Q4 2020 WAVE Life Sciences Ltd Earnings Call
Good morning, and welcome to the wave life Sciences.
Fourth quarter and full year, 'twenty 'twenty financial resort 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'll now turn the call over to Kate Rausch head.
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 with the fourth quarter and full year of 2020 operating results on.
On the call with me today are Dr. Paul Donahue, our president and CEO, Dr. Mike <unk>, our Chief Medical Officer head of Therapeutics Discovery and development and Cameron our CFO, Dr. Ken roads, our senior Vice President of Therapeutics Discovery and Dr. Varghese, Our Chief Technology Officer will also be available for questions. Following the prepared the Max portion of.
On the call.
This morning, we issued a news release detailing our fourth quarter and full year of adult.
Please note that this news release and the slide presentation that accompanies this webcast are available in the investors section of our website Www Dot wave life Sciences dotcom.
Before we begin I would like to remind you that discussions during this conference call will include forward looking statements.
Statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in the forward looking statements.
The factors that could cause actual results to differ are discussed in the press release issued today.
The SEC filings, including our annual report on form 10-K for the year ended December 31st 2020.
We undertake no obligation to update or revise any forward looking statements or any of them.
I'd now like to turn the call over to Paul Bono, President and CEO of week Life Sciences Huh.
Thanks, Kate good morning to everyone on the call and thank you for joining us.
During the call today I will provide opening remarks, after which Mike <unk> will give an update of our new clinical trials kicking off this year and Kyle will briefly discuss our financial results.
After our prepared remarks, Ken growth and chunk of of argues will be available for Q&A.
2020, with the productive year for wave, resulting from focused and deliberate execution that was driven by our commitment to developing transformative medicines for our patients.
As we start 2021, I would like to reflect on the progress we made which has positioned us to have five programs in the clinic this year.
In our neurology pipeline, we progressed, our precision HD program amidst the backdrop of the global come down and we are on track for data readout at the end of the month, we are delivering on our guidance to advanced three new programs into the clinic. This year, our snip the reprogramming HD, our C&I and owner of 72 program and the AOS in F. T D.
And our exon 53 program and do share all of which incorporate our new Pn chemistry.
We also achieved several milestones for the CNS programs, we are advancing with Takeda, including the first demonstration of substantial and widespread target engagement in the in Hps.
We continue to expand our prism platform into new modality and made significant progress last year on advancing our novel <unk> mediated RNA editing modality, culminating with the announcement of our first aid our editing program for Alpha one antitrypsin deficiency.
Highlighting the progress of both our pipelines of platform, we published five papers within the past 12 months and we expect to continue to publish more.
From a capital position, we raised over $150 million in 2020, ensuring wave as well resource to advance our pipeline and deliver proof of concept results to support growth in 2021 and beyond.
Turning to 2021, we anticipate a very busy year of updates on our programs.
Starting with the upcoming readout of our precision HD programs in Huntington's disease.
These programs consists of core phase <unk> studies and open label extension studies for both W. V. E 121 of one and <unk> 121 of two targeting SNP, one and two respectively.
On slide six we provide an overview of the data we expect to report from the precision HD program at the end of this month.
These include biomarker and safety data from all cohorts of precision HD, two core trial, including the 32 milligram cohort along with all complete cohorts up to and including the 16 milligram cohort from the precision HD One court trial.
We will also share data from the patients who have received multiple doses of eight or 60 milligram from the <unk> 121 of one or <unk> 121, or two and the open label extension trials, we anticipate sharing data on multiple biomarkers, including the Huntington nearer of filament light chain and wild type Huntington.
This will clearly be a robust dataset, which we expect will enable us to make a decision regarding potential phase III development for either candidate.
Before turning to our pipeline program I will touch on our novel Pn chemistry backbone modification, which I've met the first generation chemistry used in the program's justice Scott.
As we first highlighted during our research webcast last year. These pn backbone chemistry of modification arent advancement from our pleasant platform and have generally been shown the increased potency exposure and durability in preclinical studies across the island thing splicing and ADR of editing applications.
Essentially our Pn chemistry has the potential to lead the compounds with favorable profile independent of sequence of tissue type and modality.
Importantly, we've already submitted multiple clinical trial applications for candidates using pn chemistry, and anticipate initiating three trials this year.
Turning to slide eight our three upcoming clinical programs targeting the SNP three the United or <unk> 72, and exon 53 reflect several advances, resulting from the evolution of our platform and our experience over the past eight years enabled by Syria of pure design. Each candidate has been optimized with Pn chemistry. We've also.
Prioritize the use of in vivo models during the preclinical development in each of these program has incorporated learnings and translational pharmacology and clinical trial design from our first generated from program.
Mike will speak further to these learning and provide an update on our planned clinical trials of later on this call.
