Good morning, ladies and gentlemen, and welcome to the Wave Life Sciences Third Quarter 2020 Earnings Call. At this time, all participants are in a listen only mode. Later, we will conduct a question and answer session and instructions will follow at that time. As a reminder, this conference call is being recorded. I would now like to turn the conference over to Graeme Morell, Investor Relations at Wave.
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 Q3 2020 financial results. This morning, we issued a news release detailing these results, which is available in the Investors section of our website, www.wavelifesciences.com. The slide presentation that accompanies this webcast will also be available on our website following this call. 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, 2019, and our quarterly report on Form 10 Q for the quarter ended September 30, 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 Doctor. Paul Bono, President and CEO of Wave Life Sciences.
Paul?
Thank you, Graham. Good morning to everyone on the call and thank you for joining us today. I hope you and your families are staying healthy and safe during these challenging times. We are excited to share the latest on our progress, new programs and future plans. I'll start us off this morning by providing an overview of recent achievements, a summary of the data that will be included in the readout for our precision HD clinical trials in the Q1 of 2021, a quick overview of our recently announced PN chemistry advancement and then I'll talk about our first ADAR editing program.
Our Chief Medical Officer and Head of Therapeutics Discovery and Development, Doctor. Mike Panzera will then discuss our 3 upcoming clinical trial submissions, including our newly announced clinical trial in Duchenne muscular dystrophy. Finally, Dave Gallero, our Interim Chief Financial Officer will discuss Wave's 3rd quarter financial results. Doctor. Chandra Varghese, our Chief Technology Officer and Doctor.
Ken Rhodes, our Senior Vice President of Therapeutics Discovery will also be available during the Q and A portion of this call. This past quarter, we continued to make significant progress with our clinical and preclinical pipeline, as well as advances in expanding the potential of our innovative Prism platform. Despite the challenges of COVID-nineteen around the world, our research and clinical teams made tremendous strides. As we look ahead to 2021, I believe we are ushering in a new and exciting phase for Wave. To start, we now anticipate having 5 clinical trials in 2021.
This includes our 2 ongoing Phase 1b2a Precision HD studies in Huntington's disease for which we continue to expect data in the Q1 of 2021 as well as our new first in human studies of WVE-three and WVE-four. As a reminder, WVE-three is our 3rd allele selective Huntington's disease candidate and WVE-four is our candidate for amyotrophic lateral sclerosis and frontal temporal dementia in patients with a hexanucleotide expansion in the C9orf72 gene. The 5th clinical trial, which we are announcing today will be for WBE N531, our candidate for patients with Duchenne muscular dystrophy amenable to exon 53 skipping. Notably, the preclinical work needed to submit the CTA was completed last year and we expect to complete this trial with no change to our cash guidance. Mike will share more about how we reached the decision to initiate this clinical trial, which is intended to assess dystrophin and initial safety as well as help us understand the impact of PN chemistry on splicing in muscle.
Of note, WVE N531, WVE003 and WVE004 all incorporate our PN backbone chemistry advancement. I'll talk more about this later. Thanks to the rapid advancements in our ADAR platform and PN chemistry, we are also announcing today that our first ADAR editing program will be an alpha-one antitrypsin deficiency or AATD. This disease is ideally suited for an RNA editing approach and we believe that our novel ADAR editing modality has the potential to address both the lung and liver manifestations of this disease. The program will also lead the way for future wave ADAR editing programs.
We believe our approach has the potential to become best in class RNA editing system with applicability in many disease areas including neurology. We are also continuing to grow our neurology pipeline through our CNS collaboration with Takeda, where we work collaboratively on up to 6 preclinical CNS targets. Our PN backbone chemistry is helping us optimize profiles for these candidates, resulting in compelling non human primate data that we will share today. On August 25, we held an investor analyst webcast where we announced advancements to our Prism platform, including our novel PN backbone chemistry. This backbone modification has been shown to improve the pharmacologic properties of our oligonucleotides across all three of our modalities, silencing, splicing and RNA editing.
Finally, we are well positioned financially to progress all of our planned and existing programs. We are reiterating that our current cash runway takes us into the Q2 of 2023. Dosing in both the 32 milligram cohort in the Precision HD Phase 1b2a clinical trials continues. And we are on track to share data from all cohorts as well as initial data from the ongoing open label extension study in the Q1 of 2021. Specifically, in the OLE, we will share data for patients who have received multiple doses of 8 or 16 milligrams at the time of the data cut.
Results in the trials are expected to include safety and tolerability as well as biomarker data including mutant Huntington knockdown, total Huntington knockdown and the effect on neurofilament light chain. We also continue to focus on the scientific challenge of measuring wild type Huntington protein and have made good progress. We believe that it's critical to understand the impact of potential treatments on wild type Huntington and look forward to keeping you updated as we strive to complete this work in time for our data readout. As I mentioned, we announced in August that we expanded our repertoire of backbone linkages with PN chemistry. This advancement has quickly become an important component of our PRISM platform as it provides another tool we can use to optimize the pharmacologic properties of our candidates.
