Q4 2024 Wave Life Sciences Ltd Earnings Call
Speaker Change: Good morning, and welcome to the WAVE Life Sciences Board quarter and full-year 2024 earnings conference call. At this time, all participants honor the synonym mode. As a reminder, this call has been recorded and webcast.
Speaker Change: I'll now turn the call over to Kate Rausch, Vice President of the Investulations and Corporate Affairs. Please go ahead.
Speaker Change: Thank you, operator, and good morning to everyone on the call. Earlier this morning we issued a press request, outlining our fourth quarter and full year, 2024 financial results in recent business highlights, including progress updates for obesity and AAPD clinical trials.
Speaker Change: Before we begin, I'd like to remind you that discussions during this conference call will include board looking statements. These statements are subject to several risks and uncertainties that could cause their actual results to different materially from those described in these board looking statements.
Speaker Change: The factors that could cause actual results to differ are discussed in the press release issue today and in our SEC filing. We undertake no obligation to update or revise any forward-looking statements 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. Thank you for joining us on today's call. Thank you for joining us on today's call.
Paul: 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 weight in realizing this vision.
Paul: We announce positive data supporting our AATD, DMD, and HD clinical programs, DRIS and 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.
Paul: We've carried this strong momentum into 2025 with the advancement of WVE-007, 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.
Paul: At first like to acknowledge that today, March 4, is World of the Wicity Day, and this year the community is highlighting ways to take action to reduce the burden of obesity and related chronic illnesses [inaudible]
Paul: 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.
Paul: In these conversations, the opportunity for healthy sustainable weight loss with our HIV-need silencing approach is resonating.
Paul: Enabled by our best-in-class SIRNA technology, we believe WVE 007 has the potential to lead the next frontier in obesity treatment for more than one billion people living with obesity global. [inaudible]
Paul: While GLP-1s are rapidly becoming standard of care among way lost therapeutics, their use is often limited by frequent dosing, loss of muscle mass, fortelerability, and high discontinuation rates.
Paul: We believe WVE 007 is uniquely positioned to provide a best-in-class approach that addresses these limitations.
Paul: 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.
Paul: Our pre-clinical data on 0-7 have not only demonstrated its potential as frontline treatment option, but have shown synergies with GLP ones, including as an add-on for individuals requiring greater loss, which would cannot tolerate higher doses of GLP ones.
Paul: We are also excited about WVE-007's potential as an off-ramp to GLP-1, enabling long-term, healthy weight maintenance, which is once or twice yearly dosing.
Paul: This maintenance approach would avoid the great re-ains that is common when discontinuing GLP1 and the associated metabolic risk avoid cycling.
Paul: Dosing is ongoing in our in-flight clinical trial of WVE 007 for adults living with obesity and overweight, and I'm pleased to say that we have already completed enrollment in the first cohort.
Paul: 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.
Paul: Turning to Alpha-1 antitrips and deficiency, and WAVE-006, our Gowneck RNA-editing oligonucleotide or AMER, WAVE-006 has the potential to be the first treatment for AATV that addresses the root cause of the disease with a convenience subcutaneous weight dose therapeutic.
Paul: We do not require IV administered LMPs or complex delivery vehicles like other treatments and development, and our approach vastly differs from DNA editing technologies, which rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral
Paul: Our restoration clinical program started with healthy volunteers, and we have now completed all plan cohorts of both single and multi-dosing at dose levels higher than those planned for any cohort in the patient study.
Paul: In our AETV patient study called Restoration 2, last year we delivered a breakthrough in RNA medicines with the first ever clinical demonstration of RNA editing in humans with WVE-006.
Paul: In our 200-mg cohort, we have served me in 6.9 micromolar circulating M-A-E-T and 10.8 micromolar of total A-E-T, two weeks post single dose in the first two patients in the study, and have observed increases in A-E-T from baseline as early as day three and as late as day 57, an impressive durability of effect.
Paul: O-6 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 the study. We have seen a surge in enrollment and demand among patients to participate in the study.
Paul: Multi-dosing is underway in the 200-milligram cohort where patients are receiving WVE 006 every other week and are pre-clinical and clinical data support potential for extended dosing intervals and subsequent cohorts.
Paul: We have also initiated the second single dose cohort at 400 milligrams and we believe this higher single dose cohort coupled with the multi-dose 200 milligram cohort will give us meaningful insights into extending the dose thing interval. [inaudible]
Paul: 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 400 mg single-dose cohort this year.
Paul: These data will further inform the therapeutic potential of WAVE 006 and our pipeline of RNA editing programs.
Paul: Behind 0-0-6, we're advancing a wholly-owned discovery pipeline addressing both hepatic and extra hepatic targets. We unveiled three of these programs in our research day last year, which collectively provides the potential to address upwards of 10 million patients.
Paul: As the year progresses, we plan on sharing new pre-clinical data from our hepatic and extra hepatic RNA editing programs with a goal of initiating clinical development of additional programs in 2026
Paul: In Dushan, Muscoa, Distrophy, all muscle biopsies have been collected and we are on track to deliver 48 week data from our forward 53 clinical trial by the end of this month.
