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

Good morning, and welcome to the Wave Life Sciences FOCUS-C9 Clinical Trial Update Conference Call. [Operator Instructions] As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences. Please go ahead.

Thank you, operator. Good morning, and thank you for joining us today. This morning, we issued a news release providing an update on our FOCUS-C9 Clinical Trial. For those participating via conference call, we have made slides available via webcast. A replay of this call will also be available in the Investors section of our website following the call. Joining me in the room today with prepared remarks are Dr. Paul Bolno, Wave's President and Chief Executive Officer; Dr. Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development; and calling in from AAN in Seattle, Dr. Merit Cudkowicz, Chief of MGH Hospital, Neurology Service and Professor of Neurology at Harvard Medical School. Following the prepared remarks, all 3 speakers will be available to take questions on the call. 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 the forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2021. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul. Paul?

Thanks, Kate, and thank you all for joining us for this exciting update. As we announced earlier this morning, we have successfully achieved clinical target engagement with WVE-004 as measured by reduction in poly(GP) protein in our ongoing FOCUS-C9 clinical trial for patients with C9orf72 associated ALS and FTD. The adaptive design of the trial enabled our team to identify this positive signal quickly. And today, Mike Panzara will discuss these data and how we are adapting the study with a goal of rapidly optimizing dose level and frequency to enable discussions with regulatory authorities later this year regarding the next phase of development. Today's update marks an important milestone for our company, our platform and our 3 clinical programs. This is a critical step forward on our progress towards building a fully integrated genetic medicines company. Our investment over the past decade in new chemistries has resulted in a robust and unique pipeline of next-generation PN-containing stereopure oligonucleotides. This next generation of oligonucleotide consistently deliver better tissue distribution as well as more potent and durable activity in preclinical studies, as described in 2 recently published nucleic acid research manuscripts. With WVE-004, we are now seeing this translate in the clinic. Data also suggests these benefits will translate across tissue types beyond the CNS, including splicing and muscles for DMD and RNA editing in liver for Alpha-1 antitrypsin deficiency. Each of these programs leverages predictive PK/PD modeling using in-vivo models to determine therapeutically active starting doses in the clinic as we demonstrated today with 004. This translation of our preclinical data into dose-dependent and durable target engagement in humans with low single doses of 004 enhances our confidence in our platform and ability to address a host of genetic diseases. As a reminder, this year, we also expect to deliver data from our ongoing clinical trial in DMD study WVE-N531 and our ongoing SELECT-HD clinical trial studying WVE-003 in Huntington's disease as well as selected development candidate for our AATD program. Today, we will focus on the progress we have made in potentially treating a genetic subset of ALS and FTD. At Wave, we have and will always work with urgency. We recognize the challenges, devastation and loss that patients and their families face when confronted with the symptoms and diagnosis of ALS and FTD, but we are committed to developing medicines that address the root genetic cause of these diseases. Joining us today is an expert who knows all too well the impacts of these genetic neurologic conditions and has committed her career to the research and care necessary to improve the lives of patients. We are grateful to have Dr. Merit Cudkowicz here to provide an overview of C9 associated ALS specifically and discuss the biological rationale for a C9 targeted potential medicine. Dr. Cudkowicz is the Chief of the Massachusetts General Hospital Neurology Service and Director of the Sean M. Healey and AMG Center for ALS and MGH. She also directs the MGH ALS program and MGH Neurologic Clinical Research Institute. Dr. Cudkowicz is also Chair of the Advisory Board for our FOCUS-C9 clinical trial. And with that, I will now turn the call to Dr. Cudkowicz.

