Q2 2021 Passage Bio Inc Earnings Call

Today's conference is scheduled to begin shortly please continue to standby. Thank you for your patience.

Operator: begin shortly; please continue to stand by. Thank you for your patience.

Bruce Goldsmith: Thank you. Thank you, and the uh... I'm gonna I'm gonna I'm... I and the and I'm gonnae, uh, and the I'm I'm.

[music].

Operator: Thank you for holding. Good morning and welcome to the Passage Bio Second Quarter 2021 Financial.

Operator: and welcome to Passage Bio's second quarter 2021 financial and operating results conference call. At this time, all participants are in a listen-only mode.

Operator: Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the company's request. At this time, I would like to turn it over to Stuart Henderson, Vice President of Investor Relations and Strategic Finance. Stuart, please begin with the topics we plan to discuss today. This release is available on the PassageBio website at Investors.passagebio.com under the press releases and statements section.

Operator: On today's call, Bruce Goldsmith, President and Chief Executive Officer, will review our second quarter 2021 financial results and discuss recent business highlights. Elisao 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 by 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 their 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, 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.

Our expectations for timing and execution of anticipated milestones, including the initiation of clinical trials and the availability of clinical data from such trials, our expectations, but our collaborators and partners the ability to execute key initiatives the ability of our lead product candidates to treat their 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.

Operator: 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 my pleasure to pass the call over to CEO Bruce Goldsmith.

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 not on my pleasure to pass the call over to CEO Bruce Goldsmith Bruce.

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.

Thanks, Stuart and thank you all for joining US. This morning, I will begin by centering my remarks around our 4 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.

Adviser 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.

Bruce Goldsmith: 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 medicine. As for our partnership and pipeline, I am 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.

These pillars provide a 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 am 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 and his dedicated expert team and the University of Pennsylvania.

Bruce Goldsmith: 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. As part of 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 will be able to evaluate several targets and technologies in parallel to enable quick decision-making.

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

We will be able to evaluate several targets and technologies in parallel to enable quick decision, making once a target has reached proof of concept. We need 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.

Bruce Goldsmith: Once a target has reached proof of concept, we may then exercise an option to advance to the development of a new genetic medicine for the underlying condition, but we are under no obligation to exercise that option. We are 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 a wide range of CNS indications beyond rare monogenic conditions will bolster our already robust pipeline and provide greater optionality for program advanced. 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.

We are initiating this effort focusing on all timers 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 a wide range of CNS indications beyond rare monogenic conditions will bolster our already robust pipeline and provide greater optionality for program advancement.

And our agreement with GTP, we have the option to license 17 total programs. So far we have exercised 7 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 will continue to do so in a data driven manner factoring in patient need product differentiation and the ability.

Bruce Goldsmith: In addition to the expansion into large indications, we maintain our current focus on rare monogenic disorders and may pursue additional options in this area as well. When exercising our remaining 10 options, we will continue to do so in a data-driven manner, factoring in patient need, product differentiation, and the ability to de-risk clinical development. 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 Hopeville, New Jersey.

To de risk clinical development programs.

For our manufacturing capabilities I am 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.

Bruce Goldsmith: 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 move 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 are proud of the caliber of talent we have attracted to Passage Bio, as illustrated in our recent announcement of new executive appointments.

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 3 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 <unk>.

As illustrated in our recent announcement of new executive appointments.

Maria <unk> 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.

Bruce Goldsmith: Maria Tornton 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 paths to commercialization. Simona King joined us later this month as chief financial officer and will be responsible for finance, accounting, tax, treasury, investor relations, functions, and information technology. Mark Foreman joined us as chief medical officer and is responsible for leading the company's translational and clinical development efforts.

Simona King joined US later this month as Chief Financial Officer, and will be responsible for finance accounting tax Treasury Investor relations functions.

And information technology.

Mark <unk> joined 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. Doral Porter, who brings tremendous experience in corporate strategy product development and commercialization is an example of the kind of talent and expertise we are able to call upon at the board level.

Bruce Goldsmith: We also have a strong board of directors supporting and guiding our company. The recent appointment of Dr. Dorell 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 are 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.

As we build our company around our 4 strategic pillars. We are hyper focused on the strong execution of our 3 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 day study for the treatment of frontal temporal dementia with granular mutations and galaxy for the study for the treatment of <unk> disease.

Bruce Goldsmith: 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 frontal temporal dementia with granuline mutations and Galaxy for the treatment study for the treatment of crab A disease in the third quarter of 2021, and reporting initial safety and 30-day biomarker data from the first cohort of patients in our Imagine 1 trial for the treatment of infantile GM1 in the fourth quarter of 2021.

The third quarter of 2021.

Reporting initial safety and 30 day biomarker data for the first cohort of patients and our imagine 1 trial for the treatment of infantile GM 1 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 galaxy trials in the first half of 2022.

Bruce Goldsmith: And reporting initial safety and 30-day biomarker data from the first cohort of patients in our uplift D and Galaxy trials in the first half of 2022. Our momentum and execution are supported by a strong balance sheet with $408 million in cash, cash equivalence, and marketable securities at quarter end. I will now turn it over to our chief R&D officer, Elisaeus, who will discuss our clinical programs in more detail.

Our momentum and execution are supported by a strong balance sheet with $408 million in cash cash equivalents in marketable securities at quarter end.

I will now turn it over to our Chief R&D Officer, LSA ethylene us who will discuss our clinical programs in more detail.

Thank you Bruce.

I will begin with simple garage and Tom is regarding site initiation and patient identification for our 3 lead programs.

Elisao Salinas: I will begin with some of the origin comments regarding site initiation and patient identification for our three lead programs. First, I will point out that this is a distinguishing characteristic of our programs, in that they are all multi-site and international in scope, so that we can be where the patients are. In total, we have a global network of multiple planet sides across nine countries and three continents.

First I will point out on those.

We see characteristic of our programs in debt.

All multi site and international on scope.

So that we can be where decisions are.

In total we have a global network of multiple climate sides of course non countries on 3 continents.

Despite ongoing challenges due to COVID-19, we have made significant headwind unexpected continue opening sites in new ways.

