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spk10: Good morning and welcome to the Wave Life Sciences first quarter 2021 financial results conference call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences. Please go ahead.
spk04: Thank you, Operator. Good morning, and thank you for joining us today to discuss our recent business progress and review Wave's first quarter 2021 operating results. On the call with me today is Dr. Paul Bolno, WAVE's President and Chief Executive Officer, Dr. Mike Panzera, Chief Medical Officer, Head of Therapeutics Discovery and Development, and Kyle Moran, Chief Financial Officer. This morning, we issued a news release detailing our first quarter financial results and provided a business update. This news release and a slide presentation to accompany this webcast are available in the investor 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 a number of 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, including our annual report on Form 10-K for the year ended December 31, 2020. 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. Paul?
spk07: Thanks, Kate. Good morning to everyone on the call, and thank you for joining us. During the call today, I will provide some opening remarks, after which Mike will give an update on our clinical trials, and Kyle will briefly review our financials. It has been an incredibly productive start to the year for WAVE as we advance three-and-a-half-generation stereopure oligonucleotides into clinical development. We have formally initiated clinical trials for WBE004, our C9OR72 candidate in ALS and FTD, and WBE003, our SNP3 candidate in Huntington's disease. We've also received important regulatory approvals towards initiating our third PN chemistry program targeting exon 53 in DMV, WBEN531. These clinical trials are designed to enable rapid proof of concept using biomarker-driven adaptive designs and are the first investigative candidates designed with our novel PN backbone chemistry modification. Next year, we expect that data from these clinical trials will enable decision-making about next steps for these programs, as well as provide insight into PN chemistry across different modalities, tissue types, and targets. We've also made substantial progress with our endogenous ADAR editing capabilities. which we believe is the most advanced in its class. We've generated a breadth of RNA editing data demonstrating activity across in vivo and in vitro systems, including in vivo editing in the central nervous system. Much of this data is being presented in an oral presentation tomorrow, May 14th, at the ASGCT annual meeting. Our first data editing program for alpha-1 antitrust and disease has generated promising initial results, and we are on track to share in vivo data this quarter. Our PRISM platform is unique and differentiated from others developing RNA therapeutics. At our foundation, we set out to embrace rather than ignore the reality and importance of stereochemistry that exists in each and every oligonucleotide. In choosing to control for the three-dimensional orientations of backbone linkages and advance single isomer therapeutics, we can apply the principles of rational drug design to our pipeline candidates, which is impossible with mixture-based oligonucleotides. This resolution enables us to define distinct profiles for our stereocure molecules, and we now have several years of clinical data to further inform our platform. Earlier this year, we announced the discontinuation of our remaining first-generation programs following the results of the PRECISION-HD trials. While we only saw modest and inconsistent reductions of mutant Huntington, it is important to note there were no clinically meaningful trends in disease progression or laboratory values, such as elevations in CSF white blood cells, proteins, and neurofilaments, light chain, or NFL. There were, however, suggestions of allele selectivity, underscoring the precision enabled by our platform. In our next generation programs, We've prioritized the use of in vivo models during preclinical development to ensure we advance clinical candidates that will reach the desired site of action and engage targets. In addition to the wealth of data collected over the past several years, we're also leveraging an influx of new talent in oligonucleotide therapeutics to further advance our understanding of design principles, pharmacology, and toxicology. The application of PN backbone chemistry modifications in the context of controlling stereochemistry was a major advancement that emerged from our platform. And based on what we have seen preclinically, this innovation has the potential to significantly improve the profiles of therapeutic oligonucleotides, independent of sequence, tissue type, or modality. Separately, our ADAR editing capability further expands our toolkit beyond silencing and splicing, enabling us to select the best modality to address the root cause of genetic diseases. We anticipate sharing more on PN chemistry and ADAR editing at a research day later this year. Our current pipeline is comprised of programs designed with next generation of PRISM, including PN chemistry. I am extremely proud of how quickly we have advanced this innovation to the clinic, and we are rapidly approaching the first of many opportunities for clinical proof of concept of PN chemistry. I'd now like to turn the call over to Mike Panzara for an update on our neurology programs. Mike. Thanks, Paul.
