Q2 2021 WAVE Life Sciences Ltd Earnings Call

2021earnings call My name is Brandon and I'll be your operator for today at this time all participants are in a listen only mode. Later, we will conduct a question and answer session during which you may dial star 1 if your other question.

Brandon: My name is Brandon, and I'll be your operator for today. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session, during which you may dial star 1 if you have a question. Please note this conference is being recorded. I will now turn the call over to Kate Rausch, Head of Investor Relations at WAVE Life Sciences. Kate, you may begin.

Please note. This conference is being recorded I will now turn the call over to Kate Rausch head of Investor Relations at Wave Life Sciences, you may begin.

Kate Rausch: Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review WAVE's second quarter 2021 operating results. On the call with me today are Paul Bolno, WAVE's President and Chief Executive Officer, Mike Panzera, Chief Medical Officer, Head of Therapeutics Discovery and Development, Paloma Giangrande, Vice President of Platform and Discovery Sciences and Biology, and Kyle Moran, Chief Financial Officer. This morning, we issued a news release detailing our second quarter financial results and provided a business update. This news release and a slide presentation to accompany this webcast are available in the investor section of our website, www.wavelifesciences.com.

Thank you operator, good morning, and thank you for joining us today to discuss our recent business progress and review we are second quarter 2021 operating result.

On the call with me today are powerful new wave, President and Chief Executive Officer, Mike <unk>, Chief Medical Officer head of Therapeutics Discovery and development Paloma Xian Grande Vice President of platform and Discovery Sciences in biology, and calmer and Chief Financial Officer.

This morning, we issued a news release detailing our second quarter financial results and provided a business update this news release and the slide presentation to accompany this webcast are available in the investors section of our website Www Dot wave life Sciences dotcom.

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 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 31, 2020, and our quarterly report on Form 10-Q for the quarter ended June 30, 2021. We undertake no obligation to update or revise any forward-looking statement for any reason.

Before we begin I would like to remind you that discussions during this conference call will include forward looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward looking statements.

The factors that could cause actual results to differ I discussed in the press release issued today and in our SEC filings, including our annual report on form 10-K for the year ended December 31, 2020, and our quarterly report on form 10-Q for the quarter ended June 32021.

Kate Rausch: I'd now like to turn the call over to Paul. Paul? Thanks, Kate.

Paul B. Bolno: Thanks, Gabe. Good morning, everyone, on the call, and thank you for joining us. During the call today, I will provide opening remarks, after which Mike will give an update on our three ongoing clinical programs. We'll then turn the call over to Paloma J. Grande to provide an update on our Discovery SAGE Alpha 1 antitrypsin program, which provides ongoing proof of concept for our ADAR editing capability. Paloma Joinway joined Moderna at the start of this year as VP, Platform Discovery Sciences and Biology. And finally, Kyle will briefly review our finances.

Clinical effects to enable decision, making on next steps for these programs.

Data generated over the next 18 months, we will also provide insights into the clinical effects of <unk> chemistry, both with interest vehicle and systemic administration as well as provide the opportunity to confirm the promise and.

The book preclinical results.

RNA editing is the most recent therapeutic approach to emerge from our prism platform, which also utilizes oligonucleotides with our novelty impactful modification.

Paul B. Bolno: Since the start of the second quarter, we achieved several important milestones. Most significantly, we started dosing in our FOCUS C9 clinical trial of WVE004, our C9ORF72 candidate in amyotrophic lateral sclerosis and frontal temporal dementia. This marked the first human dosing with an oligonucleotide containing our next generation PN chemistry, which is a critical and very exciting milestone for the company. Right behind C9, we're advancing two additional clinical trials, the Select HD trial of WVE003, our SNF3 candidate in HD, and a clinical trial of WVEN531, our Exon 53 candidate in DM.

For this new modality, we designed the oligonucleotides to engage the endogenous ADR to achieve RNA editing.

During the second quarter, we share proof of concept data that demonstrates restoration of functional alpha 1 antitrypsin protein with in vivo editing and important achievements from both the platform and for this exciting program.

We will review these data later on the call.

These recent accomplishments are direct result of our investment in our prism platform and our Swift execution advancing pn chemistry from concept to discovery into therapeutic molecules.

Since the founding of wave, we have been innovating, a an oligonucleotide chemistry to optimize our therapeutic candidates using the resolution of stereo pure design.

Our novel Pn chemistry, as the first significant new modification that we've advanced which has demonstrated a step change in pharmacology across many in vitro and in vivo studies.

These studies show that the addition of even just a few properly placed and backbone chemistry modifications. So oligonucleotides consistently enhances potency distribution and durability of effect.

These improvements appear to be independent of sequence tissue time form modality, enabling us to expand the use of these chemistry modifications to build our next generation oligonucleotide pipeline.

Less than a year after first in billing this new chemistry, we have ongoing clinical studies for <unk> modified candidates and are now dosing in the first of these clinical trials with others soon to follow in the coming weeks.

Given the complexities of many nucleic acid therapeutics today. It is important to note that novel chemistry, it's scalable.

Paul B. Bolno: Each of these innovative, adaptive clinical trials is designed to quickly establish a dose level and frequency and, ultimately, clinical effects to enable decision making on next steps for these programs. Data generated over the next 18 months will also provide insight into the clinical effects of p.n.

We are manufacturing the supply for all 3 clinical trials and multiple preclinical therapeutic programs within our GMP manufacturing facility.

We have a robust portfolio of oligonucleotides led by our clinical programs WB zero-zero 4 in ALS and NCD <unk>.

<unk> 003 in HD and <unk> in fact, everyone and DMT.

These ongoing clinical trials all include biomarker assessments, and clinical data, which will enable potential path to registration and unlock value for our additional pipeline programs, including those in collaboration with Takeda and our wholly owned targets.

Paul B. Bolno: chemistry both with intracecal and systemic administration, as well as provide the opportunity to confirm the promised same in vivo preclinical results. RNA editing is the most recent therapeutic approach to emerge from our PRISM platform, which also utilizes oligonucleotides with a novel PN backbone modification. For this new modality, we designed the oligonucleotides to engage the endogenous ADAR to achieve RNA editing. During the second quarter, we shared proof-of-concept data that demonstrated restoration of functional alpha-1 antitrypsin protein with in-vivo ADAR editing, an important achievement for both the platform and for this exciting program. Colombo will review these data later on in the call.

Our chemistry experience with optimizing silencing in exon skipping compounds enables us to rapidly apply our prism platform to develop RNA editing oligonucleotides and accelerate this capability such that we are now among the leaders advancing anr editing towards the clinic.

Our Syria to our editing oligonucleotides are fully chemically modified and incorporate PM backbone modification.

They are also single stranded and shortened length altogether. These features enable simplified delivery avoiding the need for AAV or nanoparticle such as LNG.

As you can see on the lower left of slide 8 once our oligonucleotides reached the target RNA. They engage in Dodge and hadar ubiquitously expressed enzyme across tissue types to correct or modified single RNA basis.

Our approach is highly specific and by staying focused at the RNA level, we avoid potentially permanent targeted D&C space assets.

The target landscape for this modality is fast enabling therapeutic applications such as restoration of protein function modification of protein function and upregulation of protein expression.

We intend to show the versatility of editing we can achieve at an upcoming research day on September 28.

Paul B. Bolno: These recent accomplishments are direct results of our investment in our PRISM platform and our swift execution advancing PN chemistry from concept to discovery into therapeutic molecules. Since the founding of WAVE, we have been innovating oligonucleotide chemistry to optimize our therapeutic candidates using the revolution of stereopure design. Our novel PN chemistry is the first significant new modification that we've advanced, which has demonstrated a step change in pharmacology across many in vitro and in vivo studies.

I would now like to turn the call over to Mike <unk> Zara current update on our clinical progress Mike.

Thanks, Paul Good morning, everyone. Today, I will provide an update on progress made over the last few months with our clinical programs.

For CNS diseases, we are advancing 2 programs in the clinic <unk> be easier zero for our candidate targeting C&I number 72 extra nucleotide repeat expansions in AOS and <unk> and <unk> are 3 targeting candidate and HD.

These are the first 2 and 2 PM modified clinical candidates designed to silence target from the CNS.

For both programs, we have demonstrated prolonged knockdown of the desired target in vivo in the CNS of transgenic disease models.

