Good morning, and welcome to the Wave Life Sciences First Quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen only mode. As a reminder, this call is being recorded and webcast. I will now turn the call over to Kate Roush, 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 Q1 2021 operating results. On the call with me today is Doctor. Paul Volna, Wave's President and Chief Executive Officer Doctor. Mike Panzera, Chief Medical Officer, Head of Therapeutics, Discovery and Development and Kyle Moran, Chief Financial Officer.
This morning, we issued a news release detailing our Q1 financial results and provided a business update. This news release and a slide presentation to accompany this webcast are available in 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 a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our Annual Report on Form 10 ks for the year ended December 31, 2020.
We undertake no obligation to update or revise any forward looking statements for any reason. I'd now like to turn the call over to Paul. Paul?
Thanks, Kate. Good morning to everyone on the call and thank you for joining us. During the call today, I will provide some opening remarks, after which Mike will give an update on our clinical trials and Kyle will briefly review our financials. It has been an incredibly productive start to the year for WAVE as we advance 3 next generation stereo pure oligonucleotides into clinical development. We have formally initiated clinical trials for WVE-four, our C9ORP-seventy two candidate in ALS and FTD and WVE-three, our SNP3 candidate in Huntington's disease.
We've also received important regulatory approvals towards initiating our 3rd PN chemistry program targeting exon 53 in DMD WBE N531. These clinical trials are designed to enable rapid proof of concept using biomarker driven adaptive designs and are the 1st investigative candidates designed with our novel PM backbone chemistry modification. Next year, we expect that data from these clinical trials will enable decision making about next steps for these programs, as well as provide insight into PN chemistry across different modalities, tissue types and targets. We've also made substantial progress with our endogenous ADAR editing capability, which we believe is the most advanced in its class. We've generated a breadth of RNA editing data demonstrating activity across in vivo and in vivo vitro systems, including in vivo editing in the central nervous system.
Much of this data is being presented in an oral presentation tomorrow, May 14, at the ASGCT Annual Meeting. Our first data editing program for Alpha-one antitrypsin disease has generated promising initial results and we are on track to share in vivo data this quarter. Our PRISM platform is unique and differentiated from others developing RNA therapeutics. At our foundation, we set out to embrace rather than ignore the reality and importance of stereochemistry that exists in each and every oligonucleotide. In choosing to control for the three-dimensional orientations of backbone linkages and advanced single isomer therapeutics, we can apply the principles of rational drug design to our pipeline candidates, which is impossible with mixture based oligonucleotides.
This resolution enables us to define distinct profiles for our Stereopure molecules and we now have several years of clinical data to further inform our platform. Earlier this year, we announced the discontinuation of our remaining 1st generation programs following the results of the PRECISION HD trials. While we only saw modest and inconsistent reductions of mutant Huntington, it is important to note there were no clinically meaningful trends in disease progression or laboratory values such as elevations in CSF white blood cells, proteins and neurofilament light chain or NfL. There were however suggestions of a label selectivity underscoring the precision in vivo by our platform. 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 set of action and engage target.
In addition to the wealth of data collected over the past several years, we're also leveraging an influx of new talent oligonucleotide therapeutics to further advance our understanding of design principles, pharmacology and toxicology. The application of PN backbone chemistry modifications in the context of controlling stereochemistry was a major advancement that emerged from our platform. And based on what we have seen preclinically, this innovation has the potential to significantly improve the profiles of therapeutic oligonucleotides independent of sequence, tissue type or modality. Separately, our ADAR editing capability further expands our toolkit beyond silencing and splicing, enabling us to select the best modality to address the root cause of genetic diseases. We anticipate sharing more on PN chemistry and ADAR editing at a research day later this year.
Our current pipeline is comprised of programs designed with next generation of PRISM, including PM Chemistry. I'm extremely proud of how quickly we have advanced this innovation to the clinic, and we are rapidly approaching the first of many opportunities for clinical proof of concept of PN chemistry. I'd now like to turn the call over to Mike Panzara for an update on our neurology programs. Mike?
Thanks, Paul. The foundational work that has been done throughout the evolution of PRISM has provided us with a diverse and robust neurology focused portfolio that is currently moving through stages of preclinical discovery and clinical development as illustrated here. As Paul just mentioned, all of our current discovery stage and preclinical programs utilize PM chemistry, including the multiple discovery programs in collaboration with our partner Takeda. These programs are yielding exciting results, including target engagement and distribution in the central nervous system of non human primates, which further validate our approach. Our therapeutics discovery portfolio continues to build upon this progress to maximize the potential of oligonucleotide therapeutics for the treatment of neurological disorders with high end metate.
Now, I'd like to discuss the programs currently in clinical development with 3 next generation candidates. Our development organization is focused on site activation and initiating dosing simultaneously in 3 clinical trials across 4 disease area. C9orf72 associated myotrophic lateral sclerosis or ALS and frontotemporal dementia or FTD with WVE-four and repeat expansions, Huntington's disease with and Duchenne muscular dystrophy with WVE N531, our exon 53 skipping candidate. Each of these clinical candidates incorporates PM chemistry and the availability of relevant preclinical models has enabled a greater understanding of PKPD relationships to guide development. Further, the learnings from our 1st generation programs are being incorporated to mitigate risk and more efficiently execute our plans.
