Q1 2022 WAVE Life Sciences Ltd Earnings Call

Okay.

Operator: Good morning, and welcome to the WAVE Life Sciences first quarter 2022 financial results call. At this time, all participants are in a listen-only mode.

Good morning, and welcome to the wave life Sciences first quarter 2022 financial results 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 VP of Investor Relations and corporate Corporate Affairs wave Life Sciences. Please go ahead.

Operator: As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, VP of Investor Relations and Corporate Affairs at WAVE Life Sciences. Please go ahead.

Kate Rausch: Good morning, and thank you for joining us today to discuss our recent business progress and review WAVE's first quarter 2022 financial results. Joining me today with prepared remarks are Dr. Paul Bolno, WAVE's President and Chief Executive Officer, Dr. Mike Panzera, Chief Medical Officer, Head of Therapeutics Discovery and Development, and Kyle Moran, Chief Financial Officer. The press release issued this morning and the slide presentation to accompany this webcast are available in the investor section of our website, www.wavelifesciences.com.

Good morning, and thank you for joining us today to discuss our recent business progress and review <unk> first quarter 2022 financial results. Joining me today with prepared remarks are Dr. Paul Paul now President and Chief Executive Officer.

Dr. Mike Bender, our Chief Medical Officer head of Therapeutics that brand development, and Kyle Moran Chief Financial Officer.

The press release issued this morning, and the slide presentation to accompany this webcast are available on the investors section of our website Www Dot wave life Sciences Dot com.

Kate Rausch: 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 several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2021, and our quarterly report on Form 10-Q for the quarter ended March 31, 2022. 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. Okay?

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 several risks and uncertainties that could cause our actual results to differ materially from those described in these forward looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filing.

Including our annual report on Form 10-K for the year ended December 31, 2021, and our quarterly report on Form 10-Q for the quarter ended March 31, 2020, we undertake no obligation to update or revise any forward looking statement for any reason.

Now like to turn the call over to Paul well.

Paul Bolno: Thank you, Kate. Good morning, and thank you all for joining. Today, I will start by highlighting our achievements so far this year and providing a business update. Mike will discuss our therapeutic pipeline. And finally, Kyle will discuss our first quarter financials. This has been an exciting first half of 2022 for WAVE.

Thanks, Kate good morning, and thank you all for joining us.

Today, I will start by highlighting our achievements so far this year and provide a business update Mike will discuss our therapeutic pipeline and finally, Kyle will discuss our first quarter financials.

This has been an exciting first half of 2022 per week, we are executing on multiple pillars to drive value for both our shareholders and the patients and families. We serve.

Paul Bolno: We are executing on multiple pillars to drive value for both our shareholders and the patients and families we serve. We remain on track to deliver data from our three clinical programs to rapidly inform their next stages of development. This was exemplified by our recent positive data announcement on our C9 program. Rapidly advance our first RNA editing AMER, Alpha-1 Antitrypsin, or AATD, program into IND-enabling toxicology studies, a key step on the path to the clinic, and leverage partnerships to unlock value from our platform, pipeline, and manufacturing.

We remain on track to deliver data from our three clinical program to rapidly inform their next stages of development. This is exemplified by our recent positive data announcement on our <unk> program.

Rapidly advance our first RNA editing Gamer Alpha one antitrypsin or AED program into IND, enabling toxicology studies, a key step on the path to the clinic.

And leverage partnerships to unlock value from our platform pipeline and manufacturing.

Paul Bolno: Starting with our clinical programs, WAVE has been at the forefront of accelerating innovation in oligonucleotide therapy, and our recent clinical data is a first glimpse of how our preclinical data are translating. As we announced in April, WVE004 demonstrated successful target engagement in the central nervous system in the ongoing FOCUS C9 study for patients with C9ORF72-associated ALS or FCD.

Starting with our clinical program.

<unk> has been at the forefront of accelerating innovation in oligonucleotides and our recent clinical data as a first glimpse of how our preclinical data are translating issue.

As we announced in April W. V E zero zero core demonstrated successful target engagement in the central nervous system and the ongoing focus <unk> nine study for patients with benign or 72 associated where SPD.

Paul Bolno: We were able to rapidly identify this positive signal with single low doses of 004 due to the innovative and adaptive design of the trial. As Mike will highlight today, the clinical trial is progressing to optimize dose and frequency for the next phase of development. As you are all aware, ALS and STD are devastating diseases of extremely high unmet need.

We were able to rapidly identify the positive signal with single low doses of all four due to the innovative adaptive design of the trial.

As Mike will highlight today, the clinical trial is advancing to optimize dose and frequency for the next phase of development.

As you are all aware E. L. F N FCB are devastating diseases extremely high unmet need.

Paul Bolno: For those with C9 mutations, these illnesses are also marked by faster rates of progression, and we are moving with urgency to advance this program. This year, we also expect to deliver data from our ongoing select HD clinical trial, studying WVE003 in Huntington's disease, and our ongoing clinical trial in DMV, studying WVEN531. These data will help us further elucidate the broad potential of CN chemistry for CNS and muscle diseases.

Are those with benign mutation. These illnesses are also marked by faster rates of progression and we're moving with urgency to advance this program.

This year, we also expect to deliver data from our ongoing select HD clinical trial studying <unk> in Huntington's disease, and our ongoing clinical trial in DMD study W V E and <unk>.

These data will help us further elucidate the broad potential and chemistry for Sienna and muscle diseases.

Paul Bolno: Beyond our current clinical portfolio, we are advancing our AAPD program using GALNC-targeted delivery. Not only does our RNA editing modality have the potential to transform the way patients are treated for this disease, but initial clinical proof of concept will substantially de-risk additional RNA editing disease targets. Finally, we remain active in our business development.

Beyond our current clinical portfolio, we are advancing our AED program using <unk> targeted delivery.

Not only does our RNA editing modality have the potential to transform the way patients are treated but its disease, but initial clinical proof of concept will substantially derisked additional RNA editing disease targets.

Finally.

We remain active in our business development areas.

Paul Bolno: There is widespread recognition of the potential for oligonucleotide therapeutics. With several key publications on our novel PN chemistry earlier this year and our recent positive clinical data, discussions with potential partners are accelerating. RNA editing, in particular, is ripe for collaboration and vastly expands the landscape of addressable genetic targets. WAVE VAMERS are enabled by our unique chemistry modifications, as well as the creativity and expertise of our science.

There is widespread recognition of the potential for oligonucleotide therapeutics with.

With several key publication on our novel Chemistry earlier, this year and our recent positive clinical data discussions with potential partners are accelerating.

RNA editing in particular is right for collaboration and vastly expands the landscape of addressable genetic targets.

Wave gamers are enabled by our unique chemistry modification as well as the creativity and expertise of our science.

Paul Bolno: In the first quarter, we announced the publication of our foundational preclinical proof of concept editing data in Nature Biotechnology, which showed that a simplified oligonucleotide approach can be used for robust, durable, and highly specific RNA-based editing without exogenous enzymes or delivery vehicles. This paper serves to further distinguish our aimers from others pursuing editing applications at both the RNA and DNA levels. We expect 2022 to continue to be an important year for partnering, including leveraging our manufacturing capability.

In the first quarter, we announced the publication of our foundational preclinical proof of concept editing data in nature, biotechnology, which showed that a simplified oligonucleotide approach can be used for robust durable and highly specific RNA based editing without exogenous enzyme for delivery vehicles.

Paper serves to further distinguish our aim or some others pursuing editing applications at both the RNA and DNA level.

We expect 2022 to continue to be an important year for partnering including leveraging our manufacturing capability.

Paul Bolno: We see vast potential to expand the reach of our platform with AMERS. There are tens of thousands of single nucleotide disease variants that are potentially amenable to ADAR editing corrections. Demonstrating clinical proof of concept in AATD would serve to de-risk additional monogenic diseases, as well as open opportunities to address large patient populations through modulation of proteins, such as disruption of protein-protein interaction. Our positive ALS-FDE clinical data offers the potential to leverage our preclinical data demonstrating potent and durable editing in the central nervous system.

We see potential to expand the reach of our platform with acres. There are tens of thousands of single nucleotide disease areas that are potentially amenable to ADR editing correction.

Demonstrating clinical proof of concept and ATB would serve to de risk additional monogenic diseases as well as open opportunities to address large patient population through modulation of proteins, such as disruption of protein protein interaction.