Paul B. Bolno: These studies show that the addition of even just a few properly placed PN backbone chemistry modifications to oligonucleotides consistently enhances potency, distribution, and durability of effects. These improvements appear to be independent of sequence, tissue type, or modality, enabling us to expand the use of these chemistry modifications to build our next generation oligonucleotide-based implant. Less than a year after first unveiling this new chemistry, we have ongoing clinical studies for three PAN-modified candidates that are now dosing in the first of these clinical trials, with others soon to follow in the coming weeks.

Jim Vivo assessments are now routine across our pipeline programs, including <unk>, including our multiple wholly owned neurology discovery programs.

Those in collaboration with our partner Takeda, where sequence homology and non human primates allows us to explore pharmacology and a more relevant species using the intended interest equal routes of delivery.

We have shown as part of these program for your ability to Potently knockdown target transcript and demonstrate widespread distribution throughout the CNS.

1 consistent observation has been the durability of target engagement with Pn modified oligonucleotides, leading to the expectation that dosing intervals in humans will be less frequent than the monthly dosing in our previous trials.

This is most clearly illustrated by our soon INR 72 program.

Our clinical candidate <unk> 4 is designed to target a hex nucleotide repeat expansion in C&I in our 72 transcript, which is 1 of the most common genetic causes of ALS and FTB. These expansions drive the common pathophysiology underlying these 2 diverse and devastating disease phenotypes and <unk> is being <unk>.

Paul B. Bolno: Given the complexities of many nucleic acid therapeutics today, it's important to note this novel chemistry is scalable. We are manufacturing the supply for all three clinical trials and multiple preclinical therapeutic programs within our GMP manufacturing facility. We have a robust portfolio of oligonucleotides led by our clinical programs WVE-004 in ALS and FTD, WVE-003 in HD, and WVE-N531 in DNA. These ongoing clinical trials all include biomarker assessments and clinical data, which will enable potential paths to registration and unlock value for our additional pipeline programs, including those in collaboration with ICAIDA and our wholly owned target.

<unk> simultaneously in a single basket life trial for both C&I and AOS and <unk>.

Not only does this make sense biologically, but the response from the community has been overwhelmingly positive, particularly amongst those with MTV or mixed AOS SGD phenotype. As these patients have to date been excluded from C&I and associated Ngls studies.

<unk> 970, <unk> protein is important is important for normal regulation of neuronal function in the immune system. These functions are well understood, which is why therapeutic approaches to target ex of nucleotide repeat containing transcripts should preserve the pre mrna vs..2 transcripts that are responsible.

For generating <unk>, 9 or 72 protein.

004, therefore selectively targets the pre <unk> transcripts that lead to loss of normalcy 972 function and production of pathological mrna products and toxic dipeptide repeat or DPR proteins.

Paul B. Bolno: Our chemistry experience with optimizing silencing and exon skipping compounds enables us to rapidly apply our PRISM platform to develop RNA editing oligonucleotides and accelerate this capability such that we are now among the leaders advancing RNA editing towards the clinic. Our stereopure editing oligonucleotides are fully chemically modified and incorporate PN backbone modification. They're also single-stranded and short in length

<unk> is an important 1 of these DPR proteins and that it is transcribed from both defense and antisense transcripts, making it a very sensitive biomarker of target engagement for toxic mrna transcripts as well as other toxic proteins.

<unk> was chosen as the biomarker for both our preclinical and clinical studies, allowing us to make certain assumptions regarding dosing and translation of preclinical observations to humans, thus guiding starting dose in our trial.

Paul B. Bolno: Altogether, these features enable simplified delivery, avoiding the need for AAV or nanoparticles such as LMP. As you can see on the lower left of slide 8, once our oligonucleotides reach the target RNA, they engage endogenous ADAR, a ubiquitously expressed enzyme across tissue types to correct or modify single RNA bases. Our approach is highly specific, and by staying focused at the RNA level, we avoid potentially permanent off-target DNA base-ups. The target landscape for this modality is vast, enabling therapeutic applications such as restoration of protein function, modification of protein function, and upregulation of protein expression. We intend to show the versatility of editing we can achieve at an upcoming research day on September 28th. I'd now like to turn the call over to Mike Pantera for an update on our clinical trials.

In addition, we plan to assess the effect of zero <unk> on CSF measurements of Neurocrine <unk> light chain, our NFL as it remains an important biomarker for providing insights into potential neuroprotective effects of treatments.

This slide illustrates the results from the fact transgenic mouse model as you can see 2 ITV doses of <unk> administered <unk> 7 days of parts results in 80% to 90% reduction in poly GP in the spinal cord and cortex for at least 6 months with sustained meaningful CNS.

Concentrations of <unk> throughout the duration of the study.

Further C&I 72 protein was unchanged over the course of the study, including at the 6 month time point, confirming Zero-zero force selectivity.

Focusing on is expected to enroll approximately 50 patients with a documented <unk> 972 expansion and confirmed AOS FTB or mixed phenotype.

And includes both single and multiple ascending portions at.

At pre defined data driven milestones and independent Committee will review unblinded data to determine each single dose level and the optimal dosing frequency of each multi dose cohort.

Michael Linden: Thanks Paul. Good morning everyone. Today we'll provide an update on the progress made over the last few months with our clinical program. For CNS diseases, we are advancing two programs in the clinic, WVE004, our candidate targeting C9R72, hexonucleotide repeat expansions in ALS and FTD, and WVE003, our SNP3 targeting candidate in HD. These are the first two PN-modified clinical candidates designed to silence targets in the CNN. For both programs, we have demonstrated prolonged knockdown of the desired target in vivo in the CNS of transgenic disease models.

Which based upon the preclinical data to date is expected to be less frequent than monthly.

Successful poly GP knockdown, along with a favorable safety and Tolerability profile would enable registrational studies for AOS and <unk> with clinical endpoints, we expect to generate clinical data from the study through 2022 to enable decision making for this program.

Our approach to Huntington's disease remains like that of C&I, and or 72 targeting lower toxic protein, while preserving beneficial protein <unk>.

<unk> 3 is designed to silence transcripts that will lead to toxic mutant Huntington protein, while sparing transcript that allows synthesis of healthy Huntington protein, thus addressing both drivers of HD progression.

Our ability to measure the effects of 003 is enabled by assets that allowed direct measurement of target engagement in the CSF mutant Huntington knockdown wild type preservation and possible neuro protection through the measurement of NFL.

Michael Linden: Such in vivo assessments are now routine across our pipeline programs, including our multiple wholly owned neurology discovery programs and those in collaboration with our partner Takeda, where sequence homology and non-human primates allow us to explore pharmacology in a more relevant species using the intended intrathecal route of delivery. We have shown, as part of these programs, the ability to potently knock down target transcripts and demonstrate widespread distribution throughout the CNS. One consistent observation has been the durability of target engagement with PN-modified oligonucleotides, leading to the expectation that dosing intervals in humans will be less frequent than the monthly dosing in our previous trials. This is most clearly illustrated by our C9R72 program.

It's unique to our approach is how we accomplished selectivity, namely by targeting a known snap called SNP tree that is associated with the <unk> expansion on the mutant allele of many patients with Huntington's disease.

Again, the purpose of this and other allele selective approach it is to maintain the beneficial effects of wild types, which should maximize the beneficial effects of mutant Huntington reduction.

If 1 thinks about this as a push and pull of positive and negative factors in the CNS. It stands to reason that non selective depletion of both wild type and mutant protein, which shifts the balance towards disease progression erasing any benefit or even potentially accelerating decline, especially in the setting of stress.

This has been our hypothesis since we began our HD program and emerging data support our position, making us resolute in this differentiated treatment approach.

Slide 16 illustrates data demonstrating the highly selected potent and durable effects of 003 on mutant Huntington and in vitro and in vivo disease models.

Michael Linden: Our clinical candidate, 004, is designed to target a hexanucleotide repeat expansion in the C9R72 transcript, which is one of the most common genetic causes of ALS and FTD. These expansions drive the common pathophysiology underlying these two diverse and devastating disease phenotypes, and 004 is being advanced simultaneously in a single basket-like trial for both C9-ALS and C9-FTD Not only does this make sense biologically, but the response from the community has been overwhelmingly positive, particularly amongst those with FTD or a mixed ALS-FTD phenotype, as these patients have to date been excluded from C9-associated ALS studies. C9R72 protein is important for normal regulation of neuronal function and the immune system.

The back HD mouse model used is somewhat limited in that it contains multiple copies of the mutant Huntington gene some of which do not have the strength free variant Nonetheless as shown on the bottom of the slide we observed potent and durable knockdown in the Huntington in Australia them out to 12 weeks with a similar effect.

Observed and cortex.

Select HD is planned to enroll approximately 36 patients with HD and confirmed snips free <unk>.