Slide nine provides an overview of our neurology focused pipeline, which includes silencing spicing in editing program.
Notably all of our current discovery and preclinical stage programs utilize the pn backbone chemistry modification, among our discovery and preclinical CNS programs that we're advancing with our partner Takeda, we continued to produce compelling in vivo data and progressed multiple discovery program towards portfolio entry and candidate nomination.
In 2020, we also made significant progress on our ADR editing modality, which we believe has many advantages in the editing space and positions us at the forefront of RNA editing.
Our approach to RNA editing employee short fully chemically modified the oligonucleotide to recruit endogenous RNA editing enzymes called Edr.
Our ADR editing compounds are optimized using our proprietary stereochemistry N P N backbone chemistry modifications, which enables us to avoid delivery vehicles, such as AAV vectors of nanoparticles and allows us the leverage established manufacturing processes.
Eight of our editing opens the door to a number of therapeutic applications, including restoring of modifying protein function in upregulation of protein protein expression, which greatly expands the landscape of disease areas that we can potentially address.
In 2020, we generated exciting proof of concept data in non human primates that resulted in successful and durable RNA editing of up to 50% of in vivo.
We're excited about the potential to acquire eight are editing in neurology and last year, we demonstrated successful RNA editing in vitro neurons and in vivo in the CNS of mice.
This year, we anticipate sharing additional non human primate aid our editing data and we are actively evaluating potential neurology programs to address with this modality.
Our first aid auditing program addressing the alpha one antitrypsin deficiency or <unk> by correcting the single point mutation on the mrna encoded by the <unk> of the Serpent <unk> gene. This mutation leads to Miss holding an aggregation of alpha one antitrypsin protein or a T in hepatocytes and a lack of flow.
The <unk> protein in the lungs, where it would protect lung tissues from neutrophil elastase.
Patients with ACD typically exhibit a progressive lung damage liver damage of both leading the frequent hospitalizations of potentially terminal longer liver disease.
Unlike the silencing approach, we believe that our novel ADR editing modality has the potential to address both of the lung and liver manifestations of ACD by editing at the RNA level, we avoid the risk of off target genomics thing and are able to titrate, our dose, thereby avoiding potential challenges with over expressing an aggregation from protein.
In the fourth quarter of 2020, we successfully demonstrated editing of the serpent <unk> the OBL transcripts to wild type in vitro in hepatocytes from a transgenic model with upwards of 60% correction of the the OBL transcripts.
This level of editing resulted in a threefold increase in the <unk> protein since our last update we have further validated the secreted proteins to be functional wild type <unk> proteins.
These in vitro results are what gives us excitement to generate preclinical in vivo data, we continue to optimize our proprietary in vivo model, which contains both humanized sort of been a one and humanised ADR and we are on track to share additional data in the first half of 2021.
I would now like to turn the call over to Mike <unk> for an update on the Huntington's franchise and our three clinical trials planned for this year Mike.
Thanks, Paul.
We ended 2020 with momentum across development programs as we continued to progress our precision HD trials towards the upcoming data readout.
As Paul described earlier, we anticipate sharing of robust datasets per a SNP one instead of two programs by the end of the month.
Looking to 2021, we successfully submitted clinical trial applications during December to initiate clinical development for W. Be easier. This year of three our third of allele selective candidate in Huntington's disease and W. V E eras, therefore, our variance selective silencing candidate and the AOS in F. T D.
In addition submission of the third Cta for W. V and 531 of candidate for DMD patients with mutations amenable to exon 53 skipping is imminent.
All of these compounds incorporate our novel PM backbone chemistry, which has led to favorable profiles and the numerous in vivo studies supporting these programs.
We owe the significant progress we've made to our team and our partners in the research and patient communities, who continuously adapted to the ongoing challenges presented by the global pandemic to achieve these objectives.
I'll discuss each of these programs in more detail today, starting with our Huntington's franchise.
We have purposely built the portfolio of allele selective HD candidates designed to lower mutant Huntington, while preserving wild type Huntington.
During the time, we have spent developing and advancing these three programs. The evidence supporting the importance of wild type Huntington has only continued to growth.
Wild type Huntington is essential for proper function of the central nervous system as part of the regeneration transcriptome, especially in the setting of physiological stress as well as having systemic effects.
Wild type Huntington carries out of central functions in both developing and adult brain that protects neurons against the various types of stress prevalent in sales with high metabolic activity, including excited of toxic oxidative and protein misfolds stress.
Wild type Huntington also plays a key role in traffic and cannot the proteins and synaptic vehicles. This trafficking function has been shown to affect synoptic plasticity, which is important for learning and memory as well as for supplying the essential growth factor Bdnf, just try it'll neurons to ensure their survival.