PN chemistry involves replacing a non bridging oxygen atom with a nitrogen containing moiety. PN modifications are neutral, allowing them to break up the charge of the backbone while retaining specificity to the complementary base pairings. Our preclinical experiments utilizing PN chemistry have demonstrated a general increase in potency, exposure and durability when compared to identical sequences without the PN modification. We are seeing the significant impact of PN chemistry on the amount of knockdown and durability across CNS tissues. As we have previously shown in mice, the PN containing molecule in this study showed meaningful persistent transcript knockdown of 80% to 90% throughout the central nervous system.
Importantly, we continue to see the effects of PN chemistry translate in our therapeutic programs. On this slide, you can see recent in vivo data for the most advanced therapeutic candidate in our CNS discovery collaboration with Takeda. In this study for an undisclosed target, non human primates received a single intrathecal injection 12 milligram dose. 1 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 across CNS tissues.
We view this new NHP data as a considerable advancement for our platform and the field in general. Further, these results have enormous implications for WAVE as we look to deepen our pipeline and add new wholly owned neurology programs in the future. Our latest pipeline chart highlights the considerable impact PN chemistry is having on our portfolio. As all of our current discovery and preclinical stage programs utilizes backbone modification. We are excited to start investigating the role of PN chemistry in the clinic through planned clinical trials at WVE-three, WVE-four and WVE N531.
The advances we've made with chiral control, PN chemistry modifications and our Prism platform have helped us to unlock our novel ADAR editing platform capability. Our approach to RNA editing employees short, fully chemically modified oligonucleotides, usually 30 nucleotides or less to recruit endogenous RNA editing enzymes called ADAR. ADAR enzymes can be used to change an A to an I which the cells read as G in RNA. Nearly half of known human pathogenic snips are G to A mutations. The capacity to leverage ADAR to correct these mutations opens the door to a number of therapeutic applications including restoring or modifying protein function and up regulating protein expression, which greatly expands the landscape of disease variants that we can potentially address.
Our technology has many advantages in the editing space and this is the forefront of RNA editing. Our decision to pursue RNA instead of DNA editing was deliberate as RNA editing avoids irreversible off target genomic patterns And because we use endogenous ADR enzymes, we avoid the risk that introducing exogenous proteins may trigger immunogenicity and off target effects. In addition, our oligonucleotides are optimized using an expanding repertoire of chemical and stereo chemical modifications available through Prism, including PN chemistry. Importantly, we employ a simplified delivery strategy that does not require AAV vectors or nanoparticles, which would allow us to leverage established oligonucleotide manufacturing processes. We saw many of these attributes 2 days post last dose with sustained editing at 45 days.
We've also shown that our ADAR editing oligonucleotides are highly specific. In this morning's press release, we announced our first ADAR editing program, which will target SERPINA-one for the treatment of alpha-one antitrypsin deficiency. Alpha-one antitrypsin deficiency or AATD is a rare inherited genetic disorder that is commonly caused by a single G to A point mutation in mRNA coded by the Z allele of the SERPINA-one gene. This mutation leads to misfolding and aggregation of alpha-one antitrypsin protein or AAT in hepatocytes and a lack of functional protein in the lungs where it would protect lung tissue from neutrophil elastase. Patients with AATD typically exhibit progressive lung damage, liver damage or both leading to frequent hospitalizations and potentially terminal lung disease or liver disease.
While the few approved therapies modestly increased circulating levels of AAT in those with lung pathology, there are currently no approved therapies to address the liver pathology. It is estimated there are approximately 250,000 patients worldwide with the most severe form of AATD. These patients are homozygous for the G to A point mutation on the Z allele. While the AATD landscape is growing quickly, we continue to see opportunities to develop a best in class treatment approach, which would have 3 key attributes. First, we would want to restore wild type AAT protein and we believe an editing approach provides the opportunity to substantially improve upon the modest levels of AAT that are delivered through augmentation therapy.
We would want to simultaneously address the aggregation of AAT in the liver. By addressing both, we potentially remove the need for augmentation therapy and give patients the option for a single therapeutic regardless of lung or liver phenotype. We would also want to develop a treatment that retains AAT's physiologic regulation. Based on publicly available information and our understanding of the disease and editing approach appears to be the only one that could address all these attributes. And we believe RNA editing is preferable to DNA editing to avoid the potential for irreversible off target edits to the genome.
Leveraging the work we already did with GalNet conjugation in NHPs, we turned our attention to correlating the corrected transcript to wild type protein. Here we show that we've accomplished this in primary mouse hepatocytes Z cell model. We saw upwards of 60% correction of the Z transcript back to wild type transcript, which prevented protein that's holding and allowed for better secretion from the hepatocyte, resulting in a threefold increase in protein concentration. The question we then asked ourselves is, do we have the right in vivo modeling systems in place to develop best in class RNA editing candidates with our ADAR platform? One important learning for us was limitations of the humanized SERPINA-one mouse model.
