Targeting CNS Diseases with Gene Therapies

June 4, 2021

The translational challenges of moving an experimental therapy from the lab to the clinic can stall the development of life-saving therapies, but Passage Bio has provided a unique solution to that challenge. The company’s strategic collaboration and licensing agreement with the University of Pennsylvania’s Gene Therapy Program leaves the discovery and preclinical work in the hands of Penn researchers and provides it with enhanced access to a broad portfolio of gene therapy candidates and future innovations. The company has built a pipeline of gene therapy candidates targeted central nervous system disorders. We spoke to Bruce Goldsmith, CEO of Passage Bio, about the company’s relationship with Penn’s Gene Therapy Program, its focus on CNS conditions, and the company’s lead program in the rare lysosomal storage disorder GM1 gangliosidosis.

Daniel Levine: Bruce. Thanks for joining us.

Bruce Goldsmith: Danny, thanks very much for the opportunity to speak with you today.

Daniel Levine: We’re going to talk about gene therapy, Passage Bio, and its focus on rare monogenic gene therapies for CNS disorders. A lot of the earliest gene therapies we’ve seen involve targeting parts of the body that are easier to deliver gene therapies to, such as the eye or the liver. You’re focused on rare monogenic diseases of the brain and central nervous system. This is an area of great need. Perhaps you can begin with the thinking behind Passage Bio to focus on CNS disorders from a strategic business point of view.

Bruce Goldsmith: Absolutely. You’ve started to allude to the reason for going after and trying to pursue treatments for CNS diseases in your introduction. The way we think about this is that the CNS, and the brain is a compartment similar to the eye for the treatment of retinal diseases, but it does have some idiosyncratic problems to overcome in terms of addressing CNS diseases. When we start to think about this, there is incredibly high unmet medical need for the patients that are suffering from CNS disorders. Monogenic disorders are caused by a reduction or loss in a single gene product. When we think about the entirety of rare diseases, there are approximately 7,000 rare diseases and about 70 percent of them, or almost 5,000, produce abnormalities within the central nervous system, which includes the brain and spinal cord. Specifically in the CNS, there are 790 rare monogenic diseases and all of these have very few treatment options. The way we think about this is that for these monogenic CNS disorders, targeted delivery of gene therapies into the brain, and there’s multiple ways of doing this, is like the retina in that you’re delivering the solution into the specific area that you’re trying to address. These gene therapies have the demonstrated the potential of restoring stable and normal expression of functional genes that hopefully then restore the CNS function. Specifically, what we’re using is AAVs as gene therapies and these are the leading platforms of the next generation of approaches and they have particular utility in CNS disorders because they show promise in hard-to-treat organs like the brain. We’ve shown in preclinical models that we can deliver these to the brain of animals and show that within the brain you can get expression of the target proteins that we’re trying to replicate. In addition, AAVs have the ability to transduce non-dividing cells and the brain is full of non-dividing cells. Finally, this offers the potential for long-term disease treatment with a single administration. Overall, putting this complete vision for Passage Bio into context, Passage Bio, as I’m sure we’ll talk about, was founded by Jim Wilson at the University of Pennsylvania Gene Therapy program. It’s the foundation that he laid about thinking about different compartments in the body and addressing these with gene therapy that really drove the foundation and the growth for Passage Bio.

Daniel Levine: One of the challenges with bringing innovative therapies from the lab to the marketplace is the translational science involved. We’ve seen a number of new business models emerge that seek to address this in different ways. I would include Passage Bio in this because of its relationship with the University of Pennsylvania Gene Therapy program (GTP). For listeners not familiar with Passage Bio and its relationship with the GTP, can you sketch that out, and the central role that relationship played in the vision of Passage Bio?

