Q4 2020 Passage Bio Inc Earnings Call
Thank you for holding good morning, and welcome to the passage bio fourth quarter and full year 2020 of financial and operating results conference call at the time, all participants are in listen only mode.
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'd like to turn it over to Stuart Henderson, Vice President of Investor Relations and strategic Finance Stuart. Please proceed.
Thank you operator.
Morning, We issued a press release sort of outlines the topics we plan to discuss today.
This release is available on the passage bio website at investors the passage bio dot com under the news and events section.
On today's call Bruce Goldsmith, President and Chief Executive Officer, and Rich Morris Chief Financial Officer will review, our fourth quarter and full year, 2020 financial results and discuss recent business highlights.
The Romano, our Chief Medical Officer, and Joe quickly, our Chief operating Officer will also be available for the Q&A portion of the call.
Yeah.
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.
Our expectations of timing and execution of the 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 candidate to treat the respective target monogenic CNS disorder.
Manufacturing plans and strategies.
And with respect to the financial performance and cash flows the comp.
And he has the ability to fund research and development programs and impacts of the COVID-19 pandemic on the company's operations and it's the ability to manage costs along with the 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 the 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 reflected the or circumstances that occur. After this call.
It is none of my pleasure to pass the call over to CEO Bruce Goldsmith Bruce.
Thanks, Stuart and thank you all for joining US this morning, let.
Let me begin by remarking on the critical year of accomplishments, we had and passage bio in 2020, despite the COVID-19 pandemic and other challenges we all faced last year.
Our companies work is grounded in the mission to develop life transforming therapies for patients with devastating CNS disorders.
We view 2020, as a foundational year and which we focused on preparing for a successful transition to a clinical stage company and 2021.
We began 2020 with the successful IPO, which gave us the strong financial position from which to build we further strengthened our financial position earlier this year with the public offering that raised $166 million and net proceeds.
And our work over the past year focused on advancing three programs all of which are set to begin clinical development and the first half of this year PV GM of one for Jim on Gangliosidosis PV care of three for Krabbe disease and P. D. F. T O two for frontal temporal dementia with granular and mutations.
We recently received regulatory clearance in the U S U K and Canada for the global P. B G. M O. One phase <unk> clinical study imagine one for the treatment of patients with infantile G M. One.
We've also activated our first site and the U S and are currently recruiting patients.
The other site Activations are in progress and we continue to expect to dose our first patient and the first quarter of 2020 one.
In early 2021, and we also received FDA clearance for the IND applications for two additional programs and early infantile krabbe disease, and and frontal temporal dementia with granular and mutations.
Other recent regulatory actions to take note of our orphan drug and rare pediatric disease designation from FDA for both the G M one and credit programs.
Adoption of a positive opinion by the European Medicines agency for PV care of three Crab Bay the.
These four a orphan drug designation.
We expect the European Commission to endorse the positive opinion by the end of the quarter.
Just recently FDA granted our F. T D program and fast track designation, which is designed to facilitate the development and expedite the review of drugs to treat serious conditions and.
And with and fill unmet medical need our FTB program also received orphan drug drug designation earlier this year from FTA.
We have also made important strides expanding our patient identification and engagement efforts, which are crucial to advancing successful gene therapy programs.
For our G. M. One program and addition to our ongoing natural history study with the pins orphan disease Center, we have collaborations with and Vijay and New York screen plus to help identify patients as early as possible, who may be able to benefit from our investigational therapies.
We are also sponsoring genetic screening and counseling for patients with F. T. D. While also engaging STD trial sites that are participating and the ongoing all F. T D and Gen feed natural history studies, which may be helpful to identify patients for enrollment and our clinical study.
On the manufacturing side, we are establishing internal and external manufacturing capabilities to meet the needs of our growing pipeline. This includes initiation of the vector manufacturing and our dedicated cgmp suite of Catlin late last year as.
As well as the planned opening of our own CMC lab and the second quarter of this year to support analytical development and clinical product testing and assay validation the.
These together with our supply chain partnerships will enable us to advance our growing pipeline and will provide us with increased control and flexibility across our global end to end clinical supply chain.
As I said at the outset, we have been able to support all of these initiatives from advancing our pipeline programs to supporting various patient identification and engagement initiatives to bolstering our manufacturing capabilities and large part because of our strong financial position and our experienced team.
And 2021, we continue to operate from a position of financial strength and our priority will be progressing our three most advanced programs through clinical development as well as continuing to expand our pipeline and the internal operations.
The advancement of passage buyouts deliver three programs to the clinical stage as well as continued advancement in our earlier pipeline demonstrates the extremely productive collaboration between passage bio and Jim Wilson and the gene therapy program of 10.
We anticipate 2021 and beyond to continue that strong partnership.
With the shared goal of advancing programs to patients with rare CNS disorders.
I will spend the next portion of my remarks updating you on each of our plan and clinical development programs.
Let's start with our imagine one study for infantile G M y.
As I mentioned, we are extremely excited to have received regulatory clearance and be moving our first assay into clinical development.
