Q4 2021 Sangamo Therapeutics Inc Earnings Call

Operator: Good day, and thank you for standing by. Welcome to the Sangamo Therapeutics fourth quarter and full year 2021 conference call. At this time, all participants are in listen-only mode.

Good day, and thank you for standing by welcome to the Sangamo Therapeutics fourth quarter and full year 2021 conference call.

At this time, all participants are in listen only mode.

Operator: After the speaker's presentation, there will be a question and answer session. To ask a question during this session, you'll need to press star then 1 on your telephone keypad. Please be advised that today's conference may be recorded. If you require operator assistance during the call, please press star then zero.

After the speaker's presentation, there will be a question and answer session.

I'll ask a question during this session you'll need to press Star then one on your telephone keypad.

Please be advised today's conference maybe recorded.

If you require operator assistance during the call. Please press Star then zero.

Operator: I'd now like to hand the conference over to your host today, Erin Feingold, Head of Corporate Communications. Please go ahead. Good afternoon, and thank you for joining us today. With me on this call are several members of the Sangamo Executive Leadership, including Sandy Macrae, Chief Executive Officer; Mark McClung, Chief Operating Officer; and Prathyusha Duraibabu, Chief Financial Officer.

I'd now like to hand, the conference over to your host today, Aaron Feingold head of corporate Communications. Please go ahead.

Okay.

Yeah.

Erin Feingold: Jason Fontenot, Chief Scientific Officer; Rob Schott, Head of Development; and Bettina Cockcroft, Chief Medical Officer. Slides from our corporate presentation can be found on our website, sangamo.com, under the Investors and Media section, Events and Presentations. This call includes forward-looking statements regarding Sangamo's current expectations. These statements include, but are not limited to:

Good afternoon, and thank you for joining us today.

With me. This afternoon on this call are several members of the executive leadership team, including Sandy Macrae, Chief Executive Officer, Mark Mcclain, Chief Operating Officer, <unk>, <unk>, Chief Financial Officer, Jason <unk>, Chief Scientific Officer.

Rob shot head of development, and Bettina Cockroft, Chief Medical Officer.

Slides from our corporate presentation can be found on our website sangamo dot com under the investors and media section events and presentations page.

Erin Feingold: Statements relating to the therapeutic and commercial potential of our product candidates, the anticipated plans and timelines of Sangamo and our collaborators for initiating and conducting clinical trials and presenting clinical data, execution of our corporate strategy, advancement of our product candidates, our initial 2022 financial guidance, and other statements that are not historical facts. However, actual results may differ materially from what we discussed. These statements are subject to certain risks and uncertainties that are discussed in our filings with the SEC, Specifically, our annual report on Form 10-K for the fiscal year ended December 31, 2021.

This call includes forward looking statements regarding single most current expectations.

These statements include but are not limited to statements.

Relating to the therapeutic and commercial potential of our product candidate <unk>.

The anticipated plans and timelines of Sangamo and our collaborators for initiating in conducting clinical trials and presenting clinical data.

<unk> of our corporate strategy.

Dampening of our product candidates.

Our initial 2020 to financial guidance and other statements that are not historical facts.

Actual results may differ materially from what we discuss today.

These statements are subject to certain risks and uncertainties that are discussed in our filings with the S. E C.

Our annual report on Form 10-K for the fiscal year ended December 31st 2021.

Sandy Macrae: The forward-looking statements stated today are made as of this date, and we undertake no duty to update such information except as required by law. On this call, we discuss our non-GAP operating expenses. Reconciliation of this measure to our GAAP operating expenses can be found in today's press release, which is available on our website. Now, I'd like to turn the call over to our CEO, Sandy Macrae. Thanks, sir, and good afternoon to everybody on the call.

Forward looking statements stated today are made as of this date and we undertake no duty to update such information, except as required by law.

Call me discuss our non-GAAP operating expenses reconciliation of this measure to our GAAP operating expenses can be found in today's press release, which is available on our website.

Now I'd like to turn the call over to our CEO Sandy Macrae.

Thanks Sarah.

And good afternoon to everybody on Nicole.

Sandy Macrae: I'd like to start by saying that 2021 was a significant year for Sangamo as we continue to advance the development of genomic medicines for patients across multiple therapeutic areas using our innovative technologies. We're very pleased with our progress despite the challenges of the second year of the pandemic. We're advancing potentially transformative genomic medicines in the clinic and strategically using our R&D capabilities to pursue indications of unmet needs. These efforts are supported by our manufacturing infrastructure, including in-house AAB and cell therapy facilities.

I'd like to start by saying that 2021 was a significant year for Sangamo as we continue to advance the development of genomic medicines for patients across multiple therapeutic areas using our innovative technologies.

We're very pleased with our progress despite the challenges in the second period of the pandemic.

We are advancing potentially transformative genomic medicines in the clinic and strategically using our R&D capabilities to pursue indications with unmet needs.

These efforts are supported by our manufacturing infrastructure, including in House <unk>.

<unk> therapy facilities.

Sandy Macrae: Our collaboration partners also help us drive toward our mission to deliver on the promise of genomic medicine, and we believe that this progress positions us as well to generate long-term value for our shareholders. In 2021, we have executed upon our strategy with several important achievements.

Our collaboration partners also help us drive towards our mission to deliver on the promise of genomic medicine, and we believe that this progress positions us well to generate long term phone we've put our shareholders.

In 2022, one we executed upon our strategy with several important achievements.

Sandy Macrae: First, we and our partners advance our three lead programs while presenting compelling clinical data. Starting with our wholly owned Phase 1-2 Fabry disease program, we presented updated data at the World Symposium earlier this month. We are encouraged by the safety and efficacy data we have seen to date. And, most importantly, the patients in the study have reported that they are feeling better. Investigators are observing improvement in some of the most challenging symptoms, including the ability to sweat in the first three treated patients. With the recent changes in the Fabry competitive landscape, we believe we are in a leading position.

First we entered partners advance our three lead programs for presenting compelling clinical data.

Starting with our wholly owned phase one to Fabry disease program, we presented updated data at the World Symposium earlier this month.

We are encouraged by the safety and met because of the data we've seen to date and most importantly, the patients in the study reported they are feeling better.

Investigators have observed improvement some of the most challenging symptoms, including the ability to sweep in the first speak treated patients.

With the recent changes in the competitive landscape. We believe we are in a leading position.

Sandy Macrae: In the second half of this year, we plan to present additional updated Phase 1-2 data. We're actively planning for a Phase 3 study, including discussions with health authorities, patient advocacy groups, and investigators. We're also delighted by the emerging phase 1-2 sickle cell disease data presented at ASH in December, showing no treatment-related adverse events in the four treated patients, improvement across several biomarkers, and most importantly, a clinically significant reduction in painful

In the second half of this year, we plan to present additional updated phase one two data.

Actively planning for a phase III study, including discussions with health authorities patient advocacy groups and investigators.

We're also delighted by the emerging phase one to sickle cell disease data presented at Ash in December showing no treatment related adverse events in the <unk> treated patients.

Movement across several Biomarkers and most importantly, clinically significant reduction in painful cyclic crisis.

Sandy Macrae: We anticipate that the next four patients treated in the study will be those with a product candidate manufactured using improved methods that have been shown in internal experiments to increase long-term progenitor cells. We expect to complete dosing of these patients in the third quarter of this year. Transition planning of the program from Sanofi to Sangamo is going well, and we are energised to have this asset back in our hands soon as we assess the best way to move the program forward for patients, be that on our own or with a potential partner.

We anticipate that the next four patients treated in this study will be dosed with a product candidate manufactured using improved methods have been shown in internal experiments to increase long term progenitor cells.

We expect to complete dosing of these patients in the third quarter of this year.

Transition planning of the program from Sanofi to saying, what's going well and we are energized to have this asset back in our hands soon as we assess the best week move the program forward for patients be dumped on a ruling or with a potential partner.

Sandy Macrae: Finally, we're encouraged by the follow-up data presented at ASH last year from our Haemophilia A program partnered with Pfizer. Updated Phase 1-2 results show sustained bleeding control in the highest dose cohort through two years following gene therapy.

Finally, we're encouraged by the follow up data presented at Ash last year from our hemophilia a program partnered with Pfizer.

Dated phase two results show sustained bleeding control in the highest dose cohort two two years following gene therapy.

Sandy Macrae: Regarding the Phase 3 study, Pfizer has announced that it hopes to obtain agreements with the health authorities to resume their final trial in the first half of 2022. The trial was previously paused when some of the patients experienced factor VIII activity greater than 150% following treatment. Pfizer is currently in the process of submitting a protocol amendment to health authorities in the countries where this trial is being conducted and preparing responses to the FDA clinical hold.

Regarding the phase III study Pfizer has announced that it hopes to obtain agreements with the health authorities to sit in that trial in the first half of 2022.

The trial was previously paused from some of the patients experience factories to activity greater than 150% following treatment.

