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

Good afternoon, and welcome to the Wave Life Sciences investor conference call. [Operator Instructions] 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.

Thank you, operator. Good afternoon, and thank you for joining us. With me here today is Dr. Paul Bolno, President and CEO of Wave Life Sciences; and Dr. Mike Panzara, Wave's Chief Medical Officer and Head of Therapeutics Discovery and Development. This afternoon, we issued a news release announcing results from our PRECISION-HD1 and PRECISION-HD2 core and open-label extension trials. That release can be found in the Investors section of our website at www.wavelifesciences.com, along with a copy of the slides to accompany today's webcast, which will be posted following this call. Before we begin, I would like to remind you that we'll be making certain forward-looking statements related to our current plans and expectations on today's call, which are subject to risks and uncertainties. Actual results may differ materially due to various factors, including those described in the Risk Factors section of our most recent Forms 10-Q, 10-K and other SEC filings. These forward-looking statements represent our views as of this call and should not be relied upon as representing our views as of any subsequent date. We undertake no obligation to publicly update or revise any of these statements. On today's call, Paul will begin with some opening remarks, after which Mike will review the PRECISION-HD clinical results. Paul will then discuss the evolution of Wave built upon our next-generation PN chemistry, and Mike will end with a review of our 3 clinical programs that are all supported by this next-generation chemistry. I'd now like to turn the call over to Paul.

Thank you, Kate. This afternoon, we announced results from our PRECISION-HD1 and PRECISION-HD2 clinical trials which, unfortunately, do not support further development of either WVE-120101 or WVE-120102. These results are clearly not what we hoped to share with you today, and I'd like to start out by recognizing the HD community and thanking the courageous trial participants and their families. It has been a difficult month for this community, and I can assure you, we remain committed to those families touched by this devastating and fatal disease. Huntington's is a difficult disease, and we are committed to our novel approach to treating it by selectively reducing mutant Huntington proteins while preserving wild-type protein, which is essential for proper function of the central nervous system. We have developed innovative approaches to execute our allele-selective HD programs, such as SNP phasing for the efficient identification of patients carrying specific SNPs, and we have developed and now validated in the clinic the first assay to evaluate wild-type Huntington proteins in CSF. We have also formed collaborations with academia, clinicians and others, and we build upon these relationships as we drive our next-generation HD program forward in the clinic. We remain committed to the HD community, and while disappointed today, we see a brighter future as we continue to apply innovations as well as learnings from our study results to advance our current clinical and preclinical programs and move this field forward. Our next-generation clinical pipeline reflects the growth and significant evolution of our company since we began. And this includes our SNP3 clinical candidate, WVE-003, for HD. Our allele-selective approach to treating this disease remains consistent, founded in the biology of Huntington and the understanding that preserving wild-type Huntington may be critically important in the setting of mutant Huntington knockdown. This approach is also unique, and WVE-003 is the only allele-selective therapy in clinical development. However, as compared to our first-generation programs, WVE-003 is different. This compound was designed with enhanced chemistry and learnings from our PRISM platform and is our first HD candidate to incorporate our novel PN chemistry backbone modification. It is our first HD trial to have a starting dose informed by preclinical in vivo models that contain our SNP target and to evaluate the pharmacodynamic effects. These results, together with tissue exposure and studies in NHPs, bolster our conviction in our oligonucleotides approach to achieve exposure in the brain, including the cortex and striatum. The clinical trial will also leverage learning for our PRECISION-HD trials, as Mike will discuss later on, which we expect to drive efficiencies that will ultimately help get faster results for patients. I will now turn the call over to Dr. Michael Panzara, our Chief Medical Officer, who will review the PRECISION-HD clinical results. Mike?

