Good morning, everyone. Thank you for attending Chardan's 8th Annual Genetic Medicine, and Cell Manufacturing Summit. My name is Daniil Gataulin. I'm one of the senior biotech analysts here at Chardan. I'm excited to introduce our next guest from Passage Bio. We have Dr. William Chou, Chief Executive Officer, and we have Eden Fucci, SVP, Technical Operations. Guys, welcome.
Thanks for having us.
Yep, thank you.
So, the format for this session is roughly a 20–25-minute fireside chat. If the members of the audience have any questions that you would like to ask during the session, feel free to type those into the question box underneath the video player, and we will do our best to ask them on your behalf. With that, we'll go ahead and get started. So first, can you please provide a few minutes' overview of Passage Bio for those audience members who are new to the story?
Sure. I'm happy to take that one. I'm gonna share a couple of slides here. Passage Bio is a clinical-stage genetic medicines company. We are focused on neurodegenerative disease. Our lead program is called PBFT02. It is an AAV1 one-time gene therapy. The first indication that we are in the clinic for is frontotemporal dementia with the granulin mutation. These patients, and there are about 18,000 of them across the U.S. and Europe, these patients have a deficiency in the protein progranulin, and our AAV1 replaces progranulin. This program, we believe, is quite differentiated in the market, and the reason we believe it's differentiated is because of the very high levels of progranulin that we've been able to achieve in the clinic. This is data that we shared in December from our first three patients.
The y-axis of CSF progranulin normal is about 3-8, and you can see all of our patients who we've treated so far have consistently had very high levels of progranulin. There's several other competitors in this space. All of them in the clinic have produced levels in about this gray area. And so we've been able to surpass that with all of our patients. And because of this strong potential of this program, we're now gonna be exploring it in other indications where we believe high progranulin can help. Those indications are FTD with the C9ORF72 mutation, sporadic ALS, and also Alzheimer's disease, particularly Alzheimer's patients who have a single nucleotide polymorphism in the GRN gene that causes them to have low levels of progranulin.
We have a strong cash position with runway out into the Q4 of 2025 that will allow us to see more of this strong clinical data. And I'm gonna let Eden talk about our in-house manufacturing capabilities.
Thanks. Excellent. Thank you. Thank you, William. So, yeah, let's, you know, that that was a great overview. We'd definitely would like to dive in into the manufacturing capabilities, now. And, Eden, if you could talk about the, you know, the CMC capabilities, manufacturing strategies for a company, and maybe mention some of the ways that your approach differs from other gene therapy companies.
Yeah, sure. We have a hybrid manufacturing and CMC model, which leverages both internal and external capabilities that can really move and adapt in coordination with our clinical development plans and overall company strategy. You know, if I was looking at what differentiates us, I would say the speed at which we can make decisions and execute from a CMC perspective is really not typical for an early-stage clinical gene therapy company. You know, to that end, our manufacturing strategy has been to utilize flexible and scalable platform technologies to enable the AAV production of multiple serotypes, multiple gene constructs, using a generally accepted platform from a regulatory point of view. We've also developed long-lasting external partnerships with our CMOs, and they give us the flexibility to increase our capacity as we grow and advance the pipeline.
We've also established an end-to-end global supply chain with the ability to manufacture, release, and distribute clinical trial materials that meet global health authority standards. Then lastly, we have internal CMC capabilities and scientific talent, which allows us to control the know-how. On top of that, we also have a very strong internal MS&T team that supports our external manufacturing. We have a very strong internal regulatory group with global gene therapy experience. Then lastly, we have GMP expertise that spans all the way from plasmid manufacturing to delivering the gene therapy to our patients.
And, let me.
Yeah.
Let me just say, so we don't do our own GMP manufacturing, right? We, we have CDMOs that do our GMP. But because we have the in-house capabilities, we can problem-solve and turn things around so much faster. I, this is my third gene therapy company that I've been a part of. There's always small things that come up. Nobody knows about them. It's something that's only internal. Our ability to turn around scientific studies fast is unlike anything, and I've been in very large companies and very small companies. It is truly differentiated, and it has already made a difference for this program.
Got it. Excellent. So you mentioned that, you know, the hybrid model. So, in with respect to CMC, how do you approach decisions with regards to which CMC capabilities are important to have in-house versus the ones it makes sense for your partners to work on?
