Sangamo Therapeutics Inc (SGMO) 2016 Q4 法說會逐字稿

+++(Please stand by for the realtime transcript.)(The Sangamo Therapeutics conference call will begin shortly.)

Operator: Ladies and gentlemen, please stand by.Your conference all will begin momentarily.Once again, ladies and gentlemen, please stay on the line.Good day and welcome to the Sangamo Therapeutics conference call.This call is being recorded.I will now pass you over to this coordinator, McDavid Stilwell, investor relations.

Good morning.And thank you for joining, Sangamo's management team on our conference call to discuss the fourth quarter and full year 2016 financial results.As we begin, I would like to point out that we'll be referring to a slide presentation this morning.You will find a link for the slide presentation on the link -- or in the events and presentations page of the investors and media section of our website at www.Sangamo.com.I would also like to remind everyone that the projections and forward-looking statements that we discuss during this conference call are based upon the information that we currently have available.This information will likely change over time.By discussing our current perception of the market and Sangamo we are not undertaking an obligation to provide updates in the future.Actual results may differ substantially from what we discuss today and no one should assume that the comments from today are still valid.We alert you to be aware of risks detailed in documents that the company files with the Securities and Exchange Commission, specifically our quarterly reports on 10-Q and the annual report on 10-K.These documents include important factors could cause the actual results to differ materially from those contained in the projections or forward-looking statements.With us are several members are several members of the Sangamo, including Sandy Mac ray, Chief Executive Officer, and Ward Wolff, our retiring Chief Financial Officer, Ed canner, chief medical officer, Michael Holmes vice president of research and Curt Herberts, chief business officer.Also with us today is Kathy Yi who joined Sangamo's new CFO following Ward's retirement.Sandy will highlight recent changes and introduce the company's areas of focus for 2017.Ed Connor will discuss our clinical development programs.Michael Holmes will provide details of technology and research programs.Ward will then briefly review, fourth quarter and full year for 2016 and the financial guidance for 2017.Following Sandy's closing remarks, we will open this call for questions.Again, we will refer to a slide presentation during this call.Those slides are to be found on the events and presentations page of the investors and media section of our website.On a link specifically for this morning's call on that page.And now, I would like to turn the call over to Sandy.

Thank you, McDavid.I want to thank everyone for joining us this morning for our call.While the occasion for today's call is the 2016 year-end review of business and financial results, I will also focus on the future.2017 will be an historic year for genome medicine, and especially for Sangamo as we conduct the first ever invivo genome clinical trials.Sangamo evolved at the start of this year to be become Sangamo Therapeutics as you will see on slide four, I want to take a message to explain this rebranding.As Sangamo, we have a 20-year heritage of being at the cutting edge of genome.We chose therapeutics in the name because we have eroll offed from a biosciences research company to an organization that is focused on the clinical development of genomic therapies.Science at Sangamo Therapeutics is our means to develop new medicines with the potential to inform the lives of patients living with serious genetic diseases.We rebranded the company but underneath that, in the middle of last year as you can see in slide 5, we have hired new talents and filled critical positions.Just yesterday we announced that Kathy Yi has joined Sangamo and will be our new CFO after Ward retires from the company in early March.Kathy joins us from Novartis where she served as head of finance for the global inhalation technical research and development organizations in both California and the swiss headquarters.She brings more than 20 years of experience, spanning various disciplines in technology and finance.We recently announced a new CMO and newly appointed chief business officer and a new head of technical operations.We now have a proper clinical development department.We have the technology and the manufacturing capability to ensure the quality of our product.We also established a commercial planning department that will work close -- and closely coordinate with the clinical development team on product planning.With all of this, we are assembling the capabilities needed to pursue our vision of developing our products from the research labs at Sangamo to clinical development to commercialization.Importantly, because science and innovation are at the core of Sangamo we have refreshed the discovery organization and we will be complimenting the scientific technologists with new biology expertise in the company.Turning to slide 6, our focus for 2017, this year our top priority, our number one priority is to conduct four clinical trials for our lead programs which include gene therapy and genome editing product candidates.We will take Sangamo's zinc finger nucleus editing technology into patients for the first ever in in Vivo genome editing trials.The genome editing and zinc medicines.Over the course of this year as we take the ZFNs into clinical trials and present and protect our architectural improvements for the last few years, we believe you will understand that this zinc finger nucleuses set the standards for advance, flexible for genome editing technology.We believe that we have now reached a state where it's not really mow LEC cluear biology but molecular engineering.We understand the science behind the interacting between zinc finger proteins and DNA and we are now improving on our delivery technology will open the of field of genome editing and recognize the full potential of this technology.Finally, a company of our size cannot do this alone.We need to be thoughtful, pragmatic and a good partner with the various companies we work with and who are interested in working with us.We were very pleased whether bioVertive into the newly forms.Biover ativ is a blood disorder focus from Biogen.Our collaboration is now engaged in late, preclinical work.Turning to slide 7, first and foremost, 2017 is a bit of clinical delivery.I deliberately repeat this to emphasize that I heard what investors want to see from Sangamo.I know what is expected of us this year.So I will now turn the call over to Ed Connor, our chief medical officer to discuss these development programs.Ed joined us at the end of November, and is a strong history of success in clinical very maniment for rare disease programs.He joins us from ultra genics an earlier work and Genentech.Ed?