Our positive.

Clinical data.

The potential to leverage our preclinical data demonstrating potent and durable editing in the central nervous.

Paul Bolno: Our PRISM platform enables us to capture learnings with each new target, and we expect to shorten our cycle times from target identification to preclinical proof of concept to clinical candidate over time. Today, in tandem with this earnings call, Dr. Paloma Giogrande is presenting our preclinical AMER data at the Tides USA company. As a reminder, we observed clinically relevant levels of AAT restoration with AMER treatment in a transgenic mouse model following multiple doses of Galnex Serpin A1 AMER, specifically.

Our prism platform enables us to capture learnings with each new target and we expect to shorten our cycle times from target identification preclinical proof of concept clinical candidate overtime.

Today in tandem with this earnings call Dr. Paloma geographic presenting our preclinical <unk> data at the tides USA company.

As a reminder, we observed clinically relevant levels of 80 restoration with E. Mercury transgenic mouse model following multiple doses of <unk>.

Specifically at.

Paul Bolno: In week 19, we observed RNA editing of approximately 60% in the liver. This level of editing resulted in total AAC serum protein levels of 18.5 micromolar, or 5-fold higher than control. The majority of the circulating AAT protein, approximately 70%, was confirmed to be healthy wild-type MAAT protein.

19, we observed Arnie editing of approximately 60% in liver.

This level of editing resulted in total AC urine protein levels of 18, five micro molar or by both higher than control.

The majority of the circulating <unk> protein approximately 70% with confirms healthy wild type.

Protein.

Paul Bolno: While there are multiple approaches being developed to address AATD, the advantage of AMERS is the ability to address both lung and liver manifestations of the disease with a single subcutaneous administered compound. Today, Paloma is also sharing new data at TIBE, demonstrating the functionality of the restored AAT protein at week 19 as measured by neutrophil elastase inhibition, as shown on slide 8 on the left. Histological analysis of liver biopsies indicates treatment with AMERS reduces the accumulation of liver ZAAT aggregates over time, as assessed by PASB staining, as shown on the right.

While there are multiple approaches being developed to address ACD. The advantages of <unk> is the ability to address both lung and liver manifestations of the disease with a single subcutaneous administered compound.

Today, Colombia is also sharing new data demonstrating.

Demonstrating the functionality of the restored AAC protein at week 19, as measured by neutrophil elastase inhibition.

As shown on slide eight on the left.

Histological analysis of liver biopsy indicate treatment with <unk> reduces accumulation of liver the AAC aggregate overtime.

Thats bypassed the ceiling as shown on the right.

Paul Bolno: We will be highlighting our AETD program data again in an oral presentation at the ASG team meeting next week. I'll now turn the call over to Mike to give an update on our clinical programs, as well as the progress advancing AATD towards clinical development.

We will be highlighting our ATB program data again in an oral presentation at the S. E T meeting next week.

Now I'll turn the call over to Mike to give an update on our clinical programs as well as the progress advancing <unk> towards clinical development Mike.

Mike Panzera: Thanks, Paul, and good morning to everyone on the call. Today, I will review our Clinical and Emerging Therapeutic Programs, starting with our recent FOCUS G9 trial data for WVE004. First, I would like to spend a moment on the C9R72 mutation. Our clinical candidate, WVE004, is designed to target the pre-mRNA variant hexanucleotide repeat expansions that result from the C9R72 mutation, the most common known genetic cause of ALS and FTD. CNNORF72 mutations lead to multiple drivers of toxicity, and WVE004 was designed with the goal of addressing each aspect of this complex but well-described biology. Hexanucleotide repeat-containing RNA transcripts, deposits, and tissues, and are toxic on their own.

Thanks, Paul and good morning to everyone on the call.

Today, I will review, our clinical and emerging therapeutic programs starting with our recent focus nine trial data for W. V 004.

Mike Panzera: But they are also translated into long dipeptide repeat proteins, or DPR proteins, that trigger cellular toxicity through a variety of downstream mechanisms. 004 selectively targets the pre-mRNA variant transcripts that contain both the hexanucleotide expansion with a goal of suppressing both the RNA and DPR-associated toxicities while preserving existing levels of c9r72 protein expression. Because the DPRs are measurable in CSF and derived from expanded mRNA transcripts, they may be used as biomarkers of target engagement with compounds such as WVE004 designed to target this pathway.

First I would like to spend a moment on the Athena and our 72 mutation our clinical candidate <unk> four is designed to target the pre mrna variant extra nucleotide repeat expansions.

Mike Panzera: In the case of 004, we selected poly-GP as our preferred DPR biomarker, both because it is the only DPR produced from both sense and antisense mRNA variants, and because of the availability of an animal model to explore in vivo target engagement to more accurately estimate the doses required for target engagement when moving into human trials. Poly-GP is also abundant in the CNS and the most valuable among the peptide repeat proteins.

Mike Panzera: In preclinical studies, we demonstrated WVE004's ability to rapidly and durably reduce polyGP by over 90% in the spinal cord and at least 80% in the cortex of a transgenic mouse after just two ICP doses seven days apart. The silencing effect in this model lasted at least six months, and normal CNRF72 protein levels were preserved over the same period, confirming the selectivity of 004. These results, along with the single and multi-dose data in non-human primates, enabled us to determine a starting dose in humans that was predicted to be safe and have the potential to engage target and yield a reduction in polyGP.

That result from C&I, North 72 mutations the most common known genetic cause of ALS and STD.

Mike Panzera: As we showed during our investor update in early April, we saw excellent translation of this modeling into, We observed robust target engagement, as shown in the figure on the right of slide 12, which prompted us to adapt the FOCUS C9 study. Specifically, single, low, 10 and 30 milligram doses of 004 significantly reduced CSF poly-GP versus placebo at several time points. Further, our modeling predicts continued decline in PolyGP with additional follow-up, as well as with the administration of multiple doses. We are now adapting the studies to fully characterize the depth of poly-GP reduction with single doses of WVE004, while continuing the multi-dose phase, which is well underway.

Mike Panzera: Specifically, we are extending the observation period for the single dose cohorts from three to six months while dosing additional patients with 30 milligrams and enrolling additional patients to receive a 20 milligram single dose. These additional data will help us identify the optimal dose level and frequency to explore in the upcoming Open Label Extension Study beginning in mid-2022 as well as the next phase of development. We anticipate that FOCUS C9 will provide additional data throughout 2022, which will be used to optimize dose level and frequency and enable discussions with regulatory authorities later this year.

<unk> 72 mutations lead to multiple drivers of toxicity and WV easier zero four was designed with the goal of addressing each aspect of this complex, but well described biology.

Mike Panzera: Lastly, we're excited to be sharing these data as an oral presentation at the upcoming European Network to Cure ALS or NCALS, which is occurring early Focus C9 is just the first example of the approach taken with our current clinical and preclinical candidates, which builds upon our own experiences, along with innovations from the PRISM platform to design CNS candidates that promise to be distinct from others in the field. Our approach begins with the capabilities of PRISM at its core and an increased understanding of the factors influencing the pharmacology of our molecules and 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 design candidates optimizing for widespread tissue distribution and target engagement with the potential for a favorable tolerability profile.

Perhaps a nucleotide repeat containing RNA transcripts deposit in tissues and are toxic on their own but they are also translated into law dipeptide repeat proteins or DPR proteins that trigger cellular toxicity through a variety of downstream mechanisms.

Mike Panzera: Finally, careful selection of relevant biomarkers, other endpoints, and patient population, along with adaptive study designs that allow real-time adjustment of dose level and frequency, positions us well to reduce development risk and drive rapid decisions. As you can see from these data, our work is beginning to bear fruit with clear proof of concept clinical data and effect on relevant biomarkers even at the starting dose. Real-time decision-making and consultation with our independent DSMB will continue, allowing us to swiftly move the programs forward.

Zero zero.

<unk> targets the pre mrna variant transcripts that contain both the hexagon good type expansion with a goal of suppressing both the army and DPR associated toxicity.

Preserving existing levels of C&I, our 72 protein expression.

Because the deep yards are measurable in CSF and derived from its standard mrna transcripts. They may be used as biomarkers of target engagement with compounds such as <unk> designed to target this pathway.

In the case of 004, we selected poly GP is our preferred DPR biomarker, both because it is the only DPR produced from both sensitive antisense mrna variance and.