This model contains mouse ADR, which behaves differently from human ADR. Our scientists therefore, to develop a proprietary model, which contains both humanized SERPINA-one and humanized ADAR. What's really exciting about this model is that we can now cross the humanized ADAR mouse with any specific disease mouse model, thus providing a modeling system that can be used across our ADAR editing programs. We're looking forward to optimizing this model further and generating data from our AETD program next year and applying the model system in neurology and other areas. At this time, I'd like to pass the call to our Chief Medical Officer and Head of Therapeutics Discovery and Development, Doctor.
Mike Pantera to discuss our 3 upcoming clinical trial initiation.
Thanks, Paul. This quarter has been highlighted by tremendous progress. We not only anticipate sharing data in the first quarter from Precision HD-1 and Precision HD-two and their OEs as Paul already mentioned, but we are also preparing to file 2 CTAs before the end of the year. 1 for WVE-three, our 3rd allele selective candidate in Huntington's disease and one for WVE-four, our variant selective silencing candidate in ALS and FTD. In addition, in the Q1 of next year, we are planning to submit a CTA for WVE N531, our candidate for DMD patients with mutations amenable to exon 53 skipping.
More on that later in my presentation. I'll start with a few words on Huntington's disease. Our work and the work of others in this area over the past few years has emboldened us in our belief that allele selectivity is critically important as a foundational concept in the treatment of HD and that preserving as much wild type Huntington as possible while lowering mutant Huntington is essential for not only proper function of the central nervous system, but systemically. In essence, this is balanced between these two proteins in a push pull scenario, a tug of war of sorts between their opposing effects that over time leads to the invariable progression of disease, a process involving intense biological stress where the beneficial effects of wild type protein may be even more important. Wild type huntingtin 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 excitotoxic, 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 for supplying the essential growth factor BDNF to striatal neurons to ensure their survival. Additionally, wild type Huntington is critical for the formation and function of cilia, which control the flow of CSF and help maintain homeostasis in the CNS. Our approach to HD is guided by the recognition that in addition to a gain of function of the mutant Huntington protein, patients with this disease have lost one copy of wild type Huntington leaving them with a smaller protective reservoir than unaffected individuals.
We believe this scenario necessitates trying to preserve as much wild type Huntington as possible to give these individuals the best opportunity for beneficial outcomes. WVE-three is our 3rd allele selective HD candidate and the first to incorporate PN chemistry. It is designed to selectively target an undisclosed SNP that we're terming SNP3 on the mutant HTT mRNA transcript while leaving wild type transcript and thus protein relatively intact. It is also the first of our HD compound evaluated in an in vivo model system to better understand PKPD relationships to guide initiation of human dosing. This slide illustrates some of the in vitro and in vivo data supporting 3's movement into the clinic.
On the left, we clearly see the in vitro selectivity of our candidate over a wide range of concentrations versus similar concentrations of a pan silencing reference compound. While we see a similar reduction in mutant huntingtin transcripts from both compounds, 3 leaves the wild type huntingtin RNA relatively intact. As I mentioned, we also examine the effect of our candidate in an in vivo model, the back HT transgenic mouse. We did this knowing that there were several limitations to the model, namely that it does not contain the wild type HCT gene and it contains multiple copies of the mutant huntingtin gene, some of which do not have the SNP3 variant, therefore setting a higher bar for SNP-three selected mutant huntingtin knockdown. Nonetheless, as shown on the right, we observed potent and durable knockdown of mutant Huntington in the striatum of back HD transgenic mice out to 12 weeks with a similar effect in the cortex, although not shown in this slide.
These demonstrations of selectivity, potency and durability leave us enthusiastic about the prospects for 3 as we prepare to enter clinic. Further, with the entry of this candidate into clinic, we are positioned to provide allele selective therapeutic options for up to 80% of people with HD. Now moving on to WVE-four, our candidate targeting C9orf72 mutations for the treatment of myotrophic lateral sclerosis and frontotemporal dementia. 4 is designed to address the GGGGCC hexanucleotide repeat expansions in the CNR72 gene that lead to reduced expression of healthy protein, accumulation of repeat containing transcripts and the abnormal expression of the neurotoxic dipeptide proteins or DPRs. C9orf72 hexanucleotide repeat expansions are the most common genetic driver of ALS and FTD, both familial and sporadic forms.
Both diseases are devastating and represent areas of high unmet need. The preclinical data from our 4 program illustrate why we are excited about the potential of this variant selective compound. In addition to in vitro data from iPSC lines that we've shared previously, the in vivo data from the C9 back transgenic mice, which express the human C9orf72 containing hexanucleotide repeat expansion clearly tell the story. After only 2 ICV doses on days 07, 4 showed potent and durable knockdown of over 90% of the polyglycineproline or polyGP DPR protein in the spinal cord and at least 80% in the cortex. This impressive effect persisted for at least 6 months, particularly exciting results as we consider dosing intervals in the clinical setting.
