Q3 2021 Sangamo Therapeutics Inc Earnings Call

November 4, 2021

Thank you all for standing by and welcome to the Sangamo third quarter 2021 teleconference call.

Operator: Thank you all for standing by, and welcome to the Sangamo 3rd quarter 2021 teleconference call. All participants are in a listen-only mode until the question-and-answer session of today's conference.

All participants are in a listen only mode until the question and answer session of today's conference.

Operator: To ask a question over the phone by that time, you may press the star key followed by the number 1. Please also note that today's call is being recorded. I'll now turn the call over to your host, Aaron Feingold, Head of Corporate Communications. Ma'am, you may now begin.

Ask the question over the phone by that time, you May press to Starkey, followed by the number one.

Please also note that today's call is being recorded.

Now turn the call over to your host.

Aaron Feingold head of corporate Communications Ma'am, you may now begin.

Good morning, and thank you for joining us today.

Speaker: Good morning, and thank you for joining us today.

With me. This morning on this call are several members of the Sangamo executive leadership team, including Sandy Macrae, Chief Executive Officer, Mark Mcclung, Chief Operating Officer, Craig He said, Jerry <unk>, Chief Financial Officer, Jason No Chief Scientific Officer, Rob.

Speaker: With me this morning on this call are several members of the Sangamo Executive Leadership Team, including Sandy Macrae, Chief Executive.

Speaker: Executive Officer

Speaker: Mark McClung, Chief Operating Officer; Prathyusha Duraibabu, Chief Financial Officer; Jason Fontenot, Chief Scientific Officer; Rob Schott, Head of Development; and Bettina Cockroft, Chief Medical Officer.

Shot head of development and the Peanuts aircrafts Chief Medical Officer.

Speaker: Chief Medical Officer

Speaker: Slides from our corporate presentation can be found on our website, sangamo.com, under the

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

Speaker: Investors and media section under the events and presentations section. This call includes forward-looking statements regarding Sangamo's current expectations. These statements include but are not limited to

This call includes forward looking statements regarding single my current expectation. These statements include but are not limited to statements relating to therapeutic and commercial potential of our product candidates the anticipated plans and timelines of Sangamo and our collaborators for conducting clinical trials in <unk>.

Speaker: We have anticipated plans and timelines for Sangamo and our collaborators for conducting clinical trials and presentations.

Speaker: Clinical Data, Execution of our

Presenting clinical data at the Keystone of our corporate strategy advancement of our product candidate <unk>.

Speaker: Corporate Strategy, the Advancement of our Product Candidates, our revised 2021 Financial Guidance, and other statements that are not historical facts. Actual results may differ materially from what we discussed today. These statements are subject to certain risks.

<unk> 2021 financial guidance and other statements that are not historical facts actual results may differ materially from what we discuss today.

Statements are subject to certain risks and uncertainties that are discussed in our filings with the S. E T.

Speaker: 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, 2020, as supplemented by our quarterly report on Form 10-Q for the fiscal quarter ended September 30, 2021. The forward-looking statements stated today are made as of this date, and we undertake

Typically our annual report on Form 10-K for the fiscal year ended December 31, 'twenty 'twenty are supplemented by our quarterly report on Form 10-Q for the fiscal quarter ended September 32021.

Forward looking statements made 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 discussed our non-GAAP operating expense reconciliation of this measure to our GAAP operating expenses can be found in today's press release, which is available on our website.

Speaker: [inaudible]

Speaker: and the evaluation of this measure to our GAAP operating expenses can be found in today's press release, which is available on our website.

Speaker: Please read the press release which is available on our website. Now, I'd like to turn the call over to our CEO, Sandy Macrae.

Right.

Now I'd like to turn the call over to our CEO Sandy Macrae. Thank you hey, good.

Alexander D. Macrae: Thank you, Aaron, and good morning to everyone on the call. This is such an important moment for Sangamo, as we share clinical data and business updates across several programs, demonstrating that we have three important assets in or progressing toward late-stage development. Our gene therapy portfolio is advancing with accumulating safety and efficacy data in our Fabry and Haemophilia A programs. Additionally, we are delighted with the preliminary proof-of-concept data demonstrating the clinical potential of our genome engineering zinc finger technology in sickle cell disease.

Good morning to everyone on the cold.

This is such an important moment for sangamo as we share clinical data and business updates across several programs demonstrating that we have three important assets and are progressing towards late stage development.

Our gene therapy portfolio is advancing with accumulating safety and efficacy data in our <unk>.

Debris and hemophilia a program.

Additionally, we are delighted with the preliminary proof of concept data demonstrated the clinical potential of our genome engineering zinc finger technology in sickle cell disease.

This morning, we announced preliminary clinical data from our phase <unk> study.

Alexander D. Macrae: This morning, we announced preliminary clinical data from our Phase 1-2 STAR study evaluating the Isoralga gene, Cipoparvivec, or ST920, our Fabry disease gene therapy product candidate. Data from this important study were evaluated from the four patients in the first two cohorts, those levels 0.5 E13 and 1 E13 BG per tig as of the cut-off date, September 17th of this year.

Good evening, I sort out good gene Super pump, a thick or S. $2 20, our fabry disease gene therapy product candidate.

Data from this important study whereby we use it in the four patients in the first two cohorts two cycles point call. It <unk> 13, and one <unk> vg per tick.

As of the cutoff date September 17th of this year.

These encouraging results showed that for the first four patients <unk> was generally well tolerated.

Alexander D. Macrae: These encouraging results showed that for the first four patients, ST920 was generally well tolerated. There were no treatment-related adverse events higher than grade 1, and no treatment-related serious adverse events; no patients experienced liver enzyme elevations or required steroid treatment. All four patients exhibited above-normal alpha-GalAe activity, which was maintained for up to one year for the first patient treated and through 14 weeks for the most recently treated patient. Levels ranged from 2 to 15 fold above normal levels at the last measurement as of the cut-off date. Interestingly, the first three patients did reported improvements in their ability to sweat, a primary and common Fabry disease symptom that limits exercise tolerance for the patient.

There were no treatment related adverse events honasan Greek one no treatment related serious adverse events, no patient experienced liver enzyme elevations or required steroid treatment.

All four patients exhibited a bulk normal alpha Gal, a activity, which were maintained for up to one year for the first patient treated.

14 weeks for most recently treated patients.

LIFO ranged from two to 15 fold above normal levels at the last measurement as of the cutoff date.

Yeah.

Interestingly the first three patient Stuart's reported improvements in ability to swing a priming common public to see symptom that limits exercise tolerance for the patient.

Okay.

Alexander D. Macrae: ERT withdrawal is now complete for one patient and is planned for the other patient on ERT based on the stability of their alpha-gallae activity following treatment. Based on these data, we've initiated phase three planning. The fifth patient in the study, who is the first patient in the third dose cohort at 3E13, was recently dosed. The sixth patient is currently in screening, also for the third dose cohort, and we expect to provide updated results throughout 2022 and present these data at a medical meeting. This morning, we also announced the preliminary proof-of-concept results from the Phase 1-2 Precision Study of SAR 445136.

<unk> is now complete for one patient in this plan for the other patient on EOG based on the stability of their own for gallium.

Following treatment.

Based on these data we have initiated the phase III planning.

The fifth patient in the study who has the first patient in the third dose cohort three <unk> was recently dosed six patients is currently in screening also for the third dose cohort.

And we expect to provide updated results throughout 2022 and present these data at a medical meeting.

This morning, we also announced the preliminary proof of concept results from the phase one two precision study.

Our 445136 and investigation of the zinc finger nuclease gene edited cell therapy in patients with sickle cell disease will be presented at ash.

Alexander D. Macrae: An investigational zinc-finger nucleus gene-edited cell therapy in patients with sickle cell disease will be presented at ASH. This program is partnered with our friends at Sanofi. The data in the abstract showed that as of June 25th, 2021, the cut-off date, none of the four patients treated required blood transfusions post-engraftment through 65 weeks of follow-up for the longest treated patients. The four treated patients all experienced increases in total hemoglobin, fetal hemoglobin, and percent F cells. No adverse events or serious adverse events related to treatment were reported as of the cut-off date. Further data will be provided in a poster presentation at ASH on December 12th.

This program is partnered with our friends at Sanofi.

The data in the abstract shows that as of June 25, 2021 cutoff date, none of the four patients treated required blood transfusion post <unk> 365 weeks of polo for the longest treated patients.

The <unk> treated patients all experienced increases in total hemoglobin fetal hemoglobin and percent test cells.

No adverse events or serious adverse events related to treatment were reported as of the cutoff date.

Further detail provided in a poster presentation at Ash on December 12.

Alexander D. Macrae: Sangamo and Sanofi are continuing to advance the sickle cell disease program. The companies recently obtained manufacturing requirements guidance from the FDA in preparation for potential further clinical studies. Separately, we at Sanofi made the business decision to cease development for the beta-thalassemia indication, allowing us to focus resources on the sickle cell disease program.

Sangamo incentive fee are continue to advance the sickle cell disease program. The company has recently obtained manufacturing requirements guidance from the FDA in preparation for potential further clinical studies separately, we incentive can meet the business decision to cease development for the beta thalassemia indication and allowing us to.

Focus resources on the sickle cell disease program.

Moving now onto our hemophilia a program partnered with Pfizer, We announced this morning. The updated follow up results from the phase one two ultra study of Judah Taco gene to conquer bank will be presented at ash.

Alexander D. Macrae: Moving now on to our haemophilia aid program partnered with Pfizer, we announced this morning the updated follow-up results from the Phase 1-2 ALTA study of Durotoccin Fetocarbovac will be presented at ASH. For the four patients in the highest-dose cohort who have been followed for at least 104 weeks as of May 19, 2021, the cut-off, mean factor VIII activity was 30.9% at week 104 In this cohort, annualized bleeding rates were zero for the first year after treatment and 0.9 throughout the total duration of follow-up. As demonstrated in this study, gene therapy was generally well tolerated in patients with severe haemophilia A. Further data will be provided in a poster presentation at ASH on December 12, 2021.

For the four patients in the highest dose cohort have been followed for at least 104 weeks as of May 19, 2021 cutoff.

Mean factory activity was 39% at week 104 as measured by Chromogenic assay.

In this cohort annualized bleeding rate was zero for the first year after treatment and Cedar point, knowing through total duration of follow up.

As demonstrated in this study the gene therapy was generally well tolerated in patients with severe hemophilia a.

Further data will provided in a poster presentation at Ash on December 12, 2021.

We and Pfizer.

Also note that some of the patients treated to date in the phase III <unk> trial experience factory levels greater than 150% pulling treatment.

To date, none of these patients have experienced thrombotic events.

Some had been treated with direct oral anticoagulants to reduce thrombotic risk.

Out of an abundance of caution Pfizer voluntary paused screening and dosing of patients in the trial in order to implement a protocol amendment, which will provide guidelines for clinical management <unk> factory levels.

Alexander D. Macrae: We and Pfizer also announced that some of the patients treated to date in the phase 3 affine trial experienced factory levels greater than 150% following treatment. To date, none of these patients have experienced thrombotic events, and some have been treated with direct oral anticoagulants to reduce thrombotic risk. However, out of an abundance of caution, Pfizer voluntarily paused screening and dosing of patients in the trial in order to implement a protocol amendment which will provide guidelines for clinical management of elevated factor VIII lips.

On November the third phase will respond but that the FDA has put this trial on clinical hold.

Biogen Sangamo are committed to resuming patient dosing as soon as possible.

We continue to believe that this gene therapy will represent an important treatment option for patients with hemophilia a.

The next step is to show the proposed protocol Amendment with health authorities in response to the clinical hold after which the companies will be able to provide updated timing for the trial.

Turning now to our kidney transplant program, we have now enrolled the first patient in our phase one two steadfast study evaluating TX 200, our wholly owned autologous car T Reg cell therapy candidate.

Alexander D. Macrae: On November 3rd, Pfizer was informed that the FDA has put this trial on clinical hold. Pfizer and Sangamo are committed to resuming patient dosing as soon as possible. We continue to believe that this gene therapy will represent an important treatment option for patients with haemophilic AIDS. The next step is to share the proposed protocol amendment with health authorities and respond to the clinical hold, after which the companies will be able to provide updated timing for the trial.

We believe that this is the first in human car T. Regs study and the dispute with this growing with much excitement as a promising approach for challenging autoimmune conditions.

In this study similar to other genetically engineered cell therapy approaches patients will undergo leukapheresis procedure from which the T. Reg cells will be isolated.

Engineered and then Cryopreserved.

The HLA <unk> negative patient will subsequently undergo kidney transplant.

Following our recovery period, we received a personalised, TX 200 therapy.

Alexander D. Macrae: Turning now to our Kidney Transplant Programme, we have now enrolled the first patient in our Phase 1-2 Steadfast Study, evaluating TX200, our wholly owned autologous CAR-T reg cell therapy candidate. We believe that this is the first in-human CAR T-REG study and that this field is growing with much excitement as a promising approach for challenging autoimmune conditions. In this study, similar to other genetically engineered cell therapy approaches, patients will undergo a lookup procedure from which their Treg cells will be isolated, engineered, and then cryopreserved.

We expect to dose the first two patients in this study by the middle of 2022.

Knowing their kidney transplants.

Yeah.

We continue to open sites and screen patients. We believe this proof of concept study may represent an important treatment for patients undergoing renal transplant and will help us understand car T. Reg biology in humans as well as advanced process development knowledge.

We hope that this study establishes the foundation for our portfolio of wholly owned car T therapies for autoimmune indications.

Finally, I'm delighted to share that Mark Mcclung has been appointed as <unk> Chief operating officer effective November one.

Alexander D. Macrae: The HLA-A2-negative patient will subsequently undergo kidney transplantation and, following a recovery period, will receive their personalized TX200 therapy. We expect to dose the first two patients in this study by the middle of 2022, following their kidney transplant. We continue to open sites and screen patients. We believe this proof of concept study may represent an important treatment for patients undergoing renal transplantation and will help us understand CAR T reg biology in humans, as well as advanced process development knowledge. We hope that this study establishes the foundation for a portfolio of wholly owned CAR Treg therapies for autoimmune indications.