Additionally, wild type Huntington, it's critical for the formation and function of Australia, which control the flow of CSF and help maintain homeostasis in the CNS.
We like to use. The example of a tug of war to illustrate the battle ongoing between the positive biological effects of wild type Huntington protein in the toxic effects of mutant Huntington from the CNS of those living with H D D.
Given that HD patients start out with approximately 50% less wild type protein and then of healthy individuals. We think this is a reasonable way to illustrate how patients gradually lose ground of disease progression, particularly if there is further depletion of the wild type protein and reservoir.
As such we believe wild type preservation may be an important driver of efficacy when considering how much mutant huntington lowering may be required to achieve clinical benefit.
Our approach to achieving allele selectivity is to target specific single nucleotide polymorphisms or snips.
And on the mutant Huntington the wheel.
Some people with HD can harbor multiple suites in which case, a given patient may be eligible for any one of the three snick targeting treatments.
Approximately 50% of the HD population carries SNP one portion of two with an overall estimate of up to 70% carrying Smith once the two or both when the groups of combined.
People with net three represent approximately 40% of BHG population and it is estimated that up to 80% carry at least one of these three snips.
Allele selective therapies have the potential to benefit of substantial portion of patients living with HD.
Today, we are focused on the symptomatic manifest population, though we believe debt within our real selective therapy, we may be able to address patients in the pre manifest setting before the onset of clinical disease.
In the U S. There are approximately 30000 people with manifest Huntington's disease, and approximately 200000 people at risk of developing HD based on their family of genetics.
In order to advance our portfolio of allele selective candidates, we have needed to innovate on the tools available to accurately and rapidly identify the patients with snips that we wanted to target.
We achieved this through novel long read sequencing technologies, such that now SNP identification is fairly routine and highly specific.
In 2020. These accomplishments were the subject of multiple publications and in partnership with the surgeon, we are expanding our ability to rapidly identify patients to include in our studies and potentially two similar support commercialization.
Our existing precision AG programs and planned near zero three trial will evaluate the CSF biomarkers to confirm target engagement neuro protection and wild type sparing.
Building on the existing mutant and total Huntington assets, we have implemented of novel methods to assess wild type Huntington.
Pleading mutant Huntington from patients CSF samples to allow for direct wild type measurement as shown on slide 18, we collect CSF and deplete mutant Huntington using antibody conjugated magnetic beads.
Allows us to directly measure of the protein that remains leading to quantitate, the <unk> of wild type Huntington.
As the importance of wild type Huntington is increasingly acknowledged we expect this ability to measure of wild type protein to be a meaningful contribution to the HD community and look forward to expanding its use.
Now turning to <unk>, our third of wheel selective candidate for HD and our first HD candidate to incorporate <unk> backbone chemistry modifications.
This net three program builds upon the wealth of learnings and experience. We have gained from our first generation HD progress.
For instance viewers in the Euro three is the first of our HD compounds evaluated in an in vivo model system to better understand the PK PD relationships and these results have informed the starting dose in a clinical trial. We are also leveraging our collaboration with assure Jim and experience of the sites from the precision HD trials to drive new efficiencies with.
Our clinical trial.
The phase <unk> clinical trial is planned to enroll up to 40 patients with the confirmed H D diagnosis or in the early stages of the disease and Kerry Smith III in association with their CAGR.
<unk> expansion.
The trial of one corporate and you've got an adaptive design with both single and multiple ascending dose portions.
Throughout the course of the study and independent data safety monitoring board or DSM being well.
Who will guide the level of dose escalation and dosing intervals to make data driven decisions regarding dose and to potentially accelerate time to proof of concept.
Safety and Tolerability of heroes are true will be evaluated along with similar biomarkers as our precision HD program, including the mutant Huntington neuro fill of in light chain and wild type Huntington to assess for allele selectivity click.
Clinical trial site activation is ongoing.
We anticipate dosing the first patient this year.
Turning to <unk> 70 per group program for the treatment of the Meyer trophic lateral sclerosis, our AOS and frontal temporal dementia or S. T D.
Our clinical candidate W. The easier with Eurosport is designed to target hedging nucleotide repeat expansion in the C&I and of our 72 transcript that lead to reduced expression of healthy protein accumulation of repeat containing toxic RNA flow side and the abnormal expression of neurotoxic dipeptide repeat.
<unk> or the PFS.
Mutations of <unk> 72 gene of the common underlying determinant of driving these diverse and devastating phenotypes.
Our variance selective targeting strategy was recently described in nature of communications in this paper, we describe our work to identify and validate the targeting site to achieve very selective knockdown of expansion containing C&I and owner of <unk> 72 transcripts.
The publication highlights of the foundational work that led to the development of the clinical candidate.
A key reason we remain excited about the potential of <unk> is clearly demonstrated on slide 22, showing preclinical data recently presented at the 31st International Symposium on AOS in motor neuron disease.
