Q3 2021 WAVE Life Sciences Ltd Earnings Call
Yes.
Good morning, and welcome to the wave Life Sciences third quarter 2021 financial results Conference call.
At this time all participants are in a listen only mode.
After the speaker's presentation, there will be a question and answer session to ask a question. During this session you will need to press star one on your telephone.
As a reminder, this call is being recorded and webcast I will now turn the call over to Kate Rausch head of Investor Relations at Wave Life Sciences. Please go ahead.
Thank you Matthew good morning, and thank you for joining us today to discuss our recent business progress review with third quarter of 2021 operating results joining.
Joining me in the room today with prepared remarks are Dr. Pablo is president and Chief Executive Officer, Dr. Sean Mccarthy, <unk>, Chief Technology Officer, Mark and Mike <unk>, Our Chief Medical Officer head of therapeutic discovery and development and Colin Moran Chief Financial Officer.
This morning, we issued a news release detailing our third quarter financial results and provided a business update.
News release, and a slide presentation to accompany this webcast will be available in the investors section of our website.
UW W. Dot wave life Sciences Dot com following the 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.
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-K for the year ended December 31, 2020, and our quarterly report on Form 10-Q for the quarter ended September 32021, we undertake no obligation to update or revise any forward looking statement for any reason.
I'd now like to turn the call over to Paul Paul.
Thanks, Kate good morning, and thank you for joining us.
Today, I will start with opening remarks, after which Andrew will walk through how we are building a pipeline of RNA editing therapeutics with neighbors. Mike will then provide an update on our therapeutic programs and started to Kyle to discuss our financials.
During the third quarter, we achieved several important milestones and made progress advancing our therapeutic pipeline, bringing us closer to our goal of delivering life changing treatments for people battling devastating diseases.
Most recently we.
Held our annual analyst and Investor Research webcast.
Remember 2008 during which we formally introduced our <unk> for RNA editing oligonucleotides and shares in both mature in vivo RNA editing data set generated to date.
This includes an update on our alpha one antitrypsin deficiency or <unk> program and use of <unk> to restore functional <unk> protein well above the therapeutic threshold.
In parallel we shared these data and multiple posters and presentation at the 2021, Ots and <unk> annual meetings.
Following these exciting and promising update we've raised approximately $30 million in proceeds from an aggregate block sale of ordinary shares through our ATM equity program with participation based on interest received from both new and existing investors.
Coupled with the cash received from Takeda under the terms of our CNS collaboration Amendment announced last month, we strengthened our balance sheet with approximately $52 million in October putting us in a position to accelerate the momentum of our emerging hamer pipeline, leading with hepatic indication.
We continue to execute on advancing our clinical therapeutic pipeline and initiated dosing in three clinical trials in the third quarter, focusing nine evaluating <unk> in ALS and SPD select HD evaluating WV zero free in HD and a clinical trial evaluating <unk>.
Good bye, everyone and exon 53 amenable BMD.
Each of these innovative adaptive clinical trials.
Designed to accelerate time to proof of concept.
We expect clinical data being generated through 2022, and these trials to enable decision making on next steps for each of these programs as well as to help define our future portfolio and platform investments.
Our ongoing clinical and emerging clinical programs include silencing modality theater splicing in muscle and RNA editing and liver as we continued to advance. These programs clinical data will enable us to further unlock value through additional targets within these tissue types using these three modalities.
As you can see on the right hand side of the slide we believe meet our editing has the potential to represent a substantial portion of our portfolio over time.
RNA editing is a novel therapeutic modality setting up an opportunity to deliver first in class innovative <unk> therapeutics.
Our initial focus is on using <unk> to correct driver mutations and restore protein expression or correct protein function.
As with ATV for Ret syndrome.
Yes.
<unk> can also be used to modulate protein function, including disrupting protein protein interaction and modifying post translational modifications for treatment of <unk> disease.
Loss of function disorders to name some examples.
During our research webcast, we shared in vitro data exemplifying, how a mers can modulate protein protein interactions using the keep one and our <unk> system.
We believe clinical proof of principle with our <unk> program also serves to de risk these applications, which represent large patient populations.
Yeah.
We've deliberately designed our portfolio and has diversified through reflects the breadth of our platform with differentiated candidates that address diseases of high unmet need.
This robust portfolio is led by our clinical programs <unk> and <unk>.
Three in HD, and $5 31, and DMT <unk>.