Thank you, sandy, and hello, everyone.I'm very excited to be here at Sangamo and to lead clinical development as we execute on the first ever in vivo genome editing clinical trials.In the two short months we have already grown significantly.We now have the right people in place and the appropriate organizational structure to translate Sangamo's cutting edge research into clinical success.We have a fully staffed clinical operations team to manage our timeline and hired two medical directors with experience in hemophilia, and other disorders to ensure we properly address the patient's unmet needs.With these recent changes I'm confident we will achieve timely and clinically meaningful result from our four lead programs in hemophilia A, hemophilia B, and MPS I and MPS II.Let me start with SB252 for hemophilia A.This is the most recent to receive IND clearance from the FDA.As you see the cartoon on slide 9, it's traditional gene therapy where the transgene is packaged into an AV vector.We use AV6 to target the uptake into liver cells delivered via a single IV infusion.It goes where the gene is expressed as its anomaly.Despite the fact that there are they are approved for hemophilia A, as well as some long lasting factor products that are being developed.They are the consequence of this as well as avoiding frequent infusions of replacement factor.Our gene therapy, SB525 holds significant potential as a one-time treatment that will eliminate factor infusions and we believe what we have is the best in class, most potent cDNA construct.Slide 10 compares nonhuman primate date for SB525 with competitor data.These are not head-to-head data I want to stress but at least in this, Sangamo appears more potent than that as far as the bioMorin.We are looking forward to initiating the Phase I and II clinical trial.You will find a summary of the protocol on slide 11.We expect this study will be relatively easy to enroll as there's significant excitement among hemophilia key opinion leaders about this approach and product in particular.We will treat three patients in each cohort with safety reviews occurring before the study advances to the next cohort.I want to shift now to the genome editing platform.Slide 12 shows a cartoon illustrating the approach for all in vee know genome editing.Here we still use AV6 as the delivery vehicle but what we infuse in a patient is a mixture of transgene and two zinc finger nucleuses.Again transvehicle delivery.In this case with its -- it's within an intra of the albumen gene.It cleaves the DNA with a double strand of break and the transgene is dropped into that break.The transgene at the bottom right of the slide is expressed using the indodgionous albumen promoter and this is one of the strongest promoters in the body.We believe that this then allows a constant production of this gene's protein from the liver.The idea is to create a one-time treatment and that the genome editing will ensure sustained protein production throughout life.SBS9, the in vivo genome editing.The IND is opened, sites are open and we are screening patients. -- and we're screening patients.The protocol summary is on slide 13.And conduct appropriate safety review in light of this being the first time this therapeutic approach has been introduced in the patients, and then proceed to a higher dose cohort over three cohorts.Hemophilia B is a more competitive space and a much smaller patient population than hemophilia A.We expect this trial will enroll more slowly than the other studies we are running but still, anticipate receiving data from the study around year end 2017 or early 2018.Moving on now to the other two gene editing programs we have, these are potential streetments for MPS 1 and MPS II and summarized on slide 14.Here the medical need is even more obvious..patients are not treated early enough, they develop a serious si quay Lawith damage to many organs in the body.It's treatment for MPS I and MPS II and is potentially life long cures if we are able to treat patients early enough in the course of their disease.To be prudent we have to start with trials in adults but we recognize that the greatest potential benefit is in the treatment of children.INDs are open for these Phase I II studies.There's good awareness and interest among families and patients for these families.Like the hemophilia B study we will enroll the first cohort using the lowest dose we believe has therapeutic potential, conduct a safety review after a period of time has passed and then advance to a higher dose cohort.Slide 15 summarizes the progress we have made with all of these studies so far.We're exactly on track with what we promised to deliver at JPMorgan earlier this year.We have GNP large scale manufacturing completed for all of our clinical trials.We have orphan designation for two of them already and another two of them are in process.Yesterday we announced that the MPS I program has received rare pediatric disease designation and we have also submitted and application for that designation for MPS II.We have the first site open for hemophilia B.And we'll have sites top for MPS I and MPS II this quarter and hemophilia A next quarter.All are open label but we will not release data until we clinically relevant results.We expect to report late this year or early 2018.I'm very pleased with the progress we have made over the past two months.We will continue to work carefully and diligently, to accomplish our goals through the reliable execution of the many small steps involved successful clinical development.I want to close by saying how excited I am to be involved in the first ever in vivo genome editing clinical trials.The technology has such enormous promise of serious genetic diseases.This is years coming as zinc finger nucleus and other promising technologies have been developed.In 2017, ZFNs will advance into studies of somatic gene editing.I will now turn the call over to Michael Holmes, VP of research.Mike?

