Voyager Therapeutics, Inc.

Good day and welcome to Voyager Therapeutics' second quarter 2022 conference call. All participants are now in listen-only mode. There will be a question and answer session at the end of this call, which will be recorded. If you require operator assistance, please press star then zero on your telephone keypad. I would now like to turn the call over to Julie Burek, Vice President of Finance at Voyager.

Thank you, Operator. Good afternoon, everyone, and welcome to this conference call to discuss our second quarter 2022 results and prioritized pipeline. A replay of today's call, including the Q&A, will be available on the investors section of our website approximately two hours after completion of this call. After our prepared remarks, we will open the call for Q&A. As a reminder, various remarks that we make during this call about the company's future expectations, plans, and prospects constitute forward-looking statements for purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the risk factors section of our most recent annual report on Form 10-K, which is on file with the SEC and as updated by our subsequent filings. In addition, Any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements, even if our views change. I'm joined today by our Chief Executive Officer, Dr. Al Sandrock. For the Q&A portion of the call, we will be joined by our Senior Vice President of Research, Dr. Todd Carter. Now, I will turn the call over to Al.

Thanks, Julie, and good afternoon, everyone. I'm extremely pleased to discuss some exciting new developments at Voyager. Voyager's mission is to pioneer the discovery of transformational AAV capsids that we hope will enable the development of life-changing gene therapies. We believe that the novel capsids derived from our proprietary tracer platform represent the breakthrough innovation that will address certain fundamental limitations that currently hamper gene therapy. We and our partners plan to leverage these capsids to advance the field of gene therapy for the central nervous system as well as other organs. We believe that our ongoing collaborations involving the tracer capsids, including those recently signed with Pfizer and Novartis, are progressing well. Both have option exercise milestones coming up in the next several quarters. Soon after joining the company as CEO earlier this year, I led a comprehensive process to evaluate Voyager's R&D programs and determine where to focus with the goal of creating important new therapies for patients and growing shareholder value while maintaining our cash runway into 2024. Today, we are excited to announce our prioritized development pipeline, which builds on advances we've made with our tracer capsids. Gene therapy has the potential to transform the treatment of many serious CNS diseases. A clear example of this is the transformational impact that Zolgensma has had for the treatment of infants with spinal muscular atrophy. However, the FDA label limits the use of Zolgensma to up to age two. The blood-brain barrier appears to preclude the use of intravenous gene therapy in older children and adults. Consequently, delivery methods such as the direct injection of gene therapy into the cerebrospinal fluid or CSF space or into the brain parenchyma have been and are being attempted On slide five, we show examples from the published literature of what happens when these delivery methods are used in non-human primate experiments. We believe the situation is analogous when similar methods are employed in humans. The example on the left panel on this slide comes from a published study in cinnamologous monkeys in which AAV9 expressing green fluorescent protein, or GFP, is injected intrathecally into the CSF space at multiple spinal levels. As you can see by the number of green stained cells, there's a clear drop-off in the number of transduced cells as you go from this lumbar spinal cord to more rostral levels, and even less in the brain, where there are a few weakly stained cells in patchy areas of the cerebral cortex and other regions. Injections into other CSS spaces, such as the Cisterna Magna, are not likely to be much better. Clearly, for most CNS disease applications, this pattern of distribution and low transduction efficiency is a major limitation and likely precludes significant clinical benefit. The panel on the right comes from a published study in which AAV5 expressing GFP was injected directly into the brain parenchyma, in this case the putamen, by means of a surgical procedure. GFP expression, as seen here by the brown staining, is highly localized to the site of injection. Intraparenchymal injections, even with convection-enhanced delivery, result in highly localized distribution. Moreover, although some CNS diseases may begin in the deep gray structures of the brain, Most eventually involve the entire brain. So the limited distribution of gene therapy that is likely to result from such localized delivery methods imposes severe benefit-risk limitations for therapeutic utility. As these limitations became increasingly clear over the past several years, Voyager scientists believed that we could do better. We set out to discover novel capsids with improved tropism. as a potential solution to the delivery and distribution challenges. We invented an approach, now known as TRACER, which has resulted in capsids