Q4 2021 WAVE Life Sciences Ltd Earnings Call

At this time all participants are in a listen only mode.

Operator: At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded for webcast. I'll now turn the call over to Kate Rausch, Head of Investor Relations at WAVE Life Sciences. Please go ahead.

As a reminder, this call is being recorded and webcast I'll now turn the call over to Kate Rausch head of Investor Relations at Wave Life Sciences. Please go ahead.

Kate Rausch: Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review WAVE's fourth quarter and full year 2021 financial results. Joining me today with prepared remarks are Dr. Paul Bolno, WAVE's President and Chief Executive Officer, Dr. Coloma Giangrande, VP of Biology and Platform Development, Dr. Mike Panzera, Chief Medical Officer, Head of Therapeutics Discovery and Development, and Kyle Moran, Chief Financial Officer. This morning, we issued a news release detailing our fourth quarter and full year 2021 financial results and provided a business update.

Thank you operator, good morning, and thank you for joining us today to discuss our recent business progress and review with fourth quarter and full year of 2021 financial results.

Joining me today with prepared remarks, I got to Pablo now its president and Chief Executive Officer, Patrick Colombia, Dune Grande VP biology, and platform development after make Pandora Chief Medical officer head of therapeutic discovery and development and calmer and Chief Financial Officer.

This morning, we issued a news release detailing our fourth quarter and full year, 2020 , one financial results and provided a business update.

Kate Rausch: This news release and a slide presentation to accompany this webcast are available in the investor section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that the discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31st, 2021. 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?

News release, and a slide presentation to accompany this webcast are available in the investors section of our website Www Dot wave life Sciences dotcom before.

Before we begin I would like to remind you that discussions during this conference call will include forward looking statements.

Statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward looking statements.

Factors that could cause actual results to differ I discussed in the press release issued today and in our.

<unk>, including our annual report on Form 10-K for the year ended December 31, 2021, we undertake no obligation to update or revise any forward looking statement for any reason.

Now, let me turn the call over to Paul Paul Thanks, Keith Good morning, and thank you all for joining us.

Paul Bolno: Thank you, Kate. Good morning, and thank you all for joining us today. Mike, our CMO and Head of Therapeutics Discovery and Development, and Paloma, VP of Biology and Platform Discovery, will then provide an update on our clinical and preclinical therapeutic programs. And lastly, WAVE CFO Kyle Moran will discuss our financials.

Today, I will begin with opening remarks, Mike our CMO and head of therapeutic discovery and development and Paloma VP of biology and platform Discovery will then provide an update on our clinical and preclinical therapeutic programs and lastly wave CFO , Kyle Moran, who will discuss our financials.

Paul Bolno: At WAVE, we continue our journey building a leading genetic medicine company grounded in our innovative RNA therapeutics platform, PRISM. The platform today reflects nearly a decade of investment in entirely new chemistry, including our PN backbone modifications, which have the potential to disrupt the pharmacology of therapeutic oligonucleotides. Over the course of 2021, we made significant progress by bringing PN chemistry into the clinic with our three neurology candidates, as well as advancing PN chemistry within a new modality, our RNA editing aimers. Today, we have a diversified portfolio that reflects the breadth of our platform.

And wave we continue our journey building, a leading genetic medicines company grounded in our innovative RNA therapeutics platform prism.

Platform today reflects nearly a decade of investment and entirely new chemistry, including our pn backbone modification, which have the potential to disrupt the pharmacology therapeutic oligonucleotides.

Over the course of 2021, we made significant progress by bringing Pn chemistry into the clinic with our three neurology candidates as well as advancing pn chemistry within a new modality, our RNA editing gamers.

Today, we have a diversified portfolio that reflects the breadth of our platform.

Paul Bolno: Clinical data this year will inform next steps for our neurology program, and we are rapidly advancing our aimers using targeted delivery for hepatic diseases, starting with Alpha-1 antitryptamine. Partnerships are an important component of our strategy to unlock value from our platform, pipeline, and other assets, such as our GMP manufacturing facility. In a growing number of preclinical studies, we have shown how PN chemistry benefits oligonucleotide therapeutics, including modalities outside of our core focus, such as RNAi.

Clinical data this year will inform next steps for our neurology programs.

And we are rapidly advancing our amer using targeted delivery for hepatic diseases, starting with Alpha one antitrypsin.

Partnerships are an important component of our strategy to unlock value from our platform pipeline and other assets such as our GMP manufacturing facility.

And a growing number of preclinical studies, we have shown how pn chemistry benefit oligonucleotide therapeutics, including modality outside of our core focus such as R&D huh.

Paul Bolno: We are seeing significant interest, and we expect 2022 to be an important year for executing on partnering opportunities. Just recently, we announced two peer-reviewed publications in nucleic acids research that describe the incorporation of TN backbone modification in stereopure oligonucleotides to improve potency, tissue distribution, and durability effects for silencing in the CNS and for splicing in DMV. Our silencing paper was designated as a breakthrough article by the journal.

We are seeing significant interest and we expect 2020 to be an important year for executing on partnering opportunity.

Just recently, we announced two peer reviewed publication nucleic acids research, which describe the incorporation of pn backbone modification.

Are you a pure oligonucleotide to improve potency tissue distribution and durability of effect for silencing in the CNS and for Spicing can dnb.

Our silencing paper was designated as a breakthrough article by the journal.

Paul Bolno: Their acknowledgement of the strength of these data and the potential of our platform to impact the field is a significant milestone for WAVE. We continue to define the broad applicability of PN chemistry for potential therapeutic use. As we first shared at our research day last year, PN modifications can be applied to siRNA, and they result in meaningful improvements as compared to state-of-the-art advanced ESD chemistry.

Their acknowledgment of the strength of these data and the potential of our platform to impact the field is a significant milestone for wave.

We continue to define the broad applicability of Pn chemistry for the potential therapeutic use as we first shared at our research day last year Pn modification can be applied to SA RNA and they result in meaningful improvement as compared to state of the art advanced chemistry.

Paul Bolno: On slide 7, we show recent results that provide another compelling example, this time with the HSD17B13 target. With a single dose of 3 mg per kg, we saw a remarkable 80% HSD silencing that persisted out 14 weeks, while the comparator lost activity at the same time point in the transgenic mouse model. We also saw significantly greater risk loading of PRISM siRNA at all time points, as shown on the right. These results are dramatically improved from our earlier hepatic discovery efforts prior to the introduction of PN chemistry. Our current portfolio includes multiple stereo-pure, PN-modified, single-stranded oligonucleotides with and without targeted delivery conjugates.

On slide seven we show recent results that provide another compelling example, this time with HST 17 <unk> target.

With a single dose of three milligrams per kilogram, we saw remarkable 80% HST silencing that persisted out 14 weeks, while the comparator last activity at the same time point in a transgenic mouse model.

We also saw significantly greater risk loading of prism SA RNA at all time points as shown on the right.

These results are dramatically improved from earlier hepatic discovery efforts prior to the introduction of Pn chemistry.

Yeah.

Our current portfolio includes multiple stereo pure pn modified single stranded oligonucleotides with and without targeted delivery conjugate.

Paul Bolno: In the clinic, we are advancing WVE004, targeting C9-ORF72 for ALS and FTD, and WVE003, an allele-selective mutant Huntington candidate for patients with HD and a CYP3 mutation. These candidates are dosed intrathecally and will give us insight into potency and duration of effect through biomarkers in the CNS. WVEN531, our exon 53 splicing candidate for patients with DMD, is administered intravenously and will provide insight into how PN modified compounds can improve muscle tissue concentration and, hopefully, the level and duration of exon skipping and dystrophin production.

In the clinic, we are advancing W. V E 004, targeting <unk> nine or 72 for AOS and F. T D and W. V E 003 allele selective mutant Huntington candidate for patients with H D. Smith.

Reputation.

These candidates are dose equally and will give us insight into potency and duration of effect through biomarkers in the CNS.

W V and by three one our exon 53 slicing candidate for patients with DMD is administered intravenously and will provide an insight into how pn modified compounds can improve muscle tissue concentration and hopefully the level and duration of exon skipping and dystrophin production.