Thanks, Ed.Good morning.At Sangamo our early research programs are focused on improvements that make ZFN genome editing appropriate for human therapeutics.Today, I want to talk to you about two programs where our advancements have the potential to bring the benefits of this technology to more patients.The first is about improvements to the ZFN platform itself that have increased on target efficiency and greatly reduced off target cutting.On slide 17, what I have expand SSD is a cartoon of zinc finger nucleuses bound to DNA.Should envision, zinc fingers as the protein finders that recognize and bind the DNA and allow the cleavage to happen.Zinc fingers are modular and comprised of five or six fingers and we have such a large and well characterized fingers that we are now able to construct a set of zinc fingers to target any chosen location of genome and achieving a cutting level of greater than 70% on the first pass.Since we are using ZFN to develop a new class of human therapeutics to help patients with genetic diseases it's critical for us to have the ability to refine and optimize ZFN performance in cells.Turning to slide 18, and work that we presented last month, at the Keystone symposium, we developed several approaches and the non-FAS fate between the zinc finger and Ann and also ratio optimization of the two ZFNs being introduced in the cells.And on slide 19, putting all ever these uses together, the new linkers.The ablation of phosphate contacts and the adjustments in ZFN ratios we are target any base in the genome with unmatched efficacy and specificity.This slide 19 shows the results from one of our targets where we have used these recent improvements in the ZFN platform.Along the bottom are all the locations where these ZFNs could cut.The red bar is the on target and it's now at 80%, although we have been able to achieve multiplication levels of greater than 80%.The bars you can't see in the graph which represent the analysis of all the potential off target sites are now below the level of quantification.We can now move the off targeted editing below where it can be detected with current state-of-the-art assays.We have used unbiased nucleotide capture assays and next generation sequencing to provide highly -- of after target cleavage.Since we are developing this technology for use in patients, it is critical that we get it right.Off target cleavage is also focus of the FDA.This rigorous detection method we use is the highest standard in the field and is in contrast to recent data reported last year by some of the newer genome editing companies which used a biased info mattic approach.Another point to highlight about these data are that this study was performed in the appropriate clinical relevant sales height at clinical stale.It's one thing to do this in a Petary dish at a research scale and a very different thing and much harder to do under the conditions that Mimic what we would do clinical.This is an example of how we are using this new technology to develop precise medicines.Turning to slide 20, the second important topic I want to discuss today is LMP delivery.Lipid Nano particles or LNP.They are up through the LDL receptor in the liver.Some of the benefits of LNP is they are not the target of neutralized antibodies and it allows for repeat administration in order to dose to effect.It will enable our technology to treat new genetically attractable diseases and eventually help more patients.Left me show you data around the use of LNPs.On slide 21, you will see data from a set of test ZF Ns targeting, TTR gene.On the left-hand side, you can see the level of editing where we can achieve 60% knock out editing in the liver, via the lipid nanoparticles.The you have roughly other 40% of cells are blood cells and fibrous tissue which do not express TTR and are not targeted for delivery by the LNPs.This is a maximum.Aof editing reflected in the 90% protein knockdown on the right-hand side.We have also done this with PCFk9 amongst other genes.We now we have the ability at least in mice and we're moving it into nonhuman primates, to knock down any gene within the liver with lipid nanoparticles.On the next slide, 22, we also believe you can use this approach to target the insertion of a therapeutic transgene in the liver.Two things to take away from this slide, the first is the targeted knock-in of a gene.We use the lipid nanoparticles to deliver the zinc fingers and use AV to deliver the transgene.The pay load that we want to drop into the albumen locus.In this specific example, we are inserting the gene that's normally inserted into the MPS II patient, into the albumen locus.That's the first dose and on the second and third dose we repeat administered ZFNs with LN Ps to drive additional editing and targeted insertion.With LNP of additional ZFNs we have different levels of editing allowing to gradually increase the.Aof payload integrated into the target site.This allows us to repeat dose until we reached the designed therapeutic dose and expand the number and the types of genome editing applications we can pursue in the liver.We are excited by LNP and look in order to showing nonhuman primate data later this year.With that, I will turn the call over to Ward, our CFO.Ward?