Paul: In the interim readout last year, we demonstrated WVE and 531's potential to be a best-in-class therapeutic for up to 10% of the boys living with the MD amenable to axon 53 skipping.
Paul: We observe a highly consistent mean muscle content adjusted dystrophy 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.
Paul: DMD is a devastating disease and there is an urgent need for more effective and safe therapeutic options for patients
Paul: We frequently hear from caregivers about the burden of weekly IB dosing and the need for therapy that can distribute to the heart and diaphragm and reach stem cells which would enhance functional benefit improve quality of life and ultimately extend survival.
Paul: The upcoming 48-week data will include dystrophin from muscle biopsies, functional measures, as well as safety and tolerability.
Paul: We are also on track to deliver feedback from regulators by the end of the month.
Paul: 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 40% of boys living with DMD, supported by our best-in-class muscle delivery.
Paul: Finally, turning to WVE-003, our first-in-class allele selective oligonucleotide for the treatment of Huntington's disease.
Paul: HD impacts more than 200,000 people in the US and Europe alone, and there are no disease modifying therapies available.
Paul: The disease is devastating, sometimes compared to having Alzheimer's, Parkinson's, and ALF all at once, and is an autodontal homobominant genetic disease that impacts multiple generations of family numbers in the world.
Paul: For more than 10 years, we have been commuted to the HD community and to using our platform's exquisite specificity and unique chemistry to pioneer a Leo selective therapeutics.
Paul: By reducing Newton's Huntington at the mRNA and protein level, WVE-003 addresses the underlying drivers of neurodegeneration.
Paul: In addition, by sparing wild-type Huntington protein, which is critical to the health of the central nervous system, WVE003 is uniquely positioned to address the full spectrum of HD, from the early asymptomatic stage through the onset of symptoms and beyond. In addition, by the early asymptomatic stage through the onset of symptoms and beyond, the early asymptomatic stage through the onset of symptoms and beyond.
Paul: It is only through our platform's specificity of stereochemical control to best-in-class chemistry that a Leo selective silencing became possible to patients.
Paul: Just last week, I attended the annual CHDI conference where our team had the opportunity to share our select HD clinical results and our plan to accelerate development of WVE-003 by using cottage atrophy as a primary endpoint, a known imaging marker that is potentially predictive of clinical outcomes.
Paul: In addition to our podium and poster presentations, we had dozens of great conversations with HD researchers and advocates and heard enormous enthusiasm for WVE-003 and our leadership and all the other elected Philanthic.
Paul: As a reminder, data from our Select HD trial showed potent and durable mutant Huntington reduction of up to 46% in preservation of the wild tech Huntington, with just three doses of WVE-003.
Paul: Importantly, there was a statistically significant correlation between a real selective mutant huntington reduction and flowing of caught atrophy marking the first time such a correlation that has been observed in hunting competencies. [inaudible]
Paul: Codate is part of the strident to one of the primary areas where HD manifests in the brain.
Paul: With atrophy beginning many years before symptom onset and continuing at a steady rate of decline of about 2 to 4% per year, correlations have been shown between caught a loss and clinical outcomes. And at the start of the year, we shared some of our own internal analyses supporting such a correlation. Thank you very much.
Paul: Specifically, we looked at natural history data sets, including track and predict HD, which showed that an absolute reduction of just 1% in the rate of caughted atrophy is associated [inaudible]
Paul: This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting rate of caught atrophy as a primary point for an efficient clinical trial.
Steve Data, along with the full clinical results from SELECT HD
Paul: We're both part of our engagement with FDA last year that led to supportive initial feedback.
Paul: Preparation is ongoing for a Global Potentially Registration Phase 23 study of WAVE 003 in adults with SNF3 and HD
Paul: Using Codate as a primary endpoint, and we remain on track to submit clinical trial applications, including an IND application for this phase 2-3 study in the second half of this year.
Paul: 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.
Paul: With that, I'll now turn the call over to Eric to share more detail on the activity to provide an update on our emerging pipeline. Thank you Paul, and thank you to everyone joining us on the call today.
Eric: At some of you may know, I spent the first part of my career as a physician scientist focusing on obesity and out-of-cordin metabolic diseases, last as a professor of medicine at Stanford. Then five years at GSK has had a few immunetic genomic science and later target discovery across all therapeutic areas before joining WAVE last spring.
Eric: For all of these reasons, I'm incredibly excited to talk about our inner beneath program, our obesity program with strong support from Jimi Unatics [inaudible]
Eric: The benefits of such reports should not be underestimated, as therapeutic targets supported by human 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.
Eric: In Ebene is a gene predominantly expressed in liver that produced the Hepatocaine Activity. Activity is a created from liver and biensis receptor act 7 and adipose tissue.
Eric: In lights of omnipresence of energy, dense food, livery, nubiny, mRNA is upregulated, resulting in higher circulating activity levels due to maladaptive response, and this promotes fast storage and an increase of abdominal obesity.
Eric: We chose to target the ligand in the beneath for several reasons. First, using our best-in-class oligon nucleotide chemistry to turn off protein production directly at the upstream source is the most efficient way to down-regulate activity of this ligand receptor.
