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

Good day, and thank you for standing by. Welcome to the Wave Life Sciences conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Kate Rausch, Vice President of Corporate Affairs and Investor Relations at Wave Life Sciences. Please go ahead.

Thank you, operator. This morning, we issued a news release announcing top line data from our FOCUS-C9 clinical trial. A replay of this webcast will be available on the website, www.wavelifesciences.com following today's 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 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. We undertake no obligation to update or revise any forward-looking statements for any reason. Joining me today with prepared remarks are Dr. Paul Bolno, Wave's President and Chief Executive Officer; and Anne-Marie Li-Kwai-Cheung, Wave's Chief Development Officer. Paul will begin the call with a brief introduction, and Anne-Marie will then provide more detail on the data. Following the prepared remarks, we will be available to take questions on the call. I'll now turn the call over to Paul.

Thank you, Kate. This morning, we reported top line data from our FOCUS-C9 clinical trial of WVE-004 in patients with C9orf72 associated ALS and FTD. While we observed potent and durable target engagement, WVE-004 did not show clinical benefit compared with placebo, and poly-GP reductions were not associated with stabilization or improvement in functional outcomes. The results do not support advancing WVE-004, and we have made the difficult decision to discontinue treatment in the FOCUS-C9 study as well as the open-label extension trial. On behalf of all of the Wave team, I would like to start by expressing my gratitude to the participants in the FOCUS-C9 trial, their families, the clinical sites and our study advisory committees for their participation and support. I would also like to thank our Wave employees for their dedication and commitment to the ALS and FTD communities and to our WVE-004 program. We set out on an ambitious path to advance an RNA therapeutic to address the complex biology of C9orf72 associated ALS and FTD. For C9 and ALS, this genetic subset has been explored by other now discontinued C9orf72 targeting oligonucleotides. Following our positive initial single-dose data last year, which showed potent and durable reductions in poly-GP, we were hopeful WVE-004's unique design and pharmacologic profile would enable us to best test the relationship between C9orf72 transcriptional variants and clinical benefit in patients. While we did again see robust poly-GP reductions with the full doses of WVE-004, the lack of any corresponding clinical benefit clearly illustrates the complexity of the disease and the limitations of poly-GP as a biomarker. Anne-Marie will cover the full top line results in a moment. For Wave, we take several learnings from the WVE-004 results. First, these data reinforce that our platform innovations, including PN chemistry and preclinical data on RNA target engagement and pharmacology are translating in the clinic. With only 10 milligrams of WVE-004 dosed every 3 months, we continue to observe potent and durable target engagement and a generally safe and well-tolerated profile. Second, today's update is an important reminder that our pipeline's current focus remains on diseases where biomarkers correlated with functional outcomes are available. Our lead programs in Huntington's disease, Duchenne muscular dystrophy and alpha-1 antitrypsin each leverage biomarkers that are correlated with clinical outcomes, something that was lacking for C9orf72 biology with poly-GP. I'll now turn the call to Anne-Marie for a more detailed discussion of the data.