Thank you, Michael and, good morning, everyone.As you will see on slide 24, for the fourth quarter of 2016, the company reported a consolidated net loss of $9.6 million or $0.14 per share, compared to a net loss of $14 million or $0.20 per share for the fourth quarter of 2015.The net loss for the full year 2016 was $71.7 million, or $1.02 per share, compared to a net loss of $40.7 million or $0.58 per share for 2015.We ended 2016 with approximately $140 million in cash, cash equivalents and short-term investments and interest receivable.Revenues in the fourth quarter of 2016 were 8.9 million, compared to $9.1 million for the same period this 2015.Fourth quarter 2016 revenues comprised revenue from Sangamo's collaboration agreements with Bioverativ and others enabling technology agreements and approximately $100,000 of revenue from research grants.For research services performed under the collaboration agreements with Bioverativ and sheriff, we recognized $1.4 million and $4 million during the quarter respectively.For a full year of 2016, we are pleased to have exceeded our revenue guidance and met our guided ranges for operating expenses and year-end cash.Revenues for the full year 2016 were $19.4 million, compared to $39.5 million in 2015.With the decrease due primarily to the strategic amendment with the agreement with shire and decrease in revenues year over year related to you're agreements with Sigma and Bioverativ.For the fourth quarter, we were $18.8 million, compared to 24.8 million for the same period in 2015.Research and development expenses were $13.9 million in the fourth quarter, 2016, compared to $19.9 million for the fourth quarter of 2015.The decrease was primariry due to the completion of our -- of all of our external manufacturing expenses in preparation for our clinical studies in 2017.General administrative expenses were $4.9 million for both the fourth quarter of 2015 and 2016.Non-stock based compensation expense was $1.9 million for the quarter and $1.1 million in research and development and $800,000 in general administrative.For the full year 2016, total operating expenses were $91.9 million, compared to $86.4 million in 2015, with the increase primarily attributed to the increased external clinical expenses as well as increased expenses relating to salaries and benefits consulting services and other corporate costs.Turning to the balance sheet, as I noted earlier, Sangamo ended the fourth quarter of 2016 with $143 million in cash, cash equivalents, short-term investments and interest receivable.Our net cash used was $12.6 million in the fourth quarter, resulting in $66.5 million, net cash used in operating activities for the full year 2016.Regarding our financial guidance for 2017, on slide 25, we expect revenues for the year to be in the range of $14 to $19 million and revenues include partial recognition of up front payments and reimbursement of research services and milestone payments from existing collaborations.We expect to incur operating expenses in the range of 100 million to 110 million in 2017, including noncash stock based compensation expense.Of note, the company manufactured and released CGMP materials in 2016, for all currently planned clinical trials.We anticipate ending 2017 with at least $60 million in cash and equivalents and this is inclusive of research funding from existing collaborators, but does not include funds arising from any new collaborations or partnerships or any other sources of capital.As you know, Sangamo has historically been a prudent custodian of shareholder cash resources.We will continue to eraffle wait appropriate collaboration and partnership opportunities that have been a hallmark of our non-dilutive financings and operating expense reimbursement.In summary, the company is in solid financial position as we begin 2017, with the cash runway fond if the clinical studies of our four lead therapeutic programs in hemophilia.We look forward to a pivotal year ahead as we advance these into the clinic.Thank you.I will now turn the call back over to Sandy.