And this transgenic mouse model to ICB injections of 004 administered seven days apart resulted in a rapid and durable knockdown of over 90% of the DPR poly glycine choline or poly GP in the spinal cord and at least 80% knockdown in the cortex.
With the durable effect out to at least six months.
Further normalcy and INR 72 protein remains unchanged at that time point.
Measurement of poly GP in the CSS as the key endpoint in a clinical study. So we are looking forward to assessing the impact of treatment and humans given these promising preclinical results.
Like us and of <unk> III trial, the planned phase one.
<unk> phase <unk> clinical trial for 004 will be adaptive with both single and multiple ascending dose portions.
The clinical trial will enroll up to 50 patients with the documented <unk> of <unk> 72 expansion and a confirmed Alice STD are mixed phenotype.
A D SMB will guide the level of dose escalation and subsequent dosing integral enabling the potential for rapid proof of concept.
Safety and Tolerability of the <unk> will be assessed along with key biomarkers of target engagement and neuro degeneration, including poly GP.
And neuro filament light chain.
A key exploratory clinical outcome measures to be assessed include the ALS FRS or <unk>.
<unk> <unk>.
Clinical trial site activation is ongoing and we anticipate dosing the first patient this year.
Finally, I would like to discuss <unk> three one our exon skipping candidate we plan to evaluate for patients with Duchenne muscular dystrophy amenable to exon 53, skipping and the first splicing candidate in our pipeline to use pn backbone chemistry modifications.
The end of <unk> three one program is guided by work in DMD with sewer dressen, which used our first generation <unk> chemistry.
Biopsies from our open label study clearly showed the <unk> reached muscle tissue, but did not achieve target engagement, apparently due to the core intracellular access of dystrophic muscle.
Our decision to advance <unk> hundred one was driven by the compelling preclinical data for the candidate as well as that of circuit compounds, incorporating <unk> backbone chemistry modification.
This evidence includes dose dependent increases in dystrophin production of up to 71% in vitro and patient derived myeloblast with Empire 31, higher concentrations and broader distribution of nonhuman primates with M 531, as compared to first generation chemistry supporting the potential for biweekly dosing.
And lastly, rescue of double knockout or D. J D. K O mice from of rapidly fatal phenotype of the pn containing exon skipping compounds as shown on slide 25.
As a reminder, the detail of mouse model has the mutation in exon 23, leading to a lack of dystrophin as well as the second mutation leading to a lack of of your trophy production, resulting in severe and rapidly fatal phenotype.
A recently completed study shown here, we compare the effects of a P. S. P O containing molecule dosed at 150 milligram per kilogram weekly two of Pn containing compound dose both at the same level and at 75 milligram per kilogram every other week as well as the PBS control of them.
On the slide there of survival curves for these treatment groups.
Other than placement of the three P M backbone linkages. These.
These molecules of the same sequence and chemistry.
Right that there is a dramatic increase in survival in those animals treated with the pn containing compounds as compared with other treatment groups, including at 75 milligram every other week of dose of 75% less than that of the other groups.
Both cohorts of mice treated with the PM containing compounds survived through the time of the study termination at 40 weeks as compared to a median survival of approximately 12 weeks for the cohort dose with the <unk> containing molecule and the median survival of only seven weeks in the PBS group.
Not shown on the figure was a separate matched control group of Mdx mice, which lived to study termination.
We are on track to submit the Cta for <unk> <unk> 31 in the first quarter of this year in fact, the submission is eminent.
The planned clinical trial will be open label and the roll up to 15 patients with DMD amenable to exon 53 skipping.
Patients will receive a bi weekly dose of <unk>, three one and dosing will be driven based upon PK data and safety observations.
The trial will be powered to detect the change in dystrophin production.
We will assess intracellular drug distribution of muscle as well as initial patient safety.
If successful there is the.
Potential to apply PM chemistry to other exon targeting compounds and discovery work is ongoing.
I will now turn the call over to Carl Doran, Our Chief Financial Officer per serve to report our financial results.
Thanks, Mike.
Wave reported a net loss of $28 8 million for the fourth quarter of 2020 compared to $56 $8 million of the same period in 2019.
For the full year ended December 31, 2020 of the company reported a net loss of $149 9 million.
As compared to $193 $6 million for the year ended December 31 2019.
Research and development expenses were $30 million in the fourth quarter of 2020 as compared to $49 $1 million from the same period in 2019.
Research and development expenses were $139 million for the full year of 2020 as compared to $175 $4 million in 2019 the.
The decrease in research and development expenses of the fourth quarter and full year was primarily due to decreases in external expenses related to ways decision to discontinue dosing program in December 2019, as well as decreases in compensation related expenses and the other external expenses driven by ways of February two.
