Thank you for holding. Good morning, and welcome to the Passage Bio Second Quarter 2021 Financial and Operating Results Conference Call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up for your questions. Please be advised this call is being recorded at the company's request.

At this time, I'd like to turn the call over to Stuart Henderson, Vice President of Investor Relations and Strategic Finance. Stuart, please begin..

[Technical Difficulty] outlines the topics we plan to discuss today. This release is available on the Passage Bio website at investors.passagebio.com under the Press Releases and statement section.

On today's call, Bruce Goldsmith, President and Chief Executive Officer will review our second quarter 2021 financial results and discuss recent business highlights. Eliseo Salinas, our Chief R&D Officer will review our key clinical updates and Jill Quigley, our Chief Operating Officer will also be available for the Q&A portion of the call.

Before we begin, please note that today's call may include a number of forward-looking statements including, but not limited to comments on, our expectations about timing and execution of anticipated milestones, including the initiation of clinical trials and the availability of clinical data from such trials; our expectations about our collaborators and partners' ability to execute key initiatives; the ability of our lead product candidates to treat the respective target CNS disorder; manufacturing plans and strategies, trends with respect to financial performance and cash flows; the company's ability to fund research and development programs; impacts of the COVID-19 pandemic on the company's operations; and its ability to manage costs along with uses of cash and other matters.

These forward-looking statements are based on assumptions that are subject to risks and uncertainties that could cause the company's actual results to differ significantly from those suggested by these statements. Given these risks and uncertainties, you should not place undue reliance on these forward-looking statements.

Please refer to the company's filings with the SEC for information concerning risk factors that could cause its actual results to differ materially from expectations, including any forward-looking statements made on this call.

Except as required by law, the company disclaims any obligation to publicly update or revise any forward-looking statements to account for or reflect events or circumstances that occur after this call. It is now my pleasure to pass the call over to CEO, Bruce Goldsmith.

Bruce?.

Thanks, Stuart. And thank you all for joining us this morning. I will begin by centering my remarks around our four strategic pillars that we believe differentiate our company. These pillars are our strong partnership with Penn's Gene Therapy Program or GTP, which is led by our Chief Scientific Advisor, Dr. Jim Wilson.

Our broad and robust pipeline, our integrated manufacturing supply chain and our solid corporate foundation, which includes a highly experienced team and a strong cash position.

These pillars provide the framework for where and how we continue to focus our efforts as we develop transformative medicines for patients with CNS disorders, and establish our company as a leader in genetic medicines.

For our partnership and pipeline, I'm excited to report that we have amended our existing strategic collaboration and license agreement with GTP to broaden the scope to include large CNS diseases. We view this as a significant inflection point in the company's evolution.

We also believe that this continues to strengthen our positive and productive collaboration with Jim Wilson, his dedicated expert team and the University of Pennsylvania.

Under the expansion into larger populations, the new exploratory research programs, which will be guided collaboratively by GTP and Passage Bio will support the identification and evaluation of biological targets and generate preclinical proof-of-concept data for these targets.

We'll be able to evaluate several targets and technologies in parallel to enable quick decision making. Once a target has reached proof-of-concept, we may then exercise an option to advance the development of a new genetic medicine for the underlying condition, but are under no obligation to exercise that option.

We're initiating this effort focusing on Alzheimer's disease and Temporal Lobe Epilepsy with the opportunity to expand to additional large CNS indications upon mutual agreement.

These research programs and our ability to select candidates across the wide range of CNS indications beyond rare monogenic conditions will bolster our already robust pipeline and provide greater optionality for program advancement. In our agreement with GTP, we have the option to license 17 total programs.

So far, we have exercised seven of these options in rare monogenic diseases, and we have 10 remaining. In addition to the expansion into large indications, we maintain our current focus on rare monogenic disorders, and may exercise additional options in this area as well.

When exercising our remaining 10 options, we'll continue to do so in a data driven manner, factoring in patient need, product differentiation and the ability to de risk clinical development programs.

For our manufacturing capabilities, I'm happy to report that we have met our goal to open our new Gene Therapy Research and Development Lab called Princeton West in Hopewell, New Jersey.

