Wave Life Sciences Ltd. (WVE) Earnings Call Transcript & Summary

Great. Hey, everyone, thanks for joining us. I'm Marty Auster, one of the SMid-Cap Biotech Analyst here at Crédit Suisse. Thanks for joining us at our 29th Annual Healthcare Conference. I have got Wave Life Sciences' CEO, Paul Bolno, to make a presentation on Wave. Paul, I'll hand it over to you. Thanks for joining us today. Have a fun presentation.

Marty, thank you so much for having us at the conference today, and we look forward to the opportunity to share more. And with that, before we begin -- there we go. We'll, obviously, be making forward-looking statements during this presentation. So I will refer everyone to our SEC filings for updates. But we're excited to be here. And we're excited to be here because there's a lot going on at Wave as we started out the year and continue on our progress to building a leading-genetic medicines company. Our foundational work has been and remains the work that we're doing on our stereopure oligonucleotide. And the benefit of this has really been continued learning and optimization of our nucleic acid platform. The innovative platform that we continue to develop allows us to implement on this backbone, new novel chemical modifications. And as we shared in August at our Research Day, we've added new backbone chemistry to our repertoire and that's the PN chemistry. And we'll be sharing more about that later and the advantages we see in pharmacology and distribution improvements with using this new backbone chemistry. What's exciting is not only be able to use this chemistry in terms of optimizing all of it, but we're able to directionally take that into new areas. Our allele selectivity work that we're doing in Huntington's disease and expanding that to the new program we'll talk about in [ sit-3 ] in Huntington's disease. But equally important beyond allele selectivity is our variant selectivity for the work that we'll be doing around our C9orf72 program for ALS and frontotemporal dementia. Beyond that work, we're continuing to push into new modalities. So we'll share work on silencing around Huntington's and ALS, but we're sharing more too of what we're doing in splicing and exon skipping and our work on neuromuscular diseases. In addition, the new modality in RNA editing, which will share a bit more at the end. All of this collectively around the platform is supported by a very strong intellectual property position. As we've taken Wave's innovative platform forward, we're moving that into our core area of neurology. Our programs to date, we have over 11 programs spanning discovery to clinical development that go from Huntington's disease to ALS, FTD, neuromuscular diseases, but also extensive work in the ataxia's, Parkinson's and Alzheimer's, remembering that we do have a collaboration with Takeda, where we can continue to expand the portfolio of work that we're doing. Internally within Wave, we're grounded in our work in clinical development. We're able to bring that clinical development expertise on to multiple global clinical trials, those that are underway, which include our Huntington's disease, SNP1 and 2 program, but in addition and as we shared in our last earnings update, we have 3 additional programs that we'll be making their transition into development. So in the fourth quarter, we'll be filing our clinical trial applications and C9orf72 trial for ALS and FTD. And in addition to that, the work on N531 for exon 53. So that brings us to the potential for 5 clinical programs as we transition into 2021. The team has amazing expertise in terms of being able to execute and extend that work. And we've also been very innovative in our clinical trial design approach. We'll be sharing more about that in the programs as they transition. And underlying all of this, is Wave's core competency that we've built in manufacturing. The ability not only to scale these programs, but the ability to continue to leverage and move more programs forward, both for ourselves as well as for our partners. Now as we said before, one of the innovations that we've been making at Wave is in our understanding of backbone linkages and the benefit of stereochemistry, when we talk about making single oligonucleotide, single isomers, is the ability to see what the contribution of any change you make on the backbone of an oligos. And what we've been able to do and we shared more, again, extensively at Research Day was with the implementation of this new PN backbone modification, being able to extend our repertoire beyond phosphorothioates. The benefit of the PN chemistry and the key feature here is that we've substituted this where sulfur would be in the phosphorothioate within nitrogen. What this backbone change does is it creates a change in the charge. It's a neutrally charged modification. So therefore, let's us really develop a different molecule, different set of charge, different physiochemical properties