Pfizer is currently in the process of submitting a protocol amendment to health authorities in the countries, where this trial is being conducted and preparing responses to the FDA clinical hold.

Sandy Macrae: Over 50% of the patients have been enrolled in the phase 3 affine trial. Second, we're progressing our pre-clinical candidates based on our second generation technologies, CAR Tregs for autoimmune disease and zinc finger transcription factors for neurological disorders.

Over 50% of the patients have been enrolled in the phase III trial.

Second we are progressing our preclinical candidates based on our second generation technologies car T Rex for autoimmune disease.

Conscription factors for neurological disorders.

Sandy Macrae: We have enrolled and expect to dose soon the first patient in our lead CAR T-RED program where we are evaluating TX200 for the prevention of immune-mediated rejection in HLA-A2 mismatched kidney transplants from a living donor. We believe that this will be the first patient ever to be dosed with a CAR Treg therapy and that we are in a leading position with several companies following us into this very promising area. We believe that our expertise across multiple technology platforms, robust cell therapy infrastructure supported by our manufacturing facilities and genomic engineering capabilities, and internal strategic and operational synergies comprise a differentiated CAR T-REC platform from which we can potentially offer patients advanced genomic medicine.

We have certain route and expect to dose the first patient in our lead car T. Reg program, where we are evaluating TX 200 for the prevention of immune mediated rejection and actually two mismatched kidney transplant from a living donor.

We believe this will be the first patient effort to be dosed with the car T therapy and that we are in a leading position with several companies pulling us into this very promising area.

Yeah.

We believe that <unk> expertise across multiple technology platforms.

Cell therapy infrastructure supported by our manufacturing facilities, and genomic engineering capabilities and internal strategic and operational synergies complain comprise a differentiated car T platform from which we can potentially offer patients advanced genomic medicines.

Sandy Macrae: In addition to our proof-of-concept study of TX200, we are progressing our preclinical allogeneic renal transplant rejection study, as well as our inflammatory bowel disorder and multiple sclerosis programs, including presenting the first preclinical data from our allogeneic IL-23R CAR-T reg candidate and IBD last year.

In addition to a proof of concept study of TX 200, we're progressing our preclinical allogeneic renal transplant rejection study.

Well as inflammatory bowel disorder, and multiple sclerosis programs, including presenting the first preclinical data from our allogeneic <unk> car T right candidate and the like.

<unk> last year.

Sandy Macrae: And finally, with regard to our zinc finger protein transcription factor technology in treating CNS disorders, in addition to our partner programs with Biogen, Novartis, Takeda, and Pfizer, we're advancing multiple internal programs. Third, we continue to hone our differentiated genome engineering platform, including improving the specificity, precision, and efficiency of our cores and finger proteins. We're also progressing our capabilities from nucleases to repressors, activators, and even base editors and are excited about our progress. We see Sangamo's capabilities as representing a one-stop shop for a range of genomic engineering capabilities that are designed to be applied therapeutically.

And finally with regard to or zinc finger protein transcription factor technology in treating CNS disorders. In addition to our partnered programs with Biogen Novartis Takeda and Pfizer, we are advancing multiple internal programs.

Third we continue to hone our differentiated genome engineering platform, including improving the specificity precision and efficiency are coursing finger proteins.

We're also progressing with capabilities from nuclear uses two pressures active nutrition, even based editors and are excited about our progress.

We see sangamo capabilities as representing a one stop shop for range of genomic engineering capabilities. They are just starting to be applied to therapeutically.

Sandy Macrae: Fourth, we continue to work diligently with our collaborators supporting the advancement of our partner programs in the clinic while driving research efforts for pre-clinical programs for which we receive reimbursement from our partners. These partnerships have been a key component of our development strategy and continue to drive value for science. We believe that the buy-in from Pharma validates our mechanistic approach across a range of advanced modalities and enables us to benefit substantially from our partner's domain expertise to develop high-quality therapeutics for patients.

Fourth we continue to work diligently with our collaborators supporting the advancement of our partner programs in the clinic, while driving research records for preclinical programs from which we receive reimbursement from our partners.

These partnerships have been a key component of our development strategy and continues to drive one wafer cycle.

We believe that the volume from pharma validates our mechanistic approach across a range of advanced modalities.

<unk> sells to benefit substantially from our partners domain expertise to develop high quality therapeutics for patients with <unk>.

Sandy Macrae: The capital provided by our partnerships helps to advance our internal pipeline of assets while providing our partner programs with the resources needed to advance the development of these potentially transformative therapies more quickly. Fifth, we completed and brought online our cell therapy manufacturing facilities in Brisbane and Balboa and now have operational AAV and cell therapy facilities in-house. We believe these facilities provide many strategic advantages, including flexibility and control. Capacity can support our R&D needs, process expertise, geographic diversification, and that supports supply chain resilience and a deep intellectual property portfolio. 6.

Capital provided by our partnerships helps advance our internal pipeline of assets, while providing our partnered programs with the resources needed to advance the development of these potentially transformative therapies more quickly.

Fifth we completed and brought online our cell therapy manufacturing facilities in Brisbane and Hong Kong.

Operational AEP cell therapy facilities in house.

We believe these facilities provide many strategic advantages, including flexible chain control.

Capacity can support our R&D needs process expertise geographic diversification and that support supply chain resilience and a deep intellectual property portfolio.

Sandy Macrae: We believe that we have a strong financial position to take us through our key upcoming cash. Our diverse and accomplished leadership team and our talented employees are passionate about our mission and have enabled our multiple 2021 accomplishments, setting us up for what we expect to be a strong 2022. I am very grateful to my leadership team and all my Sangamo colleagues for their dedication and hard work in the second challenging year of the pandemic.

Six we believe that we have a strong financial position to take us through our key coming catalysts.

Our diverse and accomplish leadership team and our talented employees are passionate about our mission and have enabled our multiple 2021 accomplishments setting us up for what we expect to be a strong 2022.

I am very grateful to my leadership team and all my segment will colleagues for their dedication and hard work and a second challenging years the pandemic.

Sandy Macrae: And with that, I'd like to turn the call over to our Head of Development, Rob Schott, who will discuss the data from our clinical programs in more detail. Thanks, Andy, and good afternoon to everyone on the call. We are delighted by our clinical execution in 2021. We believe the presentation last year of important proof of concept data supports late stage development for our Febree and sickle cell programs. At the World Symposium earlier this month, we presented updated preliminary results from the Phase 1-2 STAR clinical study evaluating Israelgalgogene psiloparvovic, or ST920, a wholly-owned gene therapy candidate for the treatment of Febree disease.

And with that I'd like to turn the call over to our head of development Rockshaft, who will discuss the data from our clinical programs in more detail.

Thanks, Andy and good afternoon to everyone on the call.

We are delighted by our clinical execution and 2021, we believe the presentation last year, an important proof of concept data supports late stage development for our February in sickle cell program.

At the World Symposium earlier this month, we presented updated preliminary results from the phase one two star clinical study evaluating <unk> <unk> or 920, a wholly owned gene therapy candidate for the treatment of Fabry disease.

Rob Schott: As of the November 9, 2021 cutoff date, the gene therapy candidate continued to be generally well-tolerated across three dose cohorts in the five treated patients with treatment-related adverse events that were assessed as grade one or mild. However, elevated alpha-gal activity has been maintained for the four patients treated in the first two dose cohorts ranging from three-fold to 15-fold above mean normal at last measurement. For the two patients on enzyme replacement therapy, alpha-gal activity measured at ERP trough was 15-fold above mean normal at week 52 for the patient in cohort one and 10-fold above mean normal at week 25 for the patient in cohort two. For the two ERT pseudo-naive patients, alpha-gal A activity was three-fold above knee normal at week 52 for the patient in cohort one and four-fold above knee normal at week 40 for the patient in

As of November nine 2021 cutoff date, the gene therapy candidates continue to be generally well tolerated across three dose cohorts in the <unk> treated patients with treatment related adverse events that were assessed as great one a mile.

Elevated alpha Gal activity has been maintained for.

<unk> patient treated in the first two dose cohorts ranging from three four particularly for above normal at last measurement.

For the two patients on enzyme replacement therapy Alpha Gal activity measured at near to trough with 15 for above normal at week 52 for the patient in cohort, one and tenfold above normal at week 25 patients in cohort two.

So the two <unk> pseudo naive patients Alpha Gal a activity with three fold above normal at week 52 for the patient in cohort, one and four fold above normal and week 40 for the patients in cohort two.

Rob Schott: The two patients in Cohort 1 have now begun the long-term follow-up study, and at the one-year mark, alpha-gal A expression remains robust; withdrawal from here has been completed for one patient and is planned for the second patient on enzyme replacement therapy based on the stability of their alpha-gal A activity following treatment. In the first patient in Cohort 3, alpha-Gal-A activity has increased into the mean normal range at week 2. As Sandy noted, three of the patients have reported clinical improvement with a greater ability to sweat. This allows for greater exercise tolerance in active individuals. The cardiac magnetic resonance imaging data suggest stabilization of important MRI parameters in two patients.