With this facility, we have enhanced our analytical development, clinical product testing and assay validation capabilities, state-of-the-art analytics are essential for optimizing vector production and appropriately characterizing our gene therapy products as we advance clinical development and eventually moved to commercial scale production.

Our strength across these first three pillars partnership, pipeline and manufacturing is underpinned by our solid corporate foundation, including the world-class leaders we have successfully recruited.

We're proud of the caliber of talent we have attracted to Passage Bio, as illustrated in our recent announcement of new executive appointments, Maria Törnsén joins us as Chief Commercial Officer and is responsible for leading and building out the company's commercial organization and strategy including determining product positioning and path to commercialization.

Simona King joins us later this month as Chief Financial Officer and will be responsible for finance, accounting, tax, treasury, Investor Relations functions, and information technology. Mark Forman joins us as Chief Medical Officer and is responsible for leading the company's translational and clinical development efforts.

We also have a strong Board of Directors supporting and guiding our company. The recent addition of Dr. Derrell Porter, who brings tremendous experience in corporate strategy, product development and commercialization is an example of the kind of talent and expertise we're able to call upon at the board level.

As we build our company around our four strategic pillars, we're hyper focused on the strong execution of our three lead clinical development programs in rare CNS disorders for which there are limited or no therapeutic options. We remain on track despite ongoing delays due to COVID-19 to deliver on several important clinical milestones.

These include dosing the first patients in our upliFT-D study for the treatment of Frontotemporal dementia with granular mutations, and GALC study for the treatment of Krabbe Disease in the third quarter of 2021.

Reporting initial safety and 30 day biomarker data for the first cohort of patients in our Imagine-1 trial for the treatment of Infantile GM1 in the fourth quarter of 2021, and reporting initial safety and 30 day biomarker data for the first cohort of patients in our upliFT-D and GALC trials in the first half of 2022.

Our momentum and execution are supported by a strong balance sheet with $408 million in cash, cash equivalents and marketable securities at quarter end. I'll now turn it over to our Chief R&D Officer, Eliseo Salinas who will discuss our clinical programs in more detail..

Thank you, Bruce. I'll begin with some overarching comments regarding site initiation and patient identification for our three lead programs. First, we point out that extinguishing characteristic of our programs, in that they are all multisite and international in scope, so that we can be where the patients are.

In total, we have a global network of multiple clinic sites across nine countries and three continents. Despite ongoing challenges due to COVID-19, we have made significant headway and expect to continue opening sites in the coming weeks.

We were also pleased with our progress through a variety of initiatives identifying patients for our clinical programs.

These initiatives include partnerships with service companies offering genetic testing and counseling for the three disease areas targeted by our lead programs and collaborations with a broad network of patient advocacy and physician groups. Now to our specific lead programs.

As many of you know, we announced in April 2021, that we dosed the first patient in our Imagine-1 trial for the lead program, PBGM01 for the treatment of patients with GM1 gangliosidosis.

The global Phase I/II trial is focused on the infantile form of the disease, which is the most severe form with a very rapid disease course and no current treatment options beyond supportive care. I am pleased to report that the Imagine-1 trial is progressing as planned.

We have completed the initiation of additional clinical sites and expect to activate them to begin enrolment in the coming weeks in those sites.

As we have discussed previously, Imagine-1 is an open label study that will enroll four distinct cohorts divided by age and those levels, with the first cohort being composed of late onset infantile patients receiving the initial dose level of PBGM01.

The primary goal of the cohort is to assess safety and tolerability to allow for dose escalation and progress into our early infantile cohorts.

We're also measuring beta gallons on our PBT levels in the CSF and serum, we look forward to reporting initial safety data and 30 day biomarker from Cohort One of the study in the fourth quarter of this year and expanding our GM1 trial globally. Turning to our Global Krabbe program.

As we discussed in our prior calls, we have received regulatory clearance to initiate our Global Phase I/II clinical trial called GALC from the FDA, the U.K.'s MHRA and Health Canada. We continue to advance site initiation processes of multiple sites and expect to dose the first patient in the third quarter.