And because of the availability of an animal model to explore in vivo target engagement to more accurately estimate doses required for target engagement when moving into human trials.

Probably GP is also abundant in the CNS and the most valuable amongst the dipeptide repeat proteins.

In preclinical studies, we demonstrated <unk> ability to rapidly and durably reduce poly GP by over 90% in the spinal cord and at least 80% in the cortex of a transgenic mouse. After just two ICP doses seven days apart.

The silencing effectiveness model last at least six months and normalcy are 72 protein levels were preserved over the same period confirming the selectivity of 004.

These results along with the single and multi dose data in nonhuman primates enabled us to determining starting dose in humans that was predicted to be safe and have the potential to engage target and yield it reduction in poly GP.

As we showed during our Investor update in early April we saw excellent translation of this modeling into clinic.

We observed robust target engagement as shown in the figure on the right of slide 12, which prompted us to adapt to focus <unk> nine study specifically single low 10, and 30 milligram doses of 004 significantly reduce CSF colleague GP versus placebo at several time points.

Further our modeling predicts continued decline in apology Pea with additional follow up as well as with the administration of multiple doses.

We are now adapting the studies to fully characterize the depth Apollo GP reduction with single doses of <unk> 004, while continuing the multi dose phase, which is well underway.

Specifically, we are extending the observation period for the single dose cohorts from three to six months, while dosing additional patients at 30 milligrams and enrolling additional patients to receive a 20 milligram single dose.

These additional data will help us identify the optimal dose level and frequency to explore in the upcoming open label extension study beginning in mid 2022 as well as the next phase of development.

We anticipate that focus jeannine will provide additional data throughout 2022, which will be used to optimize dose level and frequency and enabled discussions with regulatory authorities later this year.

Lastly, we're excited to be sharing these data as an oral presentation at the upcoming European network, the cure ALS or <unk>, which is occurring in early June .

Focusing on is just the first example of the approach taken with our current clinical and preclinical candidates, which built upon our own experiences along with innovations from the prism platform to design CNS candidates the promise to be distinct from others in the field.

Our approach begins with the capabilities of prison at its core and an increased understanding of the factors influencing the pharmacology of our molecules and 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 zero stereo chemistry, we can now rationally design 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 along with adaptive studies designs that allow real time adjustment of dose level and frequency.

This positions us well to reduce development risk and drive rapid decision, making.

As you can see from these data our work is beginning to bear fruit with clear proof of concept clinical data and effect on relevant biomarker, even at the starting dose.

The real time decision, making in consultation with our independent the SMB will continue allowing us to swiftly move the programs forward.

Mike Panzera: Further, this outcome makes us even more optimistic about our other programs and data readouts this year. For example, for WVE003, our allele-selective oligonucleotide for patients with Huntington's disease that harbors SNP3 in association with a Mutant Huntington Mutation, the SELECT-HD clinical trial is ongoing. Like FOCUS C9, the SELECT-HD study is adaptive with a goal of accelerating time to proof of concept. Dose escalation continues, and we expect to share clinical data for 003 and 2022 to provide further insight into PN chemistry and enable decision making for this program. WVE N531 is a splicing oligonucleotide targeting exon 53 skipping and Duchenne muscular dystrophy.

Further this outcome makes us even more optimistic about our other programs and data Readouts this year.

<unk> 003, or allele selective oligonucleotide for patients with Huntington's disease that harbor three in association with a.

Mutant Huntington mutation the select HD clinical trial is ongoing like.

Like focus denying the select HD study has adapted with a goal of accelerating time to proof of concept dose escalation continues and we expect to share clinical data for 003 in 2022 to provide further insight in Japan chemistry, and enable decision making for this program.

W E N 531.

Pricing I would with nucleotide targeting exon 53 skipping in Duchenne muscular dystrophy as a reminder, we shared some of the pharmacokinetic data from the <unk> study.

Mike Panzera: As a reminder, we shared some of the Pharmacokinetic data from the DMV study with WVE N531 last quarter, demonstrating an improved pharmacological profile with PN chemistry compared to our first generation DMV compound. We expect clinical data, including muscle biopsies, to enable decision-making in 2022. Lastly, we continue to make excellent progress advancing our AATD program and are on track to select an AATD-AIMER development candidate and initiate IND-enabling toxicology studies in the third quarter of this year, at which point we expect to share more detail on the expected timing of the CTA filing. I will now turn the call over to Kyle Moran, our CFO. Kyle?

With W. B empires, III, one last quarter, demonstrating an improved pharmacological profile with pn chemistry compared to our first generation DMD compound.

We expect clinical data, including muscle biopsies to enabled decision making in 2022.

Lastly, we continue to make excellent progress advancing our <unk> program and are on track to select an ATV Amer development candidate and initiate IND, enabling toxicology studies in the third quarter of this year at which point, we expect to share more detail on the expected timing of Cta filings.

I will now turn the call over to Kyle Moran, our CFO Kyle.

Thanks, Mike net.

Kyle Moran: Thanks, Mike. The net loss for the three months ended March 31, 2022 was $37.8 million. We reported $1.8 million in revenue for the first quarter of 2022, which was primarily related to gap revenue earned under our collaboration with Takeda. R&D expenses were $27.5 million for the first quarter of 2022 as compared to $33.4 million for the same period in 2021. This was primarily due to decreased external expenses related to our previously discontinued clinical program, partially offset by increased internal and external expenses related to our present platform, including ADAR editing and other ongoing programs.

Net loss for the three months ended March 31, 2022 was $37 8 million, we reported $1 $8 million of revenue for the first quarter of 2022, which was primarily related to GAAP revenue earned under our collaboration with Takeda.

R&D expenses were 27 points.

$5 million for the first quarter of 2022.

As compared to $33 4 million the same period in 2021.

This was primarily due to decreased external expenses related to our previously discontinued clinical program.

Partially offset by increased internal and external expenses related to our prism platform.

Including eight our editing and other ongoing programs.

Kyle Moran: DNA expenses were $12.4 million in the first quarter of 2022, as compared to $10.1 million last year, primarily due to an increase in compensation related special services and other DNA operating expenses. We ended the first quarter with $111.7 million in cash, and cash equivalents in short-term investments.

G&A expenses were $12 $4 million for the first quarter of 2022 as compared to $10 $1 million last year, primarily due to increases in compensation related professional services and other G&A operating expenses.

We ended the first quarter with $111 7 million in cash cash equivalents and short term investments.

Paul Bolno: We continue to expect that our cash, cash equivalents, and short-term investments will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, we do not include potential milestone or opt-in payments under our Takeda collaboration in our cash runway. I'll now turn the call back over to Paul.

We continue to expect that our cash cash equivalents and short term investments will enable us to fund our operating and capital expenditure requirements.

Into the second quarter of 2023.

As a reminder, we do not include potential milestone or opt in payments under our Takeda collaboration and our cash runway.

I'll now turn the call back over to Paul Paul.

Paul Bolno: Thanks, Kyle. I'm proud of our team for their hard work and dedication, and especially for delivering on the first significant clinical milestone for WAVE and for patients living with C9-associated ALS and FTD. We expect to deliver additional data for WVE-004 this year, as well as data from our HD and DMV programs. Each of these data sets will further unlock value and inform the next steps of development. With the increased number of recent high-impact publications in the first quarter, coupled with our positive data on WVE004 demonstrating translation of our robust preclinical data, we are evaluating a number of partnering opportunities. Interest spans different therapeutic areas and modalities and includes leveraging our manufacturing capabilities. These partnerships are expected to support the expansion and acceleration of both our platform and pipeline, as well as strengthen our financial position.

Thanks, Kyle I am proud of our team for their hard work and dedication and especially for delivering on the first significant clinical milestone for wave and for patients living with teenagers associated AOS and that T. D. We.

We expect to deliver additional data for WB E zero zero for this year as well as data from our HD and DNP programs.

Each of these datasets will further unlock value and inform the next steps in development.

With the increased number of recent high impact publications in the first quarter, coupled with our positive data on <unk> demonstrating translation of a robust preclinical data we are evaluating a number of partnering opportunities inter span the different therapeutic areas and modalities and includes leveraging our manufacturing capability.

These partnerships are expected to support the expansion and acceleration of both our platform and pipeline as well as strengthen our financial position, we look forward to sharing updates throughout this year.

