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spk02: Good morning and welcome to the Wave Life Sciences second quarter 2022 financial results in the business update 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, VP of Investor Relations and Corporate Affairs 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 second quarter 2022 financial results. Joining me today are Dr. Paul Bologno, President and Chief Executive Officer, Dr. Mike Panzera, Chief Medical Officer and Head of Therapeutic Discovery and Development, Dr. Chandra Varghese, Chief Technology Officer and Head of Platform Discovery Sciences, and Kyle Moran, Chief Financial Officer. The press release issued this morning and the slide presentation to accompany this webcast are available on the Investors section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the test release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2021, and our quarterly report on Form 10-Q for the quarter ended June 30, 2022. 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?
spk10: Thanks, Kate. Good morning, and thank you all for joining us. In the second quarter, we continue to make meaningful progress both on our therapeutic program and our platform. I will start with some recent highlights. I'll then turn the call over to Mike, who will provide updates on our innovative pipeline Chandra will then share some examples of how we continue to expand the addressable biological targets with our unique RNA-based editing platform. And finally, Kyle will discuss our financials. I'm excited to begin today's call by announcing the selection of WVE-006 as our first RNA editing development candidate for alpha-1 antitrypsin deficiency, or AATD. We're also announcing that we expect to initiate clinical development of 006 in 2023. O6 is a first-in-class RNA editing candidate and the most advanced therapeutic program currently in development to harness an endogenous enzyme for editing. There are approximately 200,000 people carrying homozygous disease mutations in the U.S. and Europe, and WVE-006 has the potential to transform how these patients are treated. Demonstrating clinical proof of concept in AETD with 006 would serve to de-risk RNA editing for additional monogenic diseases as well as open opportunities to address larger disease implications through modulation of proteins such as disruption of protein-protein interactions and upregulation. Continued investment in our PRISM platform has positioned us as leaders in oligonucleotide innovation, and we continue to be encouraged by the translation of our guide strands across multiple modalities. Earlier this year, we shared positive target engagement data from our ongoing focused C9 clinical trials in C9 ALS and FTD, which demonstrated how our preclinical data are now translating in patients. New pharmacokinetic data from our ongoing DMD and HC studies, which Mike will share today, further support this clinical translation of differentiated pharmacology. We remain on track to share data from all three of our clinical studies this year. In June, we completed a successful follow-on offering, which put WAVE in a strong, well-capitalized position entering the second half of 2022. We continue to execute on multiple pillars of value creation, including delivering clinical updates and rapidly advancing our novel RNA-based editing pipeline led by WVE-006. We also continue to advance discussions with potential strategic partners who share our vision for broad applications of WAVE platform and support expansion of our pipeline while unlocking value in GMP manufacturing. I'll now turn the call over to Mike to provide an update on our pipeline.