Yeah, sure. So the way we approach determining kind of what CMC capabilities we decided to internalize versus ex-outsource comes down to a few key considerations. You know, and first, and most importantly, it's what are the capabilities that we believed are critical to have full control over to ensure our success? And as Will mentioned, we decided to internalize all of the CMC technical capabilities. And I'd like to mention that, you know, based on where we're at today as a company, we've really right-sized that group to maintain operational efficiency while also being able to achieve all of our technical objectives. Secondly, as also mentioned, all of our GMP manufacturing is outsourced. So, you know, when we look at capabilities, if they're readily available, we're gonna go out and just get those, and that's CMC manufacturing.
And then thirdly, you know, when we look across the portfolio, it's really what's the desired end state, and how do we get there? You know, and this really drives the specifics around when and how we invest over time. You know, and so we decided very early on in the company lifecycle to internalize all of those core CMC technical functions. And that includes analytical and process development, QC testing, while again, outsourcing all of the GMP manufacturing. And the reason why we decided to invest early to internalize those capabilities is because it takes substantial time to build out organizational maturity and scientific expertise specific to our product to then reach that high level of performance to then tackle complex problems and development goals such as developing cell-based potency methods or evaluating new platform technologies for manufacturing. And then that's where we're at today.
Got it. Okay. So, you guys have several partnerships that are ongoing. The first one I wanted to talk about is the partnership with Penn, Penn GTP. How does this play into CMC for the company's current development stage and, you know, overall bigger focus?
Yeah. I mean, we continue to have a very strong collaboration with Penn GTP and the Vector Core group. And this relationship gives us access to novel serotypes, vectors for gene transfer and gene regulation, vector delivery technologies, the new analytics, and new manufacturing technologies. And for any program that's developed out of Penn GTP, they're responsible for all of the preclinical and non-clinical development up through and including the initial IND submissions. And then on the CMC side, that handoff between us and GTP occurs with the manufacturing of the first GMP clinical lot. And then we're responsible for any CMC development beyond that. And it's also worth noting that throughout product development, we can consult with them on any topic on an as-needed basis.
Got it. Makes sense. And moving on maybe with your partnership with Catalent, can you expand how that has worked, you know, so far and how that aligns with your goals?
Yeah, certainly. So as we mentioned here last year, we took steps over a year ago with Catalent to better align our relationship with our current business needs and pipeline. To that end, we modified our agreement to eliminate the annual minimum contract manufacturing commitments while still maintaining a strong relationship, and importantly, that includes preferred pricing with Catalent to manufacture our products. You know, and I can say we partnered very closely with Catalent to support our manufacturing needs over the last four years, and we found them to be a very reliable partner.
Okay. Got it. So, more broadly, I guess, we've seen some CDMO acquisitions in the space announced recently. To what extent could these dynamics in the CDMO space impact your program? And, maybe to take it one step further, what can you do as a company to minimize chances of issues at partner sites?
Sure. So that the acquisition of Catalent by Novo Holdings was largely driven by the market demand for semaglutide. You know, and while that acquisition at some point could impact Catalent's cell and gene therapy business unit, initial indications are that there's no immediate plans to change the cell and gene therapy operations in a way that would impact our access to capacity either in the near term or long term. When you think about ways of de-risking issues at a partner site, you know, first you need to recognize there are some factors and risks that you can't really predict or influence such as an acquisition. In this case, you know, you need to be ready to quickly evaluate the situation when it arises and react according to what's best for your program and company.
But to minimize the impact of foreseeable or known risks, from my experience, it comes down to a few factors. You know, first, you know, you're gonna perform due diligence up front, which is standard. But remember that due diligence is something that you should be doing all the time throughout the course of your relationship. And then secondly, remember to be hands-on in your approach to managing projects and manufacturing campaigns. And it's very important to not just let them go off and run on their own. And then lastly, you know, cultivating open lines of communication up and down the organization.
You know, when you treat a CMO as a partner and you're willing to come to the table, provide support, and problem-solve as a team, you will not only identify and mitigate those potential risks before they materialize, you're also gonna more effectively work through issues together as they present themselves.
Gotcha. Okay. I guess to move on, I guess, more specifically to your programs and, you know, developing them further, assuming that you continue to see the encouraging data for FTD-GRN, what is your strategy about scaling up for potential commercial stages?