Thank you, Ward.I hope we have shown you that Sangamo now has a balanced portfolio, preclinical very maniment and early research and you can see that on slide 27.We have the four lead product candidates that are going into the clinic with our new clinical development group, we start to recruit patients very soon and we expect data at the end of this year, or at the beginning of next.We are also excited about our middle portfolio, which includes a hemophilia program and Huntington's with shire.Other early research, zinc finger nucleus architecture improvements and the hopes for delivery promise to yield exciting new programs in future years.In short, we have accomplished everything we promised earlier this year.And unfortunately we are on track to accomplish in 2017 the plans we laid out at the beginning of the year.We expect to maintain this momentum throughout the year.We have made great strides in the recruiting front and completed 9 replenishment of our senior leadership and we made significant progress in the clinical setting and the newly implemented systems and programs and our science is better than ever.Before we move to your questions, I want to bring us back to the priorities and themes of 2017, slide 28.I joined Sangamo because of the promise of the science here, which has exceeded my expectations.This year, we will finally advance this genome editing plat norm into in vivo clinical trials.This will be a remarkable moment for Sangamo but also for science in general as for the first time ever we will permanently insert a new gene into a patient's DNA.We look forward to keeping you updated on our progress and also especially to sharing data with you late this year and early 2018.Operator, we are now ready for questions.

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Operator: Ladies and gentlemen, if you have a question or a comment at this time, please press star and then the one key on your touch-tone phone.If your question has been answered and you wish to remove your ewe from the Kew, please press the pound key.Our first question comes from Gina Wang with Jeffries.

Thank you for taking my questions an congratulations on all the progress.My first question is on the lipid nanoparticle, I'm wondering from a scientific point of view, have you explored combining the zinc finger nucleus mRNA with the donor sequence, the nanoparticle, with the lipid nanoparticle delivering the ZFN and the AAV delivered genome sequence.

Thank you for your question.Mike.

If I got your question correctly, we presented data combining ZFN delivery using LNPs and your question was, I believe, have we tried it where essentially the donor was also delivered via a lipid Nano particle.

That the right question?

Yes.

No, that's something that we are certainly looking at, as a way of trying to further expand our use of lipid Nano particles.This is a very challenging -- sort of challenging approach to try to get right, the lipid Nano particles have worked with messenger RNA but they have note worked as well with the use of DNA delivery.That's something we are working on but that's still at the early stages.

