ISEE (2019 - Q3)

Good day, and welcome to IVERIC Bio's Third Quarter 2019 Results Conference Call. Today's conference is being recorded. At this time, I would like to turn the conference over to Kathy Galante. Please go ahead. Kathy Ga

Good morning, and welcome to IVERIC Bio's conference call. Representing IVERIC Bio today are: Mr. Glenn Sblendorio, Chief Executive Officer and President; Dr. David Guyer, Executive Chairman; Dr. Kourous Rezaei, Chief Medical Officer; Mr. David Carroll, Chief Financial Officer; and Mr. Keith Westby, Chief Operating Officer. I would like to remind you that today, we will be making statements relating to IVERIC bio's future expectations regarding operational, financial and research and development matters, including statements regarding our expectations to use our previously announced clinical trial of Zimura for the treatment of geographic atrophy as a pivotal trial, our development strategy for Zimura, our hypothesis regarding complement inhibition as a mechanism of action for the treatment of geographic atrophy, our projected use of cash and cash balances, the timing, progress and results of clinical trials and other research and development activities, the potential utility and development potential about product candidates and the potential for our business development strategy. These statements constitute forward-looking statements for the 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 statement, including risks relating to the initiation and the progress of research and development programs and clinical trials; availability of data from these programs; reliance on university collaborators and other third parties; establishment of manufacturing capabilities; expectations for regulatory matters; need for additional financing and negotiation; and consummation of business development transactions and other risks. 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, 2019, 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 except as required by law. I would now like to turn the call over to Glenn.

Thanks, Kathy, and good morning. everyone. As always, we appreciate you joining our call this morning. As you are aware, two weeks ago, we announced that intravitreal administration of both the 2 milligram and the 4 milligram doses of Zimura, our novel complement C5 inhibitor met the pre-specified primary efficacy endpoint with statistical significance and clinical relevance in our OPH 2003 randomized double mass share control clinical trial for geographic atrophy, secondary to dry age-related macular degeneration. We're very excited about this and it offers a potential to positively impact and transform the lives of dry A and B patients with GA, which leads to profound and irreversible vision loss. The study was specifically designed with randomization, double masking and sham control to potentially serve as an initial registration trial, provided that Zimura was well tolerated and the efficacy benefit over sham met statistical significance. This was pre-specified both in our protocol and statistical analysis plan. Furthermore, since reporting the initial top line results, independent biostatisticians have confirmed to us that our pre-specified sensitivity analysis reflect marked robustness, supporting the primary analysis. Hence, the company's priority would be to move Zimura forward in GA secondary to dry A and B in the most expeditious way. Here are key activities: first, we believe the present trial, OPH 2003, can serve as our first pivotal trial for registration. We believe that only one additional pivotal randomized, double masked, sham controlled clinical trial will be needed to demonstrate the safety and efficacy of Zimura in GA secondary to dry MD in the manner sufficient to support regulatory approval in this indication. This assumes that the full data set continues to support top line results that we reported and is subject to regulatory review to assess the robustness of these data if and when we seek approval. Second, we are initiating the second pivotal Phase 3 clinical trial with the goal of enrolling our first patient in the first quarter of 2020. Our clinical team has significant drug development experience, operational expertise and clinical know-how in conducting clinical trials for retinal diseases, and we are already in the process of identifying U.S. and international clinical trial sites to complete the second pivotal trial in the most expeditious manner. Third, we will initiate the second pivotal clinical trial utilizing our balance sheet cash. We estimate that the total expected cost of the second pivotal Zimura clinical trial in GA could range between $30 million and $40 million depending on final trial design, with additional external CMC cost for process development validation, which is like to range between $10 million and $20 million. We are of course exploring all options for future development of Zimura, including plans for potential partnering. This past weekend, the previously announced top line data were presented at the International Symposium on Ocular, Pharmacology and Therapeutics, also known as ISOP, in Valencia, Spain. These data have also been accepted to be presented at the Asian Pacific Vitreoretinal Society in Shanghai, China, November 22 through the 24, 2019. Age-related macular degeneration or AMD is the most common cause of visual loss in developed countries, especially in people older than 50 years old of age. As the worldwide population continues to live longer, the prevalence of AMD is only going to increase, with a reported projection of 196 million in 2020 and 288 million in 2040 worldwide. Dry AMD is reported to account for 85% to 90% of all AMD cases. Wet AMD, which accounts for approximately 10% to 15% of all AMD cases, has various anti-VEGF treatment options available to patients. However, there are no currently USFDA or EMEA approved treatment options available for patients with dry AMD or GA, which is the most advanced form of dry AMD, indicating an urgent and significant unmet medical need. In addition to GA secondary to dry AMD, we are also assessing the safety and efficacy of Zimura in a Phase 2B randomized, double masked, sham controlled screening trial in patients with autosomal recessive Stargardt disease. Earlier this year, we completed patient enrollment in this trial and it is on track with initial top line data expected in the second half of 2020. In addition to complement integration, hdrA1 inhibition may also play a role in the progression of GA. We here are also continuing preclinical development of our hdr1 inhibitor program, and expect to file an IMD for this program in 2021. While bringing Zimura to patients is an important priority, we also have a deep commitment to move forward our gene therapy portfolio in orphan inherited retinal diseases. Natural history studies in IMD enabling activities for IC-100, our adoption VA ADRP program are on track. We expect to initiate a Phase 1 2 clinical trial for IC-100 in patients with RHO ADROP in the second half of 2020. IVERIC Bio is now in a strong position of having a diversified retina focused portfolio with Zimura as a late stage clinical program for large market retinal disease and an early stage gene therapy programs in inherited retinal diseases. We are committed to efficiently progress these programs and create value for shareholders. Before I turn the call over to Kourous, I'd like to remind everyone that we will be hosting a Zimura R&D symposium for investors and analysts on Wednesday, November 20 from 8 a.m. to 10 a.m. in New York. The event will feature a presentation of previously announced clinical trial results, Zimura program in GA secondary to dry AMD and will include discussions with retinal specialists and key opinion leaders in AMD. We hope you'll be able to attend. Please reach out to Kathy if you're interested in registering for this event. And I'd now like to turn the call over to Kourous.