Paul Bolno: With AMERS, we are initially focused on hepatic indications and using targeted gown neck mediated delivery, which is expected to enable subcutaneous dosing in the clinic. We are unique in our RNA-based editing approach, as our GalNet-conjugated aimers are short, stabilized with chemical modifications, including TN, and designed to engage endogenous ADAR enzymes.

With <unk>, we are initially focused on hepatic indication and using targeted calmac mediated delivery, which is expected to enable subcutaneous dosing in the clinic.

We are unique in our RNA based editing approach as our <unk> conjugated <unk>, our short stabilized with chemical modifications, including Pn and designed to engage endogenous adar enzymes.

Paul Bolno: Success with any of our ongoing programs unlocks a broad universe of targets in the CNS, muscle, and our liver. We expect to share clinical data in 2022 for WVE004, 003, and N531 to provide insight into the clinical effects of TN chemistry and enable decision making for each program. By using chemically modified guide strands to engage endogenous machinery, our RNA-based editing approach is distinct from others.

Success with any of our ongoing programs unlocked a broad universe of targets in the CNS muscle and deliver.

We expect to share clinical data in 2022 for W. V E near 04003, and then 531 to provide insight into clinical effects of Pn chemistry and enabled decision making for each program.

By using chemically modified guidance trends to engage and dodges machinery or RNA base editing approach is distinct from others. We are very excited about the broad potential of AME.

Paul Bolno: We are very excited about the broad potential of AIMS. Our wholly owned LEAD AAPD program represents a significant commercial opportunity, with approximately 200,000 people carrying homozygous disease immunization in the U.S. and Europe. Demonstrating clinical proof of concept in ATD would serve to de-risk additional monogenic diseases, as well as open opportunities to address large patient populations through modulation of protein, such as disruption of protein protein interacts. When We Build WAVE.

Our wholly owned lead ATB program represents a significant commercial opportunity with approximately 200000 people carrying homozygous communications in the U S and Europe .

Demonstrating clinical proof of concept and ATB 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.

Yes.

When we built waves.

Paul Bolno: We recognize the growing momentum in RNA therapeutics and anticipated the value of having an internal GMT manufacturing facility. Our manufacturing team is made up of experts in oligonucleotide synthesis who have successfully delivered clinical supply for six global studies at WAVE to date. With this facility, we can support the supply of innovative oligonucleotide genetic medicines at all stages of product development with any chemist. And we are now evaluating using our additional capacity to support new partners.

We recognize the growing momentum in RNA therapeutics and anticipated the value in having an internal GMP manufacturing facility.

Our manufacturing team is made up of expertise oligonucleotide synthesis that have successfully delivered clinical supply for six global study at wave to date.

With this facility, we can support the supply of innovative oligonucleotide genetic medicines at all stages of product development with any chemistry, and we are now evaluating utilizing our additional capacity to support new partners.

We plan to build on this capability throughout 2022.

Mike Panzera: We plan to build on this capability throughout 2022. I'd now like to turn the call over to Mike Pendera for an update on our clinical pipeline. Mike. Thanks, Paul.

I'd now like to turn the call over to Mike <unk> for an update on our clinical pipeline Mike.

Thanks, Paul.

Mike Panzera: The addition of PN backbone modifications in the context of stereopurity and the prism platform distinguishes our current clinical candidates not only from our first generation programs but from any other oligonucleotides in development today. Let's start with a review of some of the preclinical data that support our view that judicious application of PN chemistry fundamentally alters the pharmacological profile of our oligonucleot I'm going to use mouse, NHP, and human data from WVE N531 to illustrate this point.

The addition of Pn backbone modifications in the context of stereo purity and prism platform distinguishes our current clinical candidates not only from our first generation programs, but from any other oligonucleotides in development today, let's start with a review of some of the preclinical data that support our view that too judicious.

<unk> Pn chemistry fundamentally alters the pharmacological profile of our oligonucleotides.

I'm going to use my.

And H P and human data from W. V E and 531 to illustrate this point.

Mike Panzera: As I will review, whenever comparing PN-modified compounds to those using first-generation PSPO chemistry, PN chemistry consistently leads to increased exon skipping activity, increased muscle exposure, longer half-life, and more durable. As described in our recent nucleic acids research paper, the addition of a few PN backbone modifications to compounds administered in mouse models boosted muscle concentrations and led to higher exon skipping and dystrophin protein levels when compared to compounds using first generation PSPO chemistry.

As I will review whenever comparing pn modified compounds to those using first generation P. S. P. O chemistry, Pn chemistry consistently leads to increased exon skipping activity increase in muscle exposure longer half life and more durable effects.

As described in our recent nucleic acids research paper. The addition of a few pn backbone modifications to compounds administered in mouse models boosted muscle concentrations led to higher exon skipping and dystrophin protein levels when compared to compounds using first generation P. S. P O chemistry.

Mike Panzera: Notably, these improvements were seen both in diaphragm and heart muscles, and as noted in the same paper, were seen at a relevant human equivalent dose of approximately 6 mg per kg administered every other week. That translated to a functional benefit in the double knockout mouse model. Building on these data, WVEN-531, currently in the clinic, utilizes a similar PN-dereochemical modification while targeting XM-53 to facilitate splicing in the muscles of boys with DMD mutations amenable to XM-53 skipping.

Notably these improvements, we're seeing broken diaphragm and heart muscles and as noted in the same paper, we're seeing at irrelevant human equivalent dose of approximately six milligram per kilogram administered every other week that translated to a functional benefits and the double knockout mouse.

All of them.

Building on these data W. E. N 531 currently in clinic use it utilize the similar pn theory chemical modifications, while targeting exon 53 to facilitate splicing and the muscles of boys with DMD mutations amenable to exon 53 skipping.

Mike Panzera: N531 was evaluated in multiple NHP studies similar to our first-generation PSPO compound suvidursin as part of the preclinical package required to support the first-in-human study. What's been stunningly consistent is that regardless of dose level, higher concentrations of N531 are present in NHP muscle, far in excess of concentrations observed in sulurous and preclinical studies. The same applies to plasma concentration.

531 was evaluated in multiple NH Pea study similar to our first generation P. S. P O compounds through Richardson as part of the preclinical package required to support first in human studies.

What's been stunningly consistent is that regardless of dose level higher concentrations and 531 or presence in NH be muscle far in excess of concentrations observed and see what are some preclinical studies.

The same applies to plasma concentration.

Mike Panzera: This illustrates the properties of this pn-modified compound hold true when moving from a loaded model into a larger and more relevant model. The relevance of this comes from the ability of N531 to facilitate exon skipping in NHPs, as shown here, even at low doses. As a reminder, in the setting of Healthy Muscle, as shown here, successful target engagement through Detection of Skid Transcript is the goal. Dystrofen is not produced in this setting.

This illustrates the properties of this pn modified compound hold true when moving from a loaded model into a larger and more relevant species.

The relevance of this comes from the ability of Empire, three one to facilitate exon skipping and hps as shown here even at low dose levels.

As a reminder, in the setting of healthy muscle as shown here successful target engagement.

Through detection skip transcript is the goal to stroke and is not produced in this setting at the lowest dose tested three milligram per kilogram or human equivalent dose of one milligram per kilogram, we confirmed successful target engagement.

Mike Panzera: At the lowest dose tested, three milligrams per kilogram, or a human equivalent dose of one milligram per kilogram, we confirmed successful target engagement. This dose level was substantially lower than where we were able to detect target engagement with ZUVA DIRS. Turning to our clinical study, we are fortunate to be able to evaluate plasma concentrations in an ongoing fashion, given that the study is open-label. In this setting, even at the starting dose, we are already seeing differences in the profile of N531 when compared to the profile of subitur C, with a substantial increase in plasma concentrations at a given dose level and a clear increase in plasma half-life.

This dose level was substantially lower than where we were able to detect target engagement to Richardson.

Mike Panzera: We currently estimate the plasma half-life of N531 to be at least a week as compared to less than 24 hours for subitur C. However, these data were collected following a single starting dose in our open-label trial, and dose escalation is ongoing.