spk05: The foundational work that has been done throughout the evolution of PRISM has provided us with a diverse and robust neurology-focused portfolio that is currently moving through stages of preclinical discovery and clinical development, as illustrated here. As Paul just mentioned, all of our current discovery stage and preclinical programs utilize PN chemistry, including the multiple discovery programs in collaboration with our partner Takeda. These programs are yielding exciting results, including target engagement and distribution in the central nervous system of non-human primates, which further validate our approach. Our therapeutics discovery portfolio continues to build upon this progress to maximize the potential of oligonucleotide therapeutics for the treatment of neurological disorders with high-end metanase. Now I'd like to discuss the programs currently in clinical development with three next-generation candidates. Our development organization is focused on site activation and initiating dosing simultaneously in three clinical trials across four disease areas. C9ORF72-associated myotrophic lateral sclerosis, or ALS, and frontodermal dementia, or FTD, with WVE004, our candidate targeting C9ORF72 hexanucleotide repeat expansions, Huntington's disease, with WVE003, our SNP3 targeting candidate, and Duchenne muscular dystrophy, with WVEN531, our exon 53 skipping candidate, Each of these clinical candidates incorporates PM chemistry, and the availability of relevant preclinical models has enabled a greater understanding of PK-PD relationships to guide development. Further, the learnings from our first-generation programs are being incorporated to mitigate risk and more efficiently execute our plans. Starting with T9R72. Our clinical candidate, WVE004, is designed to target a hexanucleotide repeat expansion in the C9RF72 transcript, which is one of the most common genetic causes of ALS and FTD. These expansions drive the common pathophysiology underlying these two diverse and devastating phenotypes. And 004 is the first C9RF72 candidate being advanced simultaneously in a single basket-like study for both C9ALS and C9-FTD. C9R72 mutations lead to multiple drivers of toxicity. The hexanucleotide repeat containing RNA transcripts deposit in tissues and are toxic on their own, but they are also translated into long dipeptide repeat proteins, or DPR proteins, that trigger cellular toxicity through a variety of downstream mechanisms. 004 selectively targets the pre-mRNA ovarian transcripts that contain the hexanucleotide expansion with the goal of suppressing both the RNA and DPR-associated toxicities while allowing C9L protein expression. In the first quarter, our foundational work to identify and validate the targeting site used to achieve this selective knockdown was published in Nature Communications. On the right of the slide 11, you can see the preclinical data that demonstrates 004's ability to rapidly and durably reduce over 90% of the DPR polyGP in the spinal cord and reduce at least 80% of polyGP in the cortex. This effect lasted at least six months only after two ICV injections of 004 administered seven days apart at the start of the study. T9 ORF72 protein was unchanged over the same period. The effect of 004 and polyGP in the CSF is a key endpoint in our clinical studies, so we were looking forward to assessing the impact of treatment in humans given these promising preclinical results. These results, along with data from non-human primates, have also allowed us to start at a dose in our clinical trial predicted to be pharmacologically active. This week at the European Network to Cure ALS Virtual Meeting, or NPALS, we introduced FOCUS-C9, an adaptive trial that is designed to enable faster optimization of dose and frequency of 004 based upon review of unblinded data throughout the study. FOCUS-C9 is a Phase 1b2a global, multicenter, randomized, double-blind, placebo-controlled trial in which we are planning to enroll approximately 50 patients with documented C9472 expansions and confirmed ALS, FTD, or mixed phenotypes. Focus C9 includes single and multiple ascending dose portions of 004 administered intrathecally. At points throughout the study, based upon predefined data-driven milestones, an independent committee will review unblinded data to determine the next single dose level to be escalated to, and the optimal frequency in the next multi-dose cohort, meaning whether the dosing interval should be monthly or less frequent. Samples are collected for biomarker analysis at multiple time points within both the single and multi-ascending dose portions to enable the assessments required to make these recommendations. Regulatory and ethics approvals have been received and clinical site activation is underway, so we anticipate dosing sometime soon. I'll now turn over to WVE-003, our allele selective candidate for Huntington's disease, which is designed to selectively lower mutant Huntington while preserving wild-type Huntington. The presentations, posters, and feedback from experts at the recent virtual CHDI-HE Therapeutics Conference only serve to bolster our confidence that we are pursuing the right approach to Huntington's. Let's review what we know. Patients with Huntington's disease have an expanded CAG repeat in their Huntington gene that leads to production of mutant Huntington protein. This is a monogenic, autosomal dominant genetic disease that is fully penetrant and affects the entire brain. Preserving wild-type Huntington is as important as lowering mutant Huntington. Add-in supports that Huntington's disease is driven by both the gain of function of mutant Huntington protein and the loss of function of wild-type protein. which is essential for homeostasis of the central nervous system. Wild-type protein is critical for the protection of neurons that are under stress and plays a key role in trafficking synaptic proteins and vesicles, including the production and transport of brain-derived neurotrophic factor, or BDNF, in the cortex. Wild-type protein is also critical for the formation and function of celiac, which control the flow of CSS, and help maintain