IVERIC bio, Inc.
Q2 2017 Earnings Call Transcript

Published: 26 Jul 2017

[Operator:]

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.

[Kathy Galante:]

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, Senior Vice President, 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 event session of our Investor Relations page on our Web site. 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 result of clinical trials and other developments activity; the potential utility or commercialization of any of our product candidate and our business development strategy 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 trial, availability of data from clinical trials, expectation for regulatory matters, need for the additional financing and negotiation and confirmation of in-license and our acquisition transaction. 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 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.

[Glenn Sblendorio:]

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 a 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 indication such as age-related [Technical Difficulty] company with the ongoing or planned clinical programs and one pre-clinical program in orphan retinal disease, this coupled with multiple ongoing or planned clinical trials and back of the eye retinal indications. During our business strategy review which we conducted over the past six months following our February announcement, became apparent to us there is a tremendous unmet need for ophthalmic orphan drugs. We believe that there were 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 rightful expertise to identify and develop science driven therapies to treat multiple ophthalmic orphan diseases which 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. We are undoubtedly familiar with some of the additional advantages afforded in the development 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 benefiting 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 vigor employed during the diligence in connection with third-party opportunities, this included a thorough review of the scientific literature regarding the role of complement in multiple ophthalmic diseases and associated market opportunities. Following the thorough diligence in 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's part of our Zimura programs. Following our detailed research and analysis, we are planning to pursue a portfolio of clinical programs that include; 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 ageing 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 competitors complement GA trial are available which is expected by year end. And fifth, a potential Phase 2a clinical trial of Zimura monotherapy a non-infectious, intermediate posterior uveitis, which we expect to start in 2018. For Fovista, a potential pre-clinical trial for therapy in retinoblastoma also expected to initiate in 2018. As you are aware, we have 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 to develop them to [Technical Difficulty] led by the soon to be started Zimura monotherapy trial for Stargardt disease, which is a devastating inherited retinal orphan diseases that causes vision loss, possibly leading to blindness during childhood or adolescence which patients have no FDA approved options or treatment. Supportive of the company strategy for the development of Zimura in Stargardt disease, our recently published independent peer review papers that highlight the potential role of complement inhibition in Stargardt disease. Additionally, a favorable clinical safety data on Zimura from our early stage AMD trial provides a basis for us to perceive directly to a randomized controlled trial to access the safety -- to access the safety and efficacy of Zimura in Stargardt disease. We intent to work closely with the FDA over the coming months to discuss the regulatory pathway for this program and plan to start this study as I mentioned 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 in our relationship with FFD 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 addressed 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 during 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 and 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 towards potentially fit into our strategic goals in addition to possible other compelling ophthalmology opportunities. As our diligence on these opportunities moving 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] [ph] the company's strategic alternatives. We have worked extensively with Leerink to look at everything from in-licensing or obtaining rights to product, product candidate or technologies to acquisitions and mergers and reverse mergers. We are committed to being opportunistic and we 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 would like to introduce him formally to you; some of you may have met him. But, Kourous joined Ophthotech over two years ago, a 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 Associated Professor of Ophthalmology and Director of Vitreoretinal Fellowship program at Rush University Medical Center and is a senior partner at Illinois Retinal Associate 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.

[Kourous Rezaei:]

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 United States. The most common inheritance pattern with 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 of 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 a model for Autosomal Recessive Stargardt disease. Photoreceptors are cells that absorb light in the retina and convert it into visual signal. They are intimately associated and integrated with the layer of cells referred to as retinal pigment epithelial cells or RPE cells. One of the main functions of RPE cells is to recycle and process the resulting byproducts always by the -- produced by photoreceptors following light absorption. In Stargardt disease due to the genetic defect [Technical Difficulty] RPE cells are unable to adequately process these waste products. It is [Technical Difficulty] build up and accumulation of waste products known as bisretinoids in RPE cells. The accumulation of bisretinoids not only activates the complement system, but also impede the clearance of complement proteins in RPE cells. End result of all three complement pathways hit 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 cell. 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 with investigator. Complement inhibition resulted in approximately two-fold decrease in waste accumulation and led to the rescue of photoreceptor cells, which was quantified as 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 [Technical Difficulty]. Independent confirmation was also noted from investigators at the Duke University demonstrating the cell damage resulting from the combination of complement activation and waste accumulation that's far more damaging than either component individually. And when complement in particular C5 first block there was a significant improvement in RPE cell viability in vitro. We believe that the finding from these studies provide the compelling preclinical rationale or the potential role of complement inhibition to address the urgent unmet medical need in Stargardt disease. [Technical Difficulty] successful intruding Stargardt disease since the [geologists] [ph] known to be localized problem with waste management and complement activation, while the rest of the eye machinery remain intact. We also believe that in general intravitreal 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 a Foundation Fighting Blindness was recently completed the largest natural history study in Stargardt disease to-date which is referred to as ProgStar. FFB is a highly distinguished organization recognized for its scientific commitment for orphan inherited retinal degenerative diseases with an established network of scientist and a robust patient registry. We have engaged every [Technical Difficulty] 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?