Yeah. Well, in order to be ready to supply a larger pivotal trial and kinda ultimately support commercial demand, we've already made initial investments into developing a commercially viable manufacturing process. You know, and to this end, we're really platform-agnostic. You know, our goal is to develop a robust manufacturing process with suitable productivity and yields that balances the cost of goods versus manufacturing burden. You know, based on our experience today, you know, a suspension or an adherent process could be commercially viable for FTD- GRN.
Yeah. Yeah. We are so right now, you know, we've publicly shared we are the process that we got from Penn is an adherent process in iCELLis. And so the process development that Eden talked about before, we really have two tracks on this. We can improve the productivity of our iCELLis. We think that is viable. But we also can move to suspension. And so we haven't made a call yet of which way we're gonna go. But like Eden said, we've been doing work on both ways of, improving our productivity.
Got it. Makes sense. I guess to take it one step further, so I think you mentioned in your introductory statements that PBFT02 could be applicable for other diseases, potentially with much larger opportunities and much larger target populations. Do you expect, you know, your current partnerships and manufacturing processes that are set up to be able to address these larger populations, or what would be your scale-up strategy here?
So first, let me tell you a little bit about some of the other indications that we're going into. I'm gonna share my screen here, 'cause I referenced them before. So I think it's first important to understand why are we going into these other indications. So the reason is because these indications share a cellular pathology. It's called TDP43 pathology. TDP43 is a protein that is usually in the nucleus of a cell. And with this pathology, it mislocalizes to the cytoplasm, causes inclusion bodies that cause neurodegeneration. So FTD- GRN, all patients have TDP43. FTD with the C9ORF72 mutation, also all patients have TDP43 pathology. And 95% of ALS patients, so all the sporadic ALS patients, also have TDP43 pathology. And what we've seen is that increasing progranulin to levels higher than is seen in normal physiology can ameliorate TDP43 pathology in preclinical models.
So these are just a couple of the preclinical models. So on the left is a knockout mouse, and you can see the Y-axis on the far left is human progranulin levels in both the wild type and the knockout mouse. If you give it an AAV that increases progranulin, you can increase progranulin levels. Importantly, in the chart second to the left, you can see TDP43 pathology is the Y-axis. And this large yellow bar, this is the knockout mouse with very large TDP43 pathology. Then that knockout mouse, given an AAV that encodes for progranulin, can have significantly reduced TDP43 pathology. Another murine model on the right shows something similar. So this is relative insoluble TDP43 pathology on the Y-axis. You see a non-transgenic mouse as an index of level one. A TDP43 mouse has twice that amount of TDP43.
And this cross mouse that is a TDP43 mouse crossed with a mouse that overexpresses progranulin, that mouse has reduced levels almost back to normal in terms of TDP43 pathology. And that cross mouse with the high progranulin has a prolonged survival. So we have a pretty fair amount of preclinical evidence that shows that raising progranulin can ameliorate TDP43. And this is why we are attacking these new indications with PBFT02. And it's also why we're moving towards the better productivity manufacturing. So for some of these larger indications such as ALS or such as, in particular, Alzheimer's disease with that SNP in the granulin gene, you're gonna need a more efficient process. And that's why we are moving and experimenting with moving towards a suspension-based process. I'm gonna stop sharing that.
Got it. Got it. Thank you. Very helpful overview here. Okay. So, I wanted to move on and talk a little bit more about your specific team in operations and manufacturing. So can you tell us a little bit more about what the team is, how many people you have there, and what have the challenges been in building out the talented group?
Sure. We have a core CMC and technical team, as we've spoken about previously. Again, that includes analytical development, process development, QC, and then all the supporting staff to make the internal aspects of our organization work, also supporting external aspects of what we do. We also have within the group quality assurance. These all, these functions all support kind of the end-to-end supply chain and delivering the vectors to the patients. I can say, you know, we've been very successful in attracting and retaining highly specialized and experienced talent in this space. The fact is, we're actively doing innovative, exciting science, and our company vision resonates with our employees.
You know, we have a team of highly motivated and capable scientists and staff who come to work every day committed to making impact because they believe that we're gonna be successful in our endeavor to treat severe diseases such as FTD- GRN.
