IVERIC bio Inc (ISEE) 2017 Q2 法說會逐字稿

Good day, everyone, and welcome to the Ophthotech Corporation second quarter earnings 2017 conference call. Today's call is being recorded. For opening remarks, I would like to turn the conference over to Kathy Galante, Vice President, Investor Relations and Corporate Communications for Ophthotech. Kathy, please go ahead.

Good morning, and welcome to our second quarter 2017 earnings call. Representing Ophthotech today is Mr. Glenn Sblendorio, Chief Executive Officer and President, Dr. David Guyer, Executive Chairman, Dr. Kourous Rezaei, SVP, Medical Strategy, Mr. Dave Carroll, Chief Financial Officer, Mr. Keith Westby, Chief Operating Officer, and Mr. Vishal Kapoor, Head of Business Development.

I would like to point out that you can access the Company's corporate presentation by going to the events section of our investor relations page on our website. I would like to also remind you that today we will be making statements relating to Ophthotech's future expectations regarding operational, financial and development matters including statements regarding the implementation of our strategic plan, our projected use of cash and cash balances, the timing, progress and results of clinical trials and other development activities, the potential utility or commercialization of any of our product candidates, and our business development strategies including any potential in-license or acquisition opportunities. These statements constitute forward-looking statements for purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995. These statements cover many events and matters that are subject to various risks that could cause actual results to differ materially from those expressed in any forward-looking statements including risks related to the initiation and conduct of clinical trials, availability of data from clinical trials, expectation for regulatory matters, need for the additional financing and negotiation and consummation of in-license and/or acquisition transactions. I refer you to our SEC filings and in particular to the Risk Factors section in our Quarterly Report on Form 10Q filed on May 3, 2017 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 of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we disclaim any obligation to do so, even if our views do change. I would now like to turn the call over to Glenn.

Thanks, Kathy, and good morning, everybody. We appreciate you joining our call this morning. It's a pleasure to address you today as the Company's Chief Executive Officer. I'm thrilled to be working with David Guyer in his role as Executive Chairman and with the highly committed and experienced members of this team that you get to hear from later in the call or during the Q&A.

We are very excited to move the company forward with a vision of becoming a leader in the development and commercialization of ophthalmic therapeutics for orphan diseases and for back of the eye indications such as age related [brief audio interruption] company with multiple ongoing or planned clinical programs and one preclinical program in orphan retinal disease. This coupled with multiple ongoing or planned clinical trials in back of the eye retinal indications.

During our business strategy review, which we conducted over the past 6 months following our February announcement, it became apparent to us that there's a tremendous unmet need for ophthalmic orphan drugs. We believe that there are many opportunities to develop orphan drugs for ophthalmic diseases and that we are well positioned to execute on a strategy to leverage our clinical experience and retinal expertise to identify and develop science driven therapies to treat multiple ophthalmic orphan diseases where there are limited or no treatment options available to patients.

We believe that by leveraging our unique ophthalmic experience and by focusing on orphan eye diseases, we will have multiple potential opportunities to bring ophthalmic therapeutics to the market. You are undoubtedly familiar with some of the additional advantages afforded in the development and commercialization of orphan drugs such as regulatory exclusivity and the potential for accelerated development for some of the orphan retinal indications. This potential for a reduction in the timeline required for a drug approval in an orphan indication would be more attractive for patients afflicted with these unfortunate conditions as well as benefitting our shareholders.

During our strategic review process, we also reassessed our ongoing clinical trials and additional opportunities related to Zimura, our C5 complement inhibitor, with the same rigor employed during the diligence in connection with third party opportunities. This included a thorough review of scientific literature regarding the role of complement in multiple ophthalmic diseases and associated market opportunities. Following the thorough diligence and market assessment, we have reached a decision to focus and accelerate the development of Zimura in multiple ophthalmic indications.

First and foremost, our commitment is guided by the scientific promise to seek out the best opportunities to build this Company. We firmly believe that that is the Stargardt and Zimura programs. Following our detailed research and analysis, we are planning to pursue a portfolio of clinical programs that includes first a randomized control clinical trial to assess the efficacy and safety of Zimura for Stargardt disease that we plan to initiate before the end of the year.