Elisao Salinas: Despite ongoing challenges due to COVID-19, we have made significant headway and expect to continue open insights in the coming weeks. We are also pleased with our progress through a variety of initiatives, identifying patients for our clinical program. 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 what was specifically bro.

We're 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 3 disease areas targeted by our lead programs and collaborations with a broad network of patient advocacy and physician groups.

Now to our specific leap programs.

As many of you know we announced the approved 2021 that we dosed the first patient in our managing 1 trial for the lead programs <unk> 1 for the treatment of patients with Gen..1 GAAP USA losses.

Elisao Salinas: 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, PBGMO1, for the treatment of patients with GM1, GAGUSA boss. The Global Phase I-2 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 well. We have completed the initiation of additional clinical sites and expect to activate them to begin enrolling in the coming weeks at those sites.

The global Phase 2 trial is focused on the infantile form for disease, which is the most severe form with a very rapid disease scores and no current treatment options beyond supportive care.

I am pleased to report that the <unk> 1 trial is progressing as planned.

We have completed the initiation of additional for the adult sides unexpected Lucky day to begin enrollment in the coming weeks in those sites.

As we have discussed previously imagine 1 is on open label study that will enroll for distinct cohorts divided by age and dose level.

Elisao Salinas: As we have discussed previously, Imagine 1 is an open-label study that will enroll four distinct cohorts divided by age and dose level, with the first cohort being composed of late-unset infantile patients receiving the initial dose level of PBGM-O-1. The primary goal of this cohort is to assess safety and colorability to allow for dose escalation and progress into our early infantile cohort. We are also measuring beta-gal enzyme activity levels in the CSF and zero.

The first cohort being composed of late onset infantile patients receiving the initial dose level of <unk>.

The primary goal of the cohort is to assess safety and tolerability to allow for dose escalation on progress.

Early infantile cohorts.

We are also measure on beta gal enzyme activity levels this year.

On cereal.

We look forward to reported initial safety data and 30 day biomarker for cohort 1 of the study in the fourth quarter of this year and extending our June 1 trial.

Elisao Salinas: We look forward to reporting initial safety data and 30-day biomarker from cohort 1 of the study in the fourth quarter of this year and extending our G&1 trial growth, turning to our global credit program. As we discussed in our prior call, we have received regulatory clearance to initiate our global phase 1-2 clinical trial called Galaxy from the FDA, the UK's NHRA, and health cancer. We continue to advance site initiation processes at multiple sites and expect to dose the first patient in the third quarter.

Turning to our global credit program.

As we discussed on our prior call. We have received regulatory clearance to initiate on global phase <unk> clinical trial called Galaxy.

From the FDA, the Uk's imagery and health Canada.

We continued to advance sites initiation processes at multiple sites unexpected dose the first patient in the third quarter.

As a reminder, galaxies on open label dose escalation study.

Elisao Salinas: As a reminder, Galaxy is an open-label dose-exhalation study of PBKR-O3 in patients with early infantile cranial crab disease. Similar to our Imaginine 1 trial, we will first evaluate an initial dose of PDKR or 3 in late-onset patients and then progress into early onset and higher dose costs. Those ascending those cohorts will be followed by a confirmatory expansion cohort that will include both age groups.

<unk> 3 in patients with early infantile krabbe disease.

Similar to our imagine 1 trial, we will first evaluate on initial dose of <unk> 3 in late onset pensions and then progressed into early onset and higher dose cohorts.

Dose ascending dose cohorts will be followed by a confirmatory expansion cohort that will include both age groups.

The primary goal of this study to assess the safety of <unk> in patients with early infantile krabbe disease.

Elisao Salinas: The primary goal of the study is to assess the safety of PBKR-O-3 in patients with early infantile tributtal disease, with the secondary goal of assessing ALC activity in both CSF and CRS. Next, we will discuss our third global clinical trial program for PBFTO2 for the treatment of frontotemporal dementia with granuline mutations or FDGRM. FTT is one of the more common causes of early onset dementia, causing impermanent behavior, language, and executive function, and, of course, a similar frequency to Alzheimer's disease in patients younger than 65 years old.

With the secondary goal of assessing <unk> activity in both CSS and Sue.

Next let's discuss our third global clinical trial program for <unk>.

<unk> for the treatment of Frontotemporal dementia, with Granularly mutations where SPD GRN.

The STB is 1 of the more common causes of early on that dimension.

Impairment CAGR.

Language and executive function on.

On a course that similar frequency to all time or disease in patients younger than 65 years old.

The rapid progression of sdd, resulting in average <unk> almost 8 years after the onset of symptoms.

Elisao Salinas: The rapid progression of FDD results in an average revival of eight years after Ronesit of Sim, were specifically focused on FDD-GRN, the disease occurs because of mutations in the GRN gene, causing a deficiency of prognolid. It is estimated that about 5 to 10% of SPD is caused by a GRNU.

We're specifically focused on SD GRN, what the disease of course because of mutations in the <unk> in June, causing a deficiency of program.

It is estimated that about 10, 5% to 10% of SPD is caused by a GRM mutation.

Our global Phase 1.2 clinical trial uplift.

Elisao Salinas: Our Global Phase 1, 2 clinical trial, Uplift D, is an open-label, dose escalation study of PDFTO2 in FPDGRN patients, and we have received regulatory authorization to initiate clinical trials in the United States and Canada. Additionally, BVTO2 received orphan designation for the treatment of FDDGRN from the European Commission in July 2021. The designation provides passive value with certain potential benefits, including clinical assistance, reduced regulatory fees, research grants, and up to 10 years of market exclusivity following regulatory approval.

<unk> is an open label dose escalation study.

<unk> 2 in <unk> in patients and we have received regulatory authorization drillship clinical trials in the United States and Canada.

Additionally.

<unk> received orphan designation for the treatment of Sdd GRN from the European Commission in July 2021.

The designation provides vessels bio was 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.

Elisao Salinas: We're advancing site initiation processes at 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 phase one of this study are to assess the safety of PVF CO2 and to evaluate its impact on biomarkers, specifically potential increases in programming levels in the CSF and CO. As we look ahead to the near-term data readout, we are incredibly excited by their potential to shape not only the future of the patients we serve but the future of gene therapy and the CNS space.