<unk> expanded role as CEO is an important organization stent for cycle, which will support the multiple multiple advancing wholly owned and partnered programs.

We look forward to March continued leadership as we continue to build the capabilities to bring genomic medicines.

Patients and to the marketplace.

Everyone at Sangamo through to this clinical momentum and we look forward to presenting updated February results through 2022, as well as working with our collaboration partners and investigators to present the ash data in December.

And with that I'll turn the Cologuard to petition for a financial update petition.

Thank you Sandy and good morning, our financial results for the quarter are available in our press release issued this morning, which can also be found on our website I want to reiterate that this is an exciting moment for us at the company and this quarter, we continued to invest in the advancement of our clinical programs, including February MTX.

Alexander D. Macrae: Finally, I'm delighted to share that Mark McClellan has been appointed as Sangamo's Chief Operating Officer, effective November 1st. Mark's expanded role as COO is an important organizational step for Sangamo, which will support the multiple-advancing, wholly-owned, and partnered program. We look forward to Mark's continued leadership as we continue to build the capabilities to bring genomic medicines to patients and to the marketplace. Everyone at Sangamo is thrilled about this clinical momentum, and we look forward to presenting updated FABRI results throughout 2022 as well as working with our collaboration partners and investigators to present the ASH data in December. And with that, I'll turn the call over to Prathyusha for a financial update.

Our preclinical research pipeline and our in house manufacturing capabilities.

With approximately 519 million in cash cash equivalents and marketable securities at the end of the quarter, we believe that our balance sheet remains strong.

Turning to 2021 full year guidance.

We expect non-GAAP operating expenses to be between $265 million to $1 $75 million for the year.

Just within the range of the guidance that we have previously provided.

This range excludes estimated noncash stock based compensation expense of approximately $35 million I will now turn the call back to Sandy for closing remarks. Thank you Patricia.

We are very excited about it is clinical data readouts, which show the advancement of our first generation genomic medicine pipeline with traditional gene therapy, an autologous cell therapy.

Prathyusha Duraibabu: Thank you, Sandy, and good morning. Our financial results for this quarter are available in the press release issued this morning, which can also be found on our website. I want to reiterate that this is an exciting moment for us as a company, and this quarter, we continue to invest in the advancement of our clinical programs, including Febreeze and TH200, our preclinical research pipeline, and our in-house manufacturing capability. With approximately 519 million in cash, cash equivalents, and marketable securities at the end of the quarter, we believe that our balance sheet remains strong.

These programs potentially pave the way for our next generation focus on genome regulation and allogeneic car T. Reg cell therapy, where we have a robust preclinical pipeline and neurological and auto immune diseases, respectively.

We are delighted with the positive momentum and look forward to updating you in the near term, but several potential catalysts, including presentation ship for patient sickle cell disease phase one two data presentation ship two year phase one to hemophilia a data and additionally, we will provide a timing update for the PC trial once the proposed <unk>.

Nicole Amendment in response to the whole issue with health authorities.

Dosing of the six patient and updated five brief phase one two data presentations throughout 2022.

Prathyusha Duraibabu: Turning to 2021 Full Year Guidance. We expect non-GAAP operating expenses to be between $265 million and $275 million for the year, which is within the range of the guidance that we have previously provided. This range excludes estimated non-cash stock-based compensation expenses of approximately $35 million.

Including at a medical meeting.

Dosing of the first two patients in the steadfast phase one two study by the middle of 2022 and.

And completion of our in house cell therapy manufacturing facility and our bolt on France location. Following the completion of our in house manufacturing facility in Brisbane, California headquarters this past quarter.

So we'll now turn it over to the operator to open the line for questions.

Thank you speakers participants we will now begin the question and answer session. As a reminder to ask a question over the phone you May press the star key followed by the number one.

Alexander D. Macrae: I will now turn the call back to Sandy for her closing remarks.

Alexander D. Macrae: We are very excited by today's clinical data readouts, which show the advancement of our first generation genomic medicine pipeline, with traditional gene therapy and autologous cell therapy. These programs potentially pave the way for our next generation focus on genome regulation and allogeneic CAR Treg cell therapy, where we have a robust preclinical pipeline in neurological and autoimmune diseases, respectively.

To withdraw your request you May press the pound key again Thats star one to ask a question.

Or the <unk> to withdraw your request.

Speakers first question is from the line of Aspen Mori of Bank of America. Your line is now open.

Hey, guys. Thanks for the question.

So on Fabry I think you previously hadn't expected to share some of the enzyme replacement therapy withdrawal data.

Alexander D. Macrae: We're delighted with the positive momentum and look forward to updating you in the near term about several potential catalysts, including presentation at ASH of four patient sickle cell disease phase 1-2 data, and presentation at ASH of two-year phase 1-2 haemophilia data. Additionally, we'll provide a timing update for the phase 3 trial once the proposed protocol amendment and response to the hold are shared with health authorities. Dosing of the sixth patient and updated Fabry phase 1-2 data presentations throughout 2022, including at a medical meeting.

And this year and Luis.

It's good to see that the timeframe, maybe a bit faster than expected, but with that in mind I guess are there any patterns you're seeing in the timeframe. It takes from from getting from a from.

The dose of SG 922 to removal of that therapy.

And it also appears that maybe the patient for kind of got to that milestone a lot quicker than patient, one who had a longer follow up.

I just wanted to see if theres anything youre seeing there and explain that thank you.

So thank you for your question I think what I'm hearing you're asking about <unk> withdrawal.

So we thought it was important to see to truly understand the.

The effect duration and we've been very pleased that will for the course of the year and the longest patients theres been a consistency of effect.

Alexander D. Macrae: Dosing of the first two patients in the Steadfast Phase 1-2 study by the middle of 2022, and completion of our in-house cell therapy manufacturing facility in our Valbon, France location following the completion of our in-house manufacturing facility in our Brisbane, California headquarters this past quarter.

We then have discussions with the investigators.

Good point.

For them and for their patients they will withdraw treatment in the first patient was suddenly withdrawn.

We recently in the second one this plan to be withdrawn this year and so we will share that data in appropriate time.

Okay. Thanks, and then I have one more on the.

Operator: So we'll now turn it over to the operator to open the line for questions. Thank you, speakers. Participants will now begin the question and answer session. As a reminder, to ask a question over the phone, you may press the star key followed by the number 1. To withdraw your request, you may press the pound key. Again, that's star one to ask a question. Order Pound Key to withdraw your request. The Speaker's first question is from the line of Aspen Morey of Bank of America. Your line is now open.

On February <unk>.

Are there any trends you're seeing among patients one in four that signal, maybe whats driving better Alpha Gal, a response that youre seeing with patients two and three.

I think two and three lower baseline <unk> III, but.

So if theres anything you can you can point to that would help out there.

Well.

So there is only four patients so it's very difficult to say anything specific.

Notable go that patients want and for our own ERP and patients two and three year note.

Operator: etc. Your line is now open.

Aspen Morey: Hey, guys, thanks for the question. So on Fabry, I think you previously hadn't expected to share some enzyme replacement therapy withdrawal data in this year-end release. It's good to see that the timeframe seems to maybe have been faster than expected. But with that in mind, I guess, are there any patterns you're seeing in the timeframe it takes from getting from one to getting from

<unk>.

It may be that there is some.

Additional effect from the ERP that is leading to that effect, but I think that is only speculation and we need to dose more patients to understand it.

Okay. Thanks, Andy appreciate it.

Next question is from Jan <unk> of Wells Fargo. Your line is now open.

Hi, Thanks for taking my questions I have.

Question on Fabry.

Maybe also additional question on that other updates.

Aspen Morey: from the dose of SG-920 to removal.

Could you Sandy comment on the dose response here.

Aspen Morey: that therapy. And it also appears that maybe the patient needs some kind of

And also I think for patients to.

Aspen Morey: got to that milestone a little quicker than the patient one who had a longer.

There was a.

Increasing enzyme levels.

Aspen Morey: I had a longer follow-up, and just wanted to see if there's anything you're seeing there to explain that.

Bob normal, but the substrate levels seems to be flat.

Alexander D. Macrae: So thank you for your question. I think what I'm hearing you're asking about is about ERT withdrawal. So we thought it was important to see, to truly understand the effect duration and we've been very pleased that over the course of a year in the longest treated patients there's been a consistency of effect, and we then have discussions with the investigators and at the appropriate point for them and for their patient they will withdraw treatment and the first patient was only withdrawn very recently and the second one is planned to be withdrawn this year and so we will share that data at an appropriate time.

So could you.

Shed some light on that finding.

So.

It's a good question and I think this has been something that's been consistently seen across all of the.

Research into Fabry disease.

Substrate levels are low.

They don't change.

The treatment period.

Just thoughts from this on the dose response that we've seen thank you sandy so.

Randy mentioned, we have now dosed two patients in cohort one and two patients in cohort two.

Still a small sample size this needs to be emphasized at this point in time.

Aspen Morey: Okay, thanks. And then I have one more on the..., on Fabry. Are there any trends you're seeing among patients one and four that signal maybe what's driving a better alpha-GalA response than you're seeing with patients two and three? I think two and three.

Regarding the levels of life with GBP three for sure and three of the four patients.

<unk> three level started off slow and as Tony mentioned.

Across program.

<unk> seen that these remained stable as they are now Scott.

Scott if you look at patients treated patients LIFO TB three levels.

Hi.

The level of license three were reduced by about 40%.

Alexander D. Macrae: 2 and 3 might have had lower baseline GB3, but if there's anything you can point to that would help out there, well, there are only four patients, so it's very difficult to say anything specific. It is notable, though, that patients one and four are on ERT, and patients two and three are not. It may be that there is some additional effect from the ERT that is leading to that effect, but I think that is only speculation, and we need to doze more patients to understand it.

10 weeks after dosing.

Reduction was maintained.

In two weeks.

So at this point in time with such a small sample size. It is really difficult to talk about those relationships I would say that throughout 2022, we anticipate to share more data.

And that data will also be set at a medical meeting so there will be more granularity.

And data to come.

But.

All want you to take away is how excited we are by this because all four patients are above the normal physiological level.

Operator: Okay. Thanks, Andy. Appreciate it. The next question is from Yanan Zhu of Wells Fargo. Your line is now open.

All four patients showed consistency of response and the time that they would be necessary.

Three of the four patients are already reporting.

Yanan Zhu: Hi, thanks for taking my questions. I have a question about Fabry.

Patients effects are very encouraging but the effect of the drug and we are already into the next higher cohort and as Bettina <unk>, who will talk about this next year.

Yanan Zhu: and maybe also additional questions on that other subject...

Yanan Zhu: [inaudible]

Yanan Zhu: In 2002, there was an increase in enzyme levels above normal, but the

Great Thanks, and on the clinical hold.

For the.

Alexander D. Macrae: Above normal, but the substrate levels seem to be... Could you shed some light on that finding? So it's a good question, and I think this has been consistently seen across all of the research into Fabry disease. If the substrate levels are low, they don't change during the treatment period. Bettina, do you have thoughts on this, on the dose response that we've seen?

Hemophilia a collaborated with the hemophilia a program I was wondering how high is the human factor eight level I thought we had the scene like.

200% from other studies so.

Could you.

Shed some light on the rationale for the for that clinical hold and.

Lastly, a question on <unk> 003, very quick ones that is.

Bettina M. Cockroft: Thank you, Sandy. So, as Sandy mentioned, we have now dosed two patients in Cohort 1 and two patients in Cohort 2. This is still a small sample size, and that needs to be emphasized at this point in time.

Cash would we see VLC data.

For the treated patients. Thank you.

So I'm going to pass the question on hemophilia two role can you talk to US yes, we are.

<unk> seen.

Bettina M. Cockroft: But regarding the levels of Lyso-GB3, for sure, in three of the four patients, those Lyso-GB3 levels started off low. And as Sandy mentioned, across programs, it has been seen that these remain stable if they are low. But to start with, if you look at patient 3, this patient's Lyso-GB3 levels start off high, and the levels of Lyso-GB3 were reduced by about 40% within 10 weeks after dosing, and this reduction was maintained through 32 weeks. So at this point in time, with such a small sample size, it is.

<unk> factor eight greater than 150% in some patients.

This is an ongoing phase III trials, so we're not getting very specific with the data.

Around this.

There were no.

The near term.

Trimble embolic events associated with these elevated levels and the decision to voluntarily pause the trial was out of an abundance of caution and as anticipated the FDA.

Followed through with the clinical hold that was.

We were notified of that late yesterday.

It is our plan to.

With Pfizer to submit a protocol amendment and have the discussion with the agency and resume the trial.

When it is appropriate to do something.

And regarding sickle cell disease.

We will show the full data set.

In December.

Great. Thanks for the update.

Bettina M. Cockroft: It's really difficult to talk about those relationships, but I would say that throughout 2022, we anticipate sharing more data, and that data will also be shared at a medical meeting, so there will be more granularity and data to come. But what I want you to take away is how excited we are by this, because all four patients are above the normal physiological level, and all four patients have shown consistency of response in the time that they've been observed.

Thank you.

Next question is from Luca <unk> of RBC capital. Your line is now open.

Oh, great. Thanks, so much for taking my question Congrats on all the progress maybe on Fabry disease exciting early proof of concept I Wonder if you can comment on how you're thinking about the phase III study design.

On hemophilia a.

Maybe if you can provide any additional color on the protocol amendment that you were thinking about to minimize the risk going forward and then maybe on beta Thal can you just expand a little bit more on the rationale behind the decision to terminate the program. Thanks, so much.

Bettina M. Cockroft: Three of the four patients are already reporting patient effects that are very encouraging about the effect of the drug, and we are already into the next higher cohort, and as Bettina says, we'll talk about that next year.

