Wave Life Sciences Ltd. (WVE) Earnings Call Transcript & Summary

Good morning, and welcome to the Wave Life Sciences RestorAATion-2 Clinical Update Conference Call. [Operator Instructions] Also, as a reminder, this conference call is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Thank you, operator. This morning, we issued a press release announcing a positive update from our ongoing RestorAATion-2 trial of WVE-006 in alpha-1 antitrypsin deficiency. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com, and the slide presentation to accompany this call will be available on the website following the prepared remarks. Before we begin, I'd 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, 2024. We undertake no obligation to update or revise any forward-looking statement for any reason. Today, Dr. Paul Bolno, President and Chief Executive Officer, will begin with opening remarks. Next, Dr. Chris Wright, Chief Medical Officer, will present the RestorAATion-2 clinical data update. Paul will conclude the prepared remarks with next steps and anticipated milestones before turning it over to Q&A. Dr. Erik Ingelsson, Chief Scientific Officer; and Dr. Chandra Vargeese, Chief Technology Officer, will also be available to answer questions. I'd now like to turn the call over to Paul.

Thanks, Kate. Good morning, and thank you for joining us today. Today, we are excited to share the full results from our first 200-milligram dose cohort and 400-milligram single-dose cohort in our RestorAATion-2 clinical trial. Our goal in RestorAATion was to recapitulate the MZ phenotype, including durable production of M protein, reduction of Z protein and the ability to produce a dynamic AAT response when needed. Within our first 200-milligram cohort, we're pleased to share that treatment with multiple doses of WVE-006 achieved 11.9 micromolar of total AAT, 7.2 micromolar of M-AAT. Circulating M-AAT and serum reached 64% of total AAT and Z-AAT protein declined over 60% from baseline. RNA editing effects were incredibly durable and sustained at least 2 months following last dose. Notably, we achieved yet another significant milestone in the field of editing with 006 as we observed the first-ever demonstration of therapeutic restoration of a Pi*ZZ individual's ability to increase serum AAT production of over 20 micromolar during an acute phase response. Chris will share more detail on this momentarily. This is a particularly meaningful achievement for individuals living with AATD, as it demonstrates that 006 can dynamically generate more healthy protein when individuals living with AATD are most susceptible to lung damage. Initial results from our second dose cohort demonstrate that a single 400-milligram dose of WVE-006 leads to serum total AAT of approximately 13 micromolar. And based on our 200-milligram results, multi-dosing is expected to drive greater AAT production. The multi-dose 400-milligram cohort is ongoing with monthly dosing, and we expect to share data in the first quarter of next year. There is an immense need for effective therapies for AATD, which is caused by the aggregation of mutant Z-AAT protein in the liver and lack of functional AAT in the lungs. Damage in the lungs occurs during exacerbations that induce an inflammatory acute phase response. Healthy individuals are able to produce elevated levels of protective functional AAT protein during these events, and it protects the lung from damage. Progressive liver disease results from Z-AAT-induced proteotoxic stress. Treatment today is limited to weekly IV augmentation therapy for lung disease, which does not allow for protective increases in AAT protein during acute phase response without additional infusions. There are no approved therapies that address AATD liver disease and the siRNA treatments in development could potentially exacerbate lung injury. There are an estimated 200,000 homozygous Pi*ZZ individuals in the U.S. and Europe. We've heard many powerful testimonials directly from the AATD community that speak to the harsh impact of this disease, which progresses over time as a result of accumulated injury and is often misdiagnosed. Risk for AATD is related to genotype with MM being healthy and MZ individuals having low risk for disease. ZZ individuals have high risk for both severe lung and liver diseases due to the lack of wild-type M-AAT protein and serum and misfolded Z-AAT protein trapped in the liver. Since the approval of weekly IV augmentation therapies to treat lung disease, the field has focused on keeping serum AAT levels above a minimum threshold, in part because ZZ individuals do not produce any M-AAT and have a limited ability to increase serum AAT levels during an acute phase response for exacerbation. Editing by RNA, at least 50% would shift ZZ individuals to an AAT biomarker profile consistent with the MZ phenotype with low risk of disease. One of the key treatment goals is to protect against lung injury by reducing the frequency and severity of exacerbations, which drive disease progression. During these events, immune activity, proteolytic enzymes and inflammation cause damage to the lungs, because AAT protein, a key protector against these insults is missing. On the left of Slide 8, you can see the kinetic profile for C-reactive protein or CRP, and AAT protein during an acute phase response. CRP spikes early and the peak level impacts the intensity of the immune response. AAT protein expression is upregulated proportional to the CRP elevation. This ability to upregulate AAT is severely impaired in ZZ individuals with AATD, which is shown on the right of this slide. The best way to limit exacerbations and the associated damage that drives disease progression would be to enable ZZ individuals to respond like an MZ or a healthy individual and make protective AAT protein when it's needed. And this is exactly what we were able to observe with 006 during an acute phase response. Designed using our proprietary chemistry, which drives potency, stability, distribution and delivery, 006 has the potential to be the first treatment for AATD that enables patients to produce protective AAT protein when needed and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapeutic. 006 corrects the Z mutation, increasing circulating levels of wild-type M-AAT protein and reducing mutant Z-AAT protein aggregation in the liver, thereby treating patients with lung manifestations, liver manifestations or both. As Chris will share momentarily, our clinical data with 006 strongly supports a differentiated therapeutic profile as we observed restoration of dynamic physiological AAT protein production during a non-drug-related acute phase response, efficient production of M-AAT and corresponding decreases in mutant Z-AAT. Now to review the clinical results, I'd like to turn the call over to our Chief Medical Officer, Dr. Chris Wright.