Turning to our clinical study.

We are fortunate to be able to evaluate plasma concentrations in an ongoing fashion given that the study is open label in this setting even at the starting dose we are already seeing differences in the profile of <unk> and 531, when compared to the profile of <unk>.

With a substantial increase in plasma concentrations at a given dose level and a clear increase in plasma half life. We currently estimate the plasma half life with and 531 to be at least a week.

As compared to less than 24 hours for stupid or something.

These data were collected following a single starting dose in our open label trial in dose escalation is ongoing.

Mike Panzera: As mentioned, dose escalation is ongoing in this trial, and we expect to begin multidose in the initial cohort once we have selected a dose level. We expect clinical data, including muscle biopsies, where we will compare the intracellular distribution of N531 to suvidursin in 2022. Turning to the CNS, we have a similar profile with PN-modified oligonucleotides in preclinical studies, including increased potency in neurons and, in mouse studies, extended durability of silence and enhanced tissue exposure in vivo.

As mentioned dose escalation is ongoing in this trial and we expect to begin multi dosing. The initial cohort once we have selected a dose level, we expect clinical data, including muscle biopsies, where we will compare the interest cellular distribution of Empire three one distributor.

In 2022.

Turning to the CNS, we have a similar profile with Pn modified all the nucleotide in preclinical studies, including increased potency in neurons and mouse studies extended durability of silencing enhanced tissue exposure in vivo.

Mike Panzera: These data were recently published in Acrylic Acids Research, and as Paul highlighted, the paper was designated as a, The FOCUS C9 clinical trial is 004 and our C9R72 targeting candidate for the treatment of ALS and FTD is ongoing. In January, the Alzheimer's Drug Discovery Foundation, or ADDF, and the Association for Frontal Temporal Dementia, or AFTD, partnered with WAVE to support our focus in Ein This decision was based on a review of our clinical study plans, preclinical data, and expertise in our study plan.

These data were recently published in nucleic acids research and as Paul highlighted the paper was designated as a breakthrough.

But focusing on clinical trial of 004 and our C&I.

Our C nine or 72 targeting candidate for the treatment of AOS and MTV is ongoing.

In January the Alzheimer's drug Discovery Foundation, or a D. D F in the Alzheimer's and the association for frontal temporal dementia or FTE partnered with wave to support our focusing on trial.

This decision was based on review of our clinical study plans preclinical data and expertise of our study team.

Mike Panzera: We are pleased to partner with these organizations as we advance this study to address these two devastating neurological diseases. As mentioned earlier, FOCUS C9 is ongoing, and we expect to share clinical data for 004 in 2022 to provide insight into PN chemistry and enable decision making for this program. Finally, I'll spend a moment on HD.

We are pleased to partner with these organizations as we advance this study to address these two devastating neurological diseases.

As mentioned earlier.

<unk> nine is ongoing and we expect to share clinical data for <unk> 004, and 2022 to provide insight into pn chemistry and enabled decision making for this program.

Mike Panzera: I'm speaking to you from the annual CHDI HD Therapeutics Conference, where later today I will be highlighting our ongoing select HD clinical trial evaluating WVE Zero-Tree, our allele-selective candidate for Huntington's disease. Interest in the importance of preserving wild-type HTT in the context of Huntington knockdown is only growing, with some of the most recent data from Roche's Generation HD program only fueling robust discussions In a poster presentation yesterday, our team highlighted our breakthrough approach to measurement of wild-type Huntington in the CSF, a critical step if treatments to preserve wild-type HTTs are to be developed.

Finally, I'll spend a moment on H D.

I'm speaking to you from the annual C. H D. I H D Therapeutics conference, where later today I will be highlighting our ongoing select HD clinical trial evaluating WP easier zero, three or allele selective Kennedy for Huntington's disease.

Interest in the importance of preserving wild type <unk> in the context of Huntington knockdown is only growing with some of the most recent data from Roche as generation HD program, only fueling robust discussions about allele selective treatment.

And a poster presentation yesterday, our team highlighted our breakthrough approach to measurement of wild type Huntington in the CSF, a critical step with wild type HDD preserving treatments are to be developed.

Mike Panzera: This assay is in place in the SELECT-HD study, and we are in discussions with a variety of stakeholders working towards making the assay available for use in the community. As I mentioned, SELECT-HD is also ongoing, and we expect to share clinical data for 003 and 2022 to provide insight into PM chemistry and enable decision-making for this program. I'd now like to turn the call over to Dr. Paloma Giangrande to provide an update on WAVE's AATD program. Paloma?

This assay is in place and the select HD study and we are in discussions with a variety of stakeholders working towards making the assay available for use in the community.

As I mentioned like H D is also ongoing and we expect to share clinical data for 003, and 2022 to provide insight in Japan chemistry and enabled decision making for this program.

I'd now like to turn the call over to Dr. Paloma junk Grande to provide an update on waves.

E program Paloma.

Paloma Giangrande: Thanks, Mike. Hello, everyone. Today, I'm excited to share some new preclinical data with you. For a quick review, Alpha 1 anti-tripsum deficiency, or AATB, is a genetic disease that resolves from a point mutation in the Serpent A1 gene, leading to missholding an aggregation of mutants via AAT protein into padisbites, in the form of globules, and lack of functional AAT in This results in progressive lung injury, liver injury, or both.

Thanks, Mike.

Hello, everyone today I'm excited to share some new preclinical data with you.

As a quick review Alpha one antitrypsin deficiency or <unk> is a genetic disease that results from a point mutation in the <unk>, one gene leading to Miss holding an aggregation of mutant <unk> protein in Japan in the form of globules and lack of functional.

<unk> in circulation.

This result in progressive lung injury liver injury.

Paloma Giangrande: Our eight data editing approach to correct AATD is focused on homozygous ideas or these patients that have the highest risk of disease. Achieving at least 50% RNA editing in hepatocytes is expected to result in levels of functional wild type MAAT protein and serum that are in the range of a heterozygous or MZ phenotype with a low risk of disease. Importantly, as the vast majority of AAT protein is produced in hepatocytes, we can leverage targeted galnac-mediated delivery to address both liver and lung pathology.

Our eight eight or editing approach to correct. A TD is focused on homeless ideas or D is the patients that have highest risk of Disney.

Achieving at least 50% RNA editing in Jakarta site is expected to result in levels of functional wildfire MAA Pea protein and serum that are in the range of the heterozygous or N V phenotype with low risk of dengue.

Importantly, as the vast majority of a pea protein is produced in hepatocytes, we can leverage targeted gundlach mediated delivery to address both liver and lung pathology.

Paloma Giangrande: As shown on slide 22, we have observed therapeutically meaningful levels of AAT restoration with AMR treatment in a transgenic mouse model. In this study, we dose GONLEC AMRs biweekly at 10 mg per kg for 19 weeks following initial loading doses.

As shown on slide 22, we have observed therapeutically meaningful levels of AAP restoration with Amer treatment in a transgenic mouse model in this study we dose godlike anglers bi weekly at 10 milligrams per kilogram or 19 weeks following initial loading.

Doses.

Paloma Giangrande: On the right, at week 19, we observed approximately 60% RNA editing in hepatocytes with AMR treatment, which resulted in total AAT protein levels of 18.5 micromolar, or 5-fold higher than TBS control-treated mice. Finally, mass spectrometry analysis confirmed that 70% of circulating AAT protein at week 19 was wild-type MAAT protein. If we look clinically at clinically validated galnet conjugated therapeutic oligonucleotides, such as in glycerin, we would expect to see longer duration of effect in the clinic, which could potentially support less frequent dosing regimens. Next, we look to see if AMR treatment had any impact on liver ZAAT protein aggregate formation in this mouse model.

Shown on the right at week 19, we observed approximately 60% RNA editing in her past hepatocytes with Amer treatment, which resulted in total AAP protein level of $18 five micro molar or five fold higher than TBS control treated mice.

Finally mass spectrometry analysis confirmed that 70% of circulating <unk> protein and week 19 was wild type MAA G probes.