Thanks, Paul. As Paul mentioned, this is not where we hoped to be today. What makes it even more difficult for us is that this comes on the heels of another devastating setback for the patient community with the cessation of dosing in the Phase III clinical studies by our colleagues at Roche. I cannot start describing our trial results without first acknowledging the difficult journey that continues for these patients and their families and to thank our trial participants for trusting us throughout these programs and whose strength drives us to continue to innovate and quickly apply any learnings from these setbacks to our next-generation clinical program. Our commitment to you remains steadfast. To summarize the findings, in the PRECISION-HD core study, there were no statistically significant reductions in mutant Huntington after single or multiple doses of WVE-120102 ranging from 2 to 32 milligrams and no dose response. In the PRECISION-HD2 open-label extension study, there were modest but inconsistent reductions in mutant Huntington over the course of the study, and data suggests that additional dose escalation is unlikely to achieve drug concentrations needed for robust mutant knockdown. There was a suggestion of allele selectivity given a lack of correlation between those with greater than 20% mutant Huntington reduction -- or observations with greater than mutant -- 20% mutant Huntington reduction and wild-type change, and I'll touch on that later. The results were consistent with Precision H2 -- HD2 up to 16 milligrams in our PRECISION-HD1 core and OLE studies. And as you know, the 32-milligram core and OLE results are pending. There were additional observations from the study. There were no changes in neurofilament light chain. There was no worsening of disease progression in treated patients versus expected based on the natural history. And the biomarker assays, including the newly developed wild-type Huntington assay, performed reliably. The focus now is advancing our next-generation compound, WVE-003 with new backbone modifications that have the potential to address the limitations of our first-generation chemistry, incorporating backbone PN chemistries we've learned to demonstrate improved preclinical in vivo pharmacology. And we're in the process now of activating sites, with dosing expected in 2021. Inclusion in this study remains a possibility for some of the patients of PRECISION-HD1 and HD2 study, and I'll touch upon that later. You will recall by now the overall design of the PRECISION-HD studies. These are single-ascending and multiple-dose studies where patients were to receive up to 4 doses of WVE-120101 or WVE-120102, depending on whether they carried the SNP1, SNP2 or both alleles in association with CAG expansion. There were 5 SAD multidose cohorts ranging from 2 to 32 milligrams, with an additional 12-milligram single-dose cohort in PRECISION-HD2 run in the U.S. in preparation for additional U.S.-based studies. Patients could receive a dose of drug in the single-dose portion, followed by 3 additional doses in the multidose portion or, in some parts of the world, enroll directly into the multidose portion. Following a washout period, patients could enroll into an open-label extension study, or OLE, for continued monthly dosing. Once a dose was determined safe by a Safety Monitoring Committee, patients had the option to escalate to the highest dose testing. Beginning with the PRECISION-HD2 study, this slide illustrates patient disposition. A total of 88 patients were enrolled across both single- and multidose cohorts. Most patients received 3 or 4 doses at each dose level, with 9 and 7 patients receiving 3 to 4 doses of either 16 or 32 milligrams, respectively. The patients recruited were representative of an early HD patient population with more stage 1 patients in the 32-milligram dose group. This slide illustrates the key biomarker analysis from the study. In this analysis, we compared percent change in CSF-mutant Huntington levels from baseline to 4 weeks after last dose received for those on treatment who had received either 3 or 4 doses of study drug compared to a pool of placebo group. On this dot plot, percent change from baseline is on the y-axis, dose is on the x-axis, and each dot represents a patient. The solid line represents the mean, the dash represents median. As one can see, there was no statistically significant reduction of mutant Huntington compared with placebo. It is important to note that this is different from our interim analysis in 2019 where we saw a small but statistically significant effect in patients and the like at that time frame. This effect was clearly lost due to several factors, primarily incomplete follow up at the time of the interim analysis, the addition of patients to this analysis and the results of the placebo group. This slide illustrates the same analysis for wild-type Huntington. There was no statistically significant change in wild-type Huntington during the course of study. The assay used for this analysis is the new wild-type assay we developed to assess for allele selectivity. I will come back to this when I review the data from the OLE. Similarly for neurofilament light chain, there was no statistically significant change, and the same was true of UHDRS-based clinical outcome measures. The cUHDRS is shown here. The TFC and TMS looked similar. Moving on to the OLE. CSF was collected before each monthly injection of study drug over the course of study. For this analysis, we plotted mutant Huntington measurements on the left and