Thank you, Paul. Before talking about the data that we observed, I'd like to start by recognizing the commitment to patients and their families as well as the investigators involved in our study and sincerely thank them for their contributions. WVE-004 is designed to target pre-mRNA variants with hexanucleotide repeat expansion that results from the C9orf72 mutation, which are hypothesized to lead to multiple drivers of toxicity in C9 ALS and FTD. These crack transcripts result in downstream dipeptide repeat proteins, including poly-GP. While poly-GP protein levels are not predictive of clinical outcomes, they do enable us to evaluate 004's affordability to silence the target transcriptional variance. The FOCUS-C9 study was comprised of 2 parts, a single-dose and multi-dose portion. In 2022, we reported positive initial single-dose data that demonstrated proof-of-concept with a robust and durable knockdown of poly-GP in 10-milligram and 30-milligram single-dose groups. Following this data, we adopted the trial to include a single-dose cohort at 20 milligrams, and we also advanced 004 in 2 10-milligram multi-dose cohorts. In the first multi-dose cohort, patients received 4 monthly doses. And in the second cohort, the patient received 2 quarterly doses. Patients will follow through 24 weeks. Today's top line results are from a planned analysis of the study. Turning to the data. Across the single and multi-dose portions of the study, 26 unique patients have been treated with WVE-004. 004 was generally safe and well tolerated across doses, with most adverse events presenting as mild in intensity. The most common adverse events in the study were related to disease progression and intrathecal administration. There's no evidence of inflammation in the CSF, as indicated by no clinically meaningful changes in CSF white blood cells or protein nor were the clinically meaningful changes in blood chemistry or hematology. Following 004 treatment, we observed a robust knockdown of poly-GP across single dosing and multiple dose regimens indicating that we have been successful in engaging target. In the 20-milligram single-dose cohort, the mean maximum poly-GP reduction from baseline was 61%. In the 10 million multi-dose cohort, we observed mean maximal poly-GP reductions of 48% and 50% for the quarterly and monthly cohorts, respectively. Exploratory assessments included monitoring of CSL -- CSF neurofilament light chain, or NfL. CSF-NfL elevations were observed in the 20-milligram single-dose cohort and the 10-milligram monthly and quarterly dose cohort. However, in the 10-milligram, quarterly cohort confidence intervals overlapped with placebo. Importantly, there was no correlation between CSF-NfL increases and changes in ALS-FRS-R. The study was not powered to detect statistically significant changes in outcomes such as ASF -- ALS-FRS-R. However, by 24 weeks of treatment, one would expect to observe early signs of clinical benefit. We treated and placebo dosing arms beginning to diverge in 004 work conferring benefit. Unfortunately, we did not observe any kinds of benefit for 004 treated patients versus placebo on any exploratory clinical outcome measure, including ALS-FRS-R. In the Q12 cohort, there was no difference in ALS-FRS-R mean changes versus placebo at any time point. In the Q4 cohort, through 24 weeks of 004 treatment, patients showed greater reduction in ALS-FRS-R mean change versus placebo. However, reductions were not statistically different from the decline seen in natural history. Additionally, there was no benefit observed for 004 treated participants with FTD versus placebo on FTD related outcome measures. As reductions in poly-GP were not associated with stabilization or improvement in functional outcomes and in the absence of biomarkers, we've even been likely to predict clinical outcomes. We made the decision to discontinue development of WVE-004. All patients in the FOCUS-C9 clinical trial as well as patients in the open-label extension will discontinue dosing of WVE-004. I'd like to again express our sincere thanks to all patients and sites who have contributed to this study. While the outcome is not what any of us would have hoped for, we do hope that will contribute to the scientific understanding of the disease and further enable a future successful treatment for people with C9orf72 ALS and FTD. I'll now turn the call back to Paul.

Thanks, Anne-Marie. This is not the outcome we hoped for. While our molecule successfully engaged target as intended, the biological impact of RNA target knockdown did not translate as we expected. As Anne-Marie just mentioned, we are encouraged that these data may advance future research on C9orf72 biology, and we are committed to sharing results from this study at an upcoming medical congress. For Wave, today's data demonstrates the potential of our multimodal platform to deliver very potent RNA targeting therapeutics with favorable safety profile and the opportunity to extend dosing intervals. It's important we spend a moment recognizing the key differences in target biology and biomarker availability for our lead pipeline programs and why we are particularly optimistic about each of these as we drive them forward to meaningful and near-term milestones. First, we are on track to share data from our SELECT-HD study in Huntington's disease in the second half of this year. It's worth pausing to highlight several unique aspects of HD Biology. In HD, the number of CAG repeat expansions in the mutant HTT gene is predictive of outcomes, including age of onset and age of death. We are able to assess mutant Huntington protein in the CSF, a biomarker that is correlated with disease progression. And importantly, our approach is unique as WVE-003 is designed to selectively target mutant HTT and spare healthy wild-type HTT. Beyond HD, we're rapidly advancing WVE-N531 towards Part B of potentially registrational study for void with DMD amenable to exon 53 skipping. Our excitement for this program is grounded in our best-in-class exon skipping data shared in December last year. In Part B, we will be assessing WVE-N531 over 24 and 48 weeks with the hope that our strong exon skipping data translates to meaningful dystrophin protein levels. With DMD, we can look to milder Becker phenotype as real-world evidence to support the therapeutic threshold for dystrophin protein. We're also leveraging our multimodal platform to pioneer first-in-class RNA medicines with a strategic focus on protein restoration and repair targets, such as alpha-1 antitrypsin. We are on track to transition WVE-006 into clinical development by way of CTA submissions in the second half of the year, which will be the industry's first RNA editing candidate. With 006, we aim to correct the mutant SERPINA1 transcript to generate healthy wild-type AAT protein in patients with a homozygous disease genotype. Over 95% of individuals with symptomatic AATD have the ZZ genotype, and there are approximately 200,000 ZZ patients in the U.S. and Europe. The ADC protein biomarker is directly measurable in a clinical trial. Importantly, we also have real world evidence with heterozygous or MZ genotype patients to guide our anticipated therapeutic threshold. These patients have a much lower risk of disease topology and our preclinical data suggests we are achieving the necessary threshold to shift ZZ patients towards MZ. We have also prioritized clinically validated markers in our preclinical emerging pipeline, and we look forward to sharing an update on our pipeline in the third quarter. We're well capitalized to execute on all these upcoming milestones with a cash runway into 2025, and plus, we have the potential to receive meaningful near-term milestone payments in 2023 and beyond, which are not included in our cash runway. We will now open up the call for questions. Operator?