Second, a modified Phase 2a trial of Zimura in combination with anti-VEGF therapy in wet age-related macular degeneration, or AMD, that we plan to initiate before the end of 2017. Third, a Phase 2a clinical trial of Zimura in combination with anti-VEGF therapy for idiopathic Polypoidal Choroidal Vasculopathy which is a rare form of wet AMD that primarily afflicts the Asian population. This we also plan to begin before the end of the year.

Fourth, continuation of our Phase 2/3 trial of Zimura as monotherapy for treatment of geographic atrophy, a form of dry AMD. We will reassess its status after the results of a competitor's complement GA trial are available, which is expected by yearend.

And fifth, a potential Phase 2a clinical trial of Zimura monotherapy in non-infectious, intermediate/posterior uveitis, which we expect to start in 2018.

For Fovista, a potential preclinical trial for therapy in retinoblastoma also expected to initiated in 2018. As you are aware and as we've talked about in the past, the National Eye Institute is conducting a Phase 1/2a trial of Fovista in combination with anti-VEGF therapy for capillary retinal hemangioma in Von Hippel-Lindau syndrome. We believe that we have sufficient financial resources to initiate these programs and develop them to key brief audio interruption led by the soon to be started Zimura monotherapy trial for Stargardt disease which is a devastating inherited retinal orphan disease that causes vision loss possibly leading to blindness during childhood or adolescence for which patients have no FDA approved options for treatment.

Supporting the Company's strategy for the development of Zimura in Stargardt disease are recently published, independent peer reviewed papers that highlight the potential role of complement inhibition in Stargardt disease. Additionally, the favorable clinical safety data on Zimura from our early stage AMD trials provides a basis for us to proceed directly to a randomized, controlled trial to assess the safety and efficacy of Zimura in Stargardt Disease. We intend to work closely with the FDA over the coming months to discuss the regulatory pathway for this program and plan to start the study, as I mentioned before, before the end of the year.

Our diligence has led us to team up with the Foundation Fighting Blindness, FFB, a highly distinguished organization recognized for its scientific commitment to orphan inherited retinal degenerative diseases. Kourous will further discuss the potential scientific rationale for complement inhibition in Stargardt disease and our relationship with FFB in more detail in a few moments.

In parallel, we are committed to our ongoing age-related retinal programs for Zimura. As many of you recall, the early Phase 1/2a studies that were completed with Zimura provide a foundation for development. But over the past few years, the development of Zimura progressed at quite a modest pace since we had invested the majority of our resources in the Fovista Phase 3 program. David will provide more details on the ongoing age-related retinal programs for Zimura later in the call.

It's important to have multiple shots on goal to augment the chances of commercializing meaningful therapeutics in order to maximize shareholder value. Therefore, we will continue to aggressively pursue our business development efforts, particularly focusing on opportunities in back of the eye. However, we are not limiting ourselves. Over the past several months we have reviewed a large number of assets and technology platforms that we are actively continuing to review in a prudent manner which would potentially fit into our strategic goals in addition to possible other compelling ophthalmology opportunities. As our diligence on these opportunities moves forward, we shall see if any transactions materialize.

Additionally, we will continue to work with Leerink Partners to assist management and the board in evaluating the Company's strategic alternatives. We have worked extensively with Leerink to look at everything from in-licensing or obtaining rights to products, product candidates or technologies, to acquisitions and mergers and reverse mergers. We are committed to being opportunistic and will consider them if new compelling opportunities arise.

In summary, we are committed to delivering treatments to patients with devastating ophthalmic diseases where there is unmet medical need and that also can create value for our shareholders. Before I turn the call over to Kourous, I'd like to introduce him formally to you. Some of you may have met him, but Kourous joined Ophthotech over two years ago and is Senior Vice President of Medical Strategy. He is a board-certified ophthalmologist who specializes in medical and surgical treatment of vitreoretinal diseases. Dr. Rezaei is an associate professor of ophthalmology and Director of the Vitreoretinal Fellowship Program at Rush University Medical Center and is a senior partner at Illinois Retina Associates in Chicago. It's my pleasure to turn the call over to Kourous who will describe in more detail the exciting science connecting complement with Stargardt disease.