CNS homeostasis. In healthy individuals, these important functions of wild-type Huntington balance out the collective stresses based on the central nervous system. However, in the case of HD, there is the added burden of the mutant protein itself. Those living with HD have been subjected to decades of toxic stress that come with mutant Huntington protein years prior to symptom onset. Looking at levels of wild-type and healthy individual or model that lack the effect of mutant protein does not adequately represent the role the healthy protein plays in the context of Huntington's disease. This smaller protective reservoir of wild-type Huntington eventually loses the battle to the expected stresses placed on the CNS along with the toxic effects of mutant Huntington, resulting in disease progression. If one thinks about this as a push-pull of positive and negative factors, In this balance of wild-type and mutant Huntington in the CNS, it stands to reason that depletion of wild-type protein along with mutant protein, as with non-selective approaches, could shift the balance towards disease progression erasing any benefit, or even potentially accelerating decline. This has been our hypothesis since we began our HD program, and the data that are emerging support our position and make us resolute in our differentiated approach to treating this disease. 0-0-3 has been improved over our prior SNP-targeting candidates by applying PM backbone chemistry modifications in the context of control over stereochemistry. Further, the presence of this SNP in a relevant animal model has allowed us to do in vivo preclinical work to determine a dose predicted to be pharmacologically active right from the start of ERS-CoV-1. Slide 16 illustrates some of these in vitro and in vivo data demonstrating that 003 is highly selective for mutant Huntington and able to achieve potent and durable knockdown of mutant Huntington in vivo in the back-HG mouse model. We investigated this model knowing that there were several limitations, including the fact that it contains multiple copies of the MHTT genes, some of which do not have the SNP-free variant. Nonetheless, as shown in the bottom of the slide, we observed potent and durable knockdown of mutant Huntington in the striatum out to 12 weeks, a similar effect observed in the cortex. Non-human primates do not have SNP3, and as such, we are not able to evaluate the pharmacodynamic effects in this model. Therefore, we used the concentration data from the back HD mouse compared with tissue concentrations in the CNS of non-human primates. and then used PKPV modeling to estimate tissue concentrations required to achieve straddle and cortical knockdown in humans with 003. These analyses are guiding the starting dose and dosing regimen plan for our clinical trial. While target engagement studies in the CNS of non-human primates were not possible for 003, they were possible for our most advanced therapeutic candidate in our CNS discovery collaboration with Takeda, WVE005. Like 003, this candidate uses PN chemistry. But unlike 003, the human transcript targeted by 005 is homologous to the monkey sequence, allowing us to assess target engagement throughout the CNS. In this study for an undisclosed target, non-human primates received a single 12 milligram intrathecal injection of 005. One month after administration, we observed that the candidate was widely distributed throughout the CNS and led to substantial knockdown of target, including in the striatum. This experiment once again highlights the potential of this next-generation chemistry. In the first quarter, we received regulatory and ethics approvals to initiate SELECT-HD, a Phase 1b-2a global multicenter randomized double-blind placebo-controlled trial of 003 in early manifest HD. targeting enrollment of approximately 36 patients carrying SNP3 in association with the expanded CAG repeat. Patients from the precision HG studies will be able to transition to select HD after a washout period, assuming they meet other inclusion and exclusion criteria. Unfortunately, based on the recently disclosed safety and efficacy data, patients who received active treatment with tomonersen in the generation HD study will not be permitted to enroll in SelectHD, although those who've received placebo in Generation HD are eligible to be screened for study entry. Like Focus C9, SelectHD has an adaptive design to enable optimization of dosing frequency and more rapid determination of target engagement. An independent committee will evaluate unblinded data in an ongoing basis to guide dose escalation and dosing interval in each cohort. Key objectives, in addition to safety and tolerability, include plasma PK, CSF exposure of 003, and changes in key biomarkers, including mutant Huntington, wild-type Huntington, and neurofilament-like chain over the course of the study. Clinical site activation is underway, and we expect to dose our first patient soon. WVE-N531 is our systemically administered candidate for patients with Duchenne muscular dystrophy, or DMD, that are amenable to exon 53 skipping. This is also our first stereotrip splicing candidate designed applying PN chemistry. As we have shared previously, when applying this format to an exon 23 targeting surrogate, Treatment of an aggressive double knockout or DKL mouse model lacking both utropin and dystropin resulted in rescue of mice treated with 75 milligrams every other week as compared with PBS or first-generation chemistry dosed at 150 milligram per kilogram weekly. Once again, application of the PN backbone modifications had a profound effect. In March 2021, we initiated clinical development of N531 with the submission of a clinical trial application. Since then, we've received regulatory approval for an open-label clinical trial that is powered to evaluate whether N531 dose every other week increases to show up in production in up to 15 boys with DMD. The trial will also assess drug concentration and muscle and initial safety. Dosing is expected to initiate this year. I'll now pass the call back over to Paul to discuss our 8R editing capability and upcoming milestones there. Paul?
