Sangamo Therapeutics Inc (SGMO) 2010 Q4 法說會逐字稿

Good afternoon and welcome to the Sangamo BioSciences teleconference to discuss fourth quarter and full year 2010 financial results. This call is being recorded. I will now pass you over to the coordinator of this event, Dr. Elizabeth Wolffe, Senior Director of Corporate Communications.

Thank you very much. Good afternoon and thank you for joining Sangamo's management team on our conference call to discuss the Company's fourth quarter and full year 2010 financial results. Also present during this call are several members of Sangamo's senior management, including Edward Lanphier, President and Chief Executive Officer, Ward Wolff, Executive Vice President and Chief Financial Officer, Dale Ando, Vice President of Therapeutic Development and Chief Medical Officer, and Phillip Gregory, Vice President of Research and Chief Scientific Officer.

Following this introduction, Edward will highlight recent activities and significant events from the past year. Ward will then briefly review fourth quarter and full financial results for 2010, Phillip will provide an update on one of our preclinical ZFP therapeutic programs, and finally, Edward will update you on our goals for 2011. Following that, we will open the call up for questions.

As we begin, I'd 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 the future performance of Sangamo with you today, 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 at a later date that our comments from today are still valid. We alert you to be aware of risks that are detailed in documents that the Company files with the Securities and Exchange Commission, specifically our quarterly reports on Form 10-Q and our annual report on Form 10-K. These documents include important factors that could cause the actual results of the Company's operations to differ materially from those contained in our projections or forward-looking statements. Now I'd like to turn the call over to Edward.

Thank you, Liz, and thank you all for joining us for our conference call to discuss our fourth quarter and full year results for 2010 as well as our plans for 2011. While the past 12 months have been an important period of maturation for our ZFP technology and for us as a therapeutic product development company, we believe that 2011 will be a transformational year for Sangamo.

In the year ahead, we have several opportunities to present groundbreaking clinical data from our lead ZFP therapeutic programs in diabetic neuropathy or DN, and in HIV/AIDS. And this, needless to say, is where the rubber meets the road for a company working to establish a novel technology platform as the basis for the development of a new class of human therapeutics.

So let me give you a few examples of recent progress along that road. In early January, we announced that we had completed enrollment of our Phase 2b clinical trial in subjects with moderate severity diabetic neuropathy on schedule, which means that we are on track to provide 180-day efficacy data in the fourth quarter of 2011.

We also enrolled more patients than anticipated, 170 subjects, rather than the 150 we had initially proposed, but more on that later. We recently announced in about four weeks from now we will present the first clinical data from our Phase 1 trials of our ZFN modified T cell therapeutic, SB-728-T for HIV/AIDS at the conference on Retroviral and Opportunistic Infections, or CROI. I'll have more to say later in this call about the type of data that we will be presenting and our overall strategy and rationale for the trials that we are conducting, including our most recently initiated trial, a Phase 1/2 trial in HIV infected subjects who are not taking any antiretroviral medication.

We also made notable progress in our preclinical programs with presentations at the annual meeting of the American Society of Hematology, or ASH, from our hemophilia program and publication of preclinical animal studies from our Parkinson's Disease program in the Journal of Neuroscience.

Our hemophilia B program is a particularly exciting story as we demonstrated permanent, functional correction of hemophilia B in a mouse model of the disease with a single, systemic treatment. I've asked Phillip Gregory, our VP of Research and Chief Scientific Officer, to describe the work in more detail and explain its significance later in the call.

The preclinical studies that were published in the Journal of Neuroscience were funded by the Michael J. Fox Foundation for Parkinson's Research and form the basis of a grant application which earned a second award from the foundation. Our most recent award of approximately $1 million will fund the next phase and the next stage of preclinical development in non human primate models of Parkinson's Disease.

Also, with relevance to our interest in Parkinson's, we are working with the Parkinson's Institute here in the Bay Area which was recently awarded a $1.3 million grant from the California Institute for Regenerative Medicine, or CIRM. We will develop ZFN modified cell lines from induced pluripotent stem cells, or IPSCs, which have been derived from skin cells taken from Parkinson's patients. The generation of these cell lines is intended to accelerate our understanding of the molecular causes of Parkinson's and provide models that could become important tools for developing novel therapies. The grant was awarded the highest score of the 226 grant applications received by CIRM from California's top research institutions. Reviewers of the proposals specifically noted that, "the project has the potential to bring about paradigm-shifting discoveries".