the mean and median percent change from baseline on the right. There were samples from 28 patients available for the analysis, with numbers of doses received ranging from 1 to 17, with a mean number of doses administered of approximately 8. One can see there were some modest reductions at some time points throughout the study, but these changes were not dose or cumulative exposure related, and extensive sensitivity analysis failed to confirm a consistent dose-related effect. Doing the same analysis for wild-type Huntington, we saw no change in wild-type Huntington levels over the course of the study. While it was tempting to say after seeing this that there was no impact on the treatment of wild-type Huntington, we were not comfortable with that conclusion given no consistent change in mutant Huntington throughout the study. We, therefore, did 2 analyses. First, we looked at trough drug concentrations in the CSF to see if there was a correlation between concentrations of WVE-120102 and mutant Huntington, namely did those who had the highest CSF drug concentrations have the greatest degree of change in mutant Huntington? What we found was that there was a modest correlation between maximum concentration and change in mutant Huntington. We then took the subset of patient observations with mutant Huntington knockdown of at least 20% and assessed whether there was a correlation between mutant Huntington knockdown of greater than 20% and wild-type Huntington change. And as shown on the slide, there was not. While not definitive, this leaves us hopeful that our SNP targeting approach has the potential to spare wild-type with next-generation compounds. Moving on to NfL. We saw no change in neurofilament light over the course of the OLE despite monthly lumbar punctures and study drug administrations in some patients for over a year, mirroring the CSF laboratory assessments that I'll cover in a moment. For our assessment of clinical efficacy, we again looked at UHDRS-based endpoints collected quarterly throughout the OLE. This slide illustrates the change from baseline over the course of the study and shows a small decline indicating disease progression in this group of patients. To understand this better and put in the context of natural history data, we leveraged some of the high-quality existing data sets that the HD scientific and patient communities have generated over decades, including Track-HD, Predict-HD and Enroll-HD obtained through collaboration with CHDI. Using these data, we first applied the PRECISION-HD core study inclusion criteria to those data sets and then used propensity score matching to match subjects who participated in both the PRECISION-HD core and OLE studies to subjects in the natural history data sets. We then compared the change in UHDRS endpoints over the course of PRECISION-HD2 core and OLE to the change seen in the matching natural history study patients using a linear mixed effects model. As you can see, the slopes or rates of change were very similar to our data set, indicating the rate of progression observed during the study was in line with the natural history of disease. Moving on to safety. Overall, adverse events were balanced between the groups with the types of common events one might expect given monthly lumbar punctures, and most were mild to moderate in intensity. The main exception to this is what we've seen in the 32-milligram dosing group where 7 of 13 patients were reported with an SAE related to treatment resulting in 6 treatment discontinuations. These events were transient and included disorientation, delirium, ataxia, slurred speech, amnesia and vertigo. We saw similar events in the OLE, but the serious AEs related to treatment with the 32-milligram dose in the OLE was lower than in the core study, apparently influenced by the dose escalation scheme that was part of the study. In addition, 2 patients were redosed following these events without recurrence. Finally, there were no clinically meaningful trends in clinical laboratory values, including CSF white blood cell and protein elevations in either study, which is consistent with the lack of increase in neurofilament. Now briefly moving on to PRECISION-HD1. The results were up to 16 milligrams in the core study were the same for both mutant Huntington and wild-type Huntington. You will recall that the 32-milligram cohort is still ongoing, although all patients have completed dosing. Similarly, for the PRECISION-HD1 OLE, there was no effect on mutant Huntington or wild-type Huntington. And there was no effect on neurofilament light in either the core or OLE study. And finally, the incidence of adverse events were balanced across the group up to the highest dose, which was 16 milligrams. And again, there were no meaningful trends in laboratory values. So in summary, the PRECISION-HD studies will be discontinued and dosing suspended effective immediately. As I noted earlier, we expect to start dosing in a Phase Ib/IIa clinical trial for 003 in 2021. As people with HD can carry multiple SNPs in association with CAG expansion, it is possible that current participants in the study may, in fact, be eligible for this new allele-targeting program. It is estimated that approximately 40% of the adults with HD carry SNP3 in association with HD mutations. Participants from the PRECISION-HD trials will be offered the opportunity to undergo screening for potential enrollment in the 003 trial, if acceptable to their physician and the study is active in their country of residence. I'll turn the call now back over to Paul.