that in non-human primates have been shown to far more efficiently transduce CNS tissue after IV delivery than any conventional AAV capsid in use today. At the core of TRACER is our proprietary expression-driven in vivo screening platform. This platform has enabled our scientists to identify novel capsids that preferentially target the CNS and other tissues of interest. TRACER has allowed our team to evaluate more than 20 million variants of AAV5 and AAV9 capsids and select only those capsids that display increased transduction in the target organ. This approach has two distinct advantages. First, we performed the initial screening along with a series of subsequent screens in non-human primates so that we're selecting for capsids that show improved tropism in species very closely related to humans, not capsids that may only show activity in mice, which past experience has taught us may not translate well to other species, let alone human beings. Second, we measure the performance of our capsids at each step of the screening process by evaluating gene expression, that is, at the level of messenger RNA. When we measure production of the desired mRNA in the target tissue, we have confidence that we are selecting capsids that not only get across the blood-brain barrier, but that also enter into cells and deliver and express their payload productively. The results from tracer have been remarkable. Our capsids have displayed more than 100-fold higher transient expression in the brain as compared to the conventional AAV capsids in non-human primates. Slide 7 highlights some of what we have observed thus far with the novel capsids derived from tracer. We have found that our novel capsids can efficiently target numerous therapeutically relevant regions of the brain, including the cerebral cortex, hippocampus, and spinal cord. after IV delivery. At the cellular level, our capsids can efficiently transduce neurons, glia, or both cell types. Remarkably, while our capsids increase targeting of neurons and glia in the CNS, at the same time, they can also detarget cells that may result in toxicity, such as liver cells and dorsal root ganglion neurons. Finally, we've also found that our capsids have improved CNS tropism across species, such as the macaque, the marmoset, and the mouse, which we believe improves the likelihood of translation into humans. In summary, we believe our data demonstrates that we can identify truly unique AAV capsids with the potential to enable promising therapeutic candidates for many CNS diseases that could not be adequately addressed using the currently available conventional AAV capsids. We're also very pleased to announce today that we have recently identified a receptor for one of our most promising tracer capsids. We plan to provide further details on this finding at an upcoming scientific conference. What I can tell you today is that we have strong data supporting the identification of a binding receptor for one of our capsids, including data that show that our capsid binds to the human isoform of the receptor. which is expressed in brain endothelial cells and other CNS cell types. We believe that the characterization of this receptor-capsid interaction further increases the probability that this capsid will cross the blood-brain barrier in humans. Importantly, this discovery may provide a path for the rational design of IV-delivered BBV penetrant capsids. Moreover, Experiments are now underway to explore the possibility that this receptor may enable the CNS delivery of other therapeutic modalities, such as proteins, antibodies, and oligonucleotides. I've discussed how our tracer platform has resulted in the generation of capsids that we believe can overcome some of the most pressing hurdles facing CNS gene therapy and have tremendous potential to treat human CNS diseases. We are now combining these unique tracer capsids with our team's deep knowledge of CNS disease biology and drug development with the aim of developing therapies against well-validated targets with potentially transformative clinical impact. I will now discuss our pipeline. Before doing so, I'd like to tell you how we prioritize the pipeline. First, we chose diseases with high unmet medical needs, serious life-threatening diseases where patients have few, if any, treatment options. Second, we chose well-validated targets for these diseases, those validated by human genetics and human clinical pathologic data that indicate that we are dealing with targets and disease-causing biological pathways. Third, we selected programs where it would be possible to rapidly and efficiently establish proof of concept or at least proof of biology in early phase clinical trials. Fourth, we chose programs where we had evidence of robust preclinical pharmacology. And finally, we focused on programs that should provide meaningful commercial opportunities. Based on these criteria, three programs are now our top priorities. BBA1 gene replacement for Parkinson's disease, SOD1 gene silencing for SOD1-mediated ALS, and anti-Tau passive immunotherapy for Alzheimer's disease. We will focus today's pipeline discussion on our prioritized internal programs and our plans to advance each toward clinical development. We note that in addition to these prioritized programs, We will also continue to conduct early research on gene therapy for Huntington's disease and