Paul Bolno: We look forward to sharing updates throughout this year. Finally, I want to acknowledge that May is both ALS and Huntington's disease awareness month. On behalf of everyone at WAVE, I'd like to express how incredibly grateful we are to these communities for their partnership and support.

Finally, I want to acknowledge that May is both ALS and huntington's disease awareness month.

On behalf of everyone at <unk> I'd like to express how incredibly grateful we are to these community for their partnership and support.

Operator: We are acutely aware that patients and families are waiting, and this drives us every day to move with urgency, creativity, and resolute focus so that we can ultimately deliver life-changing treatment. With that, we'll open up the call to questions. Operator. Ladies and gentlemen, if you have a question or a comment at this time, please press the star, then the one key on your touchtone telephone. If this question has been answered, do you wish to move yourself? Press the pound.

We are acutely aware that patients and families are waiting and this drives us every day to move with urgency creativity and resolute focus so that we can ultimately deliver life changing treatment.

With that we'll open up the call for questions operator.

Ladies and gentlemen, if you have a question or a comment at this time. Please press. The Star then the one key on your Touchtone telephone.

Question has been answered or you wish to move yourself from the queue. Please press the pound key.

Operator: Our first question comes from Joon Lee with True. Hi, thanks for taking our questions. In the setting of BIOGEN terminating their C9 North program in ALS, what gives you the confidence that your program is better poised for success? Our understanding is that their antigen follicle also preserves wild-type form, so the slightly different mechanism.

First question comes from Junior Securities.

Hi, Thanks for taking our questions.

Setting of Biogen terminating the <unk> program and less what gives you the confidence that Youll program is better poised for success. Our understanding is that their insistence always will also preserves swap take form.

Slightly different.

Joon Lee: And I have a quick follow-up. Yeah, I'll turn it over to Mike. Yeah, hi Jin.

And I have a quick follow up.

Mike Panzera: Um, yeah. So, simply, we haven't seen any details of it yet. So that's the first thing to point out. But we have a different chemistry, different sequence, different potency, clearly, just looking at the dose levels, different durability, certainly pre-clinical. There are just a lot of differences.

Thank you and I'll turn it over to Mike Yeah, Hi, Jim Yeah. So I mean, I simply we haven't seen any details of it yet. So that's the first thing to point out, but we have a different chemistry different sequence different potency clearly just looking at the dose levels.

Different durability, certainly pre clinically.

Paul Bolno: And I think we chose our candidates based on the biology I outlined. And so, I mean, we really haven't seen anything that changes our confidence that the approach is going to be worthwhile or changes any of what the literature is saying is the best hypothesis for treating the disease. I think just to follow up on that and Mike's point on potency is important. I mean, what we've seen is translation of our chemistry pre-clinically to clinically.

And Theres, just a lot of differences and I think we chose.

Our candidate based upon the biology as I outlined.

And so I mean, we really haven't seen anything of that.

<unk>, our competence to the approach.

There's going to be a worthwhile.

Or change any what the literature is saying is the best hypothesis for treating the disease.

Just to follow up on that and Mike's point on potency is important.

What we've seen is translation of our chemistry preclinical data clinically and if you remember we saw not just total EBITDA stability at very low doses. So in 'twenty. So a dose response single dose.

Paul Bolno: And if you remember, we saw not just potency but durability at very low doses, so 10, 20, so dose response, single dose, single low doses that substantially not just lowered poly-GP protein but then actually, as we said, are continuing to follow those patients out even farther. So, as Mike alluded to, in the absence of knowing what they saw, we had a press release that was about a termina- well, that we, they had a termina- press release, right? We didn't have a data press release yet.

Single low doses that substantially not just lowered highly GP protein, but then actually as we said are continuing to follow those patients out even farther so.

As Mike alluded to in the absence of knowing what they saw we had a press release that was about determining that we had a termination press release right. We didn't have a data press release, yet. So I think we're confident in our preclinical data translating I think we have been following us merits COVID-19 shared on our call that we gave on the data update that poly GP as a.

Paul Bolno: So I think we're confident in our preclinical data translating, I think we have, and our following is merited COVID shared on our call that we gave on the data update, that poly-GP is a good predictive biomarker for ALS to follow. And I'll bring up one more point on dosing. The doses in the announcement that we saw with Biogen and Ionis had substantial loading doses, so their data was for five doses around 90.

A good predictive biomarker for AOS to follow.

And.

Paul Bolno: So again, being low single dose data gives us, you know, at least the confidence going back to our preclinical data, potent durable effects, and we have to continue to follow these patients out, as Mike said on the call, see what happens with repeat dosing and where we ultimately get to. But there's a lot of confidence in the community, within WAVE, around the data we're generating, but we'll all have to wait and see.

I'm being up one more point on dosing the doses and the announcement that we saw.

With Biogen and I own it had substantial loading dose. So their data was I didn't get five doses around 90, so again being low single dose data gives us.

At least the confidence going back to our preclinical data potent durable effects and we have to continue to follow these patients.

Mike said on the call.

What happens with repeat dosing it in where we don't make it too, but theres a lot of confidence in the community within wave around the data, we're generating but we'll all have to wait and see.

Operator: Great, looking forward to the updated data. And all of your trials, including the Huntington's and DMV, are utilizing adaptive trial design, and you have guided data release in the second half of the year. Does that imply that you have hit a certain pre-specified threshold, and if so, are you able to share what that is? Thank you. Yeah, I think just to reiterate, while they are adaptive in design, you know, we haven't guided them to any point in the year other than 2022. And I say that because, like the C9, and I think C9 is a great example, there are events that could trigger the unbinding, and obviously, when that happens, sharing of that data.

Great.

Fortunate that updated data and all of your trials and putting the for the Huntington's and Dnb are utilizing adaptive trial design and you have guided to data released in the second half of the year does that imply that you have hit certain pre specified threshold and if so are you able to share what that is.

Paul Bolno: And so when the DSMB meets and sees that that trial will change, we'll provide an update. So we haven't guided those data to the back half of the year. Rather, we've guided them over the course of this year, and while SNP3, the HG study, and DMV started after the C9 study, you know, that data could come at any point after a DSMB review. So we're not kind of guiding to the back half of the year.

Yes, I think just to reiterate while they are adaptive and design, we haven't guided to any point in the year other than in 2022, and I say that because like 50 969 is a great example, there are events that could trigger the unwinding and obviously when that happens sharing of that data and so when the DSM be teased at that.

Trial will change we will provide an update so we haven't guided those data to the back half of the year, rather we've guided over the course of this year and while NIM three to HD study in DMD started after the <unk> nine study.

Data could come at any point after the SNB review, so we're not kind of guiding to the back half of the year.

Thank you.

Operator: Thank you. Our next question comes from Salim Syed. Good morning, guys.

Our next question comes from Selim side with Mizuho.

Salim Syed: Thanks for the questions. Paul or Mike, I guess a couple for me on the C9 trial regarding the functional measures. Can you just maybe give us your updated thoughts there? When, when do you expect to see a functional benefit in this particular trial, and I guess, and I guess, are you planning to have that functional data in hand prior to you going to regulatory authorities for the next phase of development? And then just a quick follow-up. Thank you. Yeah, hi Salim, this is Mike.

Great. Good morning, guys. Thanks for the questions.

Paul or Mike I guess, a couple from me.

On the <unk> trial regarding the functional measures can you just maybe give us your updated thoughts there when when do you expect to see a functional benefit.

Hum.

In this particular trial and I guess and I guess are you planning to have that functional data.

In hand prior to you going to regulatory authorities for.

For the next phase of development and then just a quick follow up thank you.

Mike Panzera: Well, I mean, as we've said previously, the ALS-FRSR in the setting of ALS patients and CDR-FTLD, which is the cognitive measure, are the primary functional measures that we're looking at in this study. But, as Dr. Sakovich pointed out when we had our data released, it takes about six to 12 months really to see much of an impact on any of these, even in the setting of a positive effect. So we would not anticipate having any functional data from the core and core study, focus C9 this year, and we would more anticipate that as we transition patients into the OLE and continue to follow them, that longer-term follow-up in the setting of continued optimized treatment would be really the place where we would see a potential effect. Okay, thanks, Mike.

Yes, hi, its claim this is Mike well I mean, as we've said previously the ALS FRS or in the setting of the less patients and C. D. R. <unk> D, which is the cognizant measure are the primary functional measures that we're looking at in the study, but as Dr. <unk> pointed out when we had our data released it takes about six.