and different pharmacologic properties. And as we'll share, we've been able to implement this modification across the portfolio. Now how does this change? And what's our rational design in using the PN chemistry backbone modification was our ability to look at both silencing as well as spacing to see the impact and change that these modifications have on the backbone of an oligonucleotide. Now the benefit here. If we look on the left, we're looking at silencing. And what we have in both these cases are matched oligos, where we have the same sequence and the only difference in the backbone chemistry and on the sequence in each one of these dots, the light blue dot is the phosphorothioate and the phosphodiester modification. And the other is a substitution of the PO for PN. And what we look at is when you change and add that PN modification and you rank order these molecules, what you see with only making that change is an improvement in silencing and equally important on the right where you'd want to see that improvement being demonstrated by the dark blue dots going higher is an improvement in skipping or splicing when you make that change to the backbone. And we'll be sharing more about this across the various programs in the in-vivo data, but this is exciting as we start to see real changes in chemistry that are taking place in enhancing the pharmacologic properties of molecules. When we look at the innovative pipeline, what we see is our current 2 programs, our SNP1 program and SNP2 program for Huntington's disease. But across the portfolio, both in the new programs that are advancing forward towards the clinic as well as those discovery programs, we're using this PN backbone modification across the portfolio, including in our new modality of RNA editing, which we'll share later. So as you can see, an extensive portfolio of programs and, importantly, not only the 2 current clinical programs, the potential for 5 clinical programs as we move into 2021. Now as we talk and shift to the portfolio and starting in Huntington's disease, we've taken a unique approach to the treatment of Huntington's disease. Huntington's is an autosomal dominant disorder. It's a toxic gain of function as it relates to this toxic protein that builds up in neurons and kill them. But a very important component of the disease in addition to that toxic gain of function is the potential for a toxic loss of function. So these patients would normally have 2 alleles that both make a healthy protein. So not only are these patients now having 1 allele that's making a bad protein, but they lost 1 allele that's making a good protein. So there's a toxic loss of function in this disease. It's extensive. There's about 30,000 patients who have Huntington's disease, meaning they're gene positive and symptomatic. But there's about another 200,000 patients at risk. So this is a really extensive devastating disease. The approach that one would want to take to treat this is one that would remove the toxic protein, but preserve the wild-type protein for patients. Now this is important because if you can treat earlier in the disease setting, meaning the pre-manifest population, you'd want to provide a treatment that preserves and protects that healthy wild-type protein. Because what happens in the body is there's this tug of war. You've got this healthy individual who's got a balance between the stresses, neuronal stress that happens in the brain, but has a healthy wild-type protein that's actually compensating for that. What happens in Huntington's disease is these patients have at birth a 50% decrease in their wild-type protein. So they start at a limitation in that fight against the stresses. Add on top of that, an aggregating effect of the mutant protein, which increases stress on the brain and you can see a migration towards symptomatic disease. The approach that we want to preserve in an allele-specific format of HD is one that prevents that loss of function and keeps that tug going in the healthy CNS function and at the same time, removes that toxic effects of mute Huntington protein. This is also important because the research is becoming more and more extensive that the wild-type protein beyond just in the developing brain is also -- plays an important role in the adult brain. We see that wild-type is critical for important functions such as neuronal function, synaptic function, brain circuits and there was a lot of work being done on BDNF trafficking between the cortex and the striatum. And this is important because it also underlined the regions of the brain that are important in Huntington's disease. Huntington's is a whole brain disease, while the striatum is often cited as a component of the disease. It is both the cortex and the striatum that require access. Also CSF circulation, we find that healthy Huntington plays a role in its allele function, which plays a role in CSF blood flow -- or CSF flow. Now our novel approach