Thank you, Paul. C9orf72 repeat expansions are 1 of the most common genetic causes of both ALS and federal temporal dementia known as FTD. This mutation is a hexanucleotide repeat expansion in the C9orf72 gene, and it's found in about 2,000 patients in the U.S. with C9 specific ALS in about 10,000 patients in the U.S. with C9 specific FTD. As you know, ALS is a uniformly fatal neurodegenerative disease. It's a progressive loss of motor neurons where people are robbed really about the ability to walk, move, breathe, speak. FTD is also a progressive neurological degenerative disease where people have personality and behavioral changes and is also fatal. Some people who carry the C9 mutations have ALS, some of FTD and some have both. And you may know these illnesses are bad, but they're also even worse when people carry these mutations. The rate of progression can be faster than what we see in sporadic disease. So we're grateful for Wave and other companies that develop treatments for this for ALS and FTD. In addition, Phase I trial, as you'll hear is a really innovative adaptive design that can get to the answer of the best dose using pharmacodynamic markers and safety in the fewest patients, and that's what we need in ALS. We need innovation and speed so that we can get to the next trials where we look at efficacy. Now we are fortunate to have a good pharmacodynamic marker of C9, and that's the dipeptide repeat proteins, also known as DPR. We know from natural history studies in the spinal fluid, poly(GP) is elevated and it's stable over time, making it a very good candidate for target engagement studies. And with that, I'll pass this back to Mike, please.