Goodness.

So it's so exciting to be talking to the phase III design.

Because we are very pleased with the.

Yanan Zhu: Great. Thanks. And on the clinical hold for the Hemophilia A, collaborated Hemophilia A program, I was wondering how high the factor VIII level is. I thought we had seen like 200 percent from other studies.

With the results, but we need to see the results of the.

Third cohort to really be able to understand which dose we're taking forward.

How do we design the study, but I can reassure you that planning and.

Alexander D. Macrae: We have seen like 200% from other studies, so could you shed some light on the rationale for that clinical hold? And lastly, a question on BIVV003, a very quick one that is at ASH, would we see VOC data for the treated patients? So I'm going to pass the question on haemophilia to Rob. Rob, can you...

Energy behind the Phase III has already started on these programs, let me pass the.

Hemophilia question to Rob and the beta Thalassemia one tomorrow.

Yes.

With regard to the protocol amendment were not disclosing any of the specifics of the protocol Amendment at this time.

But the protocol amendment is being considered and will be.

Rob Schott: Yeah, we we have seen them.

Rob Schott: in elevations of factor VIII greater than 150% in some patients. This is an ongoing phase 3 trial, so we're not getting very specific with the data around this.

Submitted promptly and in discussion with the agency in response to the clinical and the current plan is to find the best way to value. The management of any patient that has a higher level, yes, there'll be monitoring and management of the patients with with levels of factor eight that are greater than 150%.

Rob Schott: venous thromboembolic events associated with these elevated levels.

But we feel it important to restate every time that conversation comes up with new patient has come to harm there'll be new adverse events related to this and this is an abundance of caution on that and I think are correct abundance of caution because this is a gene therapy that we need to take very seriously and do the best for the patients.

Rob Schott: elevated levels in the decision to voluntarily pause the trial without an abundance of caution. And, as anticipated, the FDA.

Rob Schott: followed through with a clinical hold that we were notified of late yesterday. It's our plan, with Pfizer, to submit a protocol amendment and have a discussion with the agency and resume the trial when it is appropriate to do so.

Mark.

Terms of the beta Thal decision. It was really a business decision that we took alongside our partners Sanofi.

Just due to the timing and relative to where the competitive set in terms of their development.

Rob Schott: and regarding sickle cell disease. We will show the full data set at ASH in December. Great, thanks for the updates. Thank you. The next question is from Luca Issi of RBC Capital. Okay, great.

We felt that it was important to really focus our efforts and our resources solely on sickle cell disease.

And drive forward together.

Got it thanks, so much guys.

Next question is from Maury Raycroft of Jefferies. Your line is now open.

Hi, everyone. Good morning, and congrats on the update today.

Operator: Thanks so much for taking my question. Congratulations on all the progress. Maybe on Fabry disease, exciting early proof of concept. I wonder if you can comment on how you're thinking about the phase 3 study design. On hemophilia A, perhaps you can provide any additional color on the protocol amendment.

For Fabry, just wondering if you can talk more about the alpha Gal data being 2% to 15 fold higher than normal seems higher than competitor data. Among 12 that showed about 5% to six fold higher.

So that's the way to contextualize your data versus competitors and how could this translate to kidney substrate reduction.

Thank you Maury Bettina do you want to talk recovery sure. Thank you Sandy so in terms of the offer.

<unk> data, we're obviously very excited to see.

Super Physiologic Alpha Gal expression that we're seeing with all four patients I think at this point. It is early to compare and probably not the right place to do comparisons across programs.

Luca Issi: The protocol amendment that you're thinking about to minimize the risk going forward. And then maybe on Beta Tau, can you just expand a little bit more on the rationale behind the decision to terminate the program? Thanks so much.

We look forward to sharing more granularity on this data at.

An upcoming meeting in 2022.

So that also goes through any additional data related to kidney.

Alexander D. Macrae: So it's so exciting to be talking about Phase 3 design because we are very pleased with the results. But we need to see the results of the third cohort to really be able to understand which dose we're taking forward and how we design the study. But I can reassure you that planning and the full energy behind Phase 3 have already started on these programs. Let me then pass the haemophilia question to Rob and the beta thalassemia one to Maureen.

Great.

You can imagine, though that having seen efficacy at the two initial cohorts and moving into third tier cohort.

It gives.

It gives us enormous.

Energy that this is going to be a mix.

The useful for patients with fabry it really is.

Compelling data earlier early as we can.

The compelling data.

And I would add that our priority, we had targeted super physiologic expressions of Alpha Gal, a and plasma to drive clearance from tissue. So this is a desired effect what were seeing.

Rob Schott: Yes, with regard to the protocol...

Got it that's all helpful and maybe just one follow up if you can compare and contrast, the fabry observations.

Rob Schott: Amendment. We're not disclosing any of the specifics of the protocol.

And gene expression and dose with your hemophilia gene therapy program.

Rob Schott: Amendment at this time, but the protocol amendment is being considered and will be submitted promptly and in

Maybe if you can talk more about that.

That's a good question I mean, we are fortunate.

Rob Schott: in discussion with the agency in response to the clinical trial.

Used <unk> 600, <unk> in several programs and we understand that the safety of it across all of the programs.

Rob Schott: and the current plan is to find the best way to guide the management of any patient that has

Rob Schott: Yes, so it would be monitoring and management of patients with levels of factor VIII that are greater than 160%.

We've had very few adverse events.

In addition, if you look at.

The point at which there is an inflection of efficacy it as opposed to one to $3 13 in hemophilia.

Rob Schott: We feel it is important to restate every time that that conversation comes up that no patient has come to harm. There have been no adverse events related to this, and this is an abundance of caution, and I think a correct abundance of caution because this is a gene therapy that we need to take very seriously and do the best for the patient. Mark? Yeah, so in terms of the Betafowl decision, it was really a business decision that we made.

And it's even earlier than that in the Fabry disease program.

Although thunder.

Very pleased with the safety and efficacy we've now seen in our two gene therapy programs.

Got it okay. Thanks for taking my questions and congrats again.

Next question is from Nicole Jeremy.

Securities. Your line is now open.

Good morning, Thanks for taking my questions and congrats on the progress.

So it has a high dialed in a little bit late and I might have missed some of the opening remarks. So I apologize if my questions are there any of that.

Mark McClung: took place alongside our partners at Sanofi.

Mark McClung: Just due to the timing and relative to where the competitive set lies in terms of their development.

But for February can you talk about how the pilots have improved over time from baseline on any color on cardiac function.

Mark McClung: We felt that it was important to really focus our effort and our resources solely on sickle cell disease and to Drive Forward together.

First you may have.

Long from infusion excursions Hoffman, how often a great level of forecast going forward to monitor.

Mark McClung: Sources solely on sickle cell disease and Drive Forward together. Got it. Thanks so much, guys. The next question is from Maury Raycroft of Jefferies. Your line is now open.

So your likeness.

A little unclear. So let me see <unk> see the I understood. Your question, it's about the patients symptoms in fabry.

Operator: Hi, everyone. Good morning and congrats on the update today. For Fabry, just wondering if you can talk more about the Alpha-Gal data being 2 to 15 fold higher than normal. Seems higher than competitor data at month 12, which showed about 5 to 6 fold higher. I guess what's the best way to contextualize your data versus competitors?

How we manage the patients in hemophilia a is that correct.

Yes.

So how long you plan for hemophilia, how long from the infusion.

Dan.

So bettina can you say, what we know about the.

Patient reported symptoms in Fabry, please yes of course.

As a reminder, again I'd like to emphasize early data that we're sharing early preliminary data.

The patients in cohort.

Maurice Thomas Raycroft: And how could this translate to kidney substrate reduction?

We get the full pace in pad on hydro.

Maurice Thomas Raycroft: Thank you, Maury. Bettina, do you want to talk about Fabry?

Reported.

Baseline.

And some of these patients three these three patients have reported improvement in sweating.

Bettina M. Cockroft: Sure. Thank you, Sandy. So in terms of the alpha-gal data, we're obviously very excited to see the superphysiologic

Exploration.

Which is.

Net favorable outcome for patients.

In that time period.

Over the course of the study that we have seen so far one of the patients also had.

Bettina M. Cockroft: alpha-gal expression that we are seeing with all four patients.

<unk>.

Seen stabilization of cardiac structural material assessments on imaging so.

Bettina M. Cockroft: At this point, it is early to compare and probably not the right place to do so.

These are preliminary report that we are gathering.

Bettina M. Cockroft: to do comparisons across programs. We look forward to sharing.

As I mentioned before we will be sharing more information over the course of next year of some of the detail.

Bettina M. Cockroft: We will be sharing more granularity on this data at an upcoming meeting in 2022, so that also goes for any additional data related to kidney substrates.

I would like to add that if you look at the totality of the data including the.

Patient observations that were related to the investigators the alpha Gal expression the adverse events that all of the data are all pointing in a favorable direction. So we would.

Bettina M. Cockroft: You can imagine that having seen efficacy in the two initial cohorts and moving into a third higher cohort, it gives us enormous energy that this is going to be a medicine that will be useful for patients with Fabry. It really is compelling data, early as it is; we find it compelling data.

We'd like you to look at the data in its totality not just each individual component.

Okay, Great and then for <unk>, how long from the infusion.

But the experience happen.

This is an ongoing phase III trials, so we arent disclosing.

The specifics around the data.

Bettina M. Cockroft: And I would add that a priori, we had targeted superphysiologic expressions of alpha-gal A and plasma to drive clearance from tissues. So this is a desired effect, what we're seeing.

We want to keep that.

<unk> III trial.

Because it's a potential registration trial.

Great. Thanks.

Next question is from Gena Wang of Barclays. Your line is now open.

Maurice Thomas Raycroft: Got it. It's all helpful. And maybe just one follow-up, if you can compare and contrast the Fabry observations and gene expression and dose with your hemophilia gene therapy program, maybe if you can talk more about that.

This is Tom thanks for taking the question.

For the Fabry.

Just one question, we keep dosing and the alpha Gal enzyme level.

Alexander D. Macrae: That's a good question. We are fortunate that we have used AAV6 now in several programs, and we understand its safety. And across all of the programs, we've had very few adverse events. In addition, if you look at the point at which there's an inflection of efficacy, it's about 1 to 3 E13 in haemophilia, and it's even earlier than that in the Fabry disease program. Other than that, we're very pleased with the safety and efficacy we've now seen in our two-gene therapy program.

Do you plan to dose higher.

Ending on the data read out.

And what do you mean, the goal of that level.

Level in the sovereign is current <unk> growth.

Is it logical level enough.

Sure.

Solid.

And how about the alpha Gal enzyme level change after the patient who withdraw it.

Yeah.

And a question on sort of <unk>.

Can we do separate one.

We make sure we cover all your questions.

Maurice Thomas Raycroft: Got it. Okay, thanks for taking my questions. Congratulations again.

We've never set.

It must be this for Alpha go because this is the first time that people have really done gene therapy in fabry disease and.

Operator: The next question is from Nicole Germino, Trooper Securities. Your line is now open.

Nicole Germino: Good morning. Thanks for taking my questions and congratulations on the progress. I dialed in a little bit late, and I might have missed some of the opening remarks, so I apologize if my questions were already addressed. But for Fabre, can you talk about how the primary symptoms have improved over time from baseline and any color on cardiac function? And for Hime, how long...

So there isn't definitive level, we've always thought it had to be better than normal physiological levels and we're pleased that the patients both on <unk> and <unk> are at that level.

And note what we're doing is withdrawing the ERP and see where.

We are at the levels provided by the gene therapy in the liver lethal.

Nicole Germino: How long from the infusion did these excursions happen, and how often are they...

And until we do that to experiment, we really wound understand this fully.

We are also dosing.

Nicole Germino: How often are factor VIII levels being assessed going forward to monitor them?

<unk>, which is three times higher than the current dose and once we see that data in its totality, we will be able to decide which dose to take forward into phase III.

Alexander D. Macrae: So your line is a little unclear, so let me read back to see if I understood your question. It's about the patient symptoms in Fabry, and it's about how we manage patients with haemophilia, is that correct?

But we felt that the first two cohorts were so compelling as Rob says with the Alpha Gal with patient safety with the patient related outcomes that came spontaneously from patients talking to investigators.

Nicole Germino: And for hemophilia, how long from the infusion did the excursions happen?

Bettina M. Cockroft: So Bettina, can you please say what we know about the patient-reported symptoms of Fabry?

Things that had been.

Bettina M. Cockroft: So, as a reminder, again, I'd like to emphasize this is early data that we're sharing, early preliminary data. The patients in CAUSE 1 and 2, three of the four patients had anhydrosis reported at baseline, and some of these patients, these three patients, have reported improvement in sweating or perspiration, which is a favorable outcome for patients, in the time period over the course of the study that we have seen so far. One of the patients also had seen stabilization of the cardiac structure on.

Are important to them like ability to exercise Crissy can no sweat that we felt that this data was exciting and compelling and wanted to share it with the broader community.

Okay great.

Helpful and maybe just a quick follow up on the cap rate that.

Comment that.

You will share additional data, including the kidney function data.

2022 medical meeting and will that be.

Right.

<unk> kidney in Cushing or it will be egfr.

Mike.

Filtration function measurement can you.

Hello.

Bettina M. Cockroft: are on serial assessment on imaging.

Second we expect patient about that.

Bettina M. Cockroft: So these are preliminary reports that we are gathering, and, as I mentioned,

It's unlikely that we'll be sharing renal biopsy data in 'twenty two.

Bettina M. Cockroft: And as I mentioned before, we will be sharing more information over the course of next summer.

The patient will undergo an initial biopsy and then some months later, our second one so that data.

Bettina M. Cockroft: Here of some of these details. I'd like to add that if you look at the totality of the data, including the patient observations that were relayed to the investigators, the alpha-gal

It is.

Is unlikely to be available in 2022.

Okay, Okay, thanks for that and for the Hemo a.