Ongoing trials all include biomarker assessments, and clinical data, which will enable potential path to registration and unlock value for additional wholly owned pipeline programs.
As a reminder, Takeda has a 50 50 option to WV, they're zero bore WV easier zero, three and a tax rate.
I'd now like to turn the call over to <unk> to discuss our neighbors Chandra.
Thanks, Paul Today I'll review some of the exciting data we shared in the third quarter with our English and describe how we are best positioned to transform RNA editing into meaningful and life changing medicines.
Our prism platform is built on the reality that there exist an enormous opportunity to tune the pharmacological properties of all of the nucleotide therapeutics.
The right combination of sequence chemistry and stereochemistry.
And is that each candidate we have a unique and proprietary chemistry toolkit the Tucson.
And we have the know how to combine and apply these modifications based on the use of the platform learning and a deep understanding of the interplay between these features.
With the chemistry, and the use of more gaining insight into aimless structures, we have overcome challenges to therapeutic RNA editing.
And make it as a reality.
This is largely because we have systematize our aim of design principles to achieve key attributes effective therapeutics.
Amos efficiently.
And events.
And we have demonstrated potent and specific editing in multiple preclinical models.
So do you have any of these everything is robust.
I'm going to ask a bloody awful EMR, which reflects many years of investment in our platform to improve the stability of single stranded Rnas.
We know the initial English yeah.
Leveraging the benefits of Gaelic conjugates T.
Cheap efficient delivery to liver.
We have also found that our aim is a loan are sufficient to drive into cellular uptake and distribution in many tissues.
Our aim must work, maybe little galvanized and deliver the CNS and beyond.
Again these achievements reflect long term investment in our prism platform and are supported by the strong and broad IP covering these design features.
Prism chemistry, including studio peer Pn backbone modification.
Have reached upwards of 90% maximum editing, it's down like eight months.
This corresponds then easy 50 single animal a range.
By comparison, our math.
CDO random control, that's not reach 50% editing even at approximately 1000 fold higher concentrations.
That's part of our eight hour editing work we have.
Optimize every dimension to engineered more ask of English.
For example, our unique consideration for English as opposed to other modalities is a defined sequence space of the target.
To navigate this need generated a heat map to show the relationship between sequence and activity.
As shown on the right of the slide 13.
These data lithium the clear pattern in the sequence that helps us achieve the most robust editing with our English.
Our in vivo studies demonstrate efficient engagement of Ada enzyme as well as the stability of our English.
As we have previously described.
Non human Primate subcutaneously mid initial doses feed chemically distinct young like beta actin English.
The famous push system delivered tissue out of 45 days post last dose.
As shown on the left.
It didn't levels of up to 50%, but durable out to this same time point as shown in the middle.
To achieve this.
Fishing editing.
English.
I think Amy.
He must need to reach the liver, but and to the south and tablet traffic.
Appropriate sub cellular compartments.
Engage the target RNA and mediated activity.
We also demonstrated these English direct.
Highly specific editing the full transcriptome RNA seek in primary human hepatocytes as shown on the right.
This was all the our decision to initiate our first therapeutic program download conjugated a much fairer ATB.
Do you have any images from liver biopsies with NH be treated the bemis for confirmed that they are successful delivery and broad distribution in hepatocytes.
We have systemic guy so EDAM design principles and can generate English efficiently created different targets as shown here for beta actin E. F Y E one and E <unk>.
When we launched our eight hour editing program me ask the question is that enough.
<unk> sells to substantially added novel targets.
Based on preclinical results such as the ones shown here on slide 16.
We are confident that the endogenous Theodore editing capacity up itself is sufficient to support therapeutic genome editing.
In the graph the highlight and he didn't levels observed in three transcripts then be evaluated editing for each concept in isolation are then three transcript we had targeted in the same experiment the same cells at the same time.
Under both conditions it didnt levels for each transcript comparable suggesting that there is an acquisition of wire off eight or editing capacity for us to tap into.
We have absorbed some of the results the young gamers in the same cell culture system.
But don't gillnet conjugate.
We tend to the ability to edit in tissues, such as the CNS.
We shared exciting data getting out associated webcast.
Mike's received a single hundred micrograms dose of AGP two amer.
The RNA editing was observed throughout the brain.
Buster editing persisting for at least four months post dose.
These results underscore the broad tissue distribution and the durability of English driven by advances in our prism platform.
Can provide an example of how we are using a much in our neurology portfolio. The top two mutations in MCP to.