spk07: Thanks, Mike. We continue to generate compelling RNA editing results with our 8R editing capability, which we believe has many advantages over others and positions us at the forefront of this space. As a reminder, our approach to RNA editing employs short, fully chemically modified oligonucleotides to recruit endogenous RNA editing enzymes called ADAR. Our ADAR editing compounds are optimized using our proprietary stereochemistry and PN chemistry, which enables us to avoid delivery vehicles such as AAB vectors or nanoparticles and allows us to leverage established manufacturing processes. To date, we've demonstrated editing activity across in vivo and in vitro systems, including durable RNA editing of up to 50% in non-human primates with galnet conjugated oligonucleotides. Our 8R editing oligonucleotides are also highly specific. Our practical approach to RNA editing opens the door to a number of therapeutic applications, such as restoring or modifying protein function and upregulation of protein expression. These applications greatly expand the landscape of disease variants that we can potentially address, and we are advancing discovery work for multiple 8R editing targets as well as evaluating new potential targets. Our first ADAR editing program uses a GalNec conjugated oligonucleotide to correct the single RNA-based mutation in the mRNA coded by the serpent A1Z allele, which triggers alpha-1 antitrypsin deficiency, or AETD. ADAR editing is a simple and efficient approach to treating this disease by simultaneously reducing aggregation of the mutated, misfolded alpha-1 protein and increasing circulating levels of wild-type alpha-1 antitrypsin protein, thus addressing both the liver and lung manifestations of AATD, all while avoiding the risk of permanent off-target changes to DNA. Last year, we successfully demonstrated upwards of 60% editing of the SERPIN A1Z allele transcript to wild-types and hepatocytes in vitro, which led to a three-fold increase in functional wild-type AAT proteins. Encouraged by these results, we move forward to successfully develop a proprietary transgenic mouse model containing both humanized serpent A1 and humanized ADAR that enables pharmacokinetic and pharmacodynamic assessment of human sequences in vivo. We are on track to share in vivo data from this model in the first half of 2021. We expect to present additional data at a scientific congress later this year. These in vivo results are expected to enable lead candidate optimization, as well as inform potential preclinical development studies and timelines. In summary, 2021 is a year of execution for WAVE and a busy time as our next generation pipeline advances in the clinic. As you heard today, we are advancing three unique clinical programs that will each provide insight into our novel PN chemistry and potentially rapid proof of concepts and clinical validation of our platform with biomarker data. We're making excellent progress with our ADAR editing capability, and in addition to the expected in vivo data update for AATD that I just mentioned, I look forward to speaking further about our RNA editing platform at a research day later this year, which we expect to share more details about on our next quarterly call. I will now turn the call over to Kyle Moran, our Chief Financial Officer, to report our financial results before turning the call over to questions. Kyle?
spk06: Thanks, Paul. We ended the first quarter with $148.5 million in cash and cash equivalents and marketable securities. This balance does not include an additional $30 million in committed research support that we received in early April under our collaboration with Takeda. Our total operating expenses for the first quarter of 2021 were $43.4 million as compared to $54.2 million last year. R&D expenses were $33.4 million as compared to $41.2 million in the same period 2020. This decrease was primarily related to a decrease in external expenses related to our discontinued Subadresin program, as well as decreases in compensation related and other external expenses. Partially offset by increases related to our clinical and preclinical activities, our hd programs and c9 or 72 program for als and ftd dna expenses were 10.1 million dollars for the first quarter of 2021 as compared to 13 million dollars last year with the decrease driven by lower compensation related and other external expenses finally we continue to expect that our existing cash and cash equivalents together with our expected and committed cash from our existing collaboration will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include potential milestone payments or other uncommitted payments under our together collaboration.
spk07: Thanks, Kyle. With that, we'll open up the call for questions. Operator.
spk10: Thank you. To ask a question, you will need to press star 1 on your telephone. And to withdraw your question, just press the pound key. please send Bob to compile the Q&A roster. Our first question will come from Salim Syed from Mizuho.
spk09: You may begin. Hi, good morning. This is Mike Linden on for Salim. Thanks so much for taking our questions, a few if possible. First, on the C9 trial design, just wondering about the protocol and how adapted these trials would be. Are they being written to be able to enroll many of the hundreds of patients and potentially be converted to registrational? I'll follow up after that.
spk07: Thank you. I'll pass the call over to Mike.
spk05: Yeah, hi. So I, you know, the way the study is designed is you can see it allows the study to be expanded as necessary to collect additional information. I mean, we made it flexible about to enable us to really, once we get recommendations from the independent committee on next steps to be able to adapt the study as necessary. So, I think we'll have to wait to see what the data show, but it's our intention to make it adaptable and flexible to enable us to direct it the way we need to, to understand the clinical meaningfulness in both ALS and AETD.
spk07: So it can expand on the number of patients based on the committee's assessment, Dan? That's the specific question, yes.
spk09: Great, thank you. And one on AETD on the upcoming data. What would you be looking for specifically to move forward into the clinic or not? How would you prioritize this if it did move forward versus the other pipeline programs?
spk07: So the prioritization for AATD and the reason we worked on generating the model was really driven based on identifying, one, the production of the protein. So again, not working on what a percent editing is. That's interesting. But what drives the progress on a medicine is does it generate the protein? So one will be protein production. Other features that we'll be evaluating, obviously, are protein, not just protein production, but protein function. So we'll be able to look at a number of those assessments, and that's going to guide our decision on translation.
spk09: Okay, great. Thank you. And last one on Alzheimer's disease mentioned today. After the denatomab data, how are you thinking about treatment, specifically from the ASO side, maybe what should we think about in terms of potential targets?
spk07: So just for clarification, I want to make sure on the, you might be thinking about frontal temporal dementia. I just want to make sure we're not thinking about Alzheimer's. So we have FTD, so frontal temporal dementia, otherwise I think it's frontal temporal degeneration is, is the one area of dementia that we mentioned today. So I want to be careful that, you know, we didn't discuss Alzheimer's disease as a, as a target therapeutic, but happy to discuss. anti-sense treatment and therapeutics for the treatment of CNS and neurologic diseases more broadly, if that's the question. But I just want to make sure we get your question correct. Yes, that would be helpful.
spk03: Thanks.