The two patients in cohort one we have now begun the long term follow up study and at the one year Mark Alpha Gal a expression remains robust.

Withdraw from your team.

When completed for one patient that was planned for the second patient.

And prime replacement therapy based on the stability of their alpha Gal a activity following treatment.

So the first patient in cohort three alpha Gal a activity has increased into the normal range.

As Sandy noted three of the patients that reported clinical improvement with a greater ability to sweat. This allows for greater exercise tolerance and active individuals.

The cardiac magnetic resonance imaging data suggest stabilization is important MRI parameters in two patients.

Rob Schott: This will be followed at intervals to confirm the cardiac benefits of therapy. One patient with a significant elevation in plasma Lyso-GB3 pretreatment showed a significant reduction from baseline of approximately 40% in his biomarker after treatment with ST920 within 10 weeks after dosing and maintained through week 36; patients with lower baseline levels of glyco-GB3 maintained steady levels through the cutoff date. The sixth patient in the study, who is the second patient in Cohort 3, was recently dosed after the cutoff date.

This will be followed at intervals to confirm the cardiac benefits of therapy.

One patient with a significant elevation in plasma lifestyle JV III pre treatment showed a significant reduction from baseline of approximately 40% in this biomarker.

Treatment with <unk> 920 within 10 weeks after dosing and maintained through week 36.

With lower baseline level, why <unk> maintained steady levels during the cutoff date.

The six patients in this study was the second patient in cohort three with recently dose. After the cutoff date, we expect to provide updated results from the STAAR study in the second half of 2022 and are currently planning for a phase III clinical trial.

Rob Schott: We expect to provide updated results from the STAR study in the second half of 2022 and are currently planning for a Phase 3 clinical trial. At ASH 2021, we announced updated preliminary proof-of-concept data from the Phase I-II Precision I study of SAR 445136 for the treatment of sickle cell disease. As of the September 22, 2021 cough date, the most recently treated patient in the study has been followed for 26 weeks, and the longest treated patient has been followed for 91 weeks.

At Ash 2021, we announced updated preliminary proof of concept data the phase <unk> precision one study of let's say our 44536 for the treatment of sickle cell disease.

As of the September 22021 cutoff date, most recently treated patients in the study has been followed for 26 weeks and the longest treated patients had been followed for 91 weeks.

Rob Schott: In all four treated patients, there were increases in total hemoglobin, fetal hemoglobin, and percent F-cells. None required blood transfusions post-engraftment, and the Thar 445136 investigational drug product had on-target BCL11A gene modification of between 61 to 78% in all four patients. There were no adverse events related to therapy with SAR 445136.

And all four treated patients there were increases in total hemoglobin fetal hemoglobin and percent F cells, none required blood transfusion posted in graphics.

With our 44536 investigational drug product at on target ECL eliminate gene modification of between 61% to 78% in all four patients.

There were no adverse events related to therapy with our 445361.

Rob Schott: One patient had a single sickle cell crisis or vaso-occlusive crisis nine months after treatment. However, there have been no additional serious adverse events reported. Additional data from this study is expected to be presented at a medical meeting in 2022, and dosing of patients in this study is expected to be completed by the third quarter of 2022. We are currently collaborating with Sanofi on planning for a transfer of its responsibilities under this program back to Sangamo this June.

One patient had a single sickle cell crisis or basal occlusive crisis nine months. After treatment. There has been no additional serious adverse events reported.

Additional data from this study are expected to be presented at a medical meeting in 2022 and dosing of patients. In this study is expected to be completed by the third quarter of 2022.

We are currently collaborating with Sanofi and planning for a transfer of its responsibilities under this program back to thank them all it's Jim.

Rob Schott: We look forward to keeping you apprised of future updates regarding this exciting clinical study. With that, I'll turn it over to Prathyusha for a financial update.

We look forward to keeping you apprised of future updates regarding this exciting clinical studies.

With that I'll turn it over to Patricia for a financial update Patricia.

Prathyusha Duraibabu: Thank you, Rob, and good afternoon. Our financial results for the fourth quarter and the full year are available in the press release we issued and can also be found on our website. I want to reiterate that 2021 was a significant year for Sangamo, with execution on many fronts as we continue to progress the advancement of our LEAD programs, our preclinical research pipeline, and our in-house manufacturing capabilities. With approximately $465 million in cash, cash equivalents, and marketable securities at the end of the year, we believe that our balance sheet remains strong for continued execution across our platform and programs. Turning to our initial 2022 full-year guidance, we expect non-GAAP operating expenses to be between $280 million and $310 million for the year. This range excludes estimated non-cash stock-based compensation expenses of approximately $14 million.

Thank you Rob and good afternoon.

Our financial results for the fourth quarter and the full year available in the press release, we shoot and can also be found on our website.

I wanted to re create the 2021 with a significant year for Sangamo with execution on many fronts as we continue to progress the advancement of our lead programs.

Clinical research pipeline and our in house manufacturing.

With approximately 465 million in cash cash equivalents and marketable securities at the end of the year, we believe that off balance sheet remains strong with continued execution across our platform and program.

Sandy Macrae: We expect a significant portion of our operating expenses to be invested in the continued progress of our LEAP programs, including February Phase 3 planning activities, Phase 1-2 activities for Tx200, and preclinical work in CAR T-reg and CNS indications. We also expect to grow our investment in sickle cell in the second half of the year, following the trans-fossil program back to Sangamo. I will now turn the call back to Sandy for her closing remarks. Thank you, Prathyusha.

Turning to our initial 2022 full year guidance.

We expect non-GAAP operating expenses to be between 280 million to $310 million for the year.

This green excludes estimated noncash stock based compensation expense of approximately $14 million.

We expect a significant portion of our operating expenses to be invested and continued focus on Felipe programs, including February 5th Preplanning active Keith. Please one plus two activities boutiques to one gig and preclinical work in coffee and peanuts indication.

We also expect to grow out investments in sickle cell in the second half of the year.

Following the canceled the program back to Sangamo.

I'll now turn the call back to Sandy for closing remarks.

Thank you Patricia.

Sandy Macrae: We're excited by where we stand as a company and believe we have a bright future. We are a fully integrated genomic medicine company building momentum with our novel science, clinical execution, and in-house manufacturing. In 2022, we look forward to providing expected updates on Phase 1-2 Fabry data, selection of a dose for cohort expansion, and Phase 3 planning. Dozing of Patients in the CAR-T REG-STEPHAS trial.

We're excited about where we stand as a company and believe we have a bright future.

We are a fully integrated genomic medicine company building momentum with our novel Science clinical execution and in house manufacturing.

In 2022, we look forward to providing expected updates on phase one to fabry data selection of the dose cohort expansion phase III planning.

Dosing of patients in the car T Reg steadfast trial.

Phase one to sickle cell data and dosing of patients in the precision one study and the transition of the program from Sanofi to Sangamo.

Operator: Phase 1-2 sickle cell data and dosing of patients in the Precision 1 study and the transition of the program from Sanofi to Sango, and Pfizer's progress with the Pivotal Phase 3 haemophilia A trial. We will now turn it over to the operator to open the line for questions. If you'd like to ask a question at this time, please press the star and then the number one key on your touchtone telephone. To withdraw your question, press the pound key. Our first question comes from Nicole Germino with Truist Security. Good afternoon, everyone.

And pfizer's progressed with the pivotal phase III hemophilia a trial.

We will now turn it over to the operator to open the line for questions.

If you'd like to ask a question at this time. Please press. The Star then the number one key on your Touchtone telephone.

To withdraw your question press the pound key.

Our first question comes from Nicole Drew me now with <unk> Securities.

Sandy Macrae: And thank you for taking my question. And congratulations on all the, If I could ask a two-part question, the first one is, in the backdrop of other companies experiencing clinical holds with their gene therapy programs, can you address the safety concerns and integration risk around your vector for Heme and for ST920 for Fabry? And second, for your CAR Treg platform, how necessary is it for a kill switch for regulatory agencies, or maybe put another way, will give you confidence that you don't need one?

Good afternoon, everyone and thank you for taking my question and congrats on all the progress.

If I could ask a two part question. The first one is in the backdrop of other companies experiencing clinical holds with their gene therapy program can you address the safety concerns the integration risks around your factor for him and for SG&A in 'twenty for Fabry and second for your car T Reg platform.

Or is it for and kill switch still regulatory agencies or maybe put another way what gives you confidence that you don't need.

Rob Schott: Thank you for your questions. I could address the first one, and then I'll pass the second one on to Rob. So, safety is really important to us, and that's why we look at safety as the primary end point of all of the studies that we do with our AV6 vaccine. We've been really pleased with the safety throughout all of the programs, the MPS programs, Haemophilia A, and now with VapriDisease, and we're gathering an increasing body of data that convinces us that this form of delivery is safe for the patients that we serve.