Which are the cost of ret syndrome.
But this target.
Correct, a specific nonsense mutation that leads to reduced the expression of <unk> a protein found in the nucleus of neurons and glial cells that.
That is required for normal brain development.
Using Ava contracts.
Obtain concentration dependent editing opened M. ECP, two transcripts containing a premature stop codon.
He observed editing up to about 70% of the transcript.
Mitch Lewis stores full length, we'd end up M ECP to protein in the in vitro system shown on slide 18.
With our current eight our capabilities. We believe we can correct other disease, causing <unk> two mutations are occurring at different locations on RNA transcript.
Our preclinical data supports the potential expansion of our therapeutic pipeline to indications affecting tissues accessible via into retail or systemic dosing such as those impacting the eye kidney lung or heart.
We have previously shared data.
English, they're acting up to 50% editing in vivo in mouse one months post single dose.
Editing in non human primates have old tissues of interest, including kidney liver lung and heart after a single subcutaneous dose.
Even the editing of a variety of immune cell types found in Pbms fish.
For 2021, you have gained momentum.
In capabilities and now we are poised to build on this as we work towards our first therapeutic candidate using our <unk> therapeutic program, which Mike will discuss in a moment.
We continue to generate exciting data to fuel our eight O pipeline and we expect these data to be shared in several scientific presentations and publications throughout 2022.
I will now turn the call over to Mike <unk> to provide the updates on our therapeutic programs Mike.
Thanks Chandra.
The third quarter was very productive FERC therapeutics discovery and development organizations.
Following on to charter as introduction about progress, where they don't editing I will start by describing our first therapeutic program evaluating <unk> as a potential treatment for HCV.
I will then provide an update update on where we are where there are three programs currently dosing in clinic and share why we believe our approach has positioned us well for success in the coming year.
<unk> is an inherited genetic disorder that is most commonly caused by a point mutation in the <unk>, a one gene commonly known as <unk>.
Yeah.
This mutation leads to Ms folding in aggregation of Alpha one antitrypsin protein or <unk>.
In hepatocytes, and a lot of functional AIG and circulation, which results in progressive lung injury liver injury or both eventually leading to end stage pulmonary and liver disease.
As there are both loss of function in data function aspects. This disease RNA editing is uniquely suited to address all therapeutic both of treatments.
There are multiple alternative approaches in development each of these only address a subset of the disease.
With <unk>, we aim to correct the serpent <unk> mrna to restore circulating functional wild type Alpha one antitrypsin protein or <unk>.
To protect the lungs.
And reduced Z <unk> protein aggregation.
<unk> in liver.
All while retaining the unique physiological regulation of M T.
With our <unk> conjugate as Jerry appeared gamers, we anticipate replacing chronic weekly IV <unk> protein augmentation therapy with a subcutaneously administered treatment.
The number of patients that could benefit from such a therapy sizable with approximately 200000 people in the U S and EU that are homozygous for the <unk> mutation, a genotype of the highest risk of lung and liver disease.
And initial experiments prior to optimization, we evaluated our neighbor labeled S. A one thus for in vivo to assess editing and protein restoration over the course of 35 days.
Following <unk> subcutaneous doses, we were encouraged by these initial results as they approached therapeutic threshold targeted by augmentation therapy in levels in patients carrying the PDI MD genotype subtype known for having a lower risk of symptomatic disease.
The RNA editing achieved resulted in a threefold increase in circulating AACE as compared to PBS controller therapeutically meaningful increase.
Further the increases in <unk> protein, where greater than or equal to three fold over PBS control lasting out to $2 35 days.
To evaluate the specificity of the SA one desk for Delek Amer.
Formed our NAC.
On the left you can see total sequencing coverage across the entire stripping a one transcript for the amer treated samples.
As a percentage of unedited T and C reads are indicated for each group.
Everything is only detected at the intended on circuits on target sequence and the serpent <unk> transfer.
Thus the protein being produced using this approach is truly wild type.
<unk> protein.
This also confirms that there is no editing a bystander residues.
Been seen with DNA targeting approaches.
Furthermore to assess off target editing for the whole transcriptome, we apply the mutation calling software to search site.
From this analysis, we observed nominal off target editing across the transcriptome.
Where potential off target editing occurred had either lower REIT coverage in the analysis or accrued at low percentage of less than 10%, indicating that these are rare events.
Thus in both analyses, we find a high percentage of editing that is specific for the target site and the serpent <unk> transfer.