Thank you, Glenn, and good morning, everyone. We are very excited about the new preclinical scientific evidence that potentially connects complement activation to Stargardt disease and we are hoping to validate this connection in a clinical trial. Stargardt disease is the most common form of juvenile macular degeneration, potentially leading to blindness in young adults and impacting approximately 32,000 to 41,000 patients in the United States. The most common inheritance pattern is the autosomal recessive impacting the ABCA4 gene, the so-called Stargardt type 1. Currently there is no FDA approved therapy for this devastating disease.

In a peer review and manuscript in the prestigious Journal of Proceedings of National Academy of Science, PNAS, researchers from the University of California Los Angeles, UCLA, demonstrated that complement inhibition rescued the degeneration of light absorbing specialized retinal cells called photoreceptors in the albino ABCA4 knockout mouse in model 4 autosomal recessive Stargardt disease. Photoreceptors are cells that absorb light in the retina and convert it into a visual signal. They are intimately associated and integrated with a layer of cells referred to as retinal pigment epithelium cells, or RPE cells. One of the main functions of RPE cells is to recycle and process the resulting byproducts or waste product produced by photoreceptors following light absorption. In Stargardt disease, due to the genetic defect [brief audio interruption] RBE cells are unable to adequately process these waste products. It is ultimately brief audio interruption buildup and escalation of waste products known as bisretinoids in RPE cells.

The accumulation of bisretinoids not only activates the complement system, but also impedes the clearance of complement proteins in RPE cells. The end result of all three complement pathways is the production of membrane attack complex, or MAC. MAC accumulation inside the RPE cells impacts the energy production department, the so-called mitochondria, which can further damage the cells. Therefore, there is a two-hit phenomenon damaging the RPE cells, waste accumulation and MAC accumulation. The consequence of RPE cell damage is photoreceptor death and therefore vision loss.

In the albino ABCA4 knockout mouse model, the role of complement activation leading to photoreceptor damage was investigated. Complement inhibition resulted in approximately twofold decrease in waste accumulation and led to the rescue of photoreceptor cells which was quantified at an approximately 30% increase in the number of photoreceptor nuclei. This suggests that the complement inhibition may potentially lead to healthier RPE cells, reduction in the progression of Stargardt disease, and improved visual outcome relative to natural history. Independent confirmation was also noted from investigators at Duke University, demonstrating that the cell damage resulting from the combination of complement activation and the waste accumulation was far more damaging than either component individually. And when complement, in particular C5, was blocked, there was a significant improvement in RPE cell viability invitro.

We believe that the findings from these studies provides a compelling preclinical rationale for the potential role of complement inhibition to address the urgent unmet medical need in Stargardt disease. One could hypothesize that complement therapy may be successful in treating Stargardt disease since their job is known to be localized problem with waste management and complement activation while the rest of the eye machinery remains intact. We also believe that in general, individual injection is more targeted to the disease and a better option than a systemic approach.

As Glenn indicated, we have entered into an agreement with the Foundation Fighting Blindness who have recently completed the largest natural history study in Stargardt disease to date which is referred to a ProgStar. FFB is a highly distinguished organization recognized for its scientific commitment to orphan inherited retinal degenerative diseases with an established network of scientists and products and patient registry. We have engaged FFB to provide us brief audio interruption with our orphan programs. In conclusion, we are excited about the potential for Zimura to provide treatment options for patients with a significant unmet need secondary to inherited eye disease. I will now turn the call over to David Guyer. David?