So thank you for your questions.

If I can just address first one and then I'll pass the second one.

So safety is really important to us that's fine.

Safety is the primary endpoint.

Studies, we've done with <unk>.

We've been really pleased by the safety.

Programs NPS programs hemophilia.

I know with Fabry disease.

An increasing body of data.

Convinces us that this form to listening is safe for the patients we serve.

Rob Schott: Now, the choice of diseases remains important because we always have to balance benefit and risk, and we spend a long time... Thoughtfully gathering preclinical data, sharing it with the regulators, starting at doses that allow us to be sure the patient's safety is maximum protected, and then sharing with the community any concerns we have as the trial progresses. I'm delighted with our progress so far. I think it's unfortunate when others have run into difficulties because it does cloud the whole field. That's the advantage of us having a vector that we've worked with and have gathered a lot of safety. Bob, can you answer this second one?

The choice of diseases remains some portion.

With us.

<unk> benefits from risk.

We spent a long time.

Hopefully encountering preclinical data sharing them with the regulators starting at doses.

Allow us to be sure that patient safety is amongst many protections and then sharing with the community any concerns.

Oh gosh.

The licenses are purposeful farm.

I think it's unfortunate another some front end.

Because it does.

I'd say advantage of us having effect.

Got it.

Yeah.

Bob can you answer the second one yes.

Jason Fontenot: Yes, I'd like some clarification to call on... Killswitch. And you're suggesting that we program that into... This is self-therapy so that we can..., turn off the T-Rex, is that it? Yeah, that's a good question. Yeah, a couple of your competitors have a kill switch. Is it necessary for regulatory agencies, or have regulatory agencies had any input on this? And if not, like is it, do you need a kill switch, or what gives you confidence that you don't need a kill switch?

I would like some clarification to call on.

Oh.

The kill switch and.

Right.

You're suggesting that we program that entity.

And to the cell therapy, so that we can.

Turn off the T. Regs is that is that the.

Yeah.

Yeah, Yeah, a couple of your competitors.

Has.

I'll kill switch is it necessary for regulatory.

Regulatory agencies.

Regulatory agencies.

Had any input on that and if not is it do you need.

Kill switch or what gives you confidence that you don't need one.

Rob Schott: Yeah, we've not been asked to engineer in a kill switch. Again, these are key regulatory cells that we're engineering for these programs. So they are responsible for inhibiting the immunologic response and rejection in the case of renal transplants.

Yes, we have not been asked to engineer in a kill switch again. These are T regulatory cells network engineering for these programs.

Right.

They are responsible for inhibitor HD.

I mean all of it.

Logic response.

And rejection in the case of renal transplant. So it's a different proposition neste engineering other types of T cells killer T cells.

Jason Fontenot: So it's a different proposition than engineering other types of T-cells, killer T-cells. I'd actually like to ask Jason to comment on that, too. Jason, can you help us with some thoughts? Yeah, thanks, Sandy and Rob. Yeah, I think I can say is that we are very confident about that approach. We've evaluated the safety and the efficacy of the cells in a variety of pre-clinical models, and we've been very happy with the results.

CD eight T cells, but I'd actually.

I'd like to ask Jason to comment on it as you know Jason can you help us.

<unk>.

Yeah, Thanks, Randy and Rob.

Yes, I think I think what I can say is that we are we're very confident about the approach that we're using in the TX 200 program.

We've evaluated.

The safety and the efficacy of the cells in a variety of preclinical models and we've been very happy with what we've seen.

Jason Fontenot: Ritu Baral, Luis Santos, our own internal experts, clinical regulatory safety, and we. We're moving forward, and we're excited to have our first patient this quarter. Other companies take different approaches, but we're confident that our approach is the best, one that is going to offer a benefit for patients. And we'll be keeping a close eye on patients as they're treated. Thank you, Jason.

Obviously consulted with our own internal experts.

Clinical regulatory safety and we've had conversations with the regulators.

We're moving forward.

Forward and we're excited to be dosing or <unk>.

First patient in this quarter.

Other companies take different approaches, but we are confident that our approach is one that offers a.

Yes.

He is going to offer a benefit for patients.

And we'll be keeping a close eye on patients as they're treated obviously this is a phase one study where safety is paramount and that's what our focus is on.

Thank you Jason.

Thanks, so much.

Yanan Zhu: Our next question comes from Yanan Zhu with Wells Fargo. Thanks for taking my questions. First, on the Fabriry program, so you mentioned you would have additional data in the second half of the year. I'm just wondering what the follow-up might be, and presumably this is going to include all six patients. So the question is the length of the follow-up, and in terms of the endpoints, I think we can assume ERT withdrawal is an important endpoint, enzyme level, and substrate, but would there be any additional clinical endpoints that are also going to be studied and reported at that stage? Thanks.

Our next question comes from Yanan, Zhu with Wells Fargo.

Hi, Thanks for taking my questions.

First on the Fabry program.

So you mentioned you will have additional data in the second half of the year that just wondering.

What might be a follow up and presumably.

Is this is going to include all.

All six patients.

Question is less.

The follow up and in terms of the endpoints.

I think what we can assume.

<unk> is the important.

Endpoint.

And then level substrate, but would there be any additional clinical endpoint.

That's also going to be studied.

We reported at that stage.

Bettina Cockcroft: Thank you for your question. So this is about the longer-term data on Fabry and what we'll be able to show. Patina, you've been following this trial very closely.

Thank you for your question. So this is the longer term to your tone on Fabry and Paul will be able to show in particular, you can point.

Volumes tracked very closely.

Bettina Cockcroft: Yes, and thank you so much for the question. Later this year, we will have accumulated more data, especially from the earlier dose patients. As you may know, the parent study these patients have been enrolled in is a one-year study, and patients that were treated at the beginning have, some of these patients have now rolled over to the long-term follow-up study, which is an additional four years of follow-up in total.

Yes, and thank you so much for the question. So later on this year, we will have accumulated more data, especially from the earlier patients.

As you May know the parents.

Patients have been enrolled in persist one study in patients that have been.

And at the beginning.

Some of these patients have now rolled off.

The long term follow up study, which is an additional four years of follow up.

Bettina Cockcroft: And we will be able to present data on the accumulation of the alpha-GalA expression over time, as well as other biomarkers, like the Gb3, and you point out your T withdrawal data. In terms of clinical endpoints, we will be collecting, once we doze naive patients moving forward, we will be collecting kidney biopsy data. This will not be available this year at this later update.

And we will be able to present.

On accumulation.

<unk> also got a expression over time as well as biomarker tied to GDP.

Todd T withdrawal data.

Terms of clinical end points.

We'll be collecting one sweep those naive patients moving forward, we will be collecting.

Kidney biopsy data this will not be available this year at this latex updates.

Bettina Cockcroft: We can expect that type of clinical data to be presented next year. We will also be presenting an update on patient-reported outcomes. And so really, as we move along, we are also intending to dose more patients, and we have patients currently in screening and in baseline. So...

We can expect that type of critical.

It had to be presented.

Next year.

He will also be presenting an update on patient reported outcomes.

So maybe.

As we move along we're also intending to dose more patients we have patients currently in screening and baseline so pace.

Bettina Cockcroft: Patients are going to... We anticipate the dose, so it can be so well. And exactly, and some of that will be a nice profile that we will be collecting from this wealth of data that we have. What we like from the data we've seen so far is, up until the one year mark that we have concrete data from, there has been no sense of decline in the four patients that have been treated for the longest.

Patients are going to.

We anticipate being dosed.

So I would give us a wealth of data.

Exactly and some that will eni's profile that we will be collecting from that as well.

Well, we like from the data we've seen so far.

Oftentimes one year Mark.

Concrete data there's.

No sense of decline.

And for patients that have been.

And treated at the longest.

Bettina Cockcroft: That the alpha-gal remains elevated, that the lyso-GB3 remains flat, that the patients remain, still get a claim of benefit, talk about symptoms like sweating, talk about, their investigators talk about stabilization of the cardiac MRI. And those are all really encouraging data that it's only through time that we'll be able to understand them. However, I want to be absolutely clear, we are fully engaged in our planning for the phase 3 study and look forward to initiating that as the data from the current study matures. Right, yeah, yeah, thank you.

The Alpha Gal.

<unk> remains elevated by some GBP three remains remains patients remain still get a claim of benefit.

Sometimes like switching talk.

The investigators talk about stabilization of the cardiac MRI.

Really encouraging news.

We'll be able to understand it.

However, I want to be absolutely clear we are full on in our planning for the phase III study.

Look forward to initiating that data from the current study matures.