Recently, we shared our ability to use prism chemistry to optimize <unk> to drive editing efficiencies of approximately 50% along with proteins restoration well above the therapeutic threshold for a fourfold increase in total <unk> as shown here with Amer SA one dashboard.
We continue to evaluate tolerability as potential candidates as well as PK PD profile durability, and the ability to reduce the AAP protein aggregates and pathology and deliver as we move towards identifying a development candidate which is inspected in 2022.
Turning to our ongoing clinical programs in the third quarter, we dosed. The initial patients in three clinical trials. These include our focus to nine clinical trial evaluating <unk> for patients with <unk> 972 associated <unk> and FCB.
Our select HD clinical trial evaluating <unk> for patients with HD with the with the SNP III genotype in association with their expansion.
And an open label clinical trial evaluating <unk> three one for patients with DMD mutations amenable to exon 53 skipping.
All three of these candidates contained PM backbone modification.
The approach taken with our clinical and preclinical candidates builds upon our own experiences along with innovations from the prism platform to design CNS candidate has the promise to be distinct from others in the field.
Our approach is illustrated in the three columns showing the elements that we believe are key to the success of our emerging CNS portfolio.
This begins with capabilities of prison prisoner at its core and an increased understanding of the factors influencing the pharmacology of our molecules along with the availability of in vivo systems to better understand PK PD relationships to predict human dosing.
Then by leveraging proprietary chemistry modifications in the context of the ability to control stereochemistry. We can now rationally designed candidates optimizing for widespread tissue distribution and target engagement with the potential for a favorable tolerability profile.
Finally careful selection of relevant biomarkers other endpoints in patient population in the context of adaptive study designs that allow for real time adjustment of dose level and frequency position us well to reduce risk and drive rapid decision making.
Here I would like to walk through an example of these principles and practice highlighting the ongoing preclinical work with a stereo pure ASO designed with Pn backbone chemistry modifications targeting an undisclosed CNS target.
As part of the optimization process, we developed several stereopair isomers with identical sequences, but deferring stereochemistry with and without DM modifications.
What this illustrates is the clear advantage of the isomer with the PM versus one without in terms of distribution of the ASO throughout the CNS tissues, one month after a single interest equal dose.
Slide 30 shows the impact in terms of target engagement and Tolerability of these different designs.
<unk> three is the compound has shown on the previous slide.
In these experiments, we assess target engagement in mice during the screening process as compared with two other isomers all containing pn backbone modification.
On the left hand side of the slide you can easily see that robust target engagement was demonstrated with all three isomers, including ice number three.
However, as you can see on the right hand side of the slide one of the three compounds ICM or too heavy dramatic lead different tolerability profile with significant body weight loss over the observation period, despite being the same sequence as the other two.
These data clearly demonstrate the optimization of sequence backbone modifications chemistry, and stereochemistry must be in a central component of any drug discovery and development effort. If the promise of these important genetic medicine is to be fully realized.
As we think about the path of our current programs to clinic demonstrated target engagement in relevant preclinical models is core to understanding our core to our development costs.
These data allow us to model the likely pharmacologically active dose in humans.
<unk> dose selection in our initial clinical trials.
<unk> 00003 have robust effects in relevant models, allowing us to start studies at dose levels predicted to engage target and proceed through the dose selection process, considering these data and the human data collected along the way.
First with 004 as shown on the top of slide 31 to ICD doses administered <unk> seven days apart resulted in a profound reduction in poly GP in the spinal cord and cortex.
This reduction persisted for at least six months corresponding to sustain tissue concentrations zero-zero for over this time period, highlighting the PK and PD effects of the stereo pure paean containing compound.
Further the effects were highly specific leaving Q 972 protein unaffected, which is important for normal regulation neurons function in the immune system.
To our knowledge. This promising profile is unique amongst other C&I and targeting compounds under development, including those in clinic.
With 003 designed to selectively target mutant Huntington and preserve the healthy or wild type HGT protein, we have shown the ability to lower mutant HGT, both in vitro and in vivo with a clear dose effect. These data are shown at the bottom of slide 31, including in vitro data and ICSC neuron.
<unk>, demonstrating specificity for mutant HGT and preservation of wildfire.
The back HD mouse model used to demonstrate on target activity of 003 is somewhat limited in that it contains multiple copies of the mutant HG two gene some of which do not have the SNP three variance. Nonetheless, we observed potent and durable knockdown in mutant Huntington in the striatum out to 12 weeks with a similar effect in the court.
