Q4 2021 Orchard Therapeutics PLC Earnings Call

Good day and welcome to the Orchard Therapeutics Q4, 2021 earnings call at this time, all participants on a listen only mode.

After the Speakers' presentation there'll be a question and answer session and instructions will be given at that time as.

As a reminder, this call may be recorded I would now like to turn the call over to CEO and cofounder Bobby Gaspar you may begin.

Hello, and welcome to Orchard Therapeutics fourth quarter and year end 2021 financial results and corporate update webcast.

And.

And cofounder Bobby Gaspar.

Before we get started I want to remind everyone. This presentation contains forward looking statements.

Please refer to the slide and our latest SEC filings for more information.

Three colleagues will be joining me on today's call.

Parker, our Chief commercial officer, who many of you know from prior events is here to discuss early launch execution with the melody and our overall commercial strategy.

Frank Thomas President and Chief operating Officer is also with Us and I'm pleased to announce Frank has extended his transition.

At the end of the year to help oversee this next phase of our development and ensure it is in the strongest possible position operationally and financially.

This continuity will be important as we progressed, our business and implement some of the changes to our portfolio that will be discussed today.

Additionally, we'll be MOBA, who recently joined the <unk> team as Chief Scientific officer will be available for Q&A. Following our prepared remarks I've done for many years going back to his early career as a cofounder of the San Rafael Telephone Institute for Gene therapy is a gene therapy pioneer.

Having made symbol contributions in the field and was most recently senior Vice President of translational Science, Idaho dentists.

We will outline during this webcast.

<unk> gene therapy platform, including the research programs intended street larger indications is a key component that will drive our growth and value creation strategy.

So we felt now was the right time to introduce who've yet to the investment community.

The business environment that we're operating in today has changed tremendously as compared to just a few years ago.

Within biotech valuations have come down substantially in the gene therapy space have been impacted even more dramatically given factors such as the regulatory environment and commercial and reimbursement landscape.

We are not standing still.

We are responding to the current environment, while ensuring our portfolio our organization and our stars aligned to support our vision of bringing these incredibly valuable medicines to patients around the world.

It is against this backdrop that we announced in this morning's press release our position.

<unk> narrowed the focus of our platform to synergistic indications, where we believe HSC gene therapy is scientifically and clinically differentiated to deliver the most value.

Importantly, the decision to narrow our portfolio and focus on the multi Ah clinical stage MPS programs in key research programs is expected to extend our runway into 2024.

US to reach several critical value creating milestones.

For the multi this one way extension will give us more time to grow revenues in Europe and establish the appropriate commercial mode.

You'll hear from Britain later of some of the recent accomplishments that give us confidence that this is the right strategy.

Also we need to ensure a runway takes us well through the regulatory approval process in the U S. In 2023 and increased focus will allow us to continue to support and even increase our investments in diagnostics newborn screening and to expand into new markets in Europe and around the world.

The runway extension also provides more time for our pipeline to mature and to continue to demonstrate what HSC gene therapy. The white modality for the programs we are advancing with.

The research programs the additional runway enables us to generate exciting data that could support the move into the clinic on our own or with partners.

So we still have an ambitious set of programs, but with a more therapeutic focus.

Wide leverage with manufacturing distribution and commercialization.

We now have a deep body of evidence that demonstrates the potential durable effects of HSC gene therapy for the treatment of certain severe genetic diseases, including MLB and MTS disorders.

Across our platform of current with all the programs, we have generated data for more than a 160 patients across seven diseases or <unk>.

Told that is collectively more than 750 years of patient data that now stretches back it's more than a decade of follow up in the air. These.

These treatment clinical trial patients.

The insights we claimed from having one of the most extensive if not the most extensive datasets in the field of gene therapy are the foundation for our go forward strategic focus and underpins our vision of ending the devastation caused by severe genetic diseases.

By executing and delivering on our mission that has guided us from source. We're confident we can create significant near term value for our shareholders and many of the communities we serve.

Now, let's take a deeper dive into why we think our platform is best positioned to address certain rare neuromuscular conditions and why we're encouraged that we can ultimately translate to clinical outcomes observed to date into regulatory and commercial success.

I'll now turn the call over to Brady, So highlights our near term euro metabolic milestone and the maladies commercial progress right.

Thanks, Bobby.

Since <unk> approval and launch in Europe , we continue to build commercial momentum with positive engagement with health technology assessment bodies and payers throughout the region as well as treating the first patient in a commercial setting.

As Bobby and I will highlight in the next few slides we are investing in the European launch of lamellar <unk> to ensure we're identifying as many treatment eligible patients as possible and in the United States. We are working urgently to submit our BLA to the FDA in late 2022 early 2023.

Our experience with <unk> is what fuels our confidence in maturing our next wave of programs for neuro degenerative disorders by the end of the year, we plan to initiate a pivotal trial for O T. L. Two O three and MTS, one Hurler syndrome and report data from the O T. L. Two O. One proof of concept trial for N. P. S. Three a we're seeing.

<unk> syndrome.

These additional indications represent exciting commercial opportunities that can leverage much of the investment we are making in the Melbourne today.

Since the launch we've invested in priority activities and initiatives, we believe will generate the most value for labelle D patients and providers.