[David Guyer:]

Thanks Kourous. As Glenn had mentioned over the past few years the development of Zimura progress had 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 [Technical Difficulty] to find a significant visual gain which is higher than what is generally seen with anti-VEGF monotherapy. While all doses were well-tolerated with no safety concerns identified. Our trial had a small sample size consistent with the 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 a development of geographic atrophy as reported by the [CAT] [ph] trial. Almost 20% of the patients of two years and approximately 38% at five 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 Laboratory in San Diego, VEGF upregualtes complement factor age which is a complement inhibitory factor. One may assume that the production of VEGF in the retina maybe in part a tissue response to suppress the complement upregulation in AMD. However, VEGF had its own side-effects including leakage in angiogenesis. In patients with wet AMD, the anti-VEGF monotherapy not only blocks the leakage in angiogenesis but also potentially blocks the complement suppressive effects of VEGF. These study show 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 specialist observe, but may also explain the ceiling effect that it is absorbed with anti-VEGF monotherapy in wet AMD patient. Therefore, we believe that supplement in 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 the 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, little seasonal enrollment in our original Phase 2a study in Zimura in this indication. Further, we will also be assessing a reference 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 competitive space three clinical trials were complement, inhibition and geographic atrophy is available in the second half of 2017. We will make the necessary strategic decision for this trial after the competitors' 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 top-line data from OPH1004, the wet AMD trial of Fovista in combination with a layer or Avastin compared to a layer 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 trial and the failure of competitors 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 will now turn the call over to David Carroll, who will briefly review the company's second quarter 2017 results.

[David Carroll:]

Thank you, David. I would like to direct everyone to our press release from this morning where we reported our Q2 results. I would like to provide a few highlights to review our expected year-end 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 2016, as lower R&D and G&A expenses offset to decline collaboration revenues. Year-to-date our net loss $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 the decline in collaboration revenues. Turning to our cash balance, our cash balance at June 30 was approximately $196 million, the company expects 2017 year-end cash balance arrangement from $145 million to $160 million excluding any potential business development activities or any other changes for the company's current clinical development program. This range reflects the impact of our age-related progress for Zimura and Fovista including the wind out of the Fovista Phase 3 trial. We expect the incremental cost representing our ongoing and new clinical program to their next phase of clinical development 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. But, we expect to substantial 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 between $175 million to $195 million in the third quarter. Please note that this will not impact our cash position or our cash taxes aide. Thank you. I would now like to turn the call back over to Glenn.

[Glenn Sblendorio:]

Thank you, Dave. First, I would 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 plan and ongoing clinical trials of 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:]

[Operator Instructions] We will take our first question today from Yigal Nochomovitz with Citigroup.

[Yigal Nochomovitz:]

Hi, guys. Thanks very much for taking the questions and for the updates on the pipeline. I appreciate the comments on Stargardt. However, could you just talk a little bit about the rationale for Zimura in non-infectious Uveitis that will be interesting as well as the rationale for Fovista in retinoblastoma? Thank you.

[Kourous Rezaei:]

Yigal, thank you for your questions. Regarding non-infectious 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 line of retinoblastoma do express PDGF receptor and blockage of PDGF receptor may have an impact on the proliferation of this cell. The potential idea is that it may be -- and retinoblastoma generally metastasizes by having seat which are cells intravitreous doesn't spend around in the body. And the idea potentially is to have anti-PDGF prevent the proliferation of these cells and prevent metastasis.

