Voyager: Anti-Tau Antibody Differentiation For AD Treatment Could Boost Prospects (VYGR)

Voyager Therapeutics, Inc. (NASDAQ:VYGR) is in the process of developing its anti-Tau antibody VY7523 for the treatment of patients with Alzheimer’s Disease [AD] in a phase 1a single-ascending dose [SAD] study. The reason investors should keep an eye on this biotech is because it is expected that it will release safety and pharmacokinetic data from this healthy volunteer study in the 1st half of 2025. This will be a major inflection point for it because it will determine whether this drug is safe for patients to take and if drug exposure for a certain period of time is experienced. Should everything go well with this initial data set, then it opens the door for two other catalysts for investors to look forward to.

One would be the initiation of a phase 1b multiple-ascending dose [MAD] study for the treatment of patients with early AD. The second of which, would then be the release of initial clinical data expected from this study. This will be Tau PET imaging data to see if the drug is actually working as intended. The AD space is quite difficult to conquer, that’s why it is not only going to rely on VY7523 as an anti-Tau antibody only. It is also in the process of developing a tau silencing gene therapy as well. The point of this is to reduce tau messenger RNA [mRNA] in hopes of offering a “one and done” type of treatment option for these patients. As far as the long-term outlook for this biotech, it is there.

That’s because it is advancing its own gene therapy, known as VY9323, for the treatment of patients with SOD1 amyotrophic lateral sclerosis [ALS]. The importance of this is the ability to use its TRACER capsid delivery platform to target this patient population. Two addition proof-of-concepts could be expanded based on a partnership with Neurocrine Biosciences (NBIX) to target patients with Parkinson’s Disease [PD] and Friedreich’s Ataxia [FA]. The point here is that all three IND submissions, to begin studies for all of these programs using its TRACER capsid delivery program, are expected in 2025. What’s ideal is that this company has plenty of cash runway to operate its business into 2027.

VY7523 For The Treatment Of Patients With Early Alzheimer’s Disease

As I stated above, the goal of Voyager Therapeutics is to develop the use of anti-tau antibody VY7523 for the treatment of patients with AD. The use of this monoclonal antibody is being advanced in the ongoing phase 1a single ascending-dose [SAD] randomized, double-blind, placebo controlled trial in healthy adult volunteers. Before going over this entire program, plus any possible catalysts to come out of it, I believe it is first important to go over what this disease is and what the possible market opportunity for it could be.

Alzheimer’s Disease [AD] is a type of disorder characterized as a type of dementia that causes loss of memory and other cognitive functions. Besides this causing a problem with patients being able to remember things or think, it interrupts daily function living tasks. The global Alzheimer’s Disease Therapeutics market is expected to reach $30.8 billion by 2033. This is a massive market opportunity and the truth is, that it is expected to continue to grow over the coming years. Consider that in 2020 there were as many as 5.8 million Americans that were living with AD, but this number is expected to triple to 14 million people by 2060. However, the focus of this company is to specifically eventually target early AD patients. This would still be a pretty sizeable population for Voyager to use VY7523 towards. That’s because it is believed that about 50% of AD patients have mild [early-stage] disease.

To see if VY7523 will work as an anti-tau antibody, it had deployed the phase 1a SAD trial. This adult healthy volunteer study is expected to enroll up to a total of 48 patients across several dosing cohorts. The main thing to note about this clinical candidate is that it is a monoclonal antibody, which has been developed to target tau protein, which is a pathological biomarker of AD. Wait a second, haven’t numerous companies that targeted AD using this tau pathology failed in the past? They have failed, but the thing to note about Voyager is that it, along with other companies, are moving away from the targeting of the N-terminal domain approach. While binding with high affinity is present targeting this domain, there is no downstream activity on biomarkers.

