Kodiak Sciences Inc. (KOD) Q3 2019 Earnings Report, Transcript and Summary

Good day, ladies and gentlemen, and welcome to the Kodiak Sciences Third Quarter 2019 Business Highlights Conference Call. [Operator Instructions] At this time, I would like to hand the conference over to Mr. John Borgeson, CFO. Please go ahead, sir.

Thank you for joining Kodiak Science's third quarter 2019 business highlights conference call. I'm John Borgeson, Kodiak's Chief Financial Officer. Joining me today are Victor Perlroth, Chairman and CEO; and Jason Ehrlich, Chief Medical Officer and Chief Development Officer. After our prepared remarks, we will open the call for Q&A. The webcast portion of this call contains a slide presentation that we will refer to during the call. Those following along on the phone, who wish to access the slide portion of this presentation, may do so on the Investor Relations section of our website. An archive of this webcast will be available on our website. I'd also like to remind you that remarks made on this call today include forward-looking statements about Kodiak. A more complete description of these and other material risks can be found and Kodiak's filings with the Securities and Exchange Commission, including its Form 10-Q for the quarterly period ended September 30, 2019, which has been filed with the SEC today. Kodiak will not undertake any obligation to update publicly any forward-looking statements whether as a result of new information, future events or otherwise. Now, I'm pleased to turn the call over to Victor Perlroth, our CEO.