<unk> focus Eni the principle preclinical data to date allow us to make certain assumptions regarding dose selection and frequency with an independent committee reviewing unblinded data to determine dose levels and the optimal frequency for future multi dose cohorts.

As of today clinical trial sites have been activated recruitment is underway and we expect to initiate dosing in the coming weeks.

While target engagement studies in the CNS of non human primates were not possible for <unk> III and <unk> for <unk>.

Homology of target sequence between <unk> mice, and nonhuman primates in some of our newer discovery programs enables us to evaluate drug distribution and target engagement in the large animal species using the intended relative clinical administration.

Michael Linden: These functions are well understood, which is why therapeutic approaches to target hexanucleotide repeat-containing transcripts should preserve the pre-mRNA V2 transcripts that are responsible for generating C9ORF72 proteins. 004 therefore selectively targets the pre-mRNA variant transcripts that lead to loss of normal C9RF72 function and production of pathological mRNA products and toxic dipeptide repeat, or DPR, proteins. PolyGP is an important one of these DPR proteins in that it is transcribed from both the SENSE and ENTISENSE transcripts, making it a very sensitive biomarker of target engagement for toxic mRNA transcripts as well as other toxic proteins.

What's been clear from these programs is that the application of stereochemistry in the PM chemistry background modifications enhanced distribution throughout the CNS, leading to widespread and sustained knockdown.

This is illustrated on slide 19 from a study for an undisclosed target with our most advanced to the KBR collaboration candidate WV easier zero, 5 which contains pn modifications and was administered as a single 12 milligram <unk> dose to non human primates.

1 months after administration, we observe broad distribution and substantial knockdown of target throughout the CNS, including the striatum.

It is this consistent widespread CNS distribution of Pn modified oligonucleotides across species, the possibility of infrequent administration and the availability of disease Biomarkers for proof of concept studies that are the key feature of our differentiated CNS portfolio moving through preclinical and clinical development.

Moving on to WD and <unk> 3.1 this is our first PM modified clinical candidates to be administered systemically.

Michael Linden: PolyGP was chosen as the biomarker for both our preclinical and clinical studies, allowing us to make certain assumptions regarding dosing and translation of preclinical observations to humans, thus guiding the starting dose in our trials. In addition, we plan to assess the effect of 004 on CSF measurements of neurofilament light chain, or NFL, as it remains an important biomarker for providing insights into potential neuroprotective effects of treatment. This slide illustrates the results from the BAC transgenic mouse model.

As also our first splicing candidate it will provide insights into the ability of pn modifications to enhance access to dystrophic muscle and restore functional dystrophin expression.

We are optimistic about this program given the compelling preclinical data comparing systemic systemically administered <unk> modified exon skipping oligonucleotide with oligonucleotides containing only PFS NPL modifications.

These data are shown on slide 21 from experiments using an aggressive double knockout or decay of DMD mouse model lacking both <unk> and distributions for stroke.

Michael Linden: As you can see, two ICV doses of 004 administered 7 days apart resulted in 80-90% reduction in polyGP in the spinal cord and cortex for at least 6 months, with sustained meaningful TNS tissue concentrations of 004 throughout the duration of the study. Further, C9R72 protein was unchanged over the course of the study, including at the six-month time point confirming 004 selectivity. FOCUS C9 is expected to enroll approximately 50 patients with a documented C9R72 expansion and confirmed ALS, FTD, or mixed phenotype. It includes both single and multiple ascending portions.

Following treatment with APM modified exon 23 targeting surrogate we saw a dramatic treatment effect rescuing all mice treated with the surrogate which was very different from the mice treated with PBS or first generation <unk> modified dsos dose equivalent life.

In fact, the mice survive, even when treated with a lower less frequent dose of the PM containing surrogate once again, highlighting the improved pharmacology of the PM containing compounds.

Just as a reminder, the relevance of these observation is the potential impact for Duchenne muscular dystrophy.

DMD is an area of significant unmet need with current exon skipping treatments demonstrating for a minimal dystrophin expression without yet establishing clinical benefit.

When.

And 531 has similar chemistry to the exon 23 surrogate use it used in the <unk> model and when applied to DMD patient derived human myoblast amenable to exon 53 skipping resulted in dose dependent increases in dystrophin restoration up to 71% of normal and not at the highest.

Michael Linden: At predefined data-driven milestones, an independent committee will review unblinded data to determine each single-dose level and the optimal dosing frequency of each multi-dose cohort, which, based upon the preclinical data to date, is expected to be less frequent than monthly. A successful PolyGP knockdown, along with a favorable safety and tolerability profile, would enable registrational studies for ALS and FTD with clinical input. We expect to generate clinical data from the study through 2022 to enable decision-making on this.

<unk> concentrations tested.

These in vitro and in vivo observations along with other preclinical data illustrating widespread distribution of <unk> 3.1 and the normal muscle of NH piece prompted us to proceed with a human proof of concept study.

As of today, our clinical trial sites are activated and recruiting <unk> patients in our first in human clinical trial for <unk>, 3.1 and boys amenable to exon 53 skipping.

This open label study is powered to determine whether <unk> 3.1 treatment intravenously leads to dystrophin production and whether the drug can readily access muscle cells. Thus addressing the limitations that led to <unk> lack of effect.

We will also be assessing safety and Tolerability of IV infusions initially at a frequency of every other week mimicking the dosing frequency and the detail animal model.

Michael Linden: Our approach to Huntington's disease remains like that of C9R72 targeting, lower toxic protein while preserving beneficials. 003 is designed to silence transcripts that will lead to toxic mutant Huntington protein while sparing transcripts that allow synthesis of healthy Huntington protein, thus addressing both drivers of HD progression.

We plan to dose the first patient in the coming weeks and plan to applied PMO chemistry backbone modifications to other exon skipping candidates. If this study is successful.

Now I will turn things over to Paloma, who will provide an update on our ADR editing capabilities.

Thank you Mark and good morning to everyone on the call.

Michael Linden: Our ability to measure the effects of 003 is enabled by assays that allow direct measurement of target engagement in the CSS, mutant huntington knockdown, wild type preservation, and possible neural protection through the measurement of NFL. What's unique to our approach is how we accomplish selectivity, namely by targeting a known SNP called SNP3 that is associated with the CAG expansion on the mutant allele of many patients with Huntington's disease. Again, the purpose of this and other allele-selective approaches is to maintain the beneficial effects of wild types, which should maximize the beneficial effects of mutant Huntington production.

I'm excited to join you today to talk about ADR editing and ARPA growth in translating this capability into a therapeutic program for us.

Paul 1 antitrypsin deficiency.

Personal note weighted approach to RNA editing was a significant drop from me when I was offered the opportunity to join the company.

Since then I have only become more enthusiastic about the science and potential either editing as a new way to treat genetic diseases.

Hey, it could be.

Heritage genetic disorder that is most commonly caused by mutation in the Z allele of the <unk> 1 gene.

This mutation leads to miss folding and aggregation of Alpha 1 antitrypsin protein or does the AP and AR.

Michael Linden: If one thinks about this as a push and pull of positive and negative factors in the CNS, it stands to reason that non-selective depletion of both wild-type and mutant protein could shift the balance towards disease progression, erasing any benefit, or even potentially accelerating decline, especially in the setting of stress. This has been our hypothesis since we began our HD program, and emerging data support our position, making us resolute in this differentiated treatment approach.

Got it.

And the lack of functional.

And the lines, which results in progressive lung damage.

Damage or book.

With 8 or editing, we aimed to correct. The RNA to restore circulating functional wild type Alpha 1 antitrypsin protein or <unk> 82 per.

Protect the life and reduce VA.

Bangladesh aggregation and liver.

All while retaining the inmate physiological regulation of AEP.

Michael Linden: Slide 16 illustrates data demonstrating the highly selective, potent, and durable effects of 003 on mutant Huntington in in vitro and in vivo disease models. The back HD mouse model used is somewhat limited in that it contains multiple copies of the mutant Huntington gene, some of which do not have the SNP3 variant. Nonetheless, as shown on the bottom of the slide, we observed potent and durable knockdown in mutant Huntington in the striatum out to 12 weeks, with a similar effect observed in cortex.

With our Golden conjugated area pure oligonucleotide.

May be able to replace chronic weekly IV AAP.

<unk> therapy with a subcutaneously administered therapy that addresses all goals of treatment.

Approximately 200000 people in the U S and EU are homozygous for the <unk> mutation, which is the highest risk of lung and liver disease.

Paul we successfully demonstrated upwards.