As a reminder, G and one is a devastating rare monogenic recessive lysosomal storage disease that impacts of patients worldwide. It is caused by mutations and the G. L. P. One gene and cutting the enzymes beta galactosidase.
We are targeting the infantile form of the disease, which is the most severe with a very rapid disease course, and no current treatment options beyond supportive care.
T V. G. M O. One utilizes of next generation AAV <unk> 68, capsid administered through the interest cisterna magna to deliver of functional G. L. B, one gene encoding beta gal to the brain and all sorts of peripheral tissues.
Published preclinical data from GTT in the peer reviewed journal human gene therapy supports the potential of P. B G. M of one is the treatment for GM on.
Our phase one two trial imagine one is of global open labeled dose escalation study of PV GMO, one administered by a single injection into the cisterna Magna and subjects that early and late onset infantile G. M. One and the study will enroll a total of four cohorts of two patients each with separate dose.
Escalation cohorts for layoffs set infantile and early onset of infantile G M. One.
As I mentioned earlier, we have activated our first site and expect to dose our first patient in this quarter.
We also expect to report 30 day initial safety and biomarker data specifically the impact on beta Gal enzyme activity from our initial cohort in mid 2021.
We are actively screening eligible patients for the trial and Activations are underway for additional sites. We plan to open 10 sites globally and currently have clinical trial authorizations and the U S U K and Canada.
We are also and discussion with regulatory agencies, and key physicians, and Brazil, and Turkey, both countries in which Theres a higher incidence of <unk> due to a founder's effect.
As we continue to bring on clinical sites, we are wrapping up of patient identification and education efforts.
This includes our partnership with and VK, a leading medical genetic testing company as well as our sponsorship of the New York screen, plus pilot program, which offers newborn screening for rare diseases.
Additionally, we have strong relationships with the site coordinators and investigators that are driving the study forward.
Turning to krabbe disease of the Ft D. G. R and we are very happy to receive IAG clearance from FDA for both programs and preparations for the phase one two trials are continuing and we anticipate the start of both trials to occur and the first half of this year with the initial 30 day safety and biomarker data Readouts in late 2021 or <unk>.
Early 2022.
As we seek to expand our reach to patients around the globe for these two indications. We are also filing for clinical trial authorizations and countries outside the U S and we'll provide further updates on those regulatory filings as appropriate.
Next I will give you a brief overview of the programs for krabbe disease and F. T. G G R and starting with Krabbe disease.
P. D care of three is being developed for the treatment of early infantile krabbe disease or Globoid sell Luca dystrophy of rare lysosomal storage disease caused by mutations and the gene encoding the enzyme collective filtering the days or galaxy.
This results and rapid progressive damage to both the brain and peripheral nervous system and if untreated leads to mortality by two years of age.
TB care of three utilizes of next generation AAV, <unk> 68, capsid to deliver DNA and coding and collect of cell surveys enzyme to patient cells.
Our phase one and two trial will be and open label dose escalation study of PD care of three administered by a single injection into the cisterna Magna and pediatric subjects with early infantile krabbe disease.
Our first goal of the study is to demonstrate the P. D care of three is safe for patients with early infantile krabbe disease. Our second goal is to demonstrate an increase and galaxy.
We hope to demonstrate this increase in the biomarker and both cerebral spinal fluid and sort of serum of patients.
The dose escalation portion of the trial will look very similar to the design for our G. M. One program separated by dosage and by age group.
And we'll be enrolling a total of four cohorts of three subjects each with separate dose escalation cohorts based on age and enrollment we will initiate dosing with the low dose of PV care of three and the first cohort of subjects, who are between four and nine months of age if.
If deemed safe and tolerable and we will move into a high dose cohort and subjects, who are also between four nine months of age and a low dose cohort and subjects, who are between one and four months of age.
Our final dose escalation cohort is planned to evaluate a high dose and subjects between one and four months of age.
These dose escalation cohorts and will be followed by a confirmatory expansion cohort for both the age groups.
The initial data readout from the first cohort will include 30 day biomarker and safety data.
As I've discussed for other programs and as the case with all rare diseases patient identification is the main focus point, especially when considering the early of devastating impacts of the disease such as crab day.
To support this weird and working with leading physicians and patient groups on and initiatives initiatives to expand newborn screening.
Turning our attention to P. D F T O two for F T D granular and.
Which is an adult condition generally affecting patients and their fifties, but can impact adult as young as the thirties F. T. D is one of the most common causes of early onset or midlife dementia.
Causing impairment and behavior of language and executive function and and occurs at a similar frequency to alzheimers disease and patients younger than 65 years old.
And approximately 5% to 10% of individuals with F. T D. Three to 6000 patients and the United States the.
This disease occurs because of mutations of the GR and gene, causing the deficiency of programming line.
The mechanism by which pro granular deficiency results and F. T. D is uncertain, but increasing evidence points to pro granule and its role and lysosomal function the.
And the rapid progression of F. T D results and average survival of only eight years after onset of symptoms.