Thanks, Paul, and good morning to everybody on the call. Today, I'm excited to share an update from multiple cohorts of our RestorAATion-2 clinical trial. Our RestorAATion program started with healthy volunteers in RestorAATion-1. This was a safety, tolerability and PK dose escalation study that proceeded through single ascending and multiple ascending dose phases, ultimately evaluating up to three 600-milligram doses of 006 administered every other week. Data from RestorAATion-1 informed the starting dose of RestorAATion-2, our open-label dose escalation study of individuals with AATD, who have the homozygous Pi*ZZ genotype. Each cohort was designed to enroll eight participants who began with a single dose of 006 and then continued into the multi-dose cohort. Participants in the first lowest dose cohort of RestorAATion-2 received a single 200-milligram dose of 006 and were followed for at least 12 weeks. These same participants then rolled over into the multi-dose portion where they received seven 200-milligram doses every other week for 12 weeks. They were then followed for 12 weeks after their final seventh dose. Today's update includes data from both the single and multi-dose portions of the 200-milligram low-dose cohort as well as data from the 400-milligram single-dose cohort. I'll quickly touch on the safety and tolerability we observed in RestorAATion-1, the healthy volunteers study. The study enrolled 29 individuals on active drug with participants receiving up to three 600-milligram doses every other week in the highest dose cohort. 006 was safe and well tolerated with the related TAE being mild in intensity. In RestorAATion-2, we enrolled eight patients with AATD into each of the 200 and 400-milligram cohorts. Baseline characteristics were similar between the cohorts with some minor differences in gender and weight. Participants mostly had no or mild evidence of liver or lung disease as required by protocol with one participant having moderate liver disease. All participants were required to be between 18 and 70, have a Pi*ZZ genotype and be non-smokers for at least 1 year prior to screening. 006 was safe and well tolerated across all doses and regimens tested. All drug-related adverse events were mild to moderate in intensity. There were no serious adverse events or study discontinuations. Additionally, there were no clinically meaningful treatment-related lab, ECG or vital sign changes. Overall, we're encouraged to see such a favorable safety profile for all evaluated doses. Now turning to our biomarker results in today's update. In the single and multiple dose cohorts, we observed a mean max total AAT of 12.9 and 11.9 micromolar, respectively. These results were consistent across participants as shown in the chart on the left, except for one individual with an acute phase response, which I will cover in more detail later. On the right side, we show the time course of RNA editing across the study periods. The bar graph shows the proportion of mutant Z-AAT in light blue and wild-type M-AAT in dark blue. Remember, individuals with the ZZ phenotype cannot make any M-AAT. So at baseline, circulating AAT protein is 100% Z-AAT. Even with a 200-milligram single dose of 006, M-AAT protein reached nearly 50% of total AAT and editing effects persisted out to 3 months, marking the end of the follow-up period. Looking at the multi-dose phase where participants received seven total doses, one every other week, M-AAT protein reached a higher proportion of total AAT than in the single-dose phase with a mean max at around 64%. This proportion of M-AAT is consistent over most of the observation period with a level still at approximately 50% edited protein 2 months after the last dose. These data indicate that the proportion of circulating M-AAT increases with multiple doses and that 006's RNA editing activity is durable. Looking at the dynamic changes in M-AAT and Z-AAT at an individual level, you