Like our other 2 programs our 2 key goals for the phase 1.2 study are to assess the safety of <unk>, 2 and to evaluate its impact on biomarkers, specifically potential increases in for granular levels in the CSF and serum.

As we look ahead to the near term data Readouts.

We are incredibly excited by their potential to shape not only the future of the patients we serve but the future of gene therapy on the CNS space.

I will end my comments by saying it is unknown.

Elisao Salinas: I will end my comments by saying it is an honor to work with the caregivers, physicians, and other health care workers in the GM1, disease, and STD community. We are grateful for the ongoing support of our clinical programs. With that, I will now turn the call over to Bruce to review our finances.

For the caregivers physicians and other sales team work at the GM, 1 forbidden fees on STD communities, we are grateful for their ongoing support of our clinical programs.

With that I will now turn the call over to Bruce to review our financials.

Bruce Goldsmith: Thank you, Elisao. 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.

Thank you for LSA.

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 30th compared to $19.9 million for the same quarter in 2020.

Bruce Goldsmith: R&D expenses were $33.1 million for the quarter ended June 30th, 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 employee headcount in the R&D function, and a $0.4 million increase in other research costs.

The increase was primarily due to an increase of $13.9 million and 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 employee head count in the R&D function and a zero point $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 3 months ended June 32020 for preclinical work performed in preparation for IND filings for our lead programs.

Bruce Goldsmith: These increases were partially offset by a $7.6 million decrease in research and development costs associated with the PEN agreement, which relates to additional costs incurred in the three months ended June 30, 2020, for preclinical work performed in preparation for I&D filings for elite programs and certain pass-through clinical manufacturing costs. GNA expenses were $15.4 million for the quarter ended June 30th, 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.

And certain pass through a 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 point million.

Million dollar increase in personnel related and share based compensation expense due to increases in employee head count.

Our professional fees and facility costs also increased by $2 million as we expanded our operations to support our research and development efforts.

Bruce Goldsmith: Our professional fees and facility costs also increased by $2 million as we expanded our operations to support our research and development efforts. Our net loss was $48.4 million for the second quarter of 2021, compared to $27.2 million in the same quarter of 2020. The net loss per basic and diluted share was 90 cents in the second quarter of 2021 compared to a 60 cent net loss per basic and diluted share in the second quarter of 2020.

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 <unk> 90 in the second quarter of 2021 compared to a 60 <unk> 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 live to deliver transformative therapies for patients with CNS disorders.

Bruce Goldsmith: 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 are 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 major 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 are especially excited about our expanded strategic agreement and collaboration with GGP 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 Alzheimers disease, and temporal lobe epilepsy, 2 diseases that affect large adult patient populations and where the need for new treatment options is significant.

We also want to emphasize that we are maintaining our focus on rare monogenic CNS disorders.

Bruce Goldsmith: We also want to emphasize that we are maintaining our focus on rare monogenic CNS disorders. As LSAO described, our clinical team, manufacturing team, and patient engagement teams are all extremely focused on our studies for patients with GM1, crab A disease, and FTD. We are committed to advancing our early stage programs and continuing 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 Galaxy trials in the third quarter of this year; two, to report initial safety and 30-day biomarker data for cohort one of the Imagine One study in the fourth quarter of this year; and three, to report initial safety and 30-day biomarker data from our Uplift D and Galaxy trials in the first half of 2022.

LSA are described our clinical team manufacturing team and patient engagement teams are all extremely focused on our studies for patients with GM, 1 krabbe disease and FTE day.

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 1 to dose the first patient in our uplifting and galaxy trials in the third quarter of this year 2 to report initial safety and 30 day biomarker data for cohort 1 of the imagine 1 study in the fourth quarter of this year and 3 to report initial safety.

30 day biomarker data from our uplift D and galaxy trials in the first half of 2022.

We are 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.

Bruce Goldsmith: We are proud of the progress we have made in building our company and advancing our pipeline as we establish ourselves as a leader in genetic medicine. With that, I will open it up for questions. Operator? Thank you. To ask a question, you will need to press Star 1 on your telephone.

With that I will open it up for questions.

Operator.

Thank you to ask a question you will need to press star 1 on your telephone to withdraw your question. Please press the pound key for Scott Smith will provide brief remarks prior to taking the first question.

Bruce Goldsmith: To withdraw your question, please press the pound key. Bruce Godsmith will provide brief remarks prior to taking the first question. Yes, Operator, and thank you for joining us this morning. Before moving to questions, I did want to take this opportunity to say a few words about Tachi Amata, who, as you likely know by now, from all the global outpouring, passed away suddenly on August 3rd. And as I think you also know, Tachi co-founded Passage Bio, along with Steve Squinto and Jim Wilson.

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 touchy Armada, who as you likely know by now from all the global <unk>.

<unk> per.

Passed away suddenly on on August 3rd and as I think you also know touchy Cofounded passage bio along with Steve's Quinto and Jim Wilson.

And I wanted to talk a few minutes about the impact that it had so.

Bruce Goldsmith: And I wanted to talk for 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. Natachi, to me, was an incredible inspirational leader, and we knew him as a founder, chairman, and mentor, but of course, he had a massive impact across the industry and the globe, and that's really demonstrated by what we're seeing in terms of all the press releases and comments honoring his contribution.

This is obviously all very fresh for us and very devastating but I did want to say a few words.

And Hitachi to me was incredible inspirational leader and we knew him as a founder and chairman and mentor.

But of course, you had a massive impact across the industry in the globe and it's really demonstrated by however, we are seeing in terms of other press releases and comments honoring his contributions.

And speaking with both.

Bruce Goldsmith: And 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 both know and work with Tachi. While having such a massive impact for patient innovation across the globe, for Passage Bio, he helped obviously set this strategy in motion with Jim and Steve and guide the strategy, but also, as a partner, to think about and help the operational build-out and set the strong foundation of the company, including the announcements that we made today.

Both our management team on the and the board late yesterday and today I can I can tell you that we're on.

All very deeply shocked and incredibly saddened.

And we are all extremely grateful for the opportunity to have both known and worked with pace.