Given that 4 was designed to be variant selective, we were further encouraged by these results from the same study demonstrating preservation of healthy C9orf72 protein at the same 6 month time point confirming selectivity of the compound. We look forward to evaluating this candidate's combination of variant selective targeting, potency and sustained activity in the clinic next year. One important aspect of our clinical program is the inclusion of patients diagnosed with ALS, FTD or both in our proof of concept clinical study. The primary objective will be to assess safety and tolerability of single and multiple doses of 4. But as in our preclinical in vivo studies, we will measure the poly GP biomarker in human CSF to assess target engagement.
We also intend to look at neurofilament like chain as well as other biomarkers. Finally, I will discuss our announcement that we plan to advance WVE N531 to the clinic next year. N531 targets exon 53 in boys with DMD who have mutations amenable to exon 53 skipping. Like 3 and 4, this candidate was designed with PM chemistry. Stepping back, you may recall that we were fully prepared to file a CTA for this candidate at the end of last year.
At that time, our preclinical data package, which included in vitro data demonstrating a dose dependent increase in dystrophin production of up to 71% in DMD patient derived myoblast supported rapidly advancing the candidate. However, as you also know, we had suspended development of N531 and other DMD programs following the discontinuation of our suvodirsen program. Since then, our assessment of muscle biopsies from the program indicated that the drug did not engage target, most likely due to poor intracellular access in dystrophic model and muscle. Based on the preclinical data for our PN containing compounds including N531, there is a possibility that we may overcome this challenge. In a clinical study is the best way to rapidly assess the impact of its chemistry on tissues distribution and splicing in dystrophic muscle.
One key piece of supported preclinical data is from an ongoing study in a mouse model for DMD with a devastating phenotype. This study was done in a double knockout or DKO mouse model, which has a mutation in exon 23 leading to a lack of dystrophin as well as a mutation leading to a lack of neutrophin. We compared the effects of a PSPO containing dosed at a 150 milligrams per kilogram weekly to a PM containing compound dosed at 75 milligram per kilogram every other week as well as a control. Other than the placement of the 3 pm backbone linkages, these molecules have the same sequence in chemistry. Despite administering 50% less drug, 50% less frequently, the mice receiving the PN containing molecule shown in light green have all reached at least 36 weeks of age.
They are thriving and the study remains ongoing, indicating the PN chemistry is having a compelling effect. Based upon a greater understanding of the suvodirsen study outcome, preclinical evidence supporting improved muscle distribution and skipping efficiency with PN chemistry and a sense of obligation to the DMD community, we are now ready to initiate a clinical trial. We are planning an open label trial with up to 15 boys with DMD, who will eventually receive N531 every other week. The trial will be powered to detect a change in dystrophin production, measure drug concentration in muscle and to assess initial safety. We plan to conduct the trial in Europe.
If successful, there is a potential to apply PN chemistry to other exons as well as the opportunity to advance other compounds for neuromuscular disease. We look forward to submitting the CTA in the Q1 of next year, continuing our mission to help patients in desperate need of new therapy. I'll now turn the call over to Dave Gallero, the Interim CFO, to bring you through our financial results. Dave?
Thanks, Mike. Wave ended the Q3 of 2020 with approximately $216,400,000 in cash and cash equivalents compared to $147,200,000 as of December 31, 2019. During the Q3 of 2020, we substantially extended our cash runway by raising $93,700,000 in net proceeds from our September 2020 public offering and $48,000,000 in net proceeds from our at the market equity program and receiving $16,800,000 in refundable tax credits. Now I would like to review our income statement for the quarter. For the Q3 of 2020, WAVE reported a net loss of $33,100,000 compared to $50,700,000 for the same period in 2019.
Research and development expenses were $28,300,000 in the Q3 of 2020, compared to $44,600,000 for the same period in the prior year. The decrease in research and development expenses in the 3rd quarter was primarily due to decreased external expenses related to suvodirsen due to our December 2019 decision to discontinue the program, as well as decreased headcount and other external expenses driven by our February 2020 cost reduction plan, partially offset by increased external expenses related to our clinical and preclinical activities related to our HD programs and our C9orf72 program for ALS and General and administrative expenses were $9,600,000 in the Q3 of 2020 compared to $12,500,000 in the same in the same period in 2019. The decrease in general and administrative expenses in the Q3 of 2020 was primarily due to the February 2020 cost reduction plan, which included workforce reduction. We expect that our existing cash and cash equivalents together with 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, we do not include potential milestones and other uncommitted payments related to our Takeda collaboration in our cash runway.
I will now turn the call back over to Paul for closing remarks. Paul?
Thanks, Dave. I hope you all are sharing in our excitement for what we expect to be a catalyst rich year ahead, driven mostly by the 5 clinical trials that we expect will be ongoing in 2021. To recap, this quarter, we expect to submit the CTAs for WVE-three and WVE-four. In the Q1 of 2021, we plan to submit a 3rd CTA for WVE N531. Also in the Q1, we expect to report data from all cohorts of the precision HD studies as well as initial OLE data.
Finally, we plan to share updates on our AATD program including data humanized model and I expect we'll have other ADAR editing updates to share as we continue to build this novel platform capability. We are well capitalized to advance our pipeline of potentially transformational programs and realize the value of our platform. And with that, we'll open up the call for questions. Operator?