Starting with C9orf72, our clinical candidate, WBE004, is designed to target a hexanucleotide repeat expansion in the C9orf72 transcript, which is one of the most common genetic causes of ALS and FTD. These expansions drive the common pathophysiology underlying these 2 diverse and devastating phenotypes. And 4 is the 1st C9R72 candidate being advanced simultaneously in a single basket like study for both C9 ALS and C9 FTD. C9R72 mutations lead to multiple drivers of toxicity. The hexanucleotide repeat containing RNA transcripts to pop it in tissues and are toxic on their own, but they are also translated into long dipeptide proteins or DPR proteins that trigger cellular toxicity through a variety of downstream mechanisms.
4 selectively targets the pre mRNA ovarian transcripts that contain the hexanucleotide expansion with the goal of suppressing both the RNA and DPR associated toxicities, while allowing C9 protein expression. In the Q1, our foundational work to identify and validate the targeting site used to achieve the selective knockdown was published in Nature Communications. On the right of the Slide 11, you can see the preclinical data that demonstrates 4's ability to rapidly and durably reduce over 90% of the DPR polygyp in the spinal cord and reduce at least 80% of polygyp in the cortex. This effect lasted at least 6 months only after 2 ICB injections of 4 administered 7 days apart at the start of the study. C9orf72 protein was unchanged over the same period.
The effect of 4 on polyGP in the CSF is a key endpoint in our clinical study, so we are looking forward to assessing the impact of treatment in humans given these promising preclinical results. These results, along with data from non human primates, have also allowed us to start at a dose in our clinical trial predicted to be pharmacologically active. This week at the European Network to Cure ALS Virtual Meeting or NPALS, we introduced FOCUS C9, an adaptive trial that is designed to enable faster optimization of dosing frequency of 4 based upon review of unblinded data throughout the study. FOCUS D9 is a Phase IbIIa global multicenterrandomizeddouble blindplacebo controlled trial in which we are planning to enroll approximately 50 patients with documented C9472 expansions and confirmed ALS, STD or mixed phenotypes. FOCUS C9 includes single and multiple ascending dose portions of 4 administered intrathecal.
At points throughout the study, based upon predefined data driven milestones, an independent committee will review unblinded data to determine next single dose level to be escalated to and the optimal frequency in the next multi dose cohort, meaning whether the dosing interval should be monthly or less frequent. Samples are collected for biomarker analysis at multiple time points within both the single and multi ascending dose portions to enable the assessments required to make these recommendations. Regulatory and EPIX approvals have been received and clinical site activation is underway, So we anticipate dosing sometime soon. I'll now turn over to WVE-three, our allele selective candidate for Huntington's disease, which is designed to selectively lower these in Huntington, while preserving wild type Huntington. The presentations, posters and feedback from experts at the recent virtual CHGI HD Therapeutics Conference only serve bolster our confidence that we are pursuing the right approach to Huntington's.
Let's review what we know. Patients with Huntington's disease have an expanded CAG repeat in their Huntington gene that leads to production of mutant Huntington protein. This is a monogenic, autosomal dominant genetic disease that is fully penetrant and affects the entire brain. Preserving wild type Huntington is as important as lowering mutant Huntington. Evin supports that Huntington's disease is driven by both the gain of function of mutant Huntington protein and the loss of function of wild type protein, which is essential for homeostasis of the central nervous system.
Wild type protein is critical for the protection of neurons that are under stress and plays a key role in trafficking synaptic proteins and vesicles, including the production and transport of brain derived neurotrophic factor or BDNF in the cortex. Wild type protein is also critical for the formation and function of celiac, which control the flow of CSF and help maintain CNS homeostasis. In healthy individuals, these important functions of wild type Huntington balance out the collective stresses based on the central nervous system. However, in the case of HD, there is the added burden of the mutant protein itself. Those living with HD have been subjected to decades of toxic stress that come with mutant Huntington protein years prior to symptom onset.
Looking at levels of wild type and healthy individual or models that lack the effect of mutant protein does not adequately represent the role the healthy protein plays in the context of Huntington's disease. This smaller protective reservoir of wild type Huntington eventually loses the battle to the expected stresses placed on the CNS along with the toxic effects of mutant Huntington, resulting in disease progression. If one thinks about this as a push pull of positive and negative factors in this balance of wild type and mutant Huntington in the CNS, it stands to reason that depletion of wild type protein along with mutant protein as with non selective approaches could shift the balance towards disease progression erasing any benefit or even potentially accelerating decline. This has been our hypothesis since we began our HD program and the data that are emerging support our position and make us resolute in our differentiated approach to treating this disease. 3 has been improved over our prior SNP targeting candidates by applying PM backbone chemistry modifications in the context of control over stereo chemistry.