Thanks, John. Good afternoon, everyone and thank you for joining us. This is the first end of quarter business highlights conference call we have hosted -- we'll dive right in. We're a public retina focused ophthalmology medicines development company. We've applied and continue to apply a creative and thoughtful approach to science and medicines design and development, most notably with our antibody biopolymer conjugate platform and our lead asset KSI-301 which we built on this platform. Our objective is to design, develop, and ultimately commercialize a new standard of care best-in-class medicines for the leading causes of blindness in the developed world which diseases are driven by the growing demographics of aging and diabetes. We are focused exclusively in ophthalmology and retina, and we believe this gives us a distinct advantage. Retina is a highly technical area for medicines development and there are increasing returns to focus over time. On Slide 4, for those of you who did not yet watch the live webcast from our October 14, R&D Day event, we encourage you to do so, and it can still be found on the IR page of our Company website. Over three hours, we took the time to introduce the platform with a bit of a deep dive into the underlying philosophy and concepts and to review the data of our KSI-301, ABC medicine, and to provide first line of sight to a registrational path for KSI-301. And Jason and I together discuss these items with clinical and market experts. The R&D Day event being not quite one month ago, as you listen to today's updates, you can see and hear the progress we are making at Kodiak, and feel the acceleration of our efforts, an acceleration that has been 10 years in the making. Here on Slide 4, you can see the components of our ABC platform, where we bring novel antibodies together with a state-of-the-art phosphorylcholine-based biopolymer to form stably linked biologics that are designed for increased durability and efficacy after intravitreal ophthalmic injection. We call them the same where it matters, administered in the same way as a biologic in an optically clear solution and formulation, and with fast and potent clinical responses, and different where it counts. Importantly, our biopolymer is not done mass or size. It's a form of macromolecular water. It is a bioconjugate with an integrated set of properties, and allows us to enhance ocular durability, enhance potency, enhance bioavailability to the retina, enhance stability and at the same time designing in a rapid systemic clearance. This is truly a next-generation platform to service a pipeline of future retinal medicines. On Slide 5, you can see the application of our ABC platform across this next generation of retinal medicines, including monospecific ABCs like KSI-301, bispecific ABCs like our KSI-501, and our new triplet ABCs deeper in our pipeline. On Slide 6, we took a no-compromise approach to the design of KSI-301, our lead assets, our anti-VEGF ABC. We have an industry-leading molecular weight which drives durability at 950,000 molecular weight versus EYLEA at 115,000 molecular weight, and most of which in our conjugate is really that phosphorylcholine-based macro-molecular water. And we achieved this molecular weight with the high formulation strength such that we are dosing 5 milligrams of product. This allows us to achieve a 3.5 times smaller excess of anti-VEGF finding units versus EYLEA at its label dose. And we have an industry-leading half-life, which over time translates into a powerful concentration advantage in the eye versus the marketed anti-VEGF biologics. Our objective at Kodiak is to develop KSI-301 to demonstrate a meaningfully differentiated profile in each of the four major retinal vascular diseases. The way to think about it is our Phase 1b study is treating -- treatment-naive patients in each of the four anti-VEGF retinal vascular diseases, wet AMD, diabetic macular edema or DME, retinal vein occlusion or RVO, and also diabetic retinopathy as a component of DME. In the design of the Phase 1 b allows us to generate data that we believe can be predictive of how KSI can perform in indication-specific pivotal studies in the same and or very similar patient populations. And we want to design each pivotal to have primary and secondary endpoints such that if we hit them, we would be clearly differentiated from the pack of existing anti-VEGF biologics in use namely EYLEA, Lucentis, the new Beovu, and Avastin. This group which Dr. Holekamp synthesized at our most recent R&D Day as essentially similar medicines traveling in a common pack. Our medicine KSI-301 has the potential to be the unique medicine, a unique biologic separate from the pack. Our objective is to run pivotal studies in each major disease and in which we have a differentiated design, and in which we have a high probability of technical and regulatory success based on our ABC design and our data being generated in our Phase 1b study. For example, in wet AMD, our objective and being explored in our DAZZLE pivotal is to bring nearly all patients to an every three-month durability interval versus 40% to 50% with peer view and to bring more than half of patients to every four months or longer between injections. And for example in DME, our objective and to be explored in a pivotal study, is to have only three loading doses versus five loading doses with EYLEA, and to bring nearly all patients to an every three, four, five, or even six-month durability interval. And in diabetic retinopathy, our objective and to be explored in pivotal study is to have no loading doses versus five loading doses for EYLEA, and to explore, two, three and four times per