Editing of the <unk>, 1 VLDL transcripts to wild type in hepatocytes in vitro.

Michael Linden: Select HD is planned to enroll approximately 36 patients with HD and confirmed SNP 3. Like with FOCUS C9, the preclinical data to date allow us to make certain assumptions regarding dose selection and frequency, with an independent committee reviewing unblinded data to determine dose levels and the optimal frequency for future multidose cohorts. As of today, clinical trial sites have been activated, recruitment is underway, and we expect to initiate dosing in the coming weeks.

This led to a 3 fold increase in functional wild type protein.

Encouraged by these initial results we move forward to successfully developed a proprietary transgenic mouse model.

Spanning both humanized, Germany, 1 in humanized, a doc that enabled pharmacokinetic and Pharmacodynamic assessment of human sequences in vivo.

Human 8 our model enables us to optimize oligonucleotides to human ADR, which is expected to improve translation into the clinic.

Following re subcutaneous doses up to unique ADR editing oligonucleotides, we achieved up to 40% editing a day 7.

Michael Linden: While target engagement studies in the CNS of non-human primates were not possible for 003 and 004, homology of target sequence between transgenic mice and non-human primates in some of our newer discovery programs enables us to evaluate drug distribution and target engagement in a large animal species using the intended route of clinical administration. What's been clear from these programs is that the application of stereochemistry and the PN chemistry backbone modifications enhance distribution throughout the CNS, leading to widespread and sustained knockout.

We are encouraged by these initial results as we are approaching the level of protection that represents and heterozygous.

And the patients with very low risk of disease.

Notably, we also did not observe any by standard editing.

Next we looked at how this level of editing impacted the circulating human protein. We saw a 3 fold increase in circulating AAC as compared to PBS control initial time point.

The magnitude of the increase is promising as it is representative of 1 the fold increase that may achieve phenotype with lower risk of disease and to total circulating AAP concentration approaching 570 micrograms per mil or 11, Mike from older in these mice.

Michael Linden: This is illustrated on slide 19 from a study for an undisclosed target with our most advanced Takeda collaboration candidate, WVE005, which contains PN modifications and was administered as a single 12 mg intrathecal dose to non-human primates. One month after administration, we observed broad distribution and substantial knockdown of the target throughout the CNS, including the striatum. It is this consistent, widespread CNS distribution of PN-modified oligonucleotides across species, the possibility of infrequent IT administration, and the availability of disease biomarkers for proof-of-concept studies that are the key features of our differentiated CNS portfolio moving through preclinical and clinical development. Moving on to WVE-N531.

This also establishes a floor from which to further optimize potency as we advance towards a clinical candidate.

You would think mass spectrometry, we investigated the isoforms of the circulating <unk> protein.

Confirm but the majority was restored wild type <unk>.

Consistent with the RNA editing result, there were no other isoforms identified that may have signaled by standard Ed.

It was very exciting to see such levels of wild type protein being generated post editing at this time point.

When we looked at longer when we look at longer duration data, we would expect to potentially see the AAP.

Increase initially as MAA reduces aggregation in the liver and DAA Pea protein is cleared.

At steady state with approximately 50% RNA correction, we expect to see a greater percentage of am AAP consistent with what is observed in Mg patients.

Michael Linden: This is our first PN-modified clinical candidate to be administered systemically. As also our first splicing candidate, it will provide insight into the ability of PN modifications to enhance access to dystrophic muscle and restore functional dystrophin expression. We are optimistic about this program given the compelling pre-clinical data comparing systemically administered PN-modified exon-skipping oligonucleotides with oligonucleotides containing only PS and PO modifications. These data are shown on slide 21 from experiments using an aggressive double knockout, or DKO, DMD mouse model lacking both utrophin and dystrophin.

As you can see on the right side of the slide. We also observed that there was a significant increase in neutrophil <unk> data inhibition post editing confirming the functionality of this restored wild type.

Protein.

In summary, we are excited to see these initial results.

Up to 40% editing in vivo translating to meaningful increases in circulating EAP that are driven by restored function of wild type protein, which again from an initial time point.

We also evaluated these compounds in a wild type mice model and achieved comparable RNA editing unfold change in AAP protein restoration.

Michael Linden: Following treatment with a PN-modified Exxon-23 targeting surrogate, we saw a dramatic treatment, rescuing all mice treated with the surrogate, which was very different from the mice treated with PBS or first-generation PSPO-modified ASOs dosed equivalent. In fact, the mice survived even when treated with a lower, less frequent dose of the PN-containing surrogate, once again highlighting the improved Just as a reminder, the relevance of these observations is the potential impact on Duchenne muscular dystrophy.

Our ongoing studies are assessing duration of activity dose response, and PK PD to provide insight into how MAA accretion levels will trend over time.

We will also be looking at the reduction in <unk> protein aggregates and changes in liver pathology.

At the same time, we are advancing optimized compounds with increased potency in new in vivo studies.

We expect to share an update on these datasets at research day and other settings in the second half of the year.

I will now hand, the call over to Kyle Kyle.

Thanks Paula.

Michael Linden: DMD is an area of significant unmet need, with current exon skipping treatments demonstrating only minimal dystrophin expression without yet establishing clinical benefits. N531 has similar chemistry to the exon 23 surrogate used in the DKO model, and when applied to DMD patient-derived human myoblasts amenable to exon 53 skipping, resulted in dose-dependent increases in dystrophin restoration up to 71% of normal at the These in vitro and in vivo observations, along with other preclinical data illustrating widespread distribution of N531 in the normal muscle of NHPs, prompted us to proceed with a human proof of concept study.

Ended the second quarter with $143.8 million from cash cash equivalents in marketable securities. This includes an additional $30 million in committed research support that we received in early April under our collaboration with Takeda.

Our total operating expenses for the second quarter of 2021 were $42.6 million.

As compared to $41.7 million last year.

R&D expenses were relatively consistent year over year at $31.6 million as compared to $31.5 billion.

In the same period in 2020.

Within R&D there were increased external expenses related to our <unk> 972 program and other discovery and development programs.

Prism and are reimbursed research and preclinical expenses related to <unk> collaboration.

These increases were almost entirely offset by decreased external expenses related to our discontinued clinical program.

G&A expenses were $11 million from the second quarter of 2021 as compared to $10.2 million last year with the increase driven by external expenses as well as compensation related expenses.

Finally, we continue to expect our existing cash and cash equivalents together with expected and committed cash from our existing collaboration will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023.

As a reminder, this does not include potential additional milestone payments and other uncommitted payments under our Takeda collaboration.

Michael Linden: As of today, our clinical trial sites are activated and recruiting eligible patients in our first-in-human clinical trial for N531 in boys amenable to exon 53 skipping. This open-label study is powered to determine whether N531 treatment intravenously leads to dystrophin production and whether the drug can readily access muscle cells, thus addressing the limitations that led to Sue Bederson's blacklist.

With that I'll turn the call back over to Paul.

Thanks, Scott with dosing underway in our <unk> 004, clinical trial and 003 and 531 soon behind we are entering a potentially transformational period of data generation per weighted.

We believe clinical data will unlock value in multiple ways.

These 3 clinical trials will provide insight into the clinical effects of pn chemistry by way of biomarker results and implications for dosing intervals as well as safety and Tolerability.

For <unk> year over year for <unk> III to interest equally delivered compounds designed to engage targets in the CNS success with these trials would derisk, our existing pipeline of CNS programs, including multiple programs in collaboration with Takeda and our undisclosed wholly owned targets.

Paloma Giangrande: We will also be assessing safety and tolerability of IV infusions initially at a frequency of every other week, mimicking the dosing frequency in the DKO animal model. We plan to dose the first patient in the coming weeks and plan to apply PN chemistry backbone modifications to other exon skipping candidates if the study is successful. Now I will turn things over to Paloma, who will provide an update on our ADAR editing capability. Paloma? Thank you.

With WV and 531 will gain insight into clinical effects on an entirely different modality exon skipping and the ability of pn chemistry to improve cellular uptake and distribution potentially unlocking our ability to apply this chemistry to other exon in DMD.

Positive results from any of these studies would enable path to registration across multiple therapeutic indications.

Our advances in chemistry sets us apart from others in the field that are enabling us to lead the way in developing hadar editing therapeutics.

Starting with <unk> conjugated oligonucleotides to deliver we are generating exciting preclinical data, but we are building on these results with new editing targets.