Finally, at the annual meeting of the Society for Neuroscience, we presented data from our preclinical studies of SB-509 in spinal cord injury and stroke models. And the final data from our Phase 2 clinical trial, SB-509-801, in subjects with amyotrophic lateral sclerosis, or ALS. As you may remember, our primary aim in this study was to assess safety and tolerability in treatment of SB-509 in this vulnerable patient population and to conduct a signal seeking study in which we assess the effects of treatment on several clinical measures of function in ALS. Treating subjects twice over a 90-day period, we observed a delayed deterioration in muscle strength in the ankle and toe in treated subjects which was very encouraging and may reflect the importance of focused, regional dosing. These data provided valuable information for the design of future studies which could include or would include more frequent and focused dosing with SB-509.

So before going into more detail on our upcoming events and plans for 2011, let me hand the call over to Ward to update you on our fourth quarter and full year 2010 financial results as well as our financial guidance for 2011. Ward?

Thank you, Edward, and good afternoon, everyone. As you know, after the close of the market today, we released our financial results for the fourth quarter and full year ended December 31, 2010 and I am pleased to review the highlights of those results.

Revenues in the fourth quarter of 2010 were $4.7 million compared to $10.2 million for the 2009 quarter. The fourth quarter 2010 revenues were comprised of revenue from Sangamo's collaboration agreements with Sigma-Aldrich and Dow AgroSciences and agreements related to protein production, as well as approximately $2.5 million of revenue from research grants. The decrease in revenues was primarily due to the completion in July 2010 of the amortization period for the commercial license fees received from Sigma in October 2009 under our expanded agreement. This was partially offset by continued revenue from Dow AgroSciences for ZFP manufacturing and research services.

As we mentioned in the press release, the increase in research grant revenues was primarily due to renewed funding for our Phase 2b clinical trial in diabetic naturopathy from the Juvenile Diabetes Research Foundation, receipt of four qualifying therapeutic development program awards to support qualified expenses incurred in Sangamo's clinical development programs, Sangamo's portion of the disease team research award from the California Institute for Regenerative Medicine, and research funding from the Michael J. Fox Foundation for Parkinson's Research.

Total operating expenses for the fourth quarter of 2010 were $13 million compared to $12.7 million for the same period in 2009. Research and development expenses were $9.9 million in the 2010 quarter and $8.7 million for the prior year quarter. The increase was primarily due to increased expenses related to our ongoing clinical trials of SB-509 and SB-728-T.

General and administrative expenses were $3.2 million in the fourth quarter of 2010 compared to $4 million in the 2009 quarter. For the fourth quarter of 2010 we reported a consolidated net loss of $8.3 million or $0.18 per share compared to a net loss of $2.4 million or $0.05 per share for the fourth quarter of 2009. For the full year 2010, revenues were $20.8 million compared to $22.2 million in 2009. Total operating expenses were $45.7 million in 2010 and $41.6 million in 2009. The net loss for 2010 was $24.9 million or $0.55 per share compared to a net loss of $18.6 million or $0.44 per share for 2009.

Turning to the balance sheet, I am pleased to report we ended 2010 with $60.6 million in cash, cash equivalents, and short term investments. Our net cash used in operating activities was $23.9 million for the year. With respect to financial guidance for this year, we expect to have a cash and investment balance in the range of approximately $35 million to $40 million at the end of 2011 exclusive of any new funding from a partnership or other sources. We also expect 2011 operating expenses to be relatively flat compared to 2010, in the range of approximately $43 million to $47 million.

In summary, 2010 was an eventful year in which we advanced both our DN and HIV programs in key clinical trials. We are pleased to have realized our financial objectives for 2010 with respect to both our operating results and net cash usage. We will continue to be focused on advancing our clinical and preclinical pipelines while maintaining our historic financial discipline.

Thank you and I will now turn the call back over to Edward

Thank you, Ward. As you've heard, we begin 2011 as we had previously guided, with $60 million, a strong cash position and one that will enable us to take our therapeutic programs forward to points of significant value inflection. Looking forward, we expect to end 2011 with approximately $35 million to $40 million in cash and cash equivalents. This cash projection does not include any new agreements or partnerships that we may develop this year.