year dosing. This could have a very phenomenal public health impact. And in retinal vein occlusion, our objective and to be explored in two pivotal studies is to have two loading doses followed by every eight-week or longer dosing versus EYLEA with its once a month regimen. So what I have discussed thus far is really a repeat in a speedier manner of what we described in the R&D Day. Now I would like to move into today's update. In the third quarter of 2019 and into the early fourth quarter, highlights of our activities at Kodiak have included. We initiated enrollment in recruitment into our pivotal DAZZLE clinical trial of KSI-301 in patients with treatment-naive wet AMD. And we are very pleased with the investigator engagement and enthusiasm. We also presented together with Dr. Charles Wykoff, promising clinical safety, efficacy and durability data from the ongoing Phase 1 b study of KSI-301 at the American Academy of Ophthalmology Retina Subspecialty Day on October 11. We presented at our R&D Day event on October 14 for the first time and accelerated development plan, and including line of sight to registration for KSI-301 by way of RVO. More recently, and since the R&D Day event, we have completed a Type B end of phase of meeting with FDA and the Phase 2 where we discussed and agreed on the recommended clinical, non-clinical and manufacturing activities to support the licensure of KSI- 301. And importantly, the order in number of clinical studies required to support an initial biologics license application, BLA in RVO, and supplemental BLAs in wet AMD, DME, and DR without DME. Specifically, we will require two pivotal studies in RVO, one in branch vein, one in central vein to support our initial BLA. Then we will require one pivotal study in wet AMD perDAZZLE study and one pivotal study in DME, each of which will confirm the other and together form an integrated supplemental BLA filing of both indications. Diabetic retinopathy without DME requires an additional pivotal study, and likely that will drive a further sBLA. Consequently, we now intend to initiate at least four U.S., EU based pivotal trials in 2020, one in central RVO, one in branch RVO, one in DME, and one in DR. These studies together with our ongoing DAZZLE study in wet AMD will be the basis of our intended BLA and submissions. We now have clarity on a 2022 vision that if successful would result in an initial FDA approval of KSI-301 in 2022 for RVO and supplemental BLA submissions in 2022 for wet AMD, DME and possibly DR. That is we now have clarity in line of sight to approval of KSI-301 in all four major anti-VEGF indications, and the ability to do so in the time and capital-efficient manner. It is really a combination of our continuing clinical data and our regulatory feedback that support our confidence to accelerate our development efforts. What we really like about our Phase 1b study design is that we're generating data in treatment-naive patients in all four of the major anti-VEGF indications of retinal vascular disease. Our data in each indication is supportive of the others and all of them are showing the expected rapid and high magnitude responses. And we like the consistency, we're seeing across that by now for data cut-offs. If you remember, the ASRS meeting in July, the European meetings of EU Retina and Macula Society in September, AAO in October, and now, in our adjacent 10-Q here in September, we see consistent results. All of this with an impressive highly differentiated durability profile, even with a limited number of loading doses in the retinal diseases, with the highest VEGF drive, that is DME and RVO. None of these data, no one disease, and no cohort is in a silo here. We now have supportive data in four of the four major indications. And remember each disease has seen typically different in variable, which makes the fact that the data is directionally supportive with magnitude responses in the expected range and a highly differentiated durability profile, impressive and therefore supportive from our view of a full-on pivotal stage development program. With studies and indications run in parallel rather than how it has been done historically, which was in series. And doing it in parallel has a number of operational, regulatory and financial efficiencies, which we plan to take advantage of. On Slide 8, our 2022 vision thus becomes clear. It's a pull-forward of all four major anti-VEGF retinal diseases, into the 2022 calendar, specifically top-line data in RVO to support our initial BLA filing in 2022. Top line data in wet AMD, DAZZLE and in DME in 2022 to support a supplemental BLA. And top-line data in DR without DME is also possible in 2022, but perhaps in 2023. As a Company then, by the end of 2022, we hope to have KSI-301 marketed in the U.S. in RVO. We hope to have our sBLA submitted for wet AMD and DME. And we hope to have top-line data for DR without DME. We also intend to have Phase a -- 1b clinical data for our KSI-501 by specific ABC, and to have a third ABC in the clinic. And we're building our pipeline capabilities with the goal to have a steady stream of retina focused INDs on an annual basis and supporting our profile as a global high science retina focused company. On Slide 9, you can find further detail of our planned efforts and catalysts for 2020, 2021 and 2022. These follow closely to division just articulated. Our operational objectives then are clear and we are rolling up our sleeves in order to do that work with the excellence it deserves. At this point, I will turn it over to Jason who will now provide more details on the underlying clinical planning as well as the next emerging Phase 1b data, Jason?