Paloma Giangrande: Thank you, Mike, and good morning to everyone on the call. I'm excited to join you today to talk about ADAR editing and our progress in translating this capability into a therapeutic program for Alpha-1 antitrypsin deficiency. On a personal note, WAVE's approach to RNA editing was a significant draw for me when I was offered the opportunity to join the company. Since then, I have only become more enthusiastic about the science and potential of ADAR editing as a new way to treat genetic diseases.

This is an exciting time for the wave team as we generate a continuous flow of data from multiple programs through 2022 to enable decision making.

We look forward to updating you on our progress.

Additionally, we hope you will tune in to our upcoming analyst and Investor Research Day on September 28, which will highlight our ADR editing capability feature new data from our <unk> program and provide updates on how we are advancing ADR headed into beyond the liver.

More detail on the research day will be shared in the coming weeks and with that we'll open up the call for questions.

Operator, thank you.

We will now begin the question and answer session. If you have a question. Please press star 1 on your Paul Keypad, if you'd like to be removed from the queue. Please Paul sorry go.

Good day.

It is not the speakers Paul please pickup your handset first before dialogue.

Paloma Giangrande: AATD is an inherited genetic disorder that is most commonly caused by a poor mutation in the Z allele of the SerpinA1 gene. This mutation leads to misfolding and aggregation of the alpha-1 antitrypsin protein, or ZAAT, in hepatocytes and a lack of functional AAT in the lungs, which results in progressive lung damage, liver damage, or both. With ADAR editing, we aim to correct the RNA to restore circulating functional wild-type alpha-1 antitrypsin protein, or MAAT, to protect the lungs and reduce ZAAT protein aggregation in the liver, all while retaining the innate physiological regulation of MAAT.

Once again, if you have a question. Please press star 1 on your phone keypad.

And on the line from Truest, we have Joon Lee. Please go ahead.

Hi. This is maybe you could argue for June.

Thanks for taking our question. Our question is related to focus the 9 study.

It would be great. If you could provide some color on your expected.

<unk>.

Treatment, specifically, considering unchanged level of C&I and or <unk> 72.

The profitability of our comprehensive sufficiency for this disease pathology. Thank you.

We're happy to take your question I'll refer to Mike to go through how we are approaching again, the targeting and clinical studies right I mean, I think that.

Paloma Giangrande: With our GalNet-conjugated stereopure oligonucleotides, we may be able to replace chronic weekly IV AAP augmentation therapy with a subcutaneously administered therapy that addresses all goals of treatment. Approximately 200,000 people in the U.S. and EU are homozygous for the ZZ mutation, which is the highest risk for lung and liver disease.

We recently did a a publication on our targeting strategy that that shows that the approach. We're taking is to take in consideration the important suggestion.

Reducing the the mutant variants while preserving the.

The healthy bearings to avoid that.

Half low insufficiency. So I think that we have considered that in our approach and has driven our targeting strategy and we anticipate that.

Paloma Giangrande: Last fall, we successfully demonstrated upwards of 60% editing of the SERPIN A1 Z-allele transcript to wild-type in hepatocytes in vitro, which led to a three-fold increase in functional wild-type AAT proteins. Encouraged by these initial results, we moved forward to successfully develop a proprietary transgenic mouse model containing both humanized SerpentA1 and humanized ADAR that enables pharmacokinetic and pharma The human ADAR mouse enables us to optimize oligonucleotides to human ADAR, which is expected to improve translation into the clinic.

The current compounds <unk> before that it is that balance of bringing down the toxins, while preserving the again the normal <unk> protein.

Great. So if I may I have a follow up question.

Europe.

<unk> 4 is a value on selected.

Yes.

Molecule also any other specific 1 offs.

Well, so it's a little different in the case of HD alright.

We have the wave of gene.

As shown in the presentation the way transcription occurs as you get these multiple transfer.

Paloma Giangrande: Following three subcutaneous doses of two unique ADAR editing oligonucleotides, we achieved up to 40% editing at day seven. We are encouraged by these initial results as we are approaching the level of corrections that represents a heterozygous MZ patient with a very low risk of disease. Notably, we also did not observe any bystander editing.

Paloma Giangrande: Next, we looked at how this level of editing impacted the circulating human AAT protein. We saw a threefold increase in circulating AAT as compared to PBS control at this initial time point. This magnitude of increase is promising, as it represents 1. the fold increase that may achieve phenotypes with lower risk of disease, and 2. total circulating AAT concentrations approaching 570 micrograms per ml, or 11 micromolar in these mice. This also establishes a floor from which to further optimize potency as we advance towards a clinical candidate.

The core OS or shapes or things that you're looking for there in terms of differentiation is the field develops.

Paloma Giangrande: Using mass spectrometry, we investigated the isoforms of this circulating AAP protein and confirmed that the majority was restored to wild-type MAAP. Consistent with the RNA editing results, there were no other isoforms identified that may have signaled bystander edit.

And then it's on C..9 on the C 9 program.

So the language here, if there's clinical data through 2022 and I'm just wondering here what the triggers are for data released publicly and if we could potentially get anything in 2021. Thank you.

Paloma Giangrande: It was very exciting to see such levels of wild-type protein being generated post-editing at this time point. When we look at longer duration data, we would expect to potentially see ZAAT increase initially as MAAT reduces aggregation in the liver, and ZAAT protein is cleared. At steady state with approximately 50% RNA correction, we expect to see a greater percentage of MAAT consistent with what is observed in MG patients. As you can see on the right side of the slide, we also observed that there was a significant increase in neutrophil elastase inhibition post-editing, confirming the functionality of this restored wild-type MAAT protein.

Okay I'll start with a Dr.

Like.

Yeah.

I think your question Eir's, great. It's something that we stay focused on at the very beginning and building that capability anyhow and building in Virginia.

Chemistry capability.

I believe we share the.

Early R&D day life cause it's nice to see the progress which is building on short chemically modified oligonucleotides that gain access to sell my bridge.

The chemistry and it.

Can be made using piano and seeing the advantage both on the potency to 8 or so using the Dodgers as I'm getting potency to it. So that is critical to getting accessibility. So the ability of vs short oligonucleotides to get into the cell into the compartment to engage in doctrine Zadar and then lastly to sustain that activity.

Reading about durability and I think that's the work that we've been set out to do over time I think it's great to see more people entering the field of endogenous aydar editing space I think what we've consistently done in Paloma alluded to on the call. Today is continue to optimize so establishing the floor the editing where we have today, which approach.

Paloma Giangrande: In summary, we are excited to see these initial results, up to 40% editing in vivo, translating to meaningful increases in circulating AAT that are driven by restored functional wild-type proteins, which again are from an initial time point. We also evaluated these compounds in a wild-type AATV mouse model and achieved comparable RNA editing and full change in AAT protein restoration. Our ongoing studies are assessing duration of activity, dose response, and PKPD to provide insight into how MAAT secretion levels will trend over time.

Now, what we think therapeutically relevant functional alpha 1 antitrypsin protein production and continuing to build on that on the pharmacology that'll go into our clinical Canada meeting potency and sustaining and growing that durability, so reducing the frequency of subcutaneous administration.

And then ultimately continuing to measure from Canada protein protect from issues. So I think others have taken different approaches in terms of their oligonucleotide designs in the toolbox.

They are using to build a chemistry I think with accelerated to work here at wave as being able to take advantage of fire.

Of our chemistry capability and Manufacturability, because we also know that 1 of the key drivers of this is not just to make preclinical molecules that we can test in rodent models in private but ultimately to take the scalability of the chemistry forward as we think about making this.

Paloma Giangrande: We will also be looking at the reduction in VAAT protein aggregates and changes in liver pathology. At the same time, we are advancing optimized compounds with increased potency in new in vivo studies. We expect to share an update on these datasets at Research Day and other settings in the second half of the year.

Potentially commercializable therapeutic.

Does that answer your from a pause on that 1 so we have to make sure in advance of the Aydar question that we'll talk about 39 question yeah.

Yeah, I think that was helpful. Thanks, Paul.

Sure.

So I assume it's on C..9 I mean the process here is.

Kyle B. Moran: Thanks, Paloma. We ended the second quarter with $143.8 million in cash, cash equivalents, and marketable securities. This includes an additional $30 million in committed research support that we received in early April under our collaboration with Takeda. Our total operating expenses for the second quarter of 2021 were $42.6 million.

The adaptive design of the study you can imagine an ongoing flow or you have recruitment dosing.

Follow up sales Independent Committee evaluation, and then recommendations to is Joseph frequency. So it's going to be this continuous plot process that is illustrated in the study design I mean, there are cause there is positive or negative feedback that could come out of those committee assessments that would prompt a disclosure this could be matilda.