Thanks, Mike. Looking ahead, we have a deep and diverse pipeline of RNA therapeutics that fully reflect Wave's evolution as a company over the past 8 years. Since our founding nearly a decade ago, we have made disciplined investments in our platform to enhance our ability to rationally design oligonucleotides, including discovery and application of our novel PN chemistry. Today, all of our clinical, preclinical and discovery pipeline programs are supported by this next-generation chemistry. In a moment, I will review some of the data that supports the use of these PN modifications and fuels our excitement for our pipeline. The foundation of our development approach for each new pipeline program is summarized on Slide 27. Years of deliberate platform exploration as well as focused preclinical and clinical work across programs have revealed valuable lessons and enabled us to address efficiencies with our first-generation candidates. Since we initiated work on our first 2 HD programs in 2014, our chemistry, in vitro and in vivo systems as well as our understanding of the interplay between sequence, stereochemistry and chemistry have evolved dramatically. We now have an ability to design more potent and durable clinical candidates that, frankly, are preclinically far superior to those explored in the PRECISION-HD trials. The clinical results that Mike just presented confirm the limitations of our first-generation programs, and I'm pleased to report that the work over the past 2 years demonstrates that we will do better. First, enabled by stereopure design, all of our next-generation programs have been optimized with PN chemistry. We apply these modifications using our deep understanding of the interaction between sequence chemistry and stereochemistry, and we have screened over 50,000 oligonucleotides to study and understand structured activity relationship, or SAR, across various modalities. In our next-generation programs, we have prioritized the use of in vivo models during preclinical development to ensure we advance clinical candidates that will reach the desired type of action and engage target. We've also incorporated learnings in the translational pharmacology and clinical trial design from our first-generation programs, such as the use of adaptive clinical trial designs for our SNP3 and C9orf72 trials. The best evidence of this evolution is the wealth of compelling in vivo preclinical data that we have presented to support the advancement of our clinical programs, SNP3 in HD, C9orf72 in ALS and FTD, and Exon 53 in DMD. Our novel PN chemistry augment stereopure PS/PO backbone modifications and is a major advancement from our PRISM platform. In preclinical studies, these modifications have generally been shown to increase potency, exposure and durability, suggesting this new chemistry has the potential to lead to compounds with favorable profile, independent of sequence, tissue type and modality. As shown on Slide 28, the potential impact of PN chemistry on potency specifically has been demonstrated across multiple modalities, including silencing, splicing and ADAR editing applications. In vivo, oligonucleotides incorporating PN chemistry have shown durable activity even in deep tissues of the brain compared with molecules with the exact same sequence and chemistry but that lack PN modification in backbone. On this slide, we demonstrate that PN-containing compound achieved persistent transcript knockdown of 80% to 90% throughout the central nervous system, including spinal cord, cortex and the striatum. It is results such as these that give us confidence in our exciting new generation of programs. Importantly, we continue to see the effects of PN chemistry translate in our therapeutic programs, including in the central nervous system of NHPs. On this slide, you can see in vivo data for the most advanced therapeutic candidate in our CNS discovery collaboration with Takeda. In this study for an undisclosed target, nonhuman primates received a single intrathecal injection, 12-milligram dose. One month after administration, we observed that the candidate was widely distributed across the CNS, including the spinal cord, cerebral cortex and hippocampus. The single dose led to approximately 90% knockdown of the target mRNA across CNS tissues, which we view as a considerable achievement for our platform and the field in general. Our preclinical in vivo data for WVE-004 is an example of the potency and durability of effect we can achieve with PN backbone modifications. Following 2 ICV injections of WVE-004, we observed rapid and durable knockdown of over 90% of the DPR poly-GP protein in the spinal cord and at least 80% knockdown in the cortex, with durable effect out to at least 6 months. As shown on Slide 31, further, normal C9orf72 protein remains unchanged at that time point, demonstrating the variant selectivity of this compound. In our Exon 53 program, we've demonstrated the impact PN chemistry can have on the rescue of the double knockout, or dKO, models from rapidly fatal phenotype. In this study, we compared the effect of a first-generation molecule dosed at 150 milligrams per kilogram weekly to a PN-containing compound dosed both at the same level and at 75 milligrams per kilogram every other week as well as a PBS control group. On Slide 32, we show survival curves for the treatment groups. And you can see there's a dramatic increase in survival in those animals treated with the PN-containing compounds as compared with the first-generation treatment group at a dose 75% less than the other groups. This survival data adds to our excitement for our Exon 53 clinical program of WVE-N531 in Duchenne muscular dystrophy, which Mike will touch on at the end of this call. I'll now turn the call back over to Mike to discuss our SNP3 clinical candidate for HD, WVE-003, and our clinical pipeline. Mike?