Great. Thanks, Merit. Good morning, everyone. So our clinical candidate, WVE-004, is designed to target a pre-mRNA-variant hexanucleotide repeat expansions that results from C9orf72 mutations, one of the most common genetic causes of ALS and FTD as was just pointed out. C9orf72 mutations lead to multiple drivers of toxicity and 004 was designed with the goal of addressing each aspect of this complex, but well described biology. The hexanucleotide repeat containing mRNA transcripts deposit in the tissues and are toxic on their own, but they're also translated into long dipeptide repeat proteins, or DPR, protein that trigger cellular toxicity through a variety of downstream mechanisms. WVE-004 selectively targets the pre-mRNA variants transcripts that contain the hexanucleotide expansion with a goal of suppressing both the RNA and GPR associated toxicities while preserving existing levels of C9orf72 protein expression. Because the DPRs are measurable in CSF and derived from expanded mRNA transcripts, natively uses biomarkers of target engagement with compounds such as 004 designed to target this pathway. In the case of WVE-004, we selected poly(GP) as our preferred GPR biomarker both because of its production from both sense and antisense mRNA variants and because of the availability of an animal model to explore in-vivo target engagement to more accurately estimate the doses required for target engagement when moving into human trials. On Slide 12, we show the preclinical data that we have shared previously, demonstrating 004's ability to rapidly and durably reduce poly(GP) by over 90% in the spinal cord and at least 80% in the cortex of a transgenic mouse after just 2 ICV doses 7 days apart. The silencing effect in this model lasted at least 6 months, as shown in the figure on the left. On the right-hand side of the slide, you can see normal C9orf72's protein levels will preserve at 6 months, confirming the selectivity of 004. These results set the stage for us to evaluate poly(GP) in the clinical setting by allowing estimates of tissue concentrations required to successfully engage the intended target. With the availability of these in-vivo preclinical data, we were able to assess pharmacokinetic and pharmacodynamic relationships following WVE-004 treatment, something we were unable to do with our first generation programs. Knowing the concentrations of 004 required to lower poly(GP) and mouse spinal cord and brain cortex, we perform single and multi-dose studies in nonhuman primates to assess the intrathecal doses required to achieve these target tissue concentrations in a more relevant species. We determined that single doses as low as 10 milligrams IT in humans were predicted to be safe with the potential to engage target in these tissues and yield a reduction in poly(GP). The FOCUS-C9 trial was designed to test this hypothesis by allowing data reviews after each dose level by an independent Data Safety Monitoring Board, or DSMB, to quickly assess whether target engagement, leading to CSF poly(GP) lowering occurred as predicted, while closely monitoring patient safety. We began the trial by randomizing and dosing 3 patients, 2 with WVE-004 and 1 placebo before proceeding through sequential dose escalations. Before each dose escalation, the independent DSMB reviewed unblinded PK, biomarker and clinical data to determine the next single dose to be given whether to start multi-dose cohorts and at what frequency. Biomarker analyses at multiple time points provided the data for these reviews and patients in each cohort are followed for 85 days or approximately 12 weeks. This process led to a second single-dose cohort dosed at 30 milligrams and a third single-dose cohort dosed at 60 milligrams. In addition, patients who received a single dose of 10 milligrams were transitioned to a multi-dose cohort, where they, in an additional 3 patients, are currently receiving 10 milligrams or placebo every 4 weeks. A DSMB meeting was also scheduled to review all available data, including CSF biomarker data from the 10-milligram and 30-milligram cohorts out to Day 85. This review revealed that 30 milligrams of 004 led to robust knockdown with drug concentrations above the threshold thought to be required for target engagement, detectable in CSF out to the last observed time point. Based upon this observation, Wave concluded and the DSMB agreed that dosing the 60-milligram cohort was no longer necessary and that additional patients should be added to lower cohorts and followed for 6 months to identify the maximum reduction of poly(GP) and the duration effect of these low single doses. Today, I will be sharing data from patients treated with placebo, 10 milligrams and 30 milligrams. Since the data review occurred midway through the 60-milligram single-dose cohort, we currently have limited short-term follow-up from these patients. So while all safety information is included in today's presentation from this cohort, biomarker data will be shared at a future update once follow-up is complete. Beginning with the patient population, we recruited both ALS and FTD patients in the study with the characteristics and disease history we had targeted. 9 had ALS, 3 had behavioral variant FTD. Not surprisingly, with small numbers, there was an imbalance between these treatment groups with patients in the 30-milligram cohort being a bit younger with a longer disease duration and a higher level of functional impairment at the time of enrollment. Nonetheless, the degree of poly(GP) knockdown from 004 appeared consistent regardless of baseline states. Slide 16 clearly demonstrates the robust target engagement and poly(GP) knockdown that prompted us to adapt the study. A single 30-milligram dose of WVE-004 significantly reduced CSF poly(GP) versus placebo after treating just 4 patients, achieving statistical significance beginning at Day 57 and continuing to Day 85 with a 34% reduction compared with placebo and a p-value of 0.011. Similarly, when looking at the percent change in poly(GP) from baseline, a statistically significant difference was seen beginning at Day 29 and continue out to the last time point in the single-dose cohort reaching a percent reduction of 34% from baseline at Day 85, p less than 0.001. In addition, at this Day 85 time point, it appears that poly(GP) has yet to have plateaued, which is why we are eager to a steady observation period to identify the maximum reduction of poly(GP) and duration of effect of low single doses to guide optimization of dose and frequency in the multidose phase of the study. It is also notable on this slide that even with a single dose of 10-milligram in just 2 treated patients, there was a statistically significant change from placebo as well as in the percent change from baseline at the Day 57 time point. As I mentioned earlier, our preclinical data predicted target engagement at 10 milligrams, but we were still surprised by these results in so few patients. This is further illustrated on Slide 17 of these plots of individual patient poly(GP) values. One can see the consistency and the reductions in how quickly poly(GP) begins to fall after treatment. When poly(GP) levels were compared to CSF concentrations of 004, the PK/PD correlations confirm the assumptions made prior to study onset regarding doses required to achieve target engagement. Our PK/PD modeling predicts continued poly(GP) reduction with continued follow-up and the administration of multiple doses. In addition to continued refinement of PK/PD models, additional exploratory assessments include monitoring of CSF neurofilament light chain, or NFL, and clinical outcome measures. CSF NFL elevations were observed in some patients in the 30-milligram and 60-milligram single dose cohorts with no meaningful changes in clinical outcome metrics, although the data set and duration are not sufficient to assess clinical effects. Exploratory assessments will continue throughout single and multi-dose phases of the FOCUS-C9 trial. Adverse events were balanced across treatment groups in the 12 patients who received single doses of WVE-004 placebo, and most events were mild to moderate in intensity. Four patients, including 1 on placebo experienced severe and/or serious adverse events, one of which occurred in the 60-milligram cohort and was reported by the investigators related to treatment. As is routine, all events were reviewed by the independent DSMB, who recommended continued dosing. There were no treatment-associated elevations in CSF by blood cell counts or protein and no other notable laboratory abnormalities associated with treatment. With today's update, we have leveraged this adaptive trial design to demonstrate target engagement and used these data to adapt dose level and follow, again, to identify the maximum reduction of poly(GP) and duration effect of low single doses of 004 to guide optimization of dose level and frequency in the multidose phase of the study. To do this, we are expanding the 30-milligram cohort to collect additional data at this dose level, given the promising data to date as well as adding additional lumbar punctures to collect CSF for 6 months after each single dose. In addition, given the suggestion of target engagement even under 10-milligram dose level, we would like to explore intermediate dose level by treating 10 patients with 20 milligrams with the potential to explore higher doses thereafter. The goal of these additional cohorts is not only to collect single-dose data, but to decide the best dose level and frequency to explore in the multidose phase. Dosing in a multi-dose cohort is well underway at 10 milligrams monthly. As mentioned earlier, our PK/PD modeling predicts continued poly(GP) reduction with continued follow-up and administration of multiple doses. These single and multi-dose cohorts are expected to yield new data throughout 2022, which will be used to optimize dose levels and frequency as well as enabling discussions with regulatory authorities later this year about the next phase of development. In summary, WVE-004 significantly reduced poly(GP) in C9 ALS and FTD patients demonstrating target engagement and clinical proof of concept. This TM containing stereo pure compound enable potent durable target engagement at low single doses of 10 and 30 milligrams with a duration of effect that opens the potential for quarterly or less frequent dosing. FOCUS-C9's adaptive trial design successfully provided early indications of target engagement and safety to enable rapid optimization of dose level and frequency. Observations in modeling from preclinical models translated well in clinic and the safety profile of the date supports continued cohort expansion and dose exploration. Finally, these results should also be considered in the context of the other clinical data that we expect to share this year from our ongoing clinical trials with WVE-003 targeting SNP3 in Huntington's disease and WVE-N531, targeting Exon 53 skipping in Duchenne muscular dystrophy to enable decision-making on those programs. We have already shared some of the pharmacokinetic data from the DMD study with WVE-N531, demonstrating an improved pharmacological profile with PM chemistry compared to our first generation compounds. We look forward to sharing more data and providing additional updates as the year progresses. I will now turn the call back over to Paul. Paul?