[Yigal Nochomovitz:]

Okay. Thanks. 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 classifications [indiscernible]?

[Kourous Rezaei:]

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

[Yigal Nochomovitz:]

Okay. Thanks. Now, on idiopathic polypoidal, IPCV, I recall that several years ago actually you had started 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 the new study. Can you just clarify given that there was some earlier work there? Thanks.

[Kourous Rezaei:]

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.

[Yigal Nochomovitz:]

Okay. Thanks. And finally, Glenn, if you could just provide a little bit of color on the BD front, obviously, you said you looked at a lot of assets, but just to be curious if you refine your sort of target set of what you are looking for and what the cadence for bringing something into the company might look like over the next 12 to 18 months? Thanks.

[Glenn Sblendorio:]

Yigal, we have looked 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 is 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 the -- what we had seen over the first six months, there is a lot of inbound, I think now that we will refine to orphan retinal disease is in the back of the eye. It allows us to target specific opportunities. So, I think the effort there are a number of people in the organization not only working on the operational program, but also supporting [indiscernible] and BD. So, we will continue to look aggressively and Leerink has been a good partner in identifying a number of opportunities. So, well, the answer to your question, we are going to continue to look, but be sure that we find the right thing that fit our strategy.

[Yigal Nochomovitz:]

Okay. Thank you very much.

[Operator:]

We will take our next question from Tyler Van Buren with Cowen & Company.

[Tyler Van Buren:]

Hey, good morning guys. Thanks for taking the questions. 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 year end. But, may 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 heard from consultants?

[Kourous Rezaei:]

Thank you for the question. At the end of the day the question becomes that whether the endpoints specifically -- the primary endpoint or the secondary endpoints are met whether we believe that there is a clinical significant in depth in the results that we think we should pursue for our own programs. So, it all depends, it's generally totality of data comes and then we have to just evaluate it and go from there.

[Tyler Van Buren:]

Understood. Okay. And I guess, the second question would be with respect to the Stargardt program, there has 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 and there is particular indication what the approach has been and why may be they haven't been successful.

[Kourous Rezaei:]

That's a very good question. I rather not comment on others drugs, but in a general philosophy as indicated, we believe that intravitreal delivery provide higher success rates 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 concentration inside the eye generally is quite difficult as we have shown in the past. And we go to higher dosages then you may face systemic safety issues. So we are very positive regarding being able to deliver intravitreal Zimura into the eye where we are -- want to get the low cost impact without having any safety issue. Then, I think that is one of the differentiating points for Zimura in comparison to previous drug that has been developed.

[Tyler Van Buren:]

Okay. That makes sense. And you showed obviously the two-fold 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?

[Kourous Rezaei:]

This is a very good question. When the study in the mouse model was -- they transpected the mice with a CRYY protein, which is something analog to complement factor age in human, which is suppresses complement because it was a gene therapy treatment, it localize impact and in generally very difficult to measure function, since the rest of retina is being -- is damaged from the result. So, they were not able to do functional analysis. It was c anatomic analysis.

[Tyler Van Buren:]

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 it 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 a Stargardt program or others?

[Kourous Rezaei:]

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.

[Glenn Sblendorio:]

Yes. Tyler, I think once we talk more about the design introduce some clarity with those milestones may be but little premature until we talk about the design of course.

[Tyler Van Buren:]

Understood. Look forward to it. Thank you.

[Operator:]

We will go next to Joseph Schwartz with Leerink Partners.

[Joseph Schwartz:]

Thanks very much. Some of my questions have been asked already. But, I was curious if you could talk about any work that you have done to show that you can modulate various complement negative regulatory proteins, which are believed to drive some of the retinal degeneration in Stargradts, such as CD-46, because as you mentioned that the mouse works that's been published recently was with a different gene therapy construct. So, then your Zimura, obviously, so, I was wondering what work have you done to show or what leads you to believe that you can potentially drive a benefit from Zimura from targeting the same bad actors in that disease?

