Good morning and welcome to the Wave Life Sciences Fourth Quarter and Full Year 2019 Conference Call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I will now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences. Please go ahead.

Thank you, operator. Good morning and thank you for joining us today to discuss our recent business progress and review Wave's fourth quarter and full year 2019 operating results. With me here today is Dr. Paul Bolno, our President and CEO; Dave Gaiero, Interim CFO; and Dr. Mike Panzara, Wave's Chief Medical Officer. This morning we issued a news release featuring our fourth quarter and full year results. Please note that this new release and the slide presentation that accompanies this webcast are available on 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 any forward-looking statements. The factors that could cause actual results to differ are discussing the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2019. We undertake no obligation to update or revise any forward-looking statements for any reason. I now like to turn the call over to Paul Bolno, President and CEO of Wave Life Sciences. Paul?

Thank you, Kate. Good morning and thank you for joining us today. I'll start today's call with a few introductory remarks and the company updates. Next, Dave Gaiero will discuss our financial results and then Mike Panzara will provide an update on our PRECISION-HD development program. I'll conclude with an update on our ADAR mediated RNA-editing program and an outlook for 2012. Wave is genetic medicines company that was founded to design and develop novel oligonucleotides therapeutics using our proprietary PRISM platform. This unique platform enables us to design therapy in a rational way, through a deep understanding of how the interplay among sequence, chemistry and stereochemistry impact key pharmacologic properties. Over the past decade, our chemistry has progressed and evolved enabling us to build a broad pipeline that includes different modalities, a range of disease targets, and innovative properties such as unique backbone modifications, allele-selective designs and novel modalities like RNA-editing. Going forward, we will continue to innovate and expand our pipeline. The foundation of this pipeline is our work in CNS, including Huntington's disease, ALS and FTD and several programs in collaboration with our partner Takeda. Over the course of our relatively short history, we've moved three programs into clinical development and have embraced and been humbled by the learnings that have come out of the used and other programs along the way. Our dedicated and experienced team is actively preparing to advance two additional programs into clinical development in the second half of this year. Finally, we have established internal manufacturing capabilities that enable us to produce oligonucleotides to support our platform, preclinical work and clinical development and provide us with increased control and visibility of our drug substance supply chain. Using PRISM, we leverage the ability to control the stereochemistry of each backbone position of oligonucleotides…

Thanks Paul. For fourth quarter of 2019, we reported a net loss of $56.8 million, compared to $37.9 million for the same period in 2018. We reported a net loss of $193.6 million for the year-ended December 31 2019, compared to $146.7 million for the year ended December 31 2018. The increase in net loss in the fourth quarter and full year was largely driven by increased research and development efforts and continued organizational growth, both of which included cost and efforts, including manufacturing, in preparation for the potential commercialization of suvodirsen. Research and development expenses were $49.1 million in the fourth quarter of 2019 compared to $39.8 million for the same period in 2018. Research and development expenses for the full year were $175.4 million, compared to $134.4 million for the prior year. The increase in research and development expenses in the fourth quarter and full year was primarily due to increase external expenses related to our clinical activities, including our HD programs and are now discontinue DMD programs as well as increased investments in PRISM and other research and development expenses. General and administrative expenses were $13.8 million for the fourth quarter of 2019, compared to $12.8 million for the same period in the prior year. General and administrative expenses were $48.9 million in 2019, compared to $39.5 million in 2018. The increase in general and administrative expenses in the fourth quarter and full year was mainly driven by our continued organizational growth to support Wave's 2019 corporate goals. We ended 2019 with approximately $147 million in cash and cash equivalents while our cash utilization rate in the first quarter of 2020 will benefit from some wind down of DMD spend. There will also be cost associated with determination of this program in the first quarter of 2020. We expect to begin to realize the result of our overall cost reduction efforts, including our workforce reduction in the second quarter of 2020. We expect that our existing cash and cash equivalents, together with expected and committed cash from existing collaboration will enable us to fund our operating and capital expenditure requirements into the third quarter of 2021. I will now turn the call over to Dr. Michael Panzara, our Chief Medical Officer who'll provide an update on our clinical development program. Mike?

