Voyager Therapeutics, Inc. (VYGR) Earnings Call Transcript & Summary

Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. Before we start, please note that this webcast is for Morgan Stanley's clients and appropriate Morgan Stanley employees only. This webcast is not for members of the press. If you are a member of the press, please disconnect and reach out separately. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have from Voyager Therapeutics, Andre Turenne, CEO; and Omar Khwaja, CMO. Well, welcome, guys.

Thanks, Jeff. Great to be here. Thanks for the invitation.

Thanks.

Definitely. So for those who may not be familiar with Voyager, can you provide a brief introduction?

Yes, happy to. So -- and thanks for everyone listening to -- on the webcast. So our mission at Voyager is to bring transformative gene therapies to patients suffering from severe neurological diseases. We've -- we were founded 6 years ago by leaders in the field. And scientifically and clinically, we've been and we are, fully focused at that intersection of AAV gene therapy and neuroscience, which is so rapidly evolving -- offers and incredible opportunities to address conditions that are currently highly debilitating and fatal. We're building a clinical stage pipeline across both rare monogenic diseases. And some of the most prevalent neurological conditions and we'll talk about some of these programs today. To do this, we're leveraging 3 different therapeutic modalities delivered through AAV gene therapy. We do gene replacement, gene knockdown and vectorized antibodies. Our pipeline as our lead asset for Parkinson's disease is in the middle of the first of 2 pivotal trials. Our second program is for Huntington's disease, and we're expecting to file in the second half of this year an IND to make this our second clinical program and we have a rich preclinical portfolio that's advancing well. Given the focus we've had all along, and we've been able to make some targeted investments in our manufacturing capabilities and our platform. Importantly, we've invested and made great progress with the next-generation tools to enable better delivery of gene therapies to the CNS, and we can also touch on this, but that is some of the work we've been doing on the next-generation capsids to allow for that. So exciting moment for us, exciting portfolio and I look forward to the discussion.

Great. Your lead program, as you mentioned, VY-AADC is partnered with Neurocrine and is being developed for Parkinson's disease. Can you talk a little bit more about this program and the target population?

Yes. Absolutely. So Parkinson's, it's a progressive neurological disease. It results in the loss of motor function. It's the second most common neurodegenerative disease after Alzheimer's. It affects around 1 million people in the U.S. alone. The center of care for Parkinson's has not significantly changed in the past decades. It's based on levodopa therapy, which raises the dopamine level and is effective in maintaining motor function early in the disease. The problem is as the disease progresses, there's dopaminergic neuron degeneration, and that results in loss of this one critical enzyme, which is AADC, amino acid decarboxylase, which directly converts levodopa into dopamine. So our approach is to replace this AADC enzyme through a onetime gene therapy delivery to be able to restore in a durable way, a sufficient amount of that enzyme to allow patients to regain motor function. It's a promising approach. You could have -- it could be a very important advance in the management of patients with moderate to advanced Parkinson's.

And the 3-year Phase Ib results were just presented at the Movement Disorder Society meeting. So for those who maybe have missed it, what are the key takeaways?

Yes. So this was just this past weekend that we presented at the MDS virtual meeting. So we were very pleased with the results, very encouraged by the congruence of data. So that includes both clinician reported outcome, [indiscernible] assessment and patient-reported outcomes across 2 studies in the Phase Ib in the moderate-to-severe Parkinson's patients. So that's 23 patients, 60-patient years of data overall. So highlights from it is that at 3 years, we saw sustained improvements in motor function and quality of life in conjunction with the real meaningful reduction in the amount of medications required to achieve that. At 3 years also, we saw 14 of 15 patients, which sustained improvement over baseline in their disease staging on the 5-point that modified Hoehn and Yahr scale, and the 15th patient remain stable. So that's a remarkable improvement of this scale for these 14 patients because they were able to regain postural stability, which is the definition of stage 3. And all the patients started, prior to the study, stage 3 or stage 4. And that's a crucial threshold in the progression of Parkinson's because that loss of postural stability that happens once you get to stage 3 and above, it increases the risk of falling and all the associated morbidity and mortality. So all of these results -- what's compelling also is that it's all in the backdrop of the fact that the Parkinson's is a progressive disease where the natural history tells us that the 3 years forward or 2 years forward, these patients would be worse off year-on-year, and that -- these standpoints on a number of these parameters despite the best medical treatment. So yes, we're excited that to our knowledge, it's the longest-term positive data set to date for a gene therapy in Parkinson's, and we're excited with the next step, which is the current study, which is a placebo-controlled trial.

And what kind of durability do you think is needed for the VY-AADC to be clinically meaningful? You had 3-year results for the Phase Ib. So do you need to replicate that in your registration studies or a long term study?

Yes, Omar will -- yes.