We know that it will be there will be protocol amendment.

And then Pat.

Any additional steps that are required in order to remove the clinical hold.

Bettina M. Cockroft: [inaudible]

Bettina M. Cockroft: , and , and , and , and ,

Rob Schott: Great. And then for Hime, how long from the infusion did the excursions happen? This is an ongoing phase three trial, so we aren't disclosing the specifics around the data. We want to keep that phase three trial protected, because it's a potential

Or the implementation of the Aro Andy correctly will be.

Only one.

It required.

I have enormous confidence in our colleagues at Pfizer, putting together an amendment that puts patients first.

Rob Schott: [inaudible]

<unk>.

Operator: The next question is from Gina Wang of Barclays. Your line is now open.

Make sure that the patients so which remains safe and then they will discuss that and presented to the agency and hopefully we'll be able to move forward with this trial.

Huidong Wang: This is Tom Porcina. Thanks for taking the question. So for the Fabry, just one question about dosing and the alpha-gal enzyme level. Do you plan to dose higher, depending on the data data? And what is your ultimate goal for that alpha-gal level in the serum?

Pfizer said over 50% of the patients have been involved known and they had.

Pre study study to collect the patients to have them ready to go into the trial. So we think this will move forward.

Huidong Wang: Is it [inaudible]?

Huidong Wang: and how about the alpha-gal enzyme level change after?

And our our sure that Pfizer is doing the right thing.

Huidong Wang: and James, after the patient who withdrew from the ER. Great questions. Well, let's, can we do family first? So we make sure we cover all your questions.

Okay. Thanks for that.

Next question is from redo barrel of Cowen. Your line is now open.

Hi, guys. Thanks for taking the question.

As part of this phase two what other clinical.

Alexander D. Macrae: We've never said it must be this for alpha-gal because this is the first time that people have really done gene therapy in Fabry disease, and so there isn't a definitive level. We've always thought it had to be better than normal physiological levels, and we're pleased to see that the patients both on ERT and off ERT are at that level. And now, what we're doing is withdrawing the ERT and seeing where the levels provided by the gene therapy in the liver level out.

I guess Ah clinical quality of life for a patient reported symptomatology are you capturing Sandy you mentioned.

Improvement in wording are there other things that are being proactively clinic.

Clinical symptomatology wise.

And then can you talk at all about sort of the curve of expression.

Alexander D. Macrae: And until we do that experiment, we really won't understand this fully. We are also dosing at 3E13, which is three times higher than the current dose. And once we see that data in its totality, we will be able to decide which dose to take forward into phase 3. But we felt the first two cohorts were so compelling, as Rob says, with the alpha-gal, with patient safety, with patient-related outcomes that came spontaneously from patients talking to the investigator about things that are important to them, like their ability to exercise because they can now sweat, that we felt that this data was exciting and compelling and wanted to share it with the broader community.

Sure.

Like for patient one.

That 15 fold at week 52 can you confirm that that's like that.

The top expression that you've seen.

For patient for that Youre sort of continuing on your way out and then anything you can say about that.

Okay. So so we measure a whole slew of things, including formal patient related outcomes, we want to be very clear this with spontaneous patients continuously talking to the investigator.

Tell them all of the changes are based new and then the investigator felt compelled to tell us because it was important.

We will we will.

We will measure.

Huidong Wang: Okay, great. That's very helpful. And maybe just a quick follow-up on the fact that you comment that you will share additional data, including the clinic function data, at the 2022 EMAC meeting, and will that be included like GB3?

This going on in the phase III.

Because.

It's not just about the end so imports important is what's important to the patient and it's things like the neuropathy like pain that they have it's the sweating its about the quality of their life and their energy and so we want to capture all these things.

Huidong Wang: kidney inclusion, or it will be EGFR, the filtration function measurement. Can you help us to set an expectation for that? It's unlikely that we'll be sharing renal biopsy data in 2022. There's a patient would undergo an initial biopsy and then some months later, a second one. So that data is unlikely to be available in 2022. Okay, thanks for that.

The second question I think youre asking so both duration, that's very pleasing to us because this is a solution we want for as long as possible for those patients and all of the patients. After once it gets to its plateau level. It has remained at that level throughout the duration of the study.

And we.

We will continue to follow these patients and report.

Hopefully the continued duration of effect.

Alexander D. Macrae: And for HEMO A, we know that there will be a protocol amendment. Other than that, do you expect any additional steps that will be required in order to remove the clinical host? or the implementation of the oral anticoagulant will be the only one that will be required. I have enormous confidence in our colleagues at Pfizer. They're putting together an amendment that puts patients first and makes sure that patients always remain safe.

Got it.

Just given the change in that.

I guess the regulatory landscape in February over the last two.

12 months or so.

Are there any plans to potentially add.

C J.

Or are you.

Is that going to be weaker.

Any kidney box evening.

We have we have plans for biopsy and this study is just that the.

<unk> will not be available within the 2022 phase.

We've always said that we would not do that biopsy and the initial patient until we sold the medicine was effective and now we see the medicines effected biopsies will be part of the routine of the study.

Alexander D. Macrae: And then they will discuss that and present it to the agency, and hopefully, we'll be able to move forward with this trial. As Pfizer has said, over 50% of the patients have been enrolled now, and they've had a pre-study study to collect the patients to have them ready to go into the trial. So we think this will move forward and are sure that Pfizer is doing the right thing.

Oh got it okay. So maybe not the biopsy from these patients that may be that.

Patients with highest dose is that the plan so.

So the first four patients did not renal biopsy and.

Future patients will okay.

Operator: The next question is from Reeder Baral of Cohen. Your line is now open.

As part of the study protocol.

Got it thanks for taking the questions.

Reeder Baral: Hi guys, thanks for taking the question. As part of this Phase 1-2, what other clinical, I guess, clinical quality of life or patient-reported symptomatology, are you capturing? Sandy, you mentioned improvement in sweating. Are there other things that are being proactively asked clinically symptomatology-wise? And then, can you talk at all about sort of the curve of expression that you're seeing, like for patient one, that 15-fold increase at week 52? Can you confirm that that's like the top expression that you've seen for patient four, that you're sort of continuing on your way up, and anything you can say about the curve?

Our pleasure.

Next question is from Ben Burnett of Stifel. Your line is now open.

Alright, Thank you very much.

My congratulations on the Fabry disease data.

I did want to ask a couple questions around this the first one.

I would also agree with some of the others on the call. It seems like the enzyme activity is quite good.

Relative to competitors, but I guess, just curious of the impact on <unk> three just wasn't more profound specific on patients one two and four I.

I guess, how what is your interpretation of those of those data and how representative is.

License <unk> III and the plasma.

What's happening inside of cells.

Question on until we biopsy.

We'll have that.

The direct correlation.

Alexander D. Macrae: Okay, so we measure a whole slew of things, including formal patient-related outcomes. But we want to be very clear, this was spontaneous, patients spontaneously talking to their investigator to tell them of their, of the changes that they've known, and the investigator felt compelled to tell us because it was important. We will, we will.

And all of the all of the fabric trials from each of our competitors and those patients who have blue lights with GPS III don't go lower if there is already very low it's hard to make it go lower and thats across all of the trials and even in the trials have done GPS III.

Even in the upper buyout trunk for example, who showed a reduction in GBP and the kidney the.

Alexander D. Macrae: We will measure this going on in phase three because it's not just about the enzyme. What's important is what's important to the patient and things like the neuropathic pain that they have. It's about the sweating. It's about the quality of their life and their energy. And so we want to capture all these things.

<unk>, who showed that effect that it had to be high lights with GPS III to show a reduction in the possible.

It's a very different system that we're producing here and we think this is for patients won't be a onetime injection.

That is effective at producing alpha Gal and is effective at producing a over a long period of time.

And that the notice of benefit and we're already having indications.

Alexander D. Macrae: The second question I think that you're asking is about duration. That's very pleasing to us because this is a solution we want for as long as possible for those patients. And in all of the patients, once it gets to its plateau level, it has remained at that level throughout the duration of the study. We will continue to follow these patients and report, hopefully, the continued duration of effect.

We've seen no we need to go to the next higher dose and hopefully show even more benefit.

And then pull that data together and decide on the design of this study for phase III and get this medicine to patients as soon as possible, but we are very pleased with the safety the efficacy the consistency and the patient benefit that we've seen so far.

Reeder Baral: Got it. And just given the change in the, I guess, the regulatory landscape in FABRI over the last 12 months or so, are there any plans to potentially add biopsy to this study? Or are you, is that going to be reserved for the next study? Kidney biopsy, I mean.

Understood. Okay. That's helpful and if I could just ask one clarifying question on patient four.

Alpha Gal activity at week 14.

You show an assessment that looks I think really good but was this assessment made.

After they are weaned off of enzyme replacement therapy or was that prior to that.

Alexander D. Macrae: We have plans for biopsy in this study, it's just that the results will not be available within the 2022 phase. We've always said that we would not do the biopsy in the initial patients until we saw that the medicine was effective. And now that we have seen that the medicine is effective, biopsies will be part of the routine of the study.

Bettina can you just clarify absolutely so.

Patient number four.

Being withdrawn from the T therapy very recently.

After the cutoff date for what you'll see on the slides that we have.

Posted on our corporate website.

Reeder Baral: Okay, so maybe not the biopsy from these patients, but maybe the fifth and sixth patient with the highest dose? Is that the plan?

So the data you're seeing is with the patients still on <unk> and just to clarify all the data points.

AIP level, so those England prior to the infusion.

Alexander D. Macrae: So the first four patients did not have renal biopsy, and future patients will as part of the study protocol. Got it. Thanks for taking the call.

<unk>.

<unk> withdrawal will have been after this data cut.

Okay.

Reeder Baral: Got it. Thanks for taking the questions.

As part of the reason that this therapy is is I think offers a better solution than <unk> is ERP has a very rapid.

Operator: The next question is from Ben Burnett of Steeple. Your line is now open.

Benjamin Jay Burnett: Hey, thank you very much. I will echo my congratulations on the Fabry disease data. I did want to ask a couple of questions around that. The first one, I also agree with some of the others on the call.

Benjamin Jay Burnett: It seems like the enzyme activity is quite good, at least relative to competitors. But I guess it's just curious that the impact on Lyso-GB3 just wasn't more profound, specifically on patients one, two, and four. I guess how your interpretation of those data and how representative is Lyso-GB3 into the plasma to what's happening inside cells.

Alexander D. Macrae: Question, and until we biopsy, we won't have that direct correlation. I'll say again, in all of the Fabry trials from each of our competitors and us, patients who have low lyso-GB3 don't go lower. If it's already very low, it's hard to make it go lower.

Alexander D. Macrae: And that's across all of the trials. And yet, even in the trials that have done GB3, even in the Abrobio trial, for example, who showed a reduction in GB3 in the kidney, they also showed that effect, that it had to be a high lyso-GB3 to show a reduction in the plasma. It's a very different system that we're producing here, and we think this is what patients want. They want a one-time injection that is safe, that is effective at producing alpha-gal, and that is effective at producing it over a long period of time, and that they notice a benefit, and we're already having indications that that's what's seen.

It may be our data.

Thank you.

So let me let me answer the second one then pasty antibodies to Bettina.

Quite this had to be treated seriously will cease a patient of gene therapy. So when they get the medicine. It stays in their body, even if the trial is paused and so we and Pfizer will continue to collect data from the patients even though the the recruitment into his paws, they're still in.

Alexander D. Macrae: Now we need to go to the next higher dose and hopefully show even more benefit, and then pull all that data together and decide on the full design of the study for phase three and get this medicine to patients as soon as possible. But we are very pleased with the safety, the efficacy, the consistency, and the patient benefit that we've seen so far.

Information about prolongation of effect on safety of the medicine being collected my policy. So it's unusual compared to a post trial for the patient stops taking the medicine.

Medicine is still there and continuing to have benefits of the patient we hope.

Benjamin Jay Burnett: Okay. And if I could just ask one sort of clarifying question: on patient four, alpha-gal activity at week 14, you show an assessment that looks, I think, really good, but was this assessment made after they were weaned off of enzyme replacement therapy, or was it prior to that?

The Tina the antibodies for the antibody so.

Think what is important to emphasize is.

Early data on for patients.

And it is early to make inferences as to whether antibodies.

And to what degree antibodies are having an effect on these patients uhm, we need to bear in mind that two of these patients are on T two or not.

Bettina M. Cockroft: Bettina, can we start back please?

Bettina M. Cockroft: Absolutely. So patient number four has only been withdrawn from ERT therapy very recently, and after the cutoff data for what you're seeing on these slides that we have posted on our corporate website. So the data you're seeing is with the patient still on ERT. And just to clarify, all the data points are at trust ERT level.

There is a lot of variability in the date at this point in time. So we have put seeing more data coming out from our next cohort cohort Street.

And being able to assess that impact in a bedroom on it.

But we haven't seen anything any correlation alternate at this point in time that would be difficult to say.

Bettina M. Cockroft: So, dozing was common prior to the ERT.

Bettina M. Cockroft: ERT infusion. So the ERT withdrawal will have been after this date. Okay.

Sure. Okay understandable. Thank you for taking that our our question again again, congrats I'm encouraging.

Alexander D. Macrae: It's part of the reason that this therapy, I think, offers a better solution than ERT. ERT has a very rapid C-max, and then it declines quickly. But we wanted to be particularly careful, and therefore we measured the trough level usually about day 14 after the ERT, at the very last point before the patient had their next dose of ERT to make sure there was no residual enzyme in the plasma. And that's something I think we all, in all the different studies from all the different companies, need to be careful about, making sure that the trough is the correct trough.

Thank you participants I'll now turn to call back over to Aaron Feingold for closing remarks.

Thank you once again for joining us today, and if I had like Janet we look forward to keep you up keeping you updated on our teacher development.

That concludes today's conference call. Thank you all for joining you may now disconnect.

[music].