can see just how consistent the effects of 006 were across participants with everybody responding to treatment. On the top left, you see a substantial increase in M-AAT protein, which persists up to 3 months following a single dose. There's a corresponding decrease in Z-AAT on the bottom left of the slide, consistent with the presence of significant RNA editing. A similar pattern with more substantial responses was observed in the MAD portion of the study, as shown in the middle of the slide in dark blue. Across both M-AAT and Z-AAT, there was a statistically greater effect in the MAD as compared to the SAD shown on the right, supporting exposure-related enhancements of the effects. In the MAD, the mean max M-AAT reached 7.2 micromolar from 0 at baseline. And there was a 60.3% reduction in mutant Z-AAT protein from 10.7 micromolar at baseline. If you look at the SAD data on the left again, you'll note one participant also seen in the box plot on the upper right, had a very strong M-AAT response, followed by a decline over about 4 weeks. In the next slide, I will focus on this response as it potentially is telling us something very unique and impactful about the effects of 006. Looking closer at this individual response, serum total AAT increased to a level exceeding 20 micromolar. There was also a moderate elevation in C-reactive protein or CRP, which is indicative of an acute phase response. After investigating this case further, it was noted that this 200-milligram single-dose participant experienced a kidney stone, which was unrelated to study drug. This presented us with a rare opportunity to assess the impact of 006 on the dynamics of endogenous AAT protein production in the context of an acute phase response. As you can see, there's a simultaneous and rapid increase in both total and M-AAT levels followed by a period in which AAT remains elevated. This pattern resembles a typical acute phase response. To the right in this slide is the natural history data that you may recall from Paul's introduction, showing ZZ individuals are not expected to have increased serum AAT levels during an acute phase response. MZ and MM individuals both up-regulate AAT when CRP levels are around 20 to 50 milligrams per liter. The observed strong AAT elevation in our ZZ participant affirms that 006 enabled an MZ response. This participant illustrates that a single 200-milligram dose of 006 resulted in substantial up-regulation of AAT when it was needed in the ZZ individual. Importantly, CRP elevations in this participant were moderate. So it's likely that 006 could result in an even greater AAT elevation with a stronger acute phase response. A long-standing goal of the AATD community has been to ensure individuals living with AATD are protected with sufficient serum AAT during exacerbations. Restoring endogenous expression dynamics of AAT during an exacerbation when it's most needed achieve this goal. These data represent the first ever therapeutic demonstrating RestorAATion of dynamic, physiologic AAT production during an acute phase response. Now turning to the 400-milligram cohort. The single dose achieved serum total AAT of 12.8 micromolar and M-AAT of 5.3 micromolar. Circulating serum M-AAT levels reached 47.2% of total AAT and Z-AAT decreased by 49% versus baseline. Relative to the 200-milligram single-dose cohort, greater M-AAT was produced and a larger decrease in Z-AAT was observed. Based on the differences between dose levels in the SAD cohorts and the impact of multiple doses in the 200-milligram cohort, we expect that the 400-milligram multiple cohort may lead to even greater effects on AAT expression. The data gathered to date, along with the PK/PD modeling supports monthly or less frequent dosing and our 400-milligram MAD cohort is currently ongoing with once monthly dosing. We look forward to sharing the complete 400-milligram data set with you in Q1 2026. I'll now turn the call back to Paul.