Thanks, Mike. Since our founding, we have embraced the reality of stereochemistry and the opportunity it allows for the rational design of therapeutic oligonucleotides as well as advance our mission of delivering meaningfully potent and durable treatments for patients living with genetically defined diseases. Today was the first demonstration of what our platform can achieve in the clinic in terms of profound potency and durability. This is a significant milestone for our organization and the patients we aim to serve, and we are only just beginning. I would like to thank all the patients and families who have participated in the clinical trial thus far. We are honored to partner with you as we work to find a treatment for these devastating diseases. These 004 data also reinforce our confidence that we will see the advantages of PN manifest and other clinical programs. Throughout 2022, we expect to deliver additional data from FOCUS-C9 as well as from our SELECT-HD clinical trial of WVE-003 for HD and our clinical trial of WVE-N531 for DMD. We also expect to select an AATD [ invert ] development candidate and initiate IND-enabling toxicology studies in the third quarter of 2022. We expect these results will unlock additional modalities and tissue types to expand our pipeline of genetic medicine. And with that, we'll open up the call for questions. Please note that Dr. Cudkowicz will be available for questions as well. Operator?

[Operator Instructions] Our first question comes from Salim Syed with Mizuho.

Congrats on data. Just a couple for me, if I can. One, I'd like to know where Dr. Cudkowicz view is on the correlation between poly(GP) and in the more of the clinical measures, ALS FRS are, CDR, FTLD and other clinical measures? And then just secondly, what are the normal physiological levels of poly(GP)? And can you just put this into context, this 34% reduction here, how close are you to normal physiological levels? And is this considered clinically relevant reduction of poly(GP) and [indiscernible].