Thanks, Kourous. As Glenn had mentioned, over the past few years, the development of Zimura progressed at a modest pace because the majority of our time and resources were dedicated to the Fovista Phase 3 program. While Zimura was being developed behind Fovista, we have been encouraged by the role of complement inhibition for wet AMD for some time and have completed a Phase 1[brief audio interruption] to find a significant visual gain which is higher than what is generally seen with anti-VEGF monotherapy. All doses were well tolerated with no safety concerns identified.

Our trial had a small sample size consistent with a Phase 1/2a study and no controls. So while potentially a signal, these findings clearly need to be further validated, which we are planning to do. Further, there have been some interesting new developments regarding the role of complement in anti-VEGF therapy. As you may be aware, one of the main reasons for loss of vision in patients receiving anti-VEGF monotherapy for wet AMD is the development of geographic atrophy as reported by the CATT trial. Almost 20% of the patients at 2 years, and approximately 38% at 5 years, developed atrophy. When one looks at biologic systems, there is generally a reason for certain physiologic or pathologic tissue responses taking place. As it turns out, based on a very recent publication from the Scripps Laboratories in San Diego, VEGF upregulates complement factor H which is complement inhibitory factor. One may assume that the production of VEGF in the retina may be in part a tissue response to suppress a complement upregulation in AMD. However, VEGF has its own side effects including leakage and angiogenesis. In patients with wet AMD, the anti-VEGF monotherapy not only blocks the leakage and angiogenesis, but also potentially blocks the complement suppressive effects of VEGF. These studies showed that VEGF suppression led to complement activation. As you may imagine, an agent that activates complement could in part not only contribute to the geographic atrophy that retinal specialists observe, but may also explain the ceiling effect that is observed with anti-VEGF monotherapy in wet AMD patients. Therefore, we believe that supplementing anti-VEGF therapy with an anti-complement agent such as Zimura in wet AMD, may have the potential to further enhance the efficacy of anti-VEGF monotherapy and decrease its potential unwanted side effects.

As Glenn mentioned, we are excited about initiating a new Phase 2a trial to assess whether we can replicate our previous 1/2a findings. Due to a new study design and updated enrollment criteria, we'll cease enrollment in our original Phase 2a study of Zimura in this indication. Further, we will also be assessing a new dosing regimen before committing to a larger and more costly trial. This trial is scheduled to start before the end of the year.

Our Phase 2/3 clinical trial of monotherapy Zimura for the treatment of geographic atrophy, a form of dry AMD, is ongoing. We decided to maintain a limited number of trial sites until the results of a competitor's Phase 3 clinical trial for complement inhibition in geographic atrophy is available in the second half of 2017. We will make the necessary strategic decision for this trial after the competitor's results are announced.

Turning to Fovista, we expect that the development program for the treatment of wet AMD will be primarily determined by the initial topline data from OPH1004, the wet AMD trial of Fovista in combination with Eylea or Avastin compared to Eylea or Avastin monotherapy and in light of the two failed Phase 3 clinical trials of Fovista in combination with Lucentis compared to Lucentis monotherapy. Data from the Fovista OPH1004 trial are expected in the third quarter of this year. We believe that the failure of the two previously completed Phase 3 clinical trials and the failure of a competitor's phase 2 trial investigating the combination of a PDGF inhibitor and a VEGF inhibitor for AMD, are indicative of a low likelihood of success for OPH1004.

We want to leave enough time for Q&A, so I'll now turn the call over to Dave Carroll who will briefly review the Company's second quarter 2017 results.

Thank you, David. I'd like to direct everyone to our press release from this morning where we reported our Q2 results. I'd like to provide a few highlights, review our expected yearend cash balance, and also describe the financial impact of our recently revised Novartis agreement.

For the quarter, our net loss totaled $22.2 million or $0.62 per share compared to a net loss of $29.9 million or $0.85 per share for Q2, 2016 as lower R&D and G&A expenses offset a decline in collaboration revenues. Year to date, our net loss totaled $65.3 million or $1.82 per share compared to a net loss of $66.2 million or $1.88 per share for 2016. Again, as lower R&D and G&A expenses offset a decline in collaboration revenues.