As you know, the broad applicability of our technology in multiple commercial markets has enabled us to develop a business model which has provided significant revenue from non-therapeutic applications. This has allowed us to move our maturing portfolio of therapeutic programs forward with a very modest cash burn. Our goal is to be as efficient as possible with our use of cash while aggressively building value.

As I said earlier, 2011 will be a transformational year for Sangamo in terms of clinical data. First, our most advanced program is in the area of diabetic neuropathy. We have an ongoing double blind, placebo controlled Phase 2b clinical trial of our ZFP therapeutic SB-509 on which we have now completed accrual. SB-509 is a neuro regenerative designed to be a first in class disease modifying drug. There is a growing incidence of diabetes. Currently available numbers suggest that there are approximately 24 million diabetics in the US alone and roughly 60% of these patients will develop neuropathy as a result of their high glucose, or high blood glucose. This complication of an already difficult disease is debilitating, frequently leading to infections of the feet and potential amputations, and places an enormous burden on the healthcare system. This is a major unmet medical need, and as there is currently nothing available to halt or reverse nerve loss, only drugs that mask the painful systems, the Juvenile Diabetes Research Foundation also recognizes this need and has invested $6 million in our studies. $3 million into a previous Phase 2 trial and an equivalent amount into our current Phase 2b trial.

The challenge of any clinical development program is to design trials that provide the best chance of seeing a significant difference between the placebo group and the treated group abound clinically meaningful, approvable endpoints over the period of the trial. We have shown that SB-509 is neuro regenerative by taking skin biopsies from subjects before and after treatment, and directly counting the number of nerves in the skin. This and other data gleaned from our previous trials have enabled us to identify what we believe is a drug responsive population.

Using this information, we have undergone a rigorous accrual process designed to exclude both the very mild and the very severe populations to select patients that we believe are going to be most responsive to treatment over the 180-day primary efficacy analysis period compared with placebo treated subjects. The trial was originally scheduled to enroll 150 subjects. However, we were able to enroll 170 patients which is indicative of the real demand in both the physician community as well as in the patient community for a drug that has a neuro regenerative mechanism. Having accrued the trial, we are in the treatment and follow-up period and we look forward to presenting data from this trial in the fourth quarter of this year.

I would now like to move onto our novel approach to the treatment of HIV/AIDS and the strategy and rationale that we have employed as we have moved this product into clinical trials. In addition to our two ongoing Phase 1 trials from which we will present data, preliminary data at CROI, we have initiated a Phase 1/2 trial in HIV in subjects who are not currently on antiretroviral therapy, or HAART. With the initiation of this trial, we are now evaluating our ZFN modified T cell approach in the full range of HIV infected patients, from those early in their infection who are not on HAART, all the way through to those patients who are failing HAART.

First, let's start with the overall rationale of what we're doing. The human immunodeficiency virus destroys the immune system and specifically CD4 T cells. As the disease progresses into AIDS, the CD4 T cell number decreases. However, there is a group people known as elite controllers who are infected with the virus yet have undetectable HID RNA in their blood and maintain normal CD4 T cell numbers without HAART. Many elite controllers have a natural mutation, the so-called delta-32 mutation, in the gene encoding the protein called CCR5 which is a receptor used by HIV to infect cells. This modification of the CCR5 protein means it cannot be used by HIV and so their CD4 T cells are resistant to infection.

In addition to the naturally occurring mutation in this elite controller population is the example of the so-called Berlin patient who had both leukemia and HIV. In this case, doctors in Germany took bone marrow cells from a donor who had this natural delta-32 mutation of the CCR5 gene, gave these cells to the HIV infected leukemia patient, and three years later, this person is both cancer free and free of HIV.

Our ZFN technology allows us to mimic this outcome. Specifically, by editing the CCR5 gene, we hope to create T cells that will be protected from HIV infection and capable of mounting an immune response, not only to opportunistic infections, but also to HIV itself, intentionally enabling a functional cure in these patients analogous to an elite controller.

There are now three clinical trials ongoing. Two Phase 1 trials and a Phase 1/2 trial. Our strategy is to evaluate this product across the spectrum of HIV infection from those who are treatment naive meaning those who are infected with the virus but who are not yet on drugs, and also still have a strong immune system, through subjects who are being successfully treated on HAART and are therefore aviremic but who may have a lower or deteriorating CD4 T cell count, through a smaller group of subjects who are failing on HAART who have become viremic again and have rapidly deteriorating CD4 T cell counts.