Thanks, Salim. I'll start and hand it off to Mike and Dr. Cudkowicz. But as you alluded to, I mean, I think as we think about the meaningfulness of knockdown, as Mike said, the early data that we had suggested that 2 doses in the tissue yielded substantial knockdown of the poly(GP) in the brain tissue. This is substantial knockdown within the CSF that we demonstrated to date, as Mike said, with a single dose that was continuing to decline. So I think it is important to note that 34% versus placebo is not just at the endpoint. It's continuing to go. Hence, why the extension of the follow-up period. So we anticipate the potential reduction, not just with the continued follow-up and observation, but as we've seen preclinically what we see in administration. So I think it's important to note that we're on a path, but we don't know where that's going yet. And that's part of the reason predative clinical trial design, as we said, that we would open up with adjustments and modifications that are being able to assess the depth of degree of knockdown. I'll turn the call over to Mike and Dr. Cudkowicz to talk about putting this in the relationship between the poly(GP), but it's also important to note that we suggested poly(GP) early when we thought about, as Mike walked through the biology and the pathology of C9 ALS that there is this toxic RNA and then that transcribed to the dipeptide, the DPRs with poly(GP) being one that can be studied to give us the best read-through into what's occurring inside the cell. And so Mike, I'll turn it over to you and Dr. Cudkowicz to talk about putting that poly(GP) in context.

Yes. I think I'm going to just briefly, I mean, just turn it over to Merit to sort of continue and to address the issues of the relevance. Merit?

Yes. A very good question. So we do follow people who carry C9 genes before they get symptomatic. And we know that from small studies, the important studies that these dipeptide repeat start to increase before symptom onset and then they stay elevated and stable. But they shouldn't be there, for example, if someone who doesn't carry the C9 mutation. So lowering them is clinically relevant. We don't have good data yet on a natural history of exactly how that correlates with ALS FRS, but we know that it's toxic and it shouldn't be there. And lowering pretty much of any amount is a positive direction. And I think through this study and other studies will eventually learn how much we need to lower it. But I'm very encouraged that it's already with a single dose lowered it by almost 40% at the 12-week mark. The other thing I just want to comment on as ALS is a very [ heterogeneic ] disease, so we don't expect to see clinical outcome and like a Phase I study with a few people and certainly at the 12-week mark, but we'll be able to tell efficacy in, obviously, future larger studies.

Our next question comes from Joon Lee with Truist Securities.

This is [ Ahmed ] on for Joon. So I would like to follow up on the first question. And that is in your preclinical studies, you showed like 90% reduction of DPR in first month in CSF and a bit lower in cortex. So I wanted to get some more color on what you would expect to see in a clinical setting with this lower reduction that you observed? It is very good, but I wanted to get your color on how you translate it or how you expect it to shape in the future using this study.

Sure. No, this is Mike. Thanks for the question. I think what the model told us is it gave us approximations of where the tissues needed to be to begin to engage target. I mean we went from a mouse to monkey to a human. So yes, with 2 mid-level to high doses, we were able to rapidly induce that poly(GP) that was durable over 6 months' time. Seeing the single-dose target engagement as we currently see it with begin as low as 10-milligram is beyond what we would have expected with a single low dose over a 12-week period of time, right? We were on the low end. We predict that this would be the low end of where we needed to be and the 30-milligram was even a bigger surprise. All patients down, up nearly 40%, as was just described. So we anticipate that it will continue to go down that with additional doses, we will continue cumulative reductions. The modeling we have, based on the animal model suggests that, that's the direction it's going, and we would anticipate that it continues to go down. As we said, we don't know what that right level is, but we will continue to knock it down and we will get to that level and have the clinical assessment to figure out the appropriate level. But I'm very confident, given these preclinical data, given the -- what the model predicts comes next with multi-dose and continued dosing of intermediate dose, we're going to continue to see these reductions and it's going to extend for a long period of time, which is why we need this 6 months of follow.

If I may squeeze another question. About the 60-milligram patient that had SAE, can you provide some more info about that case and what was the observation for that patient?

Well, as we said in the slide, this is a patient who had confusion and what they are called the cerebellar syndrome, which was some imbalance, we're continuing to evaluate what that was. And it was the fourth patient dose in the cohort. It's not something we've seen at -- in other patients dosed at that dose level. So we're just continuing to investigate. And that's really all we can say right now.

Our next question comes from Paul Matteis with Stifel.