Thank you, Victor, and good afternoon, everyone. It's been an exciting quarter for the Kodiak clinical team. And before getting into the updated Phase 1 b data, I wanted to take just a moment to thank everybody who has contributed our clinical investigators, the whole Kodiak team here, our partners and most importantly, the patients who are participating in our clinical studies of KSI-301. So as Victor mentioned, current intravitreal anti-VEGF medicines require frequent eye injections in order to achieve the best clinical results. So personally as an ophthalmologist and drug developer, I'm really excited about the potential of our ABC platform and of KSI-301 to address this challenge. We believe the emerging KSI-301 Phase 1b clinical data support meaningfully differentiated clinical profiles of KSI-301 relative to the standard of care in each of the major retinal diseases treated today with the existing anti-VEGF therapies. So looking at Slide 10 then as Victor said, we're deepening and accelerating the development program for KSI-301 on the basis of the data and our recent end of phase meeting with the FDA. This was really a very collaborative discussion and the net result of that meeting was that we can achieve a potential approval for KSI-301 in the key anti-VEGF indications on the basis of the plan described on the slide here. So two pivotal and RVO for an initial BLA. And then one pivotal study each in wet AMD and DME pro forma basis of a supplement. And then one additional pivotal study for DR without DME that would be a third supplement for BLA or second supplement. The information shown on Slide 10 reflects our current thinking as to the duration and the size of these studies. Now getting these studies going is, of course, a big operational lift and we're really pleased so far with the infrastructure that we've put in place for a DAZZLE study and the progress we're making there. And so we plan to leverage and expand that to efficiently run these additional studies in parallel. So changing gears then to the Phase 1b data and the data update, let's move to Slide 11. A few words first about the objectives of the Phase 1b study. It's designed to provide us scientific and clinical proof of concept for the safety, efficacy, and durability of KSI-301, and the ABC platform in patients with the most common retinal diseases treated with anti-VEGF, so wet AMD, DME and DR, and retinal vein occlusion. And we are studying treatment-naive patients in Phase 1b because we believe this is the most representative population that will provide the most confidence in the design of our current and our proposed pivotal studies. So in the next few slides, I'll briefly review the study design, the retreatment criteria and the baseline characteristics just as a reminder. So on the next slide, Slide 12, in the Phase 1b study, so these treatment-naive patients with AMD, DME and RVO received three monthly loading doses of KSI-301 at either the 2.5 milligram or 5 milligram dose levels and then they're followed thereafter. The study is open-label, the patients are randomized to the two different dose levels at a 1:3 ratio. After the three initial monthly doses, patients are followed and additional retreatments occurred according to the disease-specific protocol specified retreatment criteria. Now the overall study duration was originally 36 weeks, and actually, now that we've seen promising safety, efficacy, and durability, we're extending that treatment and follow-up period to 72 weeks or 18 months. Outcomes of the study include vision, which is measured as change in best-corrected visual acuity or BCVA using the standard ETDRS testing protocol and retinal anatomy which is measured as change in retinal central subfield thickness or CST using optical coherence tomography imaging or OCT. We also seen other images in the study such as [indiscernible] geography, color fundus photos and OCT and geography. Turning to Slide 13, these are the retreatment criteria which are specific to each disease state and we designed these criteria in conjunction with the Phase 1b investigators and based on the evolving knowledge from previous clinical trials as well as our objective which was to understand the clinical durability of KSI-301 in these different patient populations. The criteria are meant to individualize the dosing regimen to the patient based on their disease activity, vision, and retinal anatomy, and of course, also we want to understand chronic safety. So in the case of wet AMD, which is the most chronic of the disease is under study, we also cap the maximum retreatment interval every six months. In addition to the protocol specified objective, criteria because this is an early phase study, investigator also have the option to retreat at their discretion if there is significant disease activity present in their opinion that meets treatment but doesn't meet the other criteria. On the next slide, Slide 14, we see the baseline characteristics of the three different groups. Again all these patients are treatment-naive and the baseline characteristics are what you would expect for a U.S.-based treatment-naive study population. Now since we allow patients with vision as good as [indiscernible] 20, 25 to enroll in the study, the baseline vision in the wet AMD and DME groups is, in particular, very good, better than even in some of the recent Phase 3 studies. Patients are presenting to the retina specialists sooner and with better vision, so it's important to allow these patients in the study. But better baseline vision does affect how much provision improvement is possible due to so called ceiling effect, so your vision can only be so good, it can improve so much, especially if you have underlying diseases like AMD or diabetic retinopathy. So these baseline characteristics are important to keep in mind when evaluating data within and across trials, particularly looking back over the trials that were done a long time ago when baseline vision might have been worse. So then turning to Slide 15, just before we get to the latest data, maybe just a couple of words about what was presented a month ago at the AAO Retina Subspecialty Day. We observed encouraging safety and efficacy data in the Phase 1B study. And I would say really very promising durability data in wet AMD next-generation intravitreal biologic to bring nearly all patients to a three-month or longer dosing interval. And at AAO we showed that 80% of wet AMD treated eyes and 78% of DME treated eyes have been extended to four months or longer without receiving retreatment. And in DME, as you know, this is a pan-retinal disease that typically has a high initial treatment burden and we observe that durability benefit following only three initial loading doses. We also saw a promising early signs of improvement in diabetic retinopathy severity and then retinal vein occlusion, a disease, which typically requires monthly therapy to achieve the best results. We observed that over half of the patients were extended beyond three months without receiving the treatment after only three loading doses. And the efficacy through 16 weeks was strong and appropriate for anti-VEGF across all the diseases. And finally, safety was quite encouraging with no cases of intraocular inflammation after over 300 doses and over 100 patients. So let's start then to look now at the latest data and I'll walk you through this. It's been about a month since AAO, and through November 8, these patients each have about one month longer follow up, and just to say at a high level across all three diseases under study, improvements in vision and retinal anatomy were observed through 20 weeks of patient follow up with stability in OCT and vision