Well, having such a massive impact for patients on innovation innovation across the globe for passage bio. He helped obviously set the strategy 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 a <unk>.

Strong foundation of the company.

Including the announcements that we made today than they were certainly.

Bruce Goldsmith: And they were certainly, you know, very much with Tocchi's guidance and wisdom in terms of pursuing the various opportunities we have. And we really do remain committed to Passenge 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 us.

Very much.

With touch his guidance and wisdom uncertain in terms of pursuing the various opportunities we have.

And we really do remain committed to passage bio submission for patients and we will also constantly think about <unk> guidance and insights as we continue.

The company has an incredibly strong foundation with a deep board.

I talked to us 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 in our both grief and commitment to the company.

Operator: 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 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 in the future. With that, I will now turn the call back over to the operator for questions.

And do so I think partially or totally with charges.

Moving to patients in mind.

And finally, I do want to mention that we absolutely.

Totally have touch it touches families in our family in our thoughts we haven't talked about this family and we really do hope that the memory of touchy.

Gives comfort to them today and overtime.

With that I will now turn the call back over to operator for questions.

Thank you and our first question comes from the line of Tesla for Mono with Jpmorgan. Your line is open. Please go ahead.

Operator: Thank you. And our first question comes from the line of Tassel Romano with J.P. Morgan. Your line is open. Please go ahead.

Yeah.

Hi, all on good morning, Thanks, very much for taking my question.

Tassel Romano: Hi, all, good morning and thanks very much for taking my question. A clarifying question for me, you've noted that you got to the first patient in the phase one, two, infantile one, GM1 study in April. Have you dosed the second patient, and if not, have you identified the patient, that will be the next patient?

A clarifying question for me.

You've noted that you dose the first patient in the channel.

<unk> and <unk> on Jan 1 study in April.

How do you dose the second patient.

And if not have you identified the patient.

That will be dose.

And then on.

Bruce Goldsmith: And then can you just remind us where you are specifically on site activation. How many sites do you have up and live now? And what is that target number that you're hoping to get to? Thanks so much.

Can you just remind us.

Where you are specifically on site activation, how many sites you have up in line.

What is that target number that youre, hoping to get Pam. Thanks, so much.

Sure I'll make a few comments and then also turn it over to Alan Thanks for the question.

Bruce Goldsmith: Sure, I'll make a few comments and then also turn it over to Alaseo. Thanks for the question. So we did, we did announce the first patient dose, as companies often do. But we've 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 online. I do note and re-emphasize what Alaseo said is that we hope across all of our studies and plan to open additional sites in the coming weeks.

So we are we did announce the first patient dosed as companies often do.

We have not got into any more details about that.

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 LSA on instead is that we hope across all of our studies and plan to open additional sites in the coming weeks.

Bruce Goldsmith: For GM1, what we're really focusing on is that we will, we have reiterated our guidance on reporting data 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 HALSA, do you want to add any comments? Yes.

For GM, 1 what we're really focusing on is debt we will.

We have reiterated our guidance on reporting data out for the first part which is just 2 patients for safety and 30 day biomarker data by the end of the year.

And I think Youre on 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 overtime and health side, you want to add any comments.

Yes.

1 important consideration as debt.

Elisao Salinas: What an important consideration is that all the trials we're doing, which is typical for gene and cell therapy, are those escalation studies where you dose one patient at a time. In our case, we're those in one patient at a time with the spacing of patients with at least 60 days between the patient and the next one. That sequential enrollment is determined by the sequential opening of sites. I'll get back to that in a second.

All the trials, we're doing which is typical for gene and cell therapy.

Sure.

Those escalation studies, where you dose 1 patient at a time.

Our case, we're dosing 1 patient per tonne.

The spacing patients with at least 60 days between the patient and the next 1.

That that sequential enrollment.

The term is a sequential opening of sites.

I will get back to that in a second.

An important aspect of our program that sometimes doesn't get.

Elisao Salinas: An important aspect of our program that sometimes doesn't get recognized or identified is that it's a vast program, a high number of countries, a high number of continents, a high number of sites. You could technically do these studies with just one site, but we elect to take a different strategy to be where the patient's arts. And it's in the public domain in clinical trial or gov that we plan to open many doors. But it would be futile and ineffective to open all those doors at the same time because, say, site number eight would have to wait 16.

Recognize are identified as debt.

As the vast program.

High number of countries high number of continence high number of sides you could technically do do studies with just 1 side.

But we elected to take a different strategy to be with the patients are.

And it's on the public domain and clinical trial on the golf that we plan to open many sides, but it would be futile and ineffective to open all dose sides at the same time.

Save pages slide number 8 we'd have to weigh 16 months to enroll their first patient. So you would lose momentum. So our strategy of opening I can activate this side is also a 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.

Elisao Salinas: 15 months to enroll their first patient, so you would lose momentum. So our strategy of opening and activating sites 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 year of size. 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.

Second on the third.

Of size, we have initiated sites in the last few weeks those sites will become active in the next in the next few weeks and overall, we're very happy with the progress still volume.

Yes.

Tassel Romano: Thanks very much. That was very helpful.

Thanks, very much on that was helpful and so sorry to hear about patchy passing.

Operator: That was helpful, and I'm so sorry to hear about Tachi's passing. Thank you. Thank you. And our next question comes from the line of Nina.

Thank you for that.

Thank you and our next question comes from the line of Neenah.

Great Oh, great cargo with Citi. Your line is open. Please go ahead.

Operator: Grito Gargo with City. Your line is open. Please go ahead.

Grito Gargo: Thank you guys. Thanks for taking the question.

Hey, guys. Thanks for taking the question.

So I guess kind of a similar question, but in regards to the other 2 studies I think last quarter. You noted that there was potential to get the first patient in the study dose maybe by the end of the second quarter or early third quarter. So I guess is there and should we perceive this as any sort of.

Grito Gargo: I guess it's kind of a similar question.

Grito Gargo: but in regards to the other two.

Grito Gargo: studies. I think last quarter you noted that there was potential to get the first patient in the FTD study dosed maybe by the end of the second quarter or so.

Bruce Goldsmith: third quarter. So I guess it's there, and should we perceive this as any sort of a delay per se? Or I guess, yeah, 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 in getting that study up and running.