I wanted to ask if you could provide a little more color on the magnitude of neurofilament changes that you observing. I guess, one, were they dose-dependent? Were they higher on 50 than they were on 30? And two, how do they compare in magnitude to what was seen with the tominersen program with Ionis since that seemed like it was ultimately an antecedent to potential tox signal or at the very least the drug not working? And then I guess maybe just lastly, kind of going back to why not dose up to 60, is it because of concerns you're adding safety? Because I guess with all these neurodegenerative diseases, we don't know how much knockdown you need, but it would seem like if you could someday get to 80% or 90%, that would certainly be better than 50% or 60%. So maybe any more color there would be great.

Yes. Paul, thanks for the question. I mean, in terms of the degree of elevation, it was really inconsistent and it didn't happen in all patients. So it only occurred in some patients, didn't seem to be related to the dose level per se. It was just something that was seen in some patients in the cohort and really something that we're following. That's the other element of this is also, as I noted in the baseline characteristics that some of the patients in the 30-milligram cohort were also -- had more advanced disease, had disability, age factors, all those things impact also the changes in neurofilament. So all of that is going to be part of the consideration there. So in terms of the ability to dose higher, I think it really, as we said, comes down to the fact that we had pretty decent drug levels 12 weeks after a single dose of 30 milligrams and the trajectory continues to go down. So it truly was that we got to a point where we said we don't need to dose at that level anymore, let's dose at these mid-dose levels, let's optimize and get to the lowest possible through administration of low doses and multi-dose and then decide if we want to go higher again. We have the ability to do that. There's nothing stopping on some dosing at higher doses. We just thought that expanding these mid cohorts is the best way to proceed as we try to find the right multiple doses.

Just a follow-up because I think Mike made an interesting point during his discussion earlier is that repeat dose modeling has demonstrated drug accumulation. So our view is until we fully hit the nature of what's achievable on single dose being careful not to start adding or pushing more doses. So as we said, when we think about quarterly dosing or even less frequently, that's where the modeling is suggesting and it's suggesting that in the context where 34% isn't the floor, but where we're continuing to see the target decline. And we do know that these declines have looked like they've been stable over time. So I think all of our preclinical data, which is really the work that we've been doing over the last several years now in preclinical modeling with PN chemistry in addition to the backbone, has been demonstrating this. And I think we want to fully generate the data to make those decisions. And I think that was really the whole premise around the adaptive clinical trial design, too, is rapidly assess dose, dose frequency and that's what we're presenting today and what we're excited to present more on this year.

Our next question comes from Luca Issi with RBC Capital.

Congrats on the data. Just following up on Paul's question earlier, I think if I recall it correctly, NFL actually did not move for your prior data set in Huntington's, while obviously we're seeing elevations here. So wondering if you can elaborate on what explains the difference there? And then I think on biomarkers, I think in the past, you guys have flat P75 in the urine as another important biomarker there. So wondering if you have any data if you've collected anything there? And then maybe third, Paul, how you're thinking about your balance sheet at this point? What's the latest thinking on extended the runway?

So I'll start and then hand to Mike and then I'll take the call back, but I think the challenges in some of the earlier studies with targeting really take a fresh approach to this, where now we've demonstrated preclinical modeling translation and actually substantial consequential targeting agent following these programs forward. I think as Mike answered in the last question, I think we feel very comfortable with the profile and continuing to establish a dose frequency to move next phase of clinical development with the data that continue to be generated. But Mike, I don't know if you want to add anything.

No. I think what all I would add is also these are different diseases. I mean the pattern of Huntington's disease and the changes that might be seen there and the impact of those changes are going to be very different than C9 ALS. In fact, the only other acute fabrication that we're aware of is a recent single dose case, where that was published in Nature Medicine, where with Poly(GP) knockdown, there was NFL change and then vice versa, just with continued dosing, it went down, it went away and then it would come back periodically. That's all we know about NFL actually in this patient population. So comparing Huntington's is a little tough. Could also ask Merit, Dr. Cudkowicz, if she wants to add anything about that in terms of the consideration for NFL and ALS.

