IVERIC bio Inc (ISEE) 2014 Q4 法說會逐字稿

Good day and welcome to the Ophthotech Corporation fourth-quarter 2014 earnings results conference call. Today's conference is being recorded.

At this time, I would like to turn the conference over to Kathy Galante, Head of Investor Relations. Please go ahead.

Good afternoon and welcome to our fourth quarter year-end 2014 earnings call. Joining me today I have Dr. David Guyer, Chief Executive Officer and Chairman of Ophthotech; Dr. Samir Patel, President and Vice Chair; Mr. Mike Atieh, Executive Vice President and Chief Financial and Business Officer; and Mr. Todd Smith, Senior Vice President and Chief Commercial Officer.

In addition, we have with us today Dr. Pravin Dugel, Managing Director at the Retinal Consultant of Arizona and Clinical Professor USC Eye Institute Tech School of Medicine. Dr. Dugel leads one of the largest retinal practices in the country and is an internationally recognized KOL. Dr. Dugel will discuss the preliminary results of an investigator sponsored study conducted by physicians at the Retinal Consultant of Arizona and presented recently at the Angiogenesis Meeting regarding Fovista combination therapy in anti-VEGF resistant patients.

Before we begin, I would like to note that Dr. Dugel's comments today will reflect his own conclusions, opinions and analysis and do not necessarily reflect Ophthotech's conclusions, opinions and analysis. And also to remind you that today we will be making forward-looking statements relating to Ophthotech's future expectations regarding its financial results, potential receipt of milestone payments, clinical and regulatory development and commercialization plans.

These statements constitute forward-looking statements for purposes of the Safe Harbor Provision under the Private Security Litigation Reform Act of 1995. These statements cover many events in matters that are subject to various risks that could cause actual results to differ materially from those expressed in any forward-looking statement. I refer you to our SEC filings and in particular to the risk factors section in our quarterly report on Form 10-Q filed on November 12, 2014 for a detailed description of the risk factors affecting our business.

In addition any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we disclaim any obligations to do so even if our views change. I would now like to turn the call over to David.

Thanks, Kathy, and thank you to everyone for joining us on the call this morning. 2014 was an important and very productive year for Ophthotech on multiple fronts. Let me briefly recap some of the highlights from the past year and early this year.

We remain on track with respect to the execution of our pivotal Phase III program evaluating the safety and efficacy of Fovista, our PDGF antagonist administered in combination with anti-VEGF therapy for the treatment of wet AMD. We are pleased with the recruitment rate in our Phase III program and believe that in the near future we will be in a position to provide more specific guidance with respect to the timing for completing patient enrollment. We expect to have initial top line data from the Phase III program available in 2016.

We believe that Fovista in combination with anti-VEGF therapy may alter relevant tissue responses in wet AMD which could translate not only into enhanced visual gain, but also prevent the inevitable vision loss typically seen in the anti-VEGF monotherapy treated eyes over the longer course of the disease. We have initiated our Fovista expansion program to evaluate this potential functional benefit in our anti-fibrosis trials.

As part of our Fovista expansion program, we are pleased to announce the initiation of our treatment burden reduction program to investigate the potential of Fovista combination therapy in reducing the treatment frequency associated with anti-VEGF monotherapy. Furthermore we expect to initiate this year a study in patients who have failed anti-VEGF monotherapy treatment. In connection with the concept of anti-VEGF treatment failure, as Kathy stated during the introduction, Dr. Pravin Dugel will shortly discuss the rational and role of PGF inhibition in anti-VEGF treatment resistant patients as part of this group's investigated sponsored trial pilot study.

The result of the study were recently presented at the Bascom Palmer Eye Institute Angiogenesis, Exudation and Degeneration meeting in Miami. In addition we are pleased to announce that ARVO has accepted the study as a poster presentation and congratulations for this acceptance are in order for Dr. Dugel and his colleagues.