First we activated five specialized treatment centers with relevant transplant and neuro metabolic expertise and geographically important countries throughout Europe to administer Lim L. D D.

These same centers would be utilized to support future potential launches in similar indications.

Second on the access and reimbursement front discussions with health technology assessment bodies and Payors.

Pin us to progress well.

In February we announced a historic agreement with the National Health service, securing reimbursement for all eligible MLP children in England and Wales.

In Germany, we received the highest possible therapeutic benefit rating and pre symptomatic patients by the Federal Joint Commission, we're continuing to advance reimbursement discussions in the region, including Italy, and France, and we are on track to secure an agreement in at least one additional market in the first half of the year.

So we believe the progress in Europe , and the value recognized by payers has differentiated this product and our team and demonstrated a willingness to ensure access for MLD patients across the continent.

We hope to build on this success in additional European markets and eventually in other parts of the world.

In order to help ensure we are identifying as many eligible patients as possible support for early diagnosis through newborn screening continues to be an area of focus we have four studies ongoing in Europe and one in the United States. These.

These studies are intended to generate data to advance screening and diagnosis at birth and support the adoption of regular screening at the state national and regional levels as appropriate. These.

These programs can also identify MLD patients to be treated commercially if reimbursement is in place at the time of diagnosis.

While our near term focus is on Europe , and the United States. We're also assessing how to best expand our geographic footprint over time into other areas, including Latin America, and Asia Pacific in a way that's scalable sustainable and supports our long term vision for value creation.

Our partnerships with general lack in Gen Pharm in Turkey, and the Middle East respectively are examples of how we have expanded our geographic footprint in a capital efficient manner. These.

These partnerships are already bearing fruit as we previously announced the patient from the Middle East has been identified and referred for reimbursed international treatment abroad at O. S. R. R qualified treatment center in Milan, Italy.

I'll hand, it back to Bobby to discuss our U S regulatory plans and the rest of the portfolio.

Thank you Brendan.

In the U S regulatory discussions for <unk> 200 continued to advance after experiencing some regulatory delays in 2020, we have stated the program back on track for near term filings.

This is being accomplished through several key interactions with the FDA in 'twenty to 'twenty, one to clarify the data required on the path forward for BLA.

We believe we have the data package to move forward with a submission and the team is now in execution mode, working with our clinical sites and CDM or partners to prepare the package.

We plan to have a pre BLA meeting with the FDA in the second half of this year and advance will fall, which we expect to submit in late 2022 to early 2023.

A key reason, we are placing renewed emphasis and focus on our neuromuscular portfolio and in particular next inline NPS programs because our experience with MLB provides validation that we can translate early signals of potentially transformative clinical outcomes into regulatory and commercial success.

Moreover, the infrastructure, we are building to support the <unk> launch is synergistic directly applicable to OTR, two or three and MTS, one furnace as well as our early stage program for the treatment of MTS re a hotel to a wall.

Specifically, we are confident the same capabilities, we have built and continue to advance in clinical regulatory manufacturing distribution patient identification referrals as well as treatment delivery can be utilized for potential future newer metabolic launches.

Importantly, newborn screening is already established in some geographies, including in the U S for M. P. S. One so some of the groundwork is already laid and provides a roadmap that can be reproduced in other key countries and regions.

Similar to MLP MTS, one H is a devastating inherited neuromuscular disorder.

Current treatment options are associated with significant limitations do not adequately address some of the borsa vim manifestations of the disease.

Based in part on the strength of the proof of concept data, which was published in the New England Journal Medicine will working to obtain the necessarily necessary regulatory clearance in mid 2022 to enable the initiation of a global Registrational study by year end.

Slide 11 helps further illustrates.

Essentially transformative impact HSC gene therapy can have a patients.

Here, we see two children with M. P. S. One others, who all participants in a proof of concept study.

Both clearly exhibits.

Symptomatic manifestations of the disease, including severe lethal deformities as well as joint Contractures and stiffness.

The photos on the left we're taken prior to the treatments with hotel two or three.

On the right you can see the same two children one on one and a half years post treatment with <unk>, two or three respectively.

In addition to the improved facial features on other physical manifestations patients with a proof of concept trial also demonstrated stable cognitive function improved voice function and resumed longitudinal growth in line with healthy children.

All patients also showed formed and sustain in golf and a gene corrected hfcs and achieved super physiological blood <unk> activity, which is the deficient enzyme which causes this disease, while one month post treatment.

This really illustrates the power of our approach.

To deliver gene corrected cells to difficult to treat areas of the body and make a potentially transformative and lasting impact, but young children affected by devastating fatal diseases.

Having discussed the promise of our clinical stage neuro metabolic programs, let's now shift our attention to how we plan to utilize our deep understanding of HSC gene therapy in the compendium of evidence, which generates a date to fully unlock the curative potential of our approach and create even greater value to the communities we serve.

Before we dive in let's highlight a few key attributes we believe make our approach so powerful.

Our platform utilizes a persons own hematopoietic stem cells for Hfcs, which are responsible for the lifelong sustained production of all blood cells and how three characteristics that make them ideal for personalized gene therapy.

They're capable of self renewal.

Second they are able to differentiate into multiple cell types in the bloodstream and third.