If we look clinically to clinically validated donlin conjugated therapeutic oligonucleotides, such hasn't closed there and we would expect to see longer duration of effect in the clinic, which could potentially support less frequent dosing regimen.

Next we look to see if amer treatment had any impact on liver Z protein aggregate termination in this mouse model.

Paloma Giangrande: As shown on slide 23, histological analysis of liver biopsies indicates treatment with AMERS reduces accumulation of liver ZAAT aggregates over time as assessed by PASB staining and IHC for ZAAT polymers. We're very excited by these initial results. And we're working on quantitative and additional liver function analysis. In summary, these results support the potential for AMERS to address key treatment goals for AATD with a subcutaneously administered redosable therapeutic. Other approaches currently under development do not address both the gain of function and loss of function aspects of this disease, thereby creating a potential need for multiple therapies. In contrast, WAVE's AMR approach addresses both aspects of this disease with a single therapy.

As shown on slide 23, histological analysis of liver biopsies indicate treatment with <unk> reduces accumulation of liver DAA T aggregates over time.

By Pasty, staining and IH IH CE <unk> polymers.

We're very excited by these initial results and we are working on quantitative and additional liver function analogy.

In summary, these results support the potential for <unk> to address key treatment goals for ATB, where they subcutaneously administered <unk> therapeutic.

Other approaches currently under development do not address both gain a function lots of punished churn aspects of this disease.

Thereby creating a potential need for multiple therapies and <unk>.

Contrast waves Amer approach addresses both aspects of this disease.

With a single therapy with.

Kyle Moran: We plan to select an AATD candidate and initiate IND-enabling toxicology studies in the third quarter of 2022. I will now turn the call over to Kyle Moran, our CFO.

We plan to select an ATB candidates and initiate IND, enabling toxicology studies in the third quarter of 2022.

Kyle Moran: Thanks, Paloma. We reported $1.8 million in revenue for the fourth quarter of 2021, as compared to $9.4 million in the fourth quarter of 2020. This decrease in revenue year over year is mainly due to the amendment of WAVE's collaboration with Takeda in October 2021, which discontinued the discovery research component of that collaboration. For the fiscal year ended December 31, 2021, we reported revenue of $41 million as compared to $20.1 million in the prior year.

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

Thanks Paloma.

We reported $1 $8 million in revenue for the fourth quarter of 2021 as compared to $9 $4 million in the fourth quarter of 2020.

This decrease in revenue year over year is mainly due to the amendment of waves collaboration with Takeda in October 2021, which just continued the discovery research component of that collaboration.

The fiscal year ended December 31, 2021, we reported revenue of $41 million as compared to $20 $1 million in the prior year.

Kyle Moran: The year-over-year increase is primarily driven by recognition of revenue related to $22.5 million for research and development services related to the Takeda Amendment, which was accounted for in the third quarter of 2021 and received in October 2021. R&D expenses were $25.8 million for the fourth quarter of 2021 as compared to $30 million in the same period of 2020. Research and development expenses were $121.9 million in 2021, as compared to $130.9 million in 2020.

The year over year increase is primarily driven by recognition of revenue related to the $22 $5 million for research and development services related to the Takeda Amendment, which was accounted for in the third quarter of 2021 and received in October 2021.

R&D expenses were $25 8 million for the fourth quarter of 2021 as compared to $30 million from the same period 2020.

Research and development expenses were $121 $9 million in 2021 as compared to $139 million in 2020.

Kyle Moran: This decrease in research and development expenses in the fourth quarter and full year was primarily due to decreased external expenses related to our previously discontinued PrecisionHD programs, partially offset by increased internal and external expenses related to WVE-004, PRISM, including ADAR editing, and other ongoing programs. General and administrative expenses were $12.1 million for the fourth quarter of 2021, as compared to $9.7 million last year, and we're $46.1 million in total for 2021 as compared to $42.5 million in 2020.

This decrease in research and development expenses in the fourth quarter and full year was primarily due to increased external expenses related to our previously discontinued precision HD programs, partially offset by increased internal and external expenses related to W. V E or poor prism, including eight our editing and other onto.

<unk> programs.

General and administrative expenses were $12 1 million for the fourth quarter of 2021 as compared to $9 $7 million last year.

$46 1 million in total for 2021 as compared to $42 $5 million in 2020.

Kyle Moran: The increase in the fourth quarter of 2021, the full year, was driven by increases in compensation related and other external, general, and administrative expenses. We ended the fourth quarter with $150.6 million in cash, cash equivalents, and marketable security.

The increase in the fourth quarter of 2021, and full year was driven by increases in compensation related and other external general and administrative expenses.

We ended the fourth quarter with $156 million in cash cash equivalents in marketable securities.

Paul Bolno: We continue to expect that our existing cash and cash equivalents will enable us to fund our operations and capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include potential milestones or opt-in payments under our Takeda collaboration. I'll now turn the call back over to Paul.

We continue to expect that our existing cash and cash equivalents will enable us to fund, our operating and capital expenditure requirements into the sector.

Quarter of 2023.

As a reminder, this does not include potential milestones for opt in payments under our Takeda collaboration.

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

Paul Bolno: Thanks, Kyle. At WAVE, our vision is to bring life-changing treatments to patients living with genetic disease. We have built a robust and versatile platform for the rational design of oligonucleotides to target the transcriptome with multiple modalities and across different therapeutic areas.

Thanks, Kyle at wave, our visions to bring life changing treatments to patients living with genetic diseases. We.

We have built a robust and versatile platform for the rational design of oligonucleotide to target the transcriptome with multiple modalities and across different therapeutic areas. We.

Paul Bolno: We are working to rapidly evaluate our PN-modified candidates across CNS, muscle, and soon liver, and data to be shared this year will serve to inform next steps for each therapeutic program. Demonstrating clinical proof of concept of our platform this year unlocks new targets to expand our pipeline, as well as deliver value for patients, caregivers, and their families. With that, we'll open up the call for questions. Operator.

We are working to rapidly evaluate our pn modified candidates across CNS muscle and soon liver and data to be shared this year will serve to inform next steps for each therapeutic program.

Demonstrating clinical proof of concept of our pump bonus year unlocks new targets to expand our pipeline as well as deliver value for patients caregivers and their families.

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

Greater.

Operator: Thank you. As a reminder, to ask a question, you will need to press star one on your telephone. To withdraw your question, press the pound key.

Thank you as a reminder to ask a question you will need to press star one on your telephone to withdraw your question press the pound key please standby, while we compile the Q&A roster.

Operator: Please stand by while we compile the Q&A roster. Our first question comes from Salim Syed of Syed Mizzouro. Please proceed. Great. Good morning, guys. Thanks for the caller. Just a couple for me, if I can.

Our first question comes from <unk> Yang of Sayed Masimo. Please proceed.

Salim Syed: You were not going to provide more granularity, it sounds like, around the timing of the various clinical data sets this year in 2022, but it would be helpful, I think, if you could at least provide perhaps the order in which the catalysts are to be implemented and maybe the minimal level of data that folks should be expecting here in terms of the number of cohorts or patients so that we can at least look at what you have on clinicaltrials.gov And then the second question is about the manufacturing facility. So a couple of your peers, i.e.

Great.

Morning, guys. Thanks for the color.

Couple from me if I can.

Paul the I understand.

You were not going to provide more granularity it sounds like around.

The timing of the various clinical data sets this year in 'twenty, two but if it would be helpful. I think if you can at least provide perhaps the order.

If we know a general order of of the catalysts and maybe the minimal level of data that folks should it be expected here in terms of number of cohorts or patients. So that we can at least.

Look at what you have on clinical trials Gov, and perhaps get a sense of when we may get data.

And then the second question is on the manufacturing facility. So a couple of your peers.

E homology.

And it's hard I've decided to solve their facility.

I'm curious here are you thinking more or less along the same lines of sell in or are you more bias towards what seemed like you noted in the slide of just having partners and doing some sort of contract manufacturing. Thank you.

Paul Bolno: Homology and Attar have decided to sell their facility, and I'm curious here, are you thinking more or less along the same lines of selling, or are you more biased towards what seemed like you noted in the slide of just having partners and doing some sort of contract manufacturing? Thank you. Sure. I'll take your last question first, and then I'll transition your first question to Mike.