Let us now turn to Zimura, our complement factor C5 inhibitor. Complement factor C5 is a central component of the complement cascade believed to play a role in the development and/or progression of age-related macular degeneration. We have recently initiated a Phase II trial of Zimura in combination with anti-VEGF therapy for patients with polypoidal choroidal vasculopathy, a variant of wet AMD.

On the dry AMD front, we previously completed a Phase IIa trial with Zimura monotherapy and geographic atrophy, a dry form of AMD. We are continuing internally and with our consultants to refine our clinical, regulatory, strategic and commercial plans for our Zimura dry AMD program and expect our Phase II/III dry AMD trial to begin in the second half of this year.

As a reminder, in November 2014 we announced that we entered into an option agreement for tivozanib for non-oncological ocular indications. This is a highly potent selective small molecule of VEGF tyrosine kinase inhibitor. These properties are attractive for successful development of a sustained release formulation, which we believe will be important for the long-term or maintenance phase of wet AMD management. We have begun work on an ocular formulation and we hope to provide more guidance in the second half of 2015.

Before handing the call over to Samir and Dr. Dugel, let me briefly turn to our Fovista ex-US licensing and commercialization agreement with Novartis. Last year we entered into one of the largest ex-US partnering deals in biotech. Thus far we have received a total of $250 million in upfront fees and enrollment milestone payments.

These fees received from Novartis consisted of a $200 million upfront fee upon the execution of the agreement in May of last year and a $50 million enrollment-based milestone fee received in October. An additional $80 million in potential enrollment-based milestone payments remain available under the agreement.

In addition we are eligible for contingent future US marketing approval and sales milestones totaling up to $700 million which include marketing approval milestones totaling up to $300 million and ex-US sales milestones totaling up to $400 million as well as a mid 30% range royalty on ex-US net sales on Fovista as a stand alone product throughout the world. Ophthotech retains all US rights to Fovista.

Finally we ended the year with a strong financial foundation of $463.6 million in cash, cash equivalents and marketable securities. This strong financial foundation will enable us to execute on our business plans for 2015 and prepare us for 2016.

With that I would like to turn the call over to Samir.

Thank you, David. Our Phase III program for Fovista in treatment (inaudible) is recruiting well and designed to investigate the superiority of Fovista in combination with anti-VEGF therapy compared to anti-VEGF monotherapy. The underlying rationale is based on overcoming anti-VEGF resistance by PDGF inhibition.

Anti-VEGF drugs are effective in wet AMD owing to their anti-permeability properties, that is by addressing leakage associated with visual loss in wet AMD. Typically they are ineffective at distributing or modifying the underlying pathology of neovascularization. Pericytes are cells which cover and protect the endothelial cells over these abnormally growing new blood vessels. They are dependent on PDGF for survival, and therefore blocking PDGF with Fovista has been shown to induce stripping of pericytes.

The resulting neovascular tissue is therefore highly vulnerable to anti-VEGF effects. This enhanced antiangiogenic effect often manifests as reduction or resolution of the neovascular complex and potential inhibition of it's sequela such as fibrosis. We believe this potential disease modifying effect by dual antagonism of PDGF and VEGF may translate into visual improvement in the wet AMD patients.

One application of this mechanism of anti-VEGF resistance could be in patients with a suboptimal response to anti-VEGF monotherapy. Dr. Dugel and his partners recently investigated this treatment resistance as part of a pilot IST study. We are delighted to have Dr. Dugel join us today to discuss the design and findings of that ongoing pilot study.

Thank you, Samir, and I appreciate the opportunity to discuss the findings from my group regarding our IST pilot study. We have a large retina practice covering the State of Arizona. Therefore most of our patients are diagnosed with age-related macular degeneration, or AMD. It is well established that anti-VEGF monotherapy results in a majority of wet AMD patients not achieving significant visual gain. On average, over the long term, patients either have no vision improvement or actually continue to loss vision.

As Samir pointed out, overcoming anti-VEGF resistance by PDGF inhibition may help our patients in a number of clinical scenarios which can be conveniently studied in patients with treatment naive disease or anti-VEGF treatment resistant patient groups. First, in the patients with treatment naive disease, the rationale and proof of concept has been well established by Ophthotech's Phase I and particularly a 449-patient Phase IIb study with Fovista combination therapy. I look forward to the results of the ongoing large confirmatory Phase III study.