Yeah.
These data makes us excited about the potential for <unk> three in HD, where there remains a high unmet need for effective treatments.
Moving on to WD <unk> and 503 won our first pn modified clinical candidates to be administered systematic systemically.
As also our <unk>. It's also the first flights and candidates and it will provide insight into the ability of pn modifications to enhance access to destroy pick muscle and restore functional dystrophin expression.
We are optimistic about this program given the compelling preclinical data comparing systemically administered <unk> monetize exon skipping oligonucleotides without them is typically tied to only containing PFS and P O modifications.
<unk> modified the oligonucleotide led to rescue of this rapidly progressive phenotype with an increase in dystrophin production and key tissues, including skeletal muscle heart and diaphragm.
In closing our current focus on advancing is on advancing our ongoing clinical trials to evaluate translation of these promising preclinical data sets.
To do this we are using innovative trial designs that include multiple biomarkers and indicate independent committee reviews to potentially accelerate time to proof of concepts, we expect to generate data through 2022 across all three of these trials to enable decision, making next year I.
I will now turn the call over to Colin Moran, our CFO Kyle.
Thanks Blake.
We recognized $36 $4 million in revenue for the third quarter of 2021 as compared to $3 $4 million in the third quarter 2020.
This increase was primarily driven by the $22 $5 million received from Takeda in October 2021, as part of the amendment to our collaboration agreement, which we recognized as revenue in the third quarter.
As well as the recognition of remaining revenue related to research support payments previously paid from Takeda.
Our total operating expenses for the third quarter 2021 were $44 million as compared to $37 $9 million last year.
R&D expenses were $31 1 million as compared to approximately $28 $3 million in the same period in 2020.
This increase was primarily primarily driven by increased expenses related to preclinical program and compensation related expenses, partially offset by decreased expenses related to our discontinued programs.
G&A expenses were $12 $9 million for the third quarter of 2021 as compared to $9 $6 million last year.
With the increase driven by compensation related and other external G&A expenses.
We ended the third quarter with $123 9 million in cash cash equivalents and marketable securities.
Balance does not include an additional $52 1 million received in October subsequent to the third quarter close, including the $22 $5 million from Takeda and the $29 6 million.
Proceeds for an aggregate back off our ATM. These.
These incremental funds will enable expanded investment on our EMR programs and aid our editing platform as we continue to advance our current urology program at the same time.
We continue to expect that our existing cash and cash equivalents will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include any potential milestone or opt in payments under our Takeda collaboration.
I'll now turn the call back over to Paul Paul.
Thanks, Kyle this quarter I am proud of the progress our team has made in advancing our diverse pipeline of genetic medicine.
We are well positioned across a host of modalities and indications and are working with a resolute sense of urgency to deliver value for patients and shareholders. We are deliberately designed a portfolio that is diversified and differentiated with candidates that address diseases of high unmet need.
Looking ahead, we are entering a period of data generation and decision, making in 2022 that will enable tremendous insights into our platforms ability to harness different endogenous cellular machinery to silence spikes, where edit a multitude of genetic targets as well as offer hope to patients and their families who have limited if any treatment options.
We expect to make decision on three clinical studies as well as announced our first HED Merck development candidate next year, and we are well capitalized to execute through these critical milestones.
We look forward to providing additional updates as we continue to drive our therapeutic programs forward and with that we'll open up the call for questions operator.
At this time, if you would like to ask a question press star one on your telephone keypad again that is still the number one.
First question is from the line of Salim Syed with Mizuho.
Great good.
Morning, guys. Thanks for the questions.
Questions. So just a couple from me if I can.
So.
Paul I appreciate the language.
I ran through 2022, obviously, we're sitting here.
November or so.
I'm, hoping you could maybe clarify for us just a little bit more here the cadence of the data that you plan to generate.
In 2022, I guess or even potentially the end of 'twenty. One what is the unwinding process for the C&I on trial and the <unk>.
Huntington's trial, how are you planning to disclose the data to the street is it youre going to take cohorts, one and two and then three and four.
Later, how are you thinking about that same question for I guess 531, given it's open label and you can see data whenever you like I presume.
And then the second question around.
<unk> added in business development now with the.
Amendment at the Takeda collaboration.
How are you thinking about therapeutic areas that youre looking to keep in house for ADR editing and those do you plan to partner out and the timing of potential collaborations.
Collaborations there thank you.