spk07: Mike. Thanks, Paul, and good morning to everyone on the call. Today, I will discuss the continued progress of our therapeutic portfolio, beginning with our CNS program. The FOCUS-C9 clinical trial for WBE-004 in patients with C9 or 72-associated ALS and FTD continues with administration of single and multiple doses underway. Back in April of this year, we announced the first data update from our FOCUS-C9 program, which demonstrated a robust dose-related target engagement, confirming translation of our preclinical work into the clinic. I share these data with the ALS community in June in an oral session at the Conference of European Network to Cure ALS or NCALS in Stockholm. The presentation highlighted not only the clinical data seen here, but the wealth of information illustrating the differentiated preclinical profile of WVE004. We anticipate delivering an update with additional single and multidose data for 004 in the second half of 2022 and are on track to initiate an open-label trial in the same timeframe. Moving on to Huntington's disease, WBE003 is our allele-selective oligonucleotide currently being evaluated in a select HD study targeting a polymorphism, SNP3, associated with the expanded CHE transcript in certain patients with HD. The goal, as we have said many times, is to preserve production of wild-type Huntington given the importance of this critical protein. Preservation of wild-type Huntington continues to be a key objective that is supported by the HD community and by emerging preclinical, and possibly clinical data. 003 is the only allele-selective program currently in clinical development. Similar to WVE-004, we were able to leverage preclinical and vivo models to establish a starting dose of 003 that was predicted to achieve CSF concentrations needed to engage targets, and we designed and implemented an adaptive trial with the goal of accelerating time-approval concepts. The select HD study is progressing well and is already yielding interesting information from blinded assessments. The right-hand side of slide 9 shows the concentrations of 003 measured in patient's cerebral spinal fluid, or CSF, in the first cohort of patients' dose in the trial. On the same graph, we have plotted the CSF concentrations observed following administration of 32 milligrams of WVE120101 and WVE12102, which were the highest doses used in the precision HD studies where we evaluated these first-generation PSPO compounds for HD. Approximately one month post this single starting dose, we are seeing CSF concentrations 20-fold greater than the maximum observed for these previous compounds. You may recall at the time we discontinued the precision HD program, we said the primary reason for doing so was modeling that indicated that we could not achieve CSF concentrations needed to engage target with those first-generation compounds. The profile 003 appears quite different. Dose escalation continues in the SPECT-HD study, and we expect to share clinical data in the second half of 2022. In Duchenne muscular dystrophy, our open-label clinical trial of WVEN531 for DMZ patients with mutations amenable to exon 53 skipping is progressing well also. You will recall in our preclinical studies in the DKO or double knockout mouse, treatment with an exon 23 surrogate of N531 resulted in significantly prolonged survival at dose levels and frequencies achievable in human studies. Of course, after converting to estimated human equivalent dose levels. These data guided our target dose selection and escalation planning in our open label clinical trials. On the right-hand side of slide 10, you can see some preliminary pharmacokinetic data from this study compared with data from suvidersin, our first-generation PSPO compound. The figure shows plasma concentrations following single doses of N531 at three dose levels compared with the top dose of suvidersin used in our discontinued phase 2-3 study. What's clear is that approximately one week following dosing, plasma concentrations of N531 were already 40-fold greater than those achieved with suitor, and dose escalation has yet to be completed. Dosing is underway at dose level 4, and we look forward to data for muscle biopsies in the fourth quarter of this year. I'll now give an update on our newest candidate, WEVE006 for AATD. WVE-006 is designed to address therapeutic goals essential when developing a novel therapy for AATD, namely restoration of circulating wild-type MAAT to address lung disease and reducing VAAT protein aggregation in the liver to address liver disease. Our hypothesis is that through RNA editing in homozygous or VZ patients, one can shift the phenotype towards a heterozygous or MZ phenotype, lowering the risk of disease pathology. In the second quarter, we shared data using one of our lead AATD aimers to restore functional AATD protein. At 19 weeks, restored AAT protein was determined to be functional as measured by robust inhibition of neutrophil elastase, as well as pesticide staining of liver biopsies demonstrating reduced accumulation of the AAT aggregates over the duration of the study. The selection of 006 to take forward into IND-enabling toxicology studies followed a thorough evaluation of multiple leaf compounds, each with potent editing capability, in preclinical studies in mice and non-human primates in order to choose the molecule with the best overall profile. Slide 13 shows the efficacy of 006 in the NSG PID mouse model, which is well-established in this space. 006 was administered subcutaneously following an initial loading dose. At week 13, serpent A1 RNA editing was approximately 50%, and serum AAT protein restoration ranged from 4 to 7 volts higher than PDS control, remaining above an 11 micromolar level throughout the dosing interval. Additional data supporting the favorable preclinical profile 006 are shown on slide 14. Potent concentration-dependent editing of Serpin A1 was observed in primary human hepatocytes derived from a donor with the MZ genotype, reaching as high as 80% with the highest concentrations tested. So where are we now with 006? IND-enabling activities are underway, and we expect CTA submissions next year. WAVE's diverse portfolio of therapeutic candidates continues to advance through development as we are beginning to see our preclinical observations translate into clinics. The data generated with each candidate continue to demonstrate the potential when principles of rational design and chemistry innovations are applied to oligonucleotides, enabling novel approaches to complex disease biology. With that, I will turn the call over to Chandra. Chandra?