In addition, other companies such a Regeneron, have also announced anti-PDGF related programs. This provides greater confidence on the target and hopefully multiple options for physicians like me and for my patients in the near future.

Second is the issue related to patients previously treated with anti-VEGF but who have had poor response. Given the limitation of anti-VEGF monotherapy over the long term, we predictably had a large pool of patients with suboptimal response to the anti-VEGF monotherapy. How we manage these patients has been a challenge in our practice as well as elsewhere since we really don't have many effective options.

Typically most of us switch anti-VEGF agents in this setting because all the currently used anti-VEGF agents are similar in efficacy. Predictably most switch studies show no improvement in vision despite an improvement in OCT in some reports. If the concept of addressing anti-VEGF resistance is applicable to treatment naive patients, there's no reason to believe that a similar rationale doesn't exist in anti-VEGF resistant patients.

We have an ongoing, open-label, 24-month anti-fibrosis pilot study at our practice which was a precursor to Ophthotech's current large multi center anti-fibrosis study. 30 patients have been enrolled and all have crossed the three-month time point. The vast majority, and to be exact, 27 out of these 30 are anti-VEGF treatment resistant, as defined in most prior studies with similar demographics, that is they have persistent or recurring [view] with no improvement in visual function. Importantly, they have previously received an average of 25 anti-VEGF injections prior to enrollment into our study.

What we found at the three-month time print, which is after three doses of Fovista administered in combination with Eylea or Avastin, if at on average patients gain 7.07 letters on standardized visual acuity charts. Particularly exciting is that the rationale for this pilot anti-fibrosis study was the hypothesis that pre-treatment with anti-PDGF prior to combination therapy may lead to an enhanced antiangiogenic affect.

In fact, the 10 patients who received pre treatment of Fovista gained an average of 11.10 letters versus 4.70 letters than those without pre-treatment at the three-month time point. It is quite encouraging when one considers the strong scientific rationale and functional improvement compared with most anti-VEGF switched studies.

However, one must caution that there are drawbacks to this study. As in most other anti-VEGF switch studies, our study was not controlled, had a small sample size and standardization and visual acuity measurements and a prior drug regimen was not uniform. We eagerly await a well designed post-spected trial to answer important questions regarding anti-VEGF treatment resistant given the significant unmet need for our patients.

For completeness, the remaining 3 patients in our study of 30 patients who are treatment naive after three monthly doses of Fovista combination therapy gained an average of 17.66 letters of vision. Thank you, Samir.

Thank you, Dr. Dugel. We appreciate the effort of your group in this trial and sharing the preliminary results. I would now like to share other updates prior to turning the call over to Mike.

We are excited to announce the formation of a Translational Scientific Advisory Board. Joining this Board are two distinguished members, Doctors Rakesh Jain and David Cheresh. Both are global leaders in the basic science and therapeutic application of pathologic angiogenesis.

Dr. Rakesh Jain is currently the Andrew Werk Cook Professor of Tumor Biology at Harvard Medical School and Director of the Edwin Steele Laboratory for Tumor Biology at the Massachusetts General Hospital. Dr. Jain has been a recipient of numerous awards and elected to the Institute of Medicine, the National Academy of Sciences and the National Academy of Engineering. He has over 600 publications to his credit and his pioneering concepts of normalization of pathologic neovascularization following antiangiogenic therapy has provided the key scientific underpinnings for the development of Fovista in combination with anti-VEGF for wet AMD.

Dr. David Cheresh is currently the distinguished Professor in the Department of pathology at the UC San Diego School of Medicine, and previously Professor at the Scripps Research Institute and the Department of Immunology. Dr. Cheresh has been a leader in identifying key pathways and mediators of pathologic angiogenesis in tumors.