Thanks, Chris. Our goal in RestorAATion-2 was to recapitulate the MZ phenotype, including durable production of M-AAT, reduction of Z-AAT and restoring the ability to produce a dynamic AAT response when needed. The results of our first cohort clearly show we have already achieved this goal. With efficient and durable RNA editing, we are restoring a biomarker profile in individuals living with AATD that is consistent with low risk of lung and liver disease, including total AAT protein levels of 13 micromolar and over 60% circulating M-AAT and serum with no bystander edited protein. Consistent with what we would expect to see in MZ individuals, we are also restoring physiologic AAT production and the ability for ZZ patients to respond with increased protein levels during an acute phase response to prevent lung damage. By reducing Z-AAT levels, we have also had the potential to prevent liver damage. Importantly, we have not observed any liver enzyme adverse events nor do we use LNP delivery, which have known risk for hepatotoxicity. With convenient subcutaneous monthly or less frequent dosing, we have potential to bring a truly transformative therapy to the AAT -- alpha-1 community, and we are incredibly encouraged by the safety profile we are observing today. GSK was early to recognize the potential of RNA editing and our multimodal platform more broadly. Their leadership in respiratory medicine development and commercialization makes them an ideal partner for 006. We also continue to advance our GSK research collaboration programs. GSK has now selected a third program to advance the development candidate following achievement of target validation, which carries an associated milestone. Additionally, this collaboration enables expansion of our wholly owned pipeline of genetically validated targets, including INHBE for the treatment of obesity. Across WVE-006 and these collaboration programs, we are eligible for substantial milestone payments of up to $3.3 billion and anticipated payments in 2025 and beyond, which are not included in our cash runway. Our data with WVE-006 continue to demonstrate the clinical translation of our RNA editing capability, including safety, greater than 60% edited protein and consistency across patients and impressive durability. Beyond 006, we are building a wholly owned editing pipeline, which leverages these learnings. Our next expected clinical program is PNPLA3, a GalNAc RNA editing program with the potential to address 9 million homozygous I148M carriers in the U.S. and Europe with liver disease. We have shown that RNA editing has the potential to be a superior approach to siRNA knockdown in liver disease patients with this genetic background due to the important role of wild-type protein. We remain on track for CTA filing in 2026 for this program. Beyond 006 and 007, our siRNA program for obesity, we are continuing to advance a wholly owned discovery pipeline addressing hepatic as well as extrahepatic targets, and these programs utilize our proprietary chemistry to achieve best-in-class RNA editing and siRNA silencing in both rare and common diseases. Last year, we shared preclinical data highlighting our ability to direct silencing and editing to high-priority extrahepatic tissues, including CNS, skeletal muscle, adipose, heart, pancreas and lung. We look forward to providing a further update from our emerging pipeline at our Analyst and Investor Research Day this fall. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. Today's results accelerate the already strong momentum of our best-in-class pipeline and the strength and differentiation of our platform, which continues to translate in the clinic. Building on today's results, we expect to share data in the first quarter of 2026 from our ongoing 400-milligram multi-dose cohort, which is evaluating a monthly dosing regimen. In addition to our strong progress in AATD, our INLIGHT clinical trial in obesity is off to an excellent start. We've expanded and completed dosing in our second cohort, which evaluates a 240-milligram dose following favorable safety and tolerability as well as robust Activin E reduction observed in Cohort 1. We remain on track to report data from the expanded Cohort 2 and data from Cohort 1 in the fourth quarter of 2025 as well as data from Cohort 3 during the first quarter of 2026. Before turning the call over to questions, I would like to take a moment to thank all individuals participating in our RestorAATion clinical program, the clinicians involved and the study staff. The patients we serve inspire the work we do every day and from everyone at Wave, we'd like to express our sincerest gratitude. And with that, I'll turn the call over to the operator for Q&A. Operator?