Sure I'll take your last question first and then ill transition. Your first question for Mike, but as it relates to manufacturing we have invested substantially over the last several years in building our capability internally, obviously delivering multiple clinical candidates for wave, but also beginning to evaluate the requests from others to support manufacturing.

Paul Bolno: But as it relates to manufacturing, we have invested substantially over the last several years in building our capability internally, obviously delivering multiple clinical candidates for WAVE, but also beginning to evaluate the requests from others to support manufacturing in our space in the field of oligonucleotide therapeutics. So we are evaluating building that with subsequent investment that comes with interest outside. So I think the key for us is that whatever we do in terms of monetization, we'll have two factors.

And in our space and I'll go to the oligonucleotide therapeutics.

So we are evaluating building that with subsequent investment that comes with interest outside so I think the key for us is.

Whenever we do in terms of monetization will have two factors one.

Paul Bolno: One, obviously, protect our ability to continue to deliver important therapeutics, so our pipeline and not put our pipeline at risk. And to make sure that whatever we do financially is one way of extending So with those two parameters, we'll be evaluating a number of opportunities over the course of 2022. As it relates to the timing of data, we've been pretty consistent. The challenges with the adaptive design mean data can come at variable time points, but I'll let Mike give some more color and clarity to the timing.

Obviously protect our ability to continue to deliver important therapeutics, so our pipeline and not put our pipeline at risk and to make sure that whatever we do financially is one way extending so with those two parameters will be evaluating a number of opportunities over the course of 2022.

As it relates to timing of data, we've been pretty consistent the challenges with the adaptive design data can come in at variable time points, but I'll, let Mike give some more color and clarity to the timing Mike.

Mike Panzera: Yeah, I mean, I think, as Paul said, as the studies are recruiting, as the DSMBs are reviewing data, or making recommendations along the way, if we got to a threshold where it was a material change to the study, we would disclose. And in terms of the order, you know, we haven't, the reason we really haven't been very specific there is they all seem to be tracking along, The same overall timeline, they're all clustering together and they're all coming through and they're at each the various as the cohorts are going through they're each being evaluated so you know I think it's really hard to pinpoint specific orders and because we are driven by the data and once we have data that changes those programs we will share those clinical and to your point about more granularity I mean we would share the data you'd expect the for for zero zero three we'd we'd share Huntington we'd share Neurofilament, I mean for there is zero four we'd you know Apology P and we're not it's not going to be just when we talk about it you know sharing the data with the decision it's going to be meaningful data that you would expect to guide us for that next phase and make decisions. But Mike, Mike, can I just push back on that a little?

Yeah, I mean, I think as Paul said, a sling as the studies rerouting as a D. Smbs are reviewing data.

Making recommendations are along the way if we got to a threshold where it was a material change to the study we would disclose and in terms of the the order.

You know we have and the reason, we really haven't been very specific areas. They all seem to be tracking along the.

Hussein overall timeline, they're all clustering together and they're all coming through in and there at each of the various.

Cohorts are going through their each being evaluated so you know I think it's really hard to pinpoint specific orders in because we are driven by the data and once we have data that changes those programs, we will share those clinical.

And to your point about more granularity I mean, we would share the data you would expect.

Yeah for sure 003 weeks, we'd share hunting mutant Huntington, we'd share never filament I mean.

4004 weeks.

G P.

We're not it's not going to be just when we talk about it.

Sharing the data.

The decision, it's going to be meaningful data that you would expect to guide us for that next phase and make decisions.

Salim Syed: I mean, you have to have a framework at this point, I would think. In order to trigger, you know, here's what we need to make a decision. Is it two cohorts? Is it three cohorts for the one for the trials that have cohorts so that you get what, you know, folks would call, quote, unquote, robust? Or is it simply like one cohort, you know, proof of concept; we can move forward and make a decision?

But Mike Mike kind of pushback on that alone.

You you have to have a framework at this point I would think.

Salim Syed: Like, is there a minimal level of data that we can at least consider here? I think, Salim, how you're framing it, and I'm glad you followed up, because I think it's really important. New ones to study versus traditional studies.

In order to trigger.

Here's what we need to make a decision is it two cohort three cohort for the one for the trials that have cohorts. So.

What folks would call quote unquote robust.

Or is it simply like one cohort.

Concept.

Can move forward and make it like.

Is.

Is there a minimal level of data that.

We can at least have you now consider.

Consider here.

I think philly, how you're framing it that I'm glad you followed up because I think it's a really important.

Paul Bolno: So when you're laying out cohort by cohort, you're thinking of a traditional milestone design of data, which is get X number and then drop that as a milestone. The adaptive design, by the nature of it, enables cohorts to have flexibility in size, duration, and dose. And so there's a parameter by which, to Mike's point of having data to make a decision does, in itself, imply that very specifically that data that is powered to tell us that there's a decision to make on that program going forward.

New one this study versus traditional study so when youre laying out cohort by cohort youre thinking of a traditional milestone combined with data would you get X number and then drop.

Drop out as a milestone.

Designed by the nature of it enables cohorts flexibility and five duration dose and so there's a parameter by which.

To mikes point of having data to make a decision does in itself imply that very specifically that data that is power to tell us that there's a decision to make on that program going forward. So by the nature of that it implies that the data is robust enough to be able to make a decision based on those biomarkers safety effects, it's not driven.

Paul Bolno: So, by the nature of that, it implies that the data is robust enough to be able to make a decision based on those biomarkers and safety effects. It's not driven by a specific cohort number or where we're going to be. It's based on the actual data that is implicit in letting us make decisions.

By a specific cohort number where we're going to be it's based on the actual data that has been put into letting us like I don't know if theres any follow ups.

Mike Panzera: Mike, I don't know if there's any follow-up to that. Yeah, I was going to say that the number of cohorts that we have is going to be based on the number of patients to be able to clearly say that there's a biomarker effect. It's going to be based on the number of cohorts necessary to potentially achieve a maximal tolerated dose and to create, I mean, we want to get to that optimal safety and target engagement point to be able to say definitively that we have de-risked the next study.

Oh, Yeah, I was going to say is that you know the number of cohorts that we have well it's going to be based on the number of patients seem to be able to clearly say that this is if there's a biomarker if at all.

Going to be based on the number of cohorts necessary to potentially achieve a maximum tolerated dose and to create I mean, we want and we want to get to that optimal safety and target engagement quaint to be able to say.

Definitively we have derisked the next study.

Mike Panzera: So there will be enough patients to do that. The committee, the DSMB, is allowed to add patients to cohorts if they feel like we need more data to fill out a cohort, but there will be multiple cohorts, and there will be enough data with enough number of patients to be able to make conclusions. It's not just going to be a couple of patients here and there. The one study that I would mention has that initial cohort that we've said on DMV.

So it will be enough patients to do that the committee. The D. S. M. B is allowed to add patients to cohort if they feel like we need more data to fill out a cohort, but it's going to be multiple cohorts and it's going to be enough data with enough number of patients to be able to to to.

Make conclusions, it's not just gonna be a couple of patients here and there.

The the one study that I would mention is has that initial cohort that we said M. D. M. B. There we are looking at a biopsy in a small number of patients to see if we've made appropriate distribution before we proceed to a larger.

Mike Panzera: There, we are looking at a biopsy and a small number of patients to see if we've made an appropriate distribution before we proceed to a larger cohort or expansion cohort. That's the one study that's a little different from the other two, but the other two have multiple cohorts, so you should expect to see multiple cohorts with an adequate number of patients to be able to definitively see that we have the data to take it to the next step or not. Okay, I got it. Very helpful. Thanks so much for the call.

Cohort expansion cohort that's the one study that's a little different than the other two but the other two have multiple cohorts. So you should expect to see multiple cohorts with with adequate number of patients to be to be able to definitively see that we have the data to make that take it to the next step or not.

Okay got it very helpful. Thanks, so much for the color.

Yes.

Operator: Thank you. Our next question comes from Joon Lee of Truist. Please proceed with your question. Good morning.