Further, the presence of this SNP in a relevant animal model has allowed us to do in vivo preclinical work to determine a dose predicted to be pharmacologically active right from the start of first program. Slide 16 illustrates some of these in vitro and in vivo data demonstrating that 3 is highly selective for mutant Huntington enabled to achieve potent and durable knockdown of mutant Huntington in vivo in the Bakkt HD mouse model. We investigated this model knowing that there were several limitations, including the fact that it contains multiple copies of the MHTT MHTT gene, some of which do not have the SNP 3 variant. Nonetheless, as shown in the bottom of the slide, we observed potentin durable knockdown on mutant Huntington in the out to 12 weeks, a similar effect observed in the quartets. Nonhuman primates do not have SNP3 and as such we are not able to evaluate the pharmacodynamic effects in this model.
Therefore, we use the concentration data from the back Hg mouse compared with tissue concentrations in the CSF and CNS of non human primates and then used PKPD modeling to estimate tissue concentrations required to achieve stratal and cortical knockdown in humans with 3. These analyses are guiding the starting dose and dosing regimen planned for our clinical trial. While target engagement studies in the CNS of nonhuman primates were not possible for 3, they were possible for our most advanced therapeutic candidate in our CNS discovery collaboration with Takeda, WVE-five. Like 3, this candidate uses PN chemistry. But unlike 3, the human transcript targeted by 5 is homologous to the monkey sequence, allowing us to assess target engagement throughout the CNS.
In this study for an undisclosed target, non human primates received a single 12 milligram intrathecal injection of 5. 1 month after administration, we observed that the candidate was widely distributed throughout the CNS and led to substantial knockdown of target including in the striatum. This experiment once again highlights the potential of this next generation chemistry. In the Q1, we received regulatory and ethics approvals to initiate Select HD, a Phase IbIIa global multicenter randomized double blind placebo controlled trial of 3 in early manifest HD. We are targeting enrollments of approximately 30 6 patients carrying SNP 3 in association with expanded CHG repeat.
Patients from the precision HD studies will be able to transition to select HD after a washout period assuming they meet other inclusion and exclusion criteria. Unfortunately, based on the recently disclosed safety and efficacy data, patients who received active treatment of Toma nursing in the Generation HD study will not be permitted to enroll in Select HD. Although those who've received placebo in generation HD are eligible to be screened for study entry. Like FOCUS C9, select HD has an adaptive design to enable optimization of dose and frequency and more rapid determination of target engagement. An independent committee will evaluate unblinded data in an ongoing basis to guide dose escalation and dosing interval in each cohort.
Key objectives in addition to safety and tolerability include plasma PK, CSF exposure of 3 and changes in key biomarkers including mutant Huntington, wild type Huntington and neurofilament light chain over the course of the study. Clinical site activation is underway and we expect to dose our first patient soon. WVE N531 is our systemically administered candidate for patients with Duchenne muscular dystrophy or DMD that are amenable to exon 53 skipping. This is also our 1st stereo pure splicing candidate designed applying PM chemistry. As we have shared previously, when applying this format to an exon 23 targeting surrogate, treatment of an aggressive double knockout or DKO mouse model lacking both eutrophin and dystrophin resulted in rescue of mice treated with 75 milligrams every other week as compared with PBS or 1st generation chemistry dosed at 150 milligram per kilogram weekly.
Once again, application of the PN backbone modifications had a profound effect. In March 2021, we initiated clinical development of N591 with the submission of a clinical trial application. Since then, we've received regulatory approval for an open label clinical trial that is powered to evaluate whether N531 dosed every other week increases dystrophin production in up to 15 boys with DMD. The trial will also assess drug concentration in muscle and initial safety. Dosing is expected to initiate this year.
I'll now pass the call back over to Paul to discuss our ADAR editing capability and upcoming milestones there. Paul?
Thanks Mike. We continue to generate compelling RNA editing results with our ADAR editing capability, which we believe has many advantages over others and positions us at the forefront of this space. As a reminder, our approach to RNA editing employees short, fully chemically modified oligonucleotides to recruit endogenous RNA editing enzymes called ADAR. Our ADAR editing compounds are optimized using our proprietary stereochemistry and PN chemistry, which enables us to avoid delivery vehicles such as AAV vectors or nanoparticles and allows us to leverage established manufacturing processes. To date, we have demonstrated editing activity across in vivo and in vitro systems, including durable RNA editing of up to 50% in non human primates with GalNec conjugated oligonucleotides.
Our ADAR editing oligonucleotides are also highly specific. Our practical approach to RNA editing opens the door to a number of therapeutic applications such as restoring or modifying protein function and upregulation of protein expression. These applications greatly expand the landscape of disease variants that we can potentially address and we are advancing discovery work for multiple ADAR editing targets as well as evaluating new potential targets. Our first ADAR editing program uses a GalNec conjugated oligonucleotide to correct the single mutation in the mRNA coded by the SERPINA1Z allele, which triggers Alpha-one antitrypsin deficiency or AATD. ADAR editing is a simple and efficient approach to treating this disease by simultaneously reducing aggregation of the mutated misfolded alpha-one protein and increasing circulating levels of wild type Alpha-one antitrypsin protein, thus addressing both the liver and lung manifestations of AATD, all while avoiding the risk of permanent off target changes to DNA.