Sandy Macrae: And I am looking forward to hearing about the Phase 3 design. So I think it may be too early to ask that question. So I might, if I may, I'm curious about what you mentioned about the base editing programs that you're working on. Obviously, this is going to be based on Zyncfingers. So my question is, does your base editor retain the Nuclease part of the Zyncfinger Nuclease, or does it forego that Nuclease part? The reason I'm asking is because I think in CRISPR-based base editors, actually the Nuclease capability, i.e. The ability to cut one strand of double-stranded DNA is actually very useful in terms of improving the editing efficiency because it prevents the degradation of the edited strand.

Right, Yes, yes, thank you and looking forward, we're hearing about the phase III design.

I think maybe too early to ask that question. So I might if I may.

Curious about what you mentioned about base editing.

Programs that you're working on.

Obviously this is going to be based on zinc fingers. So my question is.

Your basic editor retain.

<unk> nuclease part.

The zinc finger nuclease or does it forego that part of the reason.

Asking is because I think in the Christopher based.

Editors.

Actually the unique case.

Capability I E the ability to cut when threatened.

The double stranded DNA is actually very useful.

In terms of improving the editing efficiency because it prevents the degradation of the.

Jason Fontenot: So in that light, I'm interested in whether or not your architecture for your base editor, basically. Thank you for a very interesting question. We've been working on face ideas for some time, and I'll get Jason to comment in a minute. What gives us great pleasure is that the Sinkfinger platform allows a range of technologies to be added to the DNA localizing Sinkfinger and allows us to choose when double-franded breaks a new place that is important or whether things like repression enhancement or base editors are the right things for the right patient compared to CRISPR, where But Jason, can you comment on this specific question?

Edited strand.

In that under that light.

Interested in whether your architecture for your based editor basically inks.

Very interesting question so.

We've been working for some time.

Jason to comment in a minute.

<unk>.

Well gives us great pleasure as that.

The same thing go platform.

Range of technologies to be added to that.

DNA localizing zinc finger and allows us to choose from a double stranded break a nucleus of our imports or other things.

Things like compression enhancements or besides the terms are the right things for the right patient.

Compared to Christopher Ferry.

Company for each of these adjacent could you comment on the specific question. Please.

Sure. Thank you Sandy.

Jason Fontenot: [inaudible] Sure, thank you. Um, you know, uh... This is the base editor that will not create double-stranded breaks to change the genome, and We are very excited about the advancements that we have made and we look forward to sharing them very soon. I think I'm going to go into the details of the architecture of the. Editors that we've designed, but it's a novel approach, and we're very excited about discussing it. Great. Thanks for the cover!

Yes.

This is the base editor.

It will not create double stranded breaks two to change.

Yeah.

In the genome and we're really excited about the advancements that we've made and we look forward to sharing them.

Very soon.

The appropriate scientific conference.

I don't think I'm going to go into the details of the architecture of the base editor that we've designed but it's it's a novel approach and we're very excited about this.

Scuffing, it and deploying it therapeutically.

Great. Thanks for the color.

Jason Fontenot: The reason we particularly like it is it uses, I think, finger architecture that we've had years of experience with and so understand how to tune and how to increase the size of the specimen. It benefits from the small size of Syncfingers, which is almost a tenth the size of some of the CRISPR architectures and therefore will allow it to be packaged in AAV in a way that the standard base editor won't, and it allows us choice, and that's what we like, and that's what our partners like.

The reason, we particularly like since it uses.

Finger architectures.

Years of experience with and you'll understand how to tune them.

Yes.

Benefits from the small size of St.

Quite sure almost attempt to signs of some of the CRISPR architectures, and therefore will allow it to be packaged.

And <unk>.

<unk> in a way.

Good morning.

And it allows us choice and that's what we like in which our partners play.

Sandy Macrae: Got it. Yeah, thanks. Thanks for highlighting that advantage. So yeah, that's a question in my mind as well. Thank you very much for all the cover.

Got it yeah. Thanks, thanks for highlighting that that's our advantage.

Question.

In my mind as well thank you very much for all the color.

Thank you.

Operator: Thank you. Our next question comes from Maurice Raycroft with Jeffreys. Hi, thank you for taking my question. This is Jing, I'm on Maurice's line.

Our next question comes from Maury Raycroft with Jefferies.

Yes.

Hi, Thank you for taking my question. This morning, so actually I have two questions. The first one is can you talk a more about where you are at with this design designing our families safely and what are the gating factors to get on it Scott.

Operator: So actually, I have two questions. The first one is, can you talk more about where you are with this design, designing a fabric space? and what are the gating factors to get all these, you know, these studies started? That's my first question. Second one is, what else can you talk about the first patients enrolled in the CAR T-REX? And can you also say if this patient has already been transplanted and if you are currently processing the CAR T-REx? So let me take the easier one, which is to start with.

Got it got it.

That's my first question second one is the what else can you talk about the first patients enrolled.

Car T rack program.

Can you also say this.

Patients that have already been transplanted and are you currently processing.

Car T Rex.

That's my question.

Sandy Macrae: Can you just talk about where we are with contraceptives in general? So we haven't shared anything about the phase three study, but as I'm sure you know, planning for a phase three takes a long time, and therefore, we've been looking at the design of this and talking to experts for at least six months, and are pleased with the progress we're making, and we'll share it more broadly at the right time. Mark, can you talk about the feedback, because we're very excited.

So let me take the easier one.

Can you just talk about where we all win.

And just in general.

So we haven't shared.

Anything about the phase III study.

Mhm.

As I'm sure you know planning for our phase III has been.

It takes a long time and therefore, we've been looking at just sign of this telco experts for.

At least six months.

We are pleased with the progress we're making sure we're appropriately at the right time.

Mark could you talk about the CMS, because we're very excited about that.

Sandy Macrae: Yeah, so we're, you know, we're about to dose the first patient with our TX200 candidate. And so we're very excited about that. And as we've talked about, we expect to dose two patients by the end of the second half of 2022. You know, we're delighted to take this forward because it'll be the first opportunity for us to really establish the biological effect of these agents and really understand what's going on. And this is critical because our goal is that TX200 establishes the foundation for a portfolio of CAR Tregs for major autoimmune indications.

Yes sure.

You know we're about to dose the first patient with our TX 200 candidates and so we're very excited about that as we've talked about we'll be expecting to dose.

Two patients by <unk>.

End of the second half of 2022.

We're delighted to take this forward because it'll be the first opportunity for us to really establish the biologic effect of these agents and really understand what's going on and this is critical because our goal is that extra 100 establishes the foundation for our portfolio of car T regs.

For major autoimmune indications and so this will inform us.

Mark McClung: And so this will inform us about using autologous stem cells. In the meantime, we're advancing allogeneic approaches. And as we've disclosed, we have, you know, preclinical candidates against MOG and multiple sclerosis, as well as IL23R for inflammatory bowel disease. And so we'll be applying the learnings that we have coming out of this trial as we advance the platform and these particular candidates. Great, thank you.

Using the autologous.

In the meantime, we're advancing allogeneic approaches and as we've disclosed we've got.

Clinical candidates against Maag, and multiple sclerosis, as well as IL 23 are for inflammatory bowel disease, and so we will be applying the learnings that we have coming out of this trial as we advance the platform, but also those particular cabinets.

Okay, great. Thank you.

Very much.

Operator: Our next question comes from Luca Issi with RBC Capital. Oh, great. Thanks so much for taking my question. Congratulations on all the progress. Two quick ones.

Our next question comes from Luca <unk> with RBC capital.

Oh, great. Thanks, so much for taking my question Congrats on all the progress.

Sandy Macrae: Maybe the first on Fabry, I will not ask you the design of the Phase 3, but maybe, at a high level, can you just talk about what gives you confidence that you can start a Phase 3 here without actually having seen the kidney biopsy data quite yet? And then maybe second, on sickle cell disease, can you just provide any additional color on the new manufacturing process here? What are some of the key parameters that you're optimizing here that gives you confidence that the new manufacturing process will drive better outcomes for patients? Thanks so much. So, let me see how I can split these up.

Two quick ones, maybe first on Fabry I will not ask you the design of the phase III, but maybe at high level could you just talk about what gives you confidence that you can start a phase III here without actually having seen the kidney biopsy data quite yet and then maybe second on sickle cell disease can you just provide any additional color on the new manufacturing processes.

What are some of the key parameters that you're optimizing here that gives you confidence that the new manufacturing process will drive better outcomes for patients. Thanks, so much.

Rob Schott: Rob, can you talk about sickle, please? And the other question I think you said was, in the absence of, if I can just make sure we answer this question correctly, in the absence of kidney biopsy data, which we expect to see in 2023, how will we decide on the GO decision and the design of phase 3? As I said, we've been designing this and talking with regulators for some time, and we believe that the data, perhaps from Avrobio, one of our, it's usually one of our competitors, where they showed very small changes in alpha-gal. We get changes in the renal biopsy data for viso-GB3.

So let me see how I can spud.

But these Rob can you talk about them.

Please.

The other question I think you said it was in the absence of those if I can.