Thank you, Glenn, and good morning, everyone. As Glenn mentioned, we recent reported that Zimura, our novel complement factor C5 inhibitor, met its pre-certified primary endpoint in reducing the rate of growth of geographic atrophy in patients with dry AMD in a randomized, double masked, sham controlled screening clinical trial that we believe can serve as the first of two pivotal trials for registration purposes. The reduction in the mean rate of GA growth with square root transformation over 12 months was 0.11 millimeters with a P value of 0.0072 for the Zimura 2 milligram group, as compared to the corresponding sham control group, and 0.124 millimeters with a P value of 0.0051 for the Zimura 4 milligram group, as compared to the corresponding sham control group. This corresponds to an approximately 27% relative reduction over 12 months for each group. These data for both those groups were statistically significant. Although efficacy data from patients receiving Zimura 1 milligram was not part of the pre-specified statistical analysis, preliminary prescriptive analysis indicated that on average, the percent GA growth from baseline to month 12 for Zimura 1 milligram group was less than for the corresponding sham control group. Therefore, the overall data for Zimura suggests in those response relationship across treatment groups. Zimura was generally well tolerated over 12 months of administration. Over the first 12 months of the trial, there were no reported Zimura related adverse event, no reported Zimura related inflammation and there have been no discontinuations attributed by investigators to Zimura from the trial. Further, there have been no ocular serious adverse events, no retinal detachments, no Zimura related increase of internal pressure and no cases of endophthalmitis were reported in the study eye in this ongoing clinical trial. During the first 12 months of the trial, the incidents of coronary vascularization in the untreated fellow eye was 10 patients or 3.5%, and in the study eye of the sham controlled group was three patients or 2.7% in the Zimura 2 milligram group of six patients or 9%, and the Zimura 4 milligram group was eight patients or 9.6%. We believe the observed CNV incidence rate in the study eye for patients receiving Zimura as compared to sham in the untreated fellow eye during the first 12 months of the trial is within an acceptable range and lower than what has been reported in the literature for another complement inhibitor currently in development for GA. The trial remains ongoing until the month 18 time point is reached. We believe that potentially superior safety profile of Zimura and lower rate of CNV incidents may be in part due to blocking of double of C5 and C3. Therefore, based on the concept and profile of Zimura, we believe we may have an advantageous safety profile over our competitor in the patient population that we are seeking to treat. I would like to go into more detail on why we believe blocking C5 may provide similar efficacy to blocking C3, but with a potentially superior safety profile. The complement cascade is a complex and important part of the innate immune system, consisting of three pathways, converging C3 and subsequent information of C5 as affecter arms. C5 may lead to the formation of C5A and C5B. C5A may lead to inflammatory activation, and C5B may lead to memory attack complex formation, both potentially leading to cell death. We believe that by blocking C5, we may prevent retinal cell degeneration and therefore prevent or slow down the progression of GA. We believe this mechanism of action could explain the similar level of efficacy relative to sham that we observed in our trial, as compared to that for C3 inhibition, and we believe that it validates the role of complement C5 inhibition in AMD. The potential superior safety profile that could help differentiate Zimura is based on not blocking complement factor C3, which generally leads to the formation of C3A and C3B. In our experience with Zimura, it has been shown that C3A may have anti-angiogenic activity and the decrease is C3A based on inhibiting C3 could potentially increase the formation of abnormal blood vessels. Zimura blocks C5 and presents the potential anti-angiogenic characteristics of C3A, which may in part explain the lower incidence of CND observed in our trial when compared to the published clinical data for C3 inhibition. With all the customer caveats associated with cross trial comparisons, including differences in trial design and patient populations. The scientific research also suggests that C3B is potent in optimization and functions in a positive feedback loop, serving as a powerful tool for the immune system in effective currents of invading pathogens and thus, protect against infection. The eyes are an immune privileged organ, and as we know from clinical experience, is sensitive to intraocular infections such as endophthalmitis, which is considered to be a serious adverse event, potentially with severe visual consequences for the patient. Our zero endophthalmitis rate in the current Zimura trial in GA highlights the potential safety advantage of blocking C5 over the reported rate of endophthalmitis in the literature for C3 inhibition, which appears to be higher than what has been generally reported for intravitreal injections in the literature. It was recently reported by NEI in the Journal of Experimental Medicine that C3 may play a role in modulating macrophages to clear degenerated photoreceptors. Genetic ablation of C3 accelerated structure and function of photoreceptor degeneration and altered retinal inflammatory gene expression in the experimental model. We know in AMD that photoreceptors are already degenerating over time, due to the nature of the disease, and may not want to accelerate this process with C3 blockage since it could potentially lead to further vision loss. The authors highlighted the complexities of the role of complement in retinal diseases and indicated that one may, and I quote, require interventions to exert calibrated modulation rather than broad and complete inhibition for optima arthritic effects [indiscernible]. To conclude, in biologic systems, a fine balance needs to be reached between safety and efficacy, and one may not want to completely turn off the innate immune system inside the eye. Based on clinical trial data to date, we believe that blocking C5 downstream in the complement cascade appears to have in general similar efficacy in reducing the rate of GA growth, as compared to sham, as well as been reported for C3 inhibition, and by keeping C3 intact, targeting C5 may potentially be advantageous from a safety point of view, as well encouraged by the safety profile of Zimura demonstrated to date. Of course, it is difficult to draw conclusions from cross trial comparisons, and thus only future properly designed trials will answer this question scientifically. I would like to now change gears and give you more detail on our clinical trial design for Zimura in GA, the primary fixed endpoint were are targeting in geographic atrophy and the baseline characteristics of our trial. The Zimura trial for GA was designed as a screening trial based on the criteria described by Doctor Thomas Fleming and Bruno Richardson [ph] in a paper published in 2004 in screening trials used at the same time as the efficacies endpoint as the anticipated Phase 3 clinical trials, and would potentially be used to support a regulatory approval. However, a screening trial generally has a smaller sample size than the anticipated Phase 3 clinical trial. A screening trial similar to our Zimura trial has three possible outcomes. First, if the estimated effect size