Thanks Dave and thanks to all of you for joining the call today. From the start, we set out to develop an allele-selective approach to treat Huntington's disease because we felt preserving wild-type huntingtin was going to be essential to impacting clinical outcomes of the disease. As you know, patients with Huntington's disease have an expanded CAG triplet repeat in their huntingtin gene, which results in the production of a mutant huntingtin protein. However, Huntington's patients still process wild-type or healthy protein as well, which is important for neuronal function and some components of Huntington's disease are likely caused by the wild-type loss of function. Two recent publications over the past few months are worth highlighting today as they support wild-type huntingtin loss of function as a likely driver as HD pathogenesis. Specifically, one publication concluded that a striatum-specific defect in synaptic vesicle endocytosis was corrected by over expression of wild-type huntingtin, but not by lowering total huntingtin. A second publication concluded that striatal projection neurons require huntingtin for motor regulation, synaptic development, cell health and survival during aging. Loss of huntingtin function could therefore play a critical role in Huntington's disease. Both of these publications support previous literature that we've discussed around the importance of wild-type huntingtin. Also, just last week, I attended the 15th Annual CHDI Conference where I was privileged to have the opportunity to meet with many of the world's experts in HD, and to hear about much of the cutting edge research underway in this disease area. During the meeting, an entire session was dedicated to understanding the importance of wild-type huntingtin and the normal and disease states in the effects of modulation, in vitro and in vivo. From this session and the Wave team's other discussions at the meeting, we gathered several critical takeaways.…

Thanks Mike. Our latest modality, RNA editing, which we initially announced at our Research Day last year continues to advance. We've developed this program over a relatively short period of time and while it's still early, we believe our technology can present several advantages over other players in the emerging RNA-editing field. In 2019, our team evaluated more than 1,000 oligonucleotide, assessing a variety of sugar or base modifications backbone chemistry and stereochemistry as well as other parameters to gain insight into the relationship between an oligonucleotide structure and its ADAR activity. Wave's approach to RNA editing has several advantages over others. First, our oligonucleotides freely enter cells and do not require lipid nanoparticles for viral delivery. Second, our oligonucleotides are based on PRISM so they are fully chemically modified as stereopure. And finally, our oligonucleotides recruit endogenous RNA-editing enzyme, ADAR, so no exogenous proteins such as CAS9 or chimeric ADAR are needed. Most recently, our team presented a poster at the inaugural International Conference on base editing enzymes and applications. These results have demonstrated that we can achieve editing efficiencies of up to 70% across primary human cell lines in vitro. Additionally, as seen on the right side of the slide, we've achieved editing across several distinct RNA transcript, validating the technology across multiple sequences in vitro. We will begin in vivo studies in the near future for this program and look forward to sharing results this year, which will guide our initial therapeutic programs. Importantly, we believe these will be the first in vivo RNA editing data using endogenous ADAR with GalNAc conjugates. In summary, 2020 is the year of execution. In the first months of this year, we've initiated 32 milligram cohort for our PRECISION-HD2 study and right-sized our organization ensuring that we have the right team…

[Operator Instructions] Your first question comes from the line of Debjit Chattopadhyay with H.C. Wainwright.

This is Aaron on for Debjit. I just wanted to ask, how many patients would you need to dose at the 32 milligram dose cohort to escalate? And how many patients in that cohort might we expect an update on in the second half?

So, hi, this is Mike. From the -- as you know, each cohort has 12 patients planned to be dosed and we would expect that in the second half of this year. We would present the full dataset from all cohorts.

Okay. And on the first part, how many would you need to dose? Do you need to dose everyone in the cohort to escalate?

Our intention is to dose the complete cohort. We're not going to be dosing less than what we are intended to.

Your next question comes from the line of Whitney Ijem with Guggenheim Securities.

This is Evan for Whitney. Just again on the PRECISION-HD trials, will you be like to providing more information on -- if you guys decide on 32 mg dose? And as you dose up, will you provide safety updates through the year?

You broke up there in your call. This is Mike again. I believe you are asking, if we'd be providing interim updates throughout the year in the 32, or if we go higher. Our intention, as I said, is to second half of this year provide you with an update on the progress of the study?

And then one follow-up, on the SNP3 trial, can you guide -- can you provide more details around trial design there? I guess, how do you plan to design this trial versus PRECISION-HD studies?

Yes. This is Mike again. I mean, what we're doing now is, obviously, the design of that trial will be based upon the final profile that we evaluate with preclinical work, which is ongoing so more to come later in the year on that.

Your next question comes from the line of Mani Foroohar with SVB Leerink.

I got two quick ones. So, does the oligo for SNP3 use a similar or identical backbone chemistry of the first two SNPs? Are there any been many modifications that you've made that you -- as you continue to extract some learnings from that program? And then the second question, how should we think about the tempo preclinical assets in the Takeda partnership? Moving into the clinic, do you anticipate advancing all six targets? Are there sort of like stage gating studies you have to do? And just trying to think about the timeline of those getting in the clinic and the scale of any potential milestone cash flows as it become early clinical assets?