Thanks, Paul. Despite these results, 2 things remain constant: our commitment to HD, and our belief that allele selectivity is critically important as a foundational concept in the treatment of HD. You have heard from me before that there is a large and growing body of evidence that suggests HD is driven by 2 factors: gain of function of mutant Huntington protein and loss of function of wild-type Huntington protein, and the ongoing battle between the positive biological effects of wild-type Huntington protein and the toxic effects of mutant Huntington in the CNS of those living with HD. Unfortunately, people who carry the AC mutation already start out at a disadvantage with approximately 50% less wild-type protein than a healthy individual, gradually losing ground to disease progression. Wild-type Huntington is essential for proper function of the central nervous system. Wild-type Huntington carries out essential functions in both developing and adult brains. It protects neurons against various types of stress prevalent in cells with high metabolic activity, including cytotoxic, oxidative and protein misfolding stress. Wild-type Huntington also plays a key role in trafficking synaptic proteins and synaptic vesicles. This trafficking function has been shown to affect synaptic plasticity, which is important for learning and memory as well as the production and transport of essential growth factor BDNF in the cortex, which supports the survival and function of striatal neurons. Additionally, wild-type Huntington is critical for the formation and the function of cilia, which control the flow of CSF and help maintain homeostasis in the CSF. As I mentioned, one important function of wild-type Huntington is to transport BDNF to the striata. While BDNF is necessary for survival of striatal neurons, they do not produce it. Rather, they receive it from cortical neurons. Preclinical evidence suggests mutant Huntington does not support effective transport of BDNF as compared to wild-type Huntington. It has been demonstrated in vitro that when HD neurons from the cortex are paired with wild-type neurons from the striatum, the corticostriatal network was dysfunctional. When this was reversed, meaning wild-type cortical neurons are paired with HD striatal neurons, the network was functional. We believe an allele-selective approach will be critical to achieving clinical benefit within HD therapy. In the push-pull of positive wild-type Huntington factors to toxic mutant Huntington factors, further depletion of wild-type protein -- the wild-type protein reservoir with nonselective approaches may cause patients to lose even more ground to disease progression. As such, we believe wild-type preservation may be an important driver of efficacy when considering how much mutant Huntington lowering may be required to achieve clinical benefit. Our SNP3 program with WVE-003 is now the most advanced allele-selective approach in clinical development. As Paul has reviewed, our work in Huntington's disease continues with our 003 program, the development of which has been guided by our successes and our failures of the past. However, what is consistent is an allele-selective approach. 003 has been improved over our prior SNP-targeting candidates through the use of stereochemistry as well as novel backbone chemistry and the use of preclinical in vivo models to guide dose selection. Creative approaches in the area of clinical trial design, advances in patient screening technology and biomarker analysis tools will also benefit us as we advance this and other programs through development. Slide 39 illustrates some of the in vitro and in vivo data supporting 003's advancement into the clinic. On the left, we clearly see the in vitro selectivity of our candidate over a wide range of concentrations versus similar concentration of a pan-silencing reference compound. While we see a similar reduction in mutant Huntington transcripts from both compounds, 003 leaves the wild-type Huntington RNA relatively intact. We also examined the mutant Huntington knockdown effect of our candidates in an in vivo model, the back HD transgenic mouse, something we did not have access to for our first-generation SNP1 and SNP2 programs. For SNP3, we investigated this model, knowing that there were several limitations, namely that the model does not contain the wild-type Huntington gene and it contains multiple copies of the mutant Huntington gene, some of which do not have the SNP3 variant, therefore, selecting a higher bar for mutant Huntington knockdown. Nonetheless, as shown on the right, we observed potent and durable knockdown in mutant Huntington with striatum, have the back HD transgenic mouse out to 12 weeks with a similar effect observed in the cortex. This demonstrates -- this demonstration of selectivity, potency and durability bolster our enthusiasm for 003 in the clinic. Also in these models, we have assessed pharmacokinetic and pharmacodynamic relationships following 003 treatment and achieved knockdown the striatum as well as cortex despite the high bar this model presents for allele-selective therapy. Similarly, we have measured pharmacokinetic effects in single and multidose studies in nonhuman primates. And we achieved concentration sufficient for target engagement using our back HD studies as a guide. Based on these NHP and back HD data, we have modeled the PK/PD relationship for 003, and the model predicts that 003 should obtain sufficient concentrations to engage mutant Huntington transcript in both the cortex and striatum within the predicted therapeutic window. The Phase Ib/IIa clinical trial is planned to enroll up to 40 patients with a confirmed diagnosis of HD who are in the early stages of disease and carry SNP3 in association with the long CAG expansion. The trial will incorporate an adaptive design with both single and multiple ascending dose portions. Throughout the course of the study, an independent Data Safety Monitoring Board will guide the level of dose escalation and dosing interval to make data-driven decisions regarding dose and to potentially accelerate time to proof-of-concept. Safety and tolerability of 003 will be evaluated along with similar biomarkers as our PRECISION-HD program, including mutant Huntington, neurofilament light chain and wild-type Huntington to assess for allele selectivity. Clinical trial site activation is ongoing, and we remain on track to dose a first patient this year. In addition to HD, we're simultaneously bringing next-generation clinical candidates to patients with ALS and FTD with WVE-004, our C9orf72 targeting candidate, and to patients with Duchenne muscular dystrophy with WVE-N531, our Exon 53 candidate, for which we submitted a CTA this month, in line with our guidance. Like WVE-003, each of these clinical candidates use PN backbone chemistry modifications and leverage preclinical models to guide development. For 004, our preclinical results include knockdown of poly glycine proline, or poly-GP, a toxic peptide related to the mutation but also an important biomarker of target engagement. Knockdown of poly-GP in the spinal cord and cortex was seen after just 2 doses in vivo with a durable effect out to at least 6 months. Measurement of CSF poly-GP will be a key biomarker in our clinical trial and critical to allowing adjustment of dosing and potential program acceleration. Similar to our SNP3 trial, our C9orf72 trial uses an adaptive design and remain on track to dose a patient this year. For Exon 53 program, we have compelling preclinical data, as Paul described, supporting the use of PN chemistry for exon skipping, including demonstration of a profound overall survival benefit in aggressive mouse model for DMD. And we also anticipate dosing a first patient this year. Looking ahead, it will be an exciting year for our next-generation clinical pipeline as we begin dosing in patients in 3 new trials. In addition, we remain on track to share new preclinical in vivo data for alpha-1 antitrypsin program using ADAR editing technology. With that, we'll open up the call for questions. Operator?