As a reminder, GALC's open label dose escalation study of PBKR03 in patient with early infantile Krabbe disease. Similar to our Imagine-1 trial, we will first evaluate an initial dose of PBKR03 in late onset patients, and then progress into early onset and higher dose cohorts.

Those ascending dose cohorts will be followed by a confirmatory expansion cohort that will include both age groups. The primary goal of this study is to assess the safety of PBKR03 in patients with early infantile Krabbe disease with the secondary goal of assessing GALC activity in both CSF and serum.

Next, let's discuss our third global clinical trial program for PBFT02 for the treatment of frontotemporal dementia with granulin mutations or FTD-GRN. FTD is one of the more common causes of early onset dementia, causing impairment in behavior, language and executive function.

And of course at similar frequency to Alzheimer's disease in patient younger than 65 years old. The rapid progression of FTD resulting an average survival of eight years after onset of symptoms. We're specifically focused on FTD-GRN where the disease occurs because of mutations in the gene causing a deficiency of programming.

It is estimated that about 5% to 10% of FTD is caused by a GRN mutation. Our global Phase I/II clinical trial upliFT-D is an open label dose escalation study of PBFT02 in FTD-GRN patients, and we have received regulatory authorization to ensure clinical trials in the United States and Canada.

Additionally, PBFT02 received orphan designation for the treatment of FTD-GRN from the European Commission in July 2021. The designation provides Passage Bio with certain potential benefits, including clinical protocol assistance, reduce regulatory fees, research grants and up to 10 years of market exclusivity following regulatory approval.

We're advancing site initiation processes of multiple sites, and we remain on track to dose the first patient in the third quarter.

Like our other two programs, our two key goals for the Phase I/II study are to assess the safety of PBFT02 and to evaluate its impact on biomarkers, specifically potential increases in for granulin levels in the CSF and serum.

As we look ahead to the near-term data readouts, we're incredibly excited about their potential to shape not only the future of the patients we serve, but the future of gene therapy and the CNS space.

I will end my comments by saying it is an honor to work with the caregivers, physicians, and other healthcare workers in the GM1 Krabbe Disease and FTD communities. We're grateful for their ongoing support of our clinical programs. With that, I'll now turn the call over to Bruce to review our financials..

Thank you, Eliseo. As I shared earlier, Simona King, our new CFO is joining us later this month, and she will be present for our next quarterly earnings report. For this quarterly report, I will provide the financial update. First, I want to reiterate our strong cash position.

As we reported in our press release this morning, we ended the quarter with cash, cash equivalents and marketable securities of approximately $408 million as compared to $305 million as of December 31 2020. We expect these cash, cash equivalents and marketable securities to fund our operations for at least the next 24 months.

R&D expenses were $33.1 million for the quarter ended June 30, compared to $19.9 million for the same quarter in 2020.

The increase was primarily due to an increase of $13.9 million in clinical manufacturing costs, a $1.7 million increase in clinical development costs, a $4.8 million increase in personnel related and share based compensation expense, due to an increase in an employee headcount in the R&D function and a $0.4 million increase in other research costs.

These increases were partially offset by a $7.6 million decrease in research and development costs associated with the PENN agreement, which relates to additional costs incurred in the three months ended June 30 2020 for preclinical work performed in preparation for IND filings for our lead programs and certain pass through clinical manufacturing costs.

G&A expenses were $15.4 million for the quarter ended June 30, compared to $7.4 million for the same quarter in 2020. The increase was primarily due to a $6.0 million increase in personnel related and share based compensation expense due to increases in employee headcount.

Our professional fees and facility costs also increased by $2 million as we expanded our operations to support our research and development efforts. Net loss was $48.4 million for the second quarter of 2021, compared to $27.2 million in the same quarter of 2020.

Net loss per basic and diluted shares was $0.90 in the second quarter of 2021, compared to a $0.60 net loss per basic and diluted share in the second quarter of 2020.

With that, I will end my remarks by underscoring that our successes to date are a direct result of the tireless effort put forth by our strong team at Passage Bio, who guided by our strategic pillars are working hard every day to deliver transformative therapies for patients with CNS disorders.

We're especially excited about our expanded strategic agreement in collaboration with GTP and the opportunity it presents to address a broader population of patients with both rare and large CNS disorders.