Naturally migrate into various tissues and organs, including the brain lung uninteresting.

And they've been broad distribution of gene corrected cells and localized delivery of therapeutic enzyme approaches.

We believe the key to expanding this approach is to apply the insights generated from our decades of experience in the field to specific conditions in areas, where HSC gene therapy as unique advantages of other modalities.

Taking a deeper dive into one of our priority research programs and not to Crohn's disease, we've been able to see and understand how HSC gene therapy could correct colitis at a very rare disease, such as chronic granulomatous disease due to the migration of gene corrected cells into the Gulf War.

And this understanding has now led us to develop a preclinical program known as <unk> four and a more common form of colitis, the not to form of Crohn's disease, which affects 7% to 10%.

<unk> disease patients or an estimated 200000 patients in the U S and EU.

<unk> is also generally characterized by more severe and refractory form optimization.

To date in vitro data suggests our approach could correct immunological defect and not too deficient sauce, we're now moving into in vivo models of disease. The neuron model and our objective for this year is to demonstrate preclinical proof of concept in that disease models.

Hotel wonderful also demonstrates the capabilities of our research team to generate novel and proprietary programs that can be leveraged within which it all serve as the basis for new ideas that may come from outside partners interested in using HSC for treating genetic disorders.

In addition to our research programs and not to Crohn's and the programming and full of F. T. D. We're also advancing a program in hereditary angioedema and partnership with farming, which has extensive experience including commercially in this indication.

The partnership looks to bring together our expertise in HSC gene therapy with our collaborators unique knowledge of the condition and treatment journey for HIV patients.

But beyond these key research programs. We've also identified ways to broaden and extend the application of our platform to other areas, we believe to have significant value.

These applications, including using.

HSE generates it answered specific regulatory T cells for the potential treatment of certain autoimmune diseases, such as multiple sclerosis. In addition, we can use gene modified HSE to virtualize monoclonal antibodies, which could enable gene modified <unk> to deliver those monoclonal antibodies to depict to difficult to reach tissues.

Our organs and this may allow us to address disorders of the CNS as well as brain tumors.

And the underlying these efforts we're looking at a few core technologies that could facilitate greater more efficient access to larger indications, including manufacturing innovations such as stable cell line, an automated cell processing as well as reduce toxicity and brain specific conditioning.

I would now like to turn the call over to Frank to discuss the path forward and how some of the portfolio and organizational updates, we're making will enable us to build a sustainable business positioned for future success.

Frank.

Thank you Bobby.

We hope our prepared remarks have helped to shed additional light on the rationale behind the portfolio updates we announced this morning.

All told the changes we plan to implement will extend our runway by an additional year into 2024, while maintaining operational focus on several value creating milestones.

The reduction in our burn rate is expected to take couple of quarters to fully realize but we should exit 2022 with a significant reduction in our quarterly operating expenses from today's levels.

While we will be a smaller organization. We believe the changes will make the company more nimble more focus and better equipped to execute on the programs in our portfolio.

As Bobby referenced at the onset of the call given the immense pressure facing the entire industry and the challenges that we and others have experienced we must now operate in a way that learns from the past and appreciates the opportunities in front of us.

As you can imagine these changes and the proposed 30% impact on our workforce are extremely difficult.

However by focusing on areas with the potential for commercial and other synergies across our neuro metabolic and research programs. We believe the company's HSC approach will have the greatest potential for differentiation and long term success.

Let me spend a minute on the programs that Orchard does not expect to put new investment dollars behind.

We are planning to discontinue investment in and seek alternatives for our rare primary immune deficiency programs, namely OTR, one O three for whiskered Aldrich syndrome or was.

OTR 102 for X C J D.

Instrument Bellus, which is marketed in Europe for <unk> kit.

For eligible patients currently in the treatment of referral process, we intend to help them receive therapy before taking any further action on the respective program.

Now seeking alternatives could mean, a number of outcomes and we've already been pursuing many of these options.

It could mean partnering the programs or the entire franchise with another commercial company.

It could mean working with our licensors to find an alternative solution to allow continued progress towards commercialization.

And it could also mean winding down the programs and returning them to our licensed stores.

While the MAA regulatory package for OTR, one O three for Wassa is submission ready, we do not intend to file ourselves so that any potential partner could take it forward with a properly aligned regulatory strategy.

Regarding the regulatory status of the program in the U S. Orchard believes the path to a potential BLA filing remains unclear and may require significant further investment in the treatment of additional patients after a functional potency assays developed.

And today in this environment, we're now prepared to take on those additional financial commitments.

We hope to be able to find a solution that recognizes the program's value while offloading much or all of the near term financial commitments to orchard.

I want to thank the many orchard employees, who have committed their time and energy to our mission, especially those who are directly impacted by the decision announced today.

I also want to acknowledge the efforts of so many outside orchard and helping these programs define the tremendous impact HSC gene therapy can have for patients impacted by rare genetic diseases.

Now looking ahead, we have a number of anticipated milestones for the next 12 to 18 months that represent significant value creation opportunities for orchard.

We've been very pleased with the commercial momentum building for La <unk>. So far in 2022, particularly in the area of reimbursement, where we expect additional progress as negotiations conclude.