Okay.Thank you.And then my follow-up question is will the partner program with Bioverativ, I know you are moving very fast and trying to go to clinic by the end of this year so I'm just wondering can you provide us some update, you know, on sickle cell on when should we expect the IND filing for those two programs?

Thank you, Gena and we are delighted that Bioverativ has been launched and shares our enthusiasm for this program.We are conducting preclinical work with them and hope to have the IND submitted very soon.

Okay.Thank you very much.

Operator: Our next question comes from Whitney Ijem with JPMorgan.

Hi, guys thanks for taking the questions.I guess first I wanted to follow-up on the Bioverativ question.Can you, I guess, give us any additional color on kind of what are the rate limiting steps for getting that IND in?And then, I guess, you said very soon, is that like a first half of the year event or before year end event?Any additional color you can give there?

I would love to, but we are -- it's the simple blocking and tackling of an IND, all the different preclinical studies that you need to have ready.I'm enthused -- you saw the zinc finger results for this particular target, which I think look wonderful.We are really enthused by this and we hope to do it soon.I can't give you any more details on the timing.

Okay.Fair enough.And then another question that I have asked before but I will ask again, just to make sure that nothing has changed.As you keep us up to date on the clinical trials ongoing this year.Will you let us know when you treat the first patient or go to the next cohort that we will use to track progress or should we expect radio silence.

We want to share with you as much as possible and the excitement about treating the first patient with in vivo genome editing and giving you data that is truly meaningful.Ed, what are your thoughts?

Well, so to Sandy's point, we will announce the first patient in and, you know, we -- as he mentioned, that is a Seminole event but as we continue to enroll patients we are going to be reviewing the data but as was mentioned, we are -- we're going to be providing updates when we have clinically relevant data in hand, which will be either at the end of this year or early 2018.

Okay.Got it.Thanks.I will hop back in queue.

Operator: Our next question comes from Charles Duncan with Piper Jaffray.

Hi, guys.Thanks for taking the questions.What do you anticipate in terms of how you would define clinical relevance of -- for those programs?

Charles thank you for your question.You know, we are -- this is a very exciting time for this company, because we are blessed with having four programs going into the clinic and there's not many companies that have that at once, and any one of them could produce clinical data by the end of 2017 or the beginning of 2018.Ed, what would you regard as clinically relevant?What kind of things are you looking for in clinical trials.

Yeah, for of the Phase I, II trials first and foremost, it's about safety, but we are also fortunate across all of these programs to have a blood biomarker that's correlated with clinical outcomes.So in the example of hemophilia A and hemophilia B, you have factor levels for MPS I and MPS II, you have IDUA, and IDS respectively, as well as urine gag.So what success looks like across all of these studies is those a safe dose and a dose that's providing therapeutic protein levels where we expect to see clinical benefit.

Okay.That's helpful.And then moving on, perhaps a question for Mike, Mike mentioned several points of technological innovation and I guess I'm wondering if you anticipate any new innovation to be incorporated in, say, for a second generation candidate for any one of the current envisions clinical programs.So he may A, or B, or MPS I or II.

That's a good question and it was a question that we spent some time discussing yesterday as a management team.The -- the timeline between having a great scientific idea and getting it into patients in the clinical is, I don't know, three years, generally by the time you have done the IND and the trial has started.So we have to be sure that the product that we are taking into clinic now is good, and we -- we believe that we are taking something that is safe and effective into patients just now.But we also have to start to plan for the next generation.We now think that we have the ability to target any nucleotide in the genome.But, Mike, you continue to dream about what's next, don't you?

Absolutely.And so I think there are a lot of exciting potentials for the generation of sort of improved or second generation products, both for sort of, I think, new applications that we're currently working off of, as well as the current programs that we have in the clinic.And so this is something that we are continuing to look at.

But, Mike, that could include can we do it quicker?So the current generation we can get good assets within two weeks.And then good clinical standard assets within two to three months, should we try to do it quicker.Can we try and include other enzymes other than thought one into the zinc fingers dox we look at transcription or editing.So there's a range of things and places we can go with this technology that is very exciting.There's no need for second generation compound at this point?