With over 200 publications to his credit, his seminal publication in nature highlighting VEGF as a negative regulator of pericyte function and vessel maturation has provided the rationale for the highest [deep] that Dr. Dugel just discussed in our ongoing anti-fibrosis study.

Last, at the American Academy of Ophthalmology Meeting in November 2014, Dr. Usha Chakravarthy presented retrospective data from our Phase IIb trial regarding the potential anti-fibrosis affect of Fovista 1.5 milligram combination therapy based on an independent masked review. At the Macular Society this week, Dr. Chakravarthy will provide a further update regarding a dose response relationship with the respect to the potential anti-fibrotic effect of Fovista combination therapy in wet AMD.

I will now turn the call over to Mike.

Thank you, Samir. Here's a brief update on our results of operations.

Collaboration revenue, which we recognize under the Novartis agreement, was $1.7 million and $41.3 million for the quarter and year ended December 31, 2014. As a reminder, the Company did not have revenue during the comparable periods in 2013.

Research and development expenses were $22.2 million for the quarter ended December 31, 2014, compared to $15.4 million for the same period in 2013. R&D expenses were $88.4 million for the year ended December 31, 2014 compared to $33.2 million for 2013.

The increase in R&D expense in the quarter and year ended December 31, 2014 relates primarily to the Fovista Phase III clinical program including clinical trial costs and cost to manufacture Fovista, and increased compensation expenses associated with additional research and development staffing. Also contributing to the increase during the year was a milestone payment of $19.8 million that we made to a third party licensor in June 2014 in connection with entering into the Novartis agreement.

General and Administrative expenses were $10.7 million for the quarter ended December 31, 2014 compared to $5.1 million for the same period in 2013. G&A expenses were $33.4 million for the year ended December 31, 2014 compared to $14.2 million in the same period in 2013.

The increased general and administrative expense in the quarter and year ended December 31, 2014 relates primarily to increases in cost to support the expansion of the Company's operations including the Company's public Company infrastructure and the hiring of additional management and corporate staffing, increased professional services and consulting fees, and increased share-based compensation.

The Company reported a net loss for the quarter ended December 31, 2014 of $35.9 million, or $1.06 per diluted share compared to a net loss of $20.4 million, or $0.65 per diluted share for the same period in 2013. The Company reported a net loss for the year ended December 31, 2014 of $98.2 million, or $2.95 per diluted share compared to the net loss of $57 million, or $6.34 per diluted share for the same period in 2013.

Cash, cash equivalents and marketable securities totaled $43.6 million at December 31, 2014 compared to $210.6 million at December 31, 2013. And now I will turn the call back over to David.

Thank you, Mike. In summary, we continue to move the Company forward with our Phase III Fovista program, the initiation of our Fovista expansion program and the continuing development of Zimura.

Thank you for your time this afternoon and for your continued support. I will now turn the call over to the Operator so we can open up the lines for any questions.

(Operator Instructions)

Yigal Nochomovitz, Oppenheimer.

Maybe if I could start with Dr. Dugel. You saw a solid effect, as you mentioned, of the pre-treatment regimen before dosing the anti-VEGF. So I'm wondering if you see any room there for further optimizing that pre-treatment window with Fovista?

And then for David or Samir, I'm wondering assuming you do validate that idea of pre-treatment in the ongoing anti-fibrosis trial, is that a concept -- is that pre-treatment concept something that you might consider advancing into a treatment-naive study down the road, which obviously would be an interesting strategy relative to some competitors that are aiming to co-formulate these mechanisms? Thanks.

That's a great question, and thank you for asking that. Of course what gives me confidence in pre-treatment is that it's really based on robust and good scientific data. Every time we inject anti-VEGF, we up-regulate PDGF, and it would make intuitive sense to go ahead and blunt that up regulation. And that's why we decided to see if we could test that hypothesis of pre-treatment.

Now pre-treatment in this trial has been done one day apart. Whether that could be lengthened, whether that could be changed will really be data based. And I think we have a lot more work to do, but I think it's very exciting that this concept of pre-treatment, which is so based on science, may actually be encouraging as far as the IST is concerned. As I say, it's a small study, we have to be cautious, but it is encouraging.