to be able to do a real specificity relies on the fact that our molecules can target a single step. These are kind of like a genetic GPS or a target where our molecule combined with a transcript that has the SNP. And by cutting at that specific site, remove that mutated allele and allow the production of the healthy protein but not the mutated protein. The current 2 studies that we have are targeting 2 different SNPs. There are SNP1 and SNP2. Both of these programs are ongoing, and we do anticipate delivering our clinical trial results from the Phase I/II study in the first quarter of 2021. Importantly, this study will deliver across the 5 cohorts. So all patients from the 2-, 4-, 8-, 16- and 32-milligram cohorts of both PRECISION-HD1 and PRECISION-HD2. And in addition to that, there is the ongoing open-label extension study data and we'll be able to do a cut prior to that data to make sure that we can share data results from that ongoing open-label extension study. What we will show at that time is obviously safety and tolerability that's important, but we'll also have the biomarkers analysis of mutant Huntington protein, total HGT and neurofilament light chain. In addition to that, we shared that we've been doing extensive work with collaborators around the wild-type Huntington assay to be able to assess wild-type Huntington levels. And we anticipate having that developed at the time we're going to have data. Importantly, while SNP1 and 2 are continuing to move forward, we're also excited about the prospects for SNP3. So moving a new program forward into Huntington's disease, that's leveraging and incorporating our new PN backbone chemistry. We see similar properties here in the sense that it is allele specific, so selective reduction in a dose-dependent manner with the mutant Huntington but also retention of the wild type. What's equally important on the right is in the back HD model. So this is an animal model, it's homozygous. It has 2 copies of the bad Huntington's. It doesn't have healthy Huntington's. There's no way to assess healthy Huntington in this model. And the other challenge of this model is that not every mutated allele has the SNP. So already as the study gets underway when compared to a pan-silencing drug, it is a higher hurdle for an allele-selective therapy because not every one of the target has the SNP. What we're excited about to see is good durable distribution and, importantly, this data is from the striatum. We have similar results in the cortex. We see not just a potent knockdown of the mutant protein, but we see it durably. And so this study looks out at 12 weeks. So we continue to see knockdown. So we're excited about bringing our SNP3 program to expand we're doing in Huntington's disease, with a clinical trial application submission expected in the fourth quarter of this year. What's important about the expansion within Huntington's disease is each one of these SNPs covers a different population. So SNP1 covers 50% of HD patients, SNP2 covers another 50% of HD patients independently, SNP3 by itself covers 40% of Huntington's disease. So each SNP individually covers a substantial number of HD patients with an allele-selective approach. As you start combining these, you can expand the patients who are amenable to therapy. Hence, SNP1 and 2 together get about 70% of HD. And if we add SNP3 on top of that, we get 10% more. So about 80% of Huntington's patients eligible for an allele-specific approach. We're excited about allele selectivity, again, not just for the treatment of manifest patients, but really the ability to move earlier in the disease population. Continuing to build on the work that we've done within neurology and in the central nervous system, we're excited also to bring forward WVE-004, our therapy at C9orf72 mutations for ALS and frontotemporal dementia. This is important because these diseases have a commonality while we have both ALS and FTD as 2 representations for the disease. The underlying genetic driver is the same, in this case, the C9orf72 mutation. This hexanucleotide repeat expansion, can these patients can go on to develop either ALS or frontotemporal dementia based on the accumulation of this protein. What's exciting about the potential for therapies here is that bringing this one program forward, we could potentially have a therapeutic to treat either disease. And we'll talk more about our clinical trial plans, but our clinical trial plans are designed to be able to address this. These are substantial diseases that are rapidly progressing and really, there is a significant unmet medical need in both cases. So we are very much focused on accelerating, moving these therapies forward. The data that we've generated in vivo that has us excited to transition this is the demonstration with our, again, incorporating new PN backbone chemistry and WVE-004. It's not just the potency, but the durability of the response. So this is a back HD model