Bruce Goldsmith: Absolutely. I will start by saying that the relationship is very strong, not only with Jim Wilson, who we’ll talk about in a second, but we get to tap into his group of experts across manufacturing, preclinical, regulatory, and clinical that we can use and collaborate with to build a stronger program. That’s one of the ancillary benefits that has come with the foundation of Passage Bio, which was really driven by Jim. Jim has built a truly amazing organization at GTP with the mission to develop and commercialize transformative genetic-based therapeutics. The mission of GTP is driven by the unmet medical need of patients with these genetic diseases. Therefore, the alignment between GTP and Passage Bio continues to be incredibly close. Our mission is to develop and commercialize those genetic medicines specifically in CNS diseases. GTP has world renowned scientists led by Jim and he’s built an organization of approximately 300 people across the various areas that I mentioned earlier. Through that we have an option to license a total of 17 programs focused on monogenic disorders of the CNS. This collaboration will run at least another four years into 2025. This gives us one of the largest pipelines in the CNS gene therapy space. The way this works through our strategic collaboration and licensing agreement is that in collaboration with us thinking about which indications we want to go after, the gene therapy program conducts the discovery and IND enabling preclinical work. That’s very important because we get to benefit from the experience of the scientists and the experts at Penn that work closely with and under the supervision of Jim to design all of these studies. That provides our team with enhanced access to a broad portfolio of gene therapy candidates. Then, we pair that with our expertise in regulatory, manufacturing, and commercial to advance these. The great thing about this is that our relationship is not static. In fact, a year ago we expanded our relationship in 2020 to also collaborate on basic research, investments in new therapeutic technologies in the gene therapy space, as well as extending the relationship.

Daniel Levine: We’ve certainly seen a lot of move within the pharmaceutical industry broadly to externalize discovery and to forge these types of relationship with academic institutions. How unique is the relationship that Passage has with the GTP at Penn?

Bruce Goldsmith: I think the two words we often talk about are breadth and depth. We do believe our relationship is well differentiated. We absolutely see other models where companies are partnered with academic institutions. It’s usually across the university or in some circumstances across multiple universities where academic groups can feed into pipelines. We think these are all great models and certainly academic partnerships are important. Jim has built at GTP a unique model, and because of the breadth he’s built, we get to capitalize on that. As I said before, he has approximately 300 people. One example of this is in manufacturing. Many groups start to think about moving towards commercialization and manufacturing with their academic partners. But, Jim has a vector core headed by some absolutely outstanding folks that can basically de-risk and optimize manufacturing. That’s a really critical component in the gene therapy space. We partner very closely with that group as they think about scaling up and then transitioning that technology into our dedicated suite at a CDMO so that we can move towards clinical manufacturing. That seamless interaction is a differentiating point. We get to do that for the 17 options we have. Obviously, Jim, as a pioneer in gene therapy and a key advisor to us, participates in our executive discussions when we think about strategy. He is a board advisor, and he’s our chief scientific advisor. We have access to all of this cutting edge research and expertise that is strategic, but also operational. As I said before, we have an opportunity to continue to grow our relationship and build on the proven track record of Jim and his team, who have brought forward many different investigational new drugs into clinical develop.

Daniel Levine: Can you go a little deeper on that? How much integration is there in terms of the work and how much of an exchange of ideas and discussion exists between GTP and Passage? Or, is there just a matter of here’s the data and a decision is made and there’s a clear handoff.