indicates lower levels of benefit, the experimental information would be judged as not plausibly more efficacious than the sham controlled, and should be discarded in its current dosage in the study's indication. Second, if the estimated effect size is moderate but clinically relevant with a relatively lower likelihood of being achieved, for example, it probably was less than 10%, if there truly was not effect, the trial information would be judged as possibly more efficacious than the sham controlled and should be evaluated differently in a subsequent Phase 3 clinical trial. And third, if the estimated effect size is more efficacious than the sham controlled with the certain evidence meeting the level of statistical significance, as was the case in our Zimura trial for both the 2 milligram and 4 milligram dose groups as compared to the corresponding sham controlled groups in GA, then the trial could count as a registration file and only one more paper trial would be required for regulatory approval. As indicated about the top line data for Zimura for GA secondary to dry A&D for both the 2 milligram and 4 milligram dose groups were statistically significant and we believe clinically relevant. Further, Zimura was generally well tolerated over 12 months. As Glenn mentioned earlier, based on our clinical trial design and assuming that the Zimura safety profile remains consistent with findings observed to date and subject to eventual regulatory review, we believe that only one additional pivotal, randomized, sham controlled clinical trial would be needed to demonstrate the safety and efficacy of Zimura in GA secondary to dry AMD in the manner sufficient to support regulatory approval in this indication. Now I would like to provide you some granularity over the primary endpoint in geographic atrophy in our trial and the baseline characteristics of the patient enrolled in this trial. The primary efficacy endpoint in our Zimura trial for GA is an objective anatomic endpoint, slowing down the growth of atrophy. In patients with geographic atrophy, retinal degeneration or atrophy developed in the macula, a location that plays a critical role in the patient's function of vision. In this area, layers of retina which are responsible for receiving light, degenerate and stop functioning over time. The enlargement of this degenerative area or atrophy over time leads to patients having difficulty performing their daily living tasks, such as recognizing faces, being able to read or drive. This disease is a chronic condition that progresses over years and generally ends in severe vision loss in both eyes. Therefore, the goal of treatment in GA is to slow down or stop the growth of these atrophic areas, and therefore preserve the healthy retina and maintain patient function of vision, allowing them to continue perform the daily living task for as long as possible. Based on this and our previous communications with the FDA, we believe that a reduction in the rate of GA growth is an approval endpoint for this indication. In our pivotal Zimura clinical trial that preexisted by primary endpoints was a mean rate of change in GA over 12 months measured by fundus autofluorescence images has three time points: baseline, month six and month 12. The captured images were evaluated then read by an independent reading center that was masked to the treatment arms of the trial. [Indiscernible] of the GA over 12 months at three time points, we utilized a model of repeated measures to compare the groups with each other. We believe that this is the appropriate model for this indication and is generally accepted by the regulatory agencies. It is reported in the literature that the baseline GA size may play a role in predicting the rate of growth over time. For example, the smaller GA may grow slower than the larger GA. Therefore, it is important that the baseline GA side is well balanced between various treatment arms and are stratified to these arms based on the lesion size. In our clinical trial, based on the data we have received to date, we believe that the baseline GA size across treatment cores was generally well balanced, and the data can be found in our 10-Q filed this morning. Further, the cores were stratified based on the baseline GA size to prevent an imbalance in various treatment arms. And to further mitigate for the impact of baseline GA size on the growth of the GA, a square root transformation was performed. It is reported in the literature and accepted in the field that taking the square root of the GA size when calculating the mean change in size over time mitigates for the impact of the baseline GA size on GA growth. As indicated above, based on the data we have received to date, we believe that the baseline connectors in our trial are well balanced. The patients were stratified based on baseline GA size, baseline vision and baseline autofluorescence pattern. We have provided further details in regard to the baseline characteristics of the enrolled patients and additional details of the clinical trial are in our 10-Q filed this morning. Further, a more comprehensive discussion, including inclusion exclusion criteria, details regarding the statistical analysis and sensitivity testing from this clinical trial can also be found in the 10-Q. It is important to point out that we have excluded patients in whom the GA was impacted the corneal center and visual acuity is the highest, since these patients would probably have not have benefited to participate in the trial and from the treatment. Based on literature, GA for patients with lesion does not involve the cornea may grow at a faster rate. We believe that the significant slowing of the GA growth we observed in this Zimura trial in a fast growing GA population may further validate the potential of Zimura in this disease. We have begun the planning of our second clinical trial and plan to enroll our first patient in the first quarter of 2020. The randomized, sham controlled, double masked pivotal clinical trial will have similar inclusion exclusion that are currently ongoing pivotal trial with the potential modification of keeping and continuing treating patients who developed CNV in the study eye during the trial. We will use the same time and efficacy end points as our first pivotal trials and will last over 12 months with patients continuing to be treated and followed for a total of 24 months to collect additional safety data. In the near future, we will update you with more specific details regarding our upcoming clinical trial design. In conclusion, we believe that the combination of statistical significant efficacy results and the clinical relevance for both Zimura 2 milligram and 4 milligram groups compared to the respective sham controlled with a lack of Zimura related AEs, no Zimura related inflammations, zero rate of serious other adverse events, zero rate of Zimura induced IOP increase, zero rate of endophthalmitis and observed incident of CNV as compared to sham in this trial potentially differentiates Zimura as a superior complement inhibitor for GA compared to blocking further upstream. The impact of Zimura on GA in an advanced form of dry AMD may open the door for its potential application in the earlier stages of the disease, mainly in dry AMD itself. We are planning to explore this opportunity, which could potentially impact the majority of AMD patients who currently do not have any treatment options available to them. We look forward to presenting and discussing these exciting results in more detail in our upcoming Zimura Symposium on Wednesday, November 20 from 8 a.m. to 10 a.m. here in New York. I now would like to turn the call over to Dave Carroll. Dave?