Your first question is from the line of June Lee with Truist Securities.
Hi guys. Thanks for the questions and the update. I have a couple of questions. For your ANR program, for the antitrypsin program, number 1, what percent editing would you need to have a therapeutic effect? And could you explain in what way your approach is better or different than the knockdown approach being taken by Alnylam and Vicerna?
And for the DMD program, can you find us again how your PN chemistry is able to over come the tissue access limitations of your prior chemistry backbone chemistry? Thank you.
Thank you, Jim. And we'll divide this into 2 parts and I'll bring Chandra in a second. As it relates to ADAR, we're excited about the differentiation as we laid out for bringing an editing approach or a correction approach forward over silencing. And while there's been a lot of excitement around silencing and we don't discount that on knocking down or the mutated protein within the liver. I think when we think and approached the Alpha-one antitrypsin deficiency, we really approached it from the area of correction.
That is how do we fix this point mutation such that we can restore the physiologic balance of the protein, enabling it to treat both the pulmonary as well as the hepatic complications, so the liver and lung. So this is a key driver for us to drive down the correction arm. As As we talk about the heterozygosity of these patients, we do know that a patient is heterozygous, so a 50% correction, so restoration doesn't manifest the disease. So we think about where the correction needs to be with a physiologic protein between that up to 50%. But you don't by no means need to 100% correction in terms of restoring normal physiology.
Chandra, is there anything you want to add to the ADAR question?
No, I think you pretty much covered.
Hey, Paul, just on that, just to finish up the ADAR question. Assuming both the NAPLAN approach works as they expect fully and then your approach works fully as you expect by editing. How would you envision these two approaches manifesting clinically differently? How would it be different clinically?
Yes. So I mean, as we know now, there's the initial therapies that are out in terms of the protein replacement to treat pulmonary complications. So there's this augmentation therapy that's there. And so there's a as well as now liver correction with silencing. I think we stand to be able to work in both, therefore, really correcting and restoring the normal protein for the wild type protein, to restore physiologic balance, letting the body use the proteins that they need for both the lung and the liver.
So it would really potentially wouldn't require the necessity of silencing or protein replacement therapy.
And the DMD?
Yes. And as it relates to DMD, and I'll let Mike continue to and answer the question. But subsequently, I mean as we shared on Research Day, there's a lot of excitement as we think about the in vivo data that we're generating across cell uptake of PN chemistry. And we'll talk about this in the context of muscle obviously for DMD. But as we just shared today, one can see that transitioning across neurons and other aspects.
Mike, do you want to answer the question on DMD?
Sure, sure Paul. Yes. So as Paul just said, I mean, we're seeing something very different terms of tissue access distribution and importantly durability, when the PNs backbones are added to identical PSPO molecules. So DMD, where we are, why we're thinking this could address these issues. First of all, the in vivo model, it targets exon 23, but you see a clear difference in terms of tissue, in terms of clinical effects, in terms of what we're seeing in that model of a PSPO versus a PN.
So clearly, we're seeing a difference there that is encouraging. The PN does seem, as Paul alluded to earlier, introduced a negative introduced neutral charges to the backbone, which changes the overall potentially effect on how that molecule accesses tissues. And as I said, the durability here is clearly different. So maybe having it in the tissues longer at higher concentrations with better access, could address this change we saw, this lack of access that we saw with suvodirsen. So the overall picture here is that, there are a lot of characteristics of the molecule and the preclinical data that we are seeing that give us hope, But you can only take that so far with an exon targeting or with an IASO targeting a different exon in an animal.
And you just need to take it into a human study to really answer that question and we can do that very efficiently as described.
Yes, just to follow-up on that. I mean, I think, Jim, one of the other as Mike alluded to with the DKO mouse study and the comparison, I think the other piece that was also important was that substantial reduction in dose. So really not just seeing that improvement, but seeing that improvement at 50% less than that PSPO drug. So 75 milligrams per kilogram and every other week, so not even weekly. So I think we see that as important.
I think we also see good distribution in that model, which is heavily sensitive across cardiac and pulmonary phenotypes with distribution to heart and diaphragm. So we're pretty excited about the characteristics there. One other point just to bring back up to alpha-one and trips and deficiency as you were asking questions about protein augmentation and it should be noted that that therapy is a weekly IV infusion. So in terms of just correcting not just in terms of the hepatic, but also being able to restore the normal protein to the lung, being able to move patients off of weekly IV administration to real correction of the physiologic protein is something we're pretty excited about bringing forward.
Great. Thank you. I'm looking forward to the data updates. Thank you, guys.
Your next question is from the line of Mani Foroohar with SVB Leerink.
Hi, good morning. This is Rick on the line for Mani. Congrats on all the progress. My first question is also on N531. So I was hoping you can elaborate a little bit more on what you're seeing in the preclinical studies with the PN chemistry.
And I guess besides tissue access, would you expect to see any improvements in either tolerability or therapeutic window compared to supridersen?