As a reminder, P. D F. T O. Two is the gene therapy that utilizes and AAV, one vector to deliver to the brain of functional granular and gene encoding the pro granular and protein.
And of preclinical study by GTT published and the peer reviewed scientific journal of animals of clinical and translational neurology a single administration of P. D. F. T O two via the optimized a the one G R and vector and demonstrated CSF pro granular and reaching levels of more than 50 fold supporting our advancement of P. The FTE.
Oh two into clinical study the.
The phase one and two program will be and open label dose escalation study of P. D. F. T O two administered by a single injection into the cisterna Magna and subjects with early symptomatic S. T D of pathogenic mutations and the pro granular and G. R. F T D G R and.
We have two key goals for the phase one two study our first goal is to demonstrate that P. D. F. T. O. Two is safe for patients with F. T T. J R and our second goal is to demonstrate increased pro granular and levels and the CSF. We are and we will enroll two cohorts of three patients each with an optional third cohort and.
And we'll initiate dosing with the Lotus of P. D F T O two and the first first cohort as is typical for a dose escalation study if the low doses well tolerated, we will study of higher dose and the second cohort.
The initial data readout from the first cohort will include safety data and 30 day biomarker data, including change from baseline and CSF program and the other levels.
As we have discussed ft D is a devastating disease that impacts patients worldwide and we are dedicated to serving patients and the U S and across geographies.
And we've continued to build relationships with patient groups to help increase the potential reach of our programs and are working to support genetic screening and counseling to patients with F. T D free of charge.
As we embark on all three clinical development programs and the safety of our patients is our top priority to address the current challenges associated with COVID-19.
We have implemented approaches such as remote assessments, where possible and costs of air services through third party vendors to facilitate travel to the increase burdens and restrictions.
We believe these measures will provide patient support while also maintaining the rigor of our clinical trials and our ability to provide these potentially life altering therapies to patients.
Again, we are very excited to have received regulatory clearance for all three of our lead programs and look forward to providing further updates as we begin dosing patients in the coming months.
Turning to manufacturing as I mentioned earlier, we have made important progress this year towards establishing both our internal and external manufacturing capabilities.
Manufacturing capacity has been a key tenant of our strategy since launching the company and secure and control of our supply chain is an important part of our differentiated approach as we continue to advance and grow our pipeline.
Some recent accomplishments include initiated vector manufacturing and our dedicated cgmp suites at the Cadillac cell and gene therapy facility, and Maryland signed a lease for our manufacturing laboratories at the Princeton and West Innovation campus, and Hopewell, New Jersey, which we plan to open and the second quarter of 2021, and which we'll see.
Support analytical development as well as clinical product testing and assay validation.
Established of flexible global end to end the clinical supply chain by entering into a number of partnerships and supply agreements. These agreements span from plasma and production for our vectors to clinical of packaging and on demand and global distribution to our clinical sites based on patient need.
We are pleased to share that our clinical supply for PB GMO one for a phase one two of match one trial manufactured through our partnership with Cadillac is already in place.
We have also manufactured clinical supplies to support initiation of our clinical study for our next two of US advanced programs for Krabbe disease and for F. T D GRN.
Finally, we want to note that in 2020, we invested to substantially expand our R&D and manufacturing internal expertise in 2020, one and we are continuing to hire key talent to ensure superb execution of our clinical trial programs and our end to end manufacturing processes with the goal to be a leader and delivering transformational gene therapies to patients.
And with that I will turn the call over to rich to give of financial update.
Thank you Bruce.
And as Bruce mentioned, we have secured incredible financial security of the past year.
Which will enable important optionality and we continue to advance and grow our pipeline.
As we reported in our press release. This morning, we ended the year with cash cash equivalents and marketable securities of approximately $305 million as compared to $159 million as of December 31 2019.
In addition, we also received $166 million and net proceeds from our recent public offering which together we expect to fund our operations for at least the next 24 months.
R&D expenses were $81 $8 million for the year ended December 31, compared to $29 $7 million for 2019.
The increase was primarily due to an increase of $24 $7 million and clinical and manufacturing costs and increase of $6 6 million and preclinical research and development costs incurred and preparation for <unk>.
The filings.
$4 $4 million increase and clinical development costs.
And of three 4 million dollar increase and consulting expenses as we prepare for clinical trials to begin and the first half of 2021.
We also had the $12 5 million dollar increase and personnel related costs, including share based compensation due to increase of employee head count and the R&D function.
G&A expenses were $31 million for the year ended December 31st.
Compared to 7.0 of million dollars for 2019.
The increase was primarily due to a $15 $3 million increase and personnel related and share based compensation expense due to increases and employee head count.
On the facility costs and professional fees also increased by $4 $6 million and $3 $3 million, respectively. As we expanded our operations to support our research and development efforts.
Net loss was $112 $2 million for the year ended December 31, 2020, compared to $45 $6 million for 2019.
Now I'll turn the call back to Bruce for closing remarks.