Last year, we successfully demonstrated upwards of 60% editing of the SERPINA1Z allele transcript to wild types and hepatocytes in vitro, which led to a 3 fold increase in functional wild type AAT protein. Encouraged by these results, we move forward to successfully develop a proprietary transgenic mouse model containing both humanized SERPINA1 and humanized ADAR that enables pharmacokinetic and pharmacodynamic assessment of human sequences in vivo. We are on track to share in vivo data from this model in the first half of twenty twenty one, and we expect to present additional data at a scientific congress later this year. These in vivo results are expected to enable lead candidate optimization as well as inform potential preclinical development studies and timelines. In summary, 2021 is a year of execution for WAVE in a busy time as our next generation pipeline advances in the clinic.
As you heard today, we are advancing 3 unique clinical programs that will each provide insight into our novel PN chemistry and potentially rapid proof of concept and clinical validation of our platform with biomarker data. We're making excellent progress with our ADAR editing capability and in addition to the expected in vivo data update for AATD that I just mentioned, I look forward to speaking further about our RNA editing platform at a research day later this year, which we expect to share more details about on our next quarterly call. I will now turn the call over to Kyle Moran, our Chief Financial Officer, to report our financial results before turning the call over to questions. Kyle?
Thanks, Paul. We ended the Q1 with 148 $500,000 in cash and cash equivalents and marketable securities. This balance does not include an additional $30,000,000 in committed research support that we received in early April under our collaboration with Takeda. Our total operating expenses for the Q1 of 2021 were $43,400,000 as compared to $54,200,000 last year. R and D expenses were $33,400,000 as compared to $41,200,000 in the same period 2020.
This decrease was primarily related to a decrease in external expenses related to our discontinued suvodirsen program as well as decreases in compensation related and other external expenses, partially offset by increases related to our clinical and preclinical activities for our HD programs and C9orf72 program for ALS and FTD. G and A expenses were $10,100,000 for the Q1 of 2021 as compared to $13,000,000 last year. With a decrease driven by lower compensation related and other external expenses. Finally, we continue to expect that our existing cash and cash equivalents together with our expected and committed cash from our existing collaboration will enable us to fund our operating and capital expenditure requirements into the Q2 of 2023. As a reminder, this does not include potential milestone payments or other uncommitted payments under our Takeda collaboration.
Thanks, Kyle. With that, we'll open up the call for questions. Operator?
Thank you. Our first question will come from the line of Samir Samir from Mizuho. You may begin.
Hi, good morning. This is Mike Linden on for Salim. Thanks so much for taking our questions. A few if possible. First on the C9 trial design, just wondering about the protocol and how adaptive these trials
would be. Are they being written
to be able to enroll many hundreds of patients to potentially be converted to registrational? I'll follow-up after that.
Thank you. I'll pass the call over to Mike.
Yeah. Hi.
So, the
way the study is designed is you can see it. It allows the study to be expanded as necessary to collect additional information. I mean, we made it flexible about to enable us to really once we get recommendations from the independent committee on next steps to be able to adapt the study as necessary. So I think we'll have to wait to see what the data show, but it's our intention to make it adaptable and flexible to enable us to direct it the way we need to, to understand the clinical meaningfulness in both ALS and FPD.
So I can't expand on number of patients based on the committee's assessment to answer this, if that's the specific question, yes.
Great. Thank you. And one on AAT on the upcoming data. What will you be looking for specifically to move forward into the clinic or not? And how would you prioritize this if it did move forward versus the other pipeline programs?
So the prioritization for AATD and the reason we worked on generating the model was really driven based on identifying, 1, the production of the protein. So again, not working on what a percent editing is, that's interesting. But what drives the progress on a medicine is does it generate the protein? So one will be protein production. Other features that we'll be evaluating obviously are protein, not just protein production, but protein function.
So we'll be able to look at a number of those assessments and that's going to guide our decision on translation.
Okay, great. Thank you. And last one on Alzheimer's disease mentioned today, after the zenanaumab data, how are you thinking about treatment specifically from the ASO side? Maybe what should we think about in terms of potential targets?
So just for clarification, I want to make sure on the you might be thinking about frontal temporal dementia. I just want to make sure we're not thinking about Alzheimer's. So we have FTD, so frontal temporal dementia, otherwise I think it's frontal temporal degeneration, is the one area of dementia that we mentioned today. So I want to be careful that we didn't discuss Alzheimer's disease as a target therapeutic. But happy to discuss antisense treatment and therapeutics for the treatment of CNS and neurologic diseases more broadly if that's the question.
But I just want to make sure we get your question correct.
Yes, that would be helpful. Thanks.