Net delay per se or.

I guess, 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.

<unk> kind of on getting that study up and running.

Thanks for the way I would characterize this as debt.

Bruce Goldsmith: Thanks, Dina. 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, you know, seemingly simple negotiations that are getting hung up because of either lack of staff or backlogs of the study initiations, such as, you know, such as other studies kind of moving ahead of us because they just simply filed earlier.

There are idiosyncratic.

Changes and differences in every site that we're trying to interact with.

A lot of them I mentioned before were IRB timing as well as <unk>.

Seemingly simple negotiations that are getting hung up because of either lack of staff or backlog of.

The study initiations such as.

Such as other studies.

Moving ahead of us because they just simply filed earlier so when we said.

Bruce Goldsmith: 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 LLSA has said, we are now having site initiation activities, and part of it was also just getting those 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, essentially,

When we updated the guidance, we were kind of saying either second quarter or third quarter, because thats, what we anticipated based on the progress we are making.

And as I also said, we are now having site initiation activities and part of it was also just getting those scheduled et cetera, and now that those are those have been either scheduled or completed.

Have better 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. The third step. So I don't think it was a specific.

Bruce Goldsmith: 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. Gotcha, perfect. Thank you. That's helpful.

1 specific issue, it's just basically the environment, we're living in right now and trying to some of the progress forward.

Got you perfect. Thank you that's helpful.

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

Operator: Thank you. And our next question comes from the line of Yaron Werber with Cowan. Your line is open.

Operator: Your line is open. Please go ahead.

Operator: Hi, good morning. This is Brendan on for your own.

Hi, Good morning. This is brendan on for your own congrats for the team on the progress on our condolences to everyone on the news from yesterday.

Brendan: Congratulations to the team on 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, and Sharko 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, you know, kind of just hoping to get your thoughts on your approach there versus others who seem to have pretty solid efficacy with an ex-devo lentiviral approach and kind of what advantages you think you might have specifically in that space. Thanks very much.

Just a quick 1 from us.

Looking ahead to the upcoming programs in MLD ALS Charcot Marie actually just looking to see when do 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 cadence or moving them forward relative to each other.

Actually really just on MLD. There you know kind of just hoping to get your thoughts on your approach there versus others, who seem to have pretty solid efficacy with like an 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 on then.

Bruce Goldsmith: Sure. I'll make a few comments and then turn to the LSA as well. So, you know, one of the things that we've been, I think, very upfront about his bit. You know, when data is available and presented by the group that's moved this forward, which is obviously Jim Wilson and the gene therapy program, we're happy to share that, and the programs continue to move forward in his groups. But We don't have any specific updates.

Bruce Goldsmith: Obviously, there was a really nice update on the MLD model back at GTC earlier this year, and we shared that, and we will do so in the future. 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.

Bruce Goldsmith: But each of these programs, the way we're thinking about this, are points of differentiation. And so maybe I'll turn over to LSA to talk about how we think about MLD and to your point about cell therapy and potential differentiation. Yes, definitely.

The cell therapy.

And potential differentiation.

Yes that for.

So the.

Elisao Salinas: Yes, definitely. So we start these programs 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 would say, even excitement, the development around Libeldy. And, of course, we have that in mind when we think about the program and the potential benefits of our gene therapy approach.

We start this programs with the end in sight.

So at the end of the day, how our construct could what our constant could add to the existing or potentially existing.

Armamentarium at that time on of course, we followed with interest and I would say even excitement the development around living Balbi and of course, we have.

The the dad in mind, when we think about the program and the potential benefits of our gene therapy approach I would say 2 things well.

Elisao Salinas: I would say two things. Well, you know, it's a very exciting development. You know, an autologist stem cell transplantation. It's a type of approach that has its benefits and risks, and it's a balance. The second is that, as you know, the... The data on Lefmeldi is very strong in certain people in populations at certain ages and with certain degrees of symptoms, and less so in others. So overall, we think that there is still a high medical need, and, of course, we are keeping an eye on that specific medical need, taking into account what LeMeldi brings to the equation and what gaps exist even with Leibaldi in the market.

It's a very exciting development.

On autologous stem cell transplantation.

It's a type of approach it has it's.

Benefits and risks and it's a balance.

On.

The second is debt as you know the date.

Mailed the is very strong in certain people for some populations at certain ages and with certain degree of symptoms and list. So we know others. So overall, we think that there is still a high medical need and of course, we are keeping an eye on that specific medical needs taking into account what will be mailed.

Brought to the equation and what gaps exist, even with rebuild in the market.

Brendan: Okay, great. Thanks very much.

Okay, great. Thank you very much.

Thank you on our next question cash on the on line.

Operator: Thank you, and our next question comes from the line of Deb Jett-Chete-Dubbe. Mr. Guggenheim, your line is open. Please go ahead.

Okay shut the T.

You can hang your line is open. Please go ahead.

Deb Jett-Chete-Dubbe: 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 assay squared out from a biomarker measurement perspective? Thanks. So, what we've committed to delivering in the fourth quarter this year is safety updates and 30-day biomarker data. And obviously, you know, we'll have to look at that data.

Okay. Thank you for taking my questions on both on the old answers on touchy sponsoring so given that the first GM on subject was dose on April what should be the expectations beyond safety and.

From an assay perspective, do you have the asset squared out.

From a.

A biomarker mentioned on your perspective.

Thanks.

So.

What we've committed to <unk>.

Delivering at the and the fourth part of this year is it.

Safety updates and a 30 day biomarker data and obviously, we'll 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.

Deb Jett-Chete-Dubbe: And as you probably know from other programs, it requires getting the data in-house, cleaning that data, and then we can take subsequent steps and share that, you know, 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, we are, you know, the study and the end points run for, you know, with several years of follow-up, and we will continue to follow patients as appropriate and then report the data also as appropriate. So I don't think we can get into exactly what we were going to present in the fourth quarter.

And then we can we can subsequent some steps and share that is appropriate in the fourth quarter and we just have to look at what is available and what we what we believe is appropriate to share that time, so we can't commit to a specific.

Follow up but obviously we are the study.

And the endpoints run for several.