2020 cost reduction plan.
The offset by increases in the external expenses related to clinical and preclinical activities related to its HD programs in the <unk> 972 program per Alice and STD.
General and administrative expenses were $9 7 million in the fourth quarter of 2020.
As compared to $13 8 million from the same period in 2019.
General and administrative expenses were $42 5 million for the.
The full year of 2020 as compared to $48 9 million in 2019.
The decrease in general and administrative expenses in the fourth quarter and full year was primarily driven by the cost reduction plan announced last February.
Wave ended the fourth quarter of 2020 with approximately $184 $5 million of cash cash equivalents at.
Compared to approximately $147 million.
As of the end of December 2019.
The increase in cash and cash equivalents year over year, primarily reflects the $93 $7 million of net proceeds from our September 2020, public offering and $59 9 million in net proceeds from its aftermarket equity program.
We continue to expect that existing cash and cash equivalents together with the committee cash from our existing collaboration will enable wave to fund its operating and capital expenditure requirements into the second quarter of 2023.
As a reminder, we do not include potential milestone payments 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, Kyle wave is entering 2021 with depth and diversity throughout our pipeline and platform and we look forward to several upcoming milestones.
At the end of the quarter, we anticipate sharing data from our precision HD study and as Mike mentioned, our Cta submission for our exon 53 candidates is imminent.
Including this exon 53 program, we are on track to initiate dosing in three new clinical trials. This year and importantly, we are well capitalized to advance all of these programs through clinical data.
Lastly, we continue to generate exciting data for our ADR editing modality and anticipate sharing preclinical data for our in vivo model and Alpha one Antitrypsin program.
With that we'll open up the call to questions.
At this time I would like to remind everyone in order to ask the question. Please press star one on the telephone keypad.
Again, the star one on your telephone keypad.
Your first question comes from the line of some of them.
The team from Mizuho Your line is open.
Great. Good morning, Thanks, so much for the questions guys.
And the color sort.
Paul obviously important datasets coming up at the end of the month I was just wondering if you can just articulate for us how you're thinking about this is the very wall Street of your question I apologize the <unk>.
<unk> here, what's the win scenario, especially on the 32 milligram data how.
How are you thinking about the various scenarios that we can get.
And then too.
More of a higher level question here.
Maybe I'll just.
The answer to the first question first of all I'll follow up with the second one thank you.
Thank you and I wouldn't kind of Wall Street question. I think this is the question that's on the line of our patients and clinicians as well so.
It is an important question for us of the company as we think about the possibility to progressive phase III.
And then I'll hand, the question over to Mike, but I think what we've continued to look at is a profile of that does two things and I think as Mike alluded to in his section the wild type of assay being an important one I think one we wanted to see if we see a reduction of 20% to 30%, which is in line with where our peers arent at the <unk> pilot.
The <unk> approach.
They are able to see an addition of wild type sparing, we do believe that that the successful profile to advance not just from the phase III studies, but also to think about the free manifest population more broadly so as we think about our profile of that could be superior to existing.
The program, we think that the profile that supports moving forward might be of anything you would add to that.
I'm, the only that I mean, I think that as <unk>.
You said it is a question that is something we've been considering with our partners and clinicians and other people in the field.
And I think the allele selectivity aspect of it we hear time and time again that even thresholds lower then that could be meaningful.
We're showing the visa allele selectivity, but as Paul said, that's why we're that's where we believe we need to be and it would be EBIT the success.
Any comment on the NFL.
Expectations.
Or how we should be thinking of NFL I.
I think what we'd like to see I mean, I think like everything else, we need to generate the data and analyze it but I think if we can analyze the data in the flat to decreasing the NFL that would be different than other profiles that have been seen but I think we have to generate the data and analyze it on two fronts and I think that the same on the knockdown I think we're going to look at and that's why the dataset is robust in the sense that will.
Looking at not just the potency as you pointed out of the 32 milligrams, but we're also going to be able to look at an open label extension data across two studies at the 60 milligram and see what happens over time. So I think we'll get a good assessment of both of those studies at the NFL levels.
At the time, we have data to share.
Got it and then just a quick follow up if I can.
The strategy wise.
Are you more excited about the HD data coming up at the end of March or the Pn chemistry pipeline follows subsequent to that.
I think we're excited about both right I mean, I think it's an opportunity we had an interim look at of partial data set in December 19, which was the snapshot at and all patients had received all doses. So I think Brian and we and that was just the two we hadn't looked at as an important so I think like.
This has been the study that we're we're anticipating of looking forward to reviewing the full data from these studies and excited about progressing the SNP three and what that brings with the Pn chemistry, not just in the <unk>, but also with the nine and then the splicing with DMD.