And just to make sure we answer this question correctly and in the absence of kidney biopsies are we should we expect to see in <unk>.

Q3, I will we just saw you Don.

Good decision.

The design of <unk>.

Yes.

As I said, we've been we've been designing this.

With particular interest for some time.

We believe that the data.

Perhaps for Matt from volume one of the issues with one of our competitors, but at least showing very small changes in alpha gal be get changes in the renal biopsy data for <unk>.

Sandy Macrae: That in itself gives us confidence that the alpha-gal we are seeing should benefit the tissues when we get to that stage. But we have to plan in advance, and we have to look at the different doses and the dose response curve and decide which one we take forward as we accrue data. And with respect, we're in difficulty.

With GPS III Boston itself gives us confidence that we.

We are seeing shoot.

Should benefit the tissues and we get to that stage. So we have to plan in advance and we have to.

Because of different doses on the dose response curve.

Slide 21, we take forward.

Two days ago.

And with respect Greg.

Okay go ahead.

Rob Schott: OK, go ahead. With respect to the sickle cell program and manufacturing, we have made some process changes. We haven't talked specifically about those process changes, but in internal experiments, we've shown that they increase the number of progenitor cells.

With respect to the sickle cell program and manufacturing.

Have made some process changes, we haven't talked specifically about those process changes, but in an internal experiments we've shown that increases the.

Number of progenitor cells. So we're optimistic that this will carry through into the clinic with better yields.

Rob Schott: So we're optimistic that this will carry through into the clinic with better use. And we're being very transparent and, I hope, realistic to say that we believe this will result in clinical benefit, but until we do the clinical experiment, we can't have a direct correlation. So that's why we, too, are very interested in seeing the data from these next three or four patients that will be dosed over the coming months. And I want to say thank you to our friends at Sanofi who are continuing to drive forward the study during the transition. Got it. Thanks so much.

And we're being.

Very transparent.

I hope realistic to see that.

We believe this will result in clinical benefit, but until we do the clinical experiment become kind of a direct correlation. So that's why we are very interested in seeing the data from these next three or four patients so reduced over the coming months.

And I wanted to see attachments. Thank you to our friends at <unk>.

Continuing to drive forward the study during the transition period.

Got it thanks, so much.

Operator: Our next question comes from Ben Burnett with Stiefel. Hi, this is Kayleigh Brazon for Ben. Thanks for taking our questions. I just had one quick one about Fabry.

Our next question comes from Ben Burnett with Stifel.

Hi, This is Kelly Grace on for Ben Thanks for taking our question.

I just had one quick one about fabry silver.

Operator: So regarding the Fabriry program, can you talk at all about the Lyso-GB3 biomarkers, specifically under what situations would you expect the biomarkers to move with the ST920 treatment? And then our second question is about hemophilia, and I was just wondering if Pfizer has already received feedback from the FDA on the necessary steps to remove the clinical hold, or if this is something they have yet to do. Thank you. So, Bettina, can you do Fabry, and Brock, can you do him?

Regarding the Fabry program can you talk at all about the license G B three.

Biomarkers, specifically under what situations would you expect the biomarker or to move with S. T 920 treatment.

And then our second one is about hemophilia and I was just wondering if there if pfizer has already received feedback from the FDA on the necessary steps to remove the clinical hold.

Or if this is something they have yet to deal. Thank you.

So nothing new to comprehend prompt you to human factors.

Bettina Cockcroft: Yes, thank you for the question. So Lyso-GV3, you will have seen we presented data on at the World Symposium just a couple of weeks ago in San Diego. And different patients are exhibiting different baseline levels to start off with our PSGB3. And so the movements that we can expect are going to differ based on this as well.

Yes. Thank you for the question so like the GBP three.

Bettina Cockcroft: I'd like to point to patient number three, who is the first patient in the cohort whose PSGB3 started higher than the other patients and for whom we've had a significant more than 40% reduction, and that within the first 10 weeks post infusion. And that reduction has been maintained over time until late..., follow up. And so I, what we look forward to is seeing the next patients, going to be those, seeing how the Lisa GV3 fares over time, depending on their baseline. And this phenomenon, Bettina, has been seen on other, in all the programs. It's got to be high to put it down.

You'll have seen we presented data on <unk>.

The wealth symposium and just a couple of weeks ago in San Diego.

And just for patients are exhibiting different baseline level.

Start off with <unk>.

G suite and so the movement that we can expect.

Based on this is what I'd like to point to patient number three.

If a patient has.

Patients in cohort two.

Like would you be three started.

And then the other patients and.

So who we've had significant more than 40%.

Docs.

And that within the first 10 weeks post infusion.

Reduction is maintained over time until the later followed up and so.

Hi.

But we look forward to seeing the next patients.

<unk> going to be dosing.

Seeing how that.

I thought you'd be three SaaS over time, depending on that baseline.

This phenomenon.

Another and all of them.

Problems is going to be hiring to be done.

Sandy Macrae: It's important to point that out, thank you, Sandy, because we have seen the same in other programs that the Lysol GV3 really does need to be at a significantly high level for us to be able to impact it with the Clean Therapy approach. And that has been seen across other programs. And so we're confident that we're seeing... This is data that is going to be encouraging as we also look at our next patient's dose at the highest level, and Raw Haemophilia.

It's important to point that out.

We have seen the same in other programs that.

He likes the GBP, three really does need to be at significantly higher levels.

For us to be able to impact it.

The gene therapy approach and that has been seen across all the programs and so we're confident that.

Team.

Data that is going to be encouraging.

Our next patients dosed at the higher dose.

And Ralph Hemophilia.

Sandy Macrae: First, I'd like to acknowledge the terrific partnership with Pfizer on this program and remind everyone that Carl was more than 50% enrolled at the time of the pause. Pfizer has guided us in markets where the trial will resume or plans to resume in the first half of 2022. So, without getting into the specifics of where we are with responding to regulatory authorities, I can point toward that guidance of resumption of trials in the first half of 2022. It's going very well, and they're putting all the restrooms in town. They are aggressively and enthusiastically pursuing this trial.

First I would like to acknowledge.

Terrific partnership with Pfizer on this program.

And remind everyone that.

Trial was more than 50% enrolled at the time it was positive.

Pfizer has guided us.

Markets that.

Trial will resume or planning to resume in the first half 2022, so without getting into the specifics of where we are with.

Responding to regulatory authorities I can point towards that guidance, the resumption of the trial and.

In the first half of this year, that's going quite well and they're counting all the restaurants.

They are aggressively and enthusiastically pursuing this trial.

Thank you.

Thank you.

Rob Schott: Thank you. Thank you. Our next question comes from Aspen Maury with Bank of America. Hey guys, thanks for the question. Maybe you can just talk through your updated thinking as you move, as you transition the sickle cell asset over to you guys, maybe to talk about how you see that progressing in terms of, you know, taking it alone, or, or maybe partnering it out. And if the priority is partnering, if there's any preference for someone with more of an OUS preference, OUS presence, as that was kind of Sanofi's niche in your prior partner.

Our next question comes from Aspen Mori with Bank of America.

Hey, guys. Thanks for the question.

Maybe you can just talk through your updated thinking as you move as you transition that's a class that over to you guys.

Maybe just talk to your updated thinking on.

How you see that progressing in terms of.

Taking it alone or maybe partnering it out.

And if the priority is partnering if there's any preference for someone with corporate all U S profile all.

Our U S presence as that was kind of status these niche.

And you put in your prior partner.

Rob Schott: And then the second question: some of your peers have implied that for the gene therapy space, FDA may be stricter on therapies or indications where there are already approved therapies available, not including gene therapies. Do you think that's a fair assessment?

Then second question some of your peers have implied that for the gene therapy space FTA, maybe stricter on therapies or indications, where there is already approved therapies available not putting gene therapies.

Do you think that's a fair assessment or has that at all been have you seen that dynamic play out with within your interactions with FDA. Thank you.

Mark McClung: Or has that at all been, have you kind of seen that dynamic play out within your interactions with the FDA? Thank you. I'm going to ask Mark to talk about the strategy around sickle cell, and then I'll touch on the general comment for the FDA. Justin, I mean, obviously, we heard on December 30th that they had made that strategic decision to transition Sickle Cell back to us. As Candy mentioned, you know, the team's been working very hard on the transition.

So I'm going to ask Mark to talk about our strategy around the cycle and then I'll touch on the general comment.

So I spent I mean, obviously we heard.

At December 30th.

That strategic decision to transition to circle back to us.

Sandy you mentioned, Jim has been working very hard on the transition and we're very pleased.

Mark McClung: We're very pleased with the engagement we have with Sanofi as we progress to the transition plan, which will culminate around June 28th of this year. Our highest priority right now is to ensure that we can complete the Phase I, II precision trial, as Rob just mentioned, utilizing that new manufacturing process, which we hope will come through and demonstrate even better results in those four patients. That totality of that data will inform, you know, kind of the way we want to proceed forward.