[Operator Instructions] And our first question is coming from the line of Joon Lee with Truist Securities.

Is there something that gets saturated in vivo with the stereopure oligos as opposed to stereorandom oligos that limits exposure or PK? I'm just curious because you don't see a dose-dependent rise in PK, whereas the stereorandom oligos have gone up to 120 milligrams with dose-dependent effects. Just curious what could be limiting the effect there, PK and exposure, and along with that clinical benefit. And I have one more follow-up.

Mike, do you want to take that to start?

Yes. I don't think this really has anything to do with whether it's stereorandom or stereopure. In essence, I think that each molecule is going to be different. And I think that the dose ranges that we're in, we clearly did do analysis, looking could we dose higher and what -- if we did go to a higher dose, would we gain some degree of increased concentration in CSF to get to a certain level that we believe would engage target, and we did not see that. We didn't believe that going higher would enable us to do that given the data we have. But I don't think that's a difference whether it's stereorandom or stereopure. I think that each of these molecules, at least where we're designing them at Wave now, each one of these stereopure molecules has its own properties. And when we see stereopure molecules with the PN in vivo, in -- at least in the nonhuman primates, they do look totally different. So I don't think this is related specifically to either stereorandom or stereopure. It is just these particular molecules do not have the potency and apparently the distribution that we needed to engage targets.

Just to follow up on that point, I mean, one of the challenges we had with our first-generation program, so SNP1, 2 and I can remember even in DMD, is the lack of the preclinical model with which to test exposure and predictive knockdown and be able to translate that to exposure levels in data. So a lot of this is, as Mike said, is stereo chemistry to our -- it's a molecule. I think what we've seen in our current program, so if we look at the in vivo data, even looking at nonhuman primate exposure in C9 with durability out 6 months, we know and see in the model of PD knockdown that we're getting that durability exposure. SNP3, we're seeing that durability exposure. DMD, we're seeing that in the dKO mouse. So I do think -- I would agree with Mike that we're not talking about a stereochemistry -- stereopure versus stereorandom as much as we are the limitations of predicting translatability in the absence of those PD models. I don't know if there's anything else you want to add to that, Mike?

No. I think that captures it.

Great. And then do you think it's -- the limitations could be due to intrathecal route of administration as much as some other factors that might play in that regard? I know the PN chemistry has better penetration, but could you also envision a different delivery, like maybe a direct injection or some kind of a port?

So I'll start, Mike. And then I think, again, it's a very similar conversation. I mean even having the intrathecal nonhuman primate data that we have for distribution and exposure, I think with our PN chemistry onto the backbone, we're seeing those levels of knockdown and target engagement via intrathecal administration. So again, I think the disappointment today is, I think, we're very clear that the first-generation chemistry hasn't reached potency and exposure levels that require us to go forward. I think the investment we made 2, 2.5 years ago in advancing PN backbone modifications and then translating them into our current 3 clinical programs, the reason those clinical programs are moving is because we've got support through intrathecal administration and distribution. I think the disappointing feature is not having those predictive models to translate. Mike, I don't know if there's anything you want to add to that?

No. I mean, I guess, in the specific about a port, you're delivering to the ventricle in the setting of a port. I doubt that would do anything differently. I mean we don't -- as Paul said, this seems to be related to the molecules rather than any sort of route or anything other than that.

I mean just to follow up, I mean, it's come up around [indiscernible]. I mean one of the things we've seen in a number of programs we shared more recently, obviously, the PN distributions have multiple reasons to the range we've seen in terms of target engagement. So again, I think that's what's driving the translation of this next-generation platform. And as we said, it's being used in all of the programs. Not just the clinical programs, but our preclinical programs with Takeda and our own pipeline programs for that reason.

Our next question is coming from the line of Salim Syed with Mizuho.

Sorry, the news couldn't be better today. So Paul or Mike, I just had a couple of questions. I wanted to focus on this potency argument. So obviously, I presume you thought at one point 32 milligram would be more potent or enough -- have enough potency than the 3 lower doses. Obviously, we didn't see that here today. We're now talking about PN chemistry having more potency. So I'm just wondering, is potency the only things that you're considering here being the key thing to toggle? Or are there other things that we should be thinking about? And then the second question is just on the SAE profile. So in the press release, it mentioned how the 32-milligram in one of the trials had more SAEs than the 3 lower doses. And so I'm just wondering what the trigger for that was? Because if you are talking about potency, how do we zero out or minimize the risk that with PN chemistry, we wouldn't see an even greater increase in SAEs?

Do you want me to take the first piece on PN, Mike, and then transition to the other question on safety?

Sure. Yes.

Yes. I mean, I think, Salim, to your point, we've seen consistently not just improvement in potency, that being one aspect, I think with the stabilization of oligo, we've seen durability and also exposure differences. So I think it's multifactorial, but it's been translating in terms of in vivo pharmacology. So I think as we think about the totality, and we've done these comparisons in terms of on-target potency, so reaching that oligo, we've seen the ability to have higher potency on the specific transcript target. And so I think that's what's really caused the shift in terms of our platform. Would you like to continue, Mike, on the other piece?