spk00: Thanks, Mike. The substantial progress to date with our WV006 program for AACD demonstrates the potential of AMERS technology for precise correction of DTA driver mutations. We like to think of our AMERS as Swiss Army Knights, and restoring or correcting protein functions is only one example of how we can use AMERS to potentially treat diseases. Recently, we have generated multiple proof-of-concept datasets that demonstrate how AMERS can activate gene pathways by modulating protein-protein interactions and upregulate RNA expression by editing RNA-binding protein motifs. These applications demonstrate the potential to design therapeutics to precisely control gene upregulation by titrating RNA editing levels and aimer dose. I'll review these in vitro and in vivo editing data sets on the next few slides. We have used the NRF Keypoint system before. This system shows the potential to edit a single site to activate a transcription factor and upregulate downstream genes. As shown on the right-hand side of slide 17, Using GALNAC AMERSH, we achieved efficient editing, resulting in a dose-dependent upregulation of NQO1, a gene regulated by the NRF2 transcription factor in vitro. We recently repeated this study in vivo and again saw efficient editing with multiple GALNAC AMERSH in the liver of mice, which resulted in downstream gene upregulation. If we properly disrupted the NRF2 protein interaction, we would expect upregulation of a key set of genes that are regulated by NRF2, which we successfully confirmed by RNA-seq transcriptome analysis as shown on the bottom right side of slide 18. Another potentially disruptive application of AMER is to upregulate RNA to treat haploid-sufficient diseases or diseases that require overexpression of target genes. We have now demonstrated the ability to upregulate several different targets, including both metabolic and immune targets, by editing RNA motifs to regulate RNA half-lives in vitro. While much of our presentations today have focused on GalNac conjugated designs, We also have achieved substantial RNA editing with systemic delivery of unconjugated amers. We do not need to use complex delivery vehicles such as lipid nanoparticles or viral vectors. In in vivo mouse studies, we observed editing of UGP2 target across multiple tissues, including kidney, adipose tissue, and a range of liver cells with a single subcutaneous dose of unconjugated animals. I'll now turn the call over to Kyle Moran, our CFO. Kyle?
spk09: Thanks, Chandra. Net loss for three months ended June 30, 2022, was $41.3 million. We reported $0.4 million in revenue for the second quarter of 2022. R&D expenses were $29.7 million for the tech quarter of 2022, as compared to $31.6 million for the same period in 2021. This was primarily due to decreased external expenses related to our previously 15 clinical programs, partially offset by increased share-based compensation expense and increased external expenses related to our AATD program. G&A expenses were $12.8 million for the second quarter of 2022, as compared to $11 million last year, primarily due to increases in compensation-related, mainly from share-based compensation, offset by decreases in other external, general, and administrative expenses. We ended the second quarter with $148.2 million in cash, cash equivalent to short-term investments. This includes net proceeds of $65.5 million from our financing in June 2022. With this financing, we extended our cash runway, and we currently expect that our existing cash, cash equivalents, and short-term investments will enable us to fund our operating capital expenditures to the end of 2023. As a reminder, we do not include potential milestones or opt-in payments under our dedicated collaboration in our cash runway. I'll now turn the call back over to Paul.
spk10: Paul? Thanks, Kyle. Over the past decade, we have established a disruptive oligonucleotide platform and are now seeing these innovations translate in the clinic. Our unique guide strands enable us to target diverse biology with multiple therapeutic modalities. In addition to what we have shared today around antisense, splicing, and RNA editing, We have previously demonstrated how PRISM can significantly improve siRNA silencing in vivo over industry state-of-the-art advanced ESD plus chemistry. These capabilities, together with our GMP manufacturing, position us well to become a leading genetic medicine company. Looking ahead, we expect several milestones in the second half of the year, including data from all three of our ongoing clinical trials. We achieved our goal of selecting an ADTB development candidate and initiating IND-enabling studies in the third quarter and expect to submit multiple clinical trial applications for WVE-006 in 2023. Importantly, we are well capitalized to execute on all these milestones. And with that, we'll open up the call for questions. Operator?