Benjamin Jay Burnett: Understand? That makes sense. OK. All right. Thank you very much for the color.

Operator: Speakers, we have time for one more question from Andreas Argyrides of Wedbush Securities. Your line is now open.

Andreas Argyrides: Good morning, and thank you for taking our questions.

Andreas Argyrides: Let me also reiterate our congratulations on this really encouraging data.

Andreas Argyrides: And I'm going to ask you all to take a short break. We'll be back in a minute. So, as always, if you have a question, feel free to reach out to me.

Andreas Argyrides: I'm a little bit shy. I'm not a big fan of talking. I'm a little shy. I'm a little bashful. I'm a little shy. I'm a little bashful. I'm a little shy. I'm a little bashful. I'm a little shy. I'm a little bashful. I'm a little shy.

Andreas Argyrides: [inaudible] the time for the ABR data. Thank you.

Alexander D. Macrae: So let me answer the second one, then pass the antibodies to Bettina. Why this had to be treated seriously was that these were patients undergoing gene therapy, so when they get the medicine, it stays in their body, even if the trial is paused. And so we and Pfizer will continue to collect data from the patient, even though the recruitment into it is paused; information about prolongation of effect and safety of the medicine is being collected by Pfizer. So it's unusual compared to a paused trial where the patient stops taking the medicine. The medicine is still there and continuing to have benefit for the patient, we hope. Bettina, the Antigone.

Bettina M. Cockroft: Yes, for the antibodies. I think what is important to emphasize is this is early data on four patients, and it is early to make inferences as to whether antibodies and to what degree they are having an effect on these patients.

Bettina M. Cockroft: [inaudible]

Andreas Argyrides: At this point in time, that would be difficult. Sure, okay, I understand.

Andreas Argyrides: Sure. Okay. Understandable. Thank you for taking our questions. And again, congrats on encouraging us.

[music].

Operator: Thank you, participants. I'll now turn the call back over to Aaron Feingold for closing remarks.

Aaron Feingold: Thank you once again for joining us today and for your questions. We look forward to keeping you updated on our future developments.

Operator: That concludes today's conference call. Thank you all for joining us. You may now disconnect.

Operator: BF-WATCH TV 2021 (inaudible)

Operator: Thank you all for standing by, and welcome to the Sangamo 3rd Quarter 2021 teleconference call. All participants are in a listen-only mode until the question-and-answer session of today's conference.

Speaker: Good morning, and thank you for joining us today.

Speaker: With me this morning on this call are several members of the Sangamo Executive Leadership Team, including Sandy Macrae, Chief Executive Officer, Mark McClung, Chief Operating Officer, Prathyusha Duraibabu, Chief Financial Officer, Jason Fontenot, and Chief Scientific Officer, Rob Schoen.

Speaker: of Development, and Bettina Cockroft, Chief Medical Officer.

Speaker: Slides from our corporate presentation can be found on our website, sangamo.com, under the Investors and Media section, under the Events and Presentations page. This call includes forward-looking statements regarding Sangamo's current expectations. These statements include, but are not limited to, statements relating to the therapeutic and commercial potential of our product candidates, the anticipated plans and timelines of Sangamo and our collaborators for conducting clinical trials and presenting clinical data, execution of our corporate strategy, advancement of our product candidates, our revised 2021 financial guidance, and other statements that are not historical facts. However, actual results may differ materially from what we discussed today. These statements are subject to certain risks and uncertainties that are discussed in our filings with the SEC.

Speaker: Specifically, our annual report on Form 10-K for the fiscal year ended December 31, 2020, as supplemented by our quarterly report on Form 10-Q for the fiscal quarter ended September 30, 2021. 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-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.

Thank you all for standing by and welcome to the Sangamo third quarter 2021 teleconference call.

All participants are in a listen only mode until the question and answer session of today's conference.

Ask the question over the phone by that time, you May press the star key followed by the number one.

Please also note that today's call is being recorded.

Alexander D. Macrae: Thank you, Aaron, and good morning to everyone on the call. This is such an important moment for Sangamo, as we share clinical data and business updates across several programs, demonstrating that we have three important assets in or progressing towards late stage development. Our gene therapy portfolio is advancing with accumulating safety and efficacy data in our Fabry and Haemophilia A programs. Additionally, we are delighted with the preliminary proof-of-concept data demonstrating the clinical potential of our genome engineering zinc finger technology in sickle cell disease.

Now turn the call over to your host.

Aaron find gold head of corporate Communications Ma'am, you may now begin.

Good morning, and thank you for joining us today.

With me. This morning on this call are several members of the Sangamo executive leadership team, including Sandy Macrae, Chief Executive Officer, Mark Mcclung, Chief operating Officer, British Sugar and I do Chief Financial Officer, Jason No Chief Scientific Officer, Rob shot.

Head of development, and Bettina Cockroft, Chief Medical Officer.

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

Alexander D. Macrae: This morning, we announced preliminary clinical data from our Phase 1-2 STAR study evaluating Isoralga gene therapy, Cipoparvivec or ST920, our fibrodisease gene therapy product candidate. Data from this important study were evaluated from the four patients in the first two cohorts, those levels 0.5 E13 and 1 E13 BG per kg as of the cut-off date, September 17th of this year.

This call includes forward looking statements regarding <unk> current expectations. These statements include but are not limited to statements relating to therapeutic and commercial potential of our product candidates the anticipated plans and timelines of Sangamo and our collaborators for conducting clinical trial.

And presenting clinical data at the Houston of our corporate strategy advancement of our product candidates, our revised 2021 financial guidance and other statements that are not historical facts actual results may differ materially from what we discussed today. These statements are subject to certain risks.

Alexander D. Macrae: These encouraging results showed that for the first four patients, ST920 was generally well tolerated. There were no treatment-related adverse events higher than grade 1, and no treatment-related serious adverse events; no patients experienced liver enzyme elevations or required steroid treatment. All four patients exhibited above-normal alpha-GalA activity which was maintained for up to one year for the first patient treated and through 14 weeks for the most recently treated patient. Levels ranged from 2 to 15 fold above normal levels at the last measurement as of the cut-off date. Interestingly, the first three patients still reported improvements in their ability to sweat, a primary and common Fabry disease symptom that limits exercise tolerance for the patient.

And uncertainties that are discussed in our filings with the S. E T. Specifically our annual report on Form 10-K for the fiscal year ended December 31, 'twenty 'twenty are supplemented by our quarterly report on Form 10-Q for the fiscal quarter ended September 32021, 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-GAAP operating expense 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. Thank you Hey, good morning to everyone on Nicole.

Our gene therapy portfolio is advancing with accumulating safety and efficacy data and our factory in hemophilia a program.

Additionally, we are delighted with the preliminary proof of concept data demonstrated the clinical potential of our Geno mentioned hearing zinc finger technology in sickle cell disease.

Yeah.

This morning, we announced preliminary clinical data from our phase <unk> study.

Hi, Suraj good gene Super Conference Vick, our SD <unk> 'twenty, our fabry disease gene therapy product candidate.

Data from this important study where he thought we use it from the four patients in the first two cohorts two cycles point, following <unk> and one <unk> vg per cake.

As of the cutoff date September <unk> of this year.

Alexander D. Macrae: An investigational zinc-finger nucleus gene-edited cell therapy in patients with sickle-cell disease will be presented at ASH. This program is partnered with our friends at Sanofi. The data in the abstract show that as of June 25th, 2021, the cut-off date, none of the four patients treated required blood transfusions, postsyngrafman, through 65 weeks of follow-up for the longest-treated patients. The four treated patients all experienced increases in total hemoglobin, fetal hemoglobin, and percent S cells. No adverse events or serious adverse events related to treatment were reported as of the cut-off date. Further data will be provided in a poster presentation at ASH on December 12th.

These encouraging results showed that for the first four patients <unk> was generally well tolerated.

No treatment related adverse events have been great. One no treatment related serious adverse events no patient experienced liver enzyme elevations are required steroid treatment.

All four patients exhibited a bulk normal alpha Gal a activity.

Which were maintained for up to one year for the first patient treated include 14 weeks for most recently treated patients life.

License range from 2% to 15 fold above normal levels at last measurement as of the cutoff date.

Interestingly the first three patients dosed reported improvements in ability to sweat our primary common pumping to see symptom that limits exercise tolerance for the patient.

Okay.

<unk> is now complete for one patient in this time for the other patient on Europe based on the stability of their off but can lead to the following treatment.

Based on these data we have initiated the phase III planning.

But this patient in this study the first patient in the third dose cohort at <unk> was recently dosed. The six patient is currently in screening also for the third dose cohort.

And we expect to provide updated results throughout 2022 and present these data at a medical meeting.

Alexander D. Macrae: Moving now on to our Haemophilia A program, partnered with Pfizer, we announced this morning the updated follow-up results from the Phase 1-2 Ulta study of Duratocra gene therapy Fetocarbovenc will be presented at ASH. For the four patients in the highest-dose cohort who have been followed for at least 104 weeks as of May 19, 2021 cut-off, mean factor VIII activity was 30.9% at In this cohort, annualized bleeding rate was zero for the first year after treatment and 0.9 throughout the total duration of follow-up. As demonstrated in this study, gene therapy was generally well tolerated in patients with severe haemophilia A. Further data will be provided in a poster presentation at ASH on December 12, 2021.

Okay.

This morning, we also announced the preliminary proof of concept results from the phase one two precision study of SCR for 456 and investigation of zinc finger nuclease gene edited cell therapy in patients with sickle cell disease will be presented at ash.

This program is partnered with their friends incentive fee.

The data in the abstract shows that as of June 25, 2021 cutoff date, none of the four patients treated required blood transfusion posted <unk> 365 weeks, So Paulo for the longest treated patients.

The four treated patients all experienced increases in total hemoglobin fetal hemoglobin and percent cash sales.

No adverse events or serious adverse events related to treatment, we reported as of the cutoff date.

Further detail provided in a poster presentation at Ash on December 12.

Sangamo and Sanofi are continuing to advance the sickle cell disease program. The company has recently obtained manufacturing requirements guidance from the FDA in preparation for potential further clinical studies separately, we incentive fee made the business decision to cease development for the beta thalassemia indication.

Alexander D. Macrae: We and Pfizer also announced that some of the patients treated to date in the phase 3 affine trial experienced factor VIII levels greater than 150% following treatment. To date, none of these patients have experienced thrombotic events, and some have been treated with direct oral anticoagulants to reduce thrombotic risk. However, out of an abundance of caution, Pfizer voluntarily paused screening and dosing of patients in the trial in order to implement a protocol amendment which will provide guidelines for clinical management of elevated factor VIII lips.

Allowing us to focus resources on the sickle cell disease program.

Okay.

Moving now onto our hemophilia a program partnered with Pfizer, We announced this morning, the updated follow up results from the phase one two <unk>.

<unk> study of <unk> for to conquer bank will be presented at ash.

For the four patients in the highest dose cohort who have been followed for at least 104 weeks as of May 19, 2021 cutoff.

Alexander D. Macrae: On November 3rd, FISO was informed that the FDA has put this trial on clinical hold. Pfizer and Sangamo are committed to resuming patient dosing as soon as possible. We continue to believe that this gene therapy will represent an important treatment option for patients with haemophilic AIDS. The next step is to share the proposed protocol amendment with health authorities and respond to the clinical hold, after which the companies will be able to provide updated timing for the trial.

Meaning factory activity was 39% at week 104 as measured by Chromogenic assay.

In this cohort annualized bleeding rate was zero for the first year after treatment and Cedar point, knowing drove total duration of follow up.

As demonstrated in this study the gene therapy was generally well tolerated in patients with severe hemophilia a.

Further data will provided a poster presentation at ash on December 12, 2021.

We and Pfizer also notes that some of the patients treated to date in the phase III <unk> trial experienced factory levels greater than 150% pulling treatment.

Alexander D. Macrae: Turning now to our kidney transplant program, we have now enrolled the first patient in our Phase 1-2 Steadfast Study, evaluating TX200, our wholly owned, autologous CAR T-REG cell therapy candidate. We believe that this is the first in-human CAR-T reg study and that this field is growing with much excitement as a promising approach for challenging autoimmune conditions. In this study, similar to other genetically engineered cell therapy approaches, patients will undergo a lookup procedure from which their Treg cells will be isolated, engineered, and then cryopreserved.

To date, none of these patients have experienced thrombotic events and.

Some have been treated with direct oral anticoagulant to reduce thrombotic risk.

Out of an abundance of caution visor voluntary pause screening and dosing of patients in the trial in order to implement a protocol amendment, which will provide guidelines for clinical management availability factory levels.

On November 3rd Faisal respond, but that the FDA has put this trial on clinical hold.

Biogen Sangamo are committed to resuming patient dosing as soon as possible.

We continue to believe that this gene therapy will represent an important treatment option for patients with hemophilia a.

The next step is to show the proposed protocol Amendment with health authorities in response to the clinical hold after which the companies will be able to provide updated timing for the trial.

We believe that this is the first in human car T. Regs study and this field is growing with much excitement as a promising approach for challenging autoimmune conditions.

In this study similar to other genetically engineered cell therapy approaches patients will undergo a leukapheresis procedure from which their T. Reg cells will be isolated.

Engineered and then Cryopreserved.

The HLA <unk> negative patient will subsequently undergo kidney transplant and following our recovery period, we received a personalised TX 200 therapy.

Alexander D. Macrae: Finally, I'm delighted to share that Mark McClellan has been appointed as Sangamo's Chief Operating Officer, effective November 1st. Mark's expanded role as COO is an important organizational step for Sangamo, which will support the multiple-advancing, wholly-owned, and partnered program. We look forward to Mark's continued leadership as we continue to build the capabilities to bring genomic medicines to patients and to the marketplace. Everyone at Sangamo is thrilled about this clinical momentum, and we look forward to presenting updated February results throughout 2022, as well as working with our collaboration partners and investigators to present the ASH data in December. And with that, I'll turn the call over to Prathyusha for a financial update.