Six to 12 months really to see much of an impact on any of the even in the setting of a positive effect. So we would not anticipate.

Having any functional data from the core on core study focus benign this year and that we would more anticipate that as we transition patients knee OA and continue to follow them that that longer term follow up in the setting of continued optimized treatment would be really the place where we would see a potential effects.

Mike Panzera: So given that, then could you maybe just outline for us, you know, what are the potential outcomes coming out of the regulatory discussions that you plan on having the way you see it right now, without the functionality? Yeah, so I think that the potential is, first of all, a way of predicting the outcomes of regulatory discussions. I mean, it's not something I like to get into.

Okay. Thanks, Mike.

Given given that then could you maybe just outline for us what.

Are the potential outcomes coming out of the regulatory discussions that you plan on having the way you see it right now without the functional.

Yeah, So I mean I think that.

But the potential is first of all.

Very much of a way of predicting outcomes of regulatory discussions I mean, it's not something I'd like to get into but I would tell you that remember the purpose of this study was to demonstrate.

Mike Panzera: But I would say that, you know, remember, the purpose of this study was to demonstrate proof of concept for the approach and target engagement, along with a favorable safety profile and go into authorities discussing the next phase of development with that position as well as to come out with a very clear and straightforward path forward. I mean, I think it is known that the authorities have been pretty clear about what it takes to develop a drug for ALS.

Proof of concept for the approach and target engagement, along with a favorable safety profile and going into authority discussing the next phase of development with that context positions us well to come out with is dairy.

Clear and.

Straightforward path forward I mean, I think it is known.

The authorities have been pretty clear about what it takes to develop the drug in a L. S.

Mike Panzera: And I'd say that with the data we have in hand and the optimized doses that we will have when we talk to them, we're in great shape to basically transition to the next phase of development. So without getting into details, I think, you know, it's pretty clear what's required in these indications, and Focus V9 sets us up to have that information ready to go. Got it. Okay. Thank you so much.

I'd say that with the data we have in hand, and the optimized dosing that we will have when we talk to them.

We're in great shape to basically transition.

To the next stage of development so.

Getting into details I think you know I think it's pretty clear what's required in these indications and focus the nine sets us up to have that information.

Ready to go.

Got it okay. Thank you so much.

Thank you.

Operator: Thank you. Our next question comes from Luca Issi with RBC News. Oh, perfect. Thanks for asking your questions and comments on the progress this quarter. This is Lisa on behalf of Luca.

Our next question comes from Luca <unk> with RBC.

Oh perfect. Thanks for taking my question. Thanks for all the progress this quarter.

Lisa Walter: I'm just wondering, I noticed in your slides that you're going to include a 20 mg dose for the C9 trial, which is the dose level in between the 10 mg and the 30 mg. Does this have anything to do with the NFL elevations that you observed at the 30 mg dose? And just on the HD program, I was wondering also if you've been able to apply any learning from the C9 study to the Huntington study? For instance, are you able to maybe start at a higher dose in HD based on the target engagement that you've seen in C9? Thanks. Hi, yeah, this is Mike again.

We saw him for Luka.

Just wondering I noticed in your slides that you've laid out.

It goes through the C nine trial.

The dose level and between the 10, Meg and not taking it.

And does this have anything to do with it.

And then final elevation, but yes.

Yes.

Just on the HD program I was wondering also if you've been able to apply any learnings from this study to the Huntington study.

For instance are you there.

April to may be start at a higher dose in each day based on the target engagement that you've seen benign. Thanks.

Mike Panzera: So regarding the 20 milligram dose, basically, that's purely from the fact that we saw target engagement at 30. That really didn't necessitate going any higher, from a dose identification standpoint, in terms of what is the minimal dose we need to have a robust effect. And given that we already saw a little bit of 10 milligrams, we just thought an intermediate dose would be prudent. It was really based upon what is the minimal dose we need to have a robust effect that's durable that we can take forward with the best dose level and frequency. So that's sort of where we got to.

Hi, Yes. This is Mike again, so regarding the 20 milligram dose.

Basically that's purely from the fact that we saw target engagement at 30.

That was.

That really didn't necessitate going any higher from a dose identification standpoint in terms of what is the minimal dose we need to have a robust effect and given that we already saw a little bit of 10 milligrams. We just got an intermediate dose would be prudent. It was really based upon what is that minimal dose we need to have a.

Just the fact, that's durable that we can take forward, what the best dose level and frequency. So that's sort of where we got to I mean, the neuro filament observations, where there are $30 60 as we've disclosed.

And we've basically.

Mike Panzera: I mean, the neurofilament observations were there at 30 and 60, as we've disclosed. And we've basically, You know, I'm going to be following that. It's exploratory, and we'll see where we end up. We'll see where we end up single dose. We could go higher if we want to, we could, we're going in right now into multiple doses. So all of that will pan out.

You know.

Going to be following that it's exploratory and we'll see where we end up we'll see where he ended up a single dose we could go higher if we want to we could we're going right now into multiple doses. So all of that will pan out, but our current 'twenty is really based upon as I said trying to get that minimal target minimal dose that gives us a robust target engagement.

Mike Panzera: But our current 20 is really based upon, as I said, trying to get that minimal target, minimal dose that gives us robust target engagement. Regarding the shared learnings across the two studies, I think that the dose selection in SELECT-HD for our SNP3 targeting program was really using the same principles that we used to establish the dose selection for FOCUS C9, based upon the preclinical data. It's a different molecule, different preclinical data, and different modeling.

Regarding the shared learnings across the two studies I think that on the dose.

Lection in select HD.

For our Smith <unk> targeting program was really using the same principles that we use to establish the dose selection for focusing nine it's based upon the preclinical data.

Different molecule different preclinical data different modeling so it's really based upon that and the entire infrastructure around the SMB reviews independent reviews adapting they were very similar and established between the studies and I think the best thing that we can learn from select from focusing nine is.

Mike Panzera: So it's really based on that, and the entire infrastructure around DSMB reviews, independent reviews, and adaptations, they were very similar and established between the studies. And I think the best thing that we can learn from SELECT, from FOCUS C9, is that it works, that we can basically use this infrastructure to rapidly see if we have a biological effect and, therefore, adapt the study and move forward. So that's the best shared learning, but each molecule is slightly different.

That it works that we can basically use this infrastructure to rapidly see if we have a biological effect and therefore, our adapt study and move forward. So that's the best shared learning, but each molecule is slightly different I think but just to follow up on that.

Paul Bolno: I think, but to follow up on that, you know, what we did see is translation of predictive modeling from preclinical to clinical with C9, and as Mike said, I think we're going to see and expect that same thing to, you know, occur in HD. So that was the principle in starting, was to start at doses where we would anticipate an engaging target, and then run the adaptive studies there. I think to pick up on that first point in Mike's discussion around looking at intermediate doses.

What we did see is translation of predictive modeling from preclinical to clinical was benign and as Mike said I think we're going to see and expect that the same thing that occur in H D. So that that was the principal and starting with just started doses, where we would anticipate engaging target and then run the adaptive studies, they're having to pick up on that first point to make.

Discussion around looking at intermediate doses remember on our preclinical data that was a repeat dose study what we see is that this is one of the advantages of being chemistry wanted to stable stays inside the cell and save catalytic for awhile and enduro and so these were single dose data and I think in this field. We're so used to looking at loading doses and other features at high doses in order to it.

Paul Bolno: Remember, in our preclinical data, that was a repeat dose study, what we see is that this is one of the advantages of PN chemistry: it is stable, stays inside the cell and stays catalytic for a while and then durable.

Paul Bolno: And so these were single dose data. And I think in this field, we're so used to looking at loading doses and other features of high doses in order to achieve target engagement that we've really reframed, hence why we established the adaptive design principles here that low single doses are engaging, and then with repeat dosing, you get that accumulating effect. And so one of the things that Mike alluded to is looking at repeat doses. Ken Bloomingham's other repeat doses and the single doses as your immediate levels to the earlier question are all going to give us the data that we need to determine what that next study looks like in terms of dose design. Got it.

Target engagement.

We've really reframe, hence why we established the adaptive design principles here that low single doses are engaging in them with repeat dosing, you'll get that accumulating effect and so one of the things as Mike alluded to is looking at repeat dose at 10, moving them to other repeat dosing and a single doses as your immediate levels to the earlier question are all going to.