spk05: I was going to say, I was going to say that, yeah, I mean, we're, as you see with the FOCUS-C9 study, the emphasis on FTD getting patients in, and actually the cortical effects that we saw in the preclinical models make us very excited about being able to access the CNS to be able to have an effect on FTD. It's, you know, we're going to be using clinically some of the clinical outcome measures that you'd want to measure cognitive change in our FTD study to be able to get at that question.
spk07: I mean, I think if we step back and think about neurologic diseases more broadly, I mean, I think one of the data sets that's compelling that Mike shared, in addition to a number of the in vivo mouse studies, is we see really great intrathecal distribution across the brain. So I think as we think about distributing to the regions of the brain that are necessary for a whole variety of neurologic diseases, we see intrathecal administration delivering this. That's not different than some of our colleagues in this space discuss around distribution. So we do believe antisense oligonucleotides can distribute. What we see with the PN is this broad distribution. So this addition of higherly controlled. So the data we're generating, the value of stereochemistry we said beginning and addressing the reality of it is all the assessments of targeting agent we're seeing are with the actual compound because we're not dealing with a mixture of 523,000, 24,000, 233 different molecules that can distribute differently. So by having single drugs, We know that the knockdown that we're seeing is based on the design of that single oligonucleotide. And I think what we've also seen is the benefit of durability. So as Mike said in the adaptive design piece, we're going to be testing and exploring that in the clinic. And so as we think about chronic administration of medicines in a whole host of different diseases, Importantly is dosing frequency. So being able not to sacrifice potency for dosing frequency is something that we're excited to continue to explore in the clinic. So as we think about the future of antisense oligonucleotides for the treatment of neurologic diseases, we think the future is promising in a data-driven way. And we'll be assessing that further across three clinical studies currently. So I hope that answers your question. We're always happy to explore that more. But I think the future looks bright for treating genetic diseases with oligonucleotides.
spk09: Thanks. That's super helpful. I guess what I was referencing was just the mention of Alzheimer's in the press release, along with other CNS indications.
spk03: Okay. Hi.
spk07: Okay. Oh, sorry. Sorry. Now I'm looking at them. I think we were talking, now I know where you're going, which is the holistic list of targets that we've been exploring in the Decatur Cloud, large indications, where we said, for example, that's why we're thinking about indications. We said, for example, what represents large neurologic indications? So Parkinson's, Alzheimer's, and other large indications. So thank you. I apologize for our... We were focused on the pipeline that we're exploring as opposed to what the potential is. So apologies for our... Misunderstanding of your question.
spk10: And our next question is off the line of June Lee from Chewis. You may begin.
spk08: Hey, thanks for taking our questions. For all of your CNS programs, in addition to the new and improved backbone chemistry, have you considered a different route of delivery? Another company has recently disclosed proceeding with intracerebral ventricular routes. using a lawyer port, I believe, for Huntington's disease. It does give you more direct access compared to intrathecal, and I'm not aware of any IP that prevents you from doing that. So I would appreciate if you could provide some perspective there and have a follow-up question.
spk07: Yeah, I mean, there's always opportunities to think about different approaches. When we think about permanent catheter placements and other, you know, drilling holes and skulls for delivery, I think our first question always is about what problem, and this is true for anything, what problem are we trying to solve for? So I think as we currently think about the data that we generated to date, intrathecal access to the central nervous system is available. We've shown that now in intrathecal non-human primate studies. We've looked at ICV injections in mice, and we see correlation in terms of distribution in CNS tissue. To date, to look at, and if we, again, also see durability, which we're assessing in the clinic, the less frequent administration also calls the question that it's not without risk to leave permanent doiling catheters in the CNS. They can get clogged. They need to be changed. And so, again, it really comes down to what is the, and every medicine is different. So we can't speak for other companies and what challenges they're addressing using the delivery mechanisms. what we assess with ours is, what are we solving for? And so when we think about intrathecal distribution, as we've demonstrated across multiple tissues, utilizing the PN enhancements on our medicines themselves, we don't right now see that. As we look at durability and different indications, we could want to solve other problems in the future. It could come up, but right now, that doesn't seem to address the solution that we have with the current administration. Mike, I don't know if there's any.
spk05: No, I'm just going to, I would just say the same thing. It's like you have to, in general, you want to go for the simplest form of administration you can that gives you the access you're looking for. So, you know, given the progress we've made with accessing all parts of the brain and these diseases through intrathecal administration, that would be the simplest approach, especially as Paul indicates, when you're talking about the durability of effect after single doses, that leads us to the approach that we don't need to do ICV with a catheter, and we can do what's necessary doing something that any neurologist can do.
spk07: I think the other thing we have now, and we have the benefit with an extensive amount of time now, been able to explore multiple animal models across multiple species. Again, ICV in mice, intrathecal in non-human primates, We also have clinical data to look at distribution, as we shared in our experience in Huntington's, understanding different concentration levels with different backbone chemistry. So I think as we look at the totality of data that we've generated and the totality of generated that our colleagues and other companies have generated, I think we see meaningful changes with the implementation of the PM backbone that's translating into animal PKPD that we're exploring currently in the clinic through adaptive designs that are gonna give us answers in the clinic.