So to answer your first question relating to the design of SNP3, I mean, as we said on the call, we've leveraged what we've learned around the PRISM platform with new 2 prime-modifications backbone designs in the interplay with stereochemistry. And so, SNP3 has a different design than SNP1 and 2. And that gives a different profile pharmacologically. To Mike's point, we are going to understand that and with the in vivo datasets that we're able to run in transgenic models, we have much better visibility into helping to design that study. So we're very excited about the implementation, not just in how we're using that in SNP3, but in C9. And to your next question with Takeda, across the multiple programs. What's interesting in the Takeda collaboration, as we've said and you alluded to it, there is up to six programs in the collaboration. Those are moving forward. We are generating datasets and as data gets generated, we provide guidance as we just did around the transition of those programs. So starting with the first program that we identified and we'll have, as we said, expect two more this year. We haven't guided beyond that and that's the best way to think about it. If you think about this category to structure, we have the potential for over $2 billion in milestones pre-commercially and in other -- I mean, sorry, $1 billion pre-commercially and about another post commercial with a 15% royalty. So, pretty substantial in terms of the activities. We're excited about the progress of the collaboration, and we will keep things going.

Your next question comes from the line of Eun Yang with Jefferies.

Based on the SNP2 data last December, as you opt the dose to 32 milligram in SNP1 and SNP2 and starting SNP3 program in the second half of this year, how do you think you're patient enrollment would be based on the data?

Yes. Hi, Eun, this is Mike. Well, I have to say -- for the SNP2, I'll start with SNP2. The release of the data at the end of last year actually helped our recruitment of fair amount simply because target engagement and good tolerability tend to peak interest in physicians and patients. So, we're not having any issues with identifying patients and that will drive this cohort in any additional cohorts that are required. Now, the interesting thing about SNP3 is that, when you have the screening for SNP1 and SNP2 complete, you also have samples that allow you to assess for SNP3. It's the same type of technology. So, we're starting in a very good place with the sites who already involved and the ability for those patients who might not have qualified for SNP1 or SNP2 to be potentially eligible for SNP3. So that's how we're going to start and then we're going to go from there. And we'll see where it goes, but we have no -- I have no concern about identification of patients in the group.

For SNP1 and SNP2 data in the second half of this year, are those data coming out at the same time, or they are coming out as they become available?

We haven't really provided guidance about the timing of that. We've just said, the second half of this year that we will be actually providing both study results.

My last question is on the financials. So based on the cash guidance, is it reasonable to think that potential collaboration milestone payments from partners would be around $30 million in 2020?

So, we have not broken out the individual cash payments from the R&D expenses, but we do expect those R&D expenses being the contributing factors to the extension of [indiscernible].

Your next question comes from the line of Salim Syed with Mizuho Securities.

This is [Bennett] from Salim Syed at Mizuho. Thanks for taking our questions. Just a couple of quick ones for us. Regarding the C9orf72 program, is there any threshold that you are planning to achieve in terms of silencing? And then from the preclinical studies, did you find any off-target genes silence it? Thanks.

So I think I'll take the first part of the question. First part of the question in terms of...

The level of threshold level.

Yes. Correct.

There are two things we are looking at a threshold because there is -- and we think they're both important in treatments. One is, potency and obviously, that's the level of knockdown and we want to see as much knockdown as possible. We haven't guided to a specific threshold but we see substantial knockdown that demonstrated on the slides we showed earlier. I think the second piece that we think is important beyond potency is durability. So, reducing the frequency of those injections and we saw, out of eight weeks, we still saw durable knockdown of target. So, again, a potential not just for potent knockdown but durability is both being equivalent. And thirdly, again being variant specific. So again, take or leaving the non-hexanucleotide repeat containing transcripts intact. So when we think about building the program and have run, our in vivo models to demonstrate that we look at potency, durability and selectivity as kind of the three critical thresholds of the program and again while we're excited about the program, that's currently advancing into the clinic.

Yes. This is Mike, just to round that out. I mean, in addition to those criteria, obviously, we are very sensitive during the design process, in the preclinical process, any sorts of off-target effects there might be because that would manifest as either specific and non-specific tolerability. So, obviously balancing all of those criteria are important for the molecule that we eventually take forward.

I mean, as we've demonstrated, and just a follow-up on that and the slide where we showed be the crystal structure and kind of our first crystal structure, we are able to look at that engagement. That degree of specificity is the key criteria in our designs and we think a core advantage program going forward.

Your next question comes from Paul Matteis with Stifel.

So I think when the original SNP1, SNP2 data came out, there were a couple controversies on The Wall Street side related to dose response and also related to the data from the mutant versus total huntingtin assays. I guess, on the latter point, do you have any updated thoughts on why you saw mutant change but no change in total huntingtin? And secondarily, is there any more granularity you can give us on what you saw that 16 mg dose? Because I feel like that's kind of the main question I get as it relates to how can we be confident that 32 mgs will look better. Thanks so much.