I do think it's important to note that we could of applied RP and chemistry to accounts silencing approach and said, let's just move forward in a way based on the following where others have been and I think our data as Mike alluded to in great detail.
I think it's important.
Around wild type of sparing led us to apply the pn chemistry to an additional specific compound into the <unk>. So I think we're.
Going forward to this data I think we're looking forward to the upcoming data around the three new programs and I think the key for US is our commitment to Huntington's disease.
Okay. Thanks, Paul Thanks, Mike I appreciate the color. Thanks, Paul.
Your next question comes from the line of Joon Lee from <unk> Securities. Your line is open.
Hi, Thanks for taking my question.
It's the result of the upcoming because of <unk>.
<unk> are below your threshold of 20%, but there is some signal that you still want to proceed with the spin one of two programs would you go up in the dose or switch to <unk> backbone altogether and related to that what proportion of I'll just slip one in two patients also have Smith III that could be treated with tirasemtiv.
QE program and.
Up to what dose are you planning to test for the ads.
III program. Thank you.
I'll take part of the question in terms of Mike and I think the question I'll take it. The reason we chose the nib III at the beginning was because of itself given the overlaps where theres SNP one two in other states. The three covers 40% of the Huntington's disease population it gives us an incremental.
The 10% on about one and above the one or two.
But it is a substantial portion of Huntington disease by itself, Mike do you want to take the other question as it relates to do dose escalation.
Yes.
So I mean, I think that if we saw some very promising.
Target engagement in a in the yeah, that's in the safety profile.
And the Lille specificity that all lines up.
It would consider going up higher.
And.
Starting that planning for phase III.
Yeah.
At the same time, because you know if we have some robust engagement in a good profile in a real specificity and we know we can go higher based on our existing.
Preclinical data in terms of the range. We can do there is no reason, we wouldnt do that but we would do that as we were beginning the planning for that next.
Phase of development and.
And then I think you asked the one last question about in terms of the dosing.
We were going to base, that's when the base that starting dose on a preclinical data and as we said that will be then be from their guided and a very day.
Data driven way by our independent data safety monitoring board.
So just.
But your preclinical data implies that the.
You used a lot higher dose worsening three then you did make one.
Is that correct.
And if so does that mean that you're also going to test a lot higher dose than <unk>.
Interest and I just wanted to.
I think the can beyond this year.
Yes, so what's interesting of remember about the one and two is we didn't have a preclinical model that kind of dosing. So a lot of the dose exposure work was done right Paul.
The in vitro and then exposure in vivo the data that's going to guide the starting dose which is why we believe we could start of the data at relevant doses of three and as Mike said to be able to accelerate that study in terms of exploring doses beyond that.
Because we have in vivo PK PD modeling on target engagement with the free so that we have to look at those programs differently around where we can guide are starting and.
And ultimately where we get to the different drugs and I think the three leveraging our <unk> chemistry, we have a lot more data in vivo data as we alluded to earlier the guide guys of the dosing decisions. Mike is there anything you want to add to that not only the one thing that you alluded to is that the.
And the beauty and the power of this platform of each one of these compounds are different from one another.
And that they had their profiles and their rationally.
Designed individually so the.
There is by definition, just like with any compounds youre going to have different numeric doses to achieve what you are looking for so that would be the only thing I'd say is that.
The beauty is having a single compound that we can then optimize from preclinical each individual preclinical study.
And I think first of all wanted to I mean, and I think the previous question addressed it I think thats why we are excited about this data set and the absence of preclinical PK PD modeling will have answers around human data at various dose higher doses of long doses in terms of the accumulation and so I think again as being the robust data set it's really going to tell us where we are.
Alright, thank you.
Your next question comes from the line of the.
The money for O'hara from the Leerink. Your line is open and the answer your question.
Hey, Thanks for taking the question.
I guess the first question is around the upcoming one hundreds of these readout.
Should we expect of the assays being used in the.
This readout should be moderate modestly different any subtle ways from what would you.
And the last time, we saw data from the study in late 2019.
You mentioned something about the <unk>.
Pull down assets.
With magnetic beads.
It's all changed the assay.
About those changes as we interpret these data sets.
And secondarily when you think alright.
Start with that and perhaps the next question just some of it.
Make sure you get that one to complete the I'll start and Mike will pick up but I think the most important pieces of music Huntington assay in the neuro filament assay are the same assay we used in the previous rehab. Those are those are assets that have been used by others and so the.
No change in the interpretation of all of those in place of run with New is really the work. The team has done an amazing job. This year of really working through how to develop an assay to assess wild type as the Mike do you want to take the second piece because that is a different assay and the total assay.
I mean, I think the the work Thats been done has to take these assets and the available reagents that have already been used in the field and already what we used in the initial assessment and modify them in a way that allows us to directly measure wild type protein. So the antibody is being used in this pull down approach of the <unk>.