We expect to see clinical and regulatory milestones for our NPS programs and also U S regulatory milestones for MLD, while advancing our commercial operations for <unk> in Europe .

We also look forward to reading out preclinical proof of concept data and our exciting research program and not to Crohn's disease. Later this year ahead of a potential IND filing in 2024.

In summary, based on the portfolio and organizational updates outlined during this call and in our press release. This morning, we feel fully aligned with the strategic anchors of our business plan.

We have the potential to drive near term value creation, and long term growth and we intend to do that with our employees our partners and the.

Broader community.

So with that I will turn the call over to the operator for questions.

If you'd like to ask a question. Please press Star then one.

Your question has been answered and you'd like to leave yourself from the queue press the pound key.

Our first question comes from Kevin <unk> with Oppenheimer. Your line is open.

Hey, great. Thanks for taking our questions I guess, just starting off with the restructuring Bobby can you just comment or clarify.

Kind of the why now component of this is driven.

Just by financial rate realities, primarily.

Or was there some specific.

Regulatory feedback with regard to <unk> that made this the right time to really evaluate a more substantial portfolio.

Repossession, Inc.

Thanks, a lot Kevin Thank you.

I mean I think this is.

Very important question and it's really about.

Number of factors firstly it is about the environment that we find ourselves in our thinking and many of them bought second gene therapy companies find themselves in as well and that there is capital constraints and we now need to think about using our resources in the best possible way and.

So when we look at our portfolio we have.

Seen extraordinary momentum with Maltby.

<unk> on the gyro metabolic side, we talked about the commercial momentum that we're getting in Europe . We now have a path to file in the U S as well.

So we feel that that demonstrate.

Where our HSC gene therapy platform can be best differentiated.

Addresses a very high unmet need there is positive reimbursement.

Gauge, but in that area. So.

The mouthy spear heads that newer metabolic franchise and then we can build on top of that with other MTS programs and of course, we've got <unk> we've got.

Three a and the synergy that we can.

And with.

The commercial infrastructure that we're building with the melody. These other programs all synergistic too.

In addition to that our early stage portfolio doesn't consume huge amount of research told us, but can have significant value for us.

<unk> already seen with IHA program, a significant BD partnerships, we formed and we think there are opportunities for partnerships with some of our other largest cell indications.

Using such before we can take those forward on outlet.

I think importantly, we can't do in the current circumstances, although we would like to we can't do everything and that's why we've made this very difficult decision to.

Divest install power investments in these.

Primary immunodeficiency.

A tough choice to make we think theres great clinical value in these in these programs there is potential for partnerships and we have had.

Hi.

Looked at that said, Paul but ultimately we're not going to take these forward and we will have to speak up.

Other alternatives, so thats really whats driven our decision theyre, all still regulatory hurdles to overcome.

With <unk> syndrome, but that's not the only factor is really the bigger.

Background in landscape upon which we made this decision.

Great. Thank you for that and then just maybe a follow up on MTS III.

Can you just give us your current thoughts as to.

How do you think about the profile to support a go no go decision on <unk>.

Yes.

Potential registration study following appropriate concepts should we think about that as really being a biomarker driven.

Or is there.

The certain level of neurocognitive improvement that you hope to be able to gather with longer follow up to inform that decision.

Yes, no that's it.

Again, a good question on NPS three a I mean I think the important thing here is.

Let me just kind of take a step back we've got five patients in a proof of.

Concept study we've showed great biomarker data. So all of these patients have engrafted, they've all got.

Our super physiological levels of.

As Jeff H and the enzyme that is deficient expression in the in the periphery.

Duction in the upfront and dextran sulfates both in the.

Both in the periphery and in the CNS, but I think we all recognize that those biomarkers are not good correlates of clinical outcome and so we really need to see with this program. So stabilization of the covenants of outcome before we made that logo a go no go decision towards <unk>.

Loss into a Registrational study and.

The important thing that is to see that a stabilization of covenants of outcome relative to the natural history on what we understand from looking at the natural history is that there was a plateau and then the decline in cognitive function from about three to four years.

Chronological age and so we need to.

Some of our patients to get to that time point to see if there's a differentiation from the natural history. So that's really the.

Why do we want to wait for that kind of clinical cognizance data before making that go no go decision.

Our next question comes from Iran, wherever with Cowen Your line is open.

Great. Thanks for taking a couple of questions maybe the first one maybe Frank Bobby.

Give us a sense when you are treating the you've treated two patients here one more coming up do you record revenues that same quarter.

How does that work and then what does the pipeline looks like in your view for the second half of the year and then secondly can you give us a sense of you started hovering potentially partnering discussions relating to two wason CJD or not yet thank you.

Okay, well, maybe I'll hand that maybe I'll hand that over to you Frank first of all and then.

Right.

Sure I'll take the first question about revenue recognition and maybe the third one on partnering.

And then I'll ask <unk> to comment on Lim L D.

So revenue recognition is going to largely depend on the ultimate deal that gets struck with the payer.

I think so far most of the discussions have focused on a single upfront payments for Labelle D patients on occasion, there may be an outcome based measure.

Measure that would be evaluated over time, but I think our expectation based on.

The patients that we've treated to date is that the vast majority of the revenue.