[Kourous Rezaei:]

That's a very good question. Thanks for asking. We have not done directly as Zimura. However, study was done from Duke University. What they looked at was, they looked incubated retinal pigment epithelial cells with complement or with this waste products or this retinal. 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 showed there was an increase in viability indicating that it's a C-5 blockage prevents the cell that is in the model. Further, it is interesting that you have -- as I discussed earlier we have the membrane attack complex that accumulate and one of the things they found that specifically in the retinal pigment epithelial cells that they discussed earlier that this MAC accumulation in the cell itself damages the REP cells. For example, impacting the mitochondria, which is where the cell [Technical Difficulty]. Now, by blocking C-5, you prevent a formation and therefore accumulation and that's what we think that this is blocking the C-5 maybe -- have a major impact in this condition.

[Joseph Schwartz:]

Okay. Thanks. And then, on the geographic atrophy program that you are currently monitoring the lampalizumab outcome for to help you decide whether or not it makes sense to move forward there. Is there other scenarios where lampalizumab could fail or deliver a modest clinical benefit. But the reason that you think that Zimura might be better in some way and be differentiated and it makes sense to advance it nonetheless?

[David Guyer:]

It's David, Joe. I think in general we would want to see a robust result hitting primary endpoints support secondary to really show that there is a proof of concept for the mechanism of action. But, saying that obviously you have to look at the whole picture that we do believe there are potential advantages of Zimura. But, we would like to use those work in a context of improving positive trial, though we can't definitely say that until we see the whole result that would be made public to get a sense on what this trial maybe. But, I think it's fair to say in general we are really looking for a positive proof of concept, obviously, its gigantic market and there will be multiple players in.

[Joseph Schwartz:]

That's helpful. Thank you for taking my questions.

[Operator:]

We will go next to Steven Willey with Stifel.

[Steven Willey:]

Yes. Good morning. Thanks for taking the questions. So, I guess you are giving cash guidance year-end 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 this study that are expected to initiate this year and next? I guess I'm just asking the question on the context, so just trying to think about how much remaining bandwidth you have on the business development front?

[David Carroll:]

Thanks for the question. I direct you back to my comments, need sort of guidance around that. You are saying that to initiate an event -- program to the next phase of clinical development $25 million to $35 million.

[Steven Willey:]

Understood. Sorry, I missed that. And just with respect to the changes that you are making I guess on 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?

[Kourous Rezaei:]

Event changing factor is that we are going to have treatment naïve patients with wet MAC or degeneration were in the previous [Technical Difficulty].

[Steven Willey:]

And that's the only difference?

[Kourous Rezaei:]

[Technical Difficulty] and there are also -- we are also doing dose ranging studies with Zimura in combination with [Technical Difficulty].

[David Guyer:]

And Steven just for clarity the older trial, I call one that was existing, the trial will be stopped, there were very few patients and then they will start with the new one. So, it's not a continuation of that's -- of course, anything new story.

[Steven Willey:]

Okay. Thanks for taking the questions.

[Operator:]

We go next to Anupam Rama with JPMorgan.

[Eric Joseph:]

Hi, guys. It's Eric in for Anupam. Thanks for taking the question. I guess most of the questions have already been asked. But, maybe I'm just wondering if you could comment a little bit more on sort of Stargardt patients are -- what therapeutics are currently used to manage them even though as you there is nothing currently approved for the indication. And secondly, perhaps, you could contrast Zimura to sort of some of the other investigative antibody approach that should have been taken and macular degeneration and how they kind of might differ in terms of finding C5 inhibiting that complex formation? Thanks.

[Glenn Sblendorio:]

Could you repeat the first question again?

[Eric Joseph:]

Yes. Just trying to get a understanding of what medical interventions are currently available for Stargardt patients even though as you know there is nothing currently approved for the indication?

[Kourous Rezaei:]

There is nothing as you pointed. You saw 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 special since it is an orphan indication with very few -- with not that many patients. And the second question?

[Eric Joseph:]

Just how does Zimura being an aptamer kind of contrast with antibody approaches in binding C5 and inhibiting MAC complex formation based on some of the preclinical studies that you done?

[Kourous Rezaei:]

One of the advantages regarding aptamer what we feel long-term would be to use it for a certain release. That I think we will provide the advantage over what other type molecule that currently being used. And I think that is one of the advantages.

[Eric Joseph:]

Got it. Thanks for taking the questions.

[Glenn Sblendorio:]

Thanks Eric.

[Operator:]

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

[Glenn Sblendorio:]

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

[Operator:]

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