I
I was going to say
I was going to say is that, yes, I mean, we're as you see with the FOCUS C9 study, the emphasis on FTD getting patients in and actually the cortical effects that we saw in the preclinical models make us very excited about being able to access the CNS to be able to have an effect on FTD. It's we're going to be using clinically some of the clinical outcome measures that you'd want to measure cognitive change in RFDD study to be able to get at that question.
I mean, I think if we did step back and think about neurologic disease more broadly, I mean, I think one of the data sets that's compelling that Mike shared in addition to a number of the in vivo mouse studies is, we see really great intrathecal distribution across the brain. So I think as we think about distributing to the regions of the brain that are necessary for a whole variety of neurologic diseases, We see intrathecal administration delivering medicines. That's not different than some of our colleagues in this space discussed around distribution. So we do believe antisense oligonucleotides can distribute. What we see with the PN is this broad distribution.
So this addition of a highly controlled. So the data we're generating, the value of stereochemistry you said beginning and addressing the reality of it is, all the assessments of target engagement we're seeing are with the actual compound, because we're not dealing with a mixture of 523,000, 104,000, 233 different molecules that could distribute differently. So by having single drugs, we know that the knockdown that we're seeing is based on the design of that single oligonucleotide. And I think what we've also seen is the benefit of durability. So as Mike said, in the adaptive design piece, we're going to be testing and then exploring that in the clinic.
And so as we think about chronic administration of medicines in a whole host of different diseases, importantly is dosing frequency. So being able not to sacrifice potency for dosing frequency is something that we're excited to continue to explore in the clinic. As we think about the future of antisense oligonucleotides for the treatment of neurologic diseases, we think the future is promising in a data driven way. And we'll be assessing that further across 3 clinical studies currently. So I hope that answers your question.
We're always happy to explore that more. But I think the future looks bright for treating genetic diseases with olefemcretab.
Thanks. That's super helpful. I guess what I was referencing was just the mention of Alzheimer's in the press release along with other CNS indications.
Okay.
Okay. All right, next question. Sorry,
now I'm working. I think we were talking now I know where you're going, which is the holistic list of targets that are that we've been exploring in the decadalot large indications where we said, for example, that's why we're thinking about indicate we said, for example, what represents large neurologic indications, so Parkinson's, Alzheimer's and other large indications. So thank you. I apologize for our we are focused on the pipeline that we're exploring as opposed to what the potential is. So apologies for misunderstanding of your question.
And our next question comes from the line of John Lee from Chorus. You may begin.
Hey, thanks for taking our questions. For
all of your
CNS programs, in addition to the new and improved backbone chemistry, have you considered a different route of delivery? Another company has recently disclosed proceeding with intracerebral ventricular route using Aloyaport, I believe, for Huntington's disease. It does give you more direct access compared to intrathecal. And I'm not aware of any IP that prevents you from doing that. So I would appreciate if you could provide some perspective there.
And I have a follow-up question.
Yes. I mean, there's always opportunity to think about different approaches. When we think about permanent catheter placements and other drilling holes and scolds for delivery, I think our first question always is about what problem and this is true for anything, what problem are we trying to solve for. So I think as we currently think about the data that we've generated to date, intrathecal access to the central nervous system is available. We've shown that now in intrathecal nonhuman primate studies.
We've looked at ICP injections in mice, and we see correlation in terms of distribution in CNS tissue. So for to date to look at and if we again also see durability, which we're assessing in the clinic, The less frequent administration also calls into question that it's not without risk to leave permanent Doilyne catheters in the CNS. They can get clogged, they need to be changed. And so again, it really comes down to what is the and every medicine is different. So we can't speak for other companies and what challenges they're addressing using the delivery mechanism.
What we assess with ours is, are we what are we solving for? And so if we think about intrathecal distribution as we've demonstrated across multiple tissues utilizing the PN enhancements on our medicines themselves, we don't right now see that. As we look at durability and different indications, we could want to solve other problems into the future that could come up, but right now that doesn't seem to address the solution that we have with the administration. Mike, I don't know if there's any
No, I'm just going to I would just say the same thing. It's like you have to in general, you're good you want to go for the simplest form of administration you can that gives you the access you're looking for. So given the progress we've made with accessing all parts of the brain and these diseases through intrathecal administration that would be the simplest approach, especially as Paul indicates, when you're talking about the durability of effect after single doses, that leads us to the approach that we don't need to do ICV with a catheter and we can do what's necessary doing something that any neurologist can do.
I think the other thing, I mean, we have now, I mean, and we have the benefit with an extensive amount of time now, been able to explore multiple animal models across multiple species, again, ICV in mice, intrathecal in non human primates. We also have clinical data to look at distribution. And as we shared in our experience in Huntington's understanding different concentration levels with different backbone chemistry. So I think as we look at the totality of data that we've generated and the totality of generated that our colleagues and other companies have generated, I think we see meaningful changes with the implementation of the PM backbone that's translating into animal PKPD that we are exploring currently in the clinic through adaptive designs, they're going to give us answers in the clinic.