over time in the monthly follow intervals. First turn next to slide 16, the latest data on durability of KSI-301 in wet AMD patients. Now, again as Victor mentioned, remember that with the current agents in wet AMD, only approximately 40% of patients can be maintained on every 12-week or three-month dosing interval over a two-year period. That's the best data from the HAWK and HARRIER brolucizumab studies. So the remaining 60% of patients require every other month therapy, monthly therapy or even on occasion, treatment as often as every two weeks. So our objective with KSI-301 in wet AMD is to do a lot better than that, develop a therapy where the vast majority of patients who are on every 12-week dosing or better with at least 50% of patients maintained on another four or five-month dosing regimen. So we presented durability data as swimmer plots, so you can see how long each individual patient was followed for and when they were retreated. Since the study is ongoing and the patients have variable follow up time based on when they were recruited, we think this is a useful and transparent way to review and understand the data. So in the Phase 1b study, we've observed thus far that 83% of the wet AMD patients have reached four months or longer until the first retreatment and actually many patients have not received their first retreatment until five or even six months after the last loading dose. So that's intriguing that we're observing a high proportion of Phase 1 b patients, about half of them so far are reaching or will reach to six-month cap without retreatment after the initial loading doses. So these emerging data underscore the potential of KSI-301 and the ABC platform to achieve truly long interval dosing with an intravitreally administered therapy. So now let's look at changes in best-corrected vision and OCT. Let's turn to the next slide, Slide 17. So visual acuity and retinal anatomy improvements continue to be durable and the follow-up data as well. These are data from the 25 wet AMD patients, pool between the 2.5 and 5 milligram dose levels who reached the week 20 visit prior to the data cut-off date of November 8, 2019. Remember that at AAO we presented data through 16 weeks on these patients, and now it's through week 20. In the period between week 12 and week 20, that is months one to three after the loading phase, the treatment effect is maintained, with only a 15.3-micron change in average central subfield thickness on OCT, and between week 16 and 20, this change was only 5.7 microns. This is consistent with an extended durability effect of KSI-301 and compares favorably to the OCT fluctuations observed with the existing anti-VEGF agents that are given on shorter dosing intervals. Similarly, the best-corrected vision was also generally stable over these intervals consistent with the prolonged duration of effect of KSI-301. As you know best-corrected visual tends to fluctuate by a small amount on a month-to-month basis in clinical trials, and we see that here, you can see the change is all within the standard or the main error bars as you might expect. So now turning to Slide 18. In the Phase 1 b study, the average retinal thickness or OCT data as reported by our investigators includes the height of pigment epithelial detachments or PEDs. PEDs anatomic features in some patients with wet AMD and treatment success in these patients does not necessarily imply complete flattening of the PED, but rather eliminating the intraretinal and subretinal fluid, particularly when the PED is very high prior to anti-VEGF treatment starting. And additionally, comparison across studies of OCT mean and CST values and mean change values can be difficult because it is often not clear or not disclosed in presentations and publications whether the data include or exclude the height of the PED among other reasons. So on this slide, the graph show the best-corrected vision and OCT, CST change and the wet AMD subjects excluding the two patients that presented with a very high PED baseline, i.e., more than 500 microns of total CST. So that's corrected vision and OCT curves are similar in shape to those are the full cohort, but the OTT center subfield thickness values are lower at baseline and over time and the SCM or [indiscernible] narrower, demonstrating the relative weight of those two patients have a small cohort, so they call, the overall mean CST value up in the prior slide. And then summary then, these two patients are sort of outliers in baseline fitness, but not in treatment response. So overall, we're really very pleased with the data out to week 20 in the wet AMD patients. So we've been reporting on the patients who are essentially the group recruited into the study first and thus have the longest follow-up time. And these are the patients that we've been successively looking at ASR, Macula Society, and AAO now. So we also wanted to show how the rest of the cohort is doing so far because there are other patients in the study. So let's move to Slide 19. So when considering the larger group of patients who have data through the first 12 weeks of the ongoing studies, we've also seen nice improvements in vision and retinal anatomy. So here's 31 wet AMD patients who have reached 12 weeks of follow-up. You can see we have 6.6 letters visual acuity improvement from baseline and the 93 micron improvement in OCT. And then on the next slide, if you exclude those two patients with a very high PEDs so I described previously, we can see through 12 weeks, an improvement of seven eye chart letters and an OCT improvement 89 microns down to an average center subfield thickness of 287 microns. So we feel really good about the vision and OCT outcomes we're seeing here, in response to KSI-301 treatment. So overall, what have we learned? These data collectively demonstrate that KSI-301 has a potent anti-VEGF effect both on best-corrected vision improvement and retinal drying in wet AMD patients. The clinical benefit appears in line with existing agents, especially when considering differences in baseline characteristics, and we are observing substantially longer durability of clinical effect with KSI-301, then you might expect with the existing agents. So although the Phase 1b study is open-label, we believe these results are representative both because the patients in the study are randomized to two dose levels and because the key assessments vision and OCT are measured objectively in a standardized reproducible manner. A very high proportion of Phase 1b, wet AMD patients who have been extended to four, five or six or even six months without receiving retreatment also further supports the design of our ongoing pivotal study, DAZZLE in which KSI-301 is administered to treatment-naive wet AMD patients on an every three, four, or five-month regimen as compared to aflibercept on an every two month regimen, each after 3 monthly loading doses. So let's move to Slide 21 now and the latest diabetic macular edema. So as you might remember in DME, currently approved [indiscernible] medicines are labeled for either monthly or every other month dosing after five monthly loading doses. And a National Eye Institute-funded DRCR.net collaborative study of DME patients, almost all patients required six initial monthly loading doses under the DRCR treatment algorithm and a median of nine to 10 doses were administered in the first year of therapy for all of the tested agents. Aflibercept, bevacizumab and ranibizumab, they all needed about the same number of injections per year. Our objective with KSI-301 in DME is thus two-fold. First, to reduce the number of initiating or loading doses, and then second to extend the treatment interval in the maintenance phase