We specifically look forward to initiating discovery research for Alzheimer's disease and Temporal Lobe Epilepsy, two diseases that affect large adult patient populations and where the need for new treatment options is significant. We also want to emphasize that we're maintaining our focus on rare monogenic CNS disorders.

As Eliseo described, our clinical team, manufacturing team and patient engagement teams are all extremely focused on our studies for patients with GM1, Krabbe Disease and FTD. We are committed to advancing our early stage programs and continue to evaluate other potential options in the rare monogenic CNS space.

As a reminder, our key near-term milestones are one to dose the first patients in our upliFT-D and GALC trials in the third quarter of this year, two to report initial safety and 30 day biomarker data for Cohort One of the Imagine-1 study in the fourth quarter of this year, and three to report initial safety and 30 day biomarker data from our upliFT-D and GALC trials in the first half of 2022.

We're proud of the progress we have made in building our company and advancing our pipeline as we establish ourselves as a leader in genetic medicines. With that, I will open it up for questions.

Operator?.

Thank you. [Operator Instructions] Bruce Goldsmith will provide brief remarks prior to taking the first question..

Yes, thank you, operator. And thank you all for joining us this morning. Before moving to questions, I did want to take this opportunity to say a few words about Tachi Yamada, who as you likely know has by now from all the global outpouring passed away suddenly on August 3.

And as I think you also know, Tachi co-founded Passage Bio along with Steve Squinto and Jim Wilson. And I wanted to talk a few minutes about the impact that he's had. So this is obviously all very fresh for us and very devastating. But I did want to say a few words. Tachi to me was an incredible inspirational leader.

And we knew him as a Founder, and Chairman and mentor. But of course, he had a massive impact across the industry and the globe.

And it's really demonstrated by what we're seeing in terms of all the press releases and comments honoring his contributions, in speaking with both our management team and the board late yesterday, and today, I can tell you that we're all very deeply shocked and incredibly saddened and we're all extremely grateful for the opportunity to have both known and worked with Tachi.

While having such a massive impact for patients innovation across the globe, for Passage Bio, he helps obviously set the strategy and meant in motion with Jim and Steve, and guide the strategy, but also as a partner, work to think about and help the operational build out and set the strong foundation of the company, including the announcements that we made today.

And they were certainly very much with Tachi's guidance and wisdom in certain terms of pursuing the various opportunities we have. And we really do remain committed to Passage Bio's mission for patients and we will also constantly think about Tachi's guidance and insights as we continue.

The company has an incredibly strong foundation with a deep board, who I talked to as I said, over the last few days, we've made management additions. And as I've talked to everybody, we just are unified in our both grief and commitment to the company. And do so I think partially or totally and with Tachi's commitment to patients in mind.

And finally, I do want to mention that we absolutely have Tachi's family in our thoughts. We often talked about his family. And we really do hope that the memory of Tachi gives comfort to them today and over time. With that, I will now turn the call back over to the operator for questions..

Thank you. And our first question comes from the line of Tessa Romero with JPMorgan. Your line is open. Please go ahead..

Hi, all. Good morning and thanks very much for taking my question. A clarifying question for me, you've noted that you've go to the first patient in the Phase I/II in infantile GM1 study in April.

Have you dosed the second patient? And if not, have you identified the patient that will be dosed? And then can you just remind us where you're specifically on site activation? How many sites do you have up in live now? And what is that target number that you're hoping to get to? Thanks so much..

Sure, I'll make a few comments and then also turn it over to Eliseo. Thanks for the question. So we did announce the first patient doses as companies often do, we have not got into any more details about the other patients that we hope to dose or really details of the forward-looking perspective on exactly when the other sites will come on.

I do note and reemphasize what Eliseo said is that we hope across all of our studies and plan to open additional sites in the coming weeks for GM1, what we're really focusing on is that we will, we have reiterated our guidance on reporting date out from the first cohort, which is just two patients for safety and 30 day biomarker data by the end of the year.

And I think your other questions were about kind of how many sites were moving forward.

And kind of the overall overarching strategy around that in terms of the activation over time and Eliseo, do you want to add any comments?.