Great, this is Samir. Thanks, Yigal. First, in the Phase 3 program, it's designed to establish the relevance of the combination therapy and enhancing visual outcome compared to monotherapy. And really that is predicated on the results in our Phase 2 study.

If we were to go ahead and draw the analogy from lessons we've learned from anti-VEGF therapy, most of the registration trials -- initial registration trials, really were based on either monthly therapy of the anti-VEGF agents, or in the case of Eylea, after an induction dose, a bimonthly regimen. Yet the way physicians typically use the anti-VEGF agents in the marketplace is more of a flexible regimen and differing flexible regimen.

So with that data in there as the background, when we look at the IST data that Dr. Dugel has, and you also look at our anti-fibrosis study, which consists both of treatment-experienced patients and treatment-naive, we'll have some data to go by for confirmation. And so based on that, we certainly think, in light of the IST, that the treatment of distant population will look at some pre-treatment regimen there.

And to your specific question on the treatment-naive, yes, we think that we're going to look at it, and we will look at what the data shows on the anti-fibrosis. And if it's confirmatory, it certainly -- just like an anti-VEGF monotherapy era that we see people looking at different regimen to optimize -- sorry, to optimize the regimen for outcome, it's something we'll certainly consider.

Okay, great. Thanks, Samir. And then I had a question on the reduction of treatment burden study. I guess we don't really know too much in the way of details about the design of that study. Could you provide us anything more there, in terms of whether it's going to be randomized or a single arm?

And if it is randomized, a little bit more detail on how the scheduling would work for the two arms? Would there be cases where you might dose Fovista without the anti-VEGF because you're seeing the need for less anti-VEGF? Or would you just space everything out so that the patients that are getting less anti-VEGF would also just get Fovista at more distant time points?

Yigal, this is Samir. To be clear, this is for treatment burden you're talking about?

Yes, yes.

Sure, so I think, first, when we talk about treatment burden, the way we approach that is, currently in most trials with monotherapy anti-VEGF, notwithstanding the bimonthly regimen that Eylea is shown to be effective after the induction dose, any quarterly regimen, to the best of our knowledge, has not shown to be beneficial.

And so, when we think about reduction of treatment burden, the basis is as follows. That neovascular regression and disease [modification] occurs via combination therapy. And if we were to take a lesion and make it a smaller lesion, if you will, then perhaps there are -- there aren't as many [side events] produced driving the disease and its activity, and perhaps less frequent need for injections will be necessary. I think there is some suggestion with anti-VEGF monotherapy that smaller lesions don't require as much treatment.

So with that as a background, that's where we think combination therapy falls. As far as the specific design is concerned, although all anti-VEGFs are roughly similar with respect to their safety and efficacy, the ideal regimen has yet to be established, and yet to be established particularly with combination therapy in a quarterly regimen. So what we're doing is we're looking at all the anti-VEGF agents, Lucentis, Eylea, and Avastin, and after the induction dose -- after the induction regimen, look at a quarterly regimen and see what the visual response is.

Because, we know that none of the anti-VEGF agents have shown a sustained beneficial effect with quarterly regimen, at least those that have been studied. So if we're able to establish that, we'll see which anti-VEGF agent that the regimen is most promising, and we'll look at the program in a more randomized fashion with one or any combination of other anti-VEGF agents.

Okay, great. And then on the new trial you announced for Zimura, number one, could you say what anti-VEGF therapy you're planning to combine with, or maybe it's all of them? And then, also, why do you see Zimura as potentially better suited to treat this polypoidal choroidal vasculopathy versus all wet AMD?

And, I have also understood that PCV patients may respond a little better to photodynamic therapy versus anti-VEGF, so did you also consider a design with Zimura plus PDT, in addition to the one you've just announced today with the plus anti-VEGF? Thanks.

Yigal, thank you, this is Samir again. This is very exploratory because we don't have the body of data with polypoidal lesions that we have with the non-polypoidal variety, which are typically what are used in most of the trials. So I think, as we stand today, it's very difficult to say what the true response is.