to three months and beyond. So let's turn then to Slide 22, and the swim lane plot for DME. So these are the data as of November 8. We have observed that 72% of DME treated eyes have been extended to four months or longer after the three loading doses of KSI-301 without receiving retreatment with most patients not yet receiving any retreatment including patients followed for as long as five to seven months after the initiating doses. So personally having worked in the DR and DME field for some time now, going back to the regional Lucentis Phase 3 studies before there was any intravitreal medicine approved in the U.S. for diabetic eye disease patients, I'm really very excited about the potential for KSI-301 based on what we're seeing here to date. So then turning to Slide 23, the visual acuity and OCT improvements continue to be durable in the follow-up data as well. So these are data for the 15 DME patients who reached the week 20 visit prior to the data cut-off in the period between week 12 and week 20, that is one to three months after the loading phase, the treatment effect is maintained, with only a small 19.2 micron change in average CST observed between week 12 and week 20. And between week 16 and 20, this change was only 13.6 microns. So again this is consistent with the extended durability effect of KSI-301, and I think it compares very favorably to existing anti-VEGF agents, particularly with a reduced number of loading doses that were given. Similarly, best-corrected vision also was stable over these intervals, consistent with the prolonged duration of effect of KSI-301. So now turning to Slide 24, so somewhat bigger group of patients who have data through the first 12 weeks of the ongoing study. And those are consistent and encouraging with an improvement in best-corrected vision of 7.1 letters, and improvement of OCT of 136 microns. So these data again collectively demonstrate the KSI-301 has a potent anti-VEGF effect in DME patients the clinical benefit appears in line with the existing agents and we are observing substantially longer durability with KSI-301 than expected from the existing medicines. And these results were achieved with fewer loading doses. So these data support a pivotal study design where KSI-301 will be given on an every three to six-month interval after three loading doses, compared to standard of care aflibercept on its approved every other month regimen after five loading doses. So let's turn then to retinal vein occlusion, on Slide 25. So RVO is a disease which has higher levels of intraocular VEGF on average than wet AMD and DME. And so we would expect the highest treatment frequency here in our Phase 1b study, as well. And you remember that since are labeled for monthly dosing and then moreover, a recent U.K. study in patients with central RVO called [indiscernible] trial demonstrated that less than monthly dosing of aflibercept bevacizumab or ranibizumab could be associated with loss of maximal treatment effect both on vision and OCT. So our objective with KSI-301 in RVO is also two-fold. First to reduce the number of floating doses, and second to extend the treatment interval up to two months or beyond compared to the current standard, which is monthly. So looking to Slide 26, the swim lane plot for RVO. In our Phase 1b study, we've observed thus far that all RVO eyes treated with 5 milligrams KSI-301 have been extended to two months or longer after the last loading dose with 50% of patients extended to three months or longer, so I continue to be really encouraged by these data as well. Let's move to Slide 27. Visual acuity and OCT improvements continue to be durable in the most recent follow-up data. On this slide, we see the 15 RVO patients who reached the week 20 visit prior to the data cut-off. In the period between week 12 and week 20 that is months one to three the loading phase, the treatment effect is maintained, with only a 9.5 micron change in average center subfield thickness on OCT. In between week 12 and 16, this change is only 21.6 microns, consistent with the observation that some patients required and received treatment at week 16 weeks after the last loading dose. So again, these data are consistent with the extended durability effect of KSI-301, and I think it again compares favorably to the existing medicines. Similarly, best-corrected was also stable over these intervals consistent with prolonged duration of effect in average improvement from baseline of 21.3 eye chart letters, which is over four eye chart lines was observed at week 20. Looking then to Slide 28, here we have the bigger group of patients with data through week 12, we have 32 patients and we can see an average vision improvement of 19.8 eye chart letters and a 401 micron improvement in OCT thickness, really pleased with these data too. So overall in RVO what have we learned? These data collectively demonstrate again that KSI-301 has a potent anti-VEGF effect both on vision improvement and retinal drying in RVO patients. Clinical benefit appears in line with the existing medicines with substantially longer durability than expected with the existing medicines. And the effects were achieved with fewer loading doses. So these data would support a pivotal study design where KSI-301 will be given on every two months or potentially longer interval compared to standard of care [indiscernible] given monthly. Okay. So that's the latest updates on efficacy and durability across the indications. Turning to Slide 29, let's look at safety. So on Slide 30 then is the latest update. The safety profile KSI-301 continues to be very encouraging with no intraocular inflammation or study eye ocular serious adverse events reported across now 338 injections given to 116 patients in the Phase 1a and Phase 1 b program as of November 9, either in single or multiple dose exposure. The systemic safety profile continues to be consistent with that expected for intravitreal anti-VEGF agents, and for patients with these diseases and in these age ranges. Maybe a brief word here about anti-drug antibodies or immunogenicity since that's a topic, that's become of maybe more interesting in the community lately. We have some more details in the 10-Q. And so far it's early data. We've tested 362 samples from the Phase 1a and 1b program, representing 103 subjects. No patients have shown pre-existing anti-drug antibodies. Only four samples from three patients have tested positive. Those four samples, all have very low titers at or below the minimum required assay dilution. So it's a very small number of patients with ADAs to date and a review of the corresponding clinical and safety data for these three subjects did not show the ADA positivity to be correlated with either loss of clinical efficacy, vision, OCT or earlier need for retreatment or correlated with any ocular or non-ocular safety finding. So although those data are preliminary, they provide an additional window into the safety of KSI-301. So that's really a lot of updates on the Phase 1b study. All materials I've presented today is, of course, part of the slide presentation that's available on the IR website and also part of our 10-Q. So just in summary, then I'm really very pleased with the continued evolution of the durability and the longer-term efficacy data and the safety profile we're seeing with KSI-301 that we are sharing with you today. I'm also really pleased with the FDA end of phase meeting outcomes and the pivotal study designs have results from those discussions and from the emerging clinical data. It gives us the confidence to move forward and accelerate the development program toward our very exciting 2020 position. And with that, I'll turn it back over to Victor.