[Operator Instructions] We'll take our first question from Joseph Schwartz with Leerink Partners.

Congratulations on these groundbreaking results. I was just wondering, does it seem like there's an asymptotic set point above which it's hard to drive M-AAT, AAT protein levels when it's not needed? And why do you think that is? And how do your models predict repeat dose 400 milligrams will work? Will it push the envelope further or push on a string?

I think, it's a great question, Joe, and I appreciate the fact that we're actually going to be able to observe this over time in addition to the dynamic response rate. So if we think about total AAT, it's a composition of Z, which obviously with editing would be expected to decline, which is what we saw. And M protein, which these patients don't have, increases. And we do see that over time, so with longer exposure, the proportion of M-AAT and serum does increase. And in fact, at higher doses, that M-AAT increases. So yes, we do think there's still a drive and more continued work that will push the M-AAT protein higher, both with time as well as increased exposure. What that is separate from? And I think this is really the unique aspect that we demonstrated today, is the dynamic response rate. And this speaks to having more substrate to edit. So what we learned today based on being able to observe what happens during an acute phase response, is during that response, you have an increase in transcription. So there's more transcript to be edited. It tells us that we've got ample drug inside the cell with a catalytic enzyme with which to be able to edit. And so it's not substrate bound. So if there's more substrate to be edited as in the case of the acute phase response, we can continue to drive that editing higher to meet the challenges as we saw getting up to 20 micromolars where it's required. I'll ask Chris or Erik, if there's anything else to share.

No, I think, Paul, you summarized it very nicely. I think the only additional thing to say is that, I think we, as a field, need to kind of move away from this threshold at baseline. And I think we're up over that threshold here already with the lowest dose. But the most important part is to have a physiologically dynamic response to insult when it's needed. So it's basically when AAT is needed as an acute phase protein, it can respond and go up to very high levels.

I think, just to piggyback on Erik's last point, because I think it's an important one as we go through Q&A is, is this notion of what's the therapeutic treatment for AATD. And I do think, the field comes at it with this concept of IV protein replacement therapy, to Erik's point on baseline. And this notion that if you infuse and sustain this kind of basal level, then it's there when you need it and needs to be at this threshold to melt the response. Again, I think the data that we demonstrated today, which demonstrates actually that you can rise to meet the occasion wherever it is to drive down and protect during exacerbations is the key therapeutic treatment for alpha-1 antitrypsin patients. I mean, that is the functional -- that's how you want to actually drive a response is being there during these acute exacerbations to meet that need and taking ZZ patients who are non-responsive to these acute phased responses and now turning them to MZ heterozygous phenotypes to mount that response is huge in terms of the treatment goals.

Our next question comes from Joon Lee with Truist.

Congrats on the data. Given competitive dynamics, including those from base editing, prime editing and gene writing and some questions around the levels of M-AAT, do you have any plans to assess clinical outcomes to potentially differentiate from a commercial standpoint? And also, as a quick clarification, in your Cohort 2, how many actually had both liver and lung manifestations or one or the other? Just wanted to understand the baseline characteristics in terms of the liver versus lung patients.