We expect to dose the first two patients in this study by the middle of 2022 following their kidney transplants.

We hope that this study establishes the foundation for our portfolio of wholly owned car T. Reg therapies for autoimmune indications.

Finally, I'm delighted to share that Mark Mcclung has been appointed as <unk> Chief operating officer effective November one.

Mark's expanded role as CEO is an important organization step for Sangamo, which will support the multiple multiple advancing wholly owned and partnered programs.

We look forward to <unk> continued leadership as we continue to build the capabilities to bring genomic medicines to patients and to the marketplace.

As we when it sank most through to this clinical momentum and we look forward to presenting updated fabry results through 2022, as well as working with our collaboration partners and investigators to present the ash data in December.

Prathyusha Duraibabu: Thank you, Sandy, and good morning. Our financial results for this quarter are available in the press release issued this morning, which can also be found on our website. I want to reiterate that this is an exciting moment for us as a company, and this quarter, we continue to invest in the advancement of our clinical programs, including FEBRI and TH200, our preclinical research pipeline, and our in-house manufacturing capabilities. With approximately 519 million in cash, cash equivalents, and marketable securities at the end of the quarter, we believe that our balance sheet remains strong.

And with that I'll turn the call over to Patricia for a financial update.

Yes.

Thank you Sandy and good morning all.

So for this quarter are available in our press release issued this morning, which can also be found on our website I want to reiterate that this is an exciting moment for us as a company and this quarter. We continued to invest in the advancement of our clinical programs, including February MTX to 100.

Preclinical research pipeline and our in house manufacturing capabilities.

With approximately $519 million in cash cash equivalents and marketable securities at the end of the quarter, we believe that our balance sheet remains strong.

Turning to 2021 full year guidance.

We expect non-GAAP operating expenses to be between 265 million to $175 million for the year.

Just within the range of the guidance that we have previously provided.

This range excludes estimated noncash stock based compensation expense of approximately $35 million.

Alexander D. Macrae: I will now turn the call back to Sandy for her closing remarks.

I will now turn the call back to Sandy for closing remarks, Thank you Patricia.

Alexander D. Macrae: We are very excited by today's clinical data readouts, which show the advancement of our first-generation genomic medicine pipeline with traditional gene therapy and autologous cell therapy. These programs potentially pave the way for our next generation focus on genome regulation and allogeneic CAR Treg cell therapy, where we have a robust preclinical pipeline in neurological and autoimmune diseases, respectively. We're delighted with the positive momentum and look forward to updating you in the near term about several potential catalysts, including presentation at ASH of four patient sickle cell disease phase 1-2 data, presentation at ASH of two year phase 1-2 haemophilia data, and additionally, we'll provide a timing update for the phase 3 trial once the proposed protocol amendment and response to the hold are shared with health authorities.

We are very excited about this is clinical data readouts could show the advancement of our first generation genomic medicine pipeline with traditional gene therapy, an autologous cell therapy. These.

We are delighted with the positive momentum and look forward to updating you in the near term, but several potential catalysts, including presentation ship for patient sickle cell disease phase one two data presentation at ash of two year phase one to hemophilia a data and additionally, we will provide a timing update for the PC trial once the proposed pud.

Cole Amendment in response to the hold is shared with health authorities.

Alexander D. Macrae: Dosing of the six patients and updated Fabry Phase 1-2 data presentations throughout 2022, including at a medical meeting. Dosing of the first two patients in the Steadfast Phase 1-2 study by the middle of 2022, and completion of our in-house cell therapy manufacturing facility in our Valbon, France location following the completion of our in-house manufacturing facility in our Brisbane, California headquarters this past quarter.

Leasing of the sixth patient and updated five brief phase one two data presentations throughout 2022.

Including at a medical meeting.

Dosing of the first two patients in the steadfast phase one two study by the middle of 2022 and.

And completion of our in house cell therapy manufacturing facility in <unk>, France location. Following the completion of our in house manufacturing facility in Brisbane, California headquarters this past quarter.

So we'll now turn it over to the operator to open the line for questions.

Thank you speakers participants we will now begin the question and answer session. As a reminder to ask a question over the phone you May press the star key followed by the number one.

To withdraw your request you May press the pound key again Thats star one to ask a question.

Or the <unk> to withdraw your request.

Okay.

Speakers first question is from the line of Aspen Mori of Bank of America. Your line is now open.

Aspen Morey: Hey guys, thanks for the question. So on Fabry, I think you previously hadn't expected to share some enzyme replacement therapy withdrawal data in this year-end release. It's good to see that the time frame seems to maybe have been faster than expected. But with that in mind, I guess, are there any patterns you're seeing in the time frame it takes from getting from the dose of SG920 to removal of that therapy? And it also appears that maybe patient 4 kind of got to that milestone a little quicker than patient 1, who had a longer follow-up. Just wanted to see if there's anything you're seeing there to explain that. Thank you.

Hey, guys. Thanks for the question.

So on February I think you previously hadn't expected to share some of the enzyme replacement therapy withdrawal data.

And this yearend Luis.

It's good to see that the timeframe, maybe faster than expected, but with that in mind I guess is there any patterns you're seeing in the timeframe. It takes from from getting from a from the dose of SG&A in 'twenty two to removal of that therapy.

And it also appears that maybe the patient for kind of got to that milestone a lot quicker than patient, one who had a longer follow up.

Just wanted to see if theres anything youre seeing there and explain that thank you.

Alexander D. Macrae: So, thank you for your question. I think what I'm hearing you're asking about is about ERT withdrawal. So, we thought it was important to see, to truly understand the effect duration, and we've been very pleased that over the course of a year in the longest-treated patients, there's been a consistency of effect, and we then have discussions with the investigators and at the appropriate point for them and for their patient they will withdraw treatment and the first patient was only withdrawn very recently and the second one is planned to be withdrawn this year and so we will share that data at an appropriate time.

So thank you for your question I think what I'm hearing you are asking about <unk> withdrawal.

So we thought it was important to see to truly understand the.

The effective duration and we've been very pleased that over the course of the year and the longest patients theres been a consistency of effect.

We then have discussions with the investigators and at the appropriate point for them and for their patients. They will withdraw treatment in the first patient was recently withdrawn.

Very recently in the second one this plan to be withdrawn this year and so we will share that data in appropriate time.

Aspen Morey: Okay, thanks. And then I have one more on the... on Fabry. Are there any trends you're seeing among patients 1 and 4 that signal maybe what's driving a better alpha-GalA response than you're seeing with patients 2 and 3? I think 2 and 3 might have had lower baseline Gb3, but if there's anything you can point to,

Okay.

Okay. Thanks, and then I had one more on the.

On February <unk>.

Are there any trends you're seeing among patients one four that signal, maybe whats driving better Alpha Gal, a response that youre seeing with patients two and three.

I think two and three lower baseline <unk> III, but.

Alexander D. Macrae: Anything you can point to that would help out there? Well, there are only four patients, so it's very difficult to say anything specific. It is notable, though, that patients 1 and 4 are on ERT, and patients 2 and 3 are not. It may be that there is some additional effect from the ERT that is leading to that effect, but I think that is only speculation, and we need to doze more patients to understand it.

So if theres anything you can you can point to that would help out there.

Well.

So there is only four patients so it's very difficult to say anything specific.

Notable go that patients want and for our own ERP and patients two and three year note.

<unk>.

It may be that there is some.

Additional effect from the ERP that is leading to that effect, but I think that is only speculation and we need to dose more patients to understand it.

Alexander D. Macrae: Okay. Thanks, Andy. I appreciate it.

Sure.

Okay. Thanks, Andy appreciate it.

Operator: The next question is from Yanan Zhu of Wells Fargo. Your line is now open. Hi, thanks for taking my questions.

Yes.

Next question is from Jan <unk> of Wells Fargo. Your line is now open.

Hi, Thanks for taking my questions I have.

Yanan Zhu: and maybe also additional questions on other updates. Fabrice, could you, Sandy, comment on the dose response here?

Question on Fabry.

Maybe also additional question on that other updates.

<unk> could you sandy comment on the dose response here.

Yanan Zhu: And also, I think for patient two, there was an increase.

And also I think for patients too.

There was a.

Yanan Zhu: There was an increase in enzyme levels above normal, but the substrate levels increased to be flat. Could you shed some light on that finding? So it's a good question, and I think this has been consistently seen across all of the research into Fabry disease. If the substrate levels are low, they don't change during the treatment period. Bettina, do you have thoughts on this, on the dose response that we've seen? Thank you, Sandy.

Increasing enzyme levels.

Bob normal, but the substrate levels seem to be flat.

So could you.

Shed some light on that finding.

So.

It's a good question and I think this has been something that's been consistently seen across all of the.

Research into Fabry disease.

Substrate levels are low.

Change in.

And the treatment period.

Bettina.

Just thoughts from this on the dose response that we've seen thank you sandy so.

Alexander D. Macrae: Thank you, Sandy. So, as Sandy mentioned, we have now dosed two patients in Cohort 1 and two patients in Cohort 2. This is still a small sample size, and that needs to be emphasized at this point in time.

Sandy mentioned, we have now dosed two patients in cohort one and two patients in cohort two.

Still a small sample size this needs to be emphasized at this point in time.

Bettina M. Cockroft: But regarding the levels of Lyso-GB3, for sure, in three of the four patients, those Lyso-GB3 levels started off low. And as Sandy mentioned, across programs, it has been seen that these remain stable if they are low to start with. If you look at patient 3, this patient's Lyso-GB3 levels start off high, and the levels of Lyso-GB3 were reduced by about 40% within 10 weeks after dosing, and this reduction was maintained through 32 weeks.

Regarding the levels of life GB three for sure and three of the four patients.

So GBP three level started off slow.

We mentioned.

<unk> program.

It has been seen that these remain stable if they are Scott. If you look at page three this patient LIFO TB three levels.

Hi.

And the level of Liza three were reduced by about 40%.

Within 10 weeks after dosing.

Production was maintained through 32 weeks.

Bettina M. Cockroft: So at this point in time, with such a small sample size, it is really difficult to talk about these relationships. I would say that throughout 2022, we anticipate sharing more data, and that data will also be shared at a medical meeting. So there will be more granularity and data to come.

So at this point in time with such a small sample size. It is really difficult to talk about those relationship I would say that throughout 2022, we anticipate to share more data.

And that data will also be set at a medical meeting so there will be more granularity.

And data to come.

But.

Bettina M. Cockroft: All I want you to take away is how excited we are by this because all four patients are above the normal physiological level, and all four patients have shown consistency of response in the time that they've been observed. Three of the four patients are already reporting patient effects that are very encouraging about the effect of the drug, and we are already into the next larger cohort. And, as Bettina says, we'll talk about this next year.

All want you to takeaway is how excited we are by this because all four patients are above the normal physiological level.

All four patients have shown consistency of response and the time that they have been observed.

Three of the four patients are already reporting.

Patient effects are very encouraging about the effect of the drug and we are already into next higher cohort and it's Bettina <unk>, who will talk about this next year.

Great Thanks, and on the clinical hold.

For the <unk>.

Alexander D. Macrae: The Hemophilia A Collaborated Hemophilia

Hemophilia a collaborated hemophilia a program I was wondering how high is the human.

Yanan Zhu: I was wondering how high...

Yanan Zhu: With factor VIII, I thought we had seen like 200% from other studies, so could you shed some light on the rationale?

After eight level I thought we had seen it like two.

200% from other studies so could you.

Yanan Zhu: for that clinical hold. And lastly, a question on BIV.

Shed some light on the rationale for the for that clinical hold.

Yanan Zhu: And lastly, a question on BIVV003, a very quick one, that is, at ASH, would we see VOC data for the treated patients? So I'm going to pass the question on hemophilia to Rob. Rob, can you talk to them?

Lastly, a question on <unk> 003, very quick ones that is at ash with we see VLC data.

For the treated patients. Thank you.

So I am going to pass the question on hemophilia two raw growth can you talk to US yes, we have seen <unk>.

Rob Schott: Yeah, we have seen elevations of...

Rob Schott: Elevations of factor VIII greater than 150% in some patients. This is an ongoing phase 3 trial, so we're not getting very specific with the data around this.

Elevations of factor eight greater than 150% in some patients.

This is an ongoing phase III trials, so we're not getting very specific with the data around that.

Rob Schott: Venous thromboembolic events associated with these elevated levels and the decision to voluntarily...

There were no.

Dennis <unk>.

<unk> embolic events associated with these elevated levels and the decision to voluntarily pause the trial was out of an abundance of caution and as anticipated the FDA.

Rob Schott: voluntarily paused the trial out of an abundance of caution. And, as anticipated, the FDA follows.

Rob Schott: followed through with a clinical hold that was, we were notified of that late yesterday. It's our plan with Pfizer to submit a protocol amendment and have a discussion with the agency and resume the trial when it is appropriate to do so, and regarding sickle cell disease.

Follow through with the clinical hold that was.

We were notified of that late yesterday.

It's our plan to win.

With Pfizer to submit a protocol amendment and have the discussion with the agency and resume the trial.

When it is appropriate to do so.

And regarding sickle cell disease.

Rob Schott: We have, and we'll show the full data set at ASH in December. Great, thanks for the updates. Thank you. Next question is from Luca Issi of RBC Capital. Well, great. Thanks so much for taking my question. Congratulations on all the progress. Maybe on Fabry disease, an exciting early proof of concept, I wonder if you can comment on how you're thinking about the phase 3 study design for hemophilia

We will show the full data set.

In December.

Great. Thanks for the update.

Thank you.

Next question is from Luca <unk> of RBC capital. Your line is now open.

Great. Thanks, so much for taking my question Congrats on all the progress maybe on Fabry disease exciting early proof of concept I Wonder if you can comment on how you're thinking about the phase III study design.

On hemophilia.

Maybe if you can provide any additional color on the political amendment that you were thinking about to minimize the risk going forward and then maybe on beta Thal can you just expand a little bit more on the rationale behind the decision to terminate the program. Thanks, so much.