Bruce Goldsmith: It’s a very close collaboration. We have ongoing steering committees and research development committees, which are the formal forums for exchanges of ideas. Then we have a pretty constant exchange informally of the progress that’s ongoing. Again, manufacturing is one component of that, but from the preclinical perspective, for example, as data is being generated and studies are being designed, we talk about what those are likely to be in the context of a clinical development strategy and we include not only our folks, but also Jim’s group for everywhere from manufacturing to regulatory input and the preclinical, because it has to be seamless. One of the strategies in larger pharmaceutical companies, for example, is to make sure that there’s constant dialogue between early research, translational research, IND enabling studies, and then into the clinic, because you have to know where you’re going in order to know what you’re doing at the beginning. There’s a constant dialogue that starts often with me and Jim, but sometimes at the team level, of thinking about how our intended clinical and commercial strategy is going to integrate with the preclinical and early work. It’s an ongoing dialogue. This becomes exceptionally close at the IND enabling stage and then carries through as we move forward to global filings because the global filings constantly need support from our group and Jim’s group. This is one of the reasons that we continue to grow in Philadelphia. We were founded in Philadelphia because of that relationship. After the IPO, there was certainly an opportunity where we could have continued to grow outside of the city, but we decided instead to open another office that could accommodate the growth that we were experiencing to be proximal to where Jim and his team are. One of the things that we did before the pandemic was we started to have meetings back and forth, not only for personal interaction, but also to share ideas, et cetera. We do look forward to doing that again when it’s safe to do so.

Daniel Levine: I should note you also work with Penn’s Orphan Disease Center. What’s that relationship and how do you leverage its work?

Bruce Goldsmith: That’s a great question. It’s another aspect of Jim’s investment in the rare disease space and his commitment to patients. The Orphan Disease Center has been a fantastic partner of ours for a number of reasons. One is, as we are bringing people on board and building our clinical, our patient interaction group, and other groups, the Orphan Disease Center has these relationships embedded in their strategy, operations, and DNA, for lack of a better term, and we work closely and coordinate on those approaches, especially as we’re launching initiatives. We do have some, for example, on patient identification and genetic testing. We’ve done that with thinking about the Orphan Disease Center’s mission in mind. The other aspect, in addition to working with physicians and advocacy groups and identifying trial sites, we also are running a natural history study that we’re funding and the Orphan Disease Center is executing. This is to help us better understand the genetic, environmental, and other factors associated with our first in-human study, which is the GM1 gangliosidosis indication that occurs in very young patients. Understanding the natural history of that disease is important for two reasons. One is that scientifically and clinically there’s really a scarcity of data. The second is that this could help us as a comparator arm for potential regulatory interactions. We consider the Orphan Disease Center an absolutely key partner in all of our endeavors.

Daniel Levine: Well, let’s talk about that program. What is GM1 gangliosidosis beyond being a lysosomal storage disorder? How does it manifest itself and progress?

Bruce Goldsmith: An important thing that we focus on is how do we hope to change the outcomes for these patients and families that are so impacted by these really severe diseases. One of the things I should mention is we talk to parents of these patients because we want to understand what’s meaningful for these parents. These diseases are truly devastating. The actual manifestation of these diseases is basically a rapid progression of neurologic decline. What that means is that there’s a progressive dysfunction in the central nervous system that shows itself by decreasing muscle tone, deafness, blindness, rigidity, GI problems, breathing problems, and other manifestations. Essentially what’s happening is that this error in a specific enzyme called beta-galactosidase causes lysosomes to misfunction and not clear out cellular debris and this results in death of neurons. So, the neurons in the brain actually die and actually peripheral [neurons] as well. Unfortunately, the patients that we’re studying have symptom onset very early between six months and 24 months, depending on the patient. Survival might be as low as two years or up to 5 to 10 years with all of these concomitant issues in developmental milestones. It’s a really tragic disease that we’re trying to address. It manifests itself essentially in very severe symptoms and then a very shortened survival.

Daniel Levine: The earliest therapies for lysosomal storage disorders focused on enzyme replacement. Why is this not a very practical or desirable approach for conditions involving the brain?

Bruce Goldsmith: That’s a great question. I think there is absolutely a role for enzyme replacement in some diseases. One of the issues with treating the brain is that you have to deliver specifically into the brain on a consistent basis. The enzyme that we’re trying to replace may not be stable for very long. So, from an enzyme replacement approach, it would have to be a fairly constant delivery directly into the site of the disease or the major manifestation area of the disease, which is the central nervous system or brain. Unfortunately, the enzymes that we’re trying to replace don’t sufficiently cross the blood-brain barrier. That means direct delivery into the brain. Those two aspects, consistent therapeutic delivery and deliveries directly into the CNS, is not really practical on an ongoing basis. Gene therapy, the hope is, that this offers the benefit of a one-time administration with both the transduction of cells and then hopefully the stable expression of those enzymes. That’s why, while ERT is important, I think it’s limited in some indications.