Thanks, Rich looking ahead, we continue to establish passage bio is a leading clinical stage company focused on developing life changing therapies for patients with rare monogenic CNS disorders. As a reminder of our key anticipated milestones for the upcoming year or two.
The dose the first patient and the phase one two trial for the treatment of patients with infantile G M. One and the first quarter of 2021.
Report initial 30 day safety and biomarker data from that trial and mid year 2021.
Initiate phase one and two trials for the treatment of F. T. D. G. R N and for the treatment of early infantile krabbe disease and the first half of 2021.
Open our CMC research and development site and the second quarter of 2021.
And finally to continue to advance preclinical programs for MLD, a L. S T and teach way and our undisclosed program and adult CNS and bring additional candidates forward.
Before taking your questions I'd like to take this opportunity to recognize and thank the team here at passage bio and our partners at tens GTP for their hard work and diligence that set the stage for it is going to be of milestone filled year to come.
At this time, we'd like to open the call up for questions operator.
As a reminder to ask a question you wanted the press star one on your telephone to withdraw your question price of the balance of <unk>. Please standby, we compile the Q&A roster.
Our first question comes from the line of on no problem Rama from JP Morgan. Your line is now open.
Hey, guys. Thanks, so much for taking my question.
Bruce just wondering what are the gating factors to dosing that first patient and GM one.
And can you remind us I think you mentioned on the call 10 sites that you're opening up for <unk> is that going to be site overlap with crabbing and MPD. Thanks, so much.
Hi, and thanks, very much for the question and and good morning.
So.
I'll talk a little bit and turn it over to Gary for additional remarks, so as we mentioned on the on the call. We do have the manufacturer of the supply of manufactured and ready to distribute so.
That's certainly and place as we I think highlighted also and his update on our clinical trials dot Gov for the trial listing.
We have we are starting to recruit with the one site open and.
And we're continuing to.
And.
And as well.
And maybe Gary you could talk about just.
So we're going through in terms of additional patient identification and then the comment on overlap between <unk> and GM on.
Thanks Bruce.
So there is we've seen a lot of interest and the trial as evidenced by the number of caregivers contacting us through our patient portal to acquire by the eligibility and enrollment.
And we as we've outlined before we are.
The number of engagement initiatives.
To help us and enrolled trial.
Including engagement with the rare disease community and specific advocacy groups. We have of course, very strong relationships and sites and study coordinators and investigators.
We are decreasing burden the trial participants by having a strategy for remote visits and video.
In home video.
And assessments as well as and hence travel service services and we're also havent been the outreach program working with the <unk> to identify patients as rapidly and as early in disease as possible regarding the sites and we're planning to open at least seven sites globally and we currently have as Bruce mentioned regulatory clearance and.
The U S, Canada, and the U K and we're also looking to open sites, and Brazil, and Turkey, where there's a higher incidence and due to the founder's effect and.
And Brazil, we're working with Dr. Rebecca Giuliani and some world renowned experts and just one example of our relationships.
Guarding overlap of sites there is some overlap between sites between.
The crab.
<unk> and J M. One program.
But the the.
The as the look of dystrophy, which is different from Jan one and so we have a concentration of sites that are well known.
Sites that received many referrals from catastrophe patients for the credit program.
Thanks, so much for taking our questions.
Thank you. Our next question comes from the line of <unk> Richter from Goldman Sachs. Your line is now open.
Okay, so onto Q&A.
You saw and.
Hello.
Yes.
Yes, yes.
Hello.
Yes. This is Bruce and just wait and see and take your questions.
Oh, so sorry about that.
Operator, maybe we lost all of it so.
Thank you. Our next question comes from the line of the around the World from Cowen. Your line is now open.
Hi, This is brendon on for your own thanks, very much for taking the questions and congrats on the team all of the solid progress on just.
A couple of quick ones from US first just about the data readout and G. M. One thanks for all of the detailed and the design.
Wondering maybe what your plans are and maybe the threshold for that relief or kind of how many patients that which dose levels youre hoping to include on.
And whether that would be kind of more of a press release or a medical meeting kind of thing.
And then just quickly on the pipeline wondering if youre planning to release any of the preclinical data from the MLP or <unk> programs. This year, thanks very much.
Hi, Brian and thanks very much for the question.
Yes. So the first question on the on the readout in mid year for for GM on which focuses you on 30 day sales.
Safety and biomarker data and particular beta galactosidase enzyme activity.
What we've said is that it'll be available and the middle of the year I don't think Theres. The medical conference that sort of the kind of completely aligned with that so we may release that the via press release.
I think we have to determine the final form of that as we approach.
And then the second part of that question was what.
And basically what kind of patient data in terms of numbers and the way. We've always positioned this is that we really desire to release data on on.
Complete cohort and and this particular trial design.
For G M. One and the late in the late onset of infantile patients cordis.
CT is two patients and so we would expect to to report on those on those two patients and obviously.
That would also be contingent on bringing that data to D. S. N V. And then also thinking about expanding.
Both to a.
Higher dose for the late onset patients and then the lower dose for early onset patients later this year as well. So that's that's how we think about the the release of the initial data.