Yes, one important consideration is that all the trials we're doing, which is typical for gene and cell therapy are dose escalation studies where you dose one patient at a time. In our case, what dosing one patient at a time with the space in patients with at least 60 days between the patient and the next one.

That sequential enrolment as is the term is a sequential opening of slides. I'll get back to that in a second.

An important aspect of our program that sometimes doesn't get recognized or identified is that it's a vast program, high number of countries, high number of continents, high number of sites, you could technically do these studies with just one site. But we elect to do to take a different strategy to be with the patients are.

And it's in the public domain in clinicaltrial.gov that we plan to open many sites. But it would be futile and ineffective to open all those sites at the same time because site number eight would have to wait 16 months to enroll their first patient, so you would lose momentum.

So our strategy of opening and activating the site is also sequential, we focus on those sites that are ready to go, have a patient identified and could start immediately. And then we move to the second and the third deal of sites. We have initiated sites in the last few weeks, those sites will become active in the next few weeks.

And overall, we're very happy with the progress so far..

Thanks very much. That was helpful. And so sorry to hear about Tachi's passing..

Thank you, Tessa..

Thank you. And our next question comes from the line of Neena Bitritto-Garg with Citi. Your line is open. Please go ahead..

Hey guys, thanks for taking the question. So I guess kind of a similar question. But in regards to the other two studies, I think last quarter, you noted that that there was potential to get the first patient in the FTD study, dosed maybe by the end of the second quarter or early third quarter.

So I guess is there, should we perceive this as any sort of a delay per se? Or I guess, yes, if you can kind of help characterize the site activation progress you've made there and whether or not you've kind of had any unexpected delays, kind of on getting that study up and running? Thanks..

Thanks, Neena. The way I would characterize this is that, there are idiosyncratic changes and differences in every site that we're trying to interact with.

And a lot of them I mentioned before, were IRB timing, as well as seemingly simple negotiations that are getting hung up because of either lack of staff or backlogs of the study initiations, such as other studies kind of moving ahead of us, because they just simply filed earlier.

So when we said, when we updated the guidance, we were kind of saying either second quarter or third quarter, because that's what we anticipated based on the progress we were making. And as Eliseo said, we're now having site initiation activities and part of it was also just getting dose scheduled, et cetera.

And now that those have been either scheduled or completed, we have better and better insights along the way in terms of when the activation of those sites, which is the second step, and then obviously enrollment of the patients is the third step. So I don't think it was a specific, any one specific issue.

It's just basically the environment we're living in right now and trying to move the programs forward..

Got you, perfect. Thank you. That's helpful..

Thank you, and our next question comes from the line of Yaron Werber with Cowen. Your line is open. Please go ahead..

Hi, good morning. This is Brendan on for Yaron. Congrats to the team in the progress and our condolences to everyone on the news from yesterday.

Just a quick one from us, actually looking ahead to the upcoming programs in MLD, ALS, Charcot-Marie, actually just looking to see, when you think we might get to see some more preclinical or some new preclinical data from those, maybe what's your sense of timing and cadences for moving them forward relative to each other? And actually, really just on MLD there, kind of just hoping to get your thoughts on your approach there versus others who seem to have pretty solid efficacy with like ex-vivo antiviral approach and kind of what advantages you think you might have, specifically in that space? Thanks very much..

Sure. I'll make a few comments and then turn it over to Eliseo as well. So one of the things that we've been, I think very upfront about is that when data is available, and presented by the group that's moved as forward is obviously, Jim Wilson in the Gene Therapy Program, we're happy to share that.

And the programs continue to move forward in his group, but we don't have any specific updates. Obviously, there was a really nice update on the MLD model back at a GTP earlier this year. And should we share that, and we will do so in the future.

And I think the way we're approaching this and certainly the exploratory programs that we just announced today in Alzheimer's and TLA, is that as the programs mature enough to give more detailed insights, we will certainly do so. And I don't think we're in a position to do that at this point.

But each of these programs, the way we're thinking about this is points of differentiation.

And so maybe I'll turn over to Eliseo as to talk about how we think about MLD and to your point about the cell therapy, and potential differentiation?.