Same antibodies that would be used in that of measurement in the mutant Huntington asset except that they are now applied to beads and we use that approach to pull out the mutant. So we can directly measure of wild type of on a total assay that is also all of the already been developed so and in terms of interpret ability I mean wood mutant it's going to be the same.
And the wildcard now has a new approach that will be presenting in.
In the context of the mute.
So that's but it's using available reagents, it's using.
Techniques that have been.
Deployed before.
Great that's really helpful.
And then considering.
Wales do there of three or three with the Blue I call it up.
And considering.
Two data how.
Should we think about the sites that are in which piece of the being rolled in the rate of it.
The rate of enrollment and the impact of screening all around the three.
And to determine when we might see that.
I'll share with my I think the step one is obviously will set the the framework once we dose and how the thinking about going forward.
I think what we've we've leveraged and we said this a couple of times, which I think is really important as.
As we're able to leverage the infrastructure of the clinical trial infrastructure, the phasing of screening infrastructure of the running of the assays I think theres a lot of.
That we took from it can take from the pointed to in terms of infrastructure architecture, and execution and be able to apply that to rapidly.
Mike I don't know if there's anything additional insights.
No I think that the sites we've been working with for years now non to do this and then it's just a matter of getting those prospective numbers on.
Smith III from patients that they have in their in their practices. So no I think once we.
Get the first patients then we will be able to.
To really see where we are.
The.
You know the echoing add onto that that is the advantage of having run the SNP phasing studies over time as we can identify with the three patients it yet.
To start the clinicians know how to run the studies.
And as we said before around having the models to predict where we can begin. The study. There is a lot of features that we think are in place now for the study to execute a lot more quickly than the first day of where we can start.
All of them.
Great. Thanks, that's really helpful.
Your next question comes from the line of Paul.
Paul Matisse from Stifel. Your line is open.
Hi, Thanks, so much for taking the question the store on for Paul.
I think you mentioned previously that it was the COVID-19 dosing delay.
But can you just give us a little color on.
Why we won't have 32 milligram data and it's the one and then kind of a follow up to that is there any reason that the 32 milligram data in HD, one will be meaningfully different than HD two data at 32 milligrams.
Okay great.
We've said last year on our call, where we provided that update there were two patients that had to be rescheduled for their dosing related related to COVID-19 and.
And because of that they will get their last dose.
The we said end of March the March so given that shift they're there they're scheduled there'll be dosed in that net debt.
That was unfortunate last year, but that's what we are dealing with in terms of the global pandemic.
In addition to your point of where we see differences. That's why we think this is the robust data set and we will be able to make it interpreted the decision by that because we'll have matched cohorts up to 16, where we can compare that pharmacology between SNP wanted to knowing that the snip.
Sorry, the sniff of 132 milligram data, we will be following on that so.
It is.
As we will always say different molecules.
Could be differences.
But we'll have the data to determine the number where we are and we'll have that data in all of the other side, but given past experience and understanding what we don't want to do is kind of a partial dataset, we'd rather because of the data set the intact and evaluated and based on the other data will have including the open label extension of datasets through 16 across the step one and two we believe we will.
Of the data that is necessary to relates to the one and two pharmacology.
Great Super helpful. Thank you.
The next question comes from the line of Luca from RBC. Your line is open.
Oh, great. Thanks for taking the question. This is Lisa Paul Chung for Lasalle.
And just again.
HD program.
We recently saw from data from the open label extension trial per Se on this from Russia, and Anderson of the European clinical trials I, just turn the data here with early buy it suggested no cognitive benefit I, it's the cab.
Sure.
In particular volume.
Just wondering what was your reaction to that data.
How should we think about implications for your program.
No. Thank you and this is the question that we focused on actually years ago. When we began our program I mean, if we think about the early days of when we decided to go into the Huntington's disease with our <unk> approach our view what the taken allele selective approach because we believe the biology supported that.
We always said is at both studies were kind of moving forward that the reason we were taking the allele selective approach and sparing wild type of the Huntington's as both of the toxic gain of function and a tactic loss of function of disease. Both are important I think Mike eloquently shared.
This tug of war concept that I think it is just so critical at least take title of imagine this really the two pronged disease.
Our view was debt sparing wild type and wild type of wild type of reduction wasn't going to be a quota.
Safety signals, but what would probably be the manifestation of treating the tactic of loss of function would be that it will become harder to see of clinical benefit with a requisite amount of of knockdown and so therefore, our approach was removed from the mutant toxic gain of function protein, but the reserve the toxic lots of function. So that you have the protein there to help.
We have to see the steady go out I mean the.
We're running.
Real specific financing clinical studies, it's interesting to watch what Pam financing does but there are two different biologic approaches that we're taking in the treatment of Huntington's disease. So we have to watch the data emerge.