Our strategy has been to initially begin to evaluate SB-728-T in Phase I trials in the aviremic population, subjects on HAART who have well controlled, undetectable virus. In the trial that we are conducting in collaboration with [Carl June] at the University of Pennsylvania and our own trial, the SB-728-902 trial, we have focused on this aviremic population. Our initial clinical observations of the pharmacology of the modified T cells have been encouraging which is why we have now moved into the viremic population at both ends of the spectrum with expansion of our Phase 1 trial into heart failures and initiation of the Phase 1/2 trial, SB-728-T-1002 in treatment naive subjects. Both of these populations will allow us to not only look at changes in the immune system, but also at the impact of the virus on the modified T cell product.

As I mentioned earlier, I am very pleased o say that preliminary data from the two Phase 1 clinical trials will be presented in oral presentations the beginning of March at CROI in Boston. We will have a total of four oral presentations and two of them will focus on these initial clinical studies.

So what data can you expect from these Phase 1 studies? The questions that we are asking in these studies are the following. How do these modified cells behave? Are they safe? Do they disappear? Do they expand? Do they traffic like normal T cells? These are basic questions that need to be answered before moving on to ask more complex questions. These data will give us a strong sense of whether ZFN modified cells have the potential to mimic an elite controller phenotype.

In addition, we will also look at the overall effect that the modified cells have on a subject's own immune system. If we are creating a compartment of the immune system that is protected from HIV infection and is immune competent, what effect could that have on the rest of the immune system and specifically the total CD4 count? Will the introduction of these modified cells affect the CD4/CD8 ratio which is a direct indication of the immunological competence? Improvement in these factors would speak directly to the primary immunological defect of HIV, destruction of CD4 T cells. We look forward to discussing these data with you in detail in early March.

The next generation of our HIV program employs these same CCR5 specific zinc finger nucleases, but in hematopoietic stem cells. T cells are terminally differentiated cells and while they can expand and circulate for a very long time, they have a lifespan of just a couple of years. In contrast, the function of hematopoietic stem cells is to continue to produce cells of the immune system and last for a lifetime. And so using zinc finger nucleases in hematopoietic progenitors, we could potentially protect the entire immune system analogous to the Berlin patient's results with every immune system cell being CCR5 negative.

Along with our academic collaborators, we are funded by a $14.5 million grant from the California Institute for Regenerative Medicine to push this forward. This work is going very well and will also be the subject of a podium presentation at CROI.

Our fourth oral presentation will focus on yet another receptor involved in HIV infection, the CXCR4 receptor which again is a target that can be disrupted by our ZFN technology. So a lot going on at CROI and as I said earlier, we look forward to discussing these data with you in detail in early March.

And with that update on our diabetic neuropathy and HIV programs, I'm going to ask Phillip to provide you with an additional example of data that will illustrate the broad power of our technology platform. Phillip?

Thanks, Edward. As you've heard from Edward, our ZFN platform provides a range of powerful gene modification tools including gene disruption, gene addition, and gene correction. And moreover can be designed to target any DNA sequence. In monogenic diseases, which are diseases that are caused by a mistake in a single gene, we can use ZFNs to correct that mistake. Our collaborator, [Cathy Hai], who is a Howard Hughes professor at Children's Hospital of Philadelphia and a leading expert in the area of hemophilia, presented some truly spectacular data that her lab has generated in a mouse model of hemophilia B using the ZFNs from Sangamo. Her late breaking abstract was one of only six accepted at the American Society of Hematology, or ASH, and was also featured in the round up of the 20 Best of ASH out of 3,500 presentations of the meeting.

Her data demonstrated a permanent correction of the human Factor 9 gene in a mouse model following a one-time systemic administration of our zinc finger nucleases. The ZFN correction process resulted in functionally relevant levels of the circulating Factor 9 protein in the bloodstream capable of correcting the coagulation defect characteristic of hemophilia. There were a couple of other important points beside the fact that we achieved a permanent functional correction.

As you heard, our initial ZFN therapeutic programs have all been in cells with the blood and blood marrow, T cells and stem cells, cells that can be removed and treated ex vivo. Factor 9 is made in the liver and we were able to deliver ZFN systemically, that is into the bloodstream, to target them to the liver. While this is a demonstration in an animal, it is clearly a significant development with important implications for the therapeutic application of the technology.