Sure. Thank you, Mike. I'd say we really don't know how NFL works for ALS. Other than, obviously, in natural history studies, we know it's elevated. It tends to be elevated more in people with faster core, but then it's stable for most people. But we don't know that it predicts anything, honestly. I mean, it's not a validated biomarker in the ALS. We've had drugs that work clinically that don't shift the neurofilament, and we've had drugs that work that do lower but have not shown robust clinical effect. So it's -- I think we were excited in the field that it might be a good biomarker, but we don't have data for that yet. And we need to include it up like you're doing here, but we need to learn what it's actually telling us.

I think to the last part of your question, regarding balance sheet. Obviously, these data are exciting. Obviously, we continue to advance this program forward and others in data, and that is all in our cash runway balance sheet without any update. Additionally, as we said on our prior earnings call, this is an important year for us to in leveraging business development. And I think these data and the data we continue to generate across our new chemistry around RNA editing open up ample opportunity for us to bring in non-dilutive capital by our business development efforts. So a lot of work occurring there. A lot of work in continuing to deliver data, and we also mentioned substantial activity in manufacturing. So at this point, the team is continuing to deliver and execute and generate data, and we will continue to advance.

The only thing I'll add is we about the urine biomarker because I noticed we didn't answer that, that's obviously -- that is something that we are collecting. It's not part of DSMB reviews and dose adjustments, but we will -- that is something we're collecting and will analyze because we feel that P75 the maybe another interesting marker that we should track.

I think the last piece as it relates to business development around our partnership that's already existing with Takeda, I mean, obviously, we've shared that. I think there's enthusiasm around our engagement of target. We'll continue that partnership potentially. And 1 should remember that, that partnership allows for us as we advance the next studies for a 50-50 RMB split and profit split. So as we think about advancing the next phases of clinical development, one should remember that this is part of that collaboration.

And last question comes from Mani Foroohar with SVB Securities.

Looking beyond some of the discussions we've had around biomarkers, et cetera, for the clinician online, from the literature we have thus far, how should we think about what functional measures we might see presuming there is a clinical benefit to be had to robust silencing here? And on what time horizon should we look you to be looking to see those functional measures potentially for regulatory purposes, but also to show some evidence that the mechanism does, in fact, have a clinical impact?

So yes, so I'll start with that, and then I'll ask Merit to add. I mean I think that we are collecting these functional measures and are continuing to follow patients longer term as we adapt the dose. And once we get to a stable dose and frequency, we will continue to collect that in a longer-term fashion. Part of -- we would anticipate part of the need for developing in both FTD and ALS are going to be somewhat different. So from ALS being a little bit shorter path than an FTD study, but we're going to consider it separately and design whatever is necessary for that. I mean I think the path for ALS is fairly clear with the ALS and other measures such as that being a key clinical outcome measures that are going to be what we follow, that actually in a reasonably short period of time will enable the determination of potential clinical benefit. So I mean that's sort of how we're thinking about it, but I'll ask Merit to weigh in on sort of her thinking about these clinical measures.

Yes. Thank you, Mike. Yes, I think we do have good clinical measures in ALS, in particular, the ALS FRS and measures of breathing and strength. I think in FTD, it's just newer clinical trials are neuro in FTD. And so those are those measures of cognition and function are good, but they're, I guess, earlier in development. I think we will learn from this adaptive study, how long future fit how long future efficacy trials have to be. With some drugs, we could tell efficacy in a Phase II/III trial with robust numbers in 6 months in ALS, but it is possible with gene therapies that might you need a little bit of time to get to your target lowering of, for example, here at GP. You might need a little longer. I think we'll learn that from this study so that we can really plan the Phase II/III study with good knowledge.

Yes. And the only thing I would add is that, as we've said, as we now get through this dosing and frequency optimization with an intention to engage regulatory abilities later this year, we'll have a really sense of where we're headed in the not-too-distant future.

There are no further questions. I'd like to turn the call back over to Paul Bolno for any closing remarks.

Thank you, everyone, for joining the call this morning to review our FOCUS-C9 update, and thank you to the Wave team for your perseverance and dedication to the patients we serve. We look forward to connecting with many of you after this call. Have a great day. Take care.

This concludes the program. You may now disconnect.