Thank you, Jason. In summary, we are very pleased with the business highlights for the third quarter and the first part of the fourth quarter. And we now open the floor to questions. Operator?

Thank you, sir. [Operator Instructions] We'll go first to Matthew Harrison, Morgan Stanley.

Hi. This is Max Skor on for Matthew. I was wondering if you can comment on KSI, CMC activities, and how the FDA feedback compares with your current plan? Thank you very much.

Sure. Thanks, Max.

And?

This is Victor. I think obviously with the no inflammation in any patient record that we maintain having in the Phase 1A and the 1B come, we feel very good about the manufactured quality of the material that we've made to-date. And we have spent a lot of time and effort and some treasurer to build a manufacturing path that we feel from a technical standpoint will scale up well. And we I think we received very positive feedback from FDA kind of on the manufacturing framework for the antibody intermediate -- for the biopolymer intermediate for the drug substance bioconjugate and also for the drug product. Another outcome from our meeting was an agreement to have a CMC specific meeting with FDA next year when we feel that we're ready for that. Certainly, we believe that our timelines in the 2022 vision that we articulate also include our views on requisite timing and activities to service the initial BLA and then those supplemental BLAs. So we have spent a lot of time and effort, thinking about and executing on our CMC plans and they are kind of included under the hood here in the 2022 vision.

Okay. Thank you very much. Operator Our next question will come from Gena Wang, Barclays.

Hi. This is Peter for Gena. Congratulations on all the updates and progress, and thank you for taking the questions. a few from us. First on the confirmatory Phase 3 study, which no longer seems to be required. Could you give us some color on FDA feedback? And it sounded like it was part of an sBLA. Could each of the sBLA be approved on its own or do both studies have to meet positive to be required? And I have a couple of more follow-ups. Thank you.

And the path that we discussed and have an agreement with from FDA is really an integrated package. So the RVO dual pivotal with their six-month endpoint, which we expect to start, let's say, mid next year performed the basis of an initial BLA submission that stands on its own. We're running the DAZZLE pivotal and wet AMD currently, and we have plans and discuss the structure for DME pivotal that we expect also to start mid next year. Neither of those pivotals will stand on their own. As part of an sBLA filing, rather or wet AMD pivotal, DAZZLE, and a new DME pivotal together will be confirmatory in a way of each other will be submitted as part of an integrated sBLA package.

Yes. So, Peter, I think the key advancement here is that rather than having to do two wet AMD studies and two DME studies, we can do one of each and submit those together as a supplement and get approved in both.

Right. And as a result of that, we're going to slightly increase the power of those individual studies, that's part of our plan. And at the same time, that represents a powerful cost efficiency and time efficiency, and operational kind of efficiency for the Company.

Got it. Just a couple more. I guess just following up on that, increase in size, assuming just for example or wet AMD assuming stand there at 12 to 13 on the baseline, like how much power increase like are you gaining with the extra 150? And do you still have the optionality of expanding patients with that analysis?

Yes. So -- that's right, Peter. So, as we discussed before, the DAZZLE study protocol has built into it a masked sample size reassessment, so that is still the plan. I think we would anticipate based on some of the other more recent Phase 3 studies that if we wanted to have, let's say at least 90% power or even more, that sample size would be what we should expect, for that study. But the exact final number will be determined on the basis of that mass sample size reassessment when we further on into recruitment. But yes, I'd say would be that quite -- the study should probably -- it should be at least 90% % powered from non-inferiority perspective.

Right.

Great. That's extremely helpful. And last one from me, I think, appreciating a small number of patients and difference in safety measurement and definitions, like when you compare magnitude of CST reduction to brolucizumab, any thoughts here? And thank you very much again and congratulations.

Yes. I mean, I think for instance, if you look at that slightly larger dataset there that we presented through week 12, where -- and for instance, if you take out those two patients with a very high PEDs and you look at the average thickness of the rest of like whatever so 287 microns at week 12. So I think that our OCT values are really appropriate, and now we're getting in that normal range. Obviously, you don't know how they directly compare to each other, outside of a head-to-head study where they're done at the same reading center, so that -- which is directly assessed greater in the same way. So I guess the bottom line is, we're very happy with where things seem to be netting out on the OCT values on the extent of the retinal drawing, and I think that overall the data including the durability, efficacy and safety kind of speak on their own as an integrated package.

Thank you.

[Operator Instructions] Next up we'll go to Gbola Amusa, Chardan.

Hi. Thanks for the increased visibility and the articulation of your path forward. So two questions. First is, could you talk a little bit more about the impact of your announced clinical trials on cash burn, maybe at a minimum, just the timing of when any upticks could happen and whether, for example, it makes sense now or later to find a partner for ex-U.S. markets? So I'll pause there before question two.