Thank you and I'll start with the first question and hand, it over to Mike can share, but I think to the comment of cadence as we said in the last quarter, we've got dosing underway across three clinical studies.
<unk> began dosing first but given the adaptive nature of the trial design.
We can't yet predict as we get into next year, where the different data Readouts will occur I think what we've also been clear about is while the independent safety monitoring committee being able to review those unblinded data, we ourselves Dave blinded to those data and so we're open for as we've said publicly in material changes to the study designs will impact.
Various disclosure updates as we move into 2022, I'll, let Mike get into any additional detail you want to share it but I think no I mean, I would say I mean that basically captures that indicate that there is a process of sharing data, including biomarker data in Pharmacopeia pharmacology data with with this committee, who then comes back.
With recommendations about what to do next and if there are material changes to the study design.
That would.
Walter what we've already disclosed.
<unk>.
That would be material to the program fees would be we would have to show that I think what's important in different about thinking about these studies and the development team has done an amazing job of really thinking about how to be innovative in the application of trial design and switches with a combination of both starting at a dose that we expect to engage target and the flexibility that comes in with adapt.
The designs, where we can spend resources. The committee has the ability to expand cohorts and move into other cohort. So that unlike a historical study, particularly in CNS, where you have to enroll blocks of patients in each cohort in order to get higher that enables us to get there more quickly and so we anticipate based on our projections.
We will have the ability to provide updates next year.
It's the same across all three I mean, you brought up the last piece of <unk> 501.
And while open label our view is to make sure that we run that study in a way that gets us two independent endpoints. So that study has.
Prescriptive ways of running itself, even in an open and in.
By setting our open label setting to.
To be able to get to that appropriate quite a bit of exposure in 2022, So I think the nature of that.
Through means that there are any possibilities once the studies initiate where there can be material update that guidance.
Navigator of the studies.
Any questions on that first part and then I'll move to the <unk> business development discussion, which is equally.
I'll just.
No I think.
Thats helpful. Paul Thanks, Thank you.
So I think the second piece is I think youre, absolutely right I mean, I think we think ADR as they can.
Hurling place for business development interest is out of the way of doing things around a new area of biology with case correction.
And I think as we've shared before following the research webcast. We have one of the most robust data set of in vivo data of editing and so it has attracted a lot of business development discussion I'm always inclined to say business development discussions while they're robust it's very hard to guide on when when the deal happened.
And I think we're going to be very deliberate to in doing deals that expand the opportunity for us because it is brought I think we are excited about the application in the starting in this case with a gallon that conjugated ADR Amer Ware.
We know that it is going to deliver there is a well precedented path to bringing subcutaneous administered down that contract gets delivered and we think there's a robust opportunity for us to expand our portfolio in that space I think there's a whole host of other therapeutic indications that we've shared data on as we've shown in human cell kidney.
In the high <unk> in the brain that add to your point that we have flexibility now across the portfolio upbringing business development back into the discussion. So that includes large indications do you think about the CNS and other applications. So I think the business development discussions are broad around genetic medicine.
But definitely highlighted the ADR discussion and will be a part of our future planning. So we are excited about bringing BD back into it.
Got it thanks, so much.
Yes.
The next question is from Joon Lee with <unk> Securities.
Uh huh.
Hi, Good morning. This is maybe could ask you on part two we have a couple of questions.
So first question is that.
Your platform came a long way and they both nicely with great preclinical data could you. Please provide some color on your competitiveness when it comes to scaling production and cost of production compared to <unk>.
Stereo random.
And then I have a great.
Yes.
It's a great question and it's one that we take pride in going back in history, and I think while it's easy to point to where their successes, sometimes those successes were harder to see in some of our programs and I think <unk> and one of the great success diversified China.
We administer apart for a thyroid oligarch.
The way that other phosphorothioate hasn't been able to be systemically systemically administered one or the other.
<unk> applications was scaling systemic production of a fully stereo pure modified oligonucleotide for exon skipping and so we were poised for commercial scalability.
<unk> been at a cost of goods that would be on par with the stereo random molecule and so through that experience don't actually the manufacturing capacity and capability to apply that across our oligonucleotides.
Smaller scale, our interest equal line for silencing ADR and exon skipping is we think again about in fact, we want so I think as we think about the robustness of the GMP manufacturing.
We've experienced several years ago that we built we scale too we have our internal GMP facility and have also been able importantly to show that we can take that process and we can transfer to our larger commercial manufacturer to scale. So we are now comfortable that manufacturing serio pure oligonucleotides is on par with turnarounds.