Yes, definitely. So we started this program with the end in sight. So at the end of the day, how our construct could, what our construct could add to the existing or potentially existing armamentarium at that time, and of course, we follow with interest, and I will say even excitement, the development at around MLD.

And of course, we have that in mind, when we think about the program and the potential benefits of our gene therapy approach. I would say two things. Well, it's a very exciting development, an autologous stem cell transplantation is a type of approach that has its benefits and risks.

And it's a balance, the second is that, as you know the data on this MLD is very strong in certain papers in populations at certain ages, and with certain degree of symptoms, and less so in others. So overall, we think that there is still a high medical need.

And of course, we're keeping an eye on that specific medical need, taking into account what MLD brought to the equation and what gaps exist even with the MLD in the market..

Okay, great. Thanks very much..

Thank you. And our next question comes from the line of Debjit Chattopadhyay of Guggenheim. Your line is open, please go ahead..

Hey, thank you for taking my questions and condolences on Tachi's passing.

So given that the first GM1 subject was dosed in April, what should be the expectations beyond safety? And from an assay perspective, do you have the assays squared out from a biomarker measurement perspective?.

Thanks, Debjit. So what we've committed to delivering in the fourth quarter of this year is safety updates and 30 day biomarker data. And obviously, we'll have to look at that data.

And as you probably know from other programs, it requires getting the data in-house, cleaning that data and then we can subsequent some steps and share that as appropriate in the fourth quarter. And we just have to look at what is available and what we believe is appropriate to share at that time. So we can't commit to a specific follow-up.

But obviously the study and the endpoints run for with several years of follow-up and we will continue to follow patients as appropriate and then report that data also as appropriate. So I don't think we can get into exactly what we're going to present in the fourth quarter.

Your second question on the assays, yes I think we've mentioned before, that both CSF essays and serum assays were being developed because of the sensitive - because of the required sensitivity and the differences in levels that were found from adult patient samples and kind of extrapolating to children.

And I will tell you that the group that is here working on the biomarkers has done a fantastic job advancing this. So, yes, those are all developing enough..

Good, and then the new licenses from Penn, that you announced today, would you provide more color on the likely choice of vectors and delivery routes? Do you plan to leverage on the existing vectors or would just need separate investment in vectors? And is it going to be via the ICM?.

All fantastic questions, and I'm sure this is not going to be a very satisfying answer. But the real answer is it depends.

And I'll expand on that by saying that, as you know, we've been - we and others have been investing with Jim on Discovery programs, and part of those Discovery programs, is certainly to pursue new vectors and capsids and also optimization of promoter transgene, et cetera just from a gene therapy perspective.

So that is certainly contemplated in this agreement to essentially first do an exploratory research program. And part of that is really to identify and characterize and evaluate the targets and obtain in-vivo proof-of-concept hopefully, or some in-vitro and or in-vivo, proof-of-concepts.

Once we reach that stage, you're absolutely right, that there may be further optimization on the two areas that you said, both the vector and the route of administration, it very well may be ICM, there may be other approaches that we will have to develop, or would be developed along the way, and maybe not we have to develop, they may be available.

And I think Eliseo wants to add another comment to that as well..

Yes, as Bruce said, it would be a bit early to speculate about target. Now, we just signed this agreement, and we're happy initiating the work. But when you look at Alzheimer's disease, and Temporal Lobe Epilepsy, it's plausible that they might require a different approach.

One, probably intraparenchymal, and the other probably intrathecal, with a broad distribution. So we are open to exploring the necessary modalities and routes of administration that might be necessary..

Appreciate it, thank you so much..

Thank you. And our next question comes from the line of Laura Chico with Wedbush. Your line is open. Please go ahead..

Thank you very much for taking my questions. And my condolences on the loss here. I think two questions first. With respect to the expanded UPenn collaboration, you mentioned a few of the larger scale CNS applications that you're considering.

My question is why now, why is this a good time to layer in the larger scale opportunities? And I think you mentioned this in the prepared remarks, but strategically how do you think about the balance versus the focus on some of the orphan indications, and then I have a quick follow-up?.

Sure, now thanks, Laura. Thank you for the question. The way we thought about this is actually not I'm going to make a brief comment, and then I'll turn it over to Eliseo. This is not abrupt consideration. This is what we believe is a natural extension of what we've built and what the partnership has delivered.