Be recognized upfront so for the patients that are receiving drug or therapy in the first quarter. Most of that revenue will be recognized in the first quarter and so on and in the future. If we ultimately end up.

With other arrangements that are based on payment over time, we'll certainly have to look at the revenue recognition for those.

Centrally differently, but I would say to date.

Especially given the number of patients and the value proposition here.

Most of the revenue will be recognized upfront based on where we are today.

On the partnering front for the PID, yes.

So this is not a decision that we just came to and it's a process that we started.

In fact in the past several months looking for potential alternatives for the PID program. So we have been engaged in some discussions those obviously have not yet resulted in a transaction we're going to continue to pursue this fronts. Obviously the announcement today may may bring forward parties that we havent thought about who may have.

Commercial footprint in the PID space, they may be rare disease companies looking to add some late stage programs to their portfolio.

We will continue the BD process on the PID.

Ultimately.

What we ultimately do with the programs will depend on any progress we make there.

So we'll see how it plays out over the next few months.

And Brian do you want to talk about the MLB.

Sure. Thanks for the question you're right we've treated two patients to date, we've got a third in.

In process right now.

We've been very pleased with the number of referrals coming into the qualified treatment centers and we're currently pursuing a number of of active leads I would say, we haven't guided towards the number of patients in the year, just given the even nature of patient identification, whether or not their treatment eligible as well.

As kind of their geography, as well as reimbursement if it's in place some of the factors that will make I think these early.

Months and years of the launch somewhat uneven in terms of patient treatment. So we havent guided but we are pleased with the progress on on patient identification as well as pursuing a number of bids right now.

Thank you.

Yes.

Our next question comes from Pete Stavropoulos with Cantor Fitzgerald. Your line is open.

Good morning, Bob Frank and team congratulations on the progress and thanks for taking my questions.

So when you think about the <unk> label.

Label, and who is approved for <unk> in the EU and for whom it is not does it affect how you're thinking about approaching these additional neuro metabolic indications specifically in terms of clinical study design, including enrollment criteria and which patients may benefit most from these candidates and perhaps would it allow for more time.

With a population where greater clinical benefit maybe observed and therefore allow for a more capital efficient program.

Yes, Thanks, a lot Pete for that question Barry.

It's really really important.

Remember the label for Malibu.

<unk> in Europe is full pre symptomatic patients in the baked installed population and for pre symptomatic and early symptomatic patients in the juvenile population and we would be looking for something similar for for the U S file as well.

The first thing to say this forms the majority of the MLP population, so what we've understood.

As we've gone through our clinical development is in that early phase either pre symptomatic or early symptomatic, where we have or having the greatest clinical impact and read this kind of extraordinary transformational impact, which also leads I think ultimately to the commercial potential.

That's where the greatest unmet need is that's where the greatest difference that we're making and that is why we've had such.

Positive.

Commercial success, thank Paul with the reimbursement agencies.

That informs how we're taking forward.

Clinical development in MTS, one and also in MTS three eight as well so for NPS. One again, we are treating patients in the most severe category, we're looking to capture patient at an early stage in the.

The disease, so that that will then.

The most the greatest benefit and simply we've also put an age restriction. So important proof of concept study for <unk> as well and we are recruiting patients who are under two years of age. So I think all of that.

Speaks to a.

A view that we have that our therapy can have the best.

Impact.

Early stages of disease that will give us the greatest clinical outcome.

Also leads to a better commercial profile in the long run. It also means it also informs our diagnostic and screening strategy and that's why we're investing in newborn screening for MLP for MTS. One remember screening is already in place in a number of states in the U S. I think it's about 30 states in the U S by the.

We get to launch hopefully that will be widespread newborn covering newborn screening coverage in the U S and also in the EU and we are also investing in newborn screening development for MTS as well so all of this speaks to.

It's our view that we have an enormous impact.

These.

Diseases metabolic franchise, we can change the whole landscape of proceeds by intervention for screening and having what is a potentially curative effect in these diseases.

Alright, thank you.

And also can you give us a sense of what progress has been made towards filing.

BLA in the U S for <unk>.

<unk> 200, and what are the key gating factors for submitting the BLA and from your interactions with the agencies to date.

Do you get a sense that they appreciate the burden of disease and the potential impact.

<unk> hundred may have on patients.

Yeah no. Thank you for that question. So this is kind of.

<unk> now has to evolve one of the reasons why we've.

We've done the restructuring that we have so that we can give ourselves runway extension to 2024 and <unk>.

Beyond the potential approval of the melding of the U S. In 'twenty 'twenty three so on that front remember last year just to recap we had very positive interactions with the FDA both on the clinical package and on the CMC side as well through all of that type B meeting on that.

The clinical front, we clarified the data package that we.

We need to submit.

We also.

Questions that the FDA asked on.

And tools for example will be the.

The school that which we measure motor function by and they wanted to submit some.

Data on that they also wanted to have and I've talked about this before wanted more.

The clarity on the natural history cohorts and whether it was representative of the patient population that we have treated and again going through that exercise and preparing all of the documentation to submit to the FDA. They were I think to your last point. They were I think very impressed by the clinical data on that.

Transport from the transformational outcome that we have shown a pompe patients and I think that's why we've had such a constructive interactions to allow us to move forward on the CMC side again.