Thank you, Kourous, and good morning, everyone. I'd like to highlight a few items from our press release from this morning, reaffirm our year in cash guidance and provide some guidance on our expected Zimura Phase 3 clinical program spend. For the quarter, our net loss totaled $14.4 million with $0.35 per share, compared to a net loss of $14.7 million of $0.41 per share for Q3 2018. Year-to-date, our net loss totaled $41.4 million or $1.00 per share versus a net loss of $41 million or $1.13 per share for the same period in 2018. This slight change in net loss is driven primarily by a $1 million tax benefit associated with the Q2 2018 settlement of a local tax audit. Turning to our expected year in cash balance, our cash balance at September 30 was approximately $95 million, a $12 million decrease from Q2. Year-to-date, our cash burn is $36 million. The company reaffirms its estimate that year in cash will range between $80 million and $85 million based on our current 2019 business plan, which includes the continuation of our gene therapy programs, the continuation of our HdrA1 development program and the continuation of our ongoing clinical development programs for Zimura. Turning to our expected Zimura Phase 3 spend, we estimate that the total external cost of the second registration trial of Zimura in GA could range between $30 million and $40 million, depending on final trial design with additional external CMC scale to validation costs ranging between $10 million and $20 million. This estimated spend, which totals between $40 and $60 million, assumes one additional trial, which begins enrolling in 2020. In 2020, we estimate that the external costs associated with the ramp up of our Phase 3 clinical program will range between $8 million and $15 million. We now expect that our existing cash resources will fund our operations through the first half of 2021. As Glenn mentioned, we are exploring all options for the future development of Zimura, including plans for potential partnering. Of course, these estimates do not reflect any additional expenditures including associated development costs, any event that the company in-licenses or acquires any new product candidates or technologies or commences any new research programs. I'll now turn the call back over to Glenn. Thank you for your time.