Thank you.

Our next question comes from Joon Lee of Truest. Please proceed with your question.

Operator: This is Les for Joon. Thank you for taking our questions. The first one is for Dr. Paloma. What proportion of patients with AATD have mostly lung or mostly liver manifestations versus both?

Good morning. This is less on for Julien. Thank you for taking my questions.

The first one is for Dr. Palmer.

What proportion of patients patients with a P. D have more seed lung or mostly liver manifestations versus both I guess, we're just curious because theres a genome editing company developing two separate jobs, one for lung and one for liver. Thanks.

Les: I guess we're just curious because there's a genome editing company developing two separate drugs, one for the lung and one for the liver. Thanks, and I have a follow-up. Yeah, so usually the liver manifestations show up earlier. So those patients tend to be younger patients. And the lung manifestations are present mostly in the older population. My understanding is that it's really a 50-50. And it's also due to lifestyle.

Thanks, and I have a follow up.

Yeah. So there's.

Usually the liver manifestations show up earlier, so those patients tend to be younger patients and lung manifestation.

Our president is mostly in the older population.

My understanding is that it's really a 50 50 and then also due to lifestyle.

Paul Bolno: So with, you know, as patients are aging, many of these patients will then develop, move into lung manifestations. So you should think about it as, and I think it was a really important nuance, that earlier point that Paloma was making around these diseases and also the genetic reason why we're focused on those ZZ patients. So those ZZ patients end up with lung and liver manifestations.

So with.

Patients are aging and many of these patients will then develop a move into the lung manifestations. So you should think about it is and I think that is a really important nuance that earlier point that plum was making rob.

And also did you.

Why were focused on those of the patients. So those are the patients end up with lung and liver manifestations. So we purposefully made a decision not to progress and and the patients that start or those that have predominantly liver disorders, but really focus on those patients by boat and that gradation happens over time.

Paul Bolno: So, you know, we purposely made a decision not to progress in MZ patients to start or those that have predominantly liver disorders but really focus on those patients on both, and that gradation happens over time. As you point out, there are approaches that focus on the lung, and there are approaches that focus on the liver.

As you point out.

There are approaches that focus on lung there's approaches that focus on liver. The way. We've designed a single program is really to tackle both aspects of the disease at its inception, and therefore as we shared with the data today at least directionally pre clinically showing now.

Paul Bolno: The way we've designed a single program is really to tackle both aspects of the disease at its inception, and therefore, as we shared with the data today, at least directionally preclinically showing now. What we were wanting to see whether it could translate as do we clear the liver aggregate means that, you know, it's reinforcing our approach of having a single therapeutic that treats both lung and liver manifestations, which would be the ZZ patient population. Great. That's very helpful. Thank you for that color.

What we were wanting to see whether it could translate as do we clear the liver aggregate means that it's reinforcing our approach of having a single therapeutic that treats both lung and liver manifestations, which would be disease the patient population.

Great. That's very helpful. Thank you for that color.

Les: And then my final question is on the cash runway. You mentioned the runway guidance for second quarter 23 does not include milestone payments from Takeda. How would you contemplate any opt-ins from Takeda that could extend that runway? We appreciate the question. I mean, I, we've always taken it upon ourselves not to anticipate, you know, milestone payments on runway. That's not to say that the data we believe coming in could be consequential in generating those. But we plan our runway guidance without that.

And then my final question is on the cash runway you mentioned runway guidance of.

Second quarter 'twenty three does not include milestone payments from Takeda.

Would you contemplate any opt ins from Takeda that could extend that runway.

Okay.

Paul Bolno: As we said earlier in the call today, there's a lot of activity on both the partnering front, as well as in leveraging manufacturing. We are active in the manufacturing process; we think about that as a business. So as we look over the course of 2022, we do see multiple levers beyond the opt-in payments with Decatur that continue to extend our runway position. But you also have to remember, and this is important to take everybody back to, the way that the CADIS is structured is that it's not just a milestone field.

We appreciate the question I mean I.

We've always taken it upon us not to anticipate milestone payments on runway, that's not to say that the data we believe coming in it could be consequential in generating those but we plan on.

Runway guidance without that.

As we said earlier in the call today, there's a lot of activity on both the partnering front as well as in leveraging manufacturing.

We are active in the manufacturing process as we think about that as a business. So as we look over the course of 2022, we do see there is multiple levers beyond the opt in payments with Takeda that continue to extend our runway position.

You also have to remember too and just one other feature.

And it's important to take everybody back to which is the way. The Takeda is structured is it's not just a milestone deal. It also had at that point of the milestone being paid for an opt in it also comes with a 50 50, RMB split which is obviously off the.

Paul Bolno: It also has, at that point of the milestone being paid for an opt-in, it also comes with a 50-50 R&D split, which is obviously offset by the profit split. And so therefore, there's a corresponding reduction in burn for those studies in addition to the milestone pay that would be great. Actually, if I may squeeze one more in on the GNP facility, what access capacity do you have and what criteria for partner selection would you target, and would it be possible to see selection this year? I lost the last one; it was dropped.

Profit split and so therefore, there's a corresponding reduction in burn, but those studies in addition to the milestone.

That's great actually if I may squeeze one more in on the GMP facility, what excess capacity that you do have and what criteria for partner selection would you target and would it be possible to seat selection this year.

I lost the last sorry.

Drop them.

Can you repeat the question.

Les: Can you repeat the question? Sure. I just wanted to get an idea of your access capacity at your GMP facility and what criteria for partner selection you would target, and will it be possible to see selection this year? Yeah, so the way we're thinking about partnering has a variety of aspects that would enable us to fill capacity. So we can bring in a number of programs again without offsetting the capacity utilization for WAVE and our programs.

Sure just wanted to get an idea of your access capacity at your GMP facility and one of the criteria for apartments selection would you target and will be possible to see selection this year.

Yeah, So I mean.

We're thinking about partnering has a variety of aspects that would enable us to fill capacity. So we can bring in a number of programs again without offsetting the capacity utilization for wave and our programs.

Paul Bolno: And we are already executing on the discussions across a whole wide variety of oligonucleotide therapeutics, whether they be CRISPR guide strands, double-stranded RNAi, and SANS events. So the opportunity to really think about, you know, following through on our mission, which is ensuring that patients get access to therapy. There's a whole way of leveraging our manufacturing access capability to do that and leverage that. You know, we're excited about advancing new sciences. We've done that with stereopure oligonucleotides, which were viewed at the onset of WAVE as a challenging manufacturing hurdle that we overcame.

And we are already executing on them on discussions across a whole wide variety of oligonucleotide therapeutics, whether they'd be Christopher guide strand double stranded RNA I fancy event. So the opportunity to really think about following through on our mission, which is assuring that patients get access to therapies, there's a whole way of leveraging our manufacturing capability.

To do that and lever that we're excited about advancing new sciences, we've done that with stereo pure oligonucleotides, which was viewed as the initial onset of waiver that a challenging manufacturing hurdle, which we overcame so we can bring that complex process development work.

Paul Bolno: So we can bring that complex process development work to Novel Therapeutics. And we will provide additional color on this over the course of the year. But the team's working hard.

The novel Therapeutics, and so we will provide additional color on this over the course of the year, but but the team is working hard.

Paul Bolno: Excellent. Thank you. Thank you. Our next question comes from Paul Matthijs of Stiefel. Please proceed. Hey there, this is Alex on behalf of Paul.

Excellent. Thank you.

Thank you. Our next question comes from Paul Matteis with Stifel. Please proceed.

Operator: Just a couple questions from us. I think, starting with Mike, it sounds like you've been able to look at, at least on a somewhat blinded basis, initial plasma concentrations in these studies in patients. I wonder if you could comment on, you know, where those are relative to some of the preclinical models; were you seeing efficacy? And then a quick financial question, underlying your runway assumptions. I wonder if you could talk a little bit about Opex assumptions for 2022. Thanks. Mike, do you want to take the first question?

Hi, there. This is Alex on for Paul just a couple of questions from US I think starting from.

Mike It sounds like you've been able to look at at least on a somewhat blinded basis.