Operator: [inaudible]

Luca Issi: So it's so exciting to be talking about Phase 3 design because we are very pleased with the results. But we need to see the results of the third cohort to really be able to understand which dose we're taking forward and how we design the study. But I can reassure you that planning and the full energy behind Phase 3 have already started on these programs. Let me then pass the haemophilia question to Rob and the beta thalassemia one to Maureen.

Goodness.

So it's so exciting to be talking about phase III design.

Because we are very pleased with the.

With the results, but we need to see the results of the.

Third cohort to really be able to understand which dose we're taking forward.

How do we design the study, but I can reassure you that planning and.

Energy behind the Phase III has already started on these programs. Let me then pass the.

Hemophilia question to Rob and the beta Thalassemia one tomorrow.

Alexander D. Macrae: Yes. With. With.

Rob Schott: With regard to the protocol amendment, we're not disclosing any of the specifics.

Yes.

With regard to the protocol amendment were not disclosing any of the specifics of the protocol Amendment at this time.

Rob Schott: I'm not proposing any of the specifics of the protocol amendment at this time.

But the protocol amendment is being considered and will be.

Rob Schott: But the protocol amendment is being considered and will be submitted.

Submitted promptly and in discussion with the agency in response to the clinical and the current plan is to find the best way to valued management of any patient that has a higher level, yes, there'll be monitoring and management of the patients with with levels of factor eight that are greater than 150%.

Rob Schott: And the current plan is to find the best way to guide the management of any patient that has a higher level.

Rob Schott: Yes, so it would be monitoring and management of patients with levels of factor VIII that are greater than 100%. But we feel it is important

But we feel it important to restate every time that conversation comes up that no patient has come to harm there've been no adverse events related to this and this is an abundance of caution on that and I think are correct abundance of caution because this is a gene therapy that we need to take very seriously and do the best for the patients.

Rob Schott: But we feel it is important to restate every time that that conversation comes up that no patient has come to harm. There have been no adverse events related to this, and this is an abundance of caution, and I think a correct abundance of caution because this is a gene therapy that we need to take very seriously and do the best for the patient.

Rob Schott: Mark. Yeah. So in terms of the BetaFowl decision, it was really a.

Mark.

Terms of the beta Thal decision. It was really a business decision that we took alongside our partners at Sanofi.

Mark McClung: business decision that we took alongside our partners at Sanofi, just due to the timing and relative to where the competitive set lies in terms of their development. We felt that it was important to really focus our effort and our resources solely on sickle cell disease and Joyce Glover.

Just due to the timing and relative to where the competitive set in terms of their development.

We felt that it is important to really focus our effort and our resources solely on sickle cell disease.

Mark McClung: and our resources solely on sickle cell disease and drive forward together. Got it. Thanks so much, guys. The next question is from Maury Raycroft of Jefferies. Your line is now open.

And drive forward together.

Got it thanks, so much guys.

Next question is from Maury Raycroft of Jefferies. Your line is now open.

Operator: Hi, everyone. Good morning and congrats on the update today. For Fabry, just wondering if you can talk more about the Alpha-Gal data being 2 to 15 fold higher than normal. It seems higher than competitor data at month 12, which showed about 5 to 6 fold higher. I guess what's the best way to contextualize your data versus competitors?

Hi, everyone. Good morning, and congrats on the update today.

For Fabry, just wondering if you can talk more about the alpha Gal data being 2% to 15 fold higher than normal seems higher than competitor data. Among 12 that showed about five to six fold higher.

So that's the way to contextualize your data versus competitors and how could this translate to kidney substrate reduction.

Thank you Maury Bettina do.

Do you want to talk recovery sure. Thank you Sandy so in terms of the <unk>.

Maurice Thomas Raycroft: And how could this translate to kidney substrate reduction?

Alpha Gal data, we're obviously very excited to see.

Maurice Thomas Raycroft: Thank you, Maury. Bettina, do you want to talk to the panel?

Super Physiologic Alpha Gal expression that we're seeing with all four patients.

Bettina M. Cockroft: Sure. Thank you, Sandy. So in terms of the alpha-gal data, we're obviously very excited to see the supraphysiologic alpha-gal expression that we are seeing in all four patients. I think at this point it is too early to compare and probably not the right place to do comparisons across proteins.

Thank at this point it is early to compare and probably not the right place to do comparisons across programs.

Look forward to sharing more granularity on this data at <unk>.

An upcoming meeting in 2022.

So that also goes through any additional data related to kidney sub.

Bettina M. Cockroft: We look forward to sharing more granularity.

Substrate.

Bettina M. Cockroft: Thank you very much.

You can imagine, though that having seen efficacy at the two initial cohorts and moving into third tier cohort.

A gift.

It gives us enormous.

Energy that this is going to be a medicine.

Be useful for patients with fabry it really is.

Compelling data earlier earliest.

The compelling data.

Bettina M. Cockroft: And I would add that, a priori, we had targeted superphysiologic expressions of alpha-gal A and plasma to drive clearance from tissues. So this is a desired...

And I would add that our priority we had targeted super physiologic expression of Alpha Gal, a and plasma to drive clearance from tissue. So this is a desired effect what were seeing.

Bettina M. Cockroft: desired effect what we're seeing.

Maurice Thomas Raycroft: Got it. It's all helpful. And maybe just one follow-up, if you can compare and contrast the Bavary observations and gene expression and dose with your hemophilia gene therapy program, maybe if you can talk more about that.

Got it that's all helpful and maybe just one follow up if you can compare.

Compare and contrast, the fabry observations.

And gene expression and dose with your hemophilia gene therapy program.

If you can talk more about that.

Alexander D. Macrae: That's a good question. We are fortunate that we have used 80v6 now in several programs, and we understand its safety. And across all of the programs, we've had very few adverse events. In addition, if you look at the point at which there's an inflection of efficacy, it's about 1 to 3 E13 in haemophilia, and it's even earlier than that in the Fabry disease program. Other than that, we're very pleased with the safety and efficacy we've now seen in our two-gene therapy program.

That's a good question I mean, we are fortunate.

<unk> six <unk> and several programs and we understand the safety of it across all of the programs.

We've had very few adverse events.

In addition.

<unk> if you look at it.

The point at which there is an inflection of efficacy its about the one to 313 in hemophilia and it's even earlier than that in the fabry disease program.

Other than that.

We're very pleased with the safety and efficacy we've now seen in our two gene therapy programs.

Maurice Thomas Raycroft: Got it. Okay, thanks for taking my questions.

Got it okay. Thanks for taking my questions and congrats again.

Operator: The next question is from Nicole Germino, Trooper Securities. Your line is now open.

Next question is from Nicole <unk>.

Securities. Your line is now open.

Nicole Germino: Good morning. Thanks for taking my questions and congrats on the progress.

Good morning, Thanks for taking my questions and congrats on the progress.

Nicole Germino: I dialed in a little bit late, and I might have missed some of the opening remarks, so I apologize if...

Hi, dialed in a little bit late and I might have.

So I apologize if my questions are there any of that.

Nicole Germino: I apologize if my questions are already addressed, but for Fabre, can you talk about how the primary symptoms improved over time from baseline and any color on cardiac function? And for Hime, how long from infusion did these excursions happen?

February can you talk about how the primary symptoms have improved over time from baseline on any color on cardiac function.

For Q&A.

Long from infusion these excursions happen and how long of a floor.

Nicole Germino: How often are factor VIII levels being assessed going forward to monitor it?

Going forward to monitor.

So your likeness.

It's a little unclear. So let me see the repack suits you see the I understood. Your question, it's about the patients symptoms in fabry and it's about how we manage the patients in hemophilia a is that correct.

Nicole Germino: And for hemophilia, how long from the infusion did the excursions happen?

Hi.

So how long you plan for hemophilia, how long from gene fusion that expansion happen.

Bettina M. Cockroft: So, Bettina, can you say what we know about the patient-reported symptoms of Fabry?

So bettina can you say, what we know about the patient reported.

<unk> in Fabry, please yes of course.

Bettina M. Cockroft: Of course. So, as a reminder, again, I'd like to emphasize this is early data that we're sharing, early, preliminary data. The patients in courses one and two, three of the four patients, had anhydrosis reported at baseline, and some of these patients, these three patients, have reported improvement in sweating or perspiration, which is a favorable outcome for patients, in the time period over the course of the study that we have seen so far. One of the patients also had seen stabilization of cardiac structure on serial assessment of imaging. So these are preliminary reports that we are gathering. And as I mentioned,

As a reminder, again I'd like to emphasize this is early data that we're sharing early preliminary data.

The patients in cohort.

Three of the full pace in pad on hydro.

Reported base.

Baseline.

And some of these patients three these three patients have reported improvement in sweating.

Exploration.

Which is.

Net favorable outcome for patients.

In the time period.

Over the course of the study that we have seen so far one of the patients also had.

<unk>.

Seen stabilization of cardiac structural material assessments on imaging.

These are preliminary report that we are gathering.

Bettina M. Cockroft: And as I said before, we will be sharing more information over the course of next year of some of these events.

As I mentioned before we will be sharing more information over the course of next year of some of the detail.

Bettina M. Cockroft: of some of these details.

Bettina M. Cockroft: I'd like to add that if you look at the totality of the data, including the patient observations that were relayed to the investigators, the alpha-gal expression, the adverse events, all of the data are all pointing in the same direction.

I would like to add that if you look at the totality of the data including the.

Patient observations that were related to the investigators the alpha Gal expression the adverse events that all of the data are all pointing in a favorable direction. So we would.

Bettina M. Cockroft: in a favorable direction. So we

Bettina M. Cockroft: We'd like you to look at the data in its totality, not just each individual record.

We'd like you to look at the data in its totality not just each individual component.

Bettina M. Cockroft: and now just each individual component.

Okay, Great and then for he may how long from the infusion.

Nicole Germino: Great, great. And then, for Hime, how long will it take from the infusion?

But the experience happen.

This is a an ongoing phase III trials, so we arent disclosing.

Nicole Germino: From the infusion, did the excursions happen?

The specifics around the data.

We want to keep that.

Phase III trial.

Because it's a potential registration trial.

Rob Schott: This is an ongoing phase three trial, so we aren't disclosing anything.

Great. Thanks.

Next question is from Gena Wang of Barclays. Your line is now open.

Rob Schott: We want to keep that Phase 3 trial protected because it's a potential registration trial.

Thank you Tom for Gena, Thanks for taking the question.

For the Fabry.

Operator: The next question is from Gina Wang of Barclays.

Just one question with the dosing and the Alpha Gal enzyme level.

Do you plan to dose higher.

Huidong Wang: This is Tom Porcino. Thanks for taking the question. Just one question about the dosing and the alpha-gal enzyme level: do you plan to...

Ending on the data read out.

And what is the ultimate goal of that.

Level in the sovereign is currently <unk>.

It seems logical level enough.

Huidong Wang: [inaudible]

Yes.

Solid.

Huidong Wang: And how about

And how about the alpha Gal enzyme level change after the patient who withdraw it.

Huidong Wang: The Alpha-Gal enzyme level changes after the patient who withdraws.

Huidong Wang: ,...

Alexander D. Macrae: Great questions for the HMOA. Well, can we do Fabriy first? So we make sure we cover all your questions.

The ERP.

Great question, a lot sort of homeaway.

Well can we do February one.

We make sure we cover all your questions.

We've never set.

It must be this for Alpha go because this is the first time that people really don't gene therapy in fabry disease.

So there isn't definitive level, we've always thought it had to be better than normal physiological levels and we're pleased that the patients both <unk> and <unk> are at that level.

And note what we're doing is withdrawing the ERP and see where.

We are at the levels provided by the gene therapy in the liver.

Let alone and until we do that to experiment, we really didn't understand this fully.

Alexander D. Macrae: And until we do that experiment, we really won't understand this fully. We are also dosing at 3E13, which is three times higher than the current dose. And once we see that data in its totality, we will be able to decide which dose to take forward into phase three. But we felt the first two cohorts were so compelling, as Rob says, with the alpha-gal, with patient safety, with patient-related outcomes that came spontaneously from patients talking to the investigator about things that are important to them, like their ability to exercise because they can now sweat, that we felt that this data was exciting and compelling and wanted to share it with the broader community.

We're also dosing.

<unk>, which is three times higher than the current dose and once we see that data in its totality, we will be able to decide which dose to take forward into phase III.

But we felt the first two cohorts were so compelling as Rob says with the Alpha Gal with patient safety with the patient related outcomes that came spontaneously from patients talking to investigators.

Things that had been that are important to them like the ability to exercise crissy can no sweat that we felt that this data was exciting and compelling and wanted to share it with the broader community.

Huidong Wang: Okay, great. That's very helpful. And maybe just a quick follow-up on the fact that you comment that you will share additional data, including prenatal function data, at the 2022, you know, medical meeting, and will that include, like,

Okay great.

Helpful and maybe just a quick follow up on the cap rate that you comment that you.

You will share additional data, including the kidney function data.

2022.

Co meeting and that'd be include light.

Huidong Wang: GB3 kidney inclusion, or it will be EGFR.

<unk> kidney in Cushing or it will be egfr.

Huidong Wang: like the filtration function measurement, can you set it?

The filtration function measurement.

Huidong Wang: you set help us to set an expectation for that. It's unlikely that we'll be sharing renal biopsy data in 2022. The patient would undergo an initial biopsy and then some months later, a second one. So that data is unlikely to be available in 2022.

<unk>.

Help us to set an expectation for that.

It's unlikely that we'll be sharing.

<unk> biopsy data in 'twenty two.

The patient will undergo an initial biopsy and then some months later, our second one so that data.

Is unlikely to be available in 2022.

Alexander D. Macrae: Thanks for that. And for the HEMO-A, we know that there will be a protocol amendment. Other than that, do you expect any...

Okay. Okay, thanks for that and for the hemo, a so we know that it will be there will be political amendment.