Eric: and Second, Galact Conjugates, Allow for a Highly Specific and Efficient Targeting Deliberate Solve.
Eric: In a beneath silencing lead to lower active in e-levels, resulting in higher adipose-like policies thereby decreased abdominal obesity, ultimately leading to healthy weight loss and an improved cardiometabolic profile.
Eric: Several large sumiunetic studies have found that carriers of heterosiglas loss of function variants in the Nbine gene have favorable metabolic profile, including reduced abdominal obesity and visual fast, certain triglycerides, APOB, fattening glucose, HV1C, and decreases in several measures of liver disease.
Eric: Specifically ALT, corrected T1, an MRI, a measure of liver inflammation and fibrosis, and lower non-alcoholic fatty liver disease activity score.
Eric: Importantly, these carers also have reduced risk of tattooed evidence and coronary heart disease.
Eric: So, essentially, the outcome study has already been done using nature's experiment, which also supports the therapeutic threshold of 50% silencing of intubini mRNA.
Eric: In addition to genetic studies and our convincing preclinical data, recent internal work has demonstrated a strong correlation of circulating active in e-levels with BMI and blood samples from healthy individuals, providing an additional confirmation of the importance of this mechanism in driving obesity and humans.
Eric: As we've seen over the past several years, there have been incredible efforts to develop new therapies in the obesity space which treats the underlying causes of disease and subsequently drive meaningful outcomes for people living with obesity
Eric: The important step back can examine that approach for our and in beneath gal like SNA, within their broader context of current treatment, such as COP-1 agonism, other therapies and development.
Speaker Change: All those transformational for BCD medicine, GLP-1 drugs are associated with many disadvantages as already mentioned by Paul.
Speaker Change: Several of these concerns have been highlighted recently, including in draft guidance from FDA earlier this year on developing therapies for weight reduction, which emphasize the agency's focus on establishing study standards that focus on sustained past loss as opposed to pound-by-pound weight loss which also involves shrinking muscle mass.
Speaker Change: WVE 007, leverages in orthogonal approach from GLP1. Focusing on peripheral action directly on a fast issue, rather than essentially acting appetite regulation.
Speaker Change: Not only does this mean that we sidestep this advantage of COQ1, but it also opens up opportunities to position our therapy in relation to centrally-acting grubs as an alternative, addition, or as an off-prem. Three-use cases supported by preclinical data that we presented at our research day last
Our first in human study of WV-007 is called in light [inaudible] we are now at the world,
Speaker Change: The studies, the sciences, the safety, tolerability, pharmacokinetics, biomarkers for target engagement, body weighting composition and other measures of metabolic health The studies, the studies, the safety, pharmacokinetics and other measures of metabolic health
Speaker Change: 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 [inaudible]
Speaker Change: We're very excited about 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.
Now, turning through our emerging pipeline over an RNA-editing program.
Speaker Change: We're continuing to advance WVE-006 in the Phase I-B to a Restoration II study in patients with AATD who have the homo-cygosis BICD mutation. Our initial proof of mechanism data demonstrated impressive potent interrability of effects with WVE-006.
Speaker Change: Our expected data-related is here will assess the ability of their 0-6 to restore healthy M-A-A-T protein levels with multiple doses, as well as a higher dose level.
Speaker Change: These data will also provide valuable learning for broader RNA editing pipeline, which will continue to advance towards the clinic.
Speaker Change: Last year, we shared preclinical data on three of our program's leveraging RNA editing, which are Holy Own and build on our learnings from WVE-006. All three programs are strongly supported by human genetics and offer novel ways to treat diseases in areas of high and ethnic need.
Speaker Change: These programs also feature readily accessible biomarkers and approaches to assess pharmacodynamics along with established regulatory paths. As with WVE-006, the leveraged galactic conjugation and proficient delivery to Lomar.
Speaker Change: Our PLN-3 program aims to correct the PLN-PMPL-A-3-I-148 environment to revert homo-saga carries to live with liver disease to the hetero-saga state.
Speaker Change: which we expect will dramatically decrease the associative fibrosis in I-148M driven liver disease.
Speaker Change: This program includes a large genetically defined population of 9 million people in the US and Europe that are not served by PLNP3 silencing or by other therapies in development.
Speaker Change: Together, our LDL R&A would be programs, comprise a comprehensive package designed to substantially lower LDL cholesterol among people with familial hypergolusolemia or FH.
Speaker Change: Both programs apply RNA editing technology, aiming to upregulate the LLR and to correct the dominant
Speaker Change: Fewer than 50% of people living with heterocycles FH reached their treatment goals with current options, including fastens and pieces canine inhibitors. And our early data indicates that LLRF regulation and FB correction could result in over 90% of these individuals reaching the treatment goal. [inaudible]
Speaker Change: This initial deceased indication of FH includes 1 million people in the US and Europe .
Speaker Change: Additionally, our LDLR regulation approach has massive upside expansion opportunities to people with stagnant intolerance or prior cardivacities with poorly controlled LDL cholesterol, two groups to comprise over 30 million people in the US and Europe combined.