Awesome.
As <unk>.
My next question would be.
Looking forward.
Your.
I also do not need any vehicle, but if it comes to a full clinical specificity would.
With this new chemistry.
Be compatible with LNP formulation or.
Exosomes formulation as well.
The short answer is yes.
Say short because to date really whats driven our exploration within the cell types that we we focus on are those where delivery and accessibility is there a spike shared earlier in the presentation across the central nervous system. After a single interest equal administration and HP, we have broad distribution in major cell types as <unk> shared with Ada.
Both with gallon that get without we do have brought in vivo distribution across cell types. So.
When we think about delivery strategies may be and I think this is the case of gallon deck, where you can give a smaller doses targeted to a specific single cell type of interests. I think those are always areas of active uptake early there is of interest, but as it relates to delivery and particularly as we think moving into the editing space I think one of the areas that has really been.
Citing for US is that our oligonucleotides are distributing not just into the settlement to the REIT compartment of itself and exerting that intended effect, but with <unk> and without and without the requirement for viral vectors for lipid nanoparticle.
Thank you very much if I may just sneak another kind of question is there any criteria for Optum playbook.
Any of the programs.
So there is it.
Often criteria that are built around the three programs that I outlined earlier.
003 for HD zero zero core for AOS, SPD and the attack III program. So those all have prescribed opt in events. They also have associated milestones with them.
It's a 50 50 profit split R&D split.
In addition to adapt and payments and so thats all triggered on demonstration of proof of mechanism.
Maybe the guests what's important for us as we think about 2022, it's executing on the clinical program and delivering data.
Thank you for much for taking our question.
Thank you.
Your next question is from Palma teeth with Stifel.
Hi, This is Katie on for Paul.
Just had a quick question on the E T D.
Graham So I know you are announcing your development candidate next year.
Beyond that I guess, what is getting this program.
And to entering the clinic. Thanks.
Alright.
Payment of the heme a program so as it relates to ACD as you pointed out I mean, obviously, the first step to the clinic and.
And so we'll be providing more guidance in 2022 around the features that are going into that program as we said earlier disclosed.
We feel really confident on potency I think we also saw durability with the early contracts you want to see how long that dosing frequency is.
Like I said, we have what we call candidates I think every company always has different terminology around candidates I think we built tolerability early into our candidates now they know that when we announce that we have a program that we intend to bring to clinic that it can go the distance. So I think that robust criteria that go into that when we announced it will set us up well to give further guidance when we think about that.
Clinical translation of ACD, but the team is working incredibly hard to accelerate that I mean, we're excited to bring the potential best.
First in class <unk> program forward and are working quickly to do that as it relates to other <unk> because we are working on the ability of coming behind that both with gallon that conjugation and again being poised without down there because we think about other issues I think that will be more updates as we get into 2022 to kind of provide the sequence of how to think about.
The growing amer portfolio as we shared with you expect to bring more ADR editing programs forward.
Built around hepatic <unk>, but under shared and we're excited about our non-GAAP net conjugated as well. So I think there's more updates as we think about 2022.
Great. Thanks.
Your next question is from the line of Luca <unk> with RBC capital.
Oh, great. Thanks, so much for taking my question Congrats on the progress I have two quick ones. So maybe the first one AOS. We obviously saw a few weeks back Biogen and honest is missing the primary end point Theyre, obviously very very different approach given that theyre going after sod one but wondering if there is like any key takeaways from that data set that maybe how you are.
Planning to use some of the key lesson learned from that program to your program going forward and then maybe the second I Wonder if you could expand a bit more on why you weren't Takeda had decided to do.
Discontinued the collaboration of your earlier pipeline. Thanks, so much.
Thank you and I'll, let Mike take the first question and then I'll come back to the stack sure. Yes. Thanks for that so I think that you captured first of all the main points very clearly this is a very different drug in a very different target. So starting in a totally different place just like targeting one mutation for one one the oncologic.
<unk> indication versus another totally different I think that in terms of what can we what can we learn.
That.
First of all they at least dating show they did show that ASO can engage targets I mean, it did it did get to the target. It was a modest effect, but it did sort of engage target.
Also there are elements of the study design and patient population that I think are really helpful. In thinking ahead I think there were some maybe some study design.