I mean, and I'll let Mike continue. I mean, I think as we alluded, one, with the distribution we're seeing, it's substantially less dose. So half the amount of drug at expanding the time interval out longer. We're seeing that those changes in a mouse that has a phenotype. And I think that's really important to know because oftentimes we talk to people talk about MDx data where there isn't a phenotype and it's purely around dystrophin.
So I think what's exciting about this model for us is this model does have a phenotype that's being corrected with this exon 23 skipping compound, as Mike said, with the PN chemistry. So we're excited about that in terms of exposure distribution and being able to evaluate that in the model. Mike, do you have anything you want to add to that?
Yes. And I would say we also expect the therapeutic window to be quite different. I mean, we're seeing that lower doses given less frequently, are leading to effects that suggests that there's clearly a difference in that therapeutic window, as well as supported by all the other preclinical studies between the humans, you don't know, which is why we've decided that the best way to proceed here is to proceed with a study that can be focused, focusing on target engagement, in a small number of patients, but definitive to give us enough information to make that determination whether there is this difference.
I got it. Thanks for that. And I have a follow-up about the Huntington's program. So could you maybe discuss some of the learnings from precision HD1 and HD2 that you're bringing with you into the dose escalation of wave 3? Do you think you'll be able to start at a the escalation at a more clinically relevant dose than the earlier studies?
Or maybe could you escalate more rapidly than precision HD1 and HD2 in the newer study?
Mike, do you want to take that question?
Yes, sure. Absolutely. So, I think we've learned a lot obviously from PRECISION HD 12. We've learned that how to run these studies, how to engage the community, how to find patients. I think the important thing here is help give us a bit more guidance on where we need to be.
So we would anticipate, therefore starting at dosing levels that would be more, in that window of where we would expect to engage target and a dose escalation scenario driven by those in vivo data as well as the data that we're going to be generating an ongoing fashion from the clinical study itself. And I think what's very important is this once again, every molecule that comes out of the PRISM platform has a different pharmacology, has a different characteristics in vivo and in vitro and that's what's going to guide how we approach the next study. So you see the study, you'll see there are elements we've adapted from our existing studies and you'll also see some pretty meaningful differences that we have that have been driven by the pharmacology of the 3 molecule.
I think the other thing just to add to that in terms of identifying patients is with to your point, Rick, with the ability now to have ongoing studies where we're screening for SNP, the apparatus around SNP phasing, we're able to do that a lot more efficiently now with the practice around SNP1 and SNP2. And also by screening those patients having a good understanding of SNP3 and where those SNP3 patients are. So as we look the totality of the SNP3 program beyond just the SNP3 characteristics of the medicine itself, the broader infrastructure for clinical trial operations is in place to do this. Absolutely.
All right, great. Thanks for taking our questions.
Thank you.
Thank you.
Your next question is from the line of Salim Syed with Mizuho.
Great. Good morning, everybody. Thanks for the color, guys. Just 3 for me, if I can. Paul, on the PRECISION trials, on the Q2 call, we had talked about site lockdowns in Australia, given half of your sites are currently there.
So I was wondering if you could just give us an update on what you're seeing with COVID-nineteen in Australia. Are you still seeing the site lockdowns there? Or are you seeing new patients coming back on into those trials, the ones that you identified? And are you close to finishing enrollment? Number 2, on the going higher than 32 milligrams, now that we're getting close to the end of the 4th quarter here, what is your framework here, to go potentially higher than the 32 milligrams, given you don't need all the data from that cohort?
And will you disclose this to The Street if you decide to go higher and how will you do that? And then just lastly on 531 DMD, if you can just give us some color as to whether you plan on keeping 100 percent of the economics there partnering that program out? Thanks so much.
Thank you. And I'll let Mike take the first two questions related to HD and then I'll answer your last question on DMD. Mike, do you want to answer the questions on HD?
Sure. So I'm first of all focusing on the environment with COVID. As we said at the last call, there were lockdowns that were clearly having differences along the way and impacting our ability to recruit. That is a moving target. But I can say that as sites have closed down, others have opened up as lockdowns end, sites open up again.
So we've been actually very fortunate that last time it was one of the big factors was Melbourne. It just shut down, Melbourne is up. And certainly, cities in different places are opening and closing. I mean, this is an evolving landscape where but we're what's been great is that, we have really good communication with the investigators. So we can anticipate when these things are happening and then redirect if necessary.
But right now, with the way we're headed, none of that has impacted our ability to have the data readout in the Q1, which is what we're reaffirming we're going to have today. In terms of the framework to go higher, with being 1 quarter away from the definitive multi dose readout, at this point, we thought it may just make the most sense to wait to see that data set, in terms of degree of knockdown, in terms of the overall profile of the product before making that decision. I mean, we can as we've said previously, we have the therapeutic window, we have the ability to go higher from a preclinical perspective, but being so close to the definitive readout, we just thought it was best to wait for that at this time. So that's where we are with that. And then I'll pass it back to Paul for the question about the partnering.