Speaker Change: We anticipate sharing new pre-clinical data from hepatic as well as extra hepatic programs this year, and we expect the initiate clinical development of multiple RNA-editing programs in 2026.
Speaker Change: But that I'd like to turn the call over to Kyle to provide an update on our financial cut.
Kyle: Thanks, Eric. Our revenue for fourth order at full year 2024 was $83.7 million dollars and $108.3 million dollars respectively.
Speaker Change: Compared to $29.1 million and $113.3 million in the prior year, quarter and year and $1.2 million in the prior year, quarter and year, quarter and year
Speaker Change: The quarter-over-quarter increase was proven primarily by the recognition of the remainder of the
Speaker Change: Research and development expenses for $44.6 million dollars in the fourth quarter of 2024 as compared to $34.1 million dollars in the same period in 2023.
Speaker Change: Research and development expenses for the full year were $159.7 million in 2024 as compared to $130.0 million in 2023.
Speaker Change: This increase was primarily driven by spending for our interview and the program, along with our AADD and D&B programs.
Speaker Change: Our GNA expenses were $16.1 million from the fourth quarter of 2024 as compared to $13.7 million in the prior year of quarter at $59.9 million from the full year of 2024 as compared to $51.3 million in 2023.
Speaker Change: Our near income was $29 million from the fourth quarter of 2024, as compared to a net loss of $16.3 million in the prior year of Florida. [inaudible]
Speaker Change: We ended the year with 302.1 million dollars from cash and cash equivalent compared to 200.4 million dollars as of December 31st, 2023.
Speaker Change: We expect that our current cash and cash improvements will be sufficient to fund operations into 2027.
Speaker Change: It's important to note the potential future milestones and other payments to wave under a GSK collaboration, Ananda Clujin, and Akash Runway.
Paul: I'm now turning the call back over to Paul for closing remarks.
Paul: Thank you, Kyle. We are off to an incredible start in 2025 and are looking forward to multiple value accretive inspection points ahead. We've been expected milestones across all four of our clinical programs and data from our growing RNA-editing pipeline.
Paul: With that, I'll turn it over to the operator for Q&A. Operator?
Speaker Change: Thank you. Ladies and gentlemen, if you are to ask a question at this time, you will need to press star 111 on your telephone and wait for your name to be announced.
Speaker Change: If you wish to withdraw your question, you may press star one one again. Please stand by while we come publicly on air roster.
Speaker Change: Now, first question coming from the line-off, Ron Feiner with JP Morgan, Yelena Snowton
Speaker Change: Hi guys, this is Ron on for Eric. We're hoping to ask about WAVE's 006. If you can give us a little bit more information on the level of protein we should expect that baseline. At the readout, I know that at the top line that news that you put out earlier. Here it is.
Speaker Change: The baseline was zero, but kind of looking at other clinical trials, such as augmentation therapy, the baseline as flow is set to six, if that's for the total, and I'd ask that for the functional, so just kind of trying to get a level set on that, thanks.
Speaker Change: Yeah, thank you. I mean, if you remember, the baseline was below the lower limit of detection on the assay, but I think and stepping back is as we look forward, we're highly encouraged that.
Speaker Change: At the starting point of a single dose, the lowest single dose is 200.
Speaker Change: We saw what would be therapeutically relevant levels of not just total 80s, so that was the 10.8 of the 11 micromolar but I think the most important thing for people to follow as we continue to generate our data as others generate data. It's to really be tracking the M protein levels across studies. [inaudible]
Speaker Change: That M protein level is important because that is definitively zero. So these patients who are entering these studies don't make any M AAT protein. And so if we continue to track M AAT protein levels in.
Speaker Change: Safe to imagine that over 60% of the protein we saw at the M-level was, sorry, the total level was M-procene.
Speaker Change: That's highly indicative of the mechanism of action 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 be followed to be consistent. I say that because while...
Speaker Change: Historically, we've tracked as an industry, total AT 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...
Speaker Change: So if you have alpha-1 antitrips and these 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 the protein coming out through the aggregate so the most consistent way to follow editing efficiency of M protein because it's zero in these these patients.
Speaker Change: Change your proportional or absolute to mirror that of the weight loss and how often are you going to do Texas counting compared to weight measurements? [inaudible]
Speaker Change: Yeah, so we haven't broken out when the decks of scans are coming in those intervals, but I think to your point, the importance of adding decks of scan is to really replicate some preclinical models, which is that weight loss that we saw definitive weight loss was coming off both. [inaudible]
Speaker Change: Fat, so with all fat spots, with no change in muscle mass in the preclinical experiments across multiple systems where we front that single dose combination. [inaudible]
Speaker Change: and on the withdraw study. So we have multiple examples of preserving muscle sparing with fat lowering. And to your point, using dexter scanning as part of that study will enable us to use that as one of the biomarkers that we can evaluate in healthy, sustainable way of loss and to clinic in the study.
Speaker Change: And then maybe one short one, what signal from the Texas County would be indicative of a healthier weight loss versus the pattern with JLP ones?
Thanks.