Daniel Levine: Your GM1 program, like your other programs uses an AA vector. What makes this a desirable vector for CNS diseases?

Bruce Goldsmith: One is that AAV has shown promise in specifically transducing neurons and other cells. What we’ve shown, and others have shown, depending on the subtype of the AAV, you can basically get stable transduction and expression of the enzymes to a high enough level. Because of the delivery of the functional copy, in animal models you can correct the manifestations of the disease. AAV is a proven platform to do that. The other important thing is that we do not need to transduce every cell in the brain, nor do we need to transduce specific cells because this particular enzyme can be taken up by neighboring cells. If you put all of that package together, there’s a very compelling case for utilizing AAV to deliver this and the other programs we’re trying to advance. You’re absolutely right, there are other approaches that could be important, but AAV is kind of a proven approach to transduce into the CNS and deliver the gene of interest.

Daniel Levine: How is this particular therapy constructed and delivered?

Bruce Goldsmith: AAV is a virus, as you probably know. It’s non replication competent once it’s grown, meaning it can’t continue to reproduce. It doesn’t create any infection. It basically attaches to cells, delivers the gene of interest, and then no longer transduces others. This is using a mammalian cell, which is a specific cell called HEK 293 that are adherent, to basically grow and replicate to produce the AAV. It’s using a technique called a triple DNA plasma transient transfection, or to transduce those cells that are grown up in manufacturing, and then essentially those viruses are harvested and we’ve selected these AAV serotypes with high CNS tropism. As we’re developing this, and this is the great part of the collaboration with the University of Pennsylvania, all of this is optimized, not only the platform, the cells, each gene that we’re trying to deliver has to optimize the promoters and the codon, and the whole regulatory elements and whole gene itself. That is all done to optimize, to try a number of those, and then to move it forward into the full production that I just described.

Daniel Levine: Passage Bio is one of three companies working to develop a gene therapy for GM1. This is an ultra-rare condition. Why are we seeing competing therapies emerge for this condition, and does that have consequences for how a program is prioritized, funded, or decisions are made about its viability as it moves through development?

Bruce Goldsmith: Certainly a great question. The way we start with thinking about diseases that we would like to address, in general in pharma and biotech, is to think about how much we can impact in a differentiated way the outcomes of patients. The University of Pennsylvania and the founders looked at the other approaches in GM1, and I would extend that to all of our therapeutic areas, to make a determination that we believe we can create a differentiated approach. We first look at how other groups are addressing the populations and ask, can we make a difference? Then, can we prove or somehow suggest that there’s a pathway to show that the differentiation could be manifested. In terms of GM1, and I will extend that to Krabbe disease and frontotemporal dementia with a granular mutation, the way we think about this is, the genetic pathways are known, they are single monogenic diseases, animal models have demonstrated a strong response, and then we layer upon this how can we show a differentiated response? The two prongs are, is this disease amenable to therapy and can we differentiate? While we do see clusters of academia and companies pursuing certain disease areas, like SMA and retinal diseases, et cetera, we think that there’s an important differentiation in GM1. I will mention that when we talk to advocacy groups, they’re incredibly excited about the multiple approaches that may be having data in the next six to 24 months. It’s an exciting time. Having worked in rare diseases before, I think it’s really important to have the focus remain on the patients. We certainly think about the potential commercial opportunity and potential portfolio decisions, but we also focus on if we can make a difference for these patients. One of the things I’ll say is, having more groups in this field is really important for identifying patients, and that’s an concept and exciting time to be leading this program.