spk02: Ladies and gentlemen, if you have a question or a comment at this time, please press star 11 on your telephone keypad. We'll pause for a moment while we compile our Q&A roster.
spk01: Our first question comes from Salim Saeed with Mizuho. Your line is open.
spk05: Great. Good morning, guys. Congrats on the progress, and thanks for the question. Paul, so I guess there's a lot of data coming between now and year-end, so I was hoping if you could just tick through the three programs here, the DMD program, the HD program, and the ALS program in terms of what do you perceive to be winning scenarios for these three programs, biopsy, how much district production you expect to see on the knockdown data for Huntington's, how much mutant Huntington knockdown data do we expect to see? And then specifically, on the Huntington's, are we going to be getting single dose data or multi-dose data? for the two programs that you didn't specify, whether it's third quarter or fourth quarter. We're thinking more, you know, pumpkin spice latte time or eggnog time for the HB and the C9 ORF. Thank you so much.
spk10: Thank you, Salim. And I'll start and I'll transition to Mike as well. But just in no particular order, and I think that's critical as we lay this out. But to start with your, since you ended with SNP3, I'll start with SNP3. So the SNP3 data will be single dose. And I think stepping back 10,000 feet and looking at all these data sets, I think they're important because they're going to give us, again, more indications, hopefully, of what we saw earlier this year with C9 on our single dose, which is potent, durable target engagement. So I think, firstly, as we think about preclinical translation to clinical translation, we'd like to see the continuation of our preclinical data extending into clinical data readouts. So SNP3 is single-dose. This is the same evaluation that we had done on C9. It'll give us the opportunity to look at target engagement on the mutant protein, preservation of wild type, which, as Mike alluded to earlier, continues to be an important metric to study, and other clinical biomarkers. Again, it will be a biomarker-driven study. As it relates to C9, we'll have continued data on both then multi- and single-dose, so again, continue to be able to look at the pharmacokinetics in target engagement. And DMD will give us the first opportunity, again, to look at preclinical to clinical translation, as we shared today, based on tissue concentrations and exposure related to the DKO mouse model, where we did see a restoration of phenotype. That's going to give us an opportunity in muscle biopsies to look at tissue exposure to target engagement. Turn it over, Mike, for any additional follow-up on that. But that's going to be the key. It's a robust data set across multiple programs, all related to PN that answer key questions related to target engagement in various tissues, the CNS versus muscle, as well as being able to look at individual disease indications for cross-silencing and splicing.
spk07: And nothing really much to add other than to address the other question is, you know, The DMD study, we've said the fourth quarter, that's open label. The patients are within dose escalation. We have a good sense of when that's going to happen. The other studies, as you know, are adaptive. They're driven by recruitment, timing of data collection, and basically the timing of the reviews by the independent committee. So that's why we've been a little bit more, a little less definitive on the timing there. It would just really depend upon those factors because those are the blind and adaptive studies.
spk05: If I could follow up, guys, thanks for the call. On the DMD specifically, do you have a number in mind in terms of this different production you're targeting on this particular readout? I know it's single.
spk10: So this particular readout, yeah, at this point in time, The target right now is being able to evaluate the translation. I think the study is really determined to see, can we see the preclinical data and exposure from the double knockout translate into humans? So this time we're not laying out what a target exposure is. We'll continue to evaluate where we are based. As Mike said, we're now into dose four, so there'll be more modeling as we get closer.