This is where VY7523 can differentiate itself, especially since it is targeting another domain with high affinity [strong binding], which is the C-terminal one. Thus, the targeting of the mid-domain region of a tau protein could end up resulting in a greater reduction of tau protein against pathological AD. Whether this ends up being proven in humans in the phase 1a healthy volunteer study remains to be seen. However, what has been presented thus far in a preclinical model has been pretty good. Consider that at the AAIC 2022 medical conference Voyager presented data showing that intravenous use of VY7523 in a mouse seeding model, inhibited the spread of pathological tau by >70%. With the N-terminal of the tau protein to be targeted, which is located on the microtubule binding region, it is believed that better downstream inhibition of tau can occur.

Hopefully, the targeting of this other domain terminal on the tau protein results in good initial exposure data. Speaking of which, this brings about a few catalysts that relate to this specific program. The first of which is that it is expected that initial safety and pharmacokinetic [PK] data will be released from this phase 1a study, in the 1st half of 2025. The reason for setting up this early-stage trial in this manner is because it is necessary to see how high of a dose or maximum tolerated dose [MTD] could be used for the next expected study. This leads to the second catalyst to consider regarding this program, which is the initiation of a phase 1b study using VY7523 for the treatment of early-stage AD patients. Should these initial findings turn out to be good, then this will lead to the initiation of the phase 1b multiple ascending dose study targeting these early ad patients in 2025. Lastly, from there, Tau PET imaging data from this MAD study would be released by the 2nd half of 2026.

Second Shot On Goal Targeting AD And Beyond

The thing about Voyager Therapeutics is that while it is using VY7253 as an anti-Tau antibody targeting this patient population, it may have another shot on goal. This would be with the development of tau silencing gene therapy targeting this specific patient population. The hope here is to create a “one and done” type of therapy that can help a patient over an extended period of time. The thing to note is that this company has been able to develop its own technology platform for being able to deliver novel capsids for gene therapy. Especially, since it has improved itself with this technology in terms of going beyond the scope of only using other types of capsids. Its old generation capsids for gene therapy delivery were not ideal.

VCAP101 and VCAP202 used widely used AAV9 for delivery, but have several drawbacks. It just wasn’t effective as it would have liked. Having said that, it has moved towards using its new VCAP-Gen2 [second generation TRACER capsid]. This could end up resulting in improved blood brain barrier [BBB] penetration, enhanced central-nervous system [CNS] tropism. Doing all of this, while achieving reduced liver targeting effects. It was shown that this next-generation capsid could have a lot going for itself. Especially, from what has been shown in multiple species in various preclinical models. Just to give you an idea of the power of the next-generation capsid, it is important to highlight a finding regarding SOD1 targeting of ALS patients. It was noted that this capsid was able to reduce SOD1 mRNA expression by up to 80% in non-human primates [NHPs] spinal cord motor neurons. The use of VCAP-Gen2 was also shown to do well against other indications as well.

Having said that, it is expected that an IND submission of this anti-SOD1 VY9323 candidate to target SOD1 ALS patients, is expected to happen in mid-2025. The thing is that there is an expansion opportunity beyond the scope of only targeting SOD1 ALS patients. This would be in terms of the partnership that it had generated with Neurocrine Biosciences as I noted in the beginning above. The other two target indications are GBA1 mutated Parkinson’s Disease [PD] and Friedreich’s Ataxia [FA]. These other indications that are going to deploy the TRACER capsid technology platform for gene therapy and IND filing for these are also expected in 2025.

Financials

According to the 10-Q SEC Filing, Voyager Therapeutics had cash, cash equivalents and marketable securities of $371 million as of June 30th of 2024. This company should have enough cash for an extended period of time. One reason is because the company is still continuing to receive collaboration revenue from respective partners. For instance, in the most recent Q2 of 2024, it had noted collaboration revenue of $29.6 million based on its partnerships with Neurocrine and Novartis (NVS). The second reason is because of its cash runway guidance.