Thanks, Gbola. And -- well, our plans are to look for additional capital in the fourth quarter of this year or in the first quarter of next year. We've had quite a lot of progress in the Company over the past couple of months and it's been great to see the increased interest in the Company, both from the standpoint of investors, but also from the standpoint of I would say, potential strategic partners for the assets, in particular with a view toward like ex-U.S. partnering, I think. We've been very thoughtful if you look back over the past 10 years in terms of buildup the Company, right, in terms of the decisions and choices we made from an R&D design standpoint, right, because at any point, you can make decisions that decrease your future optionality in the R&D side of a Company. But we've also been thoughtful from the corporate side in terms of decisions that we've made that could decrease our future optionality. I think as we look at cash burn, obviously, we're excited by the potential right in our 2022 vision, right, as we talked about in terms of the efficiencies that come out of -- at the end of Phase 2 meeting, and the ability and the desire to run our studies more in parallel, right. to capture those efficiencies. But also, of course, recognize the cash burn required to really do that. I think we're very pleased with the growing interest in the Company and definitely feel that the capital needed to run the plan in 2020, 2021 and 2022 right through approval can be there for the Company based on the interest that we're seeing. I think we don't necessarily believe that we have to raise all the capital at one time. I mean that's certainly is not our current plan. I think we are looking forward to raising capital like inappropriate tranches, right over in the next several years, starting in say Q4, Q1. And we also, as you know, there is an increasing set of kind of alternative financing kind of approaches that Kodiak as a company with the kind of, let's say, increasingly de-risked assets, that we have can turn to, right, not just necessarily ex-U.S. partnering, of course, we do own global territorial rights for the product, currently. So I think the long answer to your question is that we think capital has many different types, is going to be available to Kodiak to make sure that we can properly execute on this kind of accelerating vision for the product and the Company. And we have our eyes on that and I think we'll hopefully have more to say over the next three months to six months.

Great. And then the second question, we've seen a couple of your gene therapy competitors being quite volatile of late. One company had competitor data around your R&D Day, then the partial clinical hold, done a lawsuit with the FDA and other things started dosing a new cohort. So my question is given that you have new data -- updated data, what's your updated perspective on where KSI-301 fits relative to the gene therapies?

And one of the things I think that's interesting -- this is Victor, and just to give a quick view, and I think Jason can speak longer. I think the better that we do with KSI-301 in terms of our durability, I think in some way, the less white space there is for more exotic approaches, right, whether there are surgical approaches or whether there are sort of earlier gene therapy players. I think as Jason mentioned, we're quite intrigued to see, quite a high percentage of patients capping out at the six-month treatment in our wet AMD cohort. And also seen a number of patients in DME, where we don't cap, right, reaching four, five, six and even seven months post-loading dose. So the better we do, I guess, as an intravitreally injected, optically clear solution, right injected in the same way with an intriguing safety profile, I guess the question is, well, why should somebody turn to a very different approach, right? Why wouldn't we want to stay with the tried and true approach? The same where it matters, right, different where it counts kind of approach. And not just for KSI-301, right, but in the context of a broader pipeline, right, as our Company focused right broadly across retina. So that's one way to look at it from a simple person's point of view. I think to dig in more deeply, Jason, if he can weigh-in, in terms of what we think some of our thoughts on gene therapy?

Yes. Victor, I think you articulated, it very nicely. I think there is, people are exploring a variety of different types of platforms and approaches because of this question of how do you get a long with a therapeutic effect in the eye. This question is really important, right? And so we've seen a lot of different types of approaches over time and you know the reality is it's a very hard problem. It's a very hard problem to solve. And so there are the surgical implants, there is intravitreal approach like our ABC platform and there's a gene therapies, either with concomitant surgery or intravitreal, those are all things that are in the clinic now. And we're platform developers here at Kodiak, right, and I think we've been thoughtful and patient, and platforms are tough, right. If you get the science, right, if you get the manufacturing, right. And so I think on the basis of the data that we're seeing, we're accelerating into a Phase 3 sort of comprehensive program where I think we can do very well in each of those studies that we described, which is, you know, let's say, independent of how the competitors may do last month, versus next month versus over time. I think we're moving ahead as expeditiously and thoughtfully as we can. And a lot of these other platforms are still quite early. And I think again as Victor said, there the better our durability continues to be or is and continues to be, I think the less whitespace there is for the exotic approaches and the surgical approaches where the short and long-term safety may not be as good as intravitreal administration, right? I mean intravitreal injections have turned out to be a way safer than anybody thought they were going to be 15 years ago when we started doing them for these kinds of retinal vascular diseases. And -- so -- yes, maybe I'll stop there.

Great. Thanks a lot and congrats on the progress.

Thanks, Gbola.

And everyone, at this time, there are no further questions. I'd like to hand things back to Victor Perlroth for any additional or closing remarks.

Thank you. Well, thank you very much for joining us today and we look forward to further progress with Kodiak. Thanks so much.