Thanks, Dave. I'd like to quickly recap the highlights from today. We believe that the OPH trial conserve is our first pivotal for registration. We believe that only one additional pivotal randomized, double masked, sham controlled clinical trial with favorable results will be needed to demonstrate the safety and efficacy of Zimura in GA secondary to dry AMD in a manner sufficient to support regulatory approval in this indication. We look forward to initiating enrollment for the second pivotal trial in the first quarter of 2020 and we believe by blocking downstream at C5, Zimura's safety profile may differentiate from other upstream complement inhibitors. We believe we are well positioned to leverage our efficient execution and deep expertise in retinal drug design and development to bring Zimura to patients as soon as feasibly possible in dry AMD. We also look forward to bring our gene therapy for our RND portfolio forward. We hope to see you all at the RND day scheduled for November 20. And thanks for your time and continued support this morning. I'd now like to turn it over to the operator for questions.

Thank you. [Operator Instructions] We'll now just take our first question from David Nierengarten from Wedbush. Your line is open. Please go ahead.

Hey, thanks for taking the question. I had one on patients who dropped out of the study for Zimura, how the data were treated and maybe more importantly, if you had additional follow up on those patients to see if there were any imbalances in how the geographic atrophy progressed in those patients so you could have a little bit of additional comparison data. I know it's not maybe relevant for the clinical trial, but for internal planning purposes and things like that for the next study. Thanks.

Thanks, David, for the question. So the MRM analysis was used also for the patients who the -- any value of the [indiscernible] was missing, and obviously as Glenn pointed out, sensitivity analysis was performed on those as well to make sure the robustness of the statistical evaluation. At this point, when the patients were out of the clinical trial, they were not followed. So we do not have that data.

Okay. And then maybe -- you mentioned differences in baseline size of the lesion contributing to the rate of growth in the future. Were there -- I know it's across clinical trials, but just remind us what the differences were in initial size of the lesion between your study and the other complements inhibitor that's out there.

Great question. So as I pointed out, one of the factors that can impact the growth of the GA over time is based on lesion size. In our trial, it was to stratify based on the lesion size and also we performed a square root transformation to further mitigate for that. And then the key component is that when you compare across groups from each dose to sham, that they are generally well balanced. And we believe ours is well balanced. And I think that data is now on our 10-Q and obviously the results from all the baseline connectors of other trials performed are also available and published. So I leave you to compare and do your own analysis on that.

All right. Thanks for taking my questions.

Thanks, David.

[Operator Instructions] There are no further questions at this time.

Well I'd like to thank everybody for joining today, and hope to talk to you soon. Bye-bye.

This concludes today's call. Thank you for your participation. You may now disconnect.