into editing efficiency, protein production. And so therefore, we know that the MZ phenotype is a stable, safe phenotype.

Speaker 2

And so therefore, what we want to do is continue to push those patients towards higher levels of m protein. So we have substantial activity at the two hundred milligram. We're going to see what that does in a repeat dosing and we could reasonably expect to see not just a higher level of that m protein, but really looking at how durable and sustainable that is as we think about dosing measurements.

Speaker 11

Got it. Thanks. And then I had just one more on your thoughts on siRNA obesity targets outside of INHIBITI such as GPR75 for example. Is this something you could explore in conjunction with the INHIBITI program? Thanks.

Speaker 2

Yes. We think about a whole range of potential ways of using both siRNA as well as editing that could target the people of metabolic disease. GPR75 is orthogonal. So as we've mentioned, we do look at orthogonal approaches to treating obesity. And with our siRNA technology, not talking about GPR75 at the moment, but we've shown substantial durable potent silencing in the CNS with potential for once a year, even potentially less frequently with administration.

Speaker 2

So we shared that data as part of the data demonstrating and distinguishing differentiation between the state of the art chemistries that are for siRNA and showing again how that's different and how we see better potency and durability with our siRNA chemistries, not just with Galenic in the liver, but also in CNS. So we are evaluating a number of targets within the metabolic.

Speaker 11

Got it. Thanks very much.

Speaker 4

Yes.

Operator

Thank you. Our next question coming from the line of Ryan Gesner with Raymond James. Your line is now open.

Speaker 5

Hi there. Good morning. For the seven program, what a late stage clinical study assessing the therapeutic as more of a maintenance therapy actually look like? And what would you anticipate an initial label to look like for this program regarding positioning as a mono add on or maintenance therapy is successful? Thank you.

Speaker 2

Yes. So, I mean, we do think a lot about the opportunities and I say more about the single dose and then the maintenance. So we're going to be generating that data as part of these datasets. So we're going to have a very good sense of behavior of inhibiting as a single agent therapy and what level of healthy sustainable we must to see and being able to drive that forward into potentially registrational study. I think the other study that we are excited to engage in, which is that you've alluded to, is that off ramp.

Speaker 2

And so being able to replicate that study that we have run, it is very feasible to look at patients on GLP-1s that are stable on a GLP-one and then to be able to dose and withdraw. And so the designing of those next studies are being planned. We are thinking about how to conduct those so that they can serve two purposes. Obviously, one, generate really important meaningful data of how we help the product potentially be used in clinic. But two, to also support a label for registration for reimbursement.

Speaker 2

So as we think about the total opportunity as both a monotherapy, but very, very important on this off ramp. I think that's going to be a really interesting study to be running real time where patients who are going to be currently on those therapies now can be withdrawn, so and studied in that context in a really substantial way. So we have those plans underway.

Speaker 5

Thanks for the question.

Speaker 2

Thank you.

Operator

Thank you. And our last question in queue coming from the line of Madison Alsatini with B. Riley. Your line is now open.

Speaker 3

Hi, thanks for taking our question. What are your plans for the MDA conference? Will you host an event around the conference to provide that regulatory update? And then second, on three,

Speaker 2

I know you had an

Speaker 3

updated analysis of CHDI, you mentioned in your prepared remarks. Just wondering if you could kind of remind us or characterize the previously reported NFL data in terms of change from baseline? And then secondly,

Operator

how

Speaker 3

do you see three's profile relative to the XL1 targeted candidates? Thanks.

Speaker 2

Yes, wonderful. I'll take the MDA question first. So while our team has a presentation that was already scheduled to be prepared, the data will be coming will not be presented at MDA coming up, I think timing wise. So I think there won't be a separate event around that. So we do expect to have the full data as well as our regulatory update by the end of the month.

Speaker 2

We don't time as we historically have always said, we don't time our data releases around conferences, but rather when the data is ready for full presentation. As it relates to the three, and I think this was a great conversation at CHGI, we'll take the Exon one off the table first because I think there was a lot of discussion. We talked to translational medicine experts about a lot of concerns about the Exon one hypothesis. And I think a lot of those concerns stem from the fact that when people went back and did the analysis of healthy brains on MRI, so patients who had autopsy but did not have HD and those who did, both sets of patients have exon one. So it was not specific for Huntington's disease.

Speaker 2

And in fact, a lot of the model systems, and I think it's always important and HD is not unique in this, when you look at translational models to predict activity and what to expect in the clinic, it's always important to do more characterization on the animal mouse models. And so to date, there's been a lot of changes that happen in mice models that don't happen in humans. I should also add, that a lot of the data that's being presented around exon one and there was a presentation I believe at the Alnylam R and D Day, actually used WAVE allele specific oligonucleotides, that were presented previously. And we had shared data that said that our allele specific oligonucleotides, and this was shared in a CHDI presentation, actually demonstrated a benefit and that that target happened to also coincide with exon one was picked up. And I think what ended up becoming is that that became an exon one study, but it was actually very importantly an allele specific oligonucleotide study that we had engaged with and work with some of the KOLs in the space.

Speaker 2

We weren't referenced in the presentation, but it is important that a lot of the emerging supportive data on Exon1 are actually being generated with wave allele specific oligonucleotides, which as we would expect, if you reduce mutant huntingtin protein and preserve wild type, as we've shown not just in preclinical studies, but ultimately in the clinic, you do see changes and potential benefit. So I highlight that around the exon one discussions today. As it relates to the NFL studies, I think a couple of important things. One, again in the full retrospective New England Journal analysis of the Tillman Urs and Generation HD1 study, there was no correlation between NFL and clinical outcomes. So it's just an important reminder.

Speaker 2

We did share the follow-up from our FDA feedback last year, which we reiterated again that NFL was not the subject of that discussion. So we do follow it. It's important that I think everyone in the field is going to measure it and continue to look for those applications. But again, NFL hasn't correlated with outcome measurements.

Speaker 3

Got it. Very helpful. Thank you.

Operator

Thank you. I'm showing no further questions. I will now turn the call back over to Doctor. Paul Bohn for final remarks.

Speaker 2

Yes. Thank you for joining our call this morning. We look forward to connecting with many of you this month when we expect to share data for FWD53. Have a great day.

Operator

This concludes today's conference call. Thank you all for your participation. You may now

Remove Ads
Powered by Quartr
Earnings Conference Call
Wave Life Sciences Q4 2024
00:00 / 00:00
Remove Ads