Give us the data that we need to determine what that next study looks like in terms of dose design.

Got it thanks for taking the question.

Operator: Thanks for taking the question. Our next question comes from Paul Matias. Hey, thanks for taking our questions. This is Alex on behalf of Paul.

Our next question comes from Paul Matteis with Stifel.

Operator: I guess a quick follow-up on trial timing this year and then an ALS question again. So, I believe the DMV study is not technically an adaptive study, which is why you were able to share some PK data. I'm curious, given that it's not as hard to predict as an adaptive study. And then for ALS, what additional data are you expecting to present, if any, at the upcoming NCALS meeting and later this year? That would be helpful. Thanks.

Hey, Thanks for taking our question. This is Alex on for Paul I guess, a quick follow up on trial timing. This year and then in AOS question again, So I believe the DMD study is not technically an adapter side, which is why you were able to share. Some PK data I'm curious given that if you could say anything more about.

About more granular timing on that given that it's not as hard to predict as an adaptive study.

And then for AOS, what additional data are you expecting to present, if any at the upcoming <unk> meeting in and later this year that'd be helpful. Thanks.

Paul Bolno: So to start with, in DMV, while it's not adaptive in nature in terms of being open label, it is blinded in the sense that the biopsies, right, the muscle biopsy stays in the boy until the point where we hit an MTD, have the three subsequent doses, and then take the biopsy. And so I think what we're seeing there is continued dose and dose escalation in that study. So at a point in time, when we hit that threshold, that would obviously be the trigger for us to take those biopsy samples. So the trial continues to progress and continues to escalate. So that's DMD.

Great and thanks for the question so to start with and D. M D well.

If not adaptive in nature in terms of being open label.

It is blinded in the sense that the biopsies right the muscle biopsy.

Muscle stays in the boy until the biopsy point, where we hit at MTV have the three subsequent doses and then take the biopsy and so I think what we're seeing there is continued dose in dose escalation in that study. So at a point in time, when we hit that threshold that would obviously be the trigger for us too.

Take those biopsy sample so trial continues to progress and continues to escalate.

Paul Bolno: Second, was the question for NCALS and the data presented there. We would anticipate presenting the data that we presented previously. And obviously, Mike, we'll go into more detail on the discussion, but it'll be the data that we that we present. Yeah, that'll be the first real opportunity we have to do that in front of the scientific community and get feedback and answer questions. So it would be what we've already presented, and then, if we were in a place where we then have additional data later in the year, whether it be for multidose or higher single doses, that would obviously be presented in the appropriate scientific venue with an expansion of data. We are governed by when the DSMB looks at the data and gives us advice on next steps. Great, that's helpful. Thanks.

So thats DMD.

Second was the question per and cows in the data presented there we would anticipate presenting the data that we presented prior and obviously, Mike will go into more detail on the discussion, but it'll be the data that we presented yeah that'll be the first real opportunity we have to do that in front of the scientific community.

Yes feedback and answer questions. So it would be what we've already presented and then as if we were at a place where we then have additional.

Data later in the year, whether it be for multi dose or higher single doses that would obviously just been presented in the appropriate scientific venue with an expansion of data we are governed by when the SMB looks at data and it gives us some advice on next steps.

Great that's helpful. Thanks.

Thank you.

Operator: Thank you. Our next question comes from Manny Faruhar with SVB Securities. Hey guys, thanks for taking the questions. A couple of quick ones.

Our next question comes from Manny for Harvest SBB Securities.

Hey, guys. Thanks for taking the question a couple of quick ones.

Manny Faruhar: So I'm looking at your guidance of cash runway through 2223. I'm comparing that versus what your cash burn for this quarter versus cash on hand is. Can you give us a sense of what assumptions we should be making about use of the ATM and the assumptions explicitly you're making in that runway guidance around milestones, business development, et cetera, but just trying to find a way to reach that guidance?

So I'm looking at your guidance of cash runway through 2023, I'm comparing that versus what your cash burn for this quarter versus cash on hand is can you give us a sense of what assumptions, we should be making about use of the ATM and the assumptions explicitly you're making in that runway guidance around.

<unk> business development et cetera, but just trying to find a way to to.

Kyle Moran: The numbers don't really seem to support it based on what you've disclosed. And then I have a follow-up. Thanks, Manny, for the question. As you can see, historically, our cash fluctuates quarter to quarter, so I don't think you can take the latest cash and then just calculate that forward.

To reach that guidance the numbers don't really seem to support it. So much you disclosed and then I have a follow up.

Sure. Thanks for the question.

As you'll see historically, our cash fluctuates quarter to quarter. So I don't think you can take the latest cash and then just calculate that forward, but we do expect our quarterly burn going forward to be lower than Q1, as we focus our spend on advancing the program into the clinical.

Kyle Moran: But we do expect our quarterly burn going forward to be lower than Q1, as we focus our spend on advancing the program through the clinical inflection point. Adam, In terms of inflows, we, as you know, historically, we have gotten cash from tax credits, but we don't include any milestones or any other items in there. So to that point, it's not calculating any incremental dilution in terms of ATM. It's not calculating anything.

Inflection points.

In terms of <unk>.

Flows we are as you know historically we have.

Gotten cash from tax credits, but we don't include any milestones or any other items in there.

So to that point its not calculating any.

Incremental dilution in terms of ATM not calculating so ongoing discussion separate from the current guidance. If you could talk about that subsequently, but I think that covers it.

Kyle Moran: So ongoing discussion separate from the current guidance. We can talk about that later, but I think that covers it. Okay, I know this has been touched on a couple of times, but I'm having a little trouble following the logic. When looking at C9-ORF, you pointed out that the competitor program, for which we don't have full data, but we do have a little bit of an understanding of their dosing schedule and discontinuation, they dosed aggressively, including a loading dose approach, and yet did not see a compelling profile. But you think that your single dose... Less aggressive approach will show success. Can you explain that logic to me?

Okay.

Been touched on a couple of times, but I'm, having a little trouble.

I'm, having a little trouble following the logic.

One of the thing about C&I or.

You pointed out that your competitor program, which we don't have full data, but we do have a little bit of understanding of the dosing schedule of discontinuation.

They dosed aggressively including a loading dose approach and yet did not see.

A compelling profile.

But you think that yours single dose less aggressive.

Less aggressive approach will show success.

Can you explain that to me I'm, just yeah, I mean, I just turned into a really basic logic I mean to date, we haven't seen any data on the biomarker or on the activity of the drug for all their safety profile right. We just happened a quick update that said they did the analysis risk benefit terminated the study so we actually collectively as a group don't know.

Paul Bolno: Yeah, I started with some really basic logic. I mean, you know, to date, we haven't seen any data on the biomarker or on the activity of the drug or on their safety profile, right? We just haven't had a quick update that said they did the analysis, and risk benefits terminated the study. We actually, collectively as a group, don't really know anything about the data.

<unk> really anything about the data we look forward to seeing the data.

Paul Bolno: We look forward to seeing the data fulsomely presented so that we can have something to react to. As Mike said, and I'll let him follow up, we see something completely different in a dosing profile. We don't need to have loading doses to initiate that kinetics of the drop of the proteins.

Presented so that we can have something to react to.

As Mike said and I'll, let him follow up.

We see something completely different than in a dosing profile, we don't need to have loading doses to initiate that the kinetics of the drop of the protein low single doses, we're seeing that tranche and it's continuing meaning.

Paul Bolno: Low single doses, we're seeing that drop, and it's continuing, meaning, you know, and it's really reframing how we think about oligonucleotides. As we shared in the full data update that we gave earlier, the PolyGP was continuing to go down, with the DSMB suggesting we push the follow-up period out another three months to see where it gets to. So the profile is just different, and it really gets us thinking about these oligonucleotides as being different in class, different potency, different durability, different safety profile. They're just different, but I'm happy to let Mike continue that.

It's really reframing, how we think about oligonucleotides as we shared on the date of the full data update that we gave earlier.

<unk> was continuing to go down with the F&B, suggesting we pushed follow up period out another three months to see where it gets too. So the profile is just different and it really gets us thinking about these oligonucleotides as being different in class different potency durability safety profile there is different.

Yeah, Yeah, Hi, Miami.