Turning to our cash balance, our cash balance at June 30 was approximately $196 million. The Company expects its 2017 yearend cash balance to range from $145 million to $160 million excluding any potential business development activities or any other changes to the Company's current clinical development programs. This range reflects the impact of our age-related development programs for Zimura and Fovista including the winddown of the Fovista Phase 3 trials. We expect the incremental costs of advancing our ongoing and new clinical programs to their next phase of clinical development will range from $25 million to $35 million, much of which will be incurred after 2017. We believe that we have sufficient resources to accomplish these tasks.

Finally, we expect to substantially complete our organizational restructuring in the third quarter. Once it's completed, we expect our cash corporate overhead expenses to be approximately $2 million per month.

Turning to the financial impact of our recently revised Novartis agreement, in July we revised our licensing and commercialization agreement with Novartis. As a result, we expect to recognize collaboration revenue of between $175 million to $195 million in the third quarter. Please note that this will not impact our cash position or our cash taxes paid. Thank you. I would now like to turn the call back over to Glenn

Thank you, Dave. First I'd like to thank all of you for listening to our call today. I would summarize by saying that we believe we have a pipeline of planned and ongoing clinical trials for both orphan retinal diseases and back of the eye indications. We truly look forward to discussions with all of you not only today but in future calls and meetings. And again, thank you. I will turn the call over to the Operator for questions.

(Operator Instructions) We will take our first question today from Yigal Nochomovitz with Citigroup.

Thanks very much for taking the questions and the updates on the pipeline. I appreciate the comments of Stargardt. However, could you just talk a little bit about the rationale for Zimura in noninfectious uveitis? That would be interesting. As well as the rationale for Fovista in retinoblastoma.

Yigal, thank you for your questions. Regarding noninfectious, intermediate or posterior uveitis, uveitis in general is an inflammatory eye condition where you have inflammation in the back of the eye that leads to decreased vision. And as you know, in general complement activation usually leads to inflammation. The idea is that by blocking complement you decrease inflammation in the back of the eye and decrease the severity of uveitis. Regarding retinoblastoma, there have been reports showing that cell lines for retinoblastoma do express PDGF receptor and blockage of PDGF receptor may have an impact on the proliferation of these cells. The potential idea is that it may be, and an original blastoma generally metastasizes by having seeds which are cells in the vitreous that then spread around in the body. And the idea and potential is to have untied PDGF prevent the proliferation of these cells and prevent the consequences.

Are you at this point able to provide any more details on the design of the Stargardt trial with respect to the size of the study and any other details around the types of patients you'd enroll?

At this point the trial is going to be a controlled trial, randomized trial. Regarding the more details, we are finalizing that internally and we will keep you posted.

On idiopathy polypoidal, IPCV, I recall that several years ago actually, you had started a study with Zimura plus anti-VEGF. It was a very small study, I think it was less than 10 patients. So is the announcement of the Phase 2a for that a restart of that study or are you starting a new study? Can you just clarify given that there was some earlier work there? Thanks.

You are absolutely correct that initial study was just looking at the safety signals. It was a very small study as you indicated. Now, based on the new information we have regarding the role of complement and anti-VEGF together, we are doing another trial looking at the larger number of patients to see if there is a signal regarding using complement inhibition in polypoidal patients.

Finally, Glenn, if you could just provide a little bit of color on the BD front. Obviously you said you've looked at a lot of assets. I'd just be curious if you've refined your sort of target set of what you're looking for and what the cadence for bringing something into the company might look like over the next 12 to 18 months. Thanks.

Yes, so we have looked at a lot of different opportunities. I think the focus has been on back of the eye and I think as we generated more data in the area of orphan, we did look at a number of orphan diseases. We haven't found anything that fits our strategy and there's a whole bunch of reasons as to why. One, it could have been knocked out because of diligence. Two, value expectations on a lot of these assets were much higher than we expected. So we continue to look. I think what we had seen over the first 6 months is a lot of inbound. I think now that we've refined to orphan retinal diseases and back of the eye, it allows us then to target specific opportunities. So I think the effort there, a number of people in the organization not only working on the operational programs, but also supporting Vishal in BD. So we'll continue to look aggressively. And Leerink has been a good partner in this in identifying a number of opportunities. So the long answer to your question, we're going to continue to look, but be sure that we find the right things that fit our strategy.