Kyle B. Moran: $41.7 million last year. R&D expenses were relatively consistent year over year at $31.6 million as compared to $31.5 million in the same period of 2020. Within R&D, there were increased external expenses related to our C9ORG72 program and other discovery and development programs, including PRISM, and our reimbursed research and preclinical expenses related to our Takeda collaboration. These increases were almost entirely offset by decreased external expenses related to our discontinued clinical program. DNA expenses were $11 million for the second quarter of 2021, as compared to $10.2 million last year, with the increase driven by external expenses as well as compensation-related expenses.

Ariel changes to study design changes in durations of treatment other aspects that suggest patients are benefiting including disclosing moving on to the next phase of development life Registrational study some sort of regulatory feedback there is a variety of things that would prompt those disclosures throughout that time for.

<unk> bye.

But again the concept is it's ongoing the data being generated a misdemeanor material nature of things that would make us disclose and it's not just unique to see 9. So I think we've purposefully I think over time, it's not about the multitude of clinical programs moving that that could generate that and that is why we brought to my ex point I think.

We've been innovative on our clinical designs as much as we have on our molecules to bring this forward in terms of generating data and then interpreting that data quickly to make decisions on programs and so I think we've got ample opportunity as we move forward now with the return of 22.

Is there is there a specific time point that you're looking at for cohort 1 for example.

Kyle B. Moran: Finally, we continue to expect that our existing cash and cash equivalents, together with expected and committed cash from our existing collaboration, will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include potential additional milestone payments and other uncommitted payments under educated collaboration. With that, I'll turn the call back over to Paul.

Are you going to wait for a certain amount of time to pass before you would even consider.

Leasing data for that first cohort or the first 2 cohorts are having how are you planning to disclose the data.

Paul cohorts minute.

Single offending so I think it's great.

Studies enroll as you saw I mean, that's on the on the trial design. There is ample opportunities where assessments are being made on target engagement across studies. So that's built into the design of the study across cohorts.

I think what we're not guiding too is in each 1 of the adopted a sampling that that's a regular regularly scheduled update on the clinical studies I think Mike did a great job of pointing out that there are material changes that would occur the study that would cause us to say, we need to disclose an update on this study and so there's opportunities where.

Paul B. Bolno: Check out, with dosing underway in our WBE004 clinical trial and 003N531 soon behind, we are entering a potentially transformational period of data generation for WAVE. We believe clinical data will unlock value in multiple ways. These three clinical trials will provide insight into the clinical effects of PN chemistry by way of biomarker results and implications for dosing intervals, as well as safety and tolerability. For WVE-004 and WVE-003, two intrathecally delivered compounds designed to engage targets in the CMS.

<unk> for example.

Forward looking we see potent CVC knockdown and the safety committee in reviewing that data as you are engaging targets substantially you don't have to move to the next cohort just expand the existing color. So where there are design changes to the study that can be informed by data that would be a deviation from what we've set out publicly as this is the clinical trial. So I think we're going to let the.

Day to drive those updates and I think it's exciting that now happy in a position where we're not running historically.

Historically and a lot of CNS studies.

Given our App experience kind of landmark events were enrolled 5 cohorts that all look the same as fixed periods of time evaluate the data at the end and then flip the card at the end of that and see where we are so what it provides and I noticed the challenging part of it.

Paul B. Bolno: Success with these trials would de-risk our existing pipeline of CNS programs, including multiple programs in collaboration with DECADA and our undisclosed wholly-owned target. With WVN531, we'll gain insight into clinical effects on an entirely different modality, exon skipping, and the ability of PN chemistry to improve cellular uptake and distribution, potentially unlocking our ability to apply this chemistry to other exons in DMD.

Periodic assessments that could provide that what that enables us to do is substantially contract. The time that it would take for us to get to the important decision as Mike said that could lead to changing that study to a registration. So we will provide updates as as the as this year progressive and others as to as to the progress we're making.

Studies.

I understand thank you very much.

From people, we have Paul better. Please go ahead.

Hey, Thanks for taking our questions is Alexandra Paul.

Paul B. Bolno: Positive results from any of these studies would enable paths to registration across multiple therapeutic industries. Our advances in chemistry set us apart from others in the field and are enabling us to lead the way in developing ADAR editing therapeutics. Starting with GalNex conjugated oligonucleotides to the liver, we are generating exciting preclinical data, and we are building on these results with new editing targets.

Just another question I've seen I'd I was wondering.

Natural history, and we have an understanding of how Polly GP lengths related disease severity and is there sort of a threshold knockdown that you're looking for or how are you thinking about that and then I have another quick follow up thanks.

Sure regarding this is Mike regarding.

The level of apology, Mike Davis is out there now suggests that the actual severity of disease may not be directly linked to the level of Apollo GP in the CSS. So you can have people who are sort of those disease carriers that have.

Paul B. Bolno: This is an exciting time for the WAVE team as we generate a continuous flow of data from multiple programs through 2022 to enable Additionally, we hope you will tune in to our upcoming Analyst and Investor Research Day on September 28th, which will highlight our ADAR editing capability, feature new data from our AATD program, and provide updates on how we are advancing ADAR editing beyond the list. More details on the research day will be shared in the coming weeks.

Apologies detectable free high level, and you're going to people, who are symptomatic and levels relatively low so as a as an indicator of progression. Those data are evolving and has to we have to see what happens with intervention studies in weather changes translate into clinical changes in the end.

The goal is to get as much knockdown as possible because of that we want to be able to lower that level.

Paul B. Bolno: And with that, we'll open up the call for questions. Operator. Thank you. Thank you.

To the maximal minimal level and the CSF detectable because remember it is just an indicator of multiple Polly.

Operator: We will now begin the question and answer session. If you have a question, please press star 1 on your phone keypad. If you'd like to be removed from the queue, please press the pound sign or the hash. If you're on a speakerphone, please pick up your handset first before dialing. Once again, if you have a question, please press star 1 on your phone keypad. And on the line from QRIST is Joon Lee. Please go ahead.

Dipeptide proteins that are there. So there are other dpr's that we are also trying to effect.

Through the treatment of which poly GP is just 1 indicator and also CSF concentrations adjusted indicator of CSF tissue levels may be.

So again, it's a marker the goal is to get it down it will confirm target engagement and it would drive us forward into a clinical efficacy study assets programs.

Yeah that makes sense and and on <unk>.

Mani Foroohar: Hi, this is Mehdi Goudazi for June. Thanks for taking our question. Our question is related to the FOCUS C9 study, and it would be great if you could provide some color on your expected efficiency of this treatment, specifically considering unchanged levels of C9 or 72 and the possibility of haploinsufficiency for this disease pathology. Thank you.

And the Aydar program sounds like it's sort of interest optimization at this point, but can you walk us through kind of the steps that you see or an iron filings.

Yeah, I mean, I think a lot of the steps forward or not sicker. So I can take take away a kind of a normal enabling safety studies that you would do to her.

Enabling safety studies and I think what's important there in terms of the approach and I think we mentioned as a whole bunch of different approaches I think as we bring forward an RNA therapeutic approach that impacting transcript, we wouldn't anticipate that this study's we'd be doing there for a gallon neck oligonucleotide would be different than other obligated.

Paul B. Bolno: We're happy to take your questions. I'll refer to Mike to go through how we're approaching the disease targeting and clinical studies.

So this is different than the biologics approach using borrowed actors or impacting deals.

So put that these are signs of that that's the standard isco preclinical.

Growth toxicology package prior to that to your point on optimization I think the first step in this program was what we delivered in the first half of this year, which is demonstrated target engagement and a relevant model that tells us that we've achieved levels that were at that threshold.

As we mentioned the call that that floor, where optimizations occurring now is the low mode until the call is about continuing to see the enhancement of editing efficiency and potency pushing up higher into that range and balancing that with durability. So again.

Michael Linden: I mean, I think that, you know, we recently did a publication on our targeting strategy that shows that the approach we're taking is to take into consideration the importance of just reducing the mutant variants while preserving the healthy variants to avoid that haploinsufficiency. So I think that we have considered that in our approach and it has driven our targeting strategy, and we anticipate that, with the current compound 004, it is that balance of bringing down the toxins while preserving the, again, the normal C9R protein.

Using the frequency of administration I think we're on track for doing that and building a compelling program in that space and that's why we're excited to give a much more comprehensive update on the progress we've made since that day to release.

As it we'll lineup with our positive advancing into clinical candidates. So more to come at the research day on a dark but that's what we've talked about with optimization. We think we're there now it's about.

Places are fine tuning the durability potency to achieve maximum level with without letting.