Daniel Levine: How does the approach Passage Bio is taking differ from what its competitors are doing?

Bruce Goldsmith: Sure. That actually is a perfect fit with what I was talking about for differentiation. Most of the difference comes down, in this field, to a choice of administration and a choice of vector. Can those lead to some point of differentiation? In terms of one of the competitors, they’re using an approach which is IV administration or systemic administration delivering throughout the body and addressing peripheral aspects of the disease for GM1. Also trying to see if there’s enough of the virus that’s being delivered that can cross the blood-brain barrier and correct the major manifestation of morbidity and mortality, which is the CNS. There are other differences as well. There’s difference with pre-existing antibodies, for example. If you’re administering systemically, you have to watch out for patients who might have an antibody to the specific AAV that you’re administering. There are differences in age groups that might be included and other aspects of outcome measures. As I said, one of the major areas of difference there is the IV route. Now, another group is using a similar route of administration, which is called delivery into the Inter Cisterna Magna or ICM injection. This other company is using a different vector. We believe that our dose is differentiated and our ability to potentially then transduce and deliver enough correction is possibly differentiated as well. There are differences with the number of patients and the type of patients that are being recruited. It really comes down to AAV vector dosing, route of administration, and then finally the patient populations that are being studied. All of this effort is doing one important thing which is identifying patients that are available for bringing into the clinical study and hopefully bringing cures forward.

Daniel Levine: What goes into the decision of how to best deliver a gene therapy for a CNS disorder? Are you taking different approaches within your program, or are you taking the same approach from condition to condition?

Bruce Goldsmith: ICM or Inter Cisterna Magna administration is currently being used in all three of our lead programs. We certainly may adopt other approaches in the future as appropriate for the disease, and also making sure that we’re optimizing delivery. ICM is delivered under anesthesia and it’s using modern neuroimaging that helps to improve the accuracy and delivery into the specific space we’re trying to get to in the CSF. Obviously, because it’s under anesthesia, it’s painless. Some people are worried about ICM being similar to a spinal tap and might be painful. ICM is currently being used in several clinical studies in both pediatric and adult populations. Jim and his group at Penn have shown that direct CNS delivery had some very important differences. One is that it results in a broad CNS distribution. There was lower overall dose delivered compared to IV systemic delivery. As I mentioned earlier, one company is moving forward with systemic delivery. There’s a reduced impact of neutralizing antibodies and there’s a single injection. What we’ve seen from other companies and other academic groups is, even as recently as to the 2021 ASGCT meeting, there are more presentations on ICM showing these kinds of benefits. We think, especially for CNS disease, it’s very important to think about delivering by ICM to improve the overall effectiveness of gene therapy.

Daniel Levine: You alluded to two of your other lead programs, one in Krabbe disease and the other in frontotemporal dementia. Are there different considerations in developing a gene therapy for an adult population rather than a pediatric population?

Bruce Goldsmith: There certainly are. As I mentioned, there are some similarities. So, we’re moving forward with ICM in both and we have very strong preclinical models in both. There absolutely are some differences. One aspect to consider is heterogeneity in the patient population. Taking GM1 or Krabbe as examples, with patients with very early onset there is a very severe outcome in terms of both survival as well as kind of the overall morbidity of the manifestations of the disease. Unfortunately, it’s a straight decline of these patients after the disease onset is detected. From a regulatory, clinical, and patient development perspective allows for a, maybe not straight forward, comparison that may be much more appropriate from a regulatory perspective, which is obviously very important. Regulatory approval is obviously critical to make these drugs widely available. In adult populations the timing of onset is typically more variable and the clinical end points are sometimes more variable as well. Now, for frontotemporal dementia, what we’ve tried to do is identify a patient population that we believe is as homogeneous as possible with some markers that suggest that the patient population may progress more rapidly. This is not, obviously, positive for the patients, but when we focus on clinical drug development, this is an important consideration, thinking about making the population as homogeneous as possible. It’s all about clinical end points strictly from a regulatory perspective. The second piece is that patient identification for adult conditions may be more difficult. This is not to diminish the difficulty in identification in children. There are, for example in Krabbe, initiatives to increase newborn screening and there’s some initiatives to hopefully get other conditions on the newborn screening panels. For adult indications, a diagnosis like FTD may be confused with other conditions such as Alzheimer’s and other dementia forms. So, correct diagnosis may happen late because there are not significant screens on the genetic basis for these conditions. Those are some of the differences. There’s one interesting misperception about the amount of drug delivery that’s needed. Adults do not have a significantly larger brain versus body mass. Gene therapy for CNS delivery is actually fairly amenable to adults versus children because adult brain mass doesn’t differ very much from say a 5 to a 10 year old. That’s generally why we have chosen the same route of administration for all of our lead programs. As I said, we may change that in the future based on data-driven needs.