Several years of follow up and we will continue to follow a patient is appropriate and that report. The data also is 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, we I think we've mentioned before that.

Bruce Goldsmith: Your second question on the assays. Yes. I think we've mentioned before that both CSF assays and serum assays were developed because of their sensitivity, 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 those. So yes, those are. are all developed and

CSF assays and CRM assays for being developed because of the sensitive because of their required sensitivity and the differences in levels at that were found from adult patient samples and kind of extrapolating to children and.

I will tell you that the group that that that is here working on on the Biomarkers has done a fantastic job advancing those so yes those are all.

Developed an in house.

Great and then the new license on strong pain that you announced today would.

Bruce Goldsmith: Good. And then the new licenses from Penn that you announced today, could you provide more color on the likely choice of vectors and delivery routes? Do you plan to leverage the existing vectors, or would this 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.

Could you provide more color on the likely choice on vectors on delivery routes.

Do you plan to leverage on the existing vectors I would've just needs.

Separate investment and vectors and is it going to be.

Via the ICM.

All fantastic questions and I am sure. This is not going to be a very satisfying answer but the real answer is it depends and.

Bruce Goldsmith: And, you know, I'll expand on that by saying that, as you know, we and others have been investing with Jim in discovery programs, and part of those discovery programs is certainly to pursue new vectors and capsids and also optimization of promoter, transgen, et cetera, just from a, from a, from a GEO, and 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 might be further optimization on the two areas that you said, both the vector and the route of administration. It very well may be ICM.

I'll expand on that by saying that as a 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 cabinets and also optimization of promoter trashing et cetera.

Just from a from a gene therapy perspective, so that is certainly contemplated in disagreement 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 <unk> in vivo proof concepts.

Once we reached that stage you are absolutely right that there may be further optimization on the 2 areas that you said both the vector at the route of administration. It very well may be ICM. There may be other approaches that we will have to develop.

Elisao Salinas: There may be other approaches that we will have to develop or will be developed along the way, and maybe not we have to develop them. They may already be available. And I think Alaseo wants to add another comment to that as well. Yeah, as Bruce said, it would be a bit early to speculate about targets, no, 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 intraperenchial, and the other probably intracical.

Or will be developed along the way and maybe not we have to develop they may be available.

And I think LSA on what's to add another comment to that as well.

Bruce said it would be a bit early to speculate about target now we just signed this agreement that we're happy initiated into work, but when you look at Alzheimer's disease and temporal lobe epilepsy, it's plausible that day my required a different approach 1 probably interest.

Inc. On.

On the other probably.

With equal with a broad distribution. So so we are open to exploring necessary modalities and and roads are on these traced on that might be necessary.

Bruce Goldsmith: with a broad distribution. So we are open to exploring necessary modalities and routes of administration that might be necessary.

Deb Jett-Chete-Dubbe: I appreciate it. Thank you so much.

I appreciate it thank you so much.

Operator: Thank you. And our next question comes from the line of Laura Chico.

Thank you on our next question comes from the line of Laura Chico.

Operator: Laura Chico with Webbush. Your line is open. Please go ahead.

Your line is open. Please go ahead.

Laura Kathryn Chico: Thank you very much for taking my questions and condolences on the loss here. I have two questions first. With respect to the expanded UPenn collaboration, you mentioned a few of the larger-scale TNs 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.

Thank you very much for taking my questions and I can do for us on the last year I think 2 questions first.

With respect to the expanded U Penn collaboration you mentioned a few other 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 no. Thanks, Laura Thank you for the question.

Bruce Goldsmith: Sure, no, thanks Laura. Thank you for the question. The way we thought about this, and it's actually not, I'm going to make a brief comment, and then I'll turn up at LSAO. This is not an abrupt consideration. This is what we believe is a natural extension of what we've built and what the partnership has delivered. You know, I'll first talk about what our pipeline looks like. We are moving into the clinic with certain programs, and in the rare monogenic space, and Alsaio 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.

The way we thought about this.

It's actually not.

I am going to make a brief comment and then I'll turn on a a jealous.

Is not a abrupt consideration this as a what we believe is a natural extension of of what we what we built and what the partnership has has delivered on.

For us to talk about what our pipeline looks like we are moving into the clinic with certain programs and in rare rare monogenic space and I will say if you can expand on this we believe more generally when you pick a target it links to a gene and links to the indication and so they are potentially is less need for explore.

For Tori work to characterize and identify characterize those targets. So the way we think about this as 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.

Bruce Goldsmith: So the way we think about this is it is in an earlier stage. It will start with an exploratory research plan. And as we do that, to your point, Laura, we are going to continue to pursue the clinical programs, and Jim will continue to advance the discovery stage programs. And we are very interested in adding to that. 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.

Hence the discovery stage per programs and we are 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 <unk> and his and his interest index expanding this and also the team that we've built here and I will take them comment on this as well, but we've brought some clinical team members and overall team members that are expert at doing exactly these programs.

Bruce Goldsmith: And LSA can comment on this as well, but we've brought in some clinical team members and overall team members that are experts at doing exactly these programs. Elsa, do you want to add a few comments? Yeah, just to say

Want to add a few comments yet.

2.

2 aspects.

Elisao Salinas: There are two aspects to this decision. One is the desire to balance and diversify our pipeline.

Decision.

1 is the desire to balance on Viva C 5 or pipeline.

When you look at our pipelines very strong.

Elisao Salinas: When you look at our pipeline, it's very strong in rare monogenic diseases, in particular pediatric leukodistrophies. We have one adult indication now in the clinic. And we felt that it would be appropriate, moving forward, to add complement indications that are non-monogenic, non-pediatric, and non-rare to provide diversity of opportunities. The second aspect is that this reflects the quality of the partnership and the increased confidence that Passage and Penn discovered working together.

In random oncogenic diseases in particular.

Lucca these trophies.

We have 1 adult indication now now knowing the clinic.

And we felt that it would be appropriate moving forward to add to add on.

A compliment on indications that are non monogenic.

Non paediatric and non rare to provide diversity of opportunities. The sink on asdic is that these reflects the quality of the partnership and the increased confidence that passage and pen. These schools are working together we scrabble.