vectorized HER2 antibodies. We hope to be able to advance these programs into later stages of research one day in the future. Let's now review each of our prioritized internal development programs in more detail. I'll start with the GBA1 Parkinson's disease program. Parkinson's disease is the second most common neurodegenerative disease, impacting about 1 million people in the U.S. alone. Up to 10% of Parkinson's disease patients have a mutation in GBA1, the most common genetic risk factor, increasing the risk of the disease approximately 20-fold. GBA1 encodes the lysosomal enzyme glucocerebrosidase, or G-case, which degrades glycosphingolipid substrates. Homozygous loss of function GBA1 mutations result in Gaucher's disease, a lysosomal storage disease, and heterozygous loss of function GBA1 mutations result in an increased risk of Parkinson's disease. Loss of function in G case leads to the accumulation of glycosphingol lipid substrates and alpha-synuclein aggregates, which are thought to be toxic to neurons. We hypothesize that the restoration of G case in patients with Parkinson's disease with GBA mutations will have therapeutic benefits. The restoration of G case may also benefit patients with idiopathic PD, where there is evidence of loss of G case in the substantia nigra, even in the absence of GBA1 mutation. Moreover, there is growing evidence of lysosomal dysfunction in general in idiopathic Parkinson's disease. As shown on slide 13 on the left panel, sorry, as shown on slide 15 on the left panel, because of loss of function mutations in the GBA1 gene, there is reduced G case activity in the relevant brain regions of patients who had Parkinson's disease or dementia with Lewy bodies who were GBA carriers. Interestingly, as alluded to earlier, there's evidence of reduced G case activity in the substantia nigra even in PD patients who did not have GBA1 mutations relative to control patients. Consequently, as shown on the right panel, substrates for the G case enzymes, such as glucosyl ceramide, are elevated in the cerebral spinal fluid in PD patients who harbor the GBA1 mutation. This provides an opportunity to demonstrate proof of biology in an early phase clinical trial. If our gene therapy restores G case enzyme expression in the brain, substrate levels in the CSF should fall to normal, providing a potential path to early clinical development de-risking. In a preclinical study presented at the ASGCT meeting this year, Voyager scientists showed that an IV-delivered gene replacement therapy in rodents increases G case protein and enzyme activity in the brain and thus lowers the level of both glucosyl ceramide and glucosyl sphingosine in the brain in a dose-dependent manner. This is shown on slide 16. We hope to achieve similar results in the clinic with one of our tracer-derived capsids, and we are moving this program forward, as shown on slide 17. We are evaluating tracer capsids in anticipation of selecting an IV-delivered capsid for this program by year-end. In the first half of 2023, we expect to finalize selection of a development candidate. Following that, in the second half of 2023, we expect to initiate a dose range finding study in non-human primates, and we anticipate initiating GLP toxicology studies in 2024. This timeline puts us on track for an IND in 2025, but we are actively reviewing options to accelerate the program. Moving now to SOD1 ALS. Amyotrophic lateral sclerosis is a rapidly progressing neurodegenerative disease that typically leads to death approximately three years after diagnosis. Current treatments are minimally effective, and there's a great need for improved therapies. Autosomal dominant superoxide dismutase 1 mutations are thought to cause a toxic gain of function that leads to the degeneration of motor neurons along the entire length of the spinal cord, the brain stem, as well as the upper motor neurons in the cerebral cortex. We believe that by reducing the expression of SOD1 in the central nervous system, we can provide therapeutic benefit to ALS patients with SOD1 mutations. From a clinical development standpoint, the ability to demonstrate reduced levels of SOD1 in CSF as a target engagement biomarker as well as the ability to measure plasma neurofilament light chain as a surrogate biomarker of clinical efficacy, greatly facilitate clinical development. Our therapeutic approach for SOD1 ALS combines a potent siRNA construct with a CNS-tropic BBB penetrant capsid. Because of the potential for broad CNS targeting, we hope to address all of the major disease manifestations, involving the entire neuraxis, namely the brain, brain stem, and spinal cord with an IV-delivered tracer-derived capsid. Preclinical data that were presented at the ASGCT conference earlier this year, shown on slide 20, demonstrate that IV delivery of siRNA gene therapy leads to robust SOD1 knockdown in all regions of the spinal cord and significant improvements in motor performance, body weight, and survival in the G93A SOD mouse model. We believe these data provide preclinical pharmacologic support for our approach, and we're eager to advance toward the clinic. Slide 21 shows the anticipated milestones for this program, which are as follows. Our NHP capsid evaluation study is underway, and we expect to select a final candidate by the end of this year. We plan to obtain a non-human primate dose range-finding