It could be a briefing it would be a good so I think we're achieving substantial levels, where we are today. It's just the finalization of what will go into the Kennedy package.

Michael Linden: Great. So, if I may, I have a follow-up question. Your WAVE-004 is a variant-selective. Is this molecule also allele-specific or not?

Great. Thanks, so much.

And our last question from RBC, we have Luka. Please go ahead.

Michael Linden: Well, so it's a little different than the case of HD, all right, where, you know, the way the gene, as was shown in the presentation, the way transcription occurs is you get these multiple transcripts, right, that are produced. And the goal here is not to silence the entire allele. The goal is to actually go after the variants that contain the expansion because not all the variants have the expansion. So you're getting the selectivity of targeting a mutant, but you're also allowing normal transcription. So in essence, we call it variant selective because the objective in C9 is a bit different from the objective in HD, and the paper that we published on this actually goes through

Oh, hi, great. Thanks for taking my question. This is Lisa I'm from out of here at 2 from I just wanted to ask first off.

So we now that I know that some biogen are expecting to report data from sideline ILS, Paul and I found though.

They're not going after sideline that just wondering how are you thinking about that data and any implications for free.

Programs.

And I also have a follow up question.

Avon 18.

Is it keeping 11 Micromolar Avon Achy in this day on the bar for success.

Think patients could get back key potentially normal level and the reason I ask is because.

Operator: From Mizzou, we have Salim Syed. Please go ahead.

We know that 11 Micromolar is the bar for Andy patients, but.

Salim Qader Syed: Great, good morning, and thanks for the questions guys and congrats on the progress. Paul or Mike, I just wanted to ask a couple of questions, one on ADAR and one on C9-NORF. On ADAR, as the field develops here, I was wondering if there are any things that you guys can point to as you compare your ADAR program to COROS or SHAPES or things that you're looking for there in terms of differentiation as the field develops.

We also know at least from Kellogg that we've talked to you that M D patients.

I always asymptomatic asymptomatic as the original I believe and they can still have that sent my grandma issue. Thank.

Thank you.

It is a great question I'll take your second 1 first and then we will transition to while we're talking about the 11th Micromolar I think there's a reason why are we doing why we don't stay focused on that and we talk about continued optimization dosing regimen. So I think key for US was the identification of could we get.

Salim Qader Syed: And then just on the C9 program, so the language here says clinical data through 2022, and I'm just wondering what the triggers are for data release publicly, and if we could potentially get anything in 2021. Thank you.

Functional.

Duration and achieved certain threshold levels exactly to your point I think that was key for US thing that we've opened the door to establishing that floor and continue to bring forward with the possible advantages are I think the key is going to be following this over time as well so it's not just about pushing.

Ah reactive protein and sustaining it it's really for the underlying thesis is Paloma explained is about restoring a functional protein that there was the body needs. It can ex be expressed with the requisite level the body needs and do the work that it needs to do over a period of time and to your point we've had discuss.

Paul B. Bolno: I'll start with ADAR and then pass over to Mike, so we can talk about C9. I think your question about ADAR is great.

Paul B. Bolno: It's something that we stayed focused on at the very beginning, building that capability in-house and building it and leveraging it off of our unique chemistry capabilities. I believe we shared this at an early R&D day last time, so it's just nice to continue to see the progress, which is building on short, chemically modified oligonucleotides that gain access to cells that leverage the best of the chemistry adaptations we've made So using PN and seeing the advantage both in the potency of ADAR, so using the endogenous enzyme and getting potency to it, so that's critical to getting accessibility, so the ability of these short oligonucleotides to get into the cell and to the compartment to engage endogenous ADAR.

And can sharing the data with where we are and where we're going with key opinion leaders and it gives a lot of enthusiasm for this approach 1 of not being a DNA modifier and importantly, where C equivalent approach and excitement about this restoration of the functional side. So again in the last day.

Making this protein protein dysfunctional and it's there and transcribed when it's needed. So I think those are the pieces of building blocks going into the program and we're excited again show. This is the floor really push the the availability of being able to to do more.

As we transition to sub 1 I'll, let Mike pick up on the other side, but I do think it's important and we look at this historically.

Harrison to a number of features I think it is exciting that we're bringing new designs new chemistries forward that have differences in terms of distribution durability exposure, that's always challenging what to compare growth from somebody else's programs in chemistry, and our own I think we're letting our data support now with extensive preclinical in vivo data that we have for.

There are programs letting those data drive those programs forward, but Olympic speak specifically just buy 1 and how we think about the space Yeah, No I think that.

Obviously, it will depend upon with the day to look like.

<unk>.

A result, demonstrating that target engagement reduction that leads to a clinically meaningful outcome was obviously certainly great for patients, but it also once again.

Paul B. Bolno: And then, lastly, to sustain that activity, as we think about durability, and I think that's the work that we've been set out to do over time. I think it's great to see more people entering the field of endogenous ADAR editing as a space. I think what we've consistently done, and as Paloma alluded to on the call today, is continue to optimize, so establishing the floor, the editing where we have today, which approach is now what we think is therapeutically relevant, functional, alpha-1 antitryps in protein production, and continuing to build on that on the pharmacology that'll go into our clinical candidate, meaning potency and sustaining and growing that, durability, so reducing the frequency of subcutaneous administration, and then, ultimately, continuing to measure the functionality of that protein over time for patients.

Validate the approach of doing enter vehicle administration with the engagement of target and neurological disease translating into translating into clinical benefit and when you think about our approach to see 9 where now with the PM pharmacology, we have all the advantages that we've been talking about this next generation approach and potential for durable.

Potential per high potency.

4 different target, but still in this disease and actually 2 diseases, when you're pulling FTE. It makes us quite optimistic about that we're on the right track and now. This is this is about gauging target and.

And then measuring that that effect in the clinic so.

Looking at it as of the potential it brings to it.

Administration, <unk> program, leading to clinical effect it actually.

Makes is pretty optimistic where we are yeah.

I think in the end and just to put a summary of that I think what we've seen in devastating neurologic diseases desire for medicines to work. So I think we are hopeful that there are approaches the als's Saddam 1 that do break observations in the sense that it well. It is a smaller area 79, and those noted overlap I think it continues to open.

Paul B. Bolno: So I think others have taken different approaches in terms of their oligonucleotide designs, of our chemistry capability and manufacturability, because we also know that one of the key drivers of this is not just to make preclinical molecules that we can test in rodent models and in primates, but ultimately to take the scalability of the chemistry forward as we think about making this a potentially commercializable therapeutic We'll pause on that one, Salim, to make sure to answer the ADAR question and then we'll talk about the C9 question.

Discussions around right.

Mr patients capital so.

We wish the best February of the space.

Great. Thank you very helpful.

Thank you I will now turn it back to Paul Paul No for closing remarks.

Thanks, everyone for joining the call. This morning to review our second quarter of 2021 corporate updates and thank you to our wave employees for their hard work and commitment to patients. We look forward to speaking to you again in our research day in the fall have a great day.

Thank you ladies and gentlemen. This concludes today's conference. Thank you for joining you may now disconnect.

Paul B. Bolno: Yeah, I think that was helpful. Thanks, Paul.

Michael Linden: Great, so on C9, the process here is the adaptive design of the study; you can imagine an ongoing flow where you have recruitment, dosing, follow-up, independent committee evaluation, and then recommendations as to dose and frequency. So it's going to be this continuous process that is illustrated in the study design. I mean, there is positive or negative feedback that could come out of those committee assessments that would prompt a disclosure. This could be material changes to study design, changes in durations of treatment, other aspects that suggest patients are benefiting, including disclosure of moving on to a next phase of development like a registrational study, some sort of regulatory feedback. There's a variety of things that would prompt those disclosures throughout that timeframe. But again, the concept is it's ongoing, the data are being generated, and it's the material nature of things that would make them public.

Paul B. Bolno: And it's not just unique to C9, so I think, you know, we've purposefully, you know, I think over time thought about the multitude of clinical programs moving that could generate that, and, you know, that is why we brought this to Mike's point. I think we've been innovative in our clinical designs as much as we have on our molecules to bring this forward in terms of generating data and then interpreting that data quickly to make decisions And so I think we've got ample opportunity as we move forward now through 2020.

Operator: Is there a specific time point that you're looking at? I mean, for Cohort 1, for example, are you going to wait for a certain amount of time to pass before you would even consider it?

Operator: Thank you. Thank you. Please study to enroll as you

Operator: Studies Enroll, as you saw, I mean that in the trial designs, there's ample opportunities where assessments are being made on target engagement. So, you know, that's built into the design and the study in the process.