spk08: Got it. And looking forward to your AR presentation tomorrow at HCT. Now, can you talk about some differences between the approach you're taking with, you know, galnet conjugated that RNA versus circular guide RNA that that's being presented used by another company, I guess we'll find out tomorrow, but just wanted to get an input that you can share on what we should be focusing on tomorrow and some perspectives on the pros and cons of different approaches. Thank you.
spk07: Yeah, I mean, I can't speak necessarily for the pros and cons of others. We're all learning about the other approaches to treating. I can speak about our approach, which, importantly, GALNIC is not, let's say, an approach. GALNIC is a targeting way for the tissue target of interest. So one of the advantages when we built the ADAR platform from the beginning, and we demonstrated this with some of our CNS data as well, is that where short oligonucleotides go and distribute, we can generate an editing capability there. So we've done and looked at that in vivo in our CNS, so looking at non-galnet conjugated distribution and correction. What we're looking at for AATD, obviously, as a hepatic target and a hepatocyte, is galnet then becomes an advantage because we can just target the cell type of interest. So I think what's really important from a platform perspective is the platform is can exist without GalNac, but we are using GalNac as well where we think about the liver specifically. So I think, you know, on both the platform context, we think we've got a really interesting approach in that we don't need to use various delivery vehicles. We can take all of our learnings around stereocontrolled PN-containing oligonucleotides and continue to demonstrate and learn from data that we've generated across multiple species and even past clinical studies experience learning about stereocontrolled oligos. and apply that to this data platform and take the advantage of, you know, Galnet conjugation for specific hepatocyte targeting. And, you know, I think tomorrow as we start to learn more about what's happening across the field, we'll be able to parse that out more, but we're excited to have a presentation tomorrow and really be there again at the forefront of ADAR RNA editing to be able to share those data.
spk08: Great. Thank you.
spk07: Yeah.
spk10: Our next question will come from the line of Manny for Ohio from SGP Link. You may begin.
spk02: Hey, guys. Thanks for taking the question. I'll ask one quick one on enrollment. When we look at rolling over placebo patients from Generation HD into Select, how many of those patients are still eligible? I worry a little bit that these patients, obviously Huntington's is a relentlessly progressive disease, so some proportion of those patients may now be meaningfully more severe than they were when they were first screened for generation. And then secondarily, whenever, based on whatever portion of those patients are likely, in your view, to roll over, how much of a head start does that give you on enrollment, InfoX, and, you know, are there other mechanisms that you can pursue, sort of changes in trial process to sort of accelerate the completion of enrollment there, given there were a couple of delays and hiccups along the way for generation previously?
spk07: I'll pass the question to Mike.
spk05: Yeah, no, hi, thanks. So regarding the movement from Generation HG, you know, right now, the way it stands is patients have, don't have, it hasn't been disclosed to patients whether they've been receiving placebo or active treatment. So we're hopeful that that will happen. And then patients can make the choice about whether they want to do that transition. And we're not exactly sure when that will be. But we're hoping that that happens relatively soon as we have disclosed to all the patients now what they've been receiving. Second of all, there is that possibility that patients will have progressed out of our inclusion criteria, which is why they are going to have to be rescreened for both inclusion and exclusion, including whether they have SNF3. So that'll be an important inclusion-exclusion criteria. But as we think about the overall population, we'd expect about 40% of them are essentially to have the appropriate SNP. Regarding the other operational things to help move things along, we've learned a lot from the generation, from the Precision HD1 and Precision HD2 studies. We've learned a lot about how to operationalize intrathecal administration more efficiently. We have a lot of site overlap between Generation HD and Precision HD, which has allowed us to paste our positions to get experienced in the screening process. We have new laboratories to do SNP identification. You know, there's a variety of things that have really helped accelerate, make us feel comfortable that we'll be able to accelerate the recruitment for Select HD, including the addition of regions that we know have higher representations of SNP3. So there's a variety of things we're doing that we're comfortable will help. In addition, with the adaptive design, you know, there's going to be all along the way, the committee is going to be looking at unblinded data to guide next steps and make recommendations. So that in and of itself is a huge change versus data generation and precision HD1 and 2. All right, thanks.
spk10: Our next question I'll call for will be Paul Matais from Stifel. We'll begin.
spk11: Thanks for taking the question. This is Alex. I'm for Paul. A couple questions on SNP3. You know, I appreciate the 005 targeting engagement data in nonhuman primates, but I was wondering if you could, you know, maybe quantify a little bit of the biodistribution that you mentioned you're seeing in non-human primates with o3 that you're using for the pkpd modeling knowing that's not really a disease model but anything you can say there would be really helpful and then secondarily i'm curious if o03 targets the exxon one fragment of mhtt and generally your thoughts on you know the exxon one fragment as a potential driver of pathology and hd thanks
spk07: Mike, you want to start?