And.
On your <unk> can you repeat your second question and I apologize.
Thanks very much.
Just about if you have any plans kind of at least of any of the preclinical data from the MLP of Atlas program.
Yes, that'll be dependent on both the.
The Congress availability and abstracts that were submitted and that might be submitted as well as the.
And the papers that are written by by Jim Wilson and his team and at GTP as you know the they're responsible for the preclinical data so until those become public in terms of any potential papers et cetera, we're not commenting on when those data would be released.
Okay, great. Thank you very much.
Thank you.
Thank you. Our next question comes from the line of <unk> Richter from Goldman Sachs. Your line is now open.
Good morning, Thanks for taking my question on price and the technical difficulties earlier on.
And you could just talk about and the natural history work that you're doing for these indications and how thats playing out.
And in cadence with running your clinical trials and then also.
And you look at the pipeline that's coming from.
And how you're thinking about prioritization of that on the board.
Sure so.
Why don't I make a brief introductory covenant and I'll give it to Gary to talk about how we're approaching kind of natural history and maybe we can focus on both GM on and krabbe disease. The basic idea that we're approaching how we're approaching this is looking at from both.
Studies that we're running for example, and G. M. One we're running the study with the orphan disease Center at patent.
To create our own net.
The history data, but we're also looking at sites that might have of data and we can pull that information and.
And the whole idea is to have this as a potential comparator once the study in terms of the expansion cohorts could read out so we don't necessarily need that data of any time in the near term, but we certainly want to generate it and make sure that there is a high quality of data for potential comparison.
And maybe Gary you can talk a little bit of out in more detail about how we're pushing this with GM on and <unk>.
Yeah, Thanks, Chris So.
And Jim one we are.
We are conducting our own.
Well through the orphan disease center at Penn.
Prospective natural history study that matches, our cohort very closely on our interventional trial protocol very closely and is also being conducted at the same sites.
Sure.
And as the study is the interventional study this is to ensure comparability of the data on.
That study is enrolling and we've seen enrollment pickup recently, so we're very happy to see that we're also planning lots of access other sources of data and we've had conversations with FDA about the strategy, but I mean by that is other other data that exists either from academic cohorts.
The publications.
And Craig Hey, Thanks.
And thanks to the fact that there are a number of academic longitudinal observational studies incredibly of infants and a wealth of natural history data as a result.
And there we don't feel that it's necessary to initiate a independent of prospective natural history study.
Instead, we are engaged with those centers, who collected that data and working with them to gain access to the data.
And so in comparison to our interventional trial.
Great. Thanks, Thanks, Gary and then on prioritization as we think about new potential indications, we essentially look at a number of different attributes the the one really critical driving factor net.
And is underlying the foundation of the company is can we produce a program that is is highly differentiated and the way. We think about this in GM, one Craig E and F. T. D is are there reasons to believe that this is the key.
Capsid the vector of the combination of.
Of those or the administration for example.
Can lead to a highly differentiated and potentially best in class approach and that's certainly the driving factor behind the selection of new potential additions to our pipeline through the 10 remaining options that we have.
And then we look at things like feasibility develop ability and obviously also commercial potential at some level as well and we put them together and when we think about develop ability and feasibility. We also think about other animal models that are somewhat predictive or highly predictive can we overcome any technical challenges.
To reach the clinic and we do this in very close collaboration with.
And with Jim Wilson, and and his group ranging from the the manufacturing and vector core group to the preclinical scientists as well and so it really isn't the integrated effort to think about.
And new indications, we could bring in and that's resulted obviously in one additional indication that we that we brought and last fall, which is an a on named adults CNS neuro degenerative disease that were highly interested in and Jim and his team are now progressing from a preclinical perspective and.
And we're certainly interested in growing our pipeline more this year as well.
Thank you that's very helpful.
Thank you. Our next question comes from the line of me now.
The change of guard from Citi. Your line is now from.
Hey, guys. Thanks for taking my question.
And so I just had a question on about that the club.
The disease study.
Non clinical trial sites some.
Of the inclusion criteria and I guess can you just talk a little bit about how well the.
The criteria that youre using to screen patients and of course bonds with what's generally screen for under some of the the newborn screening programs in terms of like galaxy activity and and things like that somebody noticed that.
Thank you, our allowing pre symptomatic patients and to the study as well.
Sure.
Thanks, Dan and thanks for your question and I'll, probably turn it over to Gerry to highlight.
Several of the inclusion criteria that we think are important and kind of talk through those considerations.
Gary.
Sorry.
Yes, so for the crowd. The study we're going to enroll early infantile krabbe disease. This is patients who at the onset before six months of age and we're enrolling patients.
Who are ages, one to nine months of age.
Yeah.
Your question was around what goes on the screening and there there are enzyme activity screening for galaxy.
What we're our inclusion criteria include Gauci activity also importantly.
Whole blood Cyclizine levels, we have a threshold there that's too.
That is because cycasin levels.