Mike Panzera: Yeah. Jaime, you use the term aggressive in terms of the approach to targeting the biomarker, and I mean, aggressive, I think, sounds like it's being used in the sense of giving high doses, five doses of 90 over four months, so 450 milligram doses to achieve something which we haven't seen, which all we do know made people clinically worse. So aggressive... doesn't necessarily always translate into benefit.

You use the term aggressive in terms of the approach to targeting the biomarker and I mean aggressive I think sounds like it's being used in the sense of giving high doses five doses of 90 over over four months, So 450 milligram dose to achieve something which we haven't seen which all we do now.

People clinically worse so aggressive.

It doesn't necessarily always translate into benefits I mean.

Mike Panzera: I mean, this is a benefit-risk equation. And the idea of where we're being, as you said, less aggressive is having a very potent and selective molecule that allows us at low doses to potentially achieve better than higher doses of a different molecule. I think our approach is really to optimize the profile with the better compound. And so I don't think you can say one's aggressive, one's not aggressive; I think one's a compound that caused a problem, and one's a compound that's clearly, even at the starting doses, leading to indicators of benefits.

This is a this is a benefit risk equation.

And the idea.

There were being as you said less aggressive as having a very potent and selective molecule that allows us at low doses to potentially achieve better than higher doses they different molecule.

I I think our approach is really to optimize the profile with the better compound and so I don't think you can say one's aggressive once not aggressive I think once a compound that cause a problem in one of the compound thats clearly even at the starting doses leading indicators of benefits. So I think thats why we are confident we just need to keep going and.

One does not necessarily.

Mike Panzera: So I think that's why we're confident we just need to keep going, and one does not necessarily have to. Yeah, I mean, I mean, that was like the thing is, I mean, Joe's thing is how about making a medicine is not progressive; it's about potency. And potency means achieving a greater effect at equivalent levels. So I think what we're seeing is what we designed is a potent molecule, therefore achieving greater knockdown at lower doses, which is advantageous in treating CNS diseases, as we've kind of followed the history of what's been done. Therapeutic Area

Yes, I mean, I mean that I always like the thing.

Dosing of how about thinking of medicine.

Aggressive it's about potency potency means achieving greater effect that equivalent level. So I think what we're seeing is what we designed is a potent molecule therefore, achieving greater knockdown at lower doses, where do that Ben pages, and we think treating CNS diseases as we've kind of followed that the history of what's been done.

The therapeutic area.

Paul Bolno: That's actually really helpful when you talk about following history. It sounds like a lot of your rationale hinges upon your confidence in your interpretation of your own preclinical data. Given the history of WAVE's challenges interpreting their own preclinical data in any predictable way, Given the previous DMV programs, repeatedly at Hopkins, etc., what changes have you made since those programs, since those disappointments, to develop an internal expertise in consistently interpreting preclinical data that you guys did not possess before?

That's actually really helpful. When you talk about following the street it sounds like a lot of your rationale.

Hinges upon your confidence and your interpretation of your own preclinical data.

Given the history of a wage challenges interpreting their own preclinical data in a predictable way.

Given the previous D&B programs repeatedly in Huntington's et cetera, what changes have you made since those progress since those disappointments.

To develop an internal expertise inconsistently interpreting preclinical data that you guys did not possess before.

Paul Bolno: Yeah, I think, you know, framed in a different way because in that day, when we evaluated pre-clinical data, if we go back to step one and two in the CNS, we didn't have predictive models to assess that starting dose and where we were. I mean, we had a number of conversations where we had to triangulate between in vitro knockdown data. And we had to look at non-human primate tissue concentrations and predict human dosing and what was happening with all of those.

Yes, I think yes.

And frame it a different way because of that day is weak.

<unk> evaluated preclinical data if we go back one and two in the CNS. We didn't have predictive models to assess that starting dose and where we were we had a number of conversations where we have to triangulate between in vitro knockdown data and we had to look at non human primate tissue concentration can predict human dosing and what was happening with oligos.

Paul Bolno: What we've changed, you know, we've said this over the course of, you know, 2021, which is just great, you know, and I think it's important that we continue to reiterate it, you know, one differentiated chemistry that's translating to different pharmacology and profiles. Two pre-clinical models now, where we can assess target engagement, we can do the pharmacology assessment, we can model that assessment, and we can plan for where we started in the clinic.

What we've changed we said this over the course of 2021.

It's great.

I think it's important that we continue to reiterate that one differentiated chemistry, that's translating to a different pharmacology and profile to preclinical models now where we can assess target engagement. We can do the pharmacology assessment, we can model that assessment and we can plan for where we started in the clinic and that was the data we shared I think it was July of <unk>.

Paul Bolno: And that was the data we shared; I think it was July of last year that we announced the initiation of the study. We were very clear that we were initiating the study on C9, modeled based on where we would anticipate target engagement based on our pre-clinical data to guide the adaptive clinical trial design. These data that we shared recently reaffirmed that for us. In the adaptive design at the first dose, the 10 milligram dose, the statistically significant dose response against placebo.

Last year, we announced the initiation of the study we were very clear that we are initiating the study on benign modeled based on where we would anticipate target engagement based on our preclinical data to guide the adaptive clinical trial design. These data that we shared recently reaffirmed that for US we thought it would.

The adaptive design at the first dose of 10 milligram dose was statistically significant dose response against placebo. So as we follow this out.

Paul Bolno: So as we followed this out, it told us that our approach to the clinic was translating, and as Mike alluded to, you know, we hope to see the same thing in HD and others. So, I think the fundamental shift to your question was really better use of modeling where we're designing that. Our pharmacology is different based on PN chemistry. I think our double knockout mouse in PMD was a great example of being able to compare a PSPO backbone, which was the backbone of the cervidursum, against the backbone in N531 with PN chemistry, seeing different distributions of the nucleus and cell muscle updates, seeing different changes in survival that were consequential, and ultimately looking at functional outcomes.

It told us that we are guiding to the clinic was translating and as Mike alluded to we hope to see the same thing in HD and others. So I think the fundamental shift to your question was really better use of modeling where we're designing that our pharmacology is different based on Pn chemistry, I think our double knockout mouse B M. D was a great example of being able to compare.

<unk> backbone, which is the backbone of a separate nurse them against.

Against the backbone and then 531 with Pn chemistry being different distribution to the nucleus and sell muscle update seeing different change in survival that was consequential and ultimately looking at functional outcomes. So.

You know wholesale the shifts in 2020 to 2021, which is really about the new chemistry and implementing it in the change like our other peer platform companies and all of us have done coupled with better predictive modeling.

Paul Bolno: So, I think, you know, wholesale, the shift in 2020 to 2021, which is really about new chemistry and implementing it, and the change like our other peer platform companies and all of those have done, coupled with better predictive modeling, really with the transformation in 2021, that led to the three clinical programs that we have today and essentially acceleration of our RNA editing platform. But it was a fundamental shift in predictive modeling. Great That's a helpful understanding of thinking.

With the transformation in 2021 that led to the three clinical programs that we have today and essentially acceleration of our RNA editing platform, but it was a fundamental shift in predictive modeling.

Operator: Thanks, guys. Thank you. Our next question comes from Tzu Chi Jiang with Jeff. Hi, thanks for taking our question. This is Suzy dialing in for Yoon.

Great. That's helpful I understand youre thinking thanks, guys.

<unk>.

Our next question comes from Suzhou, Hong with Jefferies.

Hi, Thanks for taking our question does it huge you dialing in for Ian.

Operator: So my first question is, when you have the data for DMD and Huntington's disease programs later this year, what are the key steps to make a decision about further development? And I have a couple of follow-up questions.

Yeah. My first question is when you have the data for D M D and Huntington's disease program.

Later this year.

A good decision for further development and I have a couple of follow ups. Thanks.

Paul Bolno: So I'm going to, I'm going to repeat your question. And please just tell me if we have it inaccurately. So you just want to know what the bar is for the next phase of development in HD and DMD? Yes, okay. Yeah, so I think, you know, what we anticipate being able to share in HD is very similar, and I think we all have an idea of what an update looks like, right? We did that in C9, which was, "Here's the data update in terms of target engagement, dose, and understanding and safety for that drug." In Huntington's disease, so it was polyGP in the case of C9.

Sorry, you started to break up towards the end, so I'm going to I'm going to repeat your question. Please just tell me if we haven't inaccurately.

Just want to know what what is the bar for next phase of development in HD and DMD.