Elisao Salinas: This collaboration started about two years less than two years ago, and the confidence and the strength of working together translated into this desire to approach what I would call less linear targets where you don't find you have one faulty gene that you need to replace. So those are the two aspects that explain why now.

Based on who started about 2 years later on.

2 years ago, and the confidence in the on there.

The strength of working together translate into this desire to to to.

To approach, what I would call list lead.

Target.

You have 1 faulty gene that you need to replace so those are the 2 aspects that explains why.

Why now.

Okay. That's helpful. And then maybe 1 quick follow up question. So at the virtual MTS meeting in July it seemed like 1 trend that was emerging was increased improvement in younger patients versus older patients in a couple of different disease settings in the contact for gene therapy. So as we're thinking about G.

Laura Kathryn Chico: 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 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 same. therapeutic window for intervention

On 1 and some of these other applications I'm curious how you anticipate the phenomenon kind of replicating here and kind of the therapeutic window for intervention any any thoughts there. Thanks.

Elisao Salinas: Any thoughts there? Thank you. Yes, yes.

Yes, yes that's.

Elisao Salinas: Yes, yes, that 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 better. But we remain very humble.

The more we advance in the treatment of this.

Good getrich diseases, the more that acts young day has to be confirmed earlier intervention seems to be seems to be better.

So.

We remain very humble we.

Elisao Salinas: We know that what we're doing is research, now clinical research, but we agree that, in general, what seems to emerge is that the 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 up the possibility of a more compensatory mechanism. So while accepting what you said as a reality, you know, I remain humbly optimistic about exploration of the effects in later on, said patience for the reason I mentioned.

We know that what we're doing is research now clinical research.

But we agree that in general.

What seems to emerge is that the earlier the treatment the better 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 for for more composite already mechanism. So while accepting what you said as a as a as.

Reality.

Humbly optimistic about exploration of the effects in later on Sept, Beijing for the reason I managed them.

Operator: Thank you. And our next question comes from the line of Young Zong with BTIG.

Thank you and our next question comes from the line of young songs with P. T. I T. Your line is open. Please go ahead.

Operator: Your line is open. Please go ahead.

Hi on Mr shall for Amy Thank you very much.

Xionang: Hi, this is Xionang for Ewing. Thank you very much for taking our questions, and we are really sorry about the past of Dr. Tachi Yamada. So my first question is about the competitive landscape of the FTT program. Your competitor recently reported some face-to-read-out on the program, and the data actually shows some positive benchmarks and the slowing disease progression compared to the natural history. I just want to know your thoughts on that because the investors seem to be reacting a little bit negative to it. And what part of the data set do you think has not met the investors' expectations, and how can your programs do better?

All of our questions and we are doing a salary about the past of Doctor Tai Chi.

So my first question is about.

Parity with Netscape off on the FPGA program on your competitor had recently reported someplace queue right out on their on our program and on the data actually show some positive marker and slowing disease progression on compared to other natural history I just want to know your thoughts on that because the <unk>.

Does seem to be on like reacting a little bit left him to it and what part of that debt us that do you think have not mattering mass testing for expectation and how kangol programs do better.

No. Thank you. Thank you for the thoughts and the question.

Bruce Goldsmith: Yeah, no, thank you. Thank you for the thoughts and the question. So I'll make some introductory comments and if Elisaio wants to add anything, I'll turn it 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 excitement for the field of patients that are suffering from frontal temporal dementia and hope that this would move forward.

So I'll make some introductory comments on <unk>.

I want to add anything turn it over to him so.

The mechanisms.

For the data.

Generated you mentioned are completely different and I think that that's 1 of the outstanding questions that we have always raised but we're also balanced in our I think.

Excitement I think for the for the field of patients with that are suffering from from for instance, number of dementia and hope that this would move forward.

So the day that you mentioned is specifically around a monoclonal antibody that delivered in a relatively high dose every for weeks and that debt blocks a receptor that uptake per.

Bruce Goldsmith: So the data you mentioned is specifically around a monoclonal antibody that is delivered at a relatively high dose every four weeks and that blocks a receptor that uptakes pro-granuline intracellularly, and then the site of action for pro-granuline is intracellular. So one of the things that 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 progenital levels are essentially getting back to relatively normal. And that further raises the question about where the prognuline is. Is it outside the cell? or is it intra neuronal?

Program Yolande.

Intracellular Lily and then the site of action for programming Allen is intercellular, so 1 of and what.

What the data showed from those studies in earlier studies is that the level of programming on that was achieved was about double.

The starting starting level in both preclinical models as well as in CSF as well as in Sierra.

And that means that the programming on the levels are essentially getting back to relatively normal.

And that that further raises the question about where the programming on line is is it outside the sales or his interest in trough neuronal.

And I think your point is that how does that <unk>.

Bruce Goldsmith: And I think your point is that how does that, you know, investors, I think, and some of the questions we've seen are how does that translate into clinical benefit, biomarkers, neural filament, light marker, etc.? And those are very complex questions to answer, and perhaps, you know, the phase two data is not mature enough to understand that, and they are running a phase three study to try to fully characterize it. The last point I'll make, and turn over to LSAO for their comments, is that our approach is a gene therapy to increase progranuline, and what we've seen in preclinical models is that we can get over 50 times the level of normal prognolum.

Investors I think in some other questions, we've seen or how does that translate into clinical benefit biomarkers neurofilament white marker et cetera.

And those are very complex questions to answer and perhaps.

The phase 2 data is not mature enough to understand that and they are running a phase III study to try to fully characterize it.

The last point on making turnover telesales for other you for their comments as our approach is a gene therapy.

Increased program, Ireland, and what we've seen in preclinical models is that we can get over 50 times the level of normal programming.

And so that gives us the opportunity to really drive for granular exogenous New program island 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.

Bruce Goldsmith: And so that gives us the opportunity to really drive prognolin, the 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, I'll say, any other thoughts?

Any other thoughts no I think you covered it.

Elisao Salinas: No, I think you're cool for it.

Okay. Thank you very much.

Xionang: Thank you very much. Thank you.

Thank you.

Operator: Thank you, and our next question comes from the line of Danielle Brill with Raymond James.