Issues given the modest effect they saw in the earlier studies that could have predicted some of these outcomes. So it goes to what I said earlier in the presentation is that you need to basically have that optimization for distribution that optimization for target engagement and Tolerability and then you need to be able to.
To design your studies too with the best candidate to enable that target engagement and Thats, where we think we've done with our <unk> nine program. So as I mentioned, we're really positioned well given the preclinical data we've seen in the way we're taking it into the clinic. So that's what I would say about that and I'll turn it over to Paul.
We believe in C&I target biology, we demonstrated as Mike shared potency durability, we've characterized it as importantly at night.
Our preclinical studies to get there and I think we're running a really robust way to do that effectively efficiently first so I think there we're excited about where our program is positioned.
As it relates to Takeda I mean, it's a relationship it's pretty expensive and I think it is important to our mind everyone that we still have a ongoing collaboration with Takeda I think sometimes people feel like the Takeda collaboration.
It ended and they are still partners. So we are partners on three two clinical programs and our third program method.
So I think it is critical to remind ourselves that there is a collaboration underway I think why the decision to amend it.
And he gave mutual discussions there is still a lot of activities I think.
I have a desire to continue to accelerate what we're doing we have the desire to have our field in CNS and I can't speak to it indicated some of the drivers around budgets and where they are I think the key is that we are strong partners to cadence as the strong CNS franchise.
And we're excited.
As we move into 2020 to evaluate our clinical programs with them and decide how to move forward together. So I think we are still very much partners. What we've done is streamlined and simplified the agreement mutually so that we can move forward.
Got it thanks, so much.
The next question is from the line of Manny <unk> with SBB Leerink.
Hey, guys. Thanks for taking my questions.
I guess, it's more of a philosophical one obviously there is.
H D H C <unk> proven tough targets for you and others.
For all go therapy.
Not easy work and targets to go after.
And you've moved on an HD in particular into two totally different snips.
How many bites of that Apple would we continue to take.
Which.
Becomes.
Not a proper use of investor capital.
Should we see results from this.
Our your next ESG update that looks at the previous would that be the appropriate time to sort of wind down that pursuit or do you think you'd continue to throw money at it.
At that target.
<unk> is showing a better dataset.
Yeah. So one I don't think we throw money, we invest and I think we invest money in a data driven way and so to your point I think the only reason we're running an HD program now is that we have the preclinical data to support moving into the clinic, one distinguishing RPM backbone chemistry again.
Within vivo data that demonstrates potency and durability in an appropriate and relevant model.
Presented subsequent data.
At meetings, but others demonstrating in vivo allele specificity.
I think in a data driven way, we're going to run that experiment.
Its conclusion I didn't get the data that support do we benefit or frankly do we do we believe that we don't have an approach for HD I mean, I think as a data driven decision secondly, as it relates to <unk> nine we do have we believe pre clinically as we look out there the most robust preclinical data set on again.
Durability and design for our <unk> program for AOS and SPD again, our second area of high unmet medical need that requires a therapy. So we're going to run that study and we're going to run that down to be able to demonstrate do we believe that we have a best in class program, there and then thirdly in.
BMD data in the double knockout mouse was unprecedented EBIT change.
Change in phenotype, not just dystrophin production like.
We actually see survival and about that's substantial and so again, we're going to test that we're going to get the data and so I think in a very deliberate way. These are three investment decision to answering data driven discussion that will then as we stand I think it's really important.
The nuance of what we say next year in data to make decisions and I think those decisions about are very much aligned with what you're saying, which is a decision to progress where decision to say we need to move to a different area and I think the fourth program advancing gives us a very different look you can look at new biology around it gives us down that conjugation.
In a way that are silencing peers can't do and really gives us a new area to progress and we're moving full steam ahead on galvanic conjugated are targeting molecules. So I think across that portfolio of preclinical programs entering meaningful question and important regions of the central nervous system as well as in the periphery in skeletal muscle.
I think that's going to answer your question coupled with the work over next year on both HR and hepatic editing, but by ACP and I think across that spectrum, we're going to be able to make investment decisions in 2022, So now being capitalized to do that.
I'm excited about 2022, I think we're going to get really important answers to pharmacology programs and platform.
Great that's crystal clear thanks, guys.
There are no further questions at this time I will now turn the call back over to Dr. Pablo now.
Thanks, everyone for joining the call. This morning to review our third quarter of 2021 corporate update and thank you to our way of employees for their hard work and commitment to patients have a great day take care Bye bye.
Yeah.
This concludes today's conference call Goodbye connect.