And the threshold, we're using 10 nano molar is has been shown to be predictive of income.
And the early infantile form of disease, the rapidly progressive early infantile form of disease.
Also have to have biallelic pathogenic <unk> mutation or the gene variance.
As described and.
And as you mentioned, we are enrolling both symptomatic and pre symptomatic patients and this trial so.
But they have so we will have to have.
A.
The minimum level of neurological and developmental.
Exhibit the minimum level of neurological developmental function of.
And that is they can't be too far progressed to be and the trial.
We're going to be enrolling the study and two separate cohorts, we're going to start with cohorts that are the older pays to children, who are 49 months of age and then with acceptable safety initiate dosing in the younger and since once of four months of age and also dose dose escalate.
And the older and Vince.
Okay.
And.
Thanks, Gary and I think to bring it back.
Two and unit to your.
To the screening criteria and how that links to newborn screening.
On the.
It's a little bit and variable because this is state by state on the on the nine or 10 states that have newborn screening in place for krabbe disease, but all do start with I believe galaxy.
Enzyme tests and then if there is a and it is also possible to look for mutations versus but those all would then precipitate a more quantitative.
Look at either of the mutations of the Galaxy enzyme levels and then also potentially cyclizine, so it lines up fairly well, but obviously.
On the screening by any state level newborn screening would obviously be followed by our own entered screening criteria as well.
So it does line up at least at the beginning quite well and obviously there it requires additional testing.
Our entry into the study.
Great. Thank you.
Thank you. Our next question comes from the line of Diebold and Walter from Chardan. Your line is now.
Yes.
Alright, thanks for taking my call.
So you've shown that you can get three of Andy's cleared very recently.
Curious about your sort of next cluster of indications and MLD PMT.
PMT to a and the.
Adult CNS indications of question is whether there are any unique device related issues on those programs or other issues that you're focused on to move them forward and get the clear.
Yes, thanks, and thanks for the question, we're really not commenting on the other approaches we haven't kind of talked about the even the vector selection or the potential target population at this point. So we'll have to wait to talk about this as we as we defined the.
Programs.
The first three indications, where a little bit different because they were far advanced at the time, we went public and and really had a lot more detail in those.
We progressed towards both filing and then obviously for the IND approvals and we're likely to follow the same pattern, which is as the program moves through for example, and.
IND, enabling studies as well as.
And potentially.
Showing activity and in various models of the disease models, we'll give more and more detail as those progress the right now we're not.
Willing to kind of give that information publicly because it just hasn't been completely defined at this point until we have of candidate.
Sure.
I mean, you got the same response to the next question So forgive me, but.
And the <unk>, we've seen for example, I think one preclinical programs, it's been sitting there for <unk>.
Five years Outswear.
Can you talk conceptually about what issues, you're trying to overcome to ensure your program moves to Kurt.
Clinic, and a reasonable amount of time.
Yes, I think yes.
Without going into a lot of the details I think what Jim and his team are looking at are.
Both the expression of of the particular enzyme as well as.
Suppression of the.
The mutation and C&I north.
And the balance of that as well as readouts in and potential disease models as well as part of the dynamic models and those would kind of give us the clear pathway forward.
Or the decisions that we have to make too to revisit the.
And the constructs and I think that that's what some of the other companies of also face. The you are alluding to so we're being very.
I think careful and.
Judicious in our in our preclinical work that again Jim's conducting to de risk this as much as possible before we before we move forward.
Alright, thanks, and congrats on the progress look forward to the biomarker data and the euro.
Thanks.
Thank you. Our next question comes from the line of Laura Chico from Wedbush Securities. Your line is now open.
Good morning, and thanks for taking the call I guess first question certainly looking forward to the safety biomarker data for <unk> and the middle of this year, but I'm wondering if you could elaborate a little bit further on potential timing of clinical data and.
And kind of given the size of the cohorts just trying to understand what would you need to see at this stage from the clinical data to advance further studies and then I have one quick follow up after that.
Yeah, no. Thanks very much for the question and thanks for joining us so.
And the way, we're thinking about the support for GM on and crap, a and also for FTR all.
Trying to look at as much natural history diseases of the disease as we can.
And to think about what could trigger the expansion and and obviously the primary goal of all of the initial cohorts is clearly safety, but then we're going to look at either enzymatic activity or in the case of F. T D.
Looking at pro granule and levels.
And and then potentially and.
And those early stages.
All of you going to have 30 days of.
Of those of those samples.
It's really to move forward to the higher dose and in order to then progress to potential expansion expansion arms and looking at at the longer term follow up for potential biomarkers of disease progression or disease.
Modification. So the early decisions I think and I'll turn it over to Gary as well if he of has any additional comments, but I think the early decisions are really about safety and initial view of.
Of the enzymatic activity or protein levels that were able to achieve Gary is that is that a fair summary of do you have any other yes.
Well I think I think you covered that very nicely.
Around the biomarker data I think what part of the question was also around when are we going to know if it's of clinically effective and the.
And just make a couple of comments here maybe.