Thank you and our next question comes from the line is Danielle proud with Raymond James Your line is open. Please go ahead.

Operator: with Raymond James. Your line is open. Please go ahead.

Hi, guys. Good morning. Thanks, So much for the question then first allow me to extend my condolences about touchy passing as well.

Danielle Brill: Hi guys, good morning. Thanks so much for the questions.

Danielle Brill: and First, allow me to extend my condolences about Tachi's passing.

So I have a couple on.

Danielle Brill: So I have a couple. First, I'm curious about how you define early symptomatic FTV in the uplift study. Do you have a maximum NFL cutoff for inclusion, or do CDR scores correlate with NF level in FD? And then, I'm curious about your thoughts on FDA's upcoming AAB vector adcom meeting. Are you at all aware of the agenda and any thoughts on potential implications for your programs? Thank you

First I'm curious about how you are defining early symptomatic FTB in the uplift study do you have a maximum NFL cut off for inclusion or do CVR scores correlate with and that's on the and that's C. D. And then I'm curious about your thoughts on the upcoming AAV vector AD Tom meeting R U.

All aware of the agenda and any thoughts on potential implications for your programs. Thank you.

Bruce Goldsmith: 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.combe. If I'm a little bit wrong, please refer to that for the final numbers.

Yes so.

Yeah on the on the FTB program.

Is 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 clinical trials Doug.

A little bit wrong, please refer to that for the final numbers, but I believe it's around 5 to 1 in terms of the CVR scores and the NFL level is actually a high level of NFL in serum. The reason those 2 things are combined is that we are.

Elisao Salinas: 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 are taking an early onset, but there have been some studies that show higher NFL levels are correlated with a faster progression. You know, 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 Elseo if there are any other comments or does that capture general? And again, I may have the cutoff on C.R. slightly incorrectly, but nope, that's perfect. No, that's incorrect.

Taking early onset, but there have been some studies that showed higher NFL levels are correlated with a faster progression.

Obviously, not great for the patients, but from a clinical study perspective. It does tend to select the patient population that is that is.

Optimal to study potentially and.

And so on pause there and ask I will sail if.

Any other comments or does that capture generally and again I may have the cut off on C. R slightly incorrectly, but nope this permit.

That is correct and that comes with it is that 1 is that on.

Bruce Goldsmith: And the concept is that one, and remember that this is a first study in patients where the objective is to pick up, hopefully, strong signals. And therefore, that's why the emphasis is on. Some 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 progression of the disease. One quick comment about the data that has been shared there recently, which is great for the field, great for patients, and great for all of us.

On remember that this is the 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 the menendez.

Presymptomatic as reflected by the CVR, a for 521 and the high level of NFL that might indicate a faster faster.

Evolution of the this is 1.1 quick comment about the the debt that has been.

Sure There recently, which is great for the field Refurbishments great for all of US I mean, 1 of the most difficult things to predict in dementia in general, including FTB is the future rates of decline for population of patients.

Bruce Goldsmith: I mean, one of the most difficult things to predict in the general population, including in FDD, is the future rate of decline of a population of patients. When you look back, you can see how this population of patients declined at this rate, but then taking the same patients, putting them in a trial, and observing them might bring surprises, as we have seen in the last 20 years of trials in dementia so far.

When you look back and you can see what this population of patients decline at this rate, but then taken the same patients put on the name of the trial and absorbing them might bring surprises as we have been seen in the last 20 years of trials in dementia. So far.

Bruce Goldsmith: 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, potential toxicity risks that will be focused on onogogenicity, so, you know, generation of oncology, hepatotoxicity, thrombotic events, and then neurotoxicity. One is kind of on MRI, and the other is on DRA, you know, generally related to DRG.

And so on the second question, Yes, we're obviously very focused on.

The the advisory committee that will come up.

Our understanding is that there will be 5 types of toxicity.

Potential toxicity risks there will be focused on.

Oncogenic Genesis so generation of oncology Hepatotoxicity.

Thrombotic events, and then Noora and then 2 types of neurotoxicity, 1 is kind of on MRI and the other is on.

Generally related to Georgi.

Bruce Goldsmith: You know, we're absolutely in discussions here internally and also with Jim and his group, who have obviously been in the leadership position in many of these potential areas. And, you know, I'll just mention DRG, for example, I think we're one of the only companies that are proactively working right now. monitoring nerve conduction velocity or sensory neuron activity in all of our studies to try to evaluate whether ICM in these patients has some kind of clinical or subclinical manifestations.

We're absolutely in discussions here internally and also with Jim and his group who have obviously been on on the <unk>.

Leadership area in many of these these potential areas and just mentioned on Deogee. For example, I think we're 1 of the only companies that are right now proactively monitoring.

Europe, conduction velocity or censoring or on activity and all of our studies to try to evaluate whether.

ICM for these patients has.

Some kind of some 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.

Bruce Goldsmith: We've never seen these, but we do believe that it's the right thing to do to continue to study them. But we've also talked about how the amount of experience in any one of these toxicity is actually still vanishingly small. So there have been, for example, MRI toxicities that have been noted, but they're also in patient populations in the tens, not in the thousands or hundreds of thousands. So this is evolving. And so I guess our general comments are that we are absolutely aware of this.

But we've also talked about that the.

The amount of experience in any 1 of these toxicity is actually still vanishingly small so there have been for example, MRI note tucked.

Toxicities that have been noted noted but they are also in patient populations in the tens not in the thousands or hundreds of thousands. So this is evolving.

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.

Bruce Goldsmith: 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 kind of 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 adcom very carefully.

Systemic talks and focus focus is us now on the DRG area, which we've been very clear about.

For the for the past couple of years and is built into our design. So that's our current perspective, we're obviously going to be looking at that at com very carefully.

Danielle Brill: Got it. Thank you so much. Very helpful.

Got it. Thank you so much very helpful.

Operator: Thank you. This does conclude today's question.

Thank you just does conclude today's question and answer session as well as today's conference. Thank.

Operator: answer session as well as today's conference. Thank you for participating, and you may now go

Thank you for participating and you may now disconnect.

[music].

Operator: and you may now disconnect.

Operator: Thank you.