Speaker Change: Yeah, we have not shared that. We can share, we'll have multiple opportunities to index the scans across the studies to give a dynamic range with which we can show that.
Great. Thank you so much, guys.
Speaker Change: Thank you. Now next question, coming from the line-up, Salim Syed, with Misoho Group, Galenis Nalpen.
Speaker Change: Great. Good morning, guys. Thanks for the questions. Paul, maybe just a few from us on D&D since we're getting that read-up pretty soon here.
Speaker Change: Are the discussions being had with the 48-week data, the discussions with regulators being had with the 48-week data, or is it just the 24?
Speaker Change: Weak, and could you perhaps just as we get closer here, book end of scenarios that we should be considering coming out?
Speaker Change: on this readout. And then just two quick clarifications here. Just remind us how much PMO switchers, if that's even a consideration in this current data set, and then also just...
Speaker Change: As you're kind of considering, you know, with the current data that you have in hand, just your pharmacokinomic work, how you're preliminary thinking about pricing here. Thank you.
Speaker Change: Yeah, no, thank you for the questions. And as you pointed out, this is around the precipice of this data. So...
Speaker Change: One, what's been consistent was that the agency is being engaged around our 24-week date, the data we had shared previously [inaudible]
Speaker Change: Obviously, we'll continue to have these data as we move forward, but the data was from the existing data sets that we have. And as I mentioned, we anticipate having that feedback in line with the data from the 48-week study. So that will be able to give an update both on the regulatory interactions as well as the data from the study.
Speaker Change: As it relates to, I'm sorry, Salim, there are 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.
Speaker Change: I think we're going to learn a lot about what a subsequent six months staying on the same dosing regimen is going to do to dystrophin kinetics. So I think there's the opportunity to understand what happens with stabilization and plateauing of dystrophin or, frankly, increasing in dystrophin. So we're going to be able to assess that over the additional six months of dosing.
Speaker Change: I think the other thing that's going to be important with further dosing is we already saw at the initial study [inaudible]
Speaker Change: was improvement in muscle repair, right? We saw reductions in CKs, we saw muscle improvement, getting to those regenerative stem cells, so a whole variety of features of improvement in muscle health, and what's going to be important as well is we'll 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 a statistically significant...
Speaker Change: in clinical outcome measurements. It's still a relatively small study. I think we do expect to observe trends. And so being able to look at 95% strive 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 dystrophy, to muscle health and muscle integrity, ultimately did he impact on...
Medical Measurements
Speaker Change: We have done a number of early discussions and do see a substantial opportunity in PMO switchers, both in our engagement with clinicians and patients.
Speaker Change: We also know that a substantial portion of the Exxon 53 patients are not on therapies so there's an opportunity not just to switch those who are currently on therapies but it's going to be great.
Speaker Change: to a less frequent regimen with potential higher dystrophy and opportunities there without change and safety risk benefit profile. So we see that as...
Speaker Change: 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 analysis and pricing funds [inaudible]
Okay, perfect, super helpful. Thanks so much.
Thank you.
Thank you.
June Lee: In our next question, coming from the line-up, Joon Lee withdrew his security seal on his
Speaker Change: Hey, congrats on the progress and thanks for taking our questions.
Speaker Change: Brut me from wrong, but our understanding is that pending outcome of the meeting PTC's having with the FDA in second quarter, there is a chance that Honeyton Laurie may be deemed an adequate surrogate endpoint reasonably likely to predict clinical outcome.
Speaker Change: If that is the case, would you still proceed with the MRI as a primary end point, and I have a quick follow-up?
Speaker Change: Yes, and I think it's an important if, but yes, I think if they were to demonstrate data along clinical measurements correlating with Newton and
Speaker Change: The FDA were willing to accept that data as a clinical surrogate biomarker for hunting facilities, meaning that mutant hunting and lowering could be associated as a reasonably likely to predict clinical benefit and the FDA would make that an endpoint.
Speaker Change: Then we're in a position to file up of our earlier data. We have a placebo control data with the highest low, I say the most substantial lowering of mutant huntington that's been seen to date at 46% lowering and on top of mutant huntington lowering spares wild type which we know is an important in the time.
Indicator to clinicians, patients, but also to the agency itself. So,
Speaker Change: We would theme that existing data that's substantial to file and view the subsequent studies we run as confirmatory and make those changes. So, if that changes in a regulatory endpoint, it's beneficial for the field and for us in particular. Thank you.
Speaker Change: Right. And then you mentioned the Huntington prevalence of more than 200,000 in the US and Europe alone, which is higher than the 50 to 60,000 historically cited by other companies. What changed and, you know, what kind of data are you looking at that tells you that the opportunity here might be much bigger than previously thought. [inaudible]
Speaker Change: I think historically as numbers get cited in early data sets, 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. Thank you.
Speaker Change: Of why we see a little specific silence thing is so critical in the disease treatment paradigm, chronic disease disease.