Got it. And in terms of the process, how are you implementing automation into your workflow? And how might you further leverage automation or maybe even AI technology to reach your goals and potentially reduce costs?
Yeah. We utilize several automation platforms for data analysis, very standard applications. And we are exploring AI technologies. But we have not yet implemented any AI systems to date.
Got it. Okay. And a couple more general questions too, you know, to gain your insight. In terms of GT, gene therapy field more broadly, it's changed considerably over the last few years, made some significant progress. What do you see as the most important advancement overall, in the gene therapy field and maybe specifically as it relates to manufacturing?
Yeah. I see this really in two main areas. You know, the first is over the last number of years, there have been significant advancements in the development of more efficient, robust, and scalable manufacturing processes. And this spans from academia to industry. And then secondly, you know, we're seeing regulatory bodies become more informed. You know, and this is highlighted by the number of recent gene therapy product approvals. And really, the FDA has shown a willingness to work with academia and industry to discuss and establish standard processes and practices through engaging at various conferences, workshops, and town halls.
Got it. Okay. And so also last year, the FDA has transitioned from the Office of Tissues and Advanced Therapies, or OTAT, to the Office of Therapeutic Products, with OTP now including offices focused on CMC for gene and cell therapies. How do you think or how do you expect this reorganization to impact your program development and program development more broadly?
Yeah. I mean, first off, we welcome the recent changes implemented by the FDA with OTP. You know, this change within the agency really speaks to the recognition of the volume of cell and gene therapies advancing the commercialization, you know, and the larger number of active programs in preclinical and clinical stages of development and their commitment to really be prepared to support that workload. You know, as I've mentioned a little bit, you know, we also appreciate the OTAT and OTP town halls held over the past approximately two years, which includes many topics on CMC related to cell and gene therapies. You know, and we applaud their efforts to communicate best practices and lessons learned to the wider development community.
Then when you boil that down to the program level within our company, you know, those regulatory interactions and regulatory reviews are paramount to our drug development and especially for these complex therapies. So over time, we expect these changes will result in an increased number of well-informed, experienced cell and gene therapy staff and reviewers at the agency, which should ultimately lead to more informative interactions and better partnering with the agency throughout the product development lifecycle.
Got it. Thanks. Makes sense. I have a couple more questions. I want to remind the audience if you have any questions that you'd like to ask, please feel free to type them into the box, into the text box under the video player. So, what other question that I have is, regarding the recent financing climate. Would you say it impacted your manufacturing priorities? And, more broadly, what impact do you think that financing climate has had on gene therapy manufacturing?
Sure. I can take that one. So first, I'll say it does seem like the financing climate has changed and that the last two years have been rough, but we do feel that it's changing right now. I think the last two years have made us approach manufacturing differently in general. So the main thing is you just can't get too far out in front of your skis in terms of investment. So we need to make sure that we are investing in CMC at a level that is appropriate for where we are in the clinic. I said before, this is my third gene therapy company. There is not a single leader of a CMC organization that ever wants the reason that we are slow on a program is because of me, because we weren't ahead of the game. And I understand that.
We understand that. We also need to balance there's a certain amount of funding, and we need to be appropriate with where we spend. I think having that partnership, between the business and the technical team on where we are, what's the appropriate amount of risk we can take, what's the appropriate amount of investment we can take, we have to be 100% aligned with our objectives.
Got it. Okay. One last question from me. What do you think investors are missing or not appreciating about Passage Bio story ?
Yeah. I think the biggest thing that investors have been missing is how differentiated our program is in this very attractive space. So, we do have a lot of competition in FTD- GRN, but I think competition validates that raising progranulin is actually gonna help these patients. And I think the closer you look at our data, the more you can see that it's differentiated. I will say that one thing that investors are not missing is we're very early on in our phase 1/2 study. I shared with you some data. It had three patients at 30 days, one patient at six months. And we've got a good tox profile in two patients who we've treated so far. So it's very early on. So what they may be missing is what we haven't shared with them yet, which is more data from our study.
And when we share more, I think people are gonna be pleased with what they see.
Got it. Makes sense. All right. Well, this brings us to the end of our session. Again, Eden, William, thank you very much for joining us. We appreciate your time. Thank you.
Thanks. Thanks a lot. Thanks for having us.