where we've looked at doses inside the model, and we've looked at not just the potency, but again, the durability. So in this case, going out after 6 months and looking at both the spinal cord and the cortex and seeing substantial, in this case, nearly 97% knockdown in the spinal cord out at 6 months and substantial knockdown equally in the cortex out that long. So again, what we're seeing is that these changes in the evaluation of the chemistry on the background of these oligonucleotides are broadly distributing, so again, cortex and spinal cord. And these molecules are able to stay durably in these cells and exert their effects. So what's important, too, in this is that we are preserving, as we said at the beginning, the variant selectivities and not just taking down the toxic hexanucleotide repeat, and this is the measurement of that dipeptide protein. So this is something that we'll be able to measure in our clinical trial as the poly-GP peptide. What we've also seen here is in the same tissues, the spinal cord and the cortex, the preservation of the healthy variant. So again, bringing a variant-selective approach forward as we think about this program. Our proof-of-concept study in the clinic will be basket like and that it will include both ALS and frontotemporal dementia patients. So one, we'll be confirming the diagnosis of those patients will be exploring single and multi doses. The study, obviously, primary endpoint will be safety and tolerability, but we will be measuring the pharmacodynamic effects on biomarkers during the study. So the poly-GP, that peptide, so we'll be able to measure that on-target PD with that peptide from CSF. We'll be looking at neurofilament light chain. But we'll also have, as we follow these patients out, the ability to look at exploratory clinical endpoints. In this case, the ALS-FRS-R for the ALS patients and the CDR-FTLD for the frontotemporal dementia patients. Again, CTA for WVE-004 is expected in this quarter, the fourth quarter of 2020. What's also giving us continued confidence across the platform, and this is new data that we shared during our earnings this week, where we could share some of the work that we're doing under the Takeda collaboration, which is looking at multiple targets in the central nervous system is that we can look at not just the transgenic mouse models where we can evaluate a number of diseases, but in this case of this therapeutic candidate that we were evaluating, we could actually look in a nonhuman primate study. And in this case, what was -- had us and our team very excited is the fact that after a single intrathecal dose of 12 milligrams, we could see 90% reduction out of a month in the lumbar cervical spinal cords, the cortex, the hippocampus. So again, demonstrating not just what we see in the rodent models, but in a much larger species, delivered intrathecally, we see sustainable knockdown across a broad range of tissues in the central nervous system. Exciting work, demonstrating the continued momentum we have with a new chemical backbone across multiple therapies. As we shift gears and that was a lot of the work that we've been doing on silencing, one will recall that we have been doing work in duchenne muscular dystrophy and exon skipping. And that work at the end of last year that we have progressed was WVE-N531. What's important is WVE-N531 was focused on moving forward with a PN chemical modification on the back of an exon skipping or splice correcting molecule. We were excited about the data and the uptake in muscle cells. That was important for us. But we also know the challenges within dystrophic muscle in terms of being able to run a study. The team spent an enormous amount of time this year really looking at both the clinical data on suvodirsen, what we could learn from that, what we could learn from preclinical experiments that would increase our confidence. And what became exceedingly important to us is to evaluate the double knockout mouse. This is a mouse model that has an extreme phenotype. It has a knockout of both utrophin as well as dystrophin. And we said this is a very high hurdle. It has a cardiac and respiratory phenotype. And so what was important for us is when you look at the PBS or the control, these animals die very, very quickly. What we evaluated was -- and yes, one has to remember because this is a mouse model, we're splicing exon 23, so it's 23 exon-skipping format. But what we were careful to do is make sure we explore and extrapolate the chemical backbone for N531 in the PN chemistry as well as maybe PS/PO counterpart. What we looked at with the PS/PO weekly at 150 milligrams per kilogram was we did see an extension in that survival. This study is currently still ongoing with our PS/PO/PN, so the exon-skipping format using the PN chemistry. But what's important here is we reduced the dose by 50%, so it's 75; milligrams per kilogram. And we also increased -- decreased the frequency