Speaker Change: 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 and re-staging Huntington's disease, we used to have a designation between pre-manifest and manifest as kind of a bifurcation. [inaudible]
Speaker Change: What's really been done in that re-staging is realizing that Huntington's disease starts well before the onset of symptoms [inaudible]
Speaker Change: and that you can have substantial changes and caught a measurement on MRI, before the onset of symptoms occur, where a patient would have historically been diagnosed with panic disease. So as we take that opportunity to say, if you have an allele-specific therapy, meaning you can treat earlier in the disease setting,
Speaker Change: Knock out the bad protein well before you get neurodegeneration and preserve wild-type protein so you don't exacerbate the onset of disease. The real opportunity 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 that more therapies continue to come forward and genetic testing continues to increase. This is the end of the video.
Speaker Change: The propensity and incidence of Huntington may be well underpredicted based on the current diagnostic criteria.
Great, thank you. Thank you.
Thank you.
Thank you
Next question, coming from the line up? [inaudible]
Joe Schwartz, Widlearing Partner, Seal Eunice Nelson
Joe Schwartz: Great, thanks very much. I was wondering how should we think about how the effect of WBE-06 could look after multiple doses of 200 milligrams? Can you share any general insights that you have from your pre-clinical, healthy, volunteer or modeling works that we can appreciate how the kinetics might evolve from the strong single-dose data you reported last year?
Joe Schwartz: Yeah, I mean, it's state of not only that we have from 06, but with PN chemistry across multiple formats, what we've seen is every time we've gone from single dose to multi doses, we've seen higher intercellular retention of drug translating to improvements in efficiency. [inaudible]
Joe Schwartz: 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 so
Joe Schwartz: Decreasing drug out and therefore improving that potency and durability quotient. So we're going to learn two things from the 200 milligram moldy dose. This one is what continues to happen on the protein dynamics. [inaudible]
Joe Schwartz: But importantly, we're also going to see what happens with that durability [inaudible]
Joe Schwartz: It's why there's 400 next milligram cohorts important because imagine we already saw the 200 milligram cohort which is therapeutically relevant levels of MAAC protein that next window that will get on the dose response between 2 to 4 will be really important. And that data so that amplitude data and we said this before the amplitude data between single doses and what happens with the multi dose. [inaudible]
Joe Schwartz: We'll 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 study. [inaudible]
Speaker Change: Okay, thanks. And then for WBE-007, 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-1 therapy at a similar time point, recognizing that these would be cross-trial comparisons, of course? Thank you very much.
Joe Schwartz: Or should we focus on the amount of non-lean body mass changes given this is a different mechanism?
Joe Schwartz: Absolutely, so we haven't provided it the cutoff point yet and we'll continue to run the study and we'll provide data from the study but it's fair to say is you think about the data from the single dose and thinking about the impressive durability of the opportunity at six month to 12 month durability but the single dose data is really reflective of what you'd expect to see with long-term treatment.
Joe Schwartz: Preclinically, we saw weight loss similar to the GLP once in Semenkow's head. 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...
Joe Schwartz: 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.
Joe Schwartz: I think where we are currently is, every medicine is put up against the same, 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. I think the full opportunity in this initial data set is really distinguished, this unique category of medicines. It happens.
Joe Schwartz: from that GLP1, where we're not doing essentially chemical starvation, we're driving a metabolic shift in phenotypes, and so we believe that these data will be supportive in addressing that thesis and being able to demonstrate. Right.
Joe Schwartz: of the difference in him and he as an independent mechanism for healthy sustainable aid funds.
Thanks for the insights.
Thank you [inaudible]
Go to www.Flydreamers.com for more.
Thank you.
Speaker Change: Our next question, coming from Delano, Roger Song with Jeffrey, Cielan Isnalvin,
Great, thanks for that.
Speaker Change: I think Paul you mentioned, you are expecting the high dose and the multidose and the high dose may be able to increase the M protein production.
Correction, and then total protein production.
So my question is...
Speaker Change: Do we know the collaboration between the M protein level and the total protein level versus the delivery and the lung function? Given so far, we only have the replacement therapy, but we have some other genetic medicine tried to increase the level a little bit higher than what you have seen being the set 200-minute web dose. Thank you.
Speaker Change: Yeah, 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 in a way that we're going to be able to do that.
Speaker Change: Constsequently, 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 to your question about what's required for lung and liver protection. So if we do think about.
Speaker Change: The heterozygous phenotype, that's 50% level of correction. So the nature of that was about 11 micromolecula. Look at the lower limits of that heterozygous population.
Speaker Change: 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 antitripsom protein in the other with a misfolded copy which isn't necessarily an apple to apples when you imagine when you're adding on protein on top of that to set a level with replacement. Thank you very much.
Speaker Change: Those patients still have a reserve of being able to may 50% have protein and production, but we take this back to what we're doing in the field of editing.
Speaker Change: The thesis was really could we restore that heterozygous population back where we know that by doing that that we could actually have been rely on the human clinical data that shows that those heterozygous patients have protection of lung functions and the reflection. [inaudible]
Speaker Change: What we're encouraging, too, and we think about the benefit of RNA editing it by editing in the promoter region, we're really restoring that functional activity back to these patients. So, we do need to think about RNA editing and a different category than how we think about protein replacement because we're really restoring that function back to these patients.