Yes. Hi, Paul, it's Mike. Regarding the first question about total and how to assess the total versus the mutant; as we said at the time, and which was only a couple of months ago, we did see this reduction in mutant. We didn't see a big change in total assay, meaning no change from placebo. We're trying to understand what that means. As we've said, that could be related to again a differential effect between mutant and wild-type. It could something that as we increase the dose, and we see clearer. Those questions still remain. So there is no update to provide on that. And in terms of the dose response, as we said also all along that, what we did see was this -- when you look at full to active versus placebo, we saw an effect, and we saw, based on analysis, suggestion of a dose effect. And it was that suggestion of the dose effect that led us to the plan that we're now executing to increase the dose. I mean, we had statistical evidence of a dose effect, that's what guided us and that's why we're comfortable that increasing the dose is going to give us a greater effect.

Okay. I guess, was numerically was 16 better than, A, better than 4 or...?

So, what we said is that, I think when you -- it is safe to assume that when you look at some of the individual comparisons, they're not going to each be statistically significant. We've said that previously. But what we did say is by looking across all the dose cohorts, pooling all of the data, what you do when you have a small dataset that's variable, you look across the cohorts in at the highest doses tested we see a statistically significant effect. That's what we said and that's why we're comfortable increasing the dose.

As we get to the end of the year, we'll be breaking all that out for you.

Yes. I mean, I think as...

Yes. Is there -- and then just maybe one more question, are there any plans to present this at a medical meeting? I think it's great you guys are presenting the suvodirsen data. I know you presented SNP3 stuff at CHDI. It seems like that would have been a great opportunity to show more color here. What are your thoughts on that? I mean, you've got AAN as another opportunity as well, where Roche shed some data last year.

Yes. I mean, we have all intention just like the suvodirsen of presenting us at a medical meeting, but we also don't want to present partial datasets at a medical meeting. That suvodirsen dataset will be a complete assessment of what we have. So that is the approach we'd like to take with HD and there are medical meetings that we're thinking about that where we would present these data, but the intention is to show the complete dataset, not an interim analysis from the ongoing study.

And I think that was some of the discussion, as you said, maybe there is, I mean, this was an interim update on an ongoing study. So, to that end, we provided that interim update because we wanted to be transparent share that the study was progressing. But we will present the full data when the full data is complete.

Your next question comes from the line of Yaron Werber with Cowen.

Hi, guys. This is [Prajal] on for Yaron. Thanks very much for taking the question. Just two quick ones from us. About the pilot on the 32 mg dose, but I was actually just wondering, how you came to actually decide on that 32 milligrams, if there was any preclinical work you felt correlated well with that dose. And why maybe you didn't thing to go even higher when -- I guess, would you -- to that effect, would you consider adding another dose cohort if safety looks good down the line do you think you can get better knockdown? And then one other question, just on the C9orf72, obviously, a pretty exciting target. Just in terms of timing for the year. Are you kind of looking at SNP3 program and C9orf72 moving roughly in parallel at this point? And are you may be thinking to focus on either ALS or FTD first as you move that one into the clinic? Thanks very much.

Yes. Hi, this is Mike. So, first of all, starting off with the 32 milligram. As you'll recall, for our preclinical work we had in vitro evidence in fibroblast of differentiation between new wild-type and that was what we had when we started. And as we've gone along now, we've collected human data which then has guided us in terms of the dose escalation as I've described. So, jump from 16 to 32 was after seeing that the 16 milligram cohort was safe at a single dose, and that started the process of going up to 32, purely based upon safety, and we thought a doubling from 16 to 32 was reasonable and probably the most that an ethics committee and the regulatory authority want doubling is a pretty big increase. So that was sort of what guided the 32. Whether we'd go to whatever double that from there, whatever. I mean, that's going to be dependent upon what we see with the 32. And in this case, we'll have more human data, human safety data, human pharmacokinetics, pharmacodynamic data that will then guide what that next dose level should be. So, that's where we'll go and that's our intention assuming that supported by the 32. So that's the intention for HD. In terms of C9orf72 versus SNP3, as it is now, teams are working diligently to move those along in parallel. Obviously, that's all guided upon the data that you generate. We look forward to engaging regulatory authorities and the community on the best ways to develop those in light of the data that we're generating from our preclinical studies, and as of now, our intention is to approach FTD and ALS in a similar way and figure out, again, the best way to develop them as close to parallel as possible.

And at this time, there are no further questions. I would like to turn the call back over to Dr. Paul Bolno.

Great. Thank you, again, everyone for your time today and for your interest in Wave Life Sciences. Have a great day. Take care.

This concludes today's conference. You may now disconnect. Good bye.