spk05: Yes. So, I mean, regarding the non-human primate data, I think that what I can say about the distribution in the non-human primate, even though it's not targeting engagement data for the SNP3 compound, we are very clearly able to achieve concentrations throughout the brain, including in deep gray structures and striatum, that would be predicted to engage target based on what we have from the back HD. And a very large window to be able to dose escalate to, again, engage target. So I think that we are quite comfortable, based on the preclinical data we have, that we are able to get into the regions that matter and engage target. And again, we're starting at a dose. that we believe is pharmacologically active right from the beginning and then the committee will tell us how close we are to that and then be able to adjust as necessary so that's regarding um that now in terms of the in terms of exxon one and what we think there i mean as we said previously um that you know a lot of the exxon one data i mean this is from post-mortem this is from It seems to be most relevant in those with extremely long expansions. Nonetheless, you know, when we're bringing down mutant protein, we would expect to be able to also have an impact on XM1.
spk07: Yeah, just to add to that, I mean, antisense oligonucleotides can reach intronic and exonic transcripts, so we should therefore hit XM1. But as Mike, I think... The most important piece, I think the data is still, you know, independently of whether or not we hit it, I think that the data is still questionable and beyond really, really long repeats. So I think as we go back and think about our targeting for SNP3, I think we can leverage a ton of experience with SNPs 1 and 2 and what we've seen in general with the enhancement of PN chemistry in certain districts. I think we can see and believe that mutant protein suppression is important. Yes, we're distributing and knocking down the mutant protein, but I think what we've learned a lot about in the first clinical trial and silencing is, and Mike alluded to post-CHDI, is a substantial focus in doubling down on our efforts that wild-type sparing is as important a driver in disease pathology as mutant protein production is. the approach that we set out two years ago established for the treatment of disease which is wild-type sparing mutant reduction you know we believe is the way to address pathology and we'll be happy generating clinical data and be able to assess that again with um step three using the new pn chemistry great thanks so much our next question will come from right uh young from jeffries you may begin
spk01: Thank you. I have a few questions. First, on ATD program, so Paul, as you mentioned, it's not just editing efficiency. You've already shown 50% in non-human primates, but producing wild-type AAT proteins and then function. So the question to you is that do you know what level of normal of wild-type AAT protein is needed in order to see some clinical benefits? What's the kind of a minimum level? So that's question one. And second question is on 004. So you are already doing site activations. So when should we expect clinical data from this trial? And lastly, The additional $30 million that you received from Takeda in April, how would that be amortized in income statement? Would that be similar to what you've done in the past? Thank you.
spk07: All right. Well, the good news is you're getting a lot of voices around the table, so it's great. I'll take the AAT question. I'll pass the mic for the second one. Kyle can answer the treatment version. Your important question is, how do we look at this in vivo data that's upcoming, and how are we looking at that in terms of advancing AETD program? I think when we think about alpha-1 antitrypsin, and I think you're spot on, we're looking at protein levels, but the SERPIT-A1 model is different because they're all, they're in humans, let's say, in that you can generate protein. And I think we'll be looking at levels of protein generated in that model to be able to model that towards kind of where one would expect to be at the human level. I think to date, one sees kind of a threshold level around 11 micro molar protein to be clinically relevant. That's kind of the basis for the number of the protein infusion products. And we know that the protein infusion products tend to tail off at the end because the protein degrades and then they have patients have to be redosed on a weekly basis. So these patients have these gaps in treatment. I think if we can have sustained correction where you don't have those drops, we would see that kind of this minimum threshold criteria where not only are we treating the hepatic issue, but really at that level, know that you're at levels that can treat the pulmonary complications. I think that would be exciting. But I think the key for us, and as we generate that data and share that more broadly, Exactly to that point, that's the data that we'll be assessing from those models in terms of translation. And I think the important piece there that we'll be assessing as well is not just the protein production, but as we demonstrated before from the in vitro correction of the AAT protein is that, you know, we could generate it and it was functional. We want to see that replicated now in the animal model. So I think we're taking the deliberate approach to make sure we generate the preclinical data that's going to position us for thinking about how this program transitions. And I think that's why we've been excited to date one around the AETD program, but I think more broadly what it really represents in WAVE's ability to bring ADAR editing into patients across a whole variety of indications. Importantly, CNS indications as well, where we don't need GalNex to be able to target neurons. So I think there's a whole variety of approaches that we can take, but obviously, able to look at on a corrected protein and be able to study that more broadly. I'll pass. Any questions? Just because of the difference, I'll just say, are there any questions there? And if not, I'll hand over to Mike to address your question. Mike, do you want to take the next one?
spk05: Sure. I mean, also, I mean, regarding next year, I mean, you know, we have three biomarker studies underway that are going to allow us to have, with these adaptive designs, that are going to allow us to have a continuous Flow of data and that's that's very exciting and I mean specifically regarding zero zero one as I indicated We're going to be dosing soon and we'll have a good sense of how the studies are moving throughout the year But what we share from the studies is going to be informed by how the studies proceed the types of data that comes in the meaning the meaningful whether there's a meaningful number of patients at any given point time and and whether the feedback we receive from the independent committees. And that feedback is going to be coming in throughout the course of this year and next. And from there, we'll guide when we disclose data and what that data will be. And we anticipate data, however, during this time that will enable us to make decisions and then provide greater insights into the chemistry. So that's sort of how it's proceeding now. It's obviously going to be driven by how quickly we can get those patients in, and we're optimistic now given site activations and the fact we're going to be dosing soon.