So before committing ourselves to a larger sample size trial, we just want to look at if there's an inflammatory component involved in these lesions. And although the studies typically have been conflicting, I think it's reasonable to state that there is a belief that they don't respond as well with anti-VEGF therapy. And to use photodynamic therapy would introduce another confounder.

So I think that we'd like to see is those patients, at least in this pilot study, that have failed, how are they responding with the combination of anti-VEGF and Zimura? And those that are treatment-naive, are we getting a uniform response before we go into a larger study? But, we would not be using photodynamic therapy in that setting and stick with pharmacotherapy. As far as anti-VEGF agents, to the best of my knowledge, I think physicians can use any anti-VEGF agent of their choice.

Great and David --

If this could be the last question to make sure we get to the other people in the queue as well.

I'm sorry, sure. David, real quick for tivo, could you say anything more about the type of sustained-release technology that you're exploring, and what have you learned about the viability of that approach since the deal back in November? Thanks.

Nothing more that we can say at this point, but we'll have updates as we make further progress.

Great, thanks so much.

Terence Flynn, Goldman Sachs.

Was wondering if you can share any more details on design of the Zimura Phase 2/3 dry AMD trial? Is it going to be all [comers], how many doses you're looking at, if there's any interim data that's going to come out of the Phase 2 portion?

And then, my second question was can you give us any update on the potential to explore combinations of Fovista with any of the Novartis anti-VEGF drugs? Thanks.

Sure, so we are presently finalizing our review both internally and with our consultants on the clinical regulatory strategy strategic and commercial for the Zimura dry AMD geographic atrophy program. And so really we can't provide anything more now, but we'll be doing that shortly. As far as again the Novartis proprietary anti-VEGF, since they are taking the lead there and it's their compound, we can't make any comments about that program either.

Eric Joseph, JPMorgan.

(Inaudible) A couple questions for Dr. Dugel to start. Wondering how non-responder wet AMD or resistant patients are generally defined both in this study, both in your pilot study and also in practice? And wondering if you had any insight into the durability of the persistency of the activity that you've observed to date, and whether there's anything pre-clinically or clinically that would point to the maintenance or possible waning of these effects over time?

Yes, thank you for the question. What you need to know is that in our study, the patients that were included, again it was a 30-patient study, 27 of those patients were previously treated, and the average number of infections that they had, that's anti-VEGF injections, prior to enrollment into the study was 25. And, the treatment interval between the injections was than six weeks or less in 89% of patients.

So these patients were treated often and were treated a lot prior to enrollment into our study. So these patients were defined as patients with persistent fluid or recurrent fluid with anti-VEGF monotherapy. And this is a large pool of patients that we have in real life, and these are the patients that really have the unmet need.

Okay, great. And on the point of durability of activity?

Well, this is a three-month study that I report, I just reported the results of a three-month look at that study. This is a 24-month anti-fibrosis IST that I'm conducting, so there will be a lot more data coming out. The next data set that will come out will be, as David earlier said, in a poster in ARVO.

Okay great, thanks. And maybe a question for Samir, David, if I could. Wondering if you could talk about how you view the size of the resistant wet AMD population relative to the overall population? And also, whether you could provide a little more detail around the size and scope of the [non-responder] trial that's currently in planning? Thanks.

Sure, it's Samir. So I think it's hard to put real numbers, but I don't think anybody would deny that it's a very large population. Because, at one end of the spectrum, if you just take the simple randomized studies that were registration trials, which demonstrated that monthly administration of anti-VEGF at one year time point, two-thirds of the patients are not able to achieve significant patient gain. And, about half of the patients aren't able to get visual acuity of 20, 40 or better, which most states require driving.

I think really very important to see the real-world phenomenon. And if you look at the data that came out of Great Britain, where they used electronic medical records and looked at big data, if you will, 92,000 intravitreal anti-VEGF injections, and you see that even at two years, on average, patients are at baseline where they presented are actually losing vision. And you must understand that patients, typically when they present to physicians with neovascular AMD, have already lost some vision.