study readout in 2023, and we anticipate initiation of GLP toxicology studies in the first half of 2024. If we achieve these milestones in a timely manner, an IND filing in the second half of 2024 is anticipated. I'll now transition to our passive immunotherapy program targeting tau. This program is based on research conducted by our team since the earliest days of the founding of our company. Our tau antibody discovery work for vectorization led to the discovery of novel antibodies selectively targeting pathological tau. These antibodies have a number of favorable characteristics supporting continued development. These include High affinity for pathological forms of tau, a protein that has been linked to a number of neurodegenerative diseases, including Alzheimer's disease. Robust efficacy in animal models of tau spreading. Clear and clear differentiation from other anti-tau antibodies, including those that have been shown to be clinically ineffective. We plan to first leverage an anti-tau antibody as an IV immunotherapy. This approach has the potential to lead to high-value clinical candidates for the treatment of Alzheimer's disease and other tauopathies with tremendous unmet need. It may also lead the way for eventual vectorization of these antibodies as gene therapy candidates. Some important advantages of this approach from a drug development standpoint are that immunotherapies with IV administration have already been shown to produce important effects in the brain in neurodegenerative diseases such as Alzheimer's disease. Moreover, we plan to use tau PET imaging, which should allow for the rapid and efficient demonstration of proof of biology in an early phase clinical trial. We've known for some time now that tau pathology propagates across certain brain regions in a stereotyped fashion in Alzheimer's disease, as shown on slide 24. and as demonstrated by the seminal work of Brock and Brock. Some investigators have pointed out that the accumulation of tau pathology correlates better with dementia than any other biomarker. Modern PET imaging studies, for example, as shown on the left panel of slide 24, have also shown the spread of tau pathology correlating with increased impairment and advancing Brock stage. In recent years, several controlled trials of amyloid-directed therapies have demonstrated the feasibility of evaluating the spread of tau pathology in longitudinal assessments of tau PET images in patients with mild cognitive impairment due to Alzheimer's disease over the course of 12- to 18-month trials. Our therapeutic hypothesis is that an antibody targeting tau may block the neuron-to-neuron spread of tau at several plausible extracellular sites, as shown on the right side of this slide, and that this may attenuate the progression of diseases such as Alzheimer's disease. Tau has been the target of several monoclonal antibodies, including those that have not demonstrated clinical efficacy. We are well aware of these studies, and we're careful to differentiate from these antibodies by targeting a different epitope, The Voyager antibody targets the C terminal, which to our knowledge has not been tested in a well-controlled efficacy trial of tau immunotherapy. Slide 26 shows that our antibody in a Rosen pathological tau spreading model is also differentiated in terms of biological activity from an N terminal antibody that is equivalent to one that has failed to show efficacy in a phase two clinical trial. We just presented this data on the panel on the right side of this slide at the AAIC meeting in San Diego. In this animal model, pathological tau called paired helicophilamentous tau is extracted and enriched from brain tissue from Alzheimer's disease patients. This material called EPHF can be injected into the hippocampus of the P301S mouse, a mouse strain that expresses a mutant human form of tau, where it induces substantial formation of pathological tau. This pathological tau also spreads to and accumulates in the contralateral hippocampus. In our studies, we began dosing seven-week-old mice with antibodies for one week, injected ePHF, continued antibody dosing afterward, and sacrificed the animal six weeks later. Levels of pathological tau accumulation were then measured in the ipsilateral and contralateral hippocampus. There was significant reduction of tau pathology in both the ipsilateral and contralateral hippocampus. In contrast, as published in 2019 and shown in the figure on the left panel on this slide, The N-terminal antibody, IPN002, has been shown to be ineffective in a very similar mouse seeding experiment. Of note, the IPN002 antibody had been immunized and, when tested in the clinic, failed to show efficacy in a Phase II clinical trial. As a result of experiments such as these, We believe that the Voyager antibody by targeting the C-terminal may have an advantage over N-terminal targeting antibodies in blocking the spread of pathological tau in the brain. We are advancing our anti-tau immunotherapy program toward the clinic, and humanization of our murine antibody is already underway. Looking ahead, we anticipate selection of a development candidate in the first half of 2023, followed by initiation of GLP toxicology studies later that year. If we achieve these milestones in a timely manner, we would target IND filing in 2024. I'll now pass the call to Julie to review our financial results.