by 50%. So it's given every other week. So with 75 milligrams per kilogram every other week, we're still treating these mice and the study remains ongoing, demonstrating that we can productively deliver the oligonucleotide if these mice are still living means we're getting -- we're treating the heart, we're treating diaphragm, getting exposure there as well as to the skeletal muscle. All again corroborating a lot of the work that we've done preclinically to support the transition to being able to evaluate this as part of an investigative study. So we'll be looking this in exon 53 amenable boys. We know the unmet medical need in DMD remains high. The community has been extraordinarily supportive of both helping us in the evaluation of this program before our decision, and we're excited to run the appropriate study to evaluate this. We're going to evaluate it in an open-label study targeting every-other-week administration in up to 15 boys with DMD. We plan to conduct this trial in Europe. And we're excited that this will give us not just an evaluation of initial safety, but the ability for us to look at drug concentration in the muscle, distribution of that drug in the muscle and being able to look at productive dystrophin levels if that's generated. We'll be able to have the potential upon success to be able to look at this PN chemistry across other exons in DMD, but equally important across other potential applications in muscle for both silencing and splicing. But we plan to submit the CTA for our DMD program in the first quarter of 2021. Now moving beyond the current program, so that takes us to the potential of how we get to the vendor of 5 clinical programs by 2021, we're also excited about the work that we're doing in ADAR RNA editing. And the application, not just on the platform of RNA editing, but also in terms of driving that application to a specific program. And as we shared on our earnings call, our program that will be initially focusing on is alpha-1 antitrypsin deficiency. Now taking the platform forward, we're excited about PRISM's ability to unlock ADAR editing. And in the case that we're focused on right now is what's called ADA-i editing. So we're using the enzyme, the ADAR enzyme that's inside the cell, being able to deliver just a small oligonucleotide that can engage with a target that then engages the internal machinery of editing the ADAR enzyme to ultimately change and edit the ADA-i. ADAR is ubiquitously expressed across tissues, including the liver and the central nervous system. So what are our advantages in this space? We've been excited because one of our core competencies at Wave in the platform is being able to develop chemically-modified oligonucleotide. So by staying under 30 base pairs, we can design a fully chemically-modified oligonucleotide that's stabilized, that can be delivered and not have to require the ability to -- we don't need a formulation around nanoparticles. We don't know you need AAVs to deliver a nonnatural protein or to deliver the nucleic acid, and we can apply conjugates to directionally target these oligos to specific tissues, such as GalNAc for the liver. By using endogenous ADAR, so using the enzyme that's already expressed in the cell, we avoid the permanent off-target effects of DNA editing. We have no immunogenicity from exogenous proteins, and we can reduce, therefore, off-target effects. When we think about the ADAR amenable disease space, it is extensive. There's about 48% of mutations that are caused by A to G that will be amenable to the ADA-i editing and over 32,000 potentially pathogenic human SNPs. So a substantial application that we can take forward with the editing, the ADAR design that we are currently exploring. Now as we think about how does one think about using this, we're excited about the ability to restore protein functions. So in the case of recessive or dominant genetically-defined diseases, there's a number of ways to restore protein function, removing stop mutations, fixing nonsense or missense mutations. We can modify protein functions. So think about ion channel permeability as a class, and we can also think about protein upregulation, so diseases of haploinsufficiency. The data that continue to -- as we built this platform, drive us forward in terms of selecting targets was the work that we had done really demonstrating for the first time in a nonhuman primate, and we shared this data in the past at our Research Day in August was the ability in GalNAc-conjugated ADAR [indiscernible] didn't to deliver nucleic acid, to be able to achieve up to 50% editing in nonhuman primates. And we could see us this was also durable and extended out at 45 days. So it gave us a lot of confidence on both the platform in terms of editing a transcript, durability and platform. What was also important for us was the evaluation of specificity and looking at the ability to hit on target and edit just the selected editing site. And