A more technical point, but again one with such significant implications for the development of this as a therapeutic, the method we used correct the mutant Factor 9 gene could be used to correct over 95% of the typical mutations observed in patients. Thus a single, off the shelf formulation for virtually all hemophilia B patients.

This was Factor 9 and hemophilia B. But there are many other monogenic diseases for which the disease gene is known. For example, mutations of the gene encoding Factor 8 are the cause of hemophilia A to name just one. Our ZFN technology is a platform that's ideally suited for addressing monogenic and rare diseases and we have active programs in several. I look forward to updating you on our progress in this area on future calls. And with that, I'll turn the call back over to Edward.

Thanks, Phillip. As you have heard, we have a very busy year ahead with data coming from our two leading clinical programs and a rich pipeline of important preclinical research. In addition to the work that we are doing internally on our therapeutic assets, our partnerships in the non therapeutic applications of technology continue to thrive.

Sigma continues to do a great job of developing our ZFN assets with its composer custom reagents, KIPs and custom cell lines, as well as their transgenic animal programs which is a huge growth area both scientifically as well as commercially.

Our collaboration with Dow AgroSciences also continues to go well. Dow is employing our ZFN technology in its core focus crops and marketing the technology as exact precision technology to companies working in other crops. These collaborations have allowed us to access capital in a way that is very different from most biotechnology companies. Over the past five years, our Sigma and Dow collaborations have brought in nearly $80 million and importantly, we have retained significant downstream value in the commercialization of these assets including, in the case of Sigma, a 10.5% royalty on sales of ZFNs and ZFN based products including transgenic animals.

On the financial side, you can expect us to continue to carefully manage our expenses this year, while working hard to build value through clinical data and new strategic partnerships. As you have heard, we expect to end 2011 with approximately $35 million to $40 million in cash and cash equivalents which is more than sufficient capital to allow us to achieve several points of significant value inflection.

This cash projection does not include any new agreements or partnerships that we may develop. However, having said that, our business model is to partner our programs at points of clear value inflection. We believe that with positive Phase 2b data from our SB-509-901 study, we will be in a good position to establish a therapeutic partnership, enabling us to move this ZFP therapeutic expeditiously into pivotal trials.

2010 was an important year for Sangamo and we expect 2011 will be an even more significant year of progress and clinical data from our ZFP therapeutic programs. You can count on us to continue to stay focused on and make substantial progress towards our goal of establishing ZFP therapeutics as a new and highly differentiated class of human pharmaceuticals.

And we look forward to keeping you informed of our progress. We will be presenting at the Bio CEO and Investor conference the week after next in New York, the Cowen Healthcare Conference in Boston in March, and the Needham Conference in New York in April.

This completes our prepared comments. I would now like to open the call for your questions.

(Operator Instructions). Charles Duncan, JMP Securities.

Hi, guys. Thanks for taking the question and congratulations on a good quarter of progress. Edward, my first question is around CROI. I do definitely appreciate the disclosure on the kinds and types of data that we could see out of CROI. But it seems to me that you are clearly studying three different types of subjects with HIV. I'm wondering if you can give us a sense of the kind of markers of disease activity impact that you might see in those different cohorts. Are there call it CD4 level counts more different, or going to be different and more important than say viral load in those different cohorts of patients?

Good question, Charles. So you sound like Dale, Dale's got a terrible cold and so he threw me into the fray here on this, but he's here with us as well. I appreciate the questions. Let me just start with sort of first principals and work from there.

So first, the data that will be presented in terms of clinical data are from a population of subjects who are on HAART and are aviremic, so let's start with that principal or that premise and move to what the experiment is. So first, what are the things that we hope to establish? Well first, we would hope to establish that we have a reliable manufacturing method for making this T cell product. And since this is the first time it's been used in man, it's really safety, safety, safety.

From an outcomes perspective, I think it's critical that people ask the kinds of questions or look for the kind of data that we discussed on the call. And that is, do these modified T cells, these ZFN CCR5 modified T cells, do they engraft, do they circulate normally, do they traffic normally, are they resistant and so on?

And then lastly, what is the impact on the patient's own immune system and you mentioned a couple of those parameters, CD4 and CD4/CD8 ratios. What I want to make sure people understand is that in this preliminary data that's being presented in this aviremic population, we will not be looking, and people should not be looking, for changes in viral load given that it's in an undetectable population. That I think we will look at in later studies in the treatment naive population as well as in the HAART failure population.