An initial pause in our concentrations in in these studies and patients I Wonder if you could comment on where those are relative to some of the preclinical models, where you've seen efficacy and then a quick financial question underlying your your runway assumption I Wonder if you could talk a little bit about opex assumptions for 2022.

Thanks.

Mike you want to take the first question.

Alex: Yeah, so I, you know, the plasma concentration data that we shared, as you see in DMV, it's an open-label study. So, with the Open-label Study, we've been able to look at these data and make the comparisons that you're asking for about preclinical versus clinical species, versus clinical, basically. So, we have not, you know, looked at the evidence across studies to make these comparisons as yet, and that's something that is ongoing. We would basically...

Yeah. So you know.

The plasma concentration data that we shared as you see in D. M. D. It's an open label study so with the open label study, we've been able to look at these.

These data and make the comparisons that you're asking for about preclinical versus clinical species, so versus clinical basically data. So we have not you know.

<unk> looked at the.

Cross studies to make these comparisons as.

As of yet.

Something that is that that.

That is ongoing.

We were basically.

Mike Panzera: Throughout these studies, there's a small group of employees that support the committee, and material changes in the study would lead to actually pulling some of us in. I mean, I'm constantly reviewing safety data across the programs and remain available to work with the Data Safety Monitoring Board. And there are going to be instances where I am exposed to unblinded information, but we have really tight firewalls in place for that should that occur.

Throughout these studies, there's a small group of employees that support the committee.

And material changes in the study would lead to actually pulling some of us in I mean, I'm constantly reviewing safety data across the programs and made it and remain available to work with the data safety monitoring board, so and there are going to be instances, where I am.

Those two unblinded information, but we have really tight firewalls in place for that should that occur in it.

Mike Panzera: And if I'm exposed to data that would result in a material change in the study, this would lead to the involvement of other members of leadership and, if inappropriate, you know, other disclosures. But that's our process. Yeah, I guess I asked another way, I think that could you could say at this point that your doses in patients, based on your modeling assumptions, at least going into it, should be at the same levels or consistent with what you've seen with efficacy within preclinical models?

I'm exposed to data that would result in a material change to the study with this would lead to involvement of other members of leadership and inappropriate.

And the other disclosures, but that's our process yeah, I guess I guess asked another way I think that could.

Could you could you say at this point that you're you're doses in patients based on your modeling assumptions at least going into it.

Should be at the same levels or are consistent with what you've seen with efficacy in preclinical models.

Mike Panzera: I think just to follow up on where Mike was going, I think that's exactly the point that we were excited about sharing today as it related to that initial PK data on N531. To Mike's point, given that it's open label, so that we can make that assessment. We are seeing, and that was the point Mike was trying to make with the day-to-day, which I think is encouraging, that we are seeing this translation of PN chemistry between rodent models, non-human primates, and the clinic.

Just to follow up on where Mike was going I mean, I think that's exactly the point that we're excited about sharing today as it related to that initial <unk>.

K data on 501 to Mikes point given that it is open label. So that we can make that assessment.

We are seeing and I think that was the point, Mike was trying to make up the data today, which.

I think he is affirming that we are seeing this translation of Pn chemistry.

Between rodent models in nonhuman primates, and then now it's early it's open label, but at least that evaluation was done simply to see are we on a trajectory and a path and I think.

Paul Bolno: Now it's early, it's open-label, but at least that evaluation was done simply to see, you know, are we on a trajectory and a path? It's nice to see we are, as Mike also said, more to come on the robust side of the data, but that's great. And then on OPEX, thoughts for 2022?

It's nice to see we are as Mike also said more to come on the robust side of the data, but that's great.

And then on Opex thoughts for 2022.

Paul Bolno: So we seem to be consistent on how you can go through the firm at the firm. Yeah, I mean, I think you can project our OPEX consistent with what we spent in Q4, where there's a little bit of a tail on precision HG studies that may come into Q1, but generally, Q4 is, It should be consistent. Great, thanks so much.

So we seem to be consistent.

You can go through the affirmative burns.

I mean, I think he can project our opex consistent with what we spent in Q4.

We're.

There's a little bit of a tail on the.

Precision HD studies.

But they are.

Come into Q1, but generally Q4 is.

It should be consistent.

Great. Thanks, so much.

Okay.

Alex: Thank you. Our next question comes from Manny Surhlar of SBB Securities. Please proceed.

Thank you. Our next question comes from Manny for four of S. DB Securities.

Please proceed.

Operator: Hey guys, thanks for taking the question. I wanted to circle back a little bit on your approach to extracting some cash flow from your existing manufacturing investment. Can you tell me a little bit about how you prioritize your capacity between what will presumably be contractual obligations to partners? And how should we think about modeling that? Is it will be driven in terms of the absolute volume of products, the number of lines, etc.

Hey, guys. Thanks for taking the question I.

I wanted to circle back a little bit on your approach to attract initial cash flows from your existing manufacturing investments.

Can you tell me as you continue to progress through clinical trials, assuming they continue to move forward into later stages require more product et cetera.

Do you prioritize your capacity between what will presumably be contractual obligations to partners.

And how should we think about modeling that is it.

Is it will be driven in terms of absolute volume of products number of lines et cetera, because these aren't entirely fungible products, where you can switch your capacity immediately so just help us think about that.

Manny Surhlar: These aren't entirely fungible products, but you can switch your capacity immediately. So just help us think about that. Yeah, I think the one piece that I call one of the core pillars of doing anything is not to distract from our operating capacity that we need in our. We built that, we've guided that, we know and model that with that capacity as ourselves. And as you may or may not recall, as part of the original Takeda agreement, we retained manufacturing rights through commercialization.

Yes, I think the one piece that I would call. It one of the core pillars of doing anything as not to distract from our operating capacity that we need with ACA facility. We felt that we had guided that we know in my model that with the capacity is for ourselves as you may or may not recall as part of the original Takeda agreement to be reached.

Manufacturing rights through commercialization. So there is a I could.

Manny Surhlar: So there is a capacity modeling that we stay within for WAVE and our pipeline as it moves forward, both ourselves and potential partners, therapeutic partners. That being said, when we built the facility from the beginning, we had the ability to add on additional capacity to the existing train. We built the facility originally with the intention, going back to where we were with the pipeline prior, to be able to actually expand and double the capacity within the existing footprint of this facility in Lexington. So we built it with manufacturing in mind going forward. We know what our operating capacities need to be going forward.

Paucity modeling that we stay within for wave and our pipeline of business forward, both ourselves and potential partners therapeutic partners.

Being said when we built the stability from the beginning we have the ability to add on additional capacity to the existing trains. We built this facility originally with the intention going back to where we were with the pipeline prior to being able to actually expand and double the capacity within the existing footprint of this facility in Lexington.

So we had built with manufacturing in mind going forward, we know what our operating capacity needs to be going forward, but what we're modeling is where that access and additional capacity could be brought on how to model that with programs that we think can fill that.

Paul Bolno: But what we're modeling is where that excess and additional capacity could be brought on, how to model that with programs that we think can fill that in a way that would be complementary to the work that's ongoing, so not disruptive of that; how those different programs come on board is the subject of the work that's been ongoing with the team. And so obviously, we'll share more on that. But we do model having that move forward. We've got a lot of flexibility in our facility.

In a way that would that would be complementary to the work that's ongoing so not this disruptive of that.

How are those different.

Those programs come on board.

It is the subject to where the work that's been ongoing with the team and so obviously, we will share more on that but we do model of having that move forward. We've got a lot of flexibility in our facility. We also know that we can have flexibility with an existing Cmos I mean, one thing we've seen in the space a lot of CMO capacity.

Paul Bolno: We also know that we can have flexibility within existing CMOs. I mean, one thing we've seen in the space is a lot of CMO capacity at commercial scale, so large scale and late stage. I think what's unique about the facility we built here in Lexington is really that ability to work on those smaller clinical scales, right. So being able to support toxin to phase two, right, that range of work is really what's unique about our facility.

The commercial scale, so large scale in late stage I think what's unique about the facility would be built here in Lexington is really that ability to do some work on those smaller clinical gal's right, so being able to support the phase two right that that range of work.