spk07: But it is an important notion when we think about just the adaptive design principle of running studies, which is different than running kind of mile marker driven studies where you've got to aggregate the data, then analyze it and aggregate and then flip the card at the end. I think, as Mike said, data is evaluated in an ongoing way by an independent committee that's going to inform things. And with those studies running now and data being generated this year and next, I think there's a variety of times where, you know, those committees could like share data. It's a little less specific, and as Mike said, we'll be able to provide more updates to guide us along the way. Tyler, you want to take the 30-minute treatment of that?
spk06: Yeah, thanks for your question. And your assumption is correct. We would account for that in the same way that we've accounted for the upfront cash payments and other committed cash payments we've gotten today, you know, with the gap revenue and amortization.
spk01: Thank you. Thank you.
spk10: And once again, that's star one for questions. Our next question will come from Luca Issi from RBC. You may begin.
spk00: Oh, great. Thanks for taking the question. This is Lisa for Luca here. A couple questions for us. So first one, you know, we have obviously seen the Phase III data from Rosh Ionis, and it seems to me that their ASO may have had a detrimental impact to patients versus placebo, as placebo directionally outperformed the high dose. And we have seen a dose-dependent increase there in ventricular volume in the brain. Did you have the same read on this data? And if so, do you think that it's possible that a wild-type sparing approach may not have caused a detrimental impact here? And the second question, you know, you've obviously discontinued SNP1 and SNP2 with the old chemistry. Just wondering, what is the plan going forward? Are you planning to explore the PN chemistry for SNP 1 and SNP 2 or only for SNP 3? Thank you.
spk07: Thank you. You know, to take the of your version, and I think like everybody else, we have to view it as we're only seeing what everybody else is seeing from the outset. So it's hard to comment on. what they saw. I think objectively you pointed out what they saw, which was a dose dependent change in clinical measurements. And importantly, those clinical measurements were cortical and striatal. So I think it's, you know, there's a jump to distribution. I think it was a broader question than just striatal distribution. So, I think as we think about that data in the context of the biology, as Mike laid out on this call, you know, I think very, very well, we do think that there's two approaches of one characterization of drug. One is obviously, to your point on hypothesis, wild-type sparing, and that if one thinks about the disease as both one of a toxic gain-of-function and a toxic loss-of-function, taking that below the 50 percent, I know there's a lot of discussion after Roche is data, people just saying, well, studies have been done in 50% reductions in normal animals and shown it's safe. I think one has to remember that the situation that those animals were under were one of 50% reduction of a normal phenotype. What we're dealing with in Huntington's patients, as we kind of have been explaining for a while now, is that those reductions that are being studied in the clinic are reductions that are happening in the setting of already a 50% reduction and under the setting of stress of patients who are progressing in disease. So one has to think about the totality of removing the neuroprotective feature of wild-like proteins, a whole host of other functions, including the cilio function, which involves CSF flow. Those are really important characteristics. So, yes, I think that's something that needs to be explored. And I think that's why we're excited about seeing that. I think we were also, you know, happy in the analysis that patients on the studies that we were looking at didn't progress. Now, you know, take that for where it is. I think as other characterization, you know, we didn't see increases or elevations in white counts of protein in NFL. So, I think if we think about the totality of both the oligo approaches as well as the wild-type sparing, I think that's driven why we believe a stereo-controlled approach of wild-type sparing is important. It's why we're excited about bringing PN into the clinic with SNP3. And to your question, yes, we can apply and have generated early data around being ready with SNP1 and 2. I think the measured approach we're going to take with PN chemistry I think the measured approach right now is, as Mike alluded to with the trial design, is let's get the data with PN chemistry with SNP3 and use that as a driver before spending more resource on SNP1 and 2. But yes, we are prepared to go back to looking at the totality of HD with an allele-specific approach.
spk05: I don't know, Mike. No, I mean, just, I mean, Mike, listen, we've been concerned from the beginning. that a non-selective approach could have detrimental effects. We have said that first, and that's why we're doing what we're doing. There are a lot of reasons that could be assessed for what happened with that phase three study, but certainly effects on wild type have to be part of the consideration, which is why, you know, we're making our wild type assay available. It's an important data set we need to understand, but we're concerned enough That we are, unfortunately, we said initially we would allow patients who have been treated with tomonersin in select HD. We've had to now not do that out of whatever is happening there because we're concerned enough not to unfortunately have to exclude those patients. So it's a concern. It's an observation. It needs to be studied. We have the tools now to study it, and we're hoping that the community asks these questions because we believe it's important.
spk00: Great. Thanks for taking our questions.
spk06: Absolutely.
spk10: Thank you. I see no further questions in the queue. I'd like to turn the call back over to Dr. Paul Bono for any closing remarks.
spk07: Thanks, everyone, for joining the call this morning to review our first quarter 2021 corporate updates. And thank you to our WAVE employees for their hard work and commitment to patients. We look forward to speaking to you all again soon. Have a nice day. Thank you.
spk10: This concludes today's conference call. Thank you for participating. You may now disconnect.
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