Sanofi as we can.

<unk> to the <unk>.

Transition plan, which will culminate around June 28.

This year, our highest priority right now is to ensure that we can complete the phase one to a precision trial as Rob just mentioned utilizing that.

New manufacturing process, which we hope.

Will.

Come through and demonstrate.

Even better results.

And those four patients.

Mark McClung: In the meantime, the teams have engaged the authorities, both in terms of feedback on manufacturing and preliminary discussions around the approach to Phase III. So, at the appropriate time, we'll provide an update on that. You know, in terms of the geographies and partnerships, we're not going to comment on that now. It's too early to provide a perspective on that.

That totality of that data will inform kind of the way we want to proceed forward in the meantime that the teams have engaged the authorities both in terms of feedback on manufacturing as well as preliminary discussions around do you approach the phase III.

So what's the appropriate time, we'll provide an update for that.

In terms of the geographies in partnerships, we're not going to comment on that now it's just too early to provide a perspective on that but.

Sandy Macrae: But I would remind you, right, that in the United States, there are about 100,000 Sickle Cell patients, of which 30,000 of those patients are severe. Outside of the U.S., there are about 150,000 patients. This is a devastating disease that affects a particular population, and our commitment is to do whatever we can to make sure that patients get access to this medicine if it's a differentiated medicine. And we'll know more as we get the clinical data, and our commitment is to ensure that we take it forward if the data suggests it should go to patients. And if I could talk to the more general one about the agency,

But I would remind you write that in the United States through about 100000 sickle cell patients of which 30000 30000 of those patients are severe outside of the U S. There's about 150000 patients.

This is a devastating.

<unk> disease.

That affects a particular population at our commitment is to do whatever we can to make sure that patients get access to this medicine, if its a differentiated medicine and we'll know more as we get the clinical data and our commitment is to ensure that we take it forward.

The data suggests that should get to patients.

If I could talk to the more general one or both.

Mark McClung: We have a great relationship with the agency, and I have an enormous respect for Peter and the FDA and what they do because I think one has to understand the exponential growth in this field that they have to deal with and train people and stay ahead of the emerging data and understand that. I think there is a bit of a reality check that we're watching now, which is More medicines are in the clinic, more new vectors are being tested, and some of them will be found to have challenges, and that's inevitable in any new field.

We have a great relationship with the agency and I have enormous respect for Pizza M. D D.

Because I think one has to understand exponential growth in this field and they have to do with them to train people and to stay ahead of the emerging data and understanding.

I think there was a bit of a reality check.

No quite shoes.

More merchants are in the clinic more new factors are being tested.

Some of them will be from Tom challenges, that's inevitable in any newfield pushed.

Mark McClung: Which takes me back to what I said to one of the earlier questions about our vector having had years of testing in many indications, the team at Sangamo having filled many INDs, and understanding the preclinical and toxicology data necessary to ensure safety. And about the inherent belief at Sangamo that everything is about the patient and that we put patient safety first and would be the first to have that conversation with the agency if we were ever concerned about what we're seeing.

Which takes me back to what I said to one of the earlier questions.

Our effect or how many times a year or so.

Testing in many indications subsequent team at Sangamo have been filled.

Many inte's understanding the preclinical and toxicology due to unnecessary to ensure safe.

Mark McClung: But at the moment, we haven't felt any difference in the agency's approach and are glad to have them as partners in the development of our medicines. Our next question comes from Ritu Baral, with Cowan. Good afternoon, guys.

And ability inherent belief of same promoter everything.

Everything has been patient and we put patient safety first.

Hum.

Be the first to have that conversation with the agency.

Our effort concern of Walmart.

In a moment.

So any difference in the agencies approach on our clock to have them as partners in the development of our medicines.

Thanks, Andy.

Our next question comes from Ritu <unk> with Cowen.

Operator: Thanks for taking the question. I had a question on Precision One, well, the Sickle Cell program in general. You know, I think at a high level, I'd love to know the metrics by which you'll gauge where the program will fit in a landscape that's getting more and more crowded.

Good afternoon, guys. Thanks for taking my question.

I have a question a question on.

The precision one well the sickle cell program in general.

I think at a high level.

Two.

No the metrics by which you'll be sort of where.

The program will put them in a.

In a landscape, that's getting more and more crowded to drill down on that.

Ritu Baral: To drill down on that, I guess what we're looking for is HPF levels, but also percent F cells. Which do you think will be a more important tell on the ultimate clinical benefit? And especially since you're reaching such high levels of percent F, do you need to show that sort of 90 percent level of percent F cells in a certain proportion of treated patients for you to say that this is? you know, this is going to be the preferred method.

Guess, what we're looking for is what's the appetite.

But also percent Upsells I guess.

Which one do you think will be.

More important or more important how on the ultimate clinical benefit.

Especially since you're reaching such high levels of percent F. D. Do you need to show that Trump 90 level a percent up sells in a.

Certain proportion of treated patients for for you to say that this is you know.

This is this is going to be the preferred.

Rob Schott: Therapeutics. So I'm going to ask Rob to comment on the technical bit and Mark on more of the strategic. But I would remind you that we have, we're in the clinic with clinical data. There are many, the competitive landscape is largely newcomers from other editing modalities, putting that into the pipeline and talking about it.

Therapeutic.

So I'm going to ask Rob to comment on the technical gotten more and more strategic.

I would remind you that we have we're.

We're in the clinic with clinical data there are many.

<unk>.

New comers from other.

Other editing modalities.

Good evening to the pipeline and talking about <unk>.

Sandy Macrae: But Rob, can you talk about what you'll use as a loop for success? What's most important to the patient is the frequency at which they have vaso-occlusive crises. That is the most important parameter, is relief of this terrible, painful, expensive sickle cell crisis. What we have seen in the four patients that we've reported is an enormous effect size. We've had a single VOC, whereas prior to treatment, they were having very frequent vaso-occlusive epilepsy.

You talk about what you will use to measure our.

Our success.

What's most important.

The patient is the frequency of which they have basically.

That is the most important parameter is released.

Painful expensive sickle cell crisis.

And what we have seen in the four patients that we reported is an enormous effect size. We've had a single POC, whereas prior to treatment. They were having very frequent basal occlusive episodes. So if you look at the magnitude of the effect of this therapy has profound.

Rob Schott: So if you look at the magnitude of the effect that this therapy has, it's profound. All of the other factors that you mentioned, percent F-cells, fetal hemoglobin, are all important, but what is most important is the durability of that effect and the impact that it has on patients' lives. And I think with time, we'll understand that relationship between percent F-cells and fetal hemoglobin and that protection, but we really need to keep our eyes on what's most important.

All of the other factors that you mentioned percent fetal hemoglobin are all important.

It's most important that durability.

Correct.

And the impact that has on patients' lives and I think with time, we'll understand that relationship between percent F cells hemoglobin and that protection, but we really need to keep our eyes on what's most important to the patient.

Nice with central.

Rob Schott: Nicely said. Do you think that it's, oh sorry, just a quick follow-up to that, do you think that that relationship is well enough understood right now, a snapshot in time, or will it be understood in the next couple of years enough that HBF, or some analysis of HBF, could be a potential approvable, or accelerated approval, pivotal endpoint, or will it really come down to VOCs or some The OCs are easy to measure.

We have a picture of it.

Oh, sorry, a quick follow up to that do you think that.

That relationship is well enough understood right now snapshot in time or will be understood. In the next couple of years enough that hbf or some analysis of H B O b a potential approvable accelerated.

Accelerated approval pivotal endpoint or will it really come down to <unk> or some other clinical aspect.

Yes, these are easy to measure.

Rob Schott: You. It's not a subtle laboratory-based finding; it's what the patients report. I think that will remain the cornerstone of assessing effective therapies, and the benefit that that provides patients, particularly in this. Got it. And a bigger picture. Thank you. Sorry. Thank you.

You did.

It's not a subtle.

Libratory based finding it's about the patients reported I think that will remain the cornerstone.

Assessing effective therapies.

And if it did that provides patients particularly in this.

Got it.

Bigger picture. Thank you sorry, thank you sorry.

Mark McClung: Yeah, so in terms of that, Regina, if I don't answer this, please clarify it for me: the CRISPR Vertex guidelines that they're going to file sometime towards the end of this year. You know, they've not shown as much of the data set yet, at least as far as I know, in terms of any further updates, in particular of the registration-directed study results, which would be expected. And so, you know, time will tell in terms of how the discussions go once they file with the agency. In the meantime, we've also seen Bluebird withdraw.

Yes, so in terms of that Virginia, if I don't answer this please.

But for me, but obviously.

The CRISPR vertex guiding that they're going to file sometime towards the end of this year.

They have not shown as much of the data set yet at least as far as I know in terms of any further updates in particular of the registration directed study.

Study results, which would be expected.

And so.

So time will tell in terms of how the discussions go once they filed with the agency in the meantime, we are also seeing bluebird withdraw.