I'll first talk about what our pipeline looks like. We're moving into the clinic with certain programs, and in rare monogenic space, and Eliseo can expand on this.

We believe more generally, when you pick a target, it links to a gene and it links to the indication and so there potentially is less need for exploratory work to characterize and identify and characterize those targets. So the way we think about this is, it is earlier stage, it will start with exploratory research plan.

And as we do that, to your point, Laura, we're going to continue to prosecute the clinical programs, Jim will continue to advance the discovery stage programs and we're very interested in adding to that.

And so it is a balanced portfolio approach and we think right now is the opportunity to do this for both where Jim is in his - interest in expanding this, and also the team that we've built here and Eliseo can comment on this as well.

But we've brought some clinical team members and overall team members that are experts at doing exactly these programs.

Eliseo, do you want to add a few comments?.

Yes, just two - there are two aspects to this decision, one is the desire to balance and diversify our pipeline.

When you look at our pipeline it's very strong in rare monogenic diseases, in particular pediatric leukodystrophies, we have one adult indication now knowing the clinic, and we felt that it would be appropriate moving forward to add a complement indications that are non-monogenic, non-pediatric, and non-rare to provide diversity of opportunities.

The second aspect is that these reflects the quality of the partnership and the increased confidence that [indiscernible] and Penn discover working together. This collaboration started about two years less than two years ago.

And the confidence and the strength of working together, translating into this desire to approach what I would call less leading our target, where if you have one faulty gene that you need to replace, so those are the two aspects that explain it right now..

Okay, that's helpful. And then maybe one quick follow-up question. So at the Virtual MPS Meeting in July, it seemed like one trend that was emerging was increased improvement in younger patients versus older patients in a couple of different disease settings in the context of gene therapy.

So as we're thinking about GM1, and some of these other applications, I'm curious how you anticipate the phenomena kind of replicating here and kind of the therapeutic window for intervention. Any thoughts there? Thanks..

Yes, the more we advance in the treatment of these pediatric diseases, the more that Axiom tends to be confirmed that earlier intervention seems to be there. So we remain very humble. We know that what we're doing is research, now clinical research.

But we agree that in general, what seems to emerge is that earlier the treatment, the better the outcomes. But on the other hand, as you know, patients whose symptoms appear later in life, tend to be less severely affected opening for more compensatory mechanisms.

So while accepting what you said, as a reality, no, I remain humbly optimistic about exploration of the effects in later onset patients for the reason I mentioned..

Thank you. And our next question comes from the line of Yun Zhong with BTIG. Your line is open, please go ahead..

Hi, this is Xion for Yun. Thank you very much for taking our questions. And we're really sorry about the pass of Dr. Tachi Yamada, so my first question is about the competitive landscape on the FTD program, your competitor had recently reported some place to read out on their program.

And that actually shows some positive biomarker in the slowing disease progression when compared to natural history. I just want to know your thoughts on that because the investors seem to be on like reacting a little bit let into it.

And what parts of the data set, do you think have not met investors expectation? And how can your programs do better?.

Yes, thank you. Thank you for the thoughts and the question. So I'll make some introductory comments. And if Eliseo wants to add anything, turn over to him, so the mechanisms for the data generated, you mentioned are completely different. And I think that that's one of the outstanding questions that we've always raised.

But we're also balanced in our - I think excitement I think for the field of patients with that are suffering from Frontotemporal dementia and hope that this would move forward.

So the data you mentioned is specifically around a monoclonal antibody that delivered a relatively high dose every four weeks and that that blocks a receptor that uptakes progranulin intracellularly. And then the site of action for progranulin is intracellular.

So one of and what the data showed from those studies and earlier studies is that the level of progranulin that was achieved was about double the starting level in both preclinical models, as well as in CSF as well as in serum. And that means that the progranulin levels are essentially getting back to relatively normal.

And that further raises the question about where the progranulin is, is it outside the cells or is it intra neuronal and I think your point is that, how does that, the investors I think in some of the questions we've seen are, how does that translate into clinical benefit biomarkers, neurofilament light marker, et cetera.