Yes. I mean I think we don't -- so the actual issue of the SAE, I mean, for 32 milligrams, I mean, we don't really know the mechanism of that. I would assume that's not going to be related, as Paul said, to a necessarily an on-target effect. I mean potency doesn't mean you're going to have more toxicity, it's about also where you're getting the drug. And it's also, there are effects of the actual -- the Cmax, the AUC, the distribution, the half-life. There's a lot of variables involved in just whether something is going to cause an SAE. In this case, these events we were seeing, as you see in the press release, were transient. They resolved, and then patients who -- several patients ended up being retreated. But again, I think it's a little bit more complicated than just saying there was an SAE because of potency. There's some aspect of the molecule at play here.

Yes. I mean just to add to Mike, I mean, he brought some very good points around looking at AUC and Cmax. I think across the parameters we've looked at and we've seen improvements with the PN chemistry, which is really why we made a decision to shift to that platform, as we said a while ago. So that's been a core advancement. I think the other piece that we've found on the preclinical development side is our assays for screening, looking at programs, have continued to improve. So I think we're continuing to identify medicine. But as we think about the safety of this, and as Mike said, I mean, the study wasn't stopped for safety. We saw no increase in NfL levels. As Mike pointed out as well, we think about clinically relevant increases in WBC than protein in the CSF, that wasn't there. So I think it was clearly, for us, a question of could we get better exposure and target engagement to get activity.

And our next question is coming from the line of Mani Foroohar with SVB Leerink.

Obviously, a tough month for Huntington's patients all around. Let's first start with the financial side of things. How should we think about puts and takes around potential reduction in spend as you wind down these 2, at least for the existing programs, either on a near-term basis or more ongoing, versus the ramp into SNP3 as well as the PN chemistry programs? And secondarily, what's the timing around the first time we'll see some view into potency of a new PN chemistry in patients? Would that be in the ALS, orf72, somewhere else? Like what's the first time we'll see that in a human so we can judge potency in patients?

So I'll start with your first question, there's no change to our cash runway guidance. So we've already been -- the SNP3 study was running independently of where this data relapsed. That study was already -- we filed a CTA in December and is running. So at this point, there's no change to cash guidance into Q2 2023 and delivering SNP3; C9; Exon 53, so N531; and advancing the ADAR platform with a lead in alpha-1 antitrypsin. So that's been consistent that there's no change to our financial spend with our current programs. As to where we're going to see data, I think that's -- we've got a number of studies that are starting. And as those studies continue, we'll be able to probably provide more guidance as to which one we'll see examples of first. But I think to that point, we have 3 clinical programs this year, all using PN chemistry in a variety of different settings from muscle to -- and systemic to intrathecal in CNS. So looking at Huntington's and C9 for ALS and FTD. So across a number of programs, we're going to have opportunities to look at the performance of PN. And we look forward to being able to share that data.

And our next question is coming from the line of Luca Issi with RBC Capital.

I have a detailed question and more a bigger-picture question. So the detailed question is do you have any color on the placebo arm for PRECISION-HD1? Wondering if you could provide any color there on what drove the 10% reduction in mutant Huntington that we actually have seen there for placebo. And then the bigger-picture question, obviously, in light of the Tominersen data showing no clinical benefit despite 30% to 40% reduction across both wild-type and mutant protein, what do you think is the percent reduction in mutant Huntington that is required for a clinical benefit? Do you need to see 10%? 30%? 50%? 80%? What will be your best guess?

Mike, do you want to start?

Yes. I mean -- he's not going -- I really don't know what to comment about the placebo. I mean there's going to be small changes like that. It's under -- as you said, in that 10% range. I wouldn't read too much into it. I mean that -- there is going to be change like that in a study, so I really wouldn't necessarily pay much attention to that. I would say in light of the Tominersen data, I mean, we do have a different approach. Actually, I think that we are very eager to see what those results would look like so we can hopefully learn more about the -- what might have happened there. And yes, that is going to guide us. But we'll be -- we're in a situation where we still believe that when you target wild-type -- mutant specifically, allowing your wild-type to remain intact, that the amount of reduction you will need is not going to be at a significantly high level. I mean, 20%, 30% is what we've been saying is what our target is because you have that wild-type protein there that is actually helping give the benefit of having healthy wild-type protein. And actually, our -- in our study, one of the things that's sort of the silver lining of the study is these analyses we did looking at our -- the observations that had these greater than 20% reductions, we do seem to show that there may be some allele selectivity here. So that gives us hope that we are on this path of not needing to show these large reductions could potentially have a meaningful effect.