Speaker Change: So we went back to our clinical data, and if you think about what we've already seen, an 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.
Speaker Change: We're encouraged to see what happens over time with repeat dosing and where the levels of protein can go, also end protein, but also looking at the durability. But again it's going to be. I'm.
Speaker Change: 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.
Speaker Change: that if you follow the translation of turning these patients to get to a no baseline level of M-protein.
Speaker Change: 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. There's a field in humans and we're highly encouraged by our initial clinical data. Thank you very much.
Thank you.
Speaker Change: Maybe just a quick one for DMD, understanding your 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 registration trial. Would that be the topic? We will get the update quarter or there will be a coming elevator. Thank you.
Speaker Change: Now, thank you. I mean, as we said, the discussion encompassed the data from...
Speaker Change: The initial interim data from the 24 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 data sets on next steps for the program.
Thank you.
Thank you [inaudible]
Count.
Thank you.
Speaker Change: And our next question coming from the line of Luca Issi with RBC Capital Markets. You'll let it snow open.
Speaker Change: Oh, great. Thanks so much for taking our question. This is Lisa Walter, Luca. How should we think about those things for RNA editing versus DNA editing versus FIRNA?
Speaker Change: So it looks like your second dose for A1ET is already at 400 milligrams versus, you know, I'm tell you I was using an eight times lower dose in their pivotal study with HDE at about 50 milligrams and the myelum is approved for TTR at a dose of 16 times lower at 25 milligrams.
Speaker Change: Appreciate that these are totally different mechanisms of action, but how should we think about total drug exposure here for ADR? Is there any risk on the safety side with going to such high doses? Thanks so much.
Speaker Change: Yeah, I mean, I think one I think you have to look at is the 200mg is lower than in cholesterol. So I think sometimes we have to think about the calculations of doses of mix per cake and what that is, total drug delivered versus the Jo absolute dose. So we're giving these at absolute doses, not dose per kilogram per patient. [inaudible]
Speaker Change: Importantly, this is the first time anybody has been exploring Adar's editing to understand the kinetics of the enzyme. So what we do realize is, the opportunity you have when you bring a whole new…
Speaker Change: Mechanism and modality forward and 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.
Speaker Change: Joseph, but Joseph to establish an efficacy threshold, but also a durability threshold.
Speaker Change: Heiley and frequent dosing. And so that's important to be able to think about the nuances of how does chemistry add to not just the potency quotient, but a durability quotient.
Speaker Change: I think the opportunity we also have for AATD specifically is to really understand the upper bounds. I mean, our initial dose let us get to therapeutic levels within a heterozygous patient population .
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: We have substantial single and multidose 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 you know what's going to what is good editing going to look like and so I think ultimately
Speaker Change: Joseph is less important than the absence of what it's doing and I think, you know, we're going to understand a lot between the two and four but also importantly what the repeat dosing it 200 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. [inaudible]
Thank you so much Paul.
Absolutely, thank you.
Speaker Change: Thank you. Now next question, coming from the lineup, Catherine Novack, with Joon Strading Hill on his mouth and...
Hi, good morning, thanks for taking my questions. [inaudible]
Katherine Novak: I just wonder if you can give any more details about the multiple dose cohorts in AATD
You know, how many patients are you anticipating granularity? [inaudible]
Katherine Novak: as to when in 2025, which you expect this, and then in conjunction with that thought on the MAT threshold, you know, understanding that the protein is not functional, so we're not really looking at total AAT. Do you think, you know, consider the 20 micromolar MAT to be the threshold for success? Thanks.
Speaker Change: Yeah, so I think stepping back, the co-each cohort, as we said, is aid patients with repeat dosage. So we've been very clear with the number of patients are going to pay. Thank you very much.
Speaker Change: So, that'll be the totality of that data set and they'll have seven jokes. So, these patients are going to get-
Speaker Change: 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.
Speaker Change: Total data set from the single and the multi with which we can look at the dynamic effects of protein production.
Speaker Change: 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 11 micromole of the nature, 50% of that is M and the other part is Z.
Speaker Change: We're already at 60% edited M-protein looking at that total, so-
Speaker Change: To your point, we're still a measure, so I don't want anybody with insurance or something to interpret it. 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 and protein is it is critical because...
Speaker Change: The M-proven is only, again, produced based on the medicine's ability to edit the transcript. And so it gives the most insight into editing efficiency, protein production. And so therefore, we know that the M-Z phenotype is...
Speaker Change: A stable safe phenotype, and so therefore what we want to do is continue to push those patients forward.
Speaker Change: higher levels of M-protein. So we have substantial activity at the 200 mg. We're going to see what that does in a repeat dosing and, you know, we could reasonably expect to see not just that higher level of that M-protein, but really looking at how durable and sustainable that is as we think about dosing regimens.
Speaker Change: Got it, thanks. And then I had just one more on, you know, your thoughts on SIR&A OBC targets outside of Inhibiting, such as, you know, GPR 75, for example, is this something you could explore in conjunction with the Inhibiting Program? Thanks.