Yes. So on the last one, and I think it's an interesting question to your point on how -- ultimately, what do clinical outcome studies look like. And I think there's no better partner for a respiratory outcome study than GSK with extensive experience in diseases of acute exacerbation in respiratory diseases. I think that is why they're excited about these data. I think this does demonstrate that ability to mount the response during acute exacerbations, which actually bode well for treating that -- those clinical outcome studies. I mean, if we think about the challenges in the field to date on IV protein replacement therapy and meeting those challenges have been -- if you have these kind of trough levels that everybody is thinking about with a protein that's immediately consumed once you have these acute phase responses, then if somebody were at the trough at a point in time where they actually had an exacerbation that would be substantial like in pneumonia. You could see that theoretically, you'd consume all of the available protein that would be there to continue to protect the lung. When you have this opportunity, you're not rate limited. The body is making more. They're generating more protein and you continue to meet those responses, which actually bode very well for continuing to follow those clinical outcome measure. And I think there's a great partner thinking about that development pathway and commercial differentiation down the road that understands the space very, very well in conjunction with us. To your first question, I'll defer to Chris who can comment on the patient disposition.

Sure. So overall, our patient population had healthy or mild to moderate lung disease as well as liver disease. You can look at the baseline table, and you'll see that there were -- the majority of patients were F0, so didn't have any fibrosis. There were a couple that had F1 and one that had F2 levels. So we didn't really -- we had allowed people into the study that had some degree of liver and lung disease since we don't really see any safety issues with this particular approach. And they all performed well from a safety perspective.

I think the other piece, getting back, Joon, to your question around just in general, the commercial differentiation besides just meeting the threshold levels and saying it's dynamic and it's there. I think, as we think about an opportunity where you've got an infrequent subcutaneously administered GalNAc molecule, so you can be thinking about quarterly, potentially even less frequently based on these dose exploration studies, I think, highly differentiate the program and actually make it very amenable to patients to be able to use that and physicians to be able to monitor patients.

And just a quick follow-up. Are there plans for Cohort 3? And what does Cohort 3 look like in terms of the dose and dosing frequency?

Yes. Obviously, as part of the collaboration, we have a partner who assumes the development on the other side. And so we're working closely with them in terms of the design of that third cohort. But I think it's safe to assume. As Chris mentioned, we've got safety well to cover 600 and repeat dose, I think it would enable us to continue to build out the PK/PD curve, which could continue to support not just more AAT protein, M-AAT protein, but most importantly, derive this frequency strategy where we better understand the pharmacokinetics in terms of how infrequently do we need to administer this to mount a substantial response.

The next question comes from Salim Syed from Mizuho.

Congrats on the data. Just one for me on Cohort 3. Paul, Chris, do you guys feel -- Erik, do you guys feel like you have what you need here in terms of total AAT and AAT, just especially now given what we understand with the acute patient data? Or are you more focused on durability or still pushing the actual levels here of AAT, M-AAT? And then just related to that, just kind of with what we understand now with this acute patient data, it seems like we're still trying to understand the biology. Is there any room in the protocol here to add an additional cohort if you feel like you need to for the -- all time?

Yes. I think great question, Salim. So stepping back, thinking about the treatment goal, at the outset, the treatment goal on MZ was could you cross the 11 micromolar threshold of total with greater than 50% M protein. So we had 12 micromolar with over 60% edited M protein. And that's still dynamically going up as we see time and the potential to increase dose. So if we think about that and, and I think the end is very important, the dynamic response, which is actually the biology of the disease. So it's not an interesting finding between it. It's actually one of the important drivers in the disease. In fact, part of the differential diagnosis for the disease, if you see an individual patient who comes with a spike in CRP, but doesn't have a corresponding elevation in alpha-1 antitrypsin deficiency, then part of that differential diagnosis is alpha-1 antitrypsin deficiency. So these are tightly linked in the literature and as part of clinical practice. And so, I mean, as the KOLs we talk to, have been talking about this being an opportunity for a long time for editing. I think they've been extraordinarily excited to see these data. As we think about those subsequent cohorts, they do give us the opportunity to do two things. One, continue to explore that dynamic range of total and M-AAT protein and what happens on those dynamics. But most importantly, as you point out, allow us to continue to explore the pharmacokinetic profile. I don't think, given what we're modeling out quarterly or less frequently as we get to that third cohort, anticipate a need for any additional cohorts beyond that, because I think we'll have flushed out the dose range finding in terms of optimizing that dosing frequency across those 3 cohorts.