It's really what's unique about our facility and so obviously its been helpful for us not to have to make adjustments to our clinical timelines based on what's happening in the external world with manufacturers and.

Paul Bolno: And so obviously, it's been helpful for us not to have to make adjustments to our clinical timelines based on what's happening in the external world with manufacturers. And we see that as an opportunity to accelerate more medicines for patients. At the same time, by doing that work, being able to bring additional potential revenue into WAVE and think about how we bring in additional capital into WAVE to offset the cost of operating the manufacturing facility. So there's a lot of things we're thinking about as we think about 2022, and how to plan for that, how to model that, how to bring in additional access to capital around that beyond revenue.

And we see that as an opportunity to accelerate more medicines for patients at the same time by doing that work being able to bring additional potential revenue in two ways to think about how we bring on additional capital into waves to offset the cost of operating and manufacturing facilities. So there's a lot of things we're thinking about as we think about 2022 and had a plan for that.

A model that had to bring in additional access to capital around that beyond revenue. So that again that will be the work that stay.

Manny Surhlar: So again, that will be the work that stay tuned for, and we'll be sharing a lot more of as we move through 2022. All right, that's helpful. Thanks, guys. Thank you. Our last question comes from Luca Issi of RBC Capital. Please proceed. Oh, great. Thanks so much for taking my questions. I have two quick ones here.

Stay tuned we'll be sharing a lot more of as we move through 2022.

Alright, that's helpful. Thanks, guys.

Thank you.

Yeah.

Our last question comes from Luca <unk> of RBC capital. Please proceed.

Operator: One on Huntington, you know, in the competitive landscape, obviously, we've seen Roche and Ionis not giving up on their molecule. They're starting a new phase two in younger patients with low disease burden following their postdoc analysis. So just wondering what your reaction to that news was and how you're thinking about implications for your program? And then maybe on C9, I think in addition to poly-GP in the CSF, you're also looking at the P75 biomarker in the urine. Can you just expand a little bit more on the significance of that biomarker and maybe what you're hoping to see there? Thanks so much.

Oh, great. Thanks, so much for taking my questions I have two quick one here and one on Huntington.

Competitive landscape, obviously, we've seen erosion of your honest not giving up on their molecule, they're starting to do phase two in younger patients with low disease burden following their post Doc analysis. So just wondering what was your reaction to that news and how youre thinking about implications for your program and then maybe on C&I I think in addition to pull the GP in the CSF you're also looking at.

75 biomarker in the urine can you just expand a little bit more on the significance of that biomarker and maybe what you're hoping to see there. Thanks so much.

Luca Issi: Yeah, and I'll give a quick discussion on the competitive landscape and then transition to probably the best person to address it is Mike, who's sitting in PHDI. But, you know, I like you, and it was interesting to see, you know, Roche moving back into the clinic. I think it reinforced for us that, you know, they made these decisions based on a belief that oligonucleotides could distribute in the CNS and that they had an approach.

Yes.

A quick discussion on the competitive landscape and then transition to the probably the best person to address it is Mike is sitting in HDI, but.

Like you I was it was interesting to see Roche moving back into the clinic I think it reinforces for us that.

There may be decisions based on our belief that oligonucleotides and distribute in the CNS and that they had an approach I think what we continue to see in the competitive landscape.

Luca Issi: I think what we continue to see in the competitive landscape, and you know, as Mike spoke earlier, and I hope, you know, we'll share more on again, is that we do see this migration to opening up the discussion around recognizing the significance of wild-type protein, and therefore, when we look at the competitive landscape, the real distinction is not between a modality, gene therapy, or oligonucleotides. It's an allele selective approach that's wild type sparing and knocks down the mutant toxic protein while pan silencing on the other side.

I spoke to earlier and I hope, we will share more on again is that we do see this migration to opening up the discussion around recognizing that the significance of wild type protein and therefore, when you look at the competitive landscape. The real distinction is not on a modality gene therapy or oligos.

And it'll be all selective approach, that's wild type sparing and knocked down the mutant toxic protein and patent silencing on the other side and I think as we move forward. We're excited about continuing to advance an allele specific therapy to Huntington's, but Mike if you want to continue on Huntington's and then 69 question.

Paul Bolno: And I think as we move forward, we're excited about continuing to advance an allele specific therapy for Huntington's. But Mike, if you want to continue on Huntington's and then take 69 questions. Yeah, so no, I think to echo Paul's point is that, I think I can tell you that, at this meeting, there was, there was interest in the fact that the approach is now the, that they're taking that younger population again. It has reinforced belief in this particular, in this particular, you know, approach of interlegal ASO administration, their confidence that they're engaging the target and now it's an aspect of, of, optimizing.

Yeah. So I think to Echo Pauls point is that I think I can tell you that at least at this meeting there was theres interest and the fact that the approach is now.

That they are taking it to that debt that are.

Younger population again, it's reinforced belief in this particular.

And this particular.

You know approach okay.

Equally so administration their confidence that theyre engaging target announced an aspect of of of optimizing but to put a second point.

Paul Bolno: But to Paul's second point, there's also a lot of discussion that that may not solve their issue, which is not our issue, which is the issue of bringing down wild type Huntington along with mutant Huntington. I think that there's still a big discussion here and a lot of interest.

Theres also a lot of discussion that that may not solve their issue, which is not our issue which is the issue of <unk>.

Hum, bringing down wild type Huntington, along with mutant Huntington I think that it's still a big discussion here and a lot of.

Hum interest.

Their restriction to a subpopulation has actually led to an enormous focus on us and patient participation in our study as a way of maybe dealing with some of the challenges that they've been dealing with it. So it's really been interesting to see the number of physicians come.

Mike Panzera: Its restriction to a subpopulation has actually led to an enormous focus on us and patient participation in our study as a way of maybe dealing with some of the challenges that they've been dealing with. So there's, it's really been interesting to see the number of physicians come to me at this meeting and want to know how the trial is going, patient groups wanting to see how patients can get access. So it has had an overall improvement in the feelings around the approach, but also waves this particular approach and the potential that it offers, involving C9.

To me at this meeting and want to know how the trial is growing patient groups wanting to see how patients can get access. So it has had an overall.

Improvement in the feelings around the approach, but also waves particular approach and the potential that it offers.

Mike Panzera: You mentioned the P75. I mean, this is a biomarker that has been associated with potentially earlier indications of progression and more associated with predicting progression in these patients, particularly in the ALS population, but potentially something we want to understand in the FTD population. So it's potentially more associated with actual functional decline than some other biomarkers. So we've included it in the study to see if we can get a better understanding of how it would relate to the more typical ones people talk about, like the poly-GP and the neurofilament. And it's super easy. It's in the urine.

Involving C. Nine you mentioned about the P. 75, I mean this is it's a biomarker that has been associated with potentially earlier indications of progression, then and more associated with predicting progression.

In these patients and that's in particularly in the U S population, but potentially something we want to understand in the TD population.

So it's it's a potentially more associated with actual functional decline than some other biomarkers. So we've included in the study to see if we can get a better understanding of how it would relate.

To the word typical when people talk about like the probably GP in the neuro element and it's super easiest in the urine. So it's something we're just exploring as a potential guide for us for hopefully future development.

Mike Panzera: So it's something we're just exploring as a potential guide for us for, hopefully, future development. Thanks so much, guys. Thank you. Thank you. I would now like to turn the conference back to Dr. Paul Bolno for closing remarks. Thanks, everyone, for joining the call this morning to review our fourth quarter 2021 financial results and corporate updates, and thank you to our WAVE employees for their hard work and commitment to patient care. Have a great day. Take care. This concludes today's conference call. Thank you for participating, and you may now disconnect. Thanks for watching!

Got it thanks, so much guys.

Thank you.

Thank you I would now like to turn the conference back to Dr. Paul <unk> for closing remarks.

Thanks, everyone for joining the call. This morning to review, our fourth quarter 2021 financial results and corporate update and.

And thank you to our wave employees for their hard work and commitment to patients have a great day take care.

This concludes today's conference call. Thank you for participating and you may now disconnect.

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