To answer that question specifically, we specifically and deliberately believe that these are good, safe, and efficacious and we are happy to move them into human clinical trials, and if they succeed, we will develop them to a registration and launch.

Okay.That's helpful.Last question, on the pediatric disease designation, Sandy, first of all, congratulations on that.I'm happy that you are going to also apply for MPS II, but could you -- could you help at least me understand -- I don't fully understand how that could turn into -- is that set up possibly pediatric disease vouchers, should that candidate get over the goal line and be FDA approved?

Ed, do you want to talk to that?

Sure.Yeah.So the RPD designation, if we do get approved would -- we would have a voucher granted, which as you know is transferable and the -- we have filed for a similar designation in MPS II.

Okay.That's helpful.Thanks for taking my questions.

Thanks.

Operator: Our next question comes from Ritu Baral with Cowen.

Good morning, thanks for taking the questions.I wanted to ask you about what doses you are thinking for SB525.So I wanted to know what you guys are thinking about dose ranges, if there's any challenges to having relatively ultra low doses for what have been traditional gene therapy of dose --

It's a great question.It's an important question because it talks to patient safety and the clinical utility of these products.And I will ask Ed to -- to speak to this.It isn't just about efficacy.It's about predictability and I think that the bioMarin challenge that they have at the moment, rather than whether they are efficacious or not.Ed, do you want to talk about how we will think about this?They are getting biovariable data that even above 300% and the consequence might have been that they were going to 6E, 13 dose levels.As we have presented at public meetings, we believe our data supports a starting dose in the E11 range.And we have built into the protocol even an ability to step down to -- to lower dose levels.The consequence, I think, of being able to start at a lower dose level, means not only that you need a more potent construct, which is what we believe we have, but you are also able to have less immune response and the consequence of the immune response may be what's driving some of the variability that's been observed with the bioMarin data, but by starting in a lower dose and mitigating that potential for immune response, we expect and hope to see a Tiger control of expression of the factor levels for SB525.

Got it.And Ed, is there any sort of number that you have in your head for clinical data release, you know, what would be meaningful to you, either a specific number of patients, say, for hemophilia B, just for argument's sake or a specific follow-up period where we could look at measurement, like, would three months be meaningful to you or would we really have to wait for six months in your mind to see the full fruition of efficacy?

Yeah, I mean, it's -- it's -- it's fairly multifactorial.Safety is paramound here and we want to look at levels and be looking at are there trans -- how long is the cortical steroid course and, you know, what if any is the impact on pharmaco dynamics in terms of using steroids.So it's challenging to use one of those parameters and identify what I would use that to say, what's clinical meaningful.As we look at other programs out, there they are generally hitting their stable ranges in around the three to four month time frame.So I think that's a reasonable estimate in terms of when we might expect to see plateau levels but, of course, there are instances when that -- when that hasn't happened.So for us, the most important thing is to be followed -- is to be following these patients closely, looking at their factor level and safety in realtime and making a determination when we think it's prudent to -- to disclose that information publicly.

Got it.And then last question on the enrollment for your hemophilia B program.Can you talk about what maybe challenges are seeing to date?Is it with screen failures or is it with patient interest and caution?How would you describe that?

So we haven't given details in that we have screened several patients.This is a small patient population.There are already very good data from spark out there.And so it's competitive.

I had thank you for taking our call.This is Yen in for Jim.First, we have a few questions on the MPS I program, and then we have a few follow-up on the -- the early -- the data phosphate ablation that you have talked about on the call.So for MPS I, could you talk about in terms of starting those, would that program have a -- you know, compared to the hemophilia, how would the starting dose, you know, differ?Would it be higher or lower?And perhaps, you know, as part of the consideration for that -- for that parameter, have you -- do you have some comment on the percentage of liver cells that needed to be modified to achieve a clinical benefit in MPS I compared with hemophilia, whether, you know, more liver cells or lower or a percentage that in your mind you need to transFebruary.