Paul Bolno: So we anticipate being able to share, and the biomarkers that we're assessing in the HD study are, obviously, the mutant Huntington that we're looking at, wild-type Huntington, and we'll continue to have NFL. But those will be the total data sets that we'll use in total to make decisions over 2022 in the case of HD. And then for DMD, we'll have muscle biopsies, where a key question we want to answer about that is, did we change tissue concentration and distribution?

Yes.

Okay. Yeah. So I think what we anticipate being able to share in HD is a very similar and I think we all have an update kind of what an update looks like right. We did that in C&I, which was here's the data update in terms of target engagement.

Understanding and safety for that drug.

This disease, so as poly GP in the case of Bob Danine, So, we anticipate being able to share his and biomarkers that we're assessing and the HD study is obviously the mutant Huntington, we're looking at wild type Huntington and we will continue to have an effect, but those would be the total data set will use in total to make decisions over 2022 in the <unk>.

Cases of HD and then for DMD will have muscle biopsies were a key question. We want to answer on that is did we change tissue concentration of distribution because if you remember last year.

Paul Bolno: Because if you remember last year, I'm sorry, not last year's, two years later, with subadursin, you know, we actually, and we shared this at one of the muscle, muscle discussion meetings after that data, we didn't see the distribution of the drug, drug got stuck in the interstitial space, we didn't see that translation in the boy's muscle compartment of the drug getting into the nucleus.

Sorry, not last year's tier sooner.

With that stupid person.

We actually and we shared this at the muscular muscle.

Earnings after that data as we didn't see distribution of drug drug got stuck in the interstitial space, we didn't see that translation the boy's muscle compartment of drug getting into the nucleus. So we'll be able to do that same assessment as part of the study to really answer the question fundamentally and then 531 different than stupid person is preclinical as the previous question is preclinical data translate.

We will also obviously be looking at Mr. Sena swap.

This will be the.

Drivers to and we will give updates during those data as to what the next steps for those things.

Paul Bolno: So we'll be able to do that same assessment as part of the study to really answer the question fundamentally, is N531 different than subadursin, is preclinical, the previous question, is preclinical data translation, and we'll also obviously deal with that. But those will be the drivers, too, and we'll give updates during those data as to what the next steps for those are. Great, thank you. So you mentioned the wild-type Huntington level data that you're going to be sharing. So I remember that a couple years ago you guys had trouble measuring the wild-type Huntington. Do you have the SA confirmed and ready to be used?

Oh, great. Thank you. So you mentioned about the wild type Huntington level data that Europe might be sharing so I remember that a couple of years ago, you guys had trouble measuring.

Do you have to S. A.

Confirmed and I'm ready to be used.

Paul Bolno: And another question I have is related to the C9 program. As you pointed out on your slide, C9 ALS could also be driven by the loss of function as well as function. And your program, as well as Biogen, only targets the gain-of-function side. Do you think that there might be some manifestations of the disease years that Biogen may not be able to address because it only targets one side of the pathophysiology? So I'll take the first question, and Michael will take the C9 question.

And another question I have is related to this jeannine program.

As you pointed out on your slide nine al as could also be driven.

The loss of function as well as kitchen, and your program as well it's biogen.

Targets the gain of function side do you think that there might be some manifestation.

He years, having buyers you may not be able to address because you'd only targets one site up the pathophysiology.

Paul Bolno: But to the assay, I mean, while disappointing in the SNP 1 and 2 study, I think the one piece that we will take solace in is that we did validate the assay for the wild type. And, you know, in conjunction with our partners at THCI and other institutes. So I think there's a lot done to have that assay ready. We use that assay often. So we feel confident in both that assay as well as in the mutant assay. So I think the tools that we need to use to evaluate the program are in place.

So I'll take the first question and Mike will take the question, but to the assay I mean, I think while disappointing on the snip, one and two study I think the one piece that we will take <unk>.

<unk> is that we did validate the assay for the wild type.

In conjunction with our partners at CACI and other.

And to do so I think there was a lot done to have that assay ready we use that assay.

We feel confident about that assay as well as in the mute that today. So I think the tools that we need to use to evaluate program.

Our in place and now based on the predictive modeling that we have with the three and the design of the study we will do that assessment now with pn containing step three molecule. So we do feel confident that we have the tools to be able to assess.

Mike Panzera: And now, you know, based on the predictive modeling that we have with Step 3 and the design of the study, we'll do that assessment now with a PN containing Step 3 molecule. So, you know, we do feel confident that we have the tools to be able to assess the outcome. And the only thing I'd add about the assay is that the assay itself, the details were presented at CHDI. And, you know, so I think that's an important thing where it's been reviewed and discussed within the scientific community.

And the only thing I'd add on the assays that the assay itself the details.

Sure.

<unk> presented at the HDI and so.

So I think thats an important thing.

Where it's been reviewed and discussed within the scientific community.

I think in terms of.

The biology of <unk>.

Mike Panzera: I think in terms of, you know, the biology of C9ALS, our approach here is to develop a compound that is as selective as possible to not make any pre-existing haploid insufficiency any worse. I mean, we know that people who are asymptomatic for the disease have that haploid insufficiency and, even in the setting of toxic protein, remain asymptomatic.

Our approach here is to develop a compound that.

Is <unk> is a selective as possible to not make any preexisting have low insufficiency.

Any worse I mean, we know that people were asymptomatic, but the disease have that have that happened sufficiency and even in the setting of the protein remain asymptomatic. So as you bring down that asymptomatic as you bring down that toxic protein and allow the tableau.

Mike Panzera: So as you bring down that asymptomatic, as you bring down that toxic protein and allow the haploid, without worsening the haploid insufficiency, we believe and, in working with the community, believe that this is still an approach that's going to yield good clinical outcomes. So we're comfortable in how we approach this. Thank you. And one last question. Did you say that you expected quarterly cash burn to be lower than in the first quarter? I just wanted to clarify that. That's correct.

Without worsening the half one sufficiency.

We believe in and working with the community believes that this is still a an approach that's going to yield.

Good clinical outcome. So we're comfortable in how we're approaching this.

Operator: Thank you. Could you elaborate on why you expect the quarterly cash burn to be lower than the first quarter as you have those clinical trials ongoing? Yeah, I mean, as I said, our cash flow influx rates go quarter to quarter based on activity based on cash outflows. And often, in the first quarter, we have outflows that are higher than other quarters. And you can see that historically. If we look back to the fourth quarter of last year, it was significantly lower than the first quarter of this year.

Thank you and one last question did you say that you expect quarterly cash burn to be lower than in the first quarter.

Just wanted to clarify that.

That's correct.

Could you elaborate on how.

Why do you expect the quarterly cash burn to be lower than the first.

Grace quarry as she has done clinical trials ongoing.

Operator: So, as I said, I don't think you can just take the first quarter cash and trend that out. I think you have to look at a longer time period and take into account the fact that in some of the prior periods, we had PhD and DMV programs ongoing, so there were high expenses there.

Yeah, I mean I.

As I said, our cash burn fluctuates quarter to quarter based on activity based on cash outflows.

Often in the first quarter, we have we.

We have outflows that are higher than other quarters.

You can see that historically.

If we look back to the fourth quarter last year, it was significantly lower than the first quarter of this year. So.

As I said I don't think even just take first quarter cash and trend that out I think you have to look at.

A longer time period and take into account the fact that.

And some of the prior periods, we had Phd in DMD programs ongoing so there were high expenses there so.

I understand it's not a straightforward calculation, but.

Kyle Moran: So I understand it's not a straightforward calculation, but we're comfortable with our projections. And, as you know, we've been consistent in our cash from WAVE statement. Thank you. And I'm not showing any further questions at this time. I'd like to turn the call back to Paul for any...

We're comfortable with our projections and.

As you know we've been consistent in our cash runway statements.

Okay, great. Thank you.

Yeah.

Yes.

And I'm not showing any further credit time I'd like to turn the call back to Paul for any closing remarks.

Paul Bolno: Thanks, everyone, for joining the call this morning to review our first quarter 2022 financial results and corporate updates, and thank you to our WAVE employees for their hard work and commitment to patients. Have a great day. Thank you. Ladies and gentlemen, this concludes today's presentation. You may now disconnect and have a wonderful day. [music]

Thanks, everyone for joining the call. This morning to review, our first quarter 2022 financial results and corporate update and thank you to our wave employees for their hard work and commitment to patients have a great day. Thank you.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect and have a wonderful day.

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