And just I mean to wrap up on HD, I mean we're excited getting to this data readout. I mean as you know we provided updates if there were any changes that impacted the updates to the readout timing and we remain on track for the Q1 of 2021 data readout. As far as DMD and the percent of economics, I think this is something that we thought very carefully about around where and how to partner. I say you often partner because you require the financial means to deliver on the data or you need to leverage some sort of operating capability or capacity to deliver that. And I think what the team has done and where we are is we can deliver this study that Mike laid out today within our runway.
And therefore, I think it's important for us to continue to generate that data for both the platform and this 100% of the economics as we push forward. But as anything, it's something that we'll continue to evaluate as we
move that
program forward. Super helpful. Thanks so much guys.
Your next question is from the line of Paul Matteis with Stifel.
This is Alex on for Paul. Just a couple on your ATD program. First, I was just curious if you could elaborate on how what proportion of the ZZ homozygous have that G to A mutation? And then along with that, curious if you could talk a little bit more about kind of the rationale for the ADAR strategy and its ability to allow for that physiologic regulation of AAT? Thanks so much.
Yes. No, great question. It's something we focused in about 5% to 15%. I know that's a reasonable range, our patients who are amenable. So our number on the 250,000 patients are the anticipated estimated patient population worldwide.
So 250,000 patients worldwide that are amenable to the correction of this mutation. I think we stayed focused on this concept of correction around bringing kind of the concept around physiologic regulation, meaning restoring. And so by correcting the transcript, therefore not knocking it out, but allowing for wild type protein that then can be used as a physiologically required. So oftentimes it's known that since it's engaging elastase in the lung, which can result from injury in the lung to activating and acquiring this protein. By having that protein around enables it to be responsive as it would be under normal circumstances.
So I think the exciting aspect of bringing this program is really bringing a different way of thinking about the treatment of the disease, which is one around correction. So not taking away a mutant protein and or requiring weekly IV protein augmentation therapy, but rather restoring physiologic balance through the correction of the transcript, which is really the hallmark of RNA editing. So we're excited about this space. And more broadly, we're excited about what it means as we think about different diseases in ADAR as a platform. So we do look at this.
Obviously, AATD is a initial therapeutic approach, but I think when we step back and say what are we learning about ADAR, we're investing in building this proprietary model that will now let us be able to cross it with multiple diseases and look at the human ADAR enzyme in the context of disease that we build models for therapeutic programs. I think we think much more broadly about the treatments that could be possible with alpha-one antitrypsin deficiency.
Thanks so much.
Your next question is from the line of Eun Yang with Jefferies.
I have more speculative questions. So on the data in the Q1 next year, hypothetically, if you see similar mutant HTT reduction at 30 2 milligram as what you saw at 16. Would you make a go no go decision at the point or still pursue a higher dose?
I think that's exactly to Mike's point what we want to stay focused on in terms of analyzing the data. So being data driven, there's a variety of biomarkers to look at and ascertain at that point. Do we believe going higher will be there? Are we at that dose because as we think about that, that's a point. I think if we see a flat towing, there's a variety of other biomarkers to assess as part of that clinical data outcome and we'll have to do that in the Q1 once we have that data.
Mike, any additional
thoughts? No, nothing else to add, Paul. I mean, we have a lot of things we're going to be looking at. So it's not the least of which is what's meaningful in this setting of very specific knockdown as opposed to pan selective, which is different. They have to be looked at differently and that'll all be part of the conversation.
But I think in terms of having tools for the allele selective therapy, it's one advantage of why we're not gating the SNP 3, so it's wb3 on that readout. So we're excited about driving that program forward independently because we do believe in this and this allele selective approach. The data that we're seeing in the literature continues to grow in wild sites sparing. And so we'll have other programs to be able assess that. But we'll have to look at the totality of the data in the Q1.
Yes, that's informative. And a last question was on DMD program, exon 53 candidate. So in vitro model, you saw dose dependent increase in dystrophin production up to 70% of a normal. And I understand that with improved durability and tissue penetration, I mean, can you extrapolate from this in vitro study data to what you could realistically expect in humans?
I think we're going to reserve speculation from the in vitro studies. I think we see substantial dystrophin production with the candidate that's going to be tested in the clinic that gives us a lot of confidence on dystrophin production and the preclinical data supporting exposure. I think coupling that with the DKO data, which is here you have a phenotype that you can correct and restore. I think that gives us confidence that indeed we are getting into dystrophic muscle and having an impact granted with the 23 molecule. But in vivo data at lower doses less frequently, which give us confidence.
I think the study that Mike laid out that we're going to be pursuing is measured for that exact reason. I think we're disciplined after our suprudersen experience that we do need to see what happens in the DMD boys. And we've had a lot of conversations with the community, haven't seen the data who are extraordinarily supportive of this approach and the data that we've generated. But we need to generate that data and we're excited to be able to do that. Mike, I don't know if you want to add to that.