The overall, depending on the age of onset for these patients therapeutic effect on developmental trajectories of some sort of.
What are our clinical and clinical.
Objectives of outcomes are.
And can take up to 24 months. So the primary efficacy endpoint is.
And so therefore, the 24 months, although we'll certainly evaluate clinical changes throughout the study of defined points.
I think it's important to remember that the children with the GM one show rapid developmental progression and have lots of development of milestone starting on six to 12 months of age.
And <unk>.
After we.
As Bruce mentioned and look at enzyme activity and disease progression markers with longer term follow up and expansion of the cohort will then the search impact on patient developmental trajectories and demonstrating that the treatment is from store developmental potential and as part of the positive effects on patients' quality of life.
That's really helpful. Gary and thank you very much and then one quick follow up.
Mentioned the <unk> <unk>.
The collaboration and wondering if you could talk a little bit how that compliments of fits into your own and how strategies to identify patients and I guess, if you could walk through the mechanics, and how that information is conveyed from and Vijay at the passage of that would be helpful. And I guess basically just could there be ways to further extend this collaboration to the other disease settings.
Outside of the <unk> that passage is working on thanks very much.
The great question and yes.
Maybe I can turn it over to.
To gel to kind of highlight how the programs work together and how we're thinking about.
Both distributing information and integrating that information into our in house and and again to your point, how it works not only with Jim on how we're thinking about the future as well Joe.
And so.
And the PE and hedge.
And you know it is providing a great service.
For a patient and so essentially what we're sponsoring and care and <unk> and.
Free genetic genetic screening and so when the patient is identified.
Yeah, that's the levels or other things and there is temporary and kicking and screaming.
And that paid for its free on that yet.
Okay.
Weighted that feed into the passage.
Obviously and I'll get patient specific information on that and importantly, the patient now has the diagnosis and hopefully early on.
Half of our large received it and they receive clinical trial information Kieran and the poultry the progression so there'll be notified about Sydney and.
Thanks Bonnie.
And then maybe what the funnel through the system and that way.
We're excited about and detailed coming on board, it's definitely important for early patient identification and.
And our longer term view towards identifying patient pumps from moving into a commercial product.
Thanks very much.
Thank you. Our next question comes from the line of David Loeb share.
And so pardon the pun.
Your line is now open.
Hi, guys. Good morning, Thanks for taking my question. This is Aaron on for <unk>.
So I just had a question on how much should we read through on the rest of the basal ganglia from the G. M. One study two the at TD study.
And it's there.
And the different vectors.
And I know that Avi one was selected price transaction of the appendant wholesales, but how well does the transduce neuro and especially relative to a b and <unk>.
Yes, thanks very much so the.
The GM, one and <unk> and Crab day program both of US <unk> 68, and if I was just in terms of your question Youre talking about the the the DRG neurons is that.
Yes.
Yes, so yes.
And maybe I'll have.
Gary comment a little bit about the AAV, one both of attainable and and other transduction as well, but let me first backup and say that we've reported and been very clear that.
All of the all of the programs do you see.
Some of DRG.
Neuronal death, and ex and apathy.
However, and all of our studies, we have not seen this results in any.
On a gross Symptomology, obviously can't ask a non human primates, but.
And we can we can assess the behavior and the ending of the studies there was not any clinical manifestations that we could we could see.
We did see a decrease in.
The the sensory neuron.
The action potentials, and conduction velocity, and we're going to be monitoring that and and.
We'll continue to do that because we think it is important to.
Investigate this and.
And patients as well.
And it's also important to note that Jim put out of paper.
Last summer the essentially across.
Multiple different studies routes of administration and also different.
If and avs.
He did see this dorsal root ganglion toxicity.
And in.
Basically across the different subsidiary of the different studies in non human primates. So it seems to be somewhat.
Agnostic as to the growth.
Capsid as well as the route of administration, although it certainly is influenced by the levels achieved in CNS and so we're going to monitor this but where we haven't seen anything clinically.
To date in terms of our actual non human primate studies.
So.
Maybe I'll turn it over to Gary to talk and give any more detail, but also to talk about.
And the AAV, one you mentioned the pinnacle sales, but that's not the only sort of gets turns do so maybe you can talk about anything that I missed on DRG and.
And the JV as well.
Thanks, and I think.
The D R T and happy to take any follow up questions here regarding the question about the.
I think you're asking about the bio distribution of those vectors.
So.
And we see we see broad brain bio distribution with both.
<unk> hundred 68, which is the bearing today of benign.
And with 81.
And it's really.
The high very very comparable the difference is with AB. One is that we also see very high transduction of the pendulum will cells the cells and line of CSF spaces, and the can secrete the railing to the CSF, we see that with a the one whereas so with much less with the with the H 68, so with the <unk>.
And we see about 50% of the Panama sales of transduce.
Where it's about one of 2% with 868.
And a disease like per granular.
FTE per granular where we.
I believe the super physiological levels and CSF for granted and Theyre going to be required to correct. The intracellular deficiency for granular.