Tyler VanBuren, Cowen & Company.

I have three. I guess the first one would be related to the Zimura geographic atrophy program and it makes total sense that you guys are waiting to see what happens with the LAMP Phase 3 results at yearend. But maybe you guys could just be as specific as possible with respect to the results that you would like to see with the Phase 3 LAMP program, kind of what percentage on the primary endpoint would be interesting to you guys with respect to what you've heard from consultants.

Well I think at the end of the day, the question becomes that whether the endpoint specifically the primary endpoint or the secondary endpoints are met. Whether we believe that there is a clinical significance in that, in the results that we think we should pursue further our own program. So it all depends. It's generally totality of data comes and then we have to just evaluate it and go from there.

Understood. I guess the second question would be with respect to the Stargardt program. There's been -- I've been aware of several programs in the past historically over the years that have kind of been stuck in Phase 2 and none of them have really progressed to the later stages. So maybe you could just kind of talk about the history of development for various drugs in this particular indication, what the approach has been and why maybe they haven't been successful?

Thank you, that's a very good question. I'd rather not comment on other's drugs. But I have to comment on this, the general philosophy as indicated. We believe that individual delivery provides higher success rate than systemic delivery. In the brain we have the blood/brain barrier and in the eye we have the blood/retinal barrier. To get a systemic drug reaching high concentrations inside the eye generally is quite difficult. As has been shown in the past. When you go to higher dosages, then you may face systemic safety issues. So we are very positive regarding being able to deliver individual Zimura into the eye where we want to get the local impact without having any safety issues. And I think that is one of the differentiating points for Zimura in comparison to previous drug that has been developed.

Okay, that makes sense. And you showed obviously the twofold decrease in waste accumulation and the 3% increase in the photoreceptor nuclei. But can you just comment on maybe any functional improvements that you saw in the mouse models with the preclinical data? Was that measured?

This is a very good question. You know, when the study in the mouse model was, they transfected the mice with a CRRY protein which is something analogous to complement factor H in humans. Which is suppressive complement. Because it was a gene therapy treatment, it had localized impact and it's generally very difficult to measure function since the rest of the retina is damaged from (inaudible). So they were not able to do functional analysis. It was all anatomic analysis.

Great. And just wrapping it up, I guess is it fair to say of all the kind of new programs that you guys announced, earlier programs that in your eyes Stargardt is potentially has the most supportive evidence and is the most interesting? And I guess regardless of that answer, when could we see some exciting proof of concept data from these programs, whether it's the Stargardt program or others?

You are absolutely correct, we are extremely excited regarding Stargardt and the role of complement in Stargardt disease. At this point our plan is to initiate the program in the second half of 2017. Currently we cannot give you any information regarding the data readout.

I think once we talk more about the design, we'll give you some clarity on what those milestones may be, but a little premature until we talk about the design.

Joseph Schwartz, Leerink Partners.

I was curious if you could talk about any work that you've done to show that you can modulate the various complement negative regulatory proteins which are believed to drive some of the retinal degeneration in Stargardt such as CD46. Because as you mentioned, the mouse work that's been published recently was with a different gene therapy construct than your Zimura obviously. So I was wondering what work have you done to show or what leads you to believe that you can potentially derive a benefit from Zimura from targeting the same bad actors in that disease?

That's a very good question, thanks for asking. We have not done directly Zimura. However, a study was done from Duke University and what they looked at was they looked at incubated retinal pigment epithermal cells with complement or with this waste product, so this retinal exam. What they found out was that when you incubate with each of them individually, you get a decrease in viability. But once you incubate them together, you get significantly more decrease in viability in the cells that was more than each of those components individually. Interestingly, when they incubated those cells with anti-C5 antibody, it shows there was an increase in viability indicating that a C5 blockage prevents cell; death in this model.