Our next question comes from Samantha Semenkow with Citi.

This is Benjamin Paluch on for Sam Semenkow. Recognizing that it's only a nano 1 with the patient that had the acute phase response, do you think the levels achieved with that patient could be sufficient to support approval?

It's a wonderful question. It's hard to contemplate approval. Obviously, above 11 micromolar and that's consistent there. I think it demonstrates that one can get there. I think, the key is continuing to explore the total profile. But to your point, while it's one patient, that's the one patient that actually represents the dynamics of the disease. And so being able to see what happens when you have an acute phase response, how ultimately do patients achieve and being able to not just achieve an increase, but a substantial increase. 20 micromolar is the lower limit of what you see in an MM patient is consequential. And so that ability to continue to explore that and obviously, with our collaborators in GSK who are thinking about not just the regulatory framework, but importantly, ways of elucidating, we keep talking about pushing the dose higher to explore total. There's also this effect of what's that dynamic response and how much this -- we saw that shortly after, so a patient leaves the office, they're more or less protected from those acute exacerbations. That's what you want. Given that, that was at the lowest single dose, and again, we're just at the beginning of the study, and able to mount a response of 20 micromolar, I think, really speaks well to editing and that editing is highly efficient. The drug is highly stable. So let's just think about the totality of the program and really exploring what do you need to have that response. And I think 20 may just be the floor. Again, this was a modest response in the kidney stone on CRP. If this were a pneumonia infection, you'd expect those CRP levels to be higher and therefore, with increase in transcription actually drive higher levels of AAT protein. So it's interesting to continue to explore.

Our next question comes from Roger Song with Jefferies.

Congrats for the data as well. Just a little bit more on the dose response from 200 to 400. So very helpful to have the spider plot for the 200 SAD and the MAD patients. As far as I can tell, so since the 200 SAD is the mean peak is driven by two patients. So just curious how consistent for the 400 SAD, because you didn't give us the plot. Just want to understand a little bit about the dose response from 200 to 400 on the SAD population and the MAD.

So I think, from the 400-milligram SAD perspective, we did see quite consistent responses. We haven't broken it down in terms of the individual responses at this time, but I mean, I think what you can appreciate is, if you remove the one outlier, which we're talking about that had the acute phase response, the SAD max comes down slightly. So you see more of a dose response, which is probably representative of the 200 versus the 400. So I mean, the 400 is already higher from the M protein production perspective. But if you adjust the SAD from 200, as I mentioned, you see that, that's a bigger gap. So again, we didn't want to sort of pull data points out and things like that. But if you sort of look at the data and understand that outlier and sort of look at the mean without it included, you do see a bigger step-up with the M-AAT with 400. And so we anticipate when you take 400 and go into a multiple dose study, you're going to see an equivalent sort of step-up just like we saw with the 200 MAD relative to the 200 SAD.

It is interesting, as Chris pointed out. If you take the M-AAT, and that's the best way of following the protein response with both repeat doses and exposure. You do see that continued increase from the 200 SAD to the 200 MAD and then ultimately, if you rebaseline that the 400. I think the ultimate goal of what we're seeing is that, that composition within the total protein of M continues to go up. And I think that end is really important. The dynamic response is ultimately what's going to be there to rise to meet the needs of patients when ultimately they have these acute exacerbations. So I think we have both the threshold, as Chris is saying, already, and you can expect to see more from 200 to 400, but particularly important is that acute phase response and being there to meet that need starts early. And I have to say, and that's why it was important for us to show not just mean plots, but actually all the patient responses. As Chris said, the responses were incredibly consistent. So everybody is seeing editing. And so it does speak to the fact that our GalNAc stable AIMers are delivering to those cells, there's adequate and substantial amounts of drug in that cell to be able to engage the machinery of ADAR. And we see that in the concept of if you put more substrate in the cell, you can generate a lot more protein.