That's a complicated.It's a good and commy indicated question.We have not revealed what dose we start any of the zinc fingers into the albumen lockers programs, which would cover hemophilia B, MPS I and MPS II, they will be a similar dosing level.But your second question is do we look on a different degree of editing as being required for MPS I, versus hemophilia.Mike, do you want to talk about that?

Certainly.I think obviously much of our data was collected from our preclinical studies in mice and this was data that we have shown at the world symposium.Essentially we are using the same doses of AV in our preclinical studies as -- for the MPS I and II programs as with the hemophilia program.And based off this we are seeing similar levels of editing and we see -- we can achieve levels of enzyme production from the liver and this seems to be sufficient for being able to reduce gag levels in the secondary tissues.So we don't have any firm data in terms of whether the requirement for genome editing that we need to achieve.We are seeing similar levels of editing that provide essentially levels of enzymes that can reduce gag levels and provide at least normalization of gag as well as other sort of secondary points that we collected.

We'll be judging the success of this not on, you know, a liver biopsy measurement of editing but on the physiological levels and understanding of the consequences of those two patients.

Got it.And in terms of clinical end points for the MPS I study, other than the -- the gag levels that's listed on clinicaltrial.com, could you talk about potential other secondary -- other end points that you might be looking at.Specifically, because I remember we talked about -- you talked about the potential blood/brain barrier crossing for the -- in your preclinical studies, with their -- would there be some end point that's geared towards looking at implications from potential crossing of the blood/brain barrier?Thanks.

Ed, do you want to touch on this.

Yeah, sure.So first, I think is with regards to biochemical end points.You mentioned urine gag and that certainly is one ever them that we'll be following closely.The other for MPS I is plasma IUA levels.And we think this is critical because in patients who are receiving enzyme replacement therapy, we know that those -- we know that the plasma IDA levels are essentially undetectable at the trough.So this will give us a fairly early read to be able to say, are we producing IDUA such that we be able to detect it at the trough prior to the patients' dose of ERT?So that gives us some confidence if we see it that we are, indeed, having the ability for the patient to produce 9 relevant enzyme.With regards to your second question, we're looking at a variety of clinical outcome measures, you know, these include things like six minute walk tests, range of motion, and some cognitive testing with regards to your question about the brain.The one item that I do want to mention is that --

But you probably don't expect to see much difference in --

Well, and that's -- and that's about what I was going to get to, is that these are all adult patients who, again, have had this disease for years, and are likely to have a fair number of fixed deficits, whether it's neuro cognitive or the six-minute walk test.And, you know, we fully expect the main benefit of this to be seen in children.We are measuring all of these outcome measures but mostly what we are going to rely on, again in the Phase I/II study is the evaluation of safety and including plasma IDUA and urine gag.

Guys, that's very helpful.So on the phosphate ablation program -- technology that you just mentioned -- talked about, is -- it's very interesting.I was wondering could you -- in terms of off target activity and the higher specificity, could you compare your findings with the -- you know, the current technology?I think at a RAC meeting it was mentioned, for example, SMCHD1 gene was one of the off target genes as an example for the current technology.Can you talk about improvement in the off target, how does the phosphate ablation compare with the current one?

So, I mean, that's a good question and we have to be sure that the current technology that we are taking into patients this year, we believe it's safe and we -- we as a company have to believe it's safe.I think what we are trying to tell you with this story about phosphate ablation and the targets we now understand how off targets happen.With the previous assets, with future assets we can predict how those happen and we can systemically and rapidly reduce that without going through the more steam-powered version that we did before.

Got it.Got it.Thank you.

Operator: And I'm not showing any further questions at this time.I would like to turn the conference back over to our hosts.

Thank you so much, for joining us this morning.And we look forward to speaking with each of you and meeting with many of you in the coming months.Thank you.Have a good day.

Ladies and gentlemen, this concludes today's presentation.You may now disconnect and have a wonderful day.