So with that said and before we go further, let me see if Dale wants to add anything or discuss anything else. He's nodding his head, but he's not speaking clearly. Phillip, anything you want to add?

No, I think you've summarized it very well.

Okay. So hopefully I addressed the question, Charles.

That does. That said, you have opened up a trial in HAART naive patients which frankly seems pretty interesting. I guess my question is, why would investigators want to pursue a HAART naive patient with this novel technology? That must say something about investigators' interest in the technology I guess is what I'm asking.

I'll turn it over to Dale and see if he wants to comment further. I think it does say, investigator trials say a lot about patients' interest in a therapy that can create a compartment of the immune system that from a vision perspective, from a goals perspective could be analogous to these elite controllers. But we're a long way from presenting data that establish that. I think you're right in terms of the interest. Dale, do you want to comment about the interest in the treatment naive population stuffy?

Yes, I think in general the interest with this type of modification of CD4 T cells is that it's an extremely novel way of approaching HIV and trying to decrease the amount of cells infected by the HIV virus in patients. So I think application of this particular [natalgous] T cell modification to patients who are not on therapy with HAART is a very natural sort of investigation to try to really elicit sort of the ability of the CD4 T cells to be protected. So I think with respect to that, compared to the patients who are aviremic, this is a very exciting application for this particular clinical indication for this product. And that's the appeal.

And finally, one housekeeping question for Ward. Ward, could you give us the stock based compensation in the quarter please?

In the quarter, Charles, the total stock based was about $2.1 million.

Okay, thanks for that added color. I'll hop back in the queue.

Joseph Schwartz, Leerink.

Hi, thanks. Congratulations on all the progress. I was wondering if you could tell us what needs to happen in order to allow SB-728-T to be administered systemically like the hemophilia mouse?

I'll ask Phillip to respond to that, but I think one of the things that we've talked about is our overall program. Two of the three applications will be discussed or presented at CROI, the first being the T cell program and then the next generation being the hematopoietic progenitors. But we definitely have an interest in what we call the in vivo application. And Phillip, do you want to talk about at a high level maybe what we're thinking about in that?

Sure. So actually we received Gates Foundation funding to look at precisely this question of whether there was a method that could be used systemically to protect the T cells, or not just T cells anymore, the appropriate logical cells direct in vivo administration. And those studies are ongoing. The questions that we're trying to address are what's the appropriate delivery mode and do we have enough of these cells to expect to create a resistant population in sufficient numbers to have the desired clinical outcome? But we're excited by the possibilities and we're continuing to explore this at the research level.

Very good. And also, if you could just back up a second and remind us of the primary distinction between ZFPs and ZFNs. And when might one approach be more desirable over the other? I know you've got many programs in each area. If you could just remind us of the basic principals and why you choose one versus the other?

Sure. Well, Phillip could do a whole week of discussion on this, but in simple terms maybe we can talk about where transcription factor is used, where a nuclease is used.

So the two arms of the technology, if you will, are transcription factor technology and nuclease technology. So the ZFP component is actually common to both, that's the targeting moiety that gives it the ability to address a particular gene in the genome. The nuclear technology gives us the ability to edit the genome directly. So we can knock out genes completely and we can correct mutations that are cause of disease and we can add new information to a location in the genome with site specificity.

The transcription factor technology is more of a volume control. We are able to either increase the amount of expression of a particular gene or we can decrease it, but not necessarily completely shut it off. So more RNAI like, if you will, on the oppression side.

And so the choice of which platform to use is really dependent on, is really driven by the disease, the biology of the gene in that disease, and the clinical outcome that we need to drive to. If more of the same is the right thing, then obviously a ZFP activator might be the right thing to use and that's what's being tested in SB-509. If you want to completely destroy and eliminate a gene, like in CCR5, then the nuclease technology is the way to go.

And if you want to correct a gene like we did with the Factor 9 work that Phillip discussed, the nuclease work plus a donor allows you to change the DNA sequence inside the cell and permanently modify, in this case permanently correct, the mistake in the gene. So it's a very general but very powerful core technology. So thanks for the question, Joe.

Ted Tenthoff, Piper Jaffray.