Speaker Change: Yeah, we think about a whole range of potential ways of using both S.I. R&A as well as petiting, that could be.
Speaker Change: I get the feel of metabolic disease. GPR 75 is orthogonal, so you know, it has-
Speaker Change: We've mentioned we do look at orthogonal approaches to treating obesity, and with our SIRNA technology, not talking about GPR 75 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. So we share that data as part of the data demonstrating distinguishing differentiation between our SIRNA technology.
Speaker Change: 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 gowness in the liver but also in CNS. So we are evaluating a number of targets within the metabolic field. [inaudible]
Got it, thanks very much.
Yeah.
Thank you [inaudible]
Speaker Change: Our next question coming from Delina, Ryan Desner with Raymond James, Yelena Snellpin
Speaker Change: Hi there, good morning. For the 007 program, what a late-stage clinical study is that in the therapeutic, as more of a maintenance therapy, you actually look like, and what would you anticipate in an initial label to look like for this program regarding positioning of the mono adon or maintenance therapy is successful? Thank you.
Speaker Change: Yeah, so I mean, I we do think a lot about the opportunities and I say more about the single dose and then the maintenance so we're gonna have to be generating that data as part of these data sets so we're gonna have a very good sense of. [inaudible]
Speaker Change: Behavior of Inhibiting is a single-agent therapy and what level of calcium-sustainable velocity and being able to drive that forward into a potentially representational study.
Speaker Change: I think the other study that we are excited to engage in, which is that you alluded to, is that off-ramp. And so being able to replicate that study that we have run.
Speaker Change: It is very feasible to look at patients on GLP1s that are stable on a GLP1 and then to be able to dose them with Trump and so the designing of those that next studies
Speaker Change: 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 essentially to use the clinic. But two, to also support a label for registration for reimbursement. So as we think about the total opportunity as both of monotherapy, but very, very important.
Speaker Change: 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 the therapies now can be withdrawn and studied in that context in a really substantial way. So we are have those plans otherwise.
Thanks for the question.
Thank you.
Speaker Change: Thank you. Now, last question, and cue coming from the line of Madison, El-Satley, would be by
Madison El-Sadi: Hi, thanks for taking our question. What are your plans for the MBA conference? Will you host an event around the conference?
Speaker Change: to provide that regulatory update. And then second, on 0, 0, 3, I know you had an updated analysis of CHDI. You mentioned in your prepared remarks.
Just wondering if you could kind of...
Speaker Change: Remind us or characterize the previously reported NFL data in terms of change from baseline.
Speaker Change: And then secondly, how do you see 003 profile relative to the Exxon 1 targeted candidates? Thanks.
Speaker Change: Yeah, 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 as MDA coming up. I think timing wise.
Speaker Change: So I think there will 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 Change: 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 presentation. As it relates to the 03 and I think this was a great conversation at CHDI. Thank you very much.
Speaker Change: We'll take the the Exxon 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 Exxon one hypothesis. And I think a lot of those concerns stem from the fact that when people went back and did the analysis of. [inaudible]
Speaker Change: Healthy Brains on MRIs, so patients who had autopsy but did not have HD in those who did, both sets of patients have X on one so it was not specific. Thank you.
Speaker Change: for Huntington Disease, and in fact a lot of the model systems, and I think it's always important, and HG is not unique in this.
Speaker Change: When you look at translational models to predict activity and what to expect in the clinic, so it's important to do more characterization on the animal mouse models. And so today, there's been a lot of changes that happen in mice models that don't happen in humans. [inaudible]
Speaker Change: I should also add that a lot of the data that's being presented around Exxon 1 and there was a presentation I believe at the Onylam R&D Day actually used WAVE allele-specific oligonucleotides.
Speaker Change: That were presented previously, and we had shared data that said that our allele-specific oligonucleicides, and this was shared as a CHDI presentation, actually demonstrated a benefit, and that that target happened to also coincide with Exxon-1 was picked up, and I think what ended up becoming is that that became an Exxon-1 study, but it was actually very importantly an allele-specific oligonucleicide study that being engaged with and work with some of the KOLs in the space. We weren't referenced in the presentation, but [inaudible]
Speaker Change: It is important that a lot of it emerging supported data on Exxon 1 are actually being generated with WAVE, a real specific oligonucleicides which, as we would expect if you reduce mutant Huntington protein and preserve wild sites, as we've shown not just in preclinical studies but ultimately in the clinic, you do see changes and potential benefits. So I highlight that around the Exxon 1 discussions today.
Speaker Change: As it relates to the NFL studies, I think a couple important things. One, again, in a full retrospective New England Journal analysis.
Speaker Change: of the Tillman Earth and Generation HD1 study. There was no correlation between NFL and clinical outcomes. So it's an important reminder.
Speaker Change: 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.
Got it, very helpful. Thank you Thank you.
Thank you for watching.
Speaker Change: Thank you. I'm showing no further questions. I will now turn the call back over to Dr. Paul Bonaparte.
Speaker Change: Yeah, 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 a forward 53. Have a great day.
Speaker Change: Who's going to today's conference call? Thank you all for your participation and you may now disconnect.
Thank you for watching!