WAVE Life Sciences Ltd to Review the SELECT-HD Clinical Trial Results Transcript

The following is excerpted from the question-and-answer section of the transcript.

Question: Joon Lee - Truist Securities - Analyst : Hey, congrats on the strong data, and thanks for taking our questions. When do you plan to have a meeting with the FDA? And would you be asking for CAVI imaging as a surrogate endpoint? And if so, how confident are you that the FDA would be willing to accept imaging as a surrogate endpoint? And I have a follow-up question.

Question: Joon Lee - Truist Securities - Analyst : Great. I'm looking forward to the updates on that. And then yesterday, CEO of Alnylam, Yvonne Greenstreet stated at the end of our prepared remarks that they're emphasizing on obesity, diabetes and metabolic disorders. That's their next focus areas. I can only imagine; she's referring to REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies.

Question: Joon Lee - Truist Securities - Analyst : All right. Thank you so much, and I'll hop back on the queue.

Question: Tiago Fauth - Wells Fargo & Company - Analyst : Hey, thanks for taking the question. I just wanted to follow up on the NfL. Wondering if there were any associated increases in white blood cells or proteins or any other signs of inflammation that correlated with that. You also mentioned that quarterly dosing might prevent -- might temper some of that NfL increases. Is that something that you would potentially explore on the registrational trial or during the open-label extension? Wondering how you're thinking about dosing optimization going forward. Thank you.

Question: Tiago Fauth - Wells Fargo & Company - Analyst : Fair enough. Perfect. Thank you.

Question: Steven Seedhouse - Raymond James Financial, Inc. - Analyst : Good morning. Congratulations on the very encouraging results and thanks for taking our questions. First one I wanted to ask about was, I just I thought there was some commentary at a recent Huntington's conference actually about accelerated approval pathways and rethinking that. And so I think you're approaching this with some existing understanding already or what the path might be even before you go to the FDA. Can you just talk about that, what you already know or what you've heard about just that the evolution of this in Huntington and the availability of the path.

Question: Steven Seedhouse - Raymond James Financial, Inc. - Analyst : Okay. And just a couple of questions on the data or two questions on the data. So the TMS increase that you're seeing in the placebo arm, it seems like it might be tracking a bit higher than natural history based on available data, at least in all Java paper we could find. So I'm curious if that's a reflection you think of the eligibility criteria for this study or was sort of rapidity of the TMS increase in the placebo arm a bit surprising? Anne-Marie Li-Kwai-Cheung - WAVE Life Sciences Ltd - Chief Development Officer I mean, it's a somewhat small study and so there can be fluctuations compared to the natural history, given it was 24 patients in or 23 actually treated in the multi-dose phase. So where is it? It might be a bit higher than natural history. I think it's more or less reflective of what we would expect to see of patients with this stage of disease and the comparison with placebo. But the difference between the two, I think is what's really REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies.

Question: Steven Seedhouse - Raymond James Financial, Inc. - Analyst : Yeah. It does look like a pretty large delta. The last question I just had. Just on the NfL increase, I just wanted to pin this down. Your hypothesis on the possible mechanism there for the increases, transient or otherwise, is this like an inflammatory response to the [oligonucleotide] you think or something else? Thanks so much.

Question: Steven Seedhouse - Raymond James Financial, Inc. - Analyst : Great. Thanks a lot. Congratulations on a really promising result.

Question: Salim Syed - Mizuho Securities Co Ltd - Analyst : Great. Morning, guys. Congratulations on the data. I guess a few from us, Paul. First, can you just answer the question whether have you ruled out? Can you file on this particular data set? Or is it definitive that you will need to run another clinical study for accelerated approval. Maybe just answer that question so I'll just have some of the data. Thanks, Paul.

Question: Salim Syed - Mizuho Securities Co Ltd - Analyst : Okay. And has there been any discussions previously on how you would think about potential size of the study or a safety package?

Question: Salim Syed - Mizuho Securities Co Ltd - Analyst : Okay, cool. And then just on the on the caudate atrophy piece here, just given that you guys have noted that you're doing work on this predicting clinical outcomes, just can you maybe quantify for us exactly what is the relationship that you guys are seeing? How you draw the relationship between atrophy in the slowing of decline in TMS? Anne-Marie Li-Kwai-Cheung - WAVE Life Sciences Ltd - Chief Development Officer So at the sort of natural history level, it can be seen that baseline caudate atrophy correlates both with and TFC disease progression and things like SDMT and TMS. So through the work of the community and the KOLs who created the new staging system, it can be very clearly seen that caudate atrophy changes early in the disease course of 20 years before clinical diagnosis and continues through the disease stage. And what we have seen in our study is a apparent slowing, of caudate atrophy compared to placebo. Again, not statistically significant. But the correlation with the mutant huntingtin knockdown, which was statistically significant, I think really provides evidence that the knockdown of mutant huntingtin with the sparing of wild-type has this opportunity to slow this worsening because during the disease course.