And and so.

Mark McClung: And so, you know, it really becomes important for us to better understand the data that's emerged and we've presented to date, but more importantly, as Rob alluded to, the additional four patients with the change in the manufacturing process to see if that has an increased benefit in terms of the HPF levels, percent F cell increases, as well as the clinical outcomes for the patients. And I think it's really whether that profile looks competitive enough that will dictate how we take the program forward. I got it.

Really it becomes important for us to better understand.

The data that's emerged and we've presented to date, but more importantly, as Rob alluded to the additional four patients.

Change in the.

Manufacturing process to see if that has been increased benefit in terms of the hbf levels set ourselves increases as well as the clinical outcomes for the patient So I think.

It's really what does that profile looks competitive enough that will dictate how we take the program forward.

Got it thanks.

Thank you.

Operator: Thanks. Thank you. Our next question comes from Gina Wang with Barclays. Thank you for taking my questions. There are two very quick ones.

Our next question comes from Gena Wang with Barclays.

Thank you for taking my questions.

Two very quick ones. The first one I'll also follow regarding the sickle cell program, what kind of clinical profile you would be thinking.

Operator: The first one is regarding the sickle cell program. What kind of clinical profile would you think is possible to keep in-house? Would that be a CRISPR-like profile, or would that be better? The second question is regarding the base editors. So I assume you use the MNAs. What about the IP part? Do you have a proper right to use that?

Possible to keeping house would that be Christopher like profile or would that be better.

And the second question is regarding the beef editors.

Can you use the M&A.

What about the IP part do you have a proper right to use that.

So do you want me to maybe why don't you talk about sickle and then Jason can speak into the base editors yet.

Sandy Macrae: Why don't you talk about sickle, and then Jason can speak to the base editors? Hi Gene, I hope you're well. I mean, in terms of that data that I just sort of alluded to, I think it's really going to be important to see the clinical profile of these next four patients. And it'll give us a sense, you know, roughly around the time that, hopefully, we'll see a little bit more of an update from CRISPR-Vertex, whether we've got a comparable product or whether we've got a differentiated product.

Hi, Gena I hope, you're well I mean in terms of that David is I, just sort of alluded to I mean, I think it's really going to be.

<unk> to see the clinical profile and the export patients and it will give us a sense.

Roughly around the time that hopefully, we'll see a little bit more of an update from Christopher vertex, whether we've got a comparable product or whether we've got a differentiated product.

At the end of the day. These are personalized cell therapies, which means they need to be manufactured for the patient.

Sandy Macrae: At the end of the day, these are personalized cell therapies, which means they need to be manufactured for the patient. As I described, there are, you know, 100,000 patients in the US, 30,000 of them are severe. And so even if there's one competitor in the market, it's going to take a long time to service the needs of the sickle cell communities, not only in the United States but, more importantly, worldwide.

As I described there is 100000 of those patients in the U S 30000 of them are severe and so even if there is one competitor in the market is going to take a long time to service the needs of the sickle cell community not only in the United States, but more importantly worldwide.

Sandy Macrae: And so, you know, if we've got an attractive profile that's the same or differentiated through CRISPR-Vertex, we will do, as I mentioned earlier, what we need to do to either find a partner or look for novel ways that we can get this therapy to patients. Jason, can you help with the set of questions?

And so if we've got an attractive profile.

Same or differentiated through Pittsburgh vertex, we will do as I mentioned earlier, what we need to do to either find a partner or look for novel ways that we can get these.

<unk> therapy to patients.

Jason can you help on the you said that your question.

Jason Fontenot: Sure. Thanks, Andy. Yeah, you know, recording the face editor, and a program that... [inaudible] I'm incredibly excited about. We have a great team of molecular biologists, structural biologists, that are continually innovating around our, And they're doing that on both the side of the zinc finger portion of the molecule where we're refining the..., and molecules to target. But they're also doing it on the functionality And so. Robin Bjorn, https://www.kenhub.com, Descriptional Activators, Transcriptional Receptors.

Sure. Thanks Randy.

Yes regarding the base editor. This is a program that I'm incredibly excited about we have.

<unk> team of molecular biologist structural biologists.

That are continually innovating around our core zinc finger platform, it and theyre doing that on both side of the zinc finger portion of the molecule where we're refining the.

Specificity and accuracy.

The molecules to target specific sequences, but theyre also doing it on the on the functionality side right and so you know.

Moving beyond the core group of functionalities that we already have in our tool kit nucleases.

Transcriptional activators transcriptional regulators we're now.

Jason Fontenot: We're now exploring the Generalities, including base heads, combinations, and epigenetics. And, you know, we've got something in our base editor program that we're really excited about. We wouldn't be moving forward if we didn't think we had freedom to operate. So we're pretty.

Exploring other new functionality, including base editing, but also.

Yes.

The combination of <unk> and epigenetic editors.

And.

We've got something in our base out of the program that we're really excited about we wouldnt be moving forward. If we didn't think we had a freedom to operate.

We're pretty comfortable with.

With a really unique.

Architecture that we've developed and Sandy pointed out we think it offers some real advantages in being able to be deployed in a single.

Viral vector.

As well as taking advantage of the great specificity and accuracy aspects of the zinc finger platform.

Thank you.

Operator: I guess the first one to start off is, what are some of the components that can result in patients having elevated Lysol Gb3 levels for FAB diseases, and how readily do these patients actually have increased Lysol Gb3? Patrick, can I make sure I understand your question, and it's about what Bettina talked about earlier, that many patients, particularly those on ERT, already have repressed lyso-TB, and a few patients, particularly naive patients, will have elevated levels, and those are the ones where we can see a benefit of our medicine and Lysol 2B3.

Our next question comes from Patrick <unk> with H C Wainwright.

Operator: And I think that you asked, are we screening for those patients? Yeah, we'll be screening for high-risk life-threatening TB3 patients. We're delighted to take all patients with Fabry, and we take three categories. We take the patients that are on ERT, we take what are called pseudo-nave, those are patients that have been on it for at least six weeks, and we take the naive patience. We're not rejecting patients if they have low levels of lyso-GP3, and we're delighted when we find a patient that has a high level.

Hi, good afternoon, everyone and congrats on the progress for this quarter. So I just kind of I just have two questions on I guess the first one to start off is what are some of the components that can result in the patients having elevated LIFO GBP level for fabry diseases, and how readily do these patients I see have increased <unk> three.

Operator: Okay, great. And then kind of just like a follow-up question. And so, for the baseline of, for patient five and patient six, do you also see these increases in Lysol GB3? Or is that something that we will see later on?

Bettina Cockcroft: Ritu, have we commented on the levels of patients by insects? Yeah, thank you for the question. We have not commented on those levels at this point in time. This is something that is part of that update that we can provide later in the year as we provide our clinical update. Okay, great. Thank you for the additional call. I'm showing no further questions in queue at this time. I'd like to turn the call back to Erin Feinfeld for closing remarks.

Some pressure coming through I understand your question is are we incidents.

It's what patina talked to earlier.

Several many patients.

<unk> already have depressed by some GPS III.

On the <unk>.

Sure.

Few patients are naive patients have elevated levels and those are the ones, where we can see a benefit of I mentioned on the ice.

I think if you asked are we screening for patients suffering.

Are you will you be screening for high license you'd be three patients.

We're delighted to take all patients with fabry.

Can we take.

Check fee contribution we take the patients.

Our own ERP, reaching polka coach even those patients have been on for six months and we take the naive patients.

We're not we're not rejecting patients have become more plentiful supplies with GPS III and we're delighted when we find a patient at some point level.

Okay, Great and then kind of just like a follow up question I had for like for the baseline of like for patients and patients. Six do you also see increases in lifestyle GBP two or is that something that we will see later on.

We commented on the levels for patients clients and sex, yes. Thank you for the for the question. We have not commented at all dose levels. At this point in time. This is something that is part of that uptick that we can provide later in the year as we provide a clinical update.

Okay, great. Thank you for any additional color.

Yes.

Yes.

I'm showing no further questions in queue at this time I'd like to turn the call back to Eric <unk> for closing remarks.

Bettina Cockcroft: Thank you all once again for joining us today and for your questions. We look forward to keeping you updated on our future developments. This concludes today's conference call. Thank you for participating. You may now disconnect.

Thank you all once again for joining us today and for your clients.

Alright, thank keeping you updated our future at all.

This concludes today's conference call. Thank you for participating you may now disconnect.

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Yes.

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Yes.

Yes.

Yeah.

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Jason Fontenot: The architecture that we've developed. As Sandy pointed out, we think it offers some real advantages in being able to be deployed in a single viral vector, as well as taking advantage of the great specificity and accuracy aspects of the ThinkFinger platform. Our next question comes from Patrick Truccio with HC Wainwright. Hi, good afternoon, everyone. Congratulations on the progress for this quarter. So I just kind of have two questions.