spk07: And the big factor, Slim, is does it look different from superdose, right? Because you've You know, you remember with suverdursin, we just couldn't get into cells. We couldn't engage target. We couldn't even see any transcript production at all with suverdursin. Here we have very different concentrations, as we've highlighted. And then we're going to be looking at distribution. And if we see dystrophin, it'd be quite exciting. So that's sort of how we're looking at that one.
spk02: Got it. Thanks so much. One moment for our next question. Our next question comes from June Lee with Truist. Your line is open.
spk11: Hi, good morning and congratulations on the course. This is Mehdi for June. So my question is related to the PN chemistry. Recent studies in Angelman published, they showed that traditional POPS backbones have sort of relatively limited penetration into deep brain tissues. So could you provide some data on the function of PN chemistry in your studies and which type of tissues and which type of distribution you got with these versus the traditional POPS backbone? Thank you.
spk10: Yeah, no, it's a great question because I think it's data that we've shared and we're happy to continue to share more. What we have shared in the past is with the addition of PN chemistry, we do see much deeper, broader penetration across the CNS. So that's translating to uptake across tissues. The data that we share related to mutant Huntington reduction from the back HD model in the corporate deck, is striatal data. So what we've seen differently with the application of PN is broader, deeper penetration. But ultimately, that is why, you know, to Salim's earlier question, I think why the data for SNP3 is going to be interesting. Because one of the things that we can't do is C9, we're going to be looking at primarily cortex spinal cord. And as it relates to HD, we know that that's cortex and deep gray structures like striatum. So these data continue to help clarify for us preclinical to clinical translation as we measure this. But we've seen that it's not tissue-specific either. We've seen deep penetration, as Mike was talking about, with looking at tissue concentrations in DMD and muscle. And so we think, you know, not only is it helping with distribution, it's helping with retention, stability. And we believe that's why we're seeing target engagement at low single doses that's also durable. And so I think these data, being able to translate it from preclinical to clinical, is going to be important. I think to your point as well, being able to dose with lower doses, you know, we think has a lot of advantages as we're going forward to be able to explore a multitude of diseases. And as we shared today, 006, our first aimer for alpha-1 antitrypsin deficiency, we shared that one of the advantages to being able to get potent, durable editing was a function of being able to apply PN chemistry on top of our chirologic homologous.
spk11: Thank you. And if I may, a very quick follow-up, other question is that could you provide any high-level plans that you have for the design of VAVE-006, how this trial would be designed?
spk10: I mean, what we'll do is, as we said, we're engaging in the IND enabling studies. Planning will be underway as we think about 2023 clinical trial updates, and we'll definitely provide a full update on the Alpha-1 antitrypsin clinical program.
spk07: And the only other thing I'd say to that is we've really been engaging outside experts in the community to sort of help us in that regard in terms of how we approach this and how we can do it in a way that accelerates time to proof of concept as we have for each of our CNS programs.
spk10: I mean, we'll share, and there'll be more opportunities, I think, about the second half of the year. The clinical community is extraordinarily excited about an RNA editing approach to being able to treat and restore protein function and protect liver. So it's an exciting time, I think, for the field to now have a candidate to be able to start exploring clinical trial designs. Awesome.
spk11: Thank you very much.
spk02: One moment for our next question. Our next question comes from Paul Matias with Stiefel. Your line is open.
spk08: Great. Thanks. This is James on for Paul. Maybe a quick one on ADAR and AAT. Do you have a sense of how much endogenous ADAR is expressed in your animal model? And how does that compare to what we know about, you know, endogenous expression levels of ADAR in humans? Thanks so much.
spk10: I mean, the model, we've shown this across now multiple models. We're using the standard model. I don't know, Chandra, if you have a specific answer on the amount of ADAR expressed in the animal model.
spk00: So in the mouse model, we are using the mouse endogenous data. And in the human ADAR mouse model that we described before, the expression levels are very similar to what we've seen in humans. And we have actually provided the data in the previous presentations.