we see that our ADAR editing oligonucleotides are highly specific. So again, avoiding those off targets that we spoke about earlier. Now applying those 2 components, so the ability to put GalNAc on an ADAR edited transcript, seeing that's highly specific, we then approached a new target. So we approached alpha-1 antitrypsin deficiency. This is important because this will come and cause as a single G to A point mutation on the Z allele. So there's about 250,000 patients who have the ZZ genotype, which is the most severe. So if you think about base editing at the Z allele, we can change the Z to an [indiscernible], highly focused on a substantial patient population. And by doing that, we're able to correct that mutated protein to a healthier wild-type protein. That approach is important because it enables us to -- by creating a wild-type protein and increase that circulation, treat both a loss of function disease in the lung and also the gain of function in the liver. So by creating that healthy protein, it increases that circulation of wild-type protein, we reduce the aggregation in liver and we believe that we can retain alpha-1 antitrypsin physiologic regulation. So being able to treat both the lung phenotypes as well as the hepatic phenotypes. Giving us thereby a differentiated approach to moving forward in the therapeutic treatment of the patients, the homozygous patients with alpha-1 and antitrypsin disease and deficiency. And we spoke often in the in-vivo studies about being able to correct the transcript. This is in-vitro data where we looked at the Serpina 1 RNA editing did not only to be able to correct the transcript, as we can see on the panel on the left, but importantly, to correlate and corroborate that correction of the transcript and correlate that to the correction of the protein. And what we saw with this current study, is that, again, it's in-vitro data, a threefold increase in the production of protein. So this was validating for us in the context of base correcting the transcript, having an important component on generating the protein. Moving this forward, both on the platform context of building our ADAR platform as well as for the program, what we knew was that there's a different expression of ADARs, this enzyme in mice. So mouse ADAR is different than human ADAR. So if we're going to be optimizing therapeutics across platform and editing, we created a proprietary mouse that has human ADAR expresses in all its tissues. And very importantly, we tested to make sure that it wasn't over expressing ADAR in those tissues. So we're testing that it has human ADAR and expressing in all tissues and at the appropriate levels. Now what we can do and are doing with this mouse that we're driving forward is we are cross that with the Serpina 1 mouse. So essentially creating a model system that has the Serpina 1 where we can look at optimizing for the target, but it has the human enzyme. So across both of these features with our in-vivo validation, what we're able to do is have a sustainable model where we can optimize therapeutics across the RNA editing space. But in specifically for the alpha-1 antitrypsin program, be able to make sure that we're optimizing it in a model with the human enzyme, thereby expediting our potential clinical transition. So what we expect in the first half of 2021 is both in-vivo mono validation as well as sharing data specifically around the alpha-1 antitrypsin program. As we said, the reason this model is important is that we've seen multiple opportunities for ADAR editing in neurology. This is an example data from an in-vivo study we did looking at distribution of an editing oligo across the central nervous system. And what we can see is that oligos are distributing and editing across a variety of tissues in the CNS. So more to come as we think about where the portfolio goes from here. So as we said, we're excited about the potential of 5 clinical programs in 2021 moving forward. We're excited about a new platform in RNA editing and the programs that are coming off of that, including alpha-1 antitrypsin. And within the cash that we have currently, our expected cash runway takes us into 2Q 2023. So that's important because we can deliver on the multiple milestones. So as we think about the fourth quarter of this year, fourth quarter is the CTA submissions for SNP3, C9, moving into the first quarter, our CTA submission for N531 in DMD, data in the first quarter for PRECISION-HD1 and 2 and continued momentum across the platform on our clinical programs and over the first half of 2020, delivering on our humanized mouse model for validating multiple approaches to ADAR and our in-vivo data on alpha-1 antitrypsin deficiency. Three new clinical programs that we discussed starting are all using our new chemistry. So we're excited about the progress and momentum we've been making today, and we appreciate the opportunity to share this with you today. Thank you.