And be prepared but I think this is aligned with some of our thinking around what happens with wildfire.
Mike I don't know if Theres. Any addition of anything you want of pattern no nothing to add Paul that captures it nicely.
Your next question comes from the line of Union from Jefferies. Your line is open.
Good morning, Thanks for taking all of your question does the sushi dialing per year.
Yes.
A few questions about the HD program. The first line is about.
About the wild type Huntington.
Just wondering if that etsy has been validated with external party.
Also for the all the data that Youre expecting to report.
Do you expect to utilize the data to guide the next day.
Have a following question on behalf of attrition.
Thank you.
Mike would you like to take the first two huntington's questions.
Sure Yeah. So.
Regarding the the assay we have been working with the developers of the original assays that we employed two.
To develop this particular assay, we have been working with to get patient samples that have allowed us to flow.
Flow through the validation process for the assay and our intention is to work with those external parties to publish the assay and share the results and share it with the community.
At large so that it can be used so this has been an.
We couldn't have done what we've done with this assay without the collaboration of external parties and we're really pleased where we are in and they are really pleased where we are.
In particular our partnership.
CHD, who.
Without their work.
Wouldn't have been able to leverage the.
The and adapt to take this.
Next step.
Regarding the OLED data I mean, that's a really important dataset I mean, when you think about.
The precision HD studies do you think about any proof of concept study.
You want to get that short term exposure to try and get a nice.
Clear short term dose response, the OLED gives you that added Paul even though it's open label and the setting of the biomarker of like we're doing it.
It really allows you to see not just a dose response, but the impact of chronic longer term dosing.
Which gives you a sense of not just an effect, but the depth of the effect with the chronic treatment as well as kind of.
As well as safety of course, but what we've seen from.
The Roche Iona studies is that the degree of mutant.
Knockdown of the degree of of.
Of the Huntington knockdown I should say in the planned selective way.
Increased with the extended duration. So it's a really important dataset that is going to help us in our decision, making as we look at dose selection and for future studies. So it's very valuable to be able to have this and we're grateful that.
The patients have.
Have opted to continue.
The studies.
Thank you.
All of the question is great.
Yeah.
Okay.
Good day.
Yes.
Yes, I think Theres two things and this is why we actually want to run the mouse model data and the work to photo of the mouse model of wanted to make sure that not only we're looking at the surf any one animal model, but we're doing it in the crops with the human eight of our MAU is that we can expedite the work that we do on.
<unk>, so that we're not optimizing sequence the edit mice, but we're optimizing a sequence of that can be clinically translated the patients because it expresses human ADR at the appropriate levels.
What's interesting and exciting about using the mouse work it while we see substantial editing efficiency in <unk>.
And we can edit Mike we can move from just looking at the percent editing of the number we know that just like a number of oligonucleotide its out of <unk>.
One for one ratio of an editing to generating protein one of the animal model really be able to start measuring the protein level. So this correlation looking at editing percentage, but really starting to establish biomarker threshold in terms of how much protein DG.
As we think about in the clinic that restoring of levels greater than the 11 micro molar of proteins idea of we know that the protein infusions. There are leaving patients uncovered for a good amount of time and so our belief is by using the model. We can really do of several things. We can continue to characterize the protein production and the fact that it's.
It's functional.
And to be able to start establishing dose responses as we would as we have for a number of our other programs and silencing in spite of things that we can then translate those molecules to the clinic. So I think we've got great data around gallon that conjugation and exposure in Hps, we've got exposure in mice using the.
Now getting the human ADR, coupled with the with the target. So I think if we can see durability and duration, we can see PK PD and generation of protein those will be the features that we'll be looking for as we set up of transition to the potential how the clinical program here, but we're very excited about ADR at the space and how we can apply broadly.
And we're excited about the <unk> program specifically.
Okay.
Thank you.
Correct.
I apologize you broke up a little bit on.
Sorry.
I expect the dosing frequency.
Yes, that's what we're going to establish as we that is the Prime example, when we look at duration two so when we think about the dosing frequency that is going to be driven based on our preclinical models.
Now with <unk>, we have of subcutaneous administration that we've looked in both large animals and the small so we know that the subcutaneous administration with GAAP inefficient, but we need to do that work in the in vivo models to explore that PK PD relationship to be able to move forward.
Okay, great. Thank you so much thank you.
And per center there are no more phone questions I will now turn the call back over to Dr.
Paul Molnar.
Thanks, everyone for joining the call. This morning to review, our fourth quarter and full year 2020, corporate update and thank you to our way of employees for their hard work and commitment to patients, especially the the global pandemic. We look forward to speaking to you again soon have a great day.
This concludes today's conference call you may now disconnect.
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Paul.
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