[Operator Instructions] Our first question comes from Joon Lee with Truist Securities.

This is Mahdi on for Joon. So our question is related to potential readthrough to WVE-003. Given the higher NfL level seen for 20-milligram single dose and 10-milligram 4x, so is that showing any sign of dose toxicity in any sense? Or how you explain this higher NfL levels? And our second question is given the results, given about 50% reduction in poly-GP that you observed, is that hypothesis for C9orf involvement in disease pathology still holding true?

Thank you for the questions. And I'll answer and refer to Anne-Marie as well. But as for your last question on threshold reduction, this is not the first C9 program in development looking at open reduction of the C9 of the poly-GP protein. We know that there was a prior study with Biogen looking at poly-GP reduction and saw a substantial reduction in poly-GP with no translation to clinical read-through. That study had been confounded with increase in white blood cell count protein and prone telemetry effects and substantial NfL elevations. So what was important in this program was, as Anne-Marie mentioned on the call, we had potent target engagement. We had infrequent administration quarterly. We had no white blood cell count, no protein. And the dosing regimen that we saw that in had an NfL level that looked equivalent within placebo. So as we think about the profile of this molecule, with examples of other molecules taking down poly-GP, I don't think we have good corroboration that poly-GP could court -- levels could correlate with the prediction of clinical outcomes. So it does reflect that we need to think about other biomarkers in this disease process. So I think we consequentially along with others in this field have looked as Teradata of the poly-GP hypothesis. That's the first question. To your point on the read-through to Huntington, we do have to fundamentally remember that these are different medicines. I think if we think about translation of preclinical data and the prediction as we go into clinical studies, I think what we can read through is that we can find therapeutic indexes for medicines that potently engage target into CNS without adversely impacting both NfL level patients. So we do believe that these data reinforce that we can safely target CNS with infrequent potent administration. And that's why those data will be important in terms of establishing that threshold. But it's not that we could just draw a straight line and say, well, maybe in some -- even small molecules you imagine different drugs have different engagements. So C9 is different than HD, 10-milligram may not be -- you can't draw a straight line and say, what we felt 20 here, what's that going to do there. There's not that level of read-through to NfL. But what is important is we could find good therapeutic impact to potently without this target and navigate through signals. Anne-Marie, is there anything else you want to add to that?

Yes, I just wanted to directly address the question. Is there any sign of dose toxicity? I think it's important to note that while we did see some NfL elevations in dosing regimens, there was no correlation between NfL and ALS-FRS-R outcomes. And in general, the safety profile was -- it was safe and horrible. The AEs were mostly related to disease progression and intrathecal administration. And we did not see any signs of CSF inflammation as measured by CSF protein and white blood cells. So we do not see signs of dose toxicity based on the safety profile.

It's a great point to see that correlation. One other question is that if we go back to the generation HD study that Roche ran, they shared their data following that very large study in Huntington's disease. Roche also saw no clinical correlation between their NfL levels and clinical progression. So I think as we think about it, we're obviously following it as a biomarker, that's why we reported that we found a dose that could navigate through it. But the data consistently within these diseases tends to be that NfL is not correlated with disease progression. But nonetheless, we'll continue to follow.

We have a question from Salim Syed from Mizuho.

Thanks so much for the straightforward on today's data, Paul, and my sympathies to the team. I guess a couple from us on HD. So regarding the data in the second half, just if you could benchmark for us the length of the duration of treatment for the multi-dose, that would be helpful. And if there's -- if you plan on disclosing any efficacy data given that length. And then secondly, will you disclose the data to Takeda prior to giving us the data? Or in other words, can we get an announcement regarding the Takeda collaboration, how they view simultaneously when you disclose it? Or would that come after the data disclosure in the second half?