spk10: I think there was an old question existing of whether or not, I think there was a question of whether or not the human model had actually amplified it. We have demonstrated and actually presented those data that there is not an overexpression. So actually, the amount of ADAR actually correlates. We've also shown that you don't exhaust ADAR. So it's not an overexpression, and you don't also exhaust the endogenous enzyme either. Great.
spk08: Thanks. That's very helpful.
spk02: And one moment for our next question. Our next question comes from Luca AC with RBC. Your line is open.
spk06: Oh, great. Thanks so much for seeing my question. Congrats on the progress. Maybe on ALS, we've obviously seen a 12% NDA getting accepted by the FDA based on NFL as a surrogate biomarker. I'm wondering what was your reaction to that news and how are you thinking about implications for you and maybe for the field more broadly? And then second, on AAT, circling back on a prior question, again, I know super early days, but how are you thinking about a phase one site design? What are the efficacy endpoints that you will be focused on in order to potentially capture benefits for both liver and lungs? Thanks so much.
spk10: So I'll start with AATD and then transition to Mike for your ALS question. But, you know, as it relates to AATD, obviously for the phase one study into phase one, two, our goal will be to establish dose frequency like we have done for others, driven primarily on the plasma biomarkers. So we're going to have the opportunity, I think, to do two things. One is validation of editing in the production of protein and to see how that correlates again with our preclinical data. That data, again, as we've shared on the call, I think serves two purposes. One, obviously, incredibly exciting for the Alpha-1 community in terms of advancing a therapeutic program and designing a program for both lung and liver. We'll also be looking at biopsies for that important point to study liver and editing. And then secondly, that really does unlock for us, and once we've established that preclinical to clinical translation, opens up modeling for us to be thinking much more broadly about our AMERs across multiple therapeutic areas. I'll turn the call over to Mike now for the question related to ALS.
spk07: Yes. You know, whenever FDA in a CNS disease now is starting to pay attention to biomarkers like this, CSF serum, whatever, it is a positive development. These are very bad diseases. These are diseases that progress and progress has been limited. So the idea that there is the potential of a easily measurable biomarker that they may now be viewing as relevant from the standpoint of, I should say, reasonably likely to predict clinical outcome, is encouraging. And we'll be watching to see how this plays out, both for us but for the community at large.
spk06: Got it. Thanks so much.
spk02: And one moment for our next question. Our last question comes from Manny Faruhar with SBB Securities. Your line is open.
spk03: Hi, good morning. This is Lenny Misongo on for Manny. I just had a question regarding the novel 06 program. Would you be able to give us an overview of the expected commercial opportunity there? Thank you.
spk10: Yeah, and we'll obviously be providing a lot more, but I mean, what's exciting for us is it is a consequential indication. We have, and one only needs to look at some of the programs that have faced challenges to see kind of what the market reaction into that. So for us, our focus has been on the 200,000 patients in the U.S. and Europe that are the homozygous patients that are amenable. So we're not even looking yet at the broader population beyond that, but there's 200,000 ZZ patients that really have the opportunity to be corrected back to the MZ phenotype. So consequential patient population, we've seen this play out in terms of the translation and other substantial evaluation programs at other companies. And it's attractive of a lot of interest, both from the patient community, the investor community, and our potential partners. So we think it's a really interesting space for us to be able to think much more broadly at. And to be able to do it, I should also remind people differently. So we've seen the silencing programs really focused on targeting siRNA in the liver. That's exciting to watch. I think we've seen the protein replacement side of companies generating commercial revenue in terms of protein replacement, IVB clean fusion. And I think our opportunity just to plant both with a single subcutaneous injection that treats both liver and lung will be consequential to the field.
spk01: Thank you. I'd now like to turn the call back over to Dr. Paul Abono for our closing remarks. Thank you.
spk10: And thank you, everyone, for joining the call this morning. This is an exciting time for our organization, and I'm grateful to every WAVE employee for their dedication and unrelenting focus on our mission and on the patients and families we serve. Have a great day.
spk02: Ladies and gentlemen, so that concludes today's presentation. You may now disconnect and have a wonderful day.
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