It was really about clarification of what needed to be.

Submitted and how it should be it should have the analysis should be conducted so with that level.

Compensation and clarity from the FDA, we are really just in execution mode, and putting everything together and we're working towards a pre BLA meeting in the second half of this year and then looking to fall late 2022 early 2023.

Alright, Thank you very much.

One of my questions.

Thank you thank you Peter.

Our next question comes from Gena Wang with Barclays. Your line is open.

Thank you for taking my questions.

Basically guiding the Malkin just wondering if you can remind us numbers of patients each.

<unk>, Germany, France, and Italy, and the rent we will see the major revenue driver.

In may of 2022.

And the second question is regarding the Mcs and launch just.

Just wondering if you can give.

<unk> start a pivotal trial design.

Okay, well, let me turn it over to grade and first of all to talk about MLD and then I'll take the question on the NPS. One H study design, so Brendan can I hand, it over to talk about.

The patient numbers etcetera in Europe .

Sure. Thanks for the question Gena, we estimate the incidents of MLD to be about one in 100000 live births. So when that translates over to Europe , it's roughly in the 50 patients or so a year.

And so when you start breaking it down by country.

I believe we mentioned for patients potentially per year, and it's similar across the different geographies in terms of a hand, a handful of patients across each country. So.

That's where we would expect the early patients to be identified and treated to your second part of your question.

Primarily fueled by the main.

Countries for which we have a qualified treatment centers with perhaps some additional treatment abroad opportunities as we've mentioned previously with the one patient in the middle east being treated in Italy.

And.

Thanks, Brian and let me take on the NPS one question about the regulatory.

The study design for the Registrational study so just to recap we have treated eight patients in a proof of concept study. The data was presented at world earlier this year and just all patients and graph did all patients showed super physiological levels of <unk> expression and reduction in substrate levels both in the periphery.

And in the CNS, but most importantly, what we saw was that in terms of clinical outcome all patients had stable cognitive.

Outcome, they had stable growth parameters.

And similar to that of the healthy chalk and also improvement in range of function as well. So we have been conducting.

We've been conducting.

Interactions with the both the FDA and with the EMA. So we had parallel funds can fast last year and we've now brought that parallel scientific advice into the design of the Registrational study.

Remember, we want to conduct a study that is fit for both the EMA and the FDA. So it's really combining both of that comment into the into the study design.

Please say that we are getting to finalizing what our study design looks like and our goal is to submit and get clearance all the IMD and Cta or Cta by midyear.

So that you're aware.

And I think I've talked about this before as well the important factors here all survival graft versus host disease, which is obviously a problem with the standard of care, which is allogeneic.

At transplants graft failure or rejection and also looking at clinical outcomes, such as cognizant outcomes as well because we know there is a limitation conference an outcome in the standard of care, which is in a trough month. In addition to that obviously there are other.

Factors such as growth such as mosquito performance. So it's really kind of combining those into the endpoints for the Registrational study and when we can show that there is a better outcome.

Gene therapy compared to transplant. So what is the duration of follow up that we need to have in order to be able to demonstrate that the number of patients who need to have enough money to get.

To demonstrate that so these are all the factors, but we are.

Working on I think I've, given you a flavor of the kind of things that we'll be looking at and we can give you more detail. Once the registration study has been cleared by the agency.

Thank you.

Our next question comes from Dae Gon Ha with Stifel. Your line is open.

Great. Good morning, Thanks for taking our questions to mostly on the regulatory front you mentioned the prioritization of the PID focus.

So specifically with regards to wash program.

Your prior commentary has been around potency assay development, how it's because of a protein that is not necessarily enzymatic developing an assay. It takes time.

Yes, with the prioritization I understand the financial kind of commitment required but can you maybe broadly comment on sort of the feasibility of gene therapy, replacing a non enzymatic protein going forward is there some kind of conclusion that one can make as to what the path forward, maybe not just for <unk>.

Was but any other proteins that may not have a catalytic function. If you will and then on second when we think broadly around just regulatory front again, Atlanta virus I mean, we've had the AAV.

<unk> Com last year in September where the panelists talked about AAV gene therapy, but not lengthy so I'm just trying to get a sense for when you interact with regulators do they appreciate sort of the nuances with differences between different lentivirus construct how certain contracts maybe more prone to say.

Searching on meter Genesis, and maybe oncogenic kind of ramifications. Thanks.

Yes.

Two very.

Question. So the first one on the.

So let me just kind of just take a step back again remember our.

Our reasons for deeper our sizing.

Evolution drug program or a number of considerations, including.

I need to extend our runway in order to focus our resources in the metabolic space. So it is not just about our regulatory traction is a much broader.

Set of considerations that we had before we came to that decision having said that.

We have had discussions with the FDA around the path forward on one of the.

The issues that has been raised is the potency assay and that there is still work to do in order to clarify a potency assay that would be.

The FDA would find acceptable I don't think that's completely out of the question I don't think.

I think it's something that can be done, but it will require more time and it will require more investment.

As I say, we are looking to invest on your metabolic franchise as well as in the <unk>. So it's not that's not doable. It will just take more time, having said all of that it is more difficult.