Based on its cash on hand, it believes that it has a cash runway, or enough funds to operate its business, into 2027. The importance of this is that it allows it to reach several clinical data readouts by then. The truth is that it is set up for a good amount of cash if its clinical products being developed work out. The reason is that it is possible that it could earn up to $8.2 billion in potential long-term milestone payments based on its partnered programs. The cash burn per quarter for this company is around $44.7 million, which consists of $34.5 million in R&D expenses and then approximately $10.2 million in G&A expenses.

Risks To Business

There are various risks that investors should be aware of before investing in Voyager Therapeutics. The first risk to consider would be regarding the development of VY7523 for the treatment of patients with early-stage AD. The risk here is that there is no assurance that there won’t be any safety issues found when this monoclonal antibody drug is given to healthy volunteers. The goal of this trial is to see if this drug is tolerable and results in effective pharmacokinetic findings to move forward towards the next-stage of clinical testing. This brings up the second risk relating to this program, which is that the findings to be produced from the healthy volunteer study may not be enough to warrant further investigation into the expected phase 1b multiple-ascending dose [MAD] study.

The second risk to consider would be regarding the development of the TRACER-derived capsid gene therapy targeting Alzheimer’s Disease patients. The goal is to be in a position to file an IND for this program targeting this patient population in 2026. There is no assurance that the pre-IND enabling studies will be enough to allow for the initiation of a phase 1 study, nor that the FDA will even allow such an early-stage trial to begin. Even if a phase 1 study is eventually initiated, the targeting of tau protein using siRNA using its TRACER-capsid platform may not be enough to see the intended results.

A third risk to consider would be regarding several other programs using TRACER-derived capsids for gene therapies targeting patients with SOD1 ALS, GBA1 Friedreich’s Ataxia [FA] and GBA1 Parkinson’s Disease [PD]. For instance, even though early evidence was shown that using VY9323 as an anti-SOD1 siRNA resulted in mRNA knockdown of 80% in non-human primates [NHP] spinal motor cord neurons after a single intravenous [IV] dose, there is no assurance that such an mRNA knockdown will be achieved in a phase 1 trial in humans. Plus, with this TRACER capsid program still in the early part of testing, there is no guarantee that the necessary knockdown will be achieved to move on towards other studies thereafter.

The fourth and final risk to consider would be regarding the ongoing partnerships that it has developed thus far. For instance, I made note of the Neurocrine Biosciences partnership to develop TRACER-derived capsids for gene therapy to treat GBA1 disorders like PD and FA. Even further than that, there seems to be something good regarding these VCAP-Gen2 capsids being developed. That’s because even Novartis wanted to be a part in developing such a gene therapy. Consider that both companies entered into a collaboration agreement to advance such capsids to help treat patients with Huntington’s Disease [HD] and spinal muscular atrophy [SMA]. The risk here is that in order for Voyager to retain these partnerships, its next-gen TRACER capsids have to achieve substantial data. At any moment’s notice, either of these big pharma companies could terminate the partnership, and this would mean a reduced pipeline. It would also mean the loss of the ability to receive long-term milestone payments for these respective programs. At which point, the biotech would be forced to raise cash by dilutive means.

Conclusion

Voyager has put itself in a position to obtain key safety and pharmacokinetic data from its phase 1a SAD, randomized, placebo-controlled study. Such data expected in the first half of next year will be crucial to proving whether the drug is safe/tolerable for patients to take. Plus, that adequate drug exposure is present to generate the necessary tau protein reduction later on. Especially, where the company believes it can improve upon the use of monoclonal antibodies targeting tau protein when going after the C-terminal, instead of the failed N-terminal many other companies failed on.

Whether such a differentiation is shown remains to be seen. However, I believe it is good that at least it also has another shot on goal in targeting the large AD treatment market space with its gene therapy TRACER-capsid technology platform. With initial safety/PK data from the phase 1a healthy volunteer study expected in the 1st half of 2025, plus the ability to continue to advance the next-generation TRACER-capsid technology platform I believe that investors could benefit with any potential gains made here.

Editor’s Note: This article discusses one or more securities that do not trade on a major U.S. exchange. Please be aware of the risks associated with these stocks.