Do you expect any additional steps that are required in order to remove the clinical hold.

Alexander D. Macrae: Do you expect any additional steps that are required in order to remove the clinical host, or will the implementation of the oral anticoagulant be the only one that would be required? I have enormous confidence in our colleagues at Pfizer. They're putting together an amendment that puts patients first and makes sure that the patient always remains safe. And then they will discuss that and present it to the agency, and hopefully, we'll be able to move forward with this trial.

The implementation of the Aro anti coagulate, we'll be the only only one.

It required.

I have enormous confidence in our colleagues at Pfizer, they're putting together an amendment.

<unk> patients first.

<unk>.

Make sure that the patients are which remains safe and then they will discuss that and presented to the agency and hopefully we'll be able to move forward with this trial.

Alexander D. Macrae: As Pfizer has said, over 50% of the patients have been enrolled now, and they've had a pre-study study to collect the patients to have them ready to go into the trial. So we think this will move forward and are sure that Pfizer is doing the right thing. Okay, thanks for that. The next question is from Rita Baral of Cohen. Your line is now open.

Pfizer said over 50% of the patients have been enrolled known.

They had.

Sure.

Pre study study to collect the patients to have them ready to go into the trials. So we think this will move forward.

And our our sure that Pfizer is doing the right thing.

Okay. Thanks for that.

Next question is from renewable or all of Cowen. Your line is now open.

Operator: Hi guys, thanks for taking the question. As part of this Phase 1-2, what other clinical, I guess, clinical quality of life or patient-reported symptomatology, are you capturing? Sandy, you mentioned improvement in sweating; are there other things that are being proactively asked clinically symptomatology-wise? And then can you talk at all about sort of the curve of expression that you're seeing, like for patient one, that 15-fold increase at week 52, can you confirm that that's like the top expression that you've seen for patient four, that you're sort of continuing on your way up, and anything you can say about the curve?

Hi, guys. Thanks for taking the question.

As part of this phase two what other clinical.

I guess Ah clinical quality of life for a patient reported symptomatology are you capturing Sandy you mentioned.

Improvement in wording are there other things that are being proactively.

Clinical symptomatology wise.

And then can you talk at all about sort of the curve.

His expression that you're seeing like for patient one.

That 15 fold at week 52 can you confirm that that's the.

Top expression that you've seen.

Patient for that Youre sort of continuing on your way out and anything you can say about the firm.

Reeder Baral: Okay, so we measure a whole slew of things, including formal patient-related outcomes. But we want to be very clear, this was spontaneous, patients spontaneously talking to their investigator to tell them of the changes that they knew, and the investigator felt compelled to tell us because it was important. We will, we will.

Yes.

Okay. So so we measure a whole slew of things, including formal patient related outcomes, we want to be very clear this with spontaneous patients continuously talking to the investigator.

Tell them all of the changes that based new and then the investigator felt compelled to tell us because it was important.

We will we will.

We will measure.

This going on in the phase III.

Because.

It's not just about the energy imports important is what's important to the patient and it's things like the neuropathy like pain that they have it submitted the sweating its about the quality of their life and their energy and so we want to capture all these things.

Alexander D. Macrae: The second question I think that you're asking is about duration. That's very pleasing to us because this is a solution we want for as long as possible for those patients. And in all of the patients, once it gets to its plateau level, it has remained at that level throughout the duration of the study. And we will continue to follow these patients and report, hopefully, the continued duration of effect.

The second question I think you are asking so both duration, that's very pleasing to us because this is a solution we want for as long as possible for those patients and all of the patients.

Once it gets to its plateau level has remained at that level throughout the duration of the study and we.

We will continue to follow these patients and report.

Hopefully the continued duration of effect.

Alexander D. Macrae: Got it. And just given the change in the, I guess, the regulatory landscape in FABRI over the last 12 months or so, are there any plans to potentially add kidney biopsy to this study? Or are you, is that going to be reserved for the next study? Kidney biopsy, you mean?

Got it.

Just given the change in the.

The regulatory landscape in fabry over the last.

12 months or so.

Are there any plans to potentially add.

Study or are you okay.

Is that going to be with you.

Any kidney biopsy.

Reeder Baral: We have plans for biopsy in this study, it's just that the results will not be available within the 2022 phase. We've always said that we would not do the biopsy in the initial patients until we saw that the medicine was effective. And now that we have seen that the medicine is effective, biopsies will be part of the routine of the study.

We have we have plans for biopsy and this study is just that.

<unk> will not be available within the 2022 phase.

We've always said that we would not do that biopsy and the initial patient until we sold the medicine was effective and now we see the medicine is effective biopsies will be part of the routine of the study.

Alexander D. Macrae: Okay, so maybe not the biopsy from these patients, but maybe the fifth and sixth patient with the highest dose? Is that the plan?

Oh got it okay. So maybe not biopsy from these patients that may be that.

Patients with highest dose is that the plan so.

Reeder Baral: So the first four patients did not have renal biopsy, and future patients will have it as part of the study protocol. Got it. Thanks for taking the question.

So the first four patients did not renal biopsy.

Future patients will okay as part of the study protocol.

Got it thanks for taking the questions.

Reeder Baral: Got it. Thanks for taking the questions.

Our pleasure.

Operator: The next question is from Ben Burnett of Steeple. Your line is now open.

Next question is from Ben Burnett of Stifel. Your line is now open.

Benjamin Jay Burnett: Hey, thank you very much. I will echo my congratulations on the Fabry disease data. I did want to ask a couple questions around this. The first one, I would also agree with some of the others on the call. It seems like the enzyme activity is quite good, at least relative to competitors. But I was just curious that the impact on Lyso-GB3 just wasn't more profound, specifically on patients one, two, and four.

Alright, Thank you very much.

My congratulations on the Fabry disease data.

I did want to ask a couple questions around this the first one.

I would also agree with some of the others on the call. It seems like the enzyme activity is quite good.

Relative to competitors, but I guess, just curious at the impact on <unk> three just wasn't more profound specific on patients one two and four I.

Benjamin Jay Burnett: I guess, how what is your interpretation of those data and how representative is it...

How what is your interpretation of those of those data and how representative is.

Alexander D. Macrae: lyso-gb3 in the plasma to what's happening inside cells.

License <unk> III and the plasma.

What's happening inside of cells.

Alexander D. Macrae: Question, and until we biopsy, we won't have that, that direct correlation. I'll say again, in all of the Fabry trials from each of our competitors and us, patients who have low LISO-GB3 don't go lower. If it's already very low, it's hard to make it go lower.

Question on until we biopsy, who we are.

We'll have that.

The direct correlation.

Sir Ken and all of the all of the public trials from each of our competitors and those patients who have blue light with GPS III don't go lower.

If it's already very low it's hard to make it go lower and thats across all of the trials and even in the trials have done GPS III.

Alexander D. Macrae: And that's across all of the trials. And yet, even in the trials that have done GB3, even in the Abrobio trial, for example, who showed a reduction in GB3 in the kidney, they also showed that effect, that it had to be a high LISO-GB3 to show a reduction in the plasma. It's a very different system that we're producing here, and we think this is what patients want. They want a one-time injection that is safe, that is effective at producing alpha-gal, and that is effective at producing it over a long period of time, and that they notice a benefit, and we're already having indications that that's what's seen.

Even in the upper bio trunk for example, who showed a reduction in GBP and the kidney the.

Also showed that effect that it had to be a high license <unk> III to show a reduction in the plasma.

It's a very different system that we're producing here and we think this is what patients want they want a onetime injection that is safe that is effective at producing alpha Gal and is effective at producing a over a long period of time.

The notice of benefit and we're already having indications.

We've seen no we need to go to the next higher dose and hopefully show even more benefit.

And then pull that data together and decide on the full design of this study for phase III and get this medicine to patients as soon as possible, but we are very pleased with the safety the efficacy the consistency and the patient benefit we've seen so far.

Alexander D. Macrae: Okay. And if I could just ask one sort of clarifying question: on patient four, alpha-gal activity at week 14, you show an assessment that looks, I think, really good, but was this assessment made after they were weaned off of enzyme replacement therapy, or was it prior to that?

Understood. Okay. That's helpful and if I could just ask one clarifying question on patient four.

Alpha Gal activity at week 14.

You show an assessment that looks I think really good but was this assessment made.

After they are weaned off of enzyme replacement therapy or was that prior to that.

Benjamin Jay Burnett: Bettina, can you just clarify, please? Absolutely not.

Bettina can you just clarify absolutely so patient number four.

Bettina M. Cockroft: Absolutely.

Bettina M. Cockroft: has only been withdrawn from ERT therapy very recently, and after the cutoff data for what you're seeing on these slides that we have posted on our corporate website. So the data you're seeing is with the patient still on ERT. And just to clarify, all the data points are at a trough ERT level, so dosing was prior to the ERT infusion. So the ERT withdrawal will have been after this data. OK.

Being withdrawn from the T therapy very recently.

After the cutoff data for what you'll.

You'll see on the slides that we have.

Posted on our corporate website. So the data you're seeing is with the patients still on <unk> and just to clarify all the data points.

Trough level.

Level.

Those England prior to the.

Infusion.

No.

The ERP withdrawal will have been after this data cut.

Okay.

Bettina M. Cockroft: Okay, okay. It's part of the reason that this therapy is, I think, offers a better solution than ERT is that ERT has a very rapid C-max, and then it declines quickly. But we wanted to be particularly careful, and therefore, we measured the trough level usually about day 14 after the ERT at the very last point before the patient had their next dose of ERT to make sure there was no residual enzyme in the plasma. And that's something I think we all, in all the different studies from all the different companies, need to be careful about, making sure that the trough is the correct trough.

As part of the reason that this therapy is is I think offers a better solution than ERP is ERP has a very rapid.

C. Max and then it declines quickly, but we wanted to be particularly careful and therefore, we measure of the trough cycle, usually about <unk> 14 after the ERP.

Very last point before the patient at the next dose of <unk> to make sure there was no residual enzyme in the plasma.

And Thats something I think we all in all the different studies from all the different companies need to be careful about is making sure that the trough is the trough.

Alexander D. Macrae: Understand? That makes sense. Okay. All right. Thank you very much for the color.

Understood that makes sense, okay, alright, thank you very much for the color.

Thank you.

Operator: Ladies and gentlemen, we have time for one more question from Andreas Argyrides of Wedbush Securities.

Speakers, we have time for one more question from Andreas <unk> of Wedbush Securities. Your line is now open.

Operator: Your line is now open.

Andreas Argyrides: Good morning, and thank you for taking our questions. Let me also reiterate our congratulations on this.

Good morning, and thank you for taking our questions.

We also reiterate our congrats on this early.

Andreas Argyrides: Congratulations on this, you know, really encouraging data. Yeah, so for Fabry, just a quick one on the pre-existing antibodies and your thoughts around any potential impact that may have. And then on hemophilia A, does the protocol amendment restart the time for the ABR data? Thank you.

<unk> data you have.

So for February just a quick one on the pre existing antibodies.

<unk> around any potential impact.

Impact that May have and then on the hemophilia a.

Protocol amendments restarts.

Time.

For the the ABR data.

Thank you.

Alexander D. Macrae: So let me answer the second one, then pass the antibodies to Bettina. Why this had to be treated seriously was that these were patients undergoing gene therapy, so when they get the medicine, it stays in their body, even if the trial is paused. And so we and Pfizer will continue to collect data from the patients, even though recruitment into it has been paused. There's still information about prolongation of effect and safety of the medicine being collected by Pfizer. So it's unusual compared to a paused trial where the patient stops taking the medicine. But the medicine is still there and continuing to have benefits for the patient we hold.

So let me answer.

The second one and then pass the antibodies to Bettina.

While this had to be treated seriously will sees a patient in gene therapy. So when they get the medicine. It stays in the body, even if the trial is paused and so we and Pfizer will continue to collect data from the patients even though.

The recruitment into is poised theres still.

Information about prolongation of effect and safety of the medicine being collected by Pfizer.

Unusual compared to.

<unk> trial for the patient stops taking the medicine. The medicine is still there and continuing to benefit for the patient we hope.

The Tina the antibodies for the antibody so.

Bettina M. Cockroft: Yes, for the antibodies... I think what is important to emphasize is this is early data on four patients, and it is early to make inferences as to whether antibodies and to what degree they are having an effect on these patients. We need to bear in mind that two of these patients are on ERT, and two are not. There is a lot of variability in the data at this point in time, so we look forward to seeing more data coming out from our next cohort, cohort three, and being able to assess that impact in a better manner.

I think what is important to emphasize is the early data for patients.

And it is early to make inferences as to whether antibodies.

And to what degree antibodies are having an effect on these patients.

You need to bear in mind that two of these patients are on <unk>, two or not there is a lot of variability in the data at this point in time. So we look forward to seeing more data coming out from our next cohort cohort III and being able to assess that impact in a better manner and we will be.

Bettina M. Cockroft: And we, but we haven't seen anything, or any correlation up to now.

Haven't seen anything any correlation alternate.

Bettina M. Cockroft: At this point in time, it would be difficult to say.

At this point in time that would be difficult to say.

Andreas Argyrides: Sure, okay, understandable. Thank you for taking our questions, and again, congrats on encouraging data.

Sure. Okay understandable, thank you for taking our questions.

And then congrats on the encouraging data.

Operator: Thank you, participants.

Thank you participants I'll now turn the call back over to Aaron <unk> for closing remarks.

Aaron Feingold: I'll now turn the call back over to Aaron Feingold for his closing remarks.

Aaron Feingold: Thank you for your closing remarks.

Thank you once again for joining us today and for your question and we look forward to keep you up keeping you updated on our future development.

Operator: Thank you once again for joining us today and for your questions. We look forward to keeping you updated on our future developments.

Operator: That concludes today's conference call. Thank you all for joining us. You may now disconnect.

That concludes today's conference call. Thank you all for joining you may now disconnect.

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