So we're talking about the two-year time point, staying at that visual loss or actually even worse. And then, if you think about the fact that we've had anti-VEGF therapy, the current anti-VEGF therapy, initially introduced in 2006, and the volume continues to grow, there is a very large percentage of patients that are treatment resistant or poor responders, if you will.

And then if you -- with respect your question for our study, I think it's reasonable to think about the patient population, as Dr. Dugel indicated, those that have persistent fluid, recurrent fluid, or any combination of those with no improvement in visual acuity. And, I think that, although it gives us great confidence to see patients who had an average of 25 injections and failed, typically those eyes, as you can imagine, are quite progressed with variable degree of atrophy and fibrosis. We'd probably think about patients who have been treatment resistant over a six-month or a year period, and then try to introduce combination therapy. And pre-treatment will certainly play some role in that design.

Okay, great. Thanks very much.

(Operator Instructions)

Joseph Schwartz, Leerink Partners.

You've already done a lot of work to provide a lot of strong scientific support around your clinical approaches. So I was curious if you could talk a little bit more about what your goals with the Translational Scientific Advisory Board are, and what we can look forward to hearing more from you on that front?

It's a great question, Joe, it's Samir. I think we're so fortunate to have two individuals that, really their work is at the heart and soul of why we developed Fovista in the first place. The whole concept of normalization of the vasculature is very -- it's consistent with what we see with anti-VEGF monotherapy.

If we look at patients who present with neovascular AMD and you don't treat them at all, maybe Dr. Dugel can comment more on this, in the days prior to anti-VEGF monotherapy, typically those patients ended up with an involuted disease and six-month (inaudible) with profound loss of vision. In the anti-VEGF era, these patients clearly have done a lot better, and yet it's over a four-, five-, six-year period that there's continued activity.

And what that really means is, compared to having no treatment, normalization has taught us that by anti-VEGF therapy you cause maturation of the vessels. And as a result, they continue to exist and succession of anti-VEGF therapy leads to reactivation. So if we understand that, that's how we design our Fovista trials to go ahead and create a neovascular immature bed so that neovascular regression could be affected and you could hopefully decrease the lifecycle of the disease and modify the underlying disease right there.

Dr. Cheresh's work is really the main impetus why we started the pre-treatment in the first place. This is a very transformational study in nature that he published showing VEGF as a negative regulator of PDGF, and really every time you inject anti-VEGF you get a rise in PDGF. And interestingly, Dr. Jain showed that many years ago in patients with rectal carcinoma, where administration of anti-VEGF led to increased pericyte coverage.

So both individuals' work intimately ties to what we're doing with pre-treatments. So, we believe we continue to leverage their expertise, they continue to give us guidance on additional ways to look at the regimen for treatment in neovascular AMD. Dr. Dugel, I don't know if you'd like to comment on the concept of maturation and what you've seen clinically?

Well, as a clinician I can certainly comment on that, and I'm certainly old enough to remember when we had no treatment and patients ended up going blind and they had fibrosis and a disciform scar. So there's no doubt in my mind that anti-VEGFs have revolutionized the way we treat patients. But, our clinical trials run for a year or two years or maybe three years, but in real life, the patients that I see, these patients aren't one- or two- or three-year patients, these patients are in my practice for many years, sometimes for decades.

And what I see in the real world is that these patients continue to require treatment, and as other studies have shown, gradually lose vision. And clearly there's a large unmet need here. So from a clinical standpoint, as a clinician, I have a pool of patients that could really use a treatment. And a possibility of the treatment coming forth I think is very exciting for me.

From a scientific point of view, it also makes sense that every time you inject with an anti-VEGF agent, you up-regulate PDGF. We know what PDGF does, which is that it recruits and matures pericytes and matures the neovascular membrane, forming a protective armor. We also know that PDGF is very pro-fibrotic, and over time, fibrosis is the biggest reason why patients lose vision, and that has been shown in many studies, including the CATT trial and IVAN.