We are using 81, because we really want to try to Brian and levels up and the CNS.
And of course, we don't know that we're going to require 50 fold normal levels, which is what we've achieved in non human primates with that maybe the one vector.
But we're very happy to be able to dose escalate and determined empirically the levels of progression on.
The dose of our product that will need to modify the disease pathophysiology and contrast, and GM one.
We expect of that.
Our our doses there, which may achieve just so let me just put that with respected and Jim and Jim One we don't expect and eat super physiological levels, but if we can bring levels back to the levels of heterozygous, which are 50%.
They're completely and they have no phenotype so on.
And even patients with 20% of <unk>.
And will activity, having very mild adult form of the disease. So we feel like the bar is much flow are there.
And that's the rationale for the different vectors and there's two different programs.
Okay, Yes that makes sense alright, thanks for the answers.
Thank you.
Thank you. Our next question comes from the line of Yasmin Rahimi from Piper Sandler Your line is now open.
Hi team. Thank you so much for the great updates I have of.
A lot of very tedious questions around back all the measurements.
Critically important data readout and met the STR. So maybe we could spend some time talking about the beta Gal assay how it works.
Their ability of associated with that Mr of certain.
On consideration and.
And for CSF collection that we should be aware too.
And on contribute or reduce variability and the assay and then secondly, maybe also help us understand what our substrates for beta Gal that he was going to be measuring and hopefully sharing with us at day 30, the significance of those biomarkers as proof of concept.
And thank you for taking my questions.
Hi, Thanks very much.
The question as well.
In terms of the the details of the beta Gal assay.
Certainly turn that over to Gary to talk through and I think you were asking not only the details but also our their idiosyncrasies in terms of.
Blood and and CNS kind of measurements.
I guess garik and maybe address that you or I can jump back on and then.
Smith.
And to do that.
Yes, so sort of just.
As I think.
Understood and we are planning to of measure.
<unk> and 30 day biomarker data.
And the program is our first data readout.
And that will include.
Levels of beta kind of activity in both the CSF and serum.
And we certainly hope to see treatment related increases and beta collectivity, and those fluids and that will depend of course on the magnitude of the increase of used to be observed and our ability to detect it.
Speak to some of your questions about the intricacies of the beta Gal actually what we're using of four metric assay.
And Thats whats used.
And across the field.
One challenge is that in the normal subjects beta gal activity and the spinal fluid and it's.
Is much lower it's about 20 fold lower than it is and serum.
And another another challenge. This assay is a bit of activity is very labor. So it requires very careful sample collection and storage.
We've worked through a lot of the analytical methods to optimize this.
These factors can make detecting CSF.
Levels, and CSF, where it's much lower of challenge.
And as I said, we've developed the analytical methods to do so and we're confident we're going to be able to measure activity and serum and hope we see of Seth.
But we're not.
We're also planning to use not just fate of Gal.
Measure beta Gal directly, but also indirectly by looking at substrates measuring various substrates would pay the gal.
And also by looking at other indicators of license on the function, so ex us and many days which shows a.
A competence of Torrey increase.
And the presence of the license, but she is on the storage will.
And we'll be looking at that as well as some other indicators will be looking at the totality of the day of the beta Gal activity, but also these other.
Io markers to understand.
The impact of our treatment on beta Gal activity.
Since almost of them.
And I would just add one thing I think we've mentioned this before this is obviously an ICM injection and while there are specific technical challenges of measuring potential CSF levels, just because of the low endogenous levels of.
Of both patients without people without the disease and people with the disease, it's going to be very low, but since we're doing the ICM injection and we're measuring both CSF and serum will be we'll be very happy to see increases and serum.
And for beta Gal independently.
Independently of CSF, just simply because.
Projecting into the brain and what we see blood levels of increase that would also be a very positive outcome and then as Gary said, we're also looking at the downstream acts of some innovation and I think carriage and sulfate and some other.
Other downstream markers as well so again the way we're thinking about this as the totality of the data as well as the different compartments, both CSF as well as us here.
Thank you Bruce for the color, maybe one follow up question.
Do we have a good understanding that the day to day variability and bid on Cal activity and blood and these patients and guess what I'm trying to understand it and it is there going to be of fluctuation between the day 30, maybe.
Dave take steel.
Or even day 30 day 31.
One of the thing so I'm not sure day to day, but I know that Gary and I have talked about that we're going to try to account for any circadian rhythm changes bye bye bye asking for collection.
Similar times during the day I'm not sure if there are and these children.
For example of monthly cycles is of Great question.
And I don't know if Gary of the answer to that either.
Or is there, we'll certainly anticipate some biological variability but.
The safe to tell you that from our.
Preclinical studies, but the mice and in on Hps, we see we see durability of effect on beta Gal activity.
And.
And so.
And we think that we've been able to still measure of treatment effect over and above the biological variability.
Great. Thank you so much for taking my questions and we're looking forward to the data.
Thanks, Yes.
Thank you ladies and gentlemen. This concludes today's conference call. Thank you for participating you may now disconnect.
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