Daniel Levine: In broad terms, is there something you can offer with regards to the clinical development timeline for these?

Bruce Goldsmith: Absolutely. Our lead program, which is infantile GM1 gangliosidosis, we’ve dosed our first patient and that study is open and enrolling. We have regulatory approvals in four different countries and we continue to open more sites. We expect to report the initial 30 day data, which is the biomarker of the enzyme we’re trying to replace and the safety, by the end of this year. For frontotemporal dementia, we do have regulatory approval in the U.S. and we’re moving forward outside the United States. In Krabbe disease we’re also approved in the U.S. and outside of the United States. Those studies will open in the second and third quarter of this year, and the 30 day data should be in the first half of next year. We are moving forward on the clinical stage. We have a pipeline behind that of additional programs that are moving forward as well.

Daniel Levine: Passage Bio is well connected within the financial community. One of your founders is out of Orbimed, another out of Frazier Healthcare Partners, and you’re out of Deerfield. I suspect Passage could have raised substantial capital through private equity. It decided to raise money through an initial public offering in 2020 as a preclinical stage company. Why is that, and what was the thinking?

Bruce Goldsmith: We had an interesting discussion just before I joined, but I was certainly part of the initial stages, about whether to go public or raise additional money. Gene therapy is an incredibly capital intensive endeavor. I think all pharmaceutical and biotechnology companies have long timeframes and do require a significant investment. So when we thought about it at the time, we had very strong backers, but we were also looking at the biotech market, which was incredibly robust, we saw a number of companies that were no longer in the clinical stage going public. Those ranged from platform technology companies to strictly drug development companies that were preclinical. We assessed the openness of the market using our board, our financial backers, and our advisors from the banking community. We thought that this was an appropriate time, given how strong the biotech market was and the reception of gene therapy and preclinical companies, especially because we had the support and the recognition from Jim Wilson’s contributions to building the foundation of the company and driving the pipeline forward. Interestingly, I think we were the last company to go public in early 2020 as the pandemic was hitting because our financials were still able to support going forward. We were able to take advantage of this just as the market was declining. I think we actually closed when the market was down 5 to 10 percent. We targeted $125 million, but raised a little over $240 million. Obviously, it was the right decision in retrospect, because we were able to raise such a robust amount. We’ve supplemented that with an additional financial raise this year. We’re very happy with our cash position. We closed the first quarter with about $430 million. This has given us enough money to move all these programs forward. I’ll note that one of the things that we said at the IPO was that we were going to file and get approved for three different drugs to move into the clinic. We did that all in the beginning of this year. So, we’ve delivered on the initial promise of Passage Bio, and we have enough cash for the operations at least for the next 24 months. We look forward to bringing not only GM1, FTD, and Krabbe forward, but additional programs as well.

Daniel Levine: Bruce Goldsmith, CEO of Passage Bio. Bruce, thanks so much for your time today,

Bruce Goldsmith: Danny, thanks very much for the opportunity to speak with you.

This interview has been lightly edited for clarity and readability.

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