Intracellular signaling protein and in <unk>. It is a protein that works interest MBA and is involved with actin polymerization and actually it doesn't have a specific role within HST. So it is difficult to demonstrate within <unk>, you have to differentiate them into immune cells to be able to characterize.

Hi.

<unk>, obviously <unk> syndrome proteins. So it is very very different from something like MLP or I guess, one for MTS three eight where there is an enzyme that is breaking down the substrate and can be measured relatively readily in.

At HFC.

This also informed our regulatory path is clear on.

This specific point.

The newer metabolic franchise.

Good.

A broader question that youre asking about these kind of signaling proteins.

Again, it is understanding that function and being able to demonstrate it effectively within transduce HSE and it is slightly more complex than it is for the.

The lysosomal storage diseases. So I think it's just a different development plan needs to be established probably needs to be done quite well in advance.

At the beginning of the development program.

I hope that answers your potency question. The second question on the Lentivirus vector.

Points.

Very important point to make here.

And I will just installed with by saying not all <unk> vectors all of the same it is about the construct and the various different elements. All the 90 <unk> and I think this is understood by the regulatory agencies and we will continue to impress that upon them.

The problems that have been seen either using gamma retroviral vectors all <unk> all win a volatile promoter used that has enhanced the sequences.

What that means is that when these.

These factors integrate near growth promoting genes oncogene.

Those sequences within the promoter has the ability to transact today's turn on.

<unk> and that is what leads to the obsessional Ms Genesis oncogenesis.

That is why we at <unk> have not used the bottle promoted a very very important but we chose not to use those kind of bottle.

Elements, we have used human promote human.

Human promoters and regulator elements. They do not have these powerful enhances sequences. So even if they sit next to an oncogene of growth from <unk>. They don't have the ability to turn that genome and across multiple programs as many as we've not seen any evidence of.

Proliferation.

Oncogenesis in these <unk> that use human promoter sequences and so we will continue to make that point to the regulators show the data that we have on in social science.

Allison is the lack of any events, thus far in all of the programs that we've kind of taken forward and I hope that that continues to demonstrate the safety profile of our approach.

To kind of add on apologies are you aware of FTA planning on holding any kind of outcome specifically for lunch viral gene therapies at all.

We are not aware of them.

Okay, great. Thank you very much.

Our next question comes from Doug <unk> with Guggenheim Securities. Your line is open.

Hi, Good morning team. This is Robert on for Doug.

What do you think the normalized price would be post year, one in Germany, and the rest of the EU.

And on the modeling front would you expect a 30% workforce reduction too curly linearly with expenses going first.

Okay, maybe I'll hand that first question to Brighton and the second question to Frank.

Yes, Thanks, Bobby and thanks for the question.

We have previously spoken about the list price of $2 875 million euros in Germany.

Of course are still in the process of.

The M&A process and pricing and reimbursement negotiations. So I think it's premature to say right now what our net price might look like coming out of that and the nature of those conversations are.

Certainly confidential, but certainly in the in the negotiations and discussions that we've had with health technology assessment as well as with the pricing and reimbursement negotiations. We've been certainly pleased with kind of the level of understanding and desire for understanding on the disease on the clinical benefit of <unk> as well as the recognition.

But the impact that <unk> has and therefore the value that it could bring so we've been encouraged in the negotiations, but nothing too to add at this point in time, while we are still in the middle of negotiations.

And maybe on the modeling side.

To step back we started the year with $220 million in cash, we've obviously guided now to runway.

Into 2024.

The impact of the proposed restructuring and the program portfolio decisions.

It's a reasonable assumption to assume that opex are going to come down by about 30% to 40%.

And that's something that'll be realized probably over a couple of quarters. So by the time, we get the exiting 2022, I think thats a reasonable assumption to make when you combine the opex reduction with.

Starting to record revenues and realized cash flows from the <unk> sales I think you should you should be able to get.

The model to support runway into 2024 and potentially beyond.

Thanks, Tim.

Thanks.

Our next question comes from customer marrow.

J P. Morgan your line is open.

Hey, guys. Thanks, so much for taking our question.

So my first one is around.

Grand Prix additional site activation. Thank you Jeff.

Estimated youre right.

How are you thinking about that.

The remainder of the year.

Any updates on kind of newborn.

Newborn screening side and kind of what progress you would like to see Dan over the course of 'twenty.

One more.

Yes.

Okay, well, let me.

Great and just talk about it.

Qualified treatment centers and the expansion and then I'll.

Follow up with you.

<unk> screening.

Great. Thanks for the question tests.

As you mentioned, we have activated and qualify our fifth treatment center, we've taken that approach.

A very efficient approach to focus on one major treatment center.

Or a country or a region. If you will that specializes in transplant as well as nerve metabolic disease.

Diseases and so we've got one in the U K, France, Italy, Germany, as well as the Netherlands. The way, we think about expansion beyond that is the way, we're thinking about expanding within Europe in terms of the pricing and reimbursement negotiations. So we're looking to activate the qualified treatment center in the Nordics in Sweden as well as in.

Spain, and then we will take additional.

Expansion from there as we kind of take a step wise approach to looking at other markets and regions.

And.

At test, let me take the point on newborn screening. So just again just to set the scene. We think newborn screening is going to be extremely important to identify patients.

Babies.