Thank you very much and thanks for the thorough update. Looking forward to the data next month. First if I may, just a quick housekeeping question. With the guidance that you guys provided with relatively flat operating expenses this year, with the current studies that are ongoing, is R&D going to be kind of shaped like last year? Or do you think it will be a little more frontend loaded or a little flatter? Just trying to get some idea of sort of how you see the timing of the studies kind of impacting that quarterly investment?

I'll start off. Ward can add any color you want. But I think the guidance we're going to give is going to be annual guidance versus quarterly guidance. I think your instincts are right in terms of where the costs will be first half versus second half, but I don't think at this point we're going to get into quarterly guidance. Ward, do you want to talk about any of it?

No, I would agree with that. I think what you said is right.

One of the things that I try and say every time I'm in a one on one or with anybody is, at least for awhile we're probably not a particularly interesting financial story. What we are hopefully is an interesting and important clinical development and product development platform. And as long as we have sufficient cash to get to those material milestones, I think to me that's the critical piece of at least how we think about the finances in our business model.

Fair enough. When you look at -- and this may be a similar question, but I just want to kind of get a sense of what the magnitude -- you guys are talking about the improvements in reagents in the ag business, and how should we be thinking about that from a contribution? Can you say what those, backing out the amortization and stuff, what those royalties might have been in 2010, even just directionally? And obviously we're expecting that to grow going forward, but when do you see those as kind of breakeven businesses? I'm trying to get a sense of when that becomes really sustainable from those non therapeutic partnerships.

Sure. Well again, I'll give a little color and Ward can dive in if he wants. To your latter point, our costs of those partnerships is essentially zero. So when you say are they profitable businesses, since we have no costs and we get revenues from them, I'd say they're "profitable businesses unto themselves". Questions are, when will those revenues begin to materially offset and bring the overall company to that point? And again, these are important partnerships. But as I guess, Ted, you and I have discussed many times and with others, these are financial guidance that will have to come from our partners.

Now that said, I would really encourage analysts and investors to listen to the Sigma-Aldrich presentation from JPMorgan and to the extent there's a transcript from their breakout session to get a sense. They were very specific about the kinds of growth and the kinds of things they expect in the zinc finger nuclease space. But we'll leave that guidance and those growth projections to our partners. Ward, anything you want to say more?

No, I agree with all that. I think directionally --

Can we just move to the therapeutic stuff then and more where the focus is? With the stuff at CROI, I'm really excited to see that data. Help us understand kind of what next steps will be in terms of driving this from -- I mean obviously we're talking about a very exciting approach here that I think would have regulatory backing. But what is this data going to provide for you for the next steps, kind of driving for example HIV to commercialization?

Sure. Great question, Ted. I think we've guided that we expect to present more data in the second half of this year and appreciate the opportunity to reiterate that guidance. And as I discussed on the call, we actually are looking across the full spectrum of the disease right now. And those data, to your question, will really help inform next steps in our development strategy. So I think that investors and analysts should look for the data at CROI and then look for more data in the second half of the year. And as though data are presented and also quite frankly are available to us, that's what really will drive and inform our next steps in terms of moving into the next phase of clinical development.

(Operator Instructions). Liana Moussatos, Wedbush Securities.

Any plans to take a monogenic/rare disease into the clinic using your technology this year or next year?

Hi, Liana. No, I wouldn't say we're guiding to being in the clinic this year. I guess I probably wouldn't comment on beyond that or 2012, but I hope and believe that you get a sense of both our enthusiasm as well as priority by our discussion of it at the ASH meeting and here on this call. Obviously being able to do this in Factor 9, across the clotting factors, across monogenic diseases, and we certainly discussed in the past our interest in Sickle Cell, in Thalassaemia and in other rare and monogenic diseases. We have a lot of interest in those and we fully intend to push those forward. But in terms of something in the clinic this calendar year, no we wouldn't guide to that.

What about a partnership?

Well I think what we've discussed in terms of partnerships is post the SB-509-901 trial and assuming positive data, we would move forward with partnering discussions around that program.

Okay, thank you very much.

Thank you. As there are no questions in queue, I'd like to turn the call back over to Edward Lanphier.

Thank you. We'd like to thank you for joining us and we look forward to speaking with you again when we release our first quarter financial information. We will be available today if there are any follow up questions.

Thank you, Sir, and thank you ladies and gentlemen, for your participation. That does conclude your program. You may disconnect your lines at this time. Have a great day.