And I just think, to piggyback off of what Mike was saying because I think it is important, is I think Roche did a lot of work, along with their colleagues at Ionis, on what a clinically relevant knockdown is. I think what we've seen in terms of some of the data that's been emerging across wild-type protein has been that reduction manifests itself in preclinical experiment as progression of disease. So I think I completely agree with Mike that I don't know necessarily about the bar on mutant changing. I think what's changed, and we've heard this from our peer companies, is a focus on wild-type sparing strategies. And I think we're there in the clinic with SNP3 to continue to test this hypothesis with a molecule that has the potential for higher potency, exposure, potential durability. So we're going to see that continue to play out. And there may be investment in the infrastructure to do that, the assays to screen patient, the assays to assess wild-type in clinical trials. And we'll continue to look. As we also saw, without seeing a change in NfL and other levels, I think we're excited to continue to be in HD and continue to run studies with allele-specific therapy. So given the exposure of SNP3 into all regions of the brain and given the potential for the specificity, at least that we've seen preclinically in the tools, I think we continue to be excited and -- to bring that to patients to continue to test this in the clinic.

[Operator Instructions] And our next question is coming from the line of Paul Matteis with Stifel.

So I wanted to clarify one thing, and then I have one follow-up. So on the clarification side, did you not do any in vivo animal work for SNP1 and 2? Obviously, you had to do preclinical tasks. But I guess, am I hearing you right that you didn't look at knockdown in vivo at all? Or did you -- at least in some context?

No. I mean I think that we discussed years ago, you remember this program goes -- takes us back to 2014, 2015. That was one of the discussions we had, I remember, with you and others at the time that it was one of the difficult features of that decision to move forward is that we had the in vitro data around potency, and then we had the in vivo NHP data around kind of distribution to reach into brain. I think the challenge is you can't extrapolate a PD relationship there because there wasn't a PD knockdown that we had there. That really drove our decision to say we'll be bringing other molecule forward for HD, particularly in a SNP-targeting fashion to assure that, one, the model has the SNP and to be able to build that PD correlation and then translate that to exposure. So you're right. I mean that's -- as we've been clear with the program. That was one of the discussions around the program when it started around the dose was the dose couldn't be selective to start based on a PD correlation. And obviously, SNP3 of starting in the clinic around the dose that can be selected off of PD relationship? Mike, I don't know if there's anything else to add to that.

No, that's exactly right. I mean the first studies for allele selectivity were fibroblast studies. They weren't -- and then the monkeys don't have the target.

Yes. Okay. And then so for SNP3, I guess, what do you think is going to be the human efficacious dose range based on your preclinical work? And what doses do you expect to start at?

Yes. So I mean I would say that we'll -- as we move along in the study, we'll have -- we'll be probably providing more of an update. But I can say that where we're going to be starting in the clinic is in a range that we already believe we will be engaging target based on the preclinical data that we have. So we are starting at a foundation based on these studies. And the way the studies are designed, the Data Safety Monitoring Committee is going to be reviewing it. It's going to be looking at these data and providing advice on levels of dose escalation. So we're starting within a range we predict to engage target, and we're going from there. And we have plenty of room to move.

Okay. And if you don't mind, I just have one last -- yes, go ahead.

Just to clarify, sorry, while responding to questions, we kind of jumped into the KD side, so the pharmacology. But obviously, we did do in vivo safety work and doing the dose exposure work. So I just don't want to leave that there were no other...

Yes, of course. Okay. And then one other question. I guess, how well do we understand the actual kinetics levels and natural history of wild-type Huntington in the CSF? Is there any context you can provide there just as it relates to kind of proving out allele specificity more broadly? Like if you don't see much of a change in wild-type Huntington, is that -- do we know that, that is driven by the drug? Or could just the levels be so low that there's really not going to be a lot of standard deviation?

Yes. So what I can say is that we just developed this assay that we don't -- I mean, the best longitudinal behavior of wild-type is what you've seen and what we have in our placebo patients. So we did -- this is -- we were very pleased that we were going to be able to -- that we didn't know we're going to be able to measure, whether we would see ultra-low levels, whether we'd be able to detect it. We were able to do all those things. So from now, our plan is to share this with people doing these natural history studies to answer that question because it's unknown.

And I think, Paul, what's interesting is now with the validation clinically of the assay and getting it into, as Mike said, as many hands, I mean, there's lots of samples in various studies, both pan-silencing, natural history and allele specific with which to continue to refine it. But I think to Mike's point, the assay performed very well. So I think the key of inventing the new assays and I think others said for a long time, would one be able to develop an assay to measure wild-type? The team persevered to develop that. So I think it's critical for the field. And the more it's used, similar to wild -- sorry, mutant, I think the more we'll understand about the performance across natural history, too.

That's all the time we have for questions today. I would now like to turn the call back over to Paul Bolno for closing remarks.

Thank you, again, everyone, for your time today. And as you've heard, while we are disappointed with the results of our first-generation HD programs, we remain steadfast in our commitment to advancing research towards an effective wild-type sparing therapy for this community. In addition, we're excited to progress our next 3 generation clinical programs this year and look forward to updating you and our patient communities in the months ahead. Thank you.

Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.