And then treat them pre symptomatically, which is where they'll get the greatest benefit from Mcnulty. So we've worked very hard.

That with Kols to develop assays that are now.

Five.

Yes.

Pilots that have either launched or are planned and they are in Germany, Italy. The U K, Spain and also in New York State is what then three of those are actively screening babies those potential for expansion as well and we're planning to initiate those and those will be in.

Other European countries. So there is a lot of activity on that front. We're also working with other U S states as well too.

Adult use.

State wide U S U S statewide screening as well and we hope that a number of states will be screening at the time of the U S launch in the second half of 2023 early 2024. So we're working very hard to say to get that in place both in Europe and in the U S and the data that.

We generate.

From these screens will come together.

Two a rusnak applications. So that is the recommended.

Uniform screening panel in the U S and obviously that will be a big step to get more states at screening for MLP. So this is a.

Mid to long term plan.

Already.

In place and you'll hear more about that as we move forward.

That's really helpful.

Question on just fine.

Initial learnings with respect to the product positioning.

And kind of the early early early time of the launch is there a specific patient type that is choosing to go online now the standard of care transplant.

Thank you so much.

Yes, no well, let me take that because I think this is a really important point.

There is not really a standard of care for MLP transplant is not used as a standard option for this disease because it is such an aggressive.

Disease, that's different for something like from something like MTS warm wet.

Paul is a standard but.

Allogeneic transplant is not a standard of care for MLP. So really for these patients is really palliative or supportive care.

And so that is why this medicine has such a profound impact so going from really nothing for these patients other than supportive care to something that is.

Achieving long term.

Yes.

I think you've seen some of the.

Some of the reports of some of these patients the pictures of some of these patients were treated.

Symptomatically or very very early in their disease and they are getting school then learning normally there.

Playing just like their schoolmates and is an extraordinary outcome that we see and I think thats why we are getting this kind of commercial momentum because it's not just the.

The physicians that are recognizing this but also now the reimbursement agencies as well and that's what we want to capitalize upon him and Thats part of our restructuring strategy.

Strategy is to be able to capitalize on this commercial momentum for MLP.

Multi bring pool with other new or metabolic programs such as.

NPS, one because we can see what a difference at this kind of Phoenix.

Okay.

That's helpful. Thanks for taking my question.

Thank you.

<unk>.

Our next question comes from David Hong with SM BC. Your line is open.

Hi, Thanks for taking the questions. So I just had a couple first on lip melty, assuming you are able to file on schedule and potentially gain an approval in the U S. Can you just talk a little bit about any any expectations that maybe.

<unk> launch and speed of commercialization May go in the U S market.

That cadence might.

Compared to what Youre seeing in Europe .

Then secondly in terms of <unk> 201 for MTS re a it looks like you plan to report some.

Additional data from the proof of concept trial by year end. So just wondering what we can expect there would that include cognitive and or clinical outcomes.

Okay.

David So let me hand, the smelter launch in the U S to Brighton and then I'll take the <unk> III.

Sure.

Yes, thanks for the question David.

We will certainly have more to say about the commercial launch in preparation in the U S. As we get to filing and closer to potential approval I do think it's safe to assume that we will follow a similar approach at least in the U S. As we have in Europe in terms of <unk>.

Efficient field force limited number of qualified treatment centers to satisfy the early demand.

For the product and.

A similar kind of pricing and reimbursement strategy, where we're able to demonstrate the value of the product given all of the factors that Bobby just mentioned in terms of not an alternative to treatment as well as the clinical impact that we've seen with <unk> over time I think generally speaking in the U S. You have a tendency to see a quicker uptake.

Than you do in Europe , but I think the challenge again within MLP is really the ability to identify treatment eligible patients within the window of opportunity for them to have benefit from lip melby. So.

As we've mentioned previously and Bobby just mentioned not too long ago newborn screening pilot.

Pilots in different states, it's going to be a key factor as well as kind of a multifactorial approach to identifying patients on.

On time, so they can benefit from the treatment. So those are some of the things that we're thinking about with the U S.

Thank you Brad.

Just on the question you asked about NPS three eight so.

Just to talk again about what the natural history shows from yesterday so.

There is no treatment for MTS.

As supportive of palliative care <unk> is not an option to allogeneic transplant is an option. It is not an option for this disease and so the natural history here is that these patients start to plateau at around about three years of <unk> and then there was a decline in cognitive function from about four years of age.

Almost.

So what we need to see really in our treated patients is a separation from that natural curve in the natural history population. So we've treated five patients so Paul.

The patients the most recently treated patients only received therapy at the end of 2021, so where do we need to wait for a while to see some.

Because those patients to get to that kind of age that I talked about between three and four years of age and to see if they are now.

Flipped from the natural history Cup and Thats, what we hope to be able to demonstrate towards the end of the year. It is going to take some time, because I say more patients showing that kind of separation will be more.

But I think this is the earliest when we can start to see some early data.

Okay. Thanks, a lot.

Thank you.

There are no further questions I'd like to turn the call back over to Bobby Gaspar for any closing remarks.

Thank you Raj thank.

Thank you everyone for your time and attention we look forward to your support as we continue.

To execute our strategic vision approach it and for the communities that we serve thank you.

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