So, I'm excited about the fact that this treatment strategy, the studies that are being done, the clinical trials that are being designed are really based on a very robust and firm biological foundation that exists. And I'm also very excited that we'll have answers. At the end of the day, we're going to have data.

There's a lot of things that we do right now that's really not based on data, things like treatment extend and things like switching agents and so forth. And I commend Ophthotech for designing studies proactively that will eventually allow me the data to make detailed scientific judgements on to treat my patients.

Thanks very much.

Stephen Willey, Stifel.

A quick one for Dr. Dugel. Obviously understanding that this is a 30-patient uncontrolled study, but wondering if there was any attempt to quantify the level of sub-retinal hyper-reflective material in these patients at baseline? And, in your clinical experience, does the magnitude of the changes in the SHRM correlate well to the changes that you see in visual acuity?

Thank you for the question. First of all, again I do want to caution you that this is a 30-patient study, in fact 27 patients who I reported as treatment resistant. So, it is an exploratory study, and all the shortcomings that this study has, I've explained that the switch studies have as well. So, you have to make sure that we realize that this is certainly not a definitive study.

But, again, we will have data. There's a larger anti-fibrosis study ongoing. You've heard about the treatment-resistant studies, you've heard about the treatment-burden studies. So again, the good news is that we are going to have data, we're not going to be left hanging.

As far as SHRM is concerned, I gain a lot of confidence in the Phase 2b study, which showed a direct relationship with the improvement in visual acuity with the reduction of SHRM. So there's -- it gives me great confidence that all the biological and markers are consistent with what we're seeing. And of course, we'll have data from a larger Phase 3 study.

We'll also have some data from IST, as well as all the other Fovista extensions that I've mentioned. But I think the concept that I'd like to bring forth here is that what we're seeing is consistent with the biology and that we will have data to make our judgment calls on.

Okay, and then I know that there was a mention of the pre-treatment in the previous question, and forgive me if I missed the details, but I understand that the Company's also sponsoring an open-label Phase 2a study evaluating pre-treatment versus simultaneous. And I'm wondering if there's any opportunity for there to be an interim data emerging out of that study that could maybe correlate some of the findings that Dr. Dugel is talking about?

Hi, it's Samir, Stephen. I'm not aware of a study that we've disclosed that has [pre-treatment]. Certainly, I mentioned that we would certainly be considering that. And, there is a pre-treatment component in the anti-fibrosis study. But based on recruitment, that's what really drives an interim data.

At this point, all I can state is the recruitment is quite strong, and we're going to do everything we can to complete the recruitment. And when and if the interim data are available, we'll certainly give you additional guidance.

Okay, thanks.

Yigal Nochomovitz, Oppenheimer.

David, just quickly, I know you mentioned that you were going to be giving some more specific guidance on the timing of enrollment in the Phase 3 soon, so we look forward to that. But I was wondering when you do report the Phase 3, should it be our expectation that all Phase 3 trials will report out at the same time? Or, could we see a staggered data release depending on timing of the three studies? Thanks.

Yes, as I mentioned, in the near future, that's the type of specific guidance that we will discuss. We're getting close.

Okay. And Dr. Dugel, real fast if I could ask, I was aware that in your interesting study, there were some differences in the visual acuity gains for the Avastin patients versus the Eylea patients. And, I was wondering if those differences could be explained based on the Avastin patients having the pre-treatment preferentially versus the Eylea patients? Thanks.

Well I think Fovista works with all anti-VEGFs, so I think it's completely agnostic to any anti-VEGFs and the biology would seem to indicate that as well. Again, it's a small study, there are only 27 patients that are analyzed, so I just don't think we can make any conclusion about one anti-VEGF or another. As far as I'm concerned, it worked with both, and it should be agnostic to all anti-VEGF agents.

Great, thank you.

It appears there are no further questions at this time. I would now like to turn the conference over to Dr. David Guyer for any additional or closing remarks.

Great, I just want to thank everyone for your interest today, and we look forward to further updates in the near future. Thank you.

This now concludes the presentation. Thank you for your participation.