Further, it is interesting that you have, as I discussed earlier, we have the membrane attack complex that accumulates. And one of the things they found that specifically in the retinal pigmented epithelial cells that I discussed earlier, that this mac accumulation in the cells itself damages the RPE cells. For example, impacting the mitochondria which is where the cell has [entered]. Now by blocking C5, you prevent MAC formation and therefore accumulation and that's why we think that blocking the C5 maybe has a major impact on this condition.

On the geographic atrophy program that you're currently monitoring, the Lampalizumab outcome to help you decide whether or not it makes sense to move forward there, are there scenarios where Lampalizumab could fail or deliver a modest clinical benefit but the reasons that you think that Zimura might be better in some way and be differentiated and it makes sense to advance it nonetheless?

It's David, Joe. I think in general we would want to see a robust result giving primary endpoints, important secondary to really show that there is proof of concept for the mechanisms of action. But saying that, obviously you have to look at the full picture. We do believe that there are potential advantages of Zimura, but we would like to use those more in the context of a proven positive trial. Although we can't definitively say that we do see the whole result that will be made public to get a sense on what the story may be, but I think it's fair to say in general we're really looking for appositive proof of concept. Obviously it's a gigantic market and there will be multiple players in it.

Stephen Willey, Stifel.

I guess you're giving cash guidance yearend in the $145 million, $160 million range, and I guess I'm just kind of curious as to how much of that will be needed to fund all of the studies that are expected to initiate this year and next. I guess I'm just asking the question in the context of just trying to think about how much remaining bandwidth you have on the business development front.

Thanks for the question. I'd direct you back to my comments. We gave sort of guidance around that. We were saying that to initiate an event to initiate an event, these programs to the next phase of clinical development, $25 million to $35 million.

Understood, sorry I missed that. And just with respect to the changes that you're making I guess in the Phase 2a wet AMD study, I think you mentioned some updated enrollment criteria changes. Can you elaborate a little bit more on how this study is going to differ from the prior study?

The differentiating factor is that we're going to have treatment naïve patients with wet macular degeneration who were in the previous trial had treatment experience.

And that's the only difference?

(inaudible) there are also, we are also doing dose ranging studies with Zimura in combination with (inaudible).

Stephen, just for clarity, the older trial I'll call it, the one that was existing, that trial will be stopped. There were very few patients and we'll start with the new one. So it's not a continuation of that. It's, as Kourous said, a new start.

Anupam Rama, JPMorgan.

Hey guys, it's Eric in for Anupam. Thanks for taking the question. I guess most of our ours have already been asked. But maybe I'm just wondering if you could comment a little bit more on sort of how Stargardt patients are -- what therapies are currently used to sort of manage them even though as you note, there is nothing currently approved for the indication. And secondly, perhaps you could contracts Zimura to sort of some of the other investigative antibody approaches that have been taken in macular degeneration and how they kind of might differ in terms of binding CR and inhibiting MAC complex formation. Thanks.

Could you repeat the first question again?

Yes, just trying to get an understanding of what medical interventions are currently available for Stargardt patients even though as you note there is nothing currently approved for the indication.

There is nothing, as you have pointed out yourself, there is nothing approved by the FDA or the European Agency for the treatment, so there is obviously no solid treatment. What anecdotally how patients are being treated, I cannot really comment on, especially since this is an orphan indication with very few, with not that many patients. And the second question?

Just how does Zimura being (inaudible) kind of contrast with antibody approaches in binding C5 and inhibiting MAC complex formation based on some of the preclinical studies that you've done.

One of the advantages regarding (inaudible) what we feel long term would be to use it for sustained release. I think it will provide that advantage over what other type of molecules are currently being used. That is one of the advantages.

Ladies and gentlemen, this does conclude our question and answer session. I will turn it back to management for closing remarks.

Thank you, everyone, for listening in today. We are excited by the programs that we presented today and we look forward to continued updates. Have a good day.

Ladies and gentlemen, thank you for your participation. This does conclude today's conference. You may now disconnect.