So yes we were pleased to see the durability of improvement across these multiple measures, motor function reduction in Parkinsonian medications, and then as Andre just highlighted the overall disease stage of the patients as well to see that improvement sustained in these advanced patients with a neurodegenerative disease sustained over 3 years. For the registrational studies, we've gained agreement with the FDA that the primary analysis will be on 12 months for the primary endpoint. However, because these patients are receiving a gene therapy, we will be -- they will enroll into open-label extension studies for a further 5 years for safety. So we will have longer duration follow-up, but the primary endpoint will be analyzed at 12 months following treatment.

Okay. That's helpful. And that kind of ties into my next question, which is that you have 2 registrational trials, RESTORE-1 and RESTORE-2. Maybe if you can talk about these 2 studies, and you kind of already have, but what you need to see to consider them successful?

Yes. So just a reminder that VY-AADC is being developed under the RMAT, regenerative medicine advanced therapy designation, from the FDA. So we've been able to benefit from a good degree of interaction with the agency on the design of the registrational program. So there are 2 studies, RESTORE-1 and RESTORE-2 that are substantially similar in design. The difference being is that RESTORE-1 is the U.S.-only study whereas RESTORE-2 will be a global study. RESTORE-1 and RESTORE-2 are designed to show a difference on the patient-reported diary of a good on time or on-time without troublesome dyskinesias over a normalized 16-hour day. And as I said, that would be 12 months after treatment compared to patients receiving sham controlled surgery. The randomization scheme is 2:1, so 2 patients on active, 1 on placebo.

Great. And you mentioned that the RESTORE-2 has international sites. What proportion of the patients in RESTORE-2 are you expecting to come from international sites? And then, I guess, based on your prior experience of the literature, is there any reason to believe that variations in geography might result in any meaningful differences between the studies?

Yes. So both good questions. So we'll give -- we plan to initiate recruitment into RESTORE-2 in the first half of next year, and we'll probably give updates together with our partner, Neurocrine, on the balance of sites in terms of geographies that we'll be recruiting in. I think in terms of the disease itself, we don't anticipate there being substantial differences in the actual patient populations that we'll recruit from different geographies into RESTORE-2. And then overall, we also believe that the territories that we're considering initiating RESTORE-2 in, that there is a fairly cohesive standard of care guidelines for patients with moderate to advanced Parkinson's that are very similar to those in the U.S. and the patients who are being recruited into RESTORE-1.

And I'll add, Jeff, to that, that we also plan to have the sites from RESTORE-1, once the RESTORE-1 is fully enrolled -- rolled over to continue -- to contribute to finishing the enrollment of RESTORE-2. So we'll get that benefit also of having many of the same sites contributing in both study.

Right. Okay. And you're planning to resume screening enrollment to RESTORE-1 by year-end with protocol amendments. Can you remind us what amendments were made and why they were implemented?

Yes, absolutely. So together with Neurocrine, we took the opportunity to confirm with the FDA some modifications for the protocol for RESTORE-1 essentially to make sure that it was a robust study to serve as 1 of 2 adequate and well-controlled trials for registration. The other thing was that we had some key operational learnings as well from the Phase Ib studies that we would like -- we wanted to implement. So I think one of the most important one was the target enrollment of approximately 85 patients to ensure that we were powered adequately on our primary endpoint, but also to change the randomization from 1:1 to 2:1. We also really modified the protocol to make it much more patient and investigator centric. So we eliminated a number of exploratory endpoints and assessments that were a little bit more burdensome for patients and were not really necessary for a registrational study, but would have been more suitable for an earlier phase study. So examples of those were removing some of the PET scans and then also some of the visits that required patients to be in the off state. One thing that's important to emphasize is that we did retain the primary endpoints and key secondary endpoints as the same from the first version of RESTORE-1.

Great. That's helpful. And when do you expect the study to complete enrollment? And I guess, do you anticipate the protocol amendments having impact on pace of enrollment?

Yes. So we're working with Neurocrine to resume screening enrollment at clinical sites in RESTORE-1. Obviously, there have been some interruptions from COVID-19 that have meant that we've had to delay our anticipated restart of the study into the second half of this year, but we happen -- we expect this to happen on a site-by-site basis, resuming in the coming weeks. In terms of time lines, we haven't updated on when we plan for finalization of recruitment. I think though, the adjustments that we made to the protocol in agreement with the agency should ensure both that the throughput of patients, the patient journey through the study, should be smoother and also particularly the change for randomization will also incentivize patients more to join the study with a change in randomization. So we're hoping that will also improve the pace of randomization as we get restarted.

And I'll add, Jeff, that -- yes, we'll plan to provide a further update, again with Neurocrine on -- when you expect the study to be fully enrolled. Once we, as Omar said, get the enrollment restarted in a COVID context and in the context of these changes to the protocol, we'll get a better sense of the base. So we will provide an update in due time here.

Okay. Well, great. Let's shift to your programs for Huntington's. What is the rationale for knocking down HTT expression? And what have you seen in the preclinical data that gives you confidence in knocking down HTT with AAV in humans?