Sure. I'll take the last question first and that's just how we interact with Takeda. Obviously, they're important partners. Oftentimes, as we're generating data and it comes forward, we do our analysis and we prepare it, and therefore, becomes material and we disclose it. And at the same time, we're introducing them to the data. So oftentimes, the proximity between our generating the data and analyzing it and making sure that when we have that data, we're fulsomely transparently sharing that data interact. In that case, we will share it, but I can't predict whether or not we would wait and hold back the announcement on -- so Takeda can fully analyze that. So we'll have to get closer. But obviously, they do see those data sets. As it relates to the data that we anticipate having in the duration, I think first and foremost, before we get to the multi-dose section is, remembering that we are -- that movement was still the single dose data, which is important as we think about the prior question on looking at dose,, the relevance to target engagement, understanding durability and obviously, since it's a Phase I/II study safety. So first and foremost will be looking at the profile of pharmacology with 003, which we need to understand independently. Obviously, these data today tell us that we can potently and durably gauge targets in CNF, but that would be the first step in that study. Based on when we have that data, as we said before, we would be able to include multi-dose data available. And as we get closer to that time point, we'll provide updates, obviously, on what level of duration and follow-up there will be in the multi-dose portion of the study.

Do you plan to disclose efficacy data then on the single -- the additional single dose data?

Yes. I think historically, if you think about the data that we cut, I mean, obviously, single-dose data and clinical efficacies are hard readout after a single dose. But as we did with a single dose with C9, we do provide full updates on each data set when we put them. They're important in making our decisions on dose and dose frequency as they go forward. Even if one wouldn't anticipate seeing things, we'll obviously be looking and sharing those data. So yes, we'll share the data that we have at this time.

Okay. One follow-up. yes, sorry, go ahead, please.

As you know, that study is a safety, tolerability and PD study, the good news is in HD, mutant Huntington is known to be a disease progression biomarker. And reduction in mutant Huntington in preclinical mouse models has been shown to impact HD like symptoms. So by disclosing knockdown in mutant Huntington and unsparing importantly of wild-type, we will be inherently making a meaningful comment on the ability of 003 to impact disease progression.

Would the expectation though be to show efficacy on the single dose? Is that your internal expectation?

I think we should have an expectation of seeing efficacy on a single dose because obviously, you're looking at UHDRS progression. You can't do that from a single time point. and the progression of disease is lower in ALS. So in a time frame like 6 months, you wouldn't expect to see meaningful progression in an untreated cohort in UHDRS. So that's why it's important that we do have a disease progression biomarker like mutant Huntington to really understand whether we're moving the needle.

Just a follow-up on ambulatory. Actually, it's the opposite. HD is slower progressing. ALS is much faster. So [indiscernible]. So I think the challenge is to that point is it is a slower progressing disease. But I think if we go back and reflect on our data single dose from last year, we were in that 25% to 30% range and we were expanding the cohort. So I think if we think about those data, coupled with today's data on target engagement, coupled with what we're going to be looking at forward, as I said, we said last year, I think we're in the zone where one would need to be to ultimately see that translation. But we've got to run the data. We've got to run the multi-dose portion of the study as well to see that. But we will be measuring it to your question.

Our next question comes from looks like Paul Matteis from Stifel.

This is Julian on for Paul. So I guess a key question here is, I guess, how do you reconcile the lack of neurofilament correlation you're setting with the ALS-FRS-R with the highest dose cohort performing statistically significantly worse than placebo? And then also, is there any color you can provide potentially on either the curves or sort of the elevations that you saw in NfL? Was there any sort of time component or dose relationship? Any detail there would be really helpful.

I'll let Anne-Marie comment on the NfL, but particularly as we think about the correlation of the performance of the placebo to your question on what -- how do we translate that? And then ultimately, looking at natural history progression, we didn't see when we compare it to a natural history or to Biogen's placebo group for that matter, that these patients did worse than that for. I don't know, Anne-Marie, if you want to follow up on the clarification so that we could feel obviously helpful where that be.

Yes. I mean, I think what our data points to is that neurofilament is a more complex biomarker than perhaps is currently appreciated. And interestingly, in the Roche Temenos in generation HD-1 study when they did the post-top analysis looking at worse outcomes for Temenos since. They didn't see a strong correlation with NfL there either. So I mean we can only conclude what the data tells us, which is in the case of 004 and that is not implicated in patients having done worse than placebo in the more frequent dose cohort. I would say that we do plan to fully disclose and present our data at an upcoming medical conference. In terms you already had in the Q12 week 10-milligram dose, NfL was overlapping in confidence intervals with placebo. Where NfL elevations were not overlapping, we see an increase, which then tends to stabilize and decrease. So we'll be happy to provide more details of this when we present the data at the next regularly available conference.