And those are very complex questions to answer. And perhaps, the Phase II data is not mature enough to understand that and they're running a Phase III study to try to fully characterize it. The last point I'll make and turn over to Eliseo for further comments is, our approach is a gene therapy to increase progranulin.

And what we've seen in preclinical models is that we can get over 50 times the level of normal progranulin. And so that gives us the opportunity to really drive progranulin, exogenous new progranulin to potentially much higher levels.

And so that, I think, is the major differentiating point and perhaps some of the questions that involve this monoclonal antibody.

So Eliseo, any other thoughts?.

No, I think you covered it..

Thank you very much..

Thank you..

Thank you. And our next question comes from the line of Danielle Brill with Raymond James, your line is open. Please go ahead..

Hi, guys. Good morning. Thanks so much for the questions. And first, allow me to extend my condolences about Tachi's passing as well. So I have a couple.

First, I'm curious about how you're defining early symptomatic FTD in the upliFT-D study? Do you have a maximum NfL cutoff for inclusion or do CDR scores correlate with FTD? And then I'm curious about your thoughts on at the upcoming AAV Vector [indiscernible] meeting, are you at all aware of the agenda and any thoughts on potential implications for your program? Thank you..

Yes, so on the FTD program, it's a great question. And actually, I think I'll reframe it slightly. So we do look at early onset symptomatic patients. And this is defined, I believe it's on clinicaltrials.gov. If I'm a little bit wrong, please refer to that for the final numbers. But I believe it's around 0.5 to 1 in terms of the CDR scores.

And the NfL level is actually a high level of NfL in serum. The reason those two things are combined is that we're taking early onset, but there have been some studies that showed higher NfL levels are correlated with a faster progression. That's obviously not great for the patients.

But from a clinical study perspective, it does tend to select the patient population that is optimal to study potentially. And so I'll pause there and ask Eliseo, if any other comments or does that capture generally and again, I may have the cut off and CDR slightly incorrectly. But no, that's perfect..

That's correct.

And the concept is that and remember that this is a first in patients where the objective is to pick up hopefully strong signals, and therefore, that's why the emphasis on patients that are already demented, and not pre symptomatic as reflected by the CDR of 0.5 to 1 and the higher level of NfL that might indicate a faster evolution of the disease.

One quick comment about the data that has been shared recently, which is great for the field, great for patients, great for all of us. I mean one of the most difficult things to predict in dementia in general, including FTD is the future rate of decline of a population of patients.

When you look back, and you can see what this populations of patients declined at this rate. But then taking the same patients, putting them in a trial and absorbing them might bring surprises, as we have seeing in the last 20 years of trials in dementia so far..

And so, on the second question, yes, we're obviously very focused on the advisory committee that will come up.

Our understanding is that there will be five types of toxicities, the real potential toxicity risks, that we'll be focused on the genecity, so generation of oncology, Hepatotoxicity, thrombotic events, and then neuro and then three types of neurotoxicity, one is kind of an MRI and the other is on generally related to DRG.

We're absolutely in discussions here internally and also with Jim and his group, who have obviously been on the leadership area in many of these potential areas.

And I just mentioned on DRG for example, I think we're one of the only companies that are right now proactively monitoring nerve conduction velocity or sensory neuron activity in all of our studies to try to evaluate whether ICM for these patients has clinical, some kind of clinical or subclinical manifestations.

We've never seen these and but we do believe that it's the right thing to do to continue to study. But we've also talked about that the amount of experience in any one of these toxicities is actually still vanishingly small.

So there have been, for example, MRI - note - toxicities that have been noted but they're also in patient populations in the 10s, not in the 1,000s or 100s of 1,000s. So, this is evolving. And so I guess our general comments are, we absolutely are aware of this, we want to be at the forefront of thinking about these potential toxicities.

But also that using ICM obviously does limit some of these systemic talks and focuses us now on the DRG area which we've been very clear about for the past couple of years and built into our design. So that's our current perspective, we're obviously going to be looking at that very carefully..

Got it, thank you so much. Very helpful..

Thank you. This does conclude today's question-and-answer session as well as today's conference. Thank you for participating and you may now disconnect..