Yes. No, the only thing I would add, I think as you captured nicely, this entire DMD space is unfortunately, lots of disappointment about what can translate pre clinically to clinically. We have a lot of evidence that suggests that we have something here that could be different. But really the best way is to get it into human beings. Take a look judiciously at we execute this study in a way that allows us to assess that profile and make determinations of next steps.
We felt that was the most responsible way to proceed.
Okay. Thank you very much.
Thank you.
Your next question is from the line of Yaron Werber with Cowen.
Hi, guys. This is Brendan on for Yaron. Thanks very much for taking on the questions. Just a couple of quick ones from us. I guess, first in HD, I just wanted to check-in on the wild type Huntington assay and kind of see where this stands.
I know in the past there's been talk of maybe some updates to the assay itself just to make sure you're really able to see differences and kind of this ileal sparing effect and just kind of I just wanted to check-in on that. And then for DMD, as we're kind of looking across the space, obviously between the exon skippers and like gene therapy, for example, we're seeing kind of different besides different mechanisms, just different results here. So just kind of trying to get your thoughts on where your bar is for this Phase 1? Are you really hoping to see a level of protein restoration and maybe improvement on NSA that we've seen with gene therapy? Or are you really aiming for the bar closer to where we've seen with the exon skipping ASOs?
Thanks.
Excellent. I mean, a short answer on the first question is, we continue to do the work as we alluded to earlier on the wild type assay and we anticipate and we're working hard to deliver that with our data in the Q1. We do we agree that that's an important way of driving that assessment. As it relates to the bar, I think what we're excited about now is restoring dystrophin and having an impact. This study is anticipated.
It is not a clinical outcome study. We're not right now looking at this in the context of that would be something that would follow as you just pointed out, the NSA and other metrics, that's something that we could continue to follow. I think the first question we want to ask is dystrophic muscle exposure, dystrophin production and safety. Those are the key drivers to give us a sense moving forward. And we're excited about the prospects based on the preclinical work, but we also want to be really measured in where we are.
I think if we see what we're seeing in the DKO mouse, which is these mice that should actually not be living, we're restoring a survival phenotype in them. And that's not just about skeletal muscle. And I think one nuance that we are excited about with the prospects of the addition of PN chemistry now is exposure to heart and diaphragm. So these mice have the full phenotypes and they're dying from cardiac and respiratory complications. So the ability to access both those other tissues beyond skeletal muscle is really what excites us about this program and at the dosing intervals and doses that we're using.
So I think there's a lot to be excited about to go forward. But again, this first study is about that measured approach to assessing that. And I'll pause. Mike, is there anything you want to add to either of those points?
No, nothing to add to that. Thanks Paul.
Great. Thanks guys.
Okay. Your next question is from the line of Luca Izzie with RBC Capital.
Terrific. Thank you for taking my questions and congratulations on all the progress here. Two quick ones for me. One, it is my understanding that all five studies that are ongoing in 2021 will be actually ex U. S?
One, is that correct? 2, if so, are you planning to open an IND in the U. S. For any of the programs? And how should we think about timelines there?
2, I think Ionis showed that their initial data for SOD1 ALS was actually more impressive for fast progressors. Do you expect the same for C9? And if so, are you planning to enrich your trials for such patients? Thank you.
Thank you for your questions. Mike, do you want to take the question?
Sure. Yes. So regarding first question about where we're conducting the study. It is our intention for I mean, as you know, precision HD1, precision HD2, we have, some sites in the U. S.
And we have some sites outside the U. S. So multi dose is outside the U. S. As we've always talked about.
So regarding other programs, we anticipate that these are going to be global studies. And we anticipate, conducting these studies, in the U. S, except for N531, as we've already said, will be just a small proof of concept study ex U. S. So I would so, that is our intention.
We're very, optimistic that we'll be able, to do that. Regarding the second question, which was again
I was just wondering about SOD1. I think are you on its show, Zach, or this SOD1? Yes. Go ahead.
I'm sorry. Yes. No, thank you. No, sorry about Rob. Yes.
So, we'll give more details of the study design early next year. But what I can say is that, I mean, one thing about C9orf 72 disease in ALS patients, it is a fairly rapidly progressive. They progress at a little more rapid rate than other groups of ALS patients. So that's going to be something that's going that will just be a factor of the population itself. The way we're approaching our C9orf72 program is really focusing on C9 disease, if you will.
These are patients, they could have ALS, they could have FTD, they can have the overlap condition, which is actually, fairly not unusual. And that we are really looking to target the disease itself at its origins in both population focusing on a biomarker readout that will allow us then to make those decisions on how we progress clinically. So that's how we're approaching it. Again, we're approaching it as a single rapidly progressive syndrome focused on target engagement at the biomarker level.
Great.
Terrific. Thanks guys.
Thank you.
I am showing no further questions at this time. I would now like to turn the conference back to Doctor. Paul Baulnaud.
Thanks everyone for joining the call this morning to review our Q3 update and thanks to our employees for their hard work and commitments to patients. We look forward to speaking with you all again soon. Have a nice day. Thank you.
Ladies and gentlemen, this concludes today's conference. Thank you for your participation and have a wonderful day. You may all disconnect.