Got it. And looking forward to your AR presentation tomorrow at ASGCT, can you talk about some differences between the approach you're taking with Galenic conjugated guide RNA versus circular guide RNA that's being used by another company. I guess we'll find out tomorrow, but just wanted to get any input that you can share on what we should be focusing on tomorrow and some perspectives on the pros and cons of different approaches? Thank you.
Yes. I mean, I can't speak necessarily for the pros and cons of others. We're all learning about the other approaches to treating. I can speak about our approach, which importantly, Galenic is not, let's say, an approach. Galenic is a targeting moiety for the tissue target of interest.
So one of the advantages when we built the ADAR platform from the beginning and we demonstrated this with some of our CNS data as well is that where short oligonucleotides go and distribute, we can generate an editing capability there. So we've done and looked at that in vivo in CNS. So looking at non GalNec conjugated distribution and correction. What we're looking at for AATD obviously is a hepatic target in the hepatocyte is Galenic then becomes an advantage because we can just target the cell type of interest. So I think what's really important from a platform perspective is the platform can exist without Galenic, but we are using Galenic as well where we think about the liver specifically.
So I think on both the platform context, we think we've got a really interesting approach in that we don't need to use various delivery vehicles. We can take all of our learnings around stereo controlled PN containing all of the nucleotides and continue to demonstrate and learn from data that we've generated across multiple species and even past clinical side of experience learning about serial controlled allogos and apply that to this data platform and take the advantage of down that conjugation for specific hepatocyte targeting. And I think tomorrow as we start to learn more about what's happening across the field, we'll be able to parse that out more. But we're excited to have a presentation tomorrow and really be there again at the forefront of ADAR RNA editing to be able to share those data. Great.
Thank you. Yes.
Our next question will come from the line of Mani Farooq from SVB Leerink. You may begin.
Hey guys, thanks for taking the question. I'll ask one quick one on enrollment. When we look at rolling over placebo patients from Generation HD into Select, how many of those patients are still eligible? I worry a little bit that obviously Huntington's is a relentlessly progressive disease. So some proportion of those patients may now be meaningfully more severe than they were when they were first screened for generation.
And secondarily, whenever based on whatever portion of those patients are likely in your view to roll over, how much of a head start does that give you on enrollment, in select and other mechanisms that you can pursue sort of changes in trial process to sort of accelerate the completion of enrollment there, given there were a couple of delays and hiccups along the way for Generation previously?
I'll pass the question to Mike.
Yes. No, hi, thanks. So regarding the movement from Generation HG, right now the way it stands is patients don't have it hasn't been disclosed to patients whether they've been receiving placebo or active treatment. So we're hopeful that that will happen and then patients can make the choice about whether they want to do that transition. And we're not exactly sure when that will be, but we're hoping that that happens relatively soon as we have disclosed to all the patients now, what they've been receiving.
2nd of all, there is that possibility that patients will have progressed out of our inclusion criteria, which is why they are going to have to be rescreened for both inclusion and exclusion, including whether they have SNU-three. So that will be an important inclusionexclusion criteria. But as we think about the overall population, we'd expect about 40% of them are essentially to have the appropriate SNP. Regarding the other operational things to help move things along, we've learned a lot from the generation from the precision HT1 and precision HT2 studies. We've learned a lot about how to operationalize intrathecal administration more efficiently.
We have a lot of site overlap between Generation HD and Precision HD, which has allowed us to patients our physicians to get experience in the screening process. We have new laboratories to do SNP identification. There's a variety of things that have really helped accelerate, make us feel comfortable that we'll be able to accelerate the recruitment for select HD, including the addition of regions that we know have higher representations of SNP3. So there's a variety of things we're doing that have that we were comfortable will help. In addition with the adaptive design, there's going to be all along the way, the committee is going to be looking at unblinded data to guide next steps and make recommendations.
So that in and of itself is a huge change versus data generation in precision HD1 and 2.
All right. Thanks.
Our next question will be from the line of Paul Matteis from Stifel. You may begin.
Thanks for taking the question. This is Alex on for Paul. A couple of questions on SNP3. I appreciate the 5 targeting data in non human primates, but I was wondering if you could maybe quantify a little bit some of the biodistribution that you mentioned you're seeing in non human primates with 3 that you're using for the PKPD modeling, knowing that's not really a disease model, but anything you can say there would be really helpful. And then secondarily, I'm curious if 3 targets the exon 1 fragment of MHT and generally your thoughts on the exon 1 fragment as a potential driver of pathology in HD?
Thanks.
Doug, you want to start? Arun?
Yes.
So I mean regarding the non human primate data, I think that the what we are what I can say about the distribution in the non human primate, even though it's not target engagement data for the SNP3 compound. We are very clearly able to achieve concentrations throughout the brain, including in deep gray structures and striatum, that would be predicted to engage target based on what we have from the back HD. So and a very large window to be able to dose escalate to, again, engage target. So I think that we are quite comfortable based on the preclinical data we have that we are able to get into the regions that matter and engage targets. So, and again, we're starting at a dose that we believe is pharmacologically active right from the beginning.