Question: Salim Syed - Mizuho Securities Co Ltd - Analyst : Okay. And just lastly, Paul, just can you remind us on manufacturing where you guys are and to the extent that you've got a path here that's relatively quick, just where you are in manufacturing for WVE-003 and perhaps just generally? REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies.

Question: Salim Syed - Mizuho Securities Co Ltd - Analyst : But regarding commercial supply, is that something that's on the radar?

Question: Salim Syed - Mizuho Securities Co Ltd - Analyst : Okay, got it. Thank you very much. Congrats again.

Question: Luca Issi - RBC Capital Markets - Analyst : Well, great. Thanks so much for taking my questions. Congrats on the data. Maybe the first one regulatory. Again, appreciate you had a strong case here for pitching the FDA potential for accelerated approval based on imaging biomarkers here. But what is the plan in a scenario where the FDA does not let you do that and actually, ask you to run a trial with UHDRS as the primary endpoint as they did with Roche, would you indicate a still move forward in that scenario? Again, any color, much appreciated. And then maybe quickly on NfL, can you just talk about the kinetics of the elevation of NfL? It looks to me that the numbers trend upwards over time and you only obviously dose three times while, I'm assuming you will need to dose much longer for the Phase 3. So just wondering how we should think about that. How confident are you that quarterly dosing will spare that signal? Any color, much appreciated. Thanks so much.

Question: Luca Issi - RBC Capital Markets - Analyst : Got it. Thanks so much.

Question: Joseph Schwartz - Leerink Partners LLC - Analyst : Thank you. Congrats on the exciting results WAVE team. I was wondering how did the patients treated with WVE-003 perform on other functional measures such as UHDRS group and TC. Can you remind us which of these functional measures have been associated the most with changes in caudate atrophy in patients with different stages of HD and natural history? Anne-Marie Li-Kwai-Cheung - WAVE Life Sciences Ltd - Chief Development Officer So on the other clinical outcomes patients did no worse than placebo, which I think is really important because -- and other programs that have been early emerging signals of patient starting to do worse on these kinds of outcomes. So that's extremely encouraging. As I mentioned earlier, for sure, in the natural history, correlations with caudate atrophy with things such as Total Functional Score which is the endpoint the FDA really anchors on overall, and things like SDMT and TMS. They're our early markers of clinical progression for patients once they enter the clinical phase of disease.

Question: Joseph Schwartz - Leerink Partners LLC - Analyst : Right, that makes sense. So it looks like you are planning to study WVE-003 in Stage 1 and 2 patients in a registrational study. I was just wondering if you could expand on those thoughts relative to the predominantly Stage 2 and 3 patients studied in SELECT-HD. and then also discuss your thoughts around a 12- to 18-month timeframe. Can you lay out your thinking about how that's likely to be sufficient? Are you thinking about a fixed duration? Or could you employ an interim analysis? Anne-Marie Li-Kwai-Cheung - WAVE Life Sciences Ltd - Chief Development Officer So in neurodegenerative diseases generally accepted that intervening earlier in the disease course is beneficial to try and slow and halt the disease before there's irrevocable damage and loss of neurons. So what we've seen today in SELECT-HD, which was predominantly a Stage 2/3, I think is actually very encouraging because these patients are a bit further in their disease course. And the beauty of WVE-003 is that we have the ability to go earlier in the disease course because of the allele-selectivity. Patients who are in Stage 1 and 2, particularly 1 are yet to have any clinical signs of disease. And so given that wild-type huntingtin is critical in [numerical] homeostasis, the ability to have this allele-selectivity gives you that opportunity to go earlier. So I think this is something that's very unique to us. But in general, the field is trying to move into earlier studies. And these are also based on learnings from other disease areas such as Alzheimer's disease. The 12-to-18-month time duration of the study is really driven by the sensitivity of the endpoint to change. So because caudate atrophy is a sensitive measure of disease progression, this gives you the ability to design a study which is smaller and shorter to enable you to detect treatment effect. You might have to repeat your third question.

Question: Joseph Schwartz - Leerink Partners LLC - Analyst : Very helpful. Thank you, again.

Question: Joon Lee - Truist Securities - Analyst : Hey, guys. Thanks for taking the follow up question from us. Paul is preservation of caudate's size and elevation in neurofilament light chain compatible. I mean, if neurofilament light chain is indeed elevated, should that lead to more progressive volume loss? And I'm just trying to understand what is real here in the data. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies.

Question: Joon Lee - Truist Securities - Analyst : Great. Well, thanks for the clarification and congrats on the data again. Very strong.

Question: Tiago Fauth - Wells Fargo & Company - Analyst : Well, thanks for bringing up a follow-up. Just a quick one on the Takeda opt-in, can you just remind us on the timing structure once you submit the opt-in package? Is there a clock time when they need to make a decision? And would you expect it to can be conditional on some regulatory input or alignment? I'm curious how that might play out over the next few months? Thanks. REFINITIV STREETEVENTS | www.refinitiv.com | Contact Us consent of Refinitiv. 'Refinitiv' and the Refinitiv logo are registered trademarks of Refinitiv and its affiliated companies.

Question: Tiago Fauth - Wells Fargo & Company - Analyst : Got it. Perfect. Thanks.