Paul B. Bolno: I think what we're not guiding to is in each one of those dots in the sampling that that's a regular, regularly scheduled update on the clinical studies. I think Mike did a great job of pointing out that there are material changes that would occur in the study that would cause us to say we need to disclose an update on the study. And so there's opportunities where, you know, for example. Again, forward-looking.

Paul B. Bolno: We see potency, we see knockdown, and the Safety Committee, in reviewing that data, says you're engaging targets substantially. You don't have to move to the next cohort; just expand the existing cohort. So where there are design changes to the study that can be informed by data, that would be a deviation from what we've set out publicly as this is a clinical trial. So I think we're going to let the data drive those updates.

Paul B. Bolno: And I think it's exciting that now, happy in a position where we're not running as historically in a lot of CNS studies, and given our past experience, kind of landmark events where we enroll five cohorts that all look the same in six periods of time, evaluate the data at the end, and then flip the card at the end of that and see where we are. So what this provides, and I know this is the challenging part of it, is the periodic assessments that can provide that.

[music].

Paul B. Bolno: And what that enables us to do is substantially contract the time that it would take for us to get to an important decision, as Mike said, that could lead to changing that study to a registrational study. So we'll provide updates as this year progresses, and others as to the progress we're making.

Operator: I understand. Thank you very much.

Operator: From Steeple, we have Paul Mettis. Please go ahead.

Alex Han: Hey, thanks for taking our question. This is Alex Han from Paul.

Michael Linden: Just another question on C9. Do we have an understanding of how poly-GP lengths relate to disease severity, and is there sort of a threshold knockdown that you're looking for, or how are you thinking about that? And then I have another quick follow-up. Thanks.

Michael Linden: Sure, regarding, this is Mike. Regarding the level of poly-GP, right, the data that is out there now suggests that the actual severity of disease may not be directly linked to the level of poly-GP in the CSF. So you can have people who are sort of those disease carriers that have poly-GP detectable at a pretty high level, and you have people who are symptomatic, and the level is relatively low. So as an indicator of progression, those data are evolving; we have to see what happens with interventional studies and whether changes translate into clinical trials. In the end, the goal is to get as much knockdown as possible because of that.

Michael Linden: We want to be able to lower that level to the minimal level in the CSF detectable because remember, it is just an indicator of multiple poly dipeptide proteins that are there. So there are other DPRs that we are also trying to affect through the treatment of which poly GP is just one indicator. And also, CSF concentrations are just an indicator of CSF; the tissue levels may be different. So again, it's a marker. The goal is to get it down. It would confirm target engagement, and it would drive us forward to a clinical efficacy study.

Michael Linden: Great, that makes sense. And on AAT and the ADAR program, it sounds like it's sort of just optimization at this point, but can you walk us through kind of the steps that you see for an IND filing?

Paul B. Bolno: Yeah, I mean, I think a lot

Paul B. Bolno: Yeah, I mean, I think a lot of the steps forward are not that different. So I can take away kind of the normal IND enabling safety studies that you would do or CTA enabling safety. And I think, you know, what's important there in terms of the approach, and, you know, I think, as Salim mentioned, there's a whole bunch of different approaches. I think as we bring forward an RNA therapeutic approach that impacts transcripts, we wouldn't anticipate that the studies we would be doing there for a gal neck oligonucleotide would be different than other oligonucleotides. This is different than the biologics approach using viral factors or impacting So, put that piece aside; that's the standard preclinical toxicology.

Operator: Prior to that, to your point on optimization, I think, you know, the first step in this program was what we delivered in the first half of this year, which was to demonstrate target engagement in a relevant model that tells us that we've achieved levels that were at that threshold, or, as we mentioned on the call, at that floor. Where optimization is occurring now, as Paloma alluded to on the call, is about continuing to see the enhancement of editing efficiency and potency, so pushing us higher into that range and balancing that with durability, so again, reducing the frequency of administration.

Operator: I think we're on track to do that and build a compelling program in that space, and that's why we're excited to give a much more comprehensive update on the progress we've made since that data release, as it will line up with our path to advancing as a clinical candidate. So, more to come at the research day on ADAR, but that's what we talked about with optimization. We think we're there, now it's about, you know, It would be great being the enemy of good.

Operator: So I think, you know, we're achieving substantial levels where we are today. It's just the finalization of what we're going to do. Great, thanks so much. And our last question from RBC is from Luca Issi. Please go ahead.

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Lisa: Oh, hi, great. Thanks for taking the question. This is Lisa on behalf of Luca here.

Operator: Two from us just wanted to ask, first off, so we know that Ionis and Biogen are expecting to report data for SOD1 ALS in the fall. And I know you're not going after SOD1, but just wondering, how are you thinking about that data and any implications for your programs? A1AT. Is achieving 11 micromolar A1AT in the serum the bar for success here, or do you think patients could get back to potentially normal levels?

Operator: And the reason I ask this is because we know that 11 micromolar is the bar for MD patients, but we also know, at least from KLLs that we've talked to, that MD patients aren't always asymptomatic as originally believed, and they can still have some liver and lung issues. Thank you.

Paul B. Bolno: It's a great question. I'll take your second one first, and then we'll transition.

Paul B. Bolno: So while we're talking about the 11 micromolar, I think there's a reason why we don't stay focused on that when we talk about continued optimization and dosing measurements. So I think key for us was the identification of whether we could get... functional AAT restoration and achieve certain threshold levels. Exactly to your point.

Paul B. Bolno: I think that was key for us saying that we've opened the door to establishing that floor and continuing to bring forward what the possible advantages are. I think the key is going to be following this over time as well. So it's not just about pushing a reactive protein and sustaining it. It's really the underlying thesis, as Paloma explained, about restoring a functional protein that's there when the body needs it. It can be expressed at the requisite levels the body needs and do the work that it needs to do over a period of time.

Paul B. Bolno: And to your point, we've had discussions about sharing the data about where we are and where we're going with key opinion leaders. I think there's a lot of enthusiasm for this approach. One, on not being a DNA modifier. And importantly, we're seeing an equivalent approach and excitement about this restoration of the functional side. So again, the elastase assay makes this protein functional, and it's there and transcribed when it's needed. So I think those are the pieces of building blocks going into the program.

Paul B. Bolno: And we're excited to, again, show this as the floor, really push the availability of being able to do more. As we transition to slide one, and I'll let Mike pick up on the other side, but I do think it's important, and we've looked at this historically in a comparison to a number of features, I think it is exciting that we're bringing new designs, new chemistries forward that have differences in terms of distribution, durability, and exposure.

Paul B. Bolno: It's always challenging to compare and read through from somebody else's programs in chemistry and our own. I think we're letting our data support now, with the extensive preclinical in vivo data that we have for our programs, drive those programs forward. But I'll let Mike speak specifically about slide one and how we think about the space.

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Michael Linden: Yeah, no, I think that, you know, obviously it will depend upon what the data look like. But, you know, a result demonstrating that, you know, in target engagement reduction that leads to a clinically meaningful outcome is obviously certainly great for patients, but it also, once again, validates the approach of doing inter-thecal administration with the engagement of target neurological disease translating into clinical benefit. And when you think about our approach to C9, where now with the PM pharmacology, we have all the advantages that we've been talking about of this next generation approach, and potential for durable effect, potential for high potency, for, you know, a different target, but still in this disease, and actually in two diseases when you pull an FTD, it makes us quite optimistic about that we're on the right track, and now this is about gauging target and then measuring that effect in the clinic.

Michael Linden: So looking at it as the potential it brings to IT administration for a C9 program leading to clinical effects, it actually..., you know, makes us pretty optimistic where we are. Yeah, I mean, I think in the end and just to put it

Paul B. Bolno: Yeah, I mean, in the end, and just to put a summary on that, I think what we've seen in devastating neurological diseases is the desire for medicines to work. So, you know, I think we are hopeful that there are approaches to ALS and SOD1 that do bring hope for patients in the sense that while it is a smaller variant than C9 and there's not an overlap, I think it continues to open up discussions around regulatory pathways for patients to have hope. So I think, you know, we wish you the best.

Operator: Great. Thank you. Very helpful.

Paul B. Bolno: Thank you. We'll now turn it back to Paul Bolno for his closing remarks.

Paul B. Bolno: Thank you everyone for joining the call this morning to review our second quarter 2021 corporate updates, and thank you to our WAVE employees for their hard work and commitment to patient care. We look forward to speaking to you again at our research day in the fall. Have a great day. Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for joining us. You may now disconnect.

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