And then the committee will tell us how close we are to that and then be able to adjust as necessary. So that's regarding that. Now in terms of the in terms of Exant-one and what we think there, I mean, as we've said previously, that a lot of the exon 1 data, I mean, this is from post mortem, this is from it seems to be most relevant in those with the extremely long expansion. Nonetheless, when we're bringing down mutant protein, we would expect to be able to also have an impact on exon1. So
Yes, just to add to that, I mean, antisense oligonucleotides can reach intronic and exonic transcript, so we should therefore end exon1. But as Mike I think the most important piece, I think the data is still independently of whether or not we hit it, I think the data is still questionable and beyond really, really long repeat. So I think as we go back and think about our targeting for CYP3, I think we can leverage a ton of experience with CYPs 1 and 2 and what we've seen in general with the enhancement of PN chemistry in terms of distribution, durability, potency. I think we can see and believe that mutant protein suppression is important. And yes, we're distributing and knocking down the mutant protein.
But I think what we've learned a lot about in the first clinical trial of pen silencing is, and Mike alluded to post CHDI is a substantial focus in doubling down on our efforts that wild type sparing is as important a driver of disease pathology as mutant protein production is. And so the approach that we set out 2 years ago established for the treatment of disease, which is wild type sparing mutant reduction, we believe is the way to address pathology. And we'll be happy to generating clinical data and be able to assess that again with CYP3 using the NuPN chemistry.
Great. Thanks so much.
The next question will come from the line of Eun Young from Jefferies. You may begin.
Thank you. I have a few questions. First on ATV program. So, apologies you mentioned it's not just editing efficiency. You've already shown 50% in non human primates, but producing wild type AAT protein, so and then function.
So question to you is that do you know what level of a normal of wild type AAT protein is needed in order to see some clinical benefits? What's the kind of a minimum level? So that's a question 1. And second question is on 4. So you are already doing site activations.
So when should we expect data clinical data from this trial? And lastly, the $30,000,000 additional $30,000,000 that you received from Takeda in April, how do that be amortized in income statement? Would that be similar to what you've done in the Thank you.
All right. Well, the good news is this question, you're getting a lot of voices around the table. So it's great. I'll take the AAT question. I'll pass it to Mike for the second one, and Kyle can answer your treatment.
Your important question is how do we look at this in vivo data that's upcoming and how are we looking at that in terms of advancing AATD program. I think when we think about, ALP-one antitrypsin, and I think you're spot on, we're looking at protein levels. The SERPINA-one model is different because they're all there than humans, let's say, and that you can generate protein. And I think we'll be looking at levels of protein generated in that model to be able to model that towards kind of where one would expect to be at the human level. I think to date, one sees kind of a threshold level around 11 micromolar of protein to be clinically relevant.
That's kind of the basis for the number of the protein infusion products. And we know that the protein infusion products tend to tail off at the end because the protein degrades and then they have patients that have to be reviewed on a weekly basis. So these patients have these gaps in treatment. I think if we can have sustained correction where maybe you don't have those drops, we would see that kind of this minimum threshold criteria where not only are we treating the hepatic issue, but really at that level know that SPIRIT levels that can treat the pulmonary complications. I think that would be exciting.
But I think the key for us and as we generate that data and share that more broadly exactly to that point, that's the data that we'll be assessing from those models in terms of translation. And I think the important piece there that we'll be assessing as well is not just the protein production, but as we demonstrated before from the in vitro correction of the AAT protein is that we could generate it and it was functional. We want to see that replicated now in the animal model. So I think we're taking the deliberate approach to make sure we generate the preclinical data that's going to position us for thinking about how this program transitions. And I think that's why we've been excited to date, 1, around the AATD program, but I think more broadly what it really represents in Wave's ability to bring ADR editing into patients across a whole variety of indications.
Importantly, CNS indications as well where we don't need GalNex to be able to target neurons. So, I think there's a whole variety of approaches that we can take, but obviously this is the first in vivo demonstration that we'll be able to look at on a corrected protein and be able to study that more broadly. I'll pass any questions just because of the I'll just say, are there any thoughts any questions there? And if not, I'll hand over to Mike to address your question. So then Mike, do you want to take the next one?
Sure. I mean, so I mean, regarding next year, I mean, we have 3 biomarker studies underway that are going to allow us to have with these adaptive designs that are going to allow us to have a continuous flow of data. And that's very exciting. And I mean specifically regarding 1, as I indicated, we're going to be dosing soon and we'll have a good sense of how the studies are moving throughout the year. But what we share from the studies is going to be informed by how the studies proceed, the types of data that comes in, meaning the meaningful whether there's a meaningful number of patients at any given point in time and whether the feedback we receive from the independent committees.
And those that feedback is going to be coming in throughout the course of this year and next. And from there, we'll guide, what when we disclose data and what that data will be. And we anticipate data, however, during this time that will enable us to make decisions and then provide greater insights into the chemistry. So that's sort of how it's proceeding now. It's obviously going to be driven by how quickly we can get those patients in and we're optimistic now given site activations and the fact we're going to be dosing soon.
But it is an important notion when we think about just the adaptive design principle of running studies, which is different than running kind of mile marker driven studies where you've got to aggregate the data and then analyze it and aggregate it and then flip the card at the end. I think as Mike said, data is evaluated in an ongoing way by an independent committee that's going to inform things. And with those studies running now and data being generated this year and that I think there's a variety of times where those committees could flag that we should share data. So it's a little less specific and as Mike said, we'll be able to provide more
updates to guidance along the way.
Kyle, do you want to take the 30 minutes or 2 minutes?
Yes. Dean, thanks for your question. And your assumption is correct. We would account for that in the same way that we've accounted for the upfront cash payments and other committed cash payments we've gotten to date with the GAAP net amortization.
Thank you.
Thank you.
Our next question comes from the line of Luca Iffy from RBC. You may begin.
Great. Thanks for taking the question. This is Lisa on for Luca here. A couple of questions for us. So first one, we have obviously seen the Phase 3 data from Roche Jonas and it seems to me that their ASO may have had a detrimental impact to patients versus placebo as placebo directionally outperformed the high dose and we have seen a dose dependent increase there in ventricular volume in the brain.
Did you have the same read on this data? And if so, do you think that it's possible that a wild type sparing approach may not have caused a detrimental impact here? And second question, you've obviously discontinued SNP1 and SNP2 with the old chemistry. Just wondering, what is the plan going forward? Are you planning to explore the PN Chem issue for SNP 1 and SNP 2 or only for SNP 3?
Thank you.
Thank you. You. To take the our viewership and I think like everybody else, we have to view it as we're only seeing what everybody else is seeing from the outset. So it's hard to comment on what they saw. I think objectively, you pointed out what they saw, which was a dose dependent change in clinical measurements.
And importantly, those clinical measurements were cortical and striatal. So I think it's there's a jump to distribution. I think it was a broader question than just straddle distribution. So I think as we think about that data in the context of the biology, as Mike laid out on this call, I think very well. We do think that there's 2 approaches of 1 characterization drug.
1 is obviously, to your point on hypothesis, wild type sparing and that if one thinks about the disease as both one of a toxic gain of function and a toxic loss of function. Taking that below the 50%, I know there's a lot of discussion after Roche's data of people just saying, well, studies have been done in 50% reductions in normal animals and shown it safe. I think one has to remember that the situation that those animals were under were 1 of 50% reduction of a normal phenotype. What we're dealing with in Huntington's patients as we kind of have been explaining for a while now, is that those reductions that are being studied in the clinic are reductions that are happening in the setting of already a 50% reduction and under the setting of stress of patients who are progressing in disease. So one has to think about the totality of removing the neuroprotective feature of wild type proteins, a whole host of other functions, including cellular function, which involves CSS flow.
Those are really important characteristics. So yes, I think that's something that needs to be explored and I think that's why we're excited about seeing that. I think we were also happy in the analysis that patients on the studies that we were looking at didn't progress. Now take that for where it is. I think as other characterization, we didn't see increases or elevations in white counts in protein in NFL.
So I think if we think about the totality of both the oligo approaches as well as the wild type sparing, I think that's driven why we believe a stereo controlled approach of wild type sparing is important. It's why we're excited about bringing PN into the clinic with SNP3. And to your question, yes, we can apply and have generated early data around being ready with SNP-one and two. I think the measured approach we're going to take with PN chemistry. I think the measured approach right now is, as Mike alluded to with the trial design, is let's get the data with PN chemistry with SNP3 and use that as a driver before spending more resources on SNP1 and two.
But yes, we are prepared to go back to looking at the totality of HD with an allele specific approach. I don't know Mike if there's
No, I mean just I mean my listen, we've been concerned from the beginning that a non selective approach could have detrimental effects. We have said that first. That's why we're doing what we're doing. There are a lot of reasons that could be assessed for what happened with that Phase 3 study, but certainly effects on wild type have to be part of the consideration, which is why we're making our wild type assay available. That's an important data set we need to understand.
But we're concerned enough that we are unfortunately, we said initially we would allow patients who have been treated with Tominexin in select HD. We've had to now not do that out of whatever is happening there because we're concerned enough, not to unfortunately have to exclude those patients. So it's a concern. It's an observation. It needs to be studied.
We have the tools now to study it and we're hoping that the community ask these questions because we believe it's important.
Great. Thanks for taking our questions.
Absolutely.
Thank you. I see no further questions in the queue. I'd like to turn the call back over to Doctor. Paul Bauendo for any closing remarks.
Thanks everyone for joining the call this morning to review our Q1 2021 corporate updates. And thank you to